Bile acids for liver-transplanted patients

Bile acids for liver-transplanted patients (Review)

Poropat G Giljaca V Stimac D Gluud C

This is a reprint of a Cochrane review prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2010 Issue 3

httpwwwthecochranelibrarycom

Bile acids for liver-transplanted patients (Review)

Copyright copy 2010 The Cochrane Collaboration Published by John Wiley amp Sons Ltd

T A B L E O F C O N T E N T S

1HEADER

1ABSTRACT

2PLAIN LANGUAGE SUMMARY

2BACKGROUND

3OBJECTIVES

3METHODS

6RESULTS

Figure 1 8

Figure 2 9

Figure 3 12

13DISCUSSION

14AUTHORSrsquo CONCLUSIONS

14ACKNOWLEDGEMENTS

14REFERENCES

18CHARACTERISTICS OF STUDIES

32DATA AND ANALYSES

Analysis 11 Comparison 1 Bile acids for liver-transplanted patients Outcome 1 All-cause mortality at maximum follow-

up 33

Analysis 12 Comparison 1 Bile acids for liver-transplanted patients Outcome 2 All-cause mortality worst-best case and

best-worst case scenarios 34

Analysis 13 Comparison 1 Bile acids for liver-transplanted patients Outcome 3 Subgroup analyses all-cause mortality at

maximum follow-up according to time of start of bile acids 35

Analysis 14 Comparison 1 Bile acids for liver-transplanted patients Outcome 4 Subgroup analyses all cause mortality at

maximum follow-up according to treatment duration 36

Analysis 15 Comparison 1 Bile acids for liver-transplanted patients Outcome 5 Number of deaths related to rejection at

maximum follow-up 37

Analysis 16 Comparison 1 Bile acids for liver-transplanted patients Outcome 6 Number of retransplantations at maximum

follow-up 38

Analysis 17 Comparison 1 Bile acids for liver-transplanted patients Outcome 7 Number of patients with acute cellular

rejection at maximum follow-up 38

Analysis 18 Comparison 1 Bile acids for liver-transplanted patients Outcome 8 Subgroup analysis number of patients

with acute cellular rejection according to time of start of bile acid 39


with acute cellular rejection according to treatment duration 41

Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients with chronic


Analysis 111 Comparison 1 Bile acids for liver-transplanted patients Outcome 11 Number of patients with steroid-

resistant rejection at maximum follow-up 42

Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl) at the end of

treatment 43

Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of hospitalisation after

liver transplantation 43

Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events 44

44APPENDICES

48WHATrsquoS NEW

48HISTORY

48CONTRIBUTIONS OF AUTHORS

48DECLARATIONS OF INTEREST

48SOURCES OF SUPPORT

49DIFFERENCES BETWEEN PROTOCOL AND REVIEW

49INDEX TERMS

iBile acids for liver-transplanted patients (Review)


[Intervention Review]

Bile acids for liver-transplanted patients

Goran Poropat1 Vanja Giljaca1 Davor Stimac1 Christian Gluud2

1Department of Gastroenterology Clinical Hospital Centre Rijeka Rijeka Croatia 2Cochrane Hepato-Biliary Group Copenhagen

Trial Unit Centre for Clinical Intervention Research Department 3344 Rigshospitalet Copenhagen University Hospital Copenhagen

Denmark

Contact address Goran Poropat Department of Gastroenterology Clinical Hospital Centre Rijeka Kresimirova 42 Rijeka 51000

Croatia goran_poropatyahoocom

Editorial group Cochrane Hepato-Biliary Group

Publication status and date New search for studies and content updated (no change to conclusions) published in Issue 3 2010

Review content assessed as up-to-date 8 February 2010

Citation Poropat G Giljaca V Stimac D Gluud C Bile acids for liver-transplanted patients Cochrane Database of Systematic Reviews2010 Issue 3 Art No CD005442 DOI 10100214651858CD005442pub2


A B S T R A C T

Background

Liver transplantation has become a widely accepted form of treatment for numerous end-stage liver diseases Bile acids may decrease

allograft rejection after liver transplantation by changing the expression of major histocompatibility complex class molecules in bile

duct epithelium and central vein endothelium

Objectives

To assess the beneficial and harmful effects of bile acids for liver-transplanted patients

Search strategy

We performed searches of The Cochrane Hepato-Biliary Group Controlled Trials Register The Cochrane Central Register of ControlledTrials in The Cochrane Library MEDLINE EMBASE and Science Citation Expanded to September 2009

Selection criteria

Randomised clinical trials comparing any dose of bile acids or duration of treatment in liver-transplanted patients versus placebo no

intervention or another intervention We included randomised clinical trials irrespective of blinding language and publication status

Data collection and analysis

Two review authors extracted and checked data independently We evaluated the risk of bias of the trials from the method of allocation

sequence generation allocation concealment blinding outcome data analysis outcome data reporting and other potential sources

of bias We used the intention-to-treat principle to perform meta-analyses and presented the outcomes as relative risks (RR) or mean

differences (MD) both with 95 confidence intervals (CI)

Main results

The updated search resulted in no new trials meeting the inclusion criteria of this review thus leaving it to the seven already included

randomised trials (six evaluating ursodeoxycholic acid versus placebo or no intervention and one evaluating tauro-ursodeoxycholic

acid versus no intervention) enrolling a total of 335 participants The administration of bile acids began one day or more after liver

transplantation All patients received the standard triple-drug immunosuppressive regimen (steroids azathioprine and cyclosporine or

tacrolimus) to suppress the allograft rejection response after liver transplantation Bile acids compared with placebo or no intervention

1Bile acids for liver-transplanted patients (Review)


did not significantly change all-cause mortality (RR 085 95 CI 053 to 136) mortality related to allograft rejection (RR 030

95 CI 001 to 712) retransplantation (RR 076 95 CI 020 to 286) acute cellular rejection or number of patients with steroid-

resistant rejection Bile acids significantly reduced the number of patients who had chronic rejection in a fixed-effect model but not in

a random-effects model meta-analysis Bile acids were safe and well tolerated by liver-transplanted patients However this observation

is based on data analysis from three trials with only 187 patients

Authorsrsquo conclusions

We did not find evidence to support or refute bile acids for liver-transplanted patients Further randomised trials are necessary before

bile acids can be recommended to liver-transplanted patients

P L A I N L A N G U A G E S U M M A R Y


Liver transplantation is a major surgical procedure that has been practiced for more than forty years and has nowadays become a

generally accepted treatment option in patients with end-stage liver disease The most common cause for liver transplantation in adults

is cirrhosis caused by various types of liver injuries such as infections (hepatitis B and C) alcohol autoimmune liver diseases early-

stage liver cancer metabolic and hereditary disorders but also diseases of unknown aetiology All transplant recipients need lifetime

immunosuppressive therapy to prevent transplant rejection

Bile acids are being used for a variety of chronic liver diseases mainly primary biliary cirrhosis and primary sclerosing cholangitis

However their mechanisms of action and beneficial and harmful effects are poorly understood This has led to the idea of the potential

use of bile acids to prevent rejection in liver-transplanted patients

Results of the seven randomised clinical trials included in the review in which patients received standard immunosuppressive treatment

(steroids azathioprine and cyclosporine or tacrolimus) with or without bile acids after liver transplantation did not show any significant

effects of bile acids on all-cause mortality mortality related to rejection acute cellular rejection steroid resistant rejection or need for

retransplantation One analysis suggested that bile acids might beneficially influence number of patients with chronic rejection but was

contradicted by the analyses The evidence that the use of ursodeoxycholic acid might have beneficial effects on chronic rejection and

length of hospitalisation is weak as it is produced from trials with high risk of bias and insufficient number of included patients That

bile acids seemed well tolerated with no reports of serious adverse events is good knowledge but much more research is needed before

their use is acquitted None of the randomised clinical trials assessed the effects of bile acids on quality of life or cost-effectiveness

B A C K G R O U N D

Liver transplantation has become a widely accepted treatment

for numerous end-stage liver diseases (Hussain 2002 Thalheimer

2002) Previous studies report an incidence of acute cellular rejec-

tion to range from 50 to 80 in adult recipients (Ascher 1988

Klintmalm 1989 Adams 1990 Wiesner 1992 FK506 1994)

However recent data suggest that the proportion of patients with

rejection is currently down to 30 (Hirschfield 2009 Knechtle

2009) Despite advances in immunosuppressive treatment and

care-quality of liver-transplanted patients allograft rejection is still

a major problem in the post-transplantation period

Acute cellular rejection usually occurs within the first 15 to 30 days

after transplantation even if immunosuppression is achieved with

tacrolimus or cyclosporine (FK506 1994 Haddad 2006 Corbani

2008) The cellular mechanisms of acute liver allograft rejection

are not completely understood (Krams 1993) Initiation of al-

lograft rejection is thought to involve the recognition of donor

class II major histocompatibility complex alloantigens by recipient

CD4+ T cells (Vierling 1992) Activated CD4+ T cells produce

cytokines that induce lymphocyte proliferation and the matura-

tion of CD8+ cytotoxic T cells which are specific for donor class I

major histocompatibility complex antigens (Calmus 1990) Both

the bile duct epithelium and central vein endothelium are rich in

class I and class II major histocompatibility complex antigens dur-

ing rejection whereas hepatocytes display a relative paucity of class

I antigens and virtually no class II antigen (Vierling 1992) There-



fore the bile duct epithelium and central vein endothelium are

the primary targets attacked by cytotoxic T cells during rejection

Impairment of the bile flow in the grafted liver may also cause re-

jection (Ericzon 1990) Mild cholestasis is a common finding after

liver transplantation and its association with clinically significant

pathology is unlikely Nevertheless severe cholestasis should be

treated as a potential cause of allograft rejection (Corbani 2008)

In the study by Fusai 2006 the development of cholestasis was sig-

nificantly related to prolonged warm ischaemia of the liver trans-

plant Cholestasis can induce hyper-expression of major histocom-

patibility complex class I molecules by hepatocytes and thereby

lymphocyte CD8+-dependent cytotoxicity (Calmus 1992)

Bile acids include chenodeoxycholic acid deoxycholic acid litho-

cholic acid and ursodeoxycholic acid (UDCA) (Fuchs 1999)

In the course of cholestasis intrahepatic accumulation of chen-

odeoxycholic acid and deoxycholic acid is thought to induce liver

damage (Palmer 1972) In fact the direct damage of membrane

phospholipids and cholesterol components caused by the deter-

gent-like properties of hydrophobic bile acids results in hepato-

cyte necrosis (Sholmerich 1984 Perez 2009) It is also suggested

that oxidative stress induced by hydrophobic bile acids plays an

important role in liver damage during cholestasis These effects

can be prevented by the addition of UDCA which modifies the

bile acid pool resulting in an increase of the hydrophilic frac-

tion and stabilisation of the cell membranes (Armstrong 1982

Perez 2009) Several studies on animal models showed evidence

of potential immunomodulatory beneficial effects of UDCA and

tauro-ursodeoxycholic acid (TUDCA) by suppressing cytokine

and immunoglobulin production and T-cell mediated cytotoxic-

ity (Yoshikawa 1998) In the study by Calmus 1990 it has been

observed that UDCA down-regulates the expression of abnormal

major histocompatibility complex class I molecules in periportal

hepatocytes in patients with primary biliary cirrhosis Treatment

with UDCA has been reported to have potential beneficial ef-

fects in various cholestatic liver conditions including primary bil-

iary cirrhosis (Gong 2008) primary sclerosing cholangitis (Chen

2003a) and cystic fibrosis (Cheng 2002)

It has previously been suggested that UDCA and perhaps tauro-

UDCA (TUDCA) may reduce the incidence of acute rejection

and steroid-resistant rejection in liver-transplanted patients when

administered with combination of immunosuppressive treatment

There are several potential mechanisms by which UDCA may in-

hibit allograft rejection in liver transplant recipients (Okolicsanyi

1986 Merion 1989 Calmus 1990 Terasaki 1991 Heuman 1993

Al-Quaiz 1994 Friman 1994 Soderdahl 1998 Yoshikawa 1998

Assy 2007 Perez 2009) However most of these studies included

a relatively small number of patients were not randomised and

often did not include histological information (Persson 1990

Friman 1992 Koneru 1993 Sharara 1995)

The previous version of this review by Chen 2003b stated that

there was no convincing beneficial effects from the use of bile acids

in liver-transplanted patients the risk of bias in the seven included

trials was high The review also found that there was a low occur-

rence of adverse events and hence the use of bile acids could be

considered safe It should be noted however that this observation

is based on reports from four trials with few patients We have

been unable to identify any other meta-analyses or systematic re-

views either This review represents an update of the Chen 2003b

Cochrane hepato-Biliary Group review

O B J E C T I V E S

To evaluate the beneficial and harmful effects of bile acids for liver-

transplanted patients by comparing bile acids versus placebo no

intervention or another intervention in randomised clinical trials

M E T H O D S

Criteria for considering studies for this review

Types of studies

We included randomised clinical trials irrespective of blinding

publication status year of publication or language We assessed

both included and excluded studies for the report of adverse events

We listed all studies reporting on adverse events in an additional

table (Table 1) However only data from the included trials were

used in the statistical analysis

Table 1 Adverse events

Study Pts in experimental

group

Patients in control

group

AE in experimental

group

AE in control group Authorrsquos conclusion

Barnes 1997 28 24 Diarrhoea (1 pt) Diarrhoea (1 pt) Adverse

reactions attributable

to study medication

were rare



Table 1 Adverse events (Continued)

Keiding 1997 54 48 Diarrhoea and diffi-

culties in swallowing

capsules (5 pts)

Diarrhoea and diffi-


capsules (5 pts)

No other presumed

drug-induced side ef-

fects were observed

Angelico 1999 16 17 No AE No AE TUDCA administra-

tion was well tol-

erated in all pa-

tients and no drug-

related side effects

were recorded

Assy 2007 14 12 Mild diarrhoea (1 pt) No AE No dose reduction

was required

pt(s) = patient(s)

AE = adverse events

Types of participants

Patients who underwent liver transplantation

Types of interventions

Any dose of a bile acid or duration of treatment versus placebo

no intervention or another intervention

We allowed co-interventions if received equally by the intervention

groups within a trial

Types of outcome measures

The primary outcome measures were

1 All-cause mortality

2 Death due to allograft rejection (acute cellular rejection or

chronic rejection or liver retransplantation because of rejection)

Acute cellular rejection was diagnosed by the combination of ab-

normal liver biochemical variables (bilirubin aspartate transam-

inase alanine transaminase alkaline phosphatases andor gam-

maglutamyl transpeptidase) clinical signs such as fever and liver

histological changes including mononuclear portal inflammation

bile duct damage and subendothelial inflammation of portal or

terminal hepatic veins (IWP 1995) Chronic rejection was charac-

terised by liver histological changes including the progressive loss

of interlobular bile ducts and arteriopathy characterised by foam

cell infiltration of the arterial intima

The secondary outcome measures were

3 Number of patients who experienced rejection - irrespective of

the type acute cellular rejection chronic rejection or both types

of rejections

4 Number of patients with acute cellular rejection

5 Number of patients with chronic rejection

6 Number of patients with steroid-resistant rejection

7 Biochemical responses serum activities of alkaline phos-

phatases gammaglutamyl transpeptidase alanine aminotrans-

ferase and aspartate aminotransferase and serum bilirubin con-

centration andor number of patients with abnormal liver bio-

chemical variables mentioned above

8 Adverse events Adverse events were defined as any untoward

medical occurrence not necessarily having a causal relationship

with the treatment but resulting in a dose reduction or discontin-

uation of treatment (ICH-GCP 1997)

9 Quality of life

10 Cost-effectiveness

Search methods for identification of studies

We performed searches of The Cochrane Hepato-Biliary GroupControlled Trials Register (September 2009)(Gluud 2010) and TheCochrane Central Register of Controlled Trials (CENTRAL) in TheCochrane Library (Issue 3 2009) by combining the terms rsquoliverrsquo

and rsquotransplantationrsquo with the individual bile acid name (litho-

cholic acid chenodeoxycholic acid ursodeoxycholic acid deoxy-

cholic acid dehydrocholic acid and tauro-ursodeoxycholic acid)

We searched MEDLINE (January 1966 to September 2009) EM-BASE (January 1980 to September 2009) and Science Citation In-dex Expanded (1945 to September 2009) by using the terms rsquoliverrsquo



and rsquotransplantationrsquo in combination with the bile acids mentioned

above (Royle 2003) The search strategies with the time span of

the searches are given in Appendix 1 We contacted the Chinese

Cochrane Centre regarding the search of The Chinese BiomedicalDatabase and received a reply that they are unable to help us with

this search Therefore the latter database could not be included

in the search strategy of this update

Further trials were identified by reading the reference lists of the

identified studies We wrote to the principal authors of the reports

of the identified randomised clinical trials in September 2009 and

enquired about additional trials which they might know of The

first team of authors had also written to pharmaceutical companies

involved in the production of bile acids to obtain information on

published or unpublished randomised clinical trials in 2002 but

no information had been received at that time


The update of this review was conducted according to the proto-

col previously published in The Cochrane Library (Chen 2003b)

and following the recommendations given by the Cochrane Hand-book for Systematic Reviews of Interventions (Higgins 2008) and the

Cochrane Hepato-Biliary Group Module (Gluud 2010)

Trial identification

Identified trials were listed and the two review authors evaluated

whether the trials fulfilled the inclusion criteria Excluded trials

were listed with the reasons for exclusion

Data extraction

GP and VG extracted the data independently and disagreements

were resolved by discussion or by CG We extracted the following

characteristics from each trial primary author number of patients

randomised patient inclusion and exclusion criteria methodolog-

ical quality follow-up (number and reasons for withdrawal) sam-

ple size calculation intention-to-treat analysis intervention reg-

imens mean age proportion of males and females aetiology of

liver disease origin of allograft matching criteria between donor

and recipient time to follow-up number of outcomes and num-

ber and type of adverse events in both the intervention and the

control groups Additional information was sought by correspon-

dence with the principal investigator or co-investigators of the trial

in cases where the relevant data were not published

Assessment of risk of bias

Risk of bias was defined as the confidence that the study design and

reporting restricted bias in the intervention comparison (Schulz

1995 Moher 1998 Kjaergard 2001 Wood 2008) Due to the risk

of overestimation of intervention effects in randomised trials with

unclear or inadequate components we assessed the risk of bias by

separate domains

Allocation sequence generation

bull Adequate if the allocation sequence was generated by a

computer or random number table Drawing of lots tossing of a

coin shuffling of cards or throwing dice was considered as

adequate if a person who was not otherwise involved in the

recruitment of participants performed the procedure

bull Unclear if the trial was described as randomised but the

method used for the allocation sequence generation was not

described

bull Inadequate if a system involving dates names or

admittance numbers were used for the allocation of patients

Such quasi-randomised studies were excluded

Allocation concealment

bull Adequate if the allocation of patients involved a central

independent unit on-site locked computer identically appearing

numbered drug bottles or containers prepared by an

independent pharmacist or investigator or serially numbered

sealed and opaque envelopes


method used to conceal the allocation was not described

bull Inadequate if the allocation sequence was known to the

investigators who assigned participants or if the study was quasi-

randomised The latter studies were excluded

Blinding

bull Adequate the trial was described as blinded the parties that

were blinded and the method of blinding was described so that

knowledge of allocation was adequately prevented during the

trial

bull Unclear the trial was described as double blind but the

method of blinding was not described so that knowledge of

allocation was possible during the trial

bull Not performed the trial was not blinded so that the

allocation was known during the trial

Incomplete outcome data

bull Adequate if the numbers and reasons for dropouts and

withdrawals in all intervention groups were described or if it was

specified that there were no dropouts or withdrawals

bull Unclear if the report gave the impression that there had

been no dropouts or withdrawals but this was not specifically

stated

bull Inadequate if the number or reasons for dropouts and

withdrawals were not described

Selective outcome reporting

bull Adequate if study protocol is available and all pre-specified

outcomes are reported in the manuscript or if the study protocol

is not available but it is clear that the report includes all expected

outcomes

bull Unclear if there are no sufficient information to permit

judgement

bull Inadequate if not all of the pre-specified outcomes were

reported andor were reported incompletely or one or more

reported outcomes were not pre-specified

Baseline imbalance



bull Adequate if there is no baseline imbalance in the main

characteristics

bull Unclear if there is no sufficient information to assess

baseline characteristics

bull Inadequate if there was a baseline imbalance due to chance

or due to imbalanced exclusion after randomisation

Early stopping

bull Adequate if sample size calculation was reported and the

trial was not stopped or the trial was stopped early by formal

stopping rules at a point where the likelihood of observing an

extreme intervention effect due to chance was low

bull Unclear if sample size calculation was not reported and it is

not clear whether the trial was stopped early or not

bull Inadequate if the trial was stopped early due to informal

stopping rules or the trial was stopped early by a formal stopping

rule at a point where the likelihood of observing an extreme

intervention effect due to chance was high

Furthermore we registered whether the randomised clinical trials

had used an intention-to-treat analysis (Gluud 2001) and had

calculated a sample size estimate

Statistical methods

We performed the analyses in RevMan 5 (RevMan 2008) Anal-

yses included all patients irrespective of compliance or follow-up

according to the intention-to-treat principle and using the last

reported observed response (rsquocarry forwardrsquo) Regarding death

both a worst-best-case scenario analysis considering all dropped-

out patients in the bile acid group as dead and the dropped-out

patients in the control group as alive and a best-worst-case sce-

nario analysis considering all dropped-out patients in the bile acid

group as alive and the dropped-out patients in the control group as

dead were performed Both a random-effects model (DerSimonian

1986) and a fixed-effect model (DeMets 1987) were used The re-

sults of the fixed-effect model were reported if there were no differ-

ences between the results produced by the two models otherwise

we reported the results produced by both models We presented

binary outcome measures as relative risks (RR) with 95 confi-

dence intervals (CI) and continuous outcome measures as mean

differences (MD) with 95 CI

The risk of type I errors increases in single trials with interim anal-

yses To avoid type I errors group sequential monitoring bound-

aries (Lan 1983) can be performed when deciding to terminate the

trial earlier than planned This requires analyses at different time

intervals to record when the P-value has become sufficiently small

that is when the cumulative Z-curve will cross the monitoring

boundaries Sequential monitoring boundaries the so called rsquotrial

sequential monitoring boundariesrsquo can also be applied to meta-

analyses In a trial sequential analysis (TSA) every trial that is

added in a cumulative meta-analysis is regarded as an interim meta-

analysis and the information it adds on helps on deciding if more

trials need to be included

The interpretation of the TSA is as follows if the cumulative Z-

curve has crossed the boundary a sufficient level of evidence is

reached and no further trials may be needed If the Z-curve has

not crossed the boundary then the evidence is insufficient in order

to reach a conclusion To construct the trial sequential monitor-

ing boundaries information size is needed It is calculated as the

minimum number of participants needed in a well-powered single

trial (Pogue 1997 Pogue 1998 Brok 2008 Wetterslev 2008) We

applied TSA since it prevents an increase of the risk of type I error

due to sparse and multiple updating in a cumulative meta-analysis

and provides us with important information in order to estimate

the level of evidence of the experimental intervention Addition-

ally TSA provides us with important information regarding the

need for additional trials and the required information size We

applied trial sequential monitoring boundaries according to an in-

formation size suggested by the trials with low risk of bias and a

50 relative risk reduction (RRR)

Subgroup analyses

We planned to perform the following subgroup analyses on the

main outcome measures (all-cause mortality and number of pa-

tients with acute rejection)

1 Risk of bias of the trials comparing the intervention effect for

trials with low risk of bias components to the intervention effect

in trials with unclear or high risk of bias components

2 Dose and duration of treatment with bile acids comparing the

intervention effect in trials administrating bile acid at or above the

median dose multiplied by duration to the intervention effect of

trials administrating bile acid at less than the median dose multi-

plied by duration

3 Time between transplantation and the start of bile acids com-

paring the intervention effect of trials having less than three days

between transplantation and starting bile acid intake to the inter-

vention effect of trials with a duration of three days or more be-

tween transplantation and the start of bile acid intake (Neuberger

1999)

4 Co-interventions comparing the intervention effect of trials

with co-interventions to the intervention effect of trials without

co-interventions

Funnel plot analysis

We planned to explore bias by funnel plot analysis (Egger 1997)

R E S U L T S

Description of studies

See Characteristics of included studies Characteristics of excluded

studies

The performed electronic searches resulted in a total of 378 ref-

erences We excluded 362 duplicates or irrelevant references by

reading abstracts We excluded eight of the 16 further assessed ref-

erences because they were observational studies case series or ran-



domised clinical trials with a different reason for exclusion They

are listed under rsquoCharacteristic of excluded studiesrsquo with reasons

for exclusion Seven references already included in the previous

version of this review and one new reference referring to an al-

ready included trial (Barnes 1997) were included in this review

We were not able to identify more trials by reading the reference

lists of the identified studies contacting the principle authors of

the identified trials or approaching pharmaceutical companies for

unpublished trials

Seven publications included in the review (five full publications

and two abstracts) were randomised clinical trials that reported

the random allocation of liver-transplanted patients into groups

receiving bile acid placebo or no treatment We listed these trials

in the table of Characteristics of included studies All seven trials

were published in English Three randomised clinical trials were

from the United States (Koneru 1993 Barnes 1997 Fleckenstein

1998) two from Italy (Sama 1991 Angelico 1999) one from

France (Pageaux 1995) and one from Denmark (Keiding 1997)

Patients

In the included trials all patients received blood group-compatible

grafts The median size of the seven trials was 40 patients (range

29 to 102 patients) In total 335 patients were randomised

Five trials were published as full publications (Pageaux 1995

Barnes 1997 Keiding 1997 Fleckenstein 1998 Angelico 1999)

which allowed us to extract detailed information on 263 of the

patients The mean age of the patients ranged from 44 to 51 years

One trial (Keiding 1997) also enrolled children ranging in age

from 0 to 13 years (median 15 years) The male to female ratio in

these five trials was 159104 The diseases that led to liver trans-

plantation were alcoholic cirrhosis in 51 patients (194) cirrho-

sis caused by chronic hepatitis C in 40 patients (152) primary

biliary cirrhosis in 36 patients (137) cryptogenic cirrhosis in

22 patients (84) metabolic diseases in 19 patients (72) pri-

mary sclerosing cholangitis in 17 patients (65) non-specified

post-hepatitis cirrhosis in 17 patients (65) cirrhosis caused by

chronic hepatitis B in 13 patients (49) 9 with autoimmune

hepatitis and cirrhosis (34) six with liver cancer (23) five

with biliary atresia (19) and 28 with other diseases (106)

Only one trial reported the severity of liver function according to

the Child-Pugh class (Barnes 1997)

Bile acids and collateral interventions

Six trials (Sama 1991 Koneru 1993 Pageaux 1995 Barnes

1997 Keiding 1997 Fleckenstein 1998) compared UDCA versus

placebo or no intervention One trial (Angelico 1999) compared

TUDCA versus no intervention Bile acid treatment began one

day after transplantation in the Keiding 1997 trial three days after

transplantation in the Koneru 1993 trial three or five days in the

Fleckenstein 1998 and Pageaux 1995 trials five days after trans-

plantation in the Barnes 1997 and Angelico 1999 trials and five

or seven days after transplantation in the Sama 1991 trial

Patients received UCDA (10 to 15 mgkg body weightday) for

two months in the Pageaux 1995 trial for three months in the

Koneru 1993 Barnes 1997 Keiding 1997 and Fleckenstein 1998

trials and for six months in the Sama 1991 trial In the Barnes

1997 trial patients were followed up for 18 months Patients in the

Fleckenstein 1998 trial and the Keiding 1997 trial were followed

up for nine months There was no post-treatment follow-up in

three trials (Sama 1991 Koneru 1993 Pageaux 1995) Patients

received TUDCA (500 mgday) for one year and no follow-up

was conducted in the Angelico 1999 trial

In addition to the bile acids or control intervention all patients

in the seven trials received standard triple-drug regimens (steroids

azathioprine and cyclosporine or tacrolimus) The patients who

had steroid-resistant rejection received treatment with immuno-

suppressive antibodies (OKT3)

Outcome measures

The outcome measures reported by most trials were all-cause mor-

tality and acute cellular rejection Three trials reported on death

related to rejection (Barnes 1997 Keiding 1997 Angelico 1999)

two trials reported the number of patients who received retrans-

plantation due to rejection (Keiding 1997 Fleckenstein 1998)

three trials reported the number of patients with chronic rejection

(Barnes 1997 Keiding 1997 Fleckenstein 1998) and four trials

reported the number of patients with steroid-resistant rejection

(Pageaux 1995 Barnes 1997 Keiding 1997 Fleckenstein 1998)

Four trials had adverse events as outcome measures (Barnes 1997

Keiding 1997 Fleckenstein 1998 Angelico 1999) Serum biliru-

bin level was only reported by the Fleckenstein 1998 trial No tri-

als provided data on other liver biochemical parameters quality

of life or cost-effectiveness

Risk of bias in included studies

Two trials reported adequate allocation sequence generation by

using computer-generated random tables (Barnes 1997 Angelico

1999) One trial (Keiding 1997) reported adequate allocation con-

cealment by using sealed serially numbered envelopes Three tri-

als (Barnes 1997 Keiding 1997 Fleckenstein 1998) reported ad-

equate blinding by using placebo with an identical appearance

and taste Five trials (Pageaux 1995 Barnes 1997 Keiding 1997

Fleckenstein 1998 Angelico 1999) reported adequate description

of incomplete outcome data by the number of withdrawals the

reasons for withdrawal or no patients dropped out The trial by

Keiding 1997 is the only one free of selective reporting since all

the pre-specified outcomes were fairly reported Two trials (Barnes

1997 Keiding 1997) performed sample-size calculations Only

the trial by Keiding 1997 seemed to be free of baseline imbalance

and it is the only trial achieving the calculated sample size and

therefore probably the only that was not terminated early Other

trials did not perform sample size calculation or the authors did

not report whether the calculated sample size was achieved The

lack of this information made it unclear for us to judge whether



a trial was terminated early that is before an adequate number

of patients was included in the trial Three trials (Barnes 1997

Keiding 1997 Fleckenstein 1998) stated that intention-to-treat

analyses were used (Figure 1 Figure 2)

Figure 1 Methodological quality graph review authorsrsquo judgements about each methodological quality

item presented as percentages across all included studies



Figure 2 Methodological quality summary review authorsrsquo judgements about each methodological quality

item for each included study



Following the assessment of risk of bias domains none of the seven

trials were considered to have low risk of bias that is having all

the nine domains for risk of bias assessed as adequate

Effects of interventions

We were able to include seven randomised clinical trials in this

review Six trials with 306 liver-transplanted patients compared

ursodeoxycholic acid (UDCA) with placebo or no intervention

and one trial with 29 liver-transplanted patients compared tauro-

UDCA (TUDCA) with no intervention

All-cause mortality

Five trials including 257 liver-transplanted patients reported on

all-cause mortality at the end of treatment or at maximum follow-

up Bile acids did not significantly reduce all-cause mortality (RR

085 95 CI 053 to 136) there were 26 deaths among 132

patients treated with bile acids (197) versus 29 deaths among

125 patients in the control groups (232) (Analysis 11) There

was no statistically significant heterogeneity (I2 = 141)

Four trials (Sama 1991 Barnes 1997 Keiding 1997 Fleckenstein

1998) showed that UDCA did not significantly reduce all-cause

mortality (RR 080 95 CI 049 to 130) 23 deaths among 116

patients treated with UCDA (198) versus 27 deaths among

108 patients in the control groups (250) The Angelico 1999

trial demonstrated that TUDCA was not able to reduce all-cause

mortality (RR 159 95 CI 030 to 833) there were 3 deaths

among 16 patients (188) versus 2 deaths among 17 patients

(118)

The Fleckenstein 1998 trial and the Sama 1991 trial did not report

the causes of deaths In the three other trials the deaths were

considered to be caused by infections (n = 11) hepatic failure (n =

7) abdominal bleeding (n = 3) renal failure (n = 2) multiple organ

failure (n = 2) hepatitis B virus fibrosis (n = 2) acute rejection

(n = 1) hepatic artery thrombosis (n = 1) encephalitis (n = 1)

lymphoproliferative disorder (n = 1) cerebral haemorrhage (n =

1) or other reasons (n = 6)

Worst-best case and best-worst case scenario analyses

In the worst-best case scenario analysis bile acids did not signif-

icantly reduce all-cause mortality when compared with placebo

or no intervention (RR 130 95 CI 086 to 196) 40 deaths

among 132 patients on bile acids (303) versus 29 deaths among

125 patients in the control groups (232) However all-cause

mortality was significantly reduced by bile acids in the best-worst

case scenario analysis (RR 058 95 CI 038 to 090) 26 deaths


in the control groups (336) (Analysis 12)

Subgroup analyses

We performed subgroup analyses regarding the time that bile acid

intake was started The Keiding 1997 trial started bile acid intake

less than three days after liver transplantation and demonstrated

no significant effect of UDCA on all-cause mortality (RR 124

95 CI 061 to 254) 14 deaths out of 54 patients (259)

versus 10 out of 48 control patients (208) The same effect

was noticed in the four other trials (Sama 1991 Barnes 1997

Fleckenstein 1998 Angelico 1999) which started bile acids three

days or more after liver transplantation (RR 063 95 CI 033

to 120) 12 deaths among 78 patients (154) versus 9 deaths

among 77 control patients (247) (Analysis 13) There were no

statistically significant differences between the two estimates

We also performed subgroup analyses regarding the duration of

bile acid treatment Bile acids were administrated for less than six

months in three trials (Barnes 1997 Keiding 1997 Fleckenstein

1998) and were not able to significantly decrease all-cause mor-

tality (RR 078 95 CI 045 to 138) 18 deaths in a group of

96 treated patients (188) versus 21 deaths among 88 control

patients (239) In the other two trials (Sama 1991 Angelico

1999) patients were treated with bile acids for six months or more

The treatment did not show statistically significant decrease in all-

cause mortality (RR 102 95 CI 043 to 24) 8 deaths in a

group of 36 treated patients (222) versus 8 deaths in a group

of 37 control patients (216) (Analysis 14) There were no sta-

tistically significant differences between the two estimates

Mortality related to allograft rejection

We did not find statistically significant reduction in mortality re-

lated to allograft rejection at maximum follow-up in the three tri-

als reporting cause of death (Barnes 1997 Keiding 1997 Angelico

1999) (RR 030 95 CI 001 to 712) 098 (0) versus 189

(11)) (Analysis 15) The only death due to acute rejection was

found in the placebo group of the Keiding 1997 trial

Number of liver retransplantations

Two trials (Fleckenstein 1998 Keiding 1997) including 132 liver-

transplanted patients reported the number of liver retransplan-

tations UDCA did not significantly reduce the risk of liver re-

transplantation at maximum follow-up (RR 076 95 CI 020

to 286) 368 (44) versus 464 (63)) (Analysis 16) In the

Keiding 1997 trial one patient in the UDCA group was retrans-

planted due to chronic rejection and four patients in the placebo

group were retransplanted either due to chronic rejection (three

cases) or acute rejection (one case) In the Fleckenstein 1998 trial

two patients in the UDCA group were retransplanted due to acute

rejection (one case) and chronic rejection (one case) respectively

Number of patients with acute cellular rejection

Seven trials reported the number of patients who had acute cellu-

lar rejection after liver transplantation Bile acids did not signifi-

cantly reduce the number of patients who experienced acute cel-

lular rejection (RR 089 95 CI 074 to 106) 93174(535)

versus 99165 (600)) There was no significant heterogeneity

(I2 = 0)

Six trials (Sama 1991 Koneru 1993 Pageaux 1995 Barnes 1997



Keiding 1997 Fleckenstein 1998) compared UDCA with placebo

or no intervention and demonstrated that UDCA did not signifi-

cantly reduce the number of patients with acute cellular rejection

after liver transplantation (RR 089 95 CI 074 to 108 85

158 (538) versus 89148 (601)) Neither did the Angelico

1999 trial demonstrate significant reduction of the number of pa-

tients with acute cellular rejection with TUDCA (RR 085 95

CI 045 to 160) 816 (500) versus 1017 (588) (Analysis

17)

Subgroup analyses

Two trials (Koneru 1993 Keiding 1997) in which the patients

started bile acids intake less than three days after liver transplan-

tation did not demonstrate any significant reduction of the risk

of acute cellular rejection by bile acids (RR 084 95 CI 063 to

111) 3870 (543) versus 4164 (641) The other five tri-

als (Sama 1991 Pageaux 1995 Barnes 1997 Fleckenstein 1998

Angelico 1999) in which the patients were started on bile acid

intake three days or more after liver transplantation did not find

a significant reduction of the risk of acute cellular rejection by bile

acids (RR 092 95 CI 072 to 117) 55104 (529) versus 58

101 (574) (Analysis 18) There was no significant difference

between the two estimates

Bile acids did not significantly reduce the risk of acute cellular

rejection in the five trials (Koneru 1993 Pageaux 1995 Barnes

1997 Keiding 1997 Fleckenstein 1998) in which the patients

received treatment with bile acids less than six months (RR 087

95 CI 071 to 107) 72138 (522) versus 76128 (594)

Neither did bile acids in the two other trials (Sama 1991 Angelico

1999) in which the patients received bile acids for more than six

months (RR 094 95 CI 065 to 136) 2136 (583) versus

2337 (622) (Analysis 19) There were no significant difference


Number of patients with chronic rejection

Three trials comparing UDCA versus placebo (Barnes 1997

Keiding 1997 Fleckenstein 1998) reported the number of patients

with chronic rejection after liver transplantation UDCA signifi-

cantly reduced the number of patients with chronic rejection in

the fixed-effect model analysis (RR 028 95 CI 008 to 095)

396 (31) versus 1088 (114) (Analysis 110) but not in the

random-effects model analysis (RR 030 95 CI 008 to 113) 3

96 (31) versus 1088 (114) There was no statistically signifi-

cant heterogeneity (I2 0) We performed trial sequential analysis

for the available data from three trials (Figure 3) with heterogene-

ity corrected required information size based on proportion of this

outcome of 12 in the control group a relative risk reduction of

50 in the intervention group at a type I error of 5 and a type

II error of 10 We obtained a required information size of 957

patients UDCA was not able to reach or break the trial sequential

monitoring boundary and only 183 out of 957 (19) patients

were randomised regarding this outcome



Figure 3 Trial sequential analysis for the number of patients with chronic rejection at maximum follow-up

We calculated the heterogeneity-corrected required information size (HCRIS) based on a proportion of 12 of

the patients in the placebo group with chronic rejection at maximum follow-up a 50 risk ratio reduction in

the bile acid group an alpha of 5 a beta of 10 and a heterogeneity of 0 Only 184 patients have been

randomised reporting this outcome which is only 19 of the HCRIS of 957 patients The cumulative Z-score

crosses the conventional boundaries for P 005 but not the monitoring boundaries

Number of patients with steroid-resistant rejection

Four trials (Pageaux 1995 Barnes 1997 Keiding 1997

Fleckenstein 1998) reported the number of patients with steroid-

resistant rejection These trials demonstrated that UDCA did not

significantly reduce the number of patients with steroid-resistant

rejection when compared with placebo (22122 (18) versus 26

112 (232) (RR 077 95 CI 047 to 127) (Analysis 111)

There was no significant heterogeneity (I2 0)

Liver biochemistry

The Fleckenstein 1998 trial reported serum bilirubin levels after

a three-month-treatment period in 30 liver-transplanted patients

There was no statistically significant difference in serum bilirubin

levels between the UDCA group and the placebo group (MD 260

mgdl 95 CI -096 to 616 mgdl) (Analysis 112)

No data were available for other liver biochemical variables

Cost-effectiveness

One trial (Barnes 1997) with 52 liver-transplanted patients re-

ported the days of hospitalisation after liver transplantation

UDCA significantly decreased the number of days of hospitali-

sation when compared with placebo (MD -850 days 95 CI -

1667 to -033 days) (Analysis 113) We were not able to extract

other medical cost from the trials

Adverse events

Among all the included and excluded trials only four reported on

adverse events however adverse events only occurred in two of

the included trials (Barnes 1997 Keiding 1997) There were no

significant differences regarding adverse events (RR 088 95 CI

030 to 260) 6112 (54) versus 6105 (57) (Analysis 114)

In the Barnes 1997 trial diarrhoea was reported by two patients

(one in the UDCA group and one in the placebo group) In the

Keiding 1997 trial five UDCA patients and five placebo patients

stopped intake of the trial medicine because of diarrhoea or dif-

ficulties in swallowing the capsules The remaining included trial

by Angelico 1999 stated that no adverse events occurred during

the study period The excluded trial by Assy 2007 was the only

one reporting on a case of mild diarrhoea in one patient in the



intervention group No other excluded studies reported on adverse

events (see Table 1)

Quality of life

None of the included studies assessed quality of life as an outcome

Other subgroup analyses

We planned to perform subgroup analyses regarding the risk of

bias of trials the dosage of bile acid and any co-intervention

However none of the trials were considered to be of low risk of

bias they all used a similar dosage of bile acid and patients in all

trials received similar immunosuppressive treatment as co-inter-

ventions (steroids azathioprine and cyclosporine or tacrolimus)

after liver transplantation Therefore we were not able to perform

the planned subgroup analyses

Funnel plot asymmetry

We did not draw a funnel plot analysis due to the limited number

of trials included in the present review

D I S C U S S I O N

In the update of this review we included no new trials assessing

the use of bile acids for liver-transplanted patients The analyses

of the seven previously included trials showed that bile acids did

not significantly affect mortality acute cellular rejection steroid-

resistant rejection retransplantation or serum bilirubin Bile acids

might significantly decrease the length of hospital stay and the

number of patients with chronic rejection included in these tri-

als but more supportive evidence is needed The number of pa-

tients with chronic rejection was not significantly influenced by

bile acids when a random-effects model was used and length of

stay was assessed in one single trial Furthermore none of the trials

were considered to be of low risk of bias and few patients were en-

rolled Therefore our positive findings may be due to bias (Schulz

1995 Moher 1998 Kjaergard 2001 Wood 2008) or random er-

rors (Wetterslev 2008 Brok 2009 Thorlund 2009) On the other

hand we are not able to exclude type II errors (that is finding

no significant differences when in fact they exist) due to the low

number of participants Therefore this topic could be of potential

interest in future large randomised trials with adequate control of

bias

All-cause mortality at one year after liver transplantation is re-

ported to be about 20 (Thuluvath 2003) which we also ob-

served for the patients included in the present review According to

our subgroup analyses neither UDCA nor TUDCA significantly

decreased all-cause mortality We also performed a subgroup anal-

ysis regarding treatment duration but we were not able to find any

difference between short (less than six months) and long treatment

duration (six months or more) Thus bile acids do not seem to

have statistically significant effects in reducing all-cause mortal-

ity after liver transplantation We performed both worst-best-case

scenario and best-worst-case scenario analyses In the worst-best-

case scenario bile acids did not differ significantly from placebo or

no intervention regarding all-cause mortality However bile acids

significantly decreased all-cause mortality in the best-worst-case

scenario analysis However such an analysis is very extreme and

may not be realistic We have also found that UDCA may be able

to decrease the risk of chronic rejection in liver-transplanted pa-

tients but trial sequential analysis could not confirm this result

Due to a limited number of patients (Ioannidis 2001) we are not

able to exclude the possibility that it may be relevant to perform

placebo-controlled trials with low risk of bias on the use of bile

acids for liver-transplanted patients

We looked into the causes of deaths that were reported by the trials

and only one trial reported one death related to rejection At the

same time the number of retransplantations was 3 among 68 liver-

transplanted patients who received treatment with UDCA and 4

among 64 liver-transplanted patients who received treatment with

placebo We noticed that all patients in the included trials received

co-interventions of standard triple-drug regimens (steroids aza-

thioprine and cyclosporine or tacrolimus) which were able to

control the possible acute or chronic rejection and prevent deaths

due to allograft rejection (FK506 1994)

The assumption that UDCA might reduce the incidence of acute

graft rejection came from the findings that UDCA could regulate

major histocompatibility complex antigen expression in bile ducts

and liver endothelia and inhibit lymphocyte activity (Calmus

1990 Terasaki 1991 Perez 2009) However in the present review

bile acids did not significantly reduce the risk of acute cellular re-

jection in liver-transplanted patients Considering that acute cellu-

lar rejection is commonly found within a few days after liver trans-

plantation (Vierling 1992) some might argue that the adminis-

tration of bile acids was started too late to prevent acute cellular

rejection We performed subgroup analyses regarding the time bile

acids were started and no statistically significant difference was

found Furthermore bile acids were not able to decrease the risk

of steroid-resistant rejection Therefore the lack of effects of bile

acids does not seem to be due to a delayed start to bile acid ad-

ministration after liver transplantation However it is a possibility

that one should start bile acids intake before liver transplantation

A retrospective study found that rejection rates differed signifi-

cantly between patients with primary biliary cirrhosis treated with

or without UDCA before liver transplantation (Heathcote 1999)

One could argue whether UDCA-induced delay in transplantation

has an adverse effect on post-transplantation outcome Since we

did not find any prospective randomised clinical trials addressing

this issue further research might be needed Furthermore some

studies may provide an explanation why UDCA was not able to

prevent acute cellular rejection These studies found that UDCA

did not appear to change the expression of major histocompatibil-

ity complex class II antigens but rather major histocompatibility

complex class I antigens (Calmus 1990) The initial mechanism

of acute rejection is thought to be recognition of MHC class II



antigens by CD4+ T cells (Vierling 1992) Moreover the inhibi-

tion of the production of interleukin-2 by peripheral blood lym-

phocytes with UDCA (Heuman 1993) might be negated by the

immunosuppressive treatment after liver transplantation (van den

Berg 1998) so that UDCA is unable to demonstrate effects on

graft rejection In a recent study by Assy 2007 a significant re-

duction in the mean dose of immunosuppressive medications was

achieved in stable liver graft recipients treated with UDCA indi-

cating a possible influence of UDCA on rejection mechanisms

In accordance with previous systematic reviews (Chen 2003a

Chen 2007 Gong 2008) bile acids were not associated with the

occurrence of serious adverse events or any major occurrence of

adverse events

In summary our results do not support or refute the use of bile

acids (UDCA and TUDCA) additional to standard immunosup-

pressive treatment in liver-transplanted patients

A U T H O R S rsquo C O N C L U S I O N SImplications for practice

There seems to be no evidence to support or refute the use of bile

acids for liver-transplanted patients receiving standard immuno-

suppressive treatment

Implications for research

We need more randomised placebo-controlled clinical trials with

enough statistical power and low risk of bias to explore the poten-

tial effects of bile acids on chronic rejection and mortality in liver-

transplanted patients Such trials should also consider evaluation

of quality of life and length of hospitalisation Such trials may

consider starting bile acid and placebo interventions before liver

transplantation we were not able to identify any randomised trials

addressing this regimen Such trials ought to be reported accord-

ing to the CONSORT statement (wwwconsort-statementorg)

However before embarking on such trials the effects of bile acids

in other patient groups should be scrutinised as they may have

small or negative effects

A C K N O W L E D G E M E N T S

We thank all the patients and investigators who were involved in

the clinical trials mentioned in this review We thank Wendong

Chen for his work and contribution on the previous version of this

review We thank the staff of The Cochrane Hepato-Biliary Group

Editorial Team especially Dimitrinka Nikolova and Sarah Louise

Klingenberg for excellent collaboration and assistance during the

update of this review

Peer Reviewers Carlo Merkel Italy M Tomikawa Japan

Contact Editor Bodil Als-Nielsen Denmark

R E F E R E N C E S

References to studies included in this review

Angelico 1999 published data only

Angelico M Tisone G Baiocchi L Palmieri G Pisani F Negrini S

et alOne-year pilot study on tauroursodeoxycholic acid as an

adjuvant treatment after liver transplantation Italian Journal of

Gastroenterology and Hepatology 199931(6)462ndash8 [MEDLINE

10575563]

Barnes 1997 published data onlylowast Barnes D Talenti D Cammell G Goormastic M Farquhar L

Henderson M et alA randomized clinical trial of ursodeoxycholic

acid as adjuvant treatment to prevent liver transplant rejection

Hepatology 199726(4)853ndash7 [MEDLINE 9328304]

Barnes D Talenti D Goormastic M Farquhar L Cammell G

Henderson M et alUrsodeoxycholic acid (UDCA) reduces hepatic

allograft rejection after orthotopic liver transplantation (OLT) - a

prospective randomized placebo-controlled double-blind trial

Hepatology 199522149A

Fleckenstein 1998 published data only

Fleckenstein JF Paredes M Thuluvath PJ A prospective

randomized double-blind trial evaluating the efficacy of

ursodeoxycholic acid in prevention of liver transplant rejection

Liver Transplantation and Surgery 19984(4)276ndash9 [MEDLINE

9649640]

Keiding 1997 published data only

Keiding S Hockerstedt K Bjoro K Bondesen S Hjortrup A

Isoniemi H et alThe Nordic multicenter double-blind randomized

controlled trial of prophylactic ursodeoxycholic acid in liver

transplant patients Transplantation 199763(11)1591ndash4

[MEDLINE 9197351]

Koneru 1993 published data only

Koneru B Tint GS Wilson DJ Leevy CB Salen F Randomised

prospective trial of ursodeoxycholic acid in liver transplant

recipients Hepatology 199318336A

Pageaux 1995 published data only

Pageaux GP Blanc P Perrigault PF Navarro F Fabre JM Souche B

et alFailure of ursodeoxycholic acid to prevent acute cellular

rejection after liver transplantation Journal of Hepatology 199523

(2)119ndash22 [MEDLINE 7499781]

Sama 1991 published data only

Sama C Mazziotti A Grigioni W Morselli AM Chianura A

Stefanini GF et alUrsodeoxycholic acid administration does not



prevent rejection after OLT Journal of Hepatology 199113(Suppl

2)68

References to studies excluded from this review

Assy 2007 published data only

Assy N Adams PC Myers P Simon V Minuk GY Wall W et

alRandomized controlled trial of total immunosuppression

withdrawal in liver transplant recipients role of ursodeoxycholic

acid Transplantation 200783(12)1571ndash6 [MEDLINE

17589339]

Clavien 1996 published data only

Clavien PA Sharara AI Camargo CA Jr Harland RC Fitz JG

Evidence that ursodeoxycholic acid prevents steroid-resistant

rejection in adult liver transplantation Clinical Transplantation

199610(6 Pt 2)658ndash62 [MEDLINE 8996761]

Friman 1992 published data only

Friman S Persson H Schersten T Svanvik J Karlberg I Adjuvant

treatment with ursodeoxycholic acid reduces acute rejection after

liver transplantation Transplantation Proceedings 199224(1)

389ndash90 [MEDLINE 1539328]

Heathcote 1999 published data onlylowast Heathcote EJ Stone J Cauch-Dudek K Poupon R Chazouilleres

O Lindor KD et alEffect of pretransplantation ursodeoxycholic

acid therapy on the outcome of liver transplantation in patients

with primary biliary cirrhosis Liver Transplantation and Surgery

19995(4)269ndash74 [MEDLINE 10388499]

Henriksson 1991 published data only

Henriksson BA Persson H Friman S Wangberg B Svanvik J

Karlberg I Adjuvant ursodeoxycholic acid prevents acute rejection

in liver transplant recipients Transplantation Proceedings 199123

(3)1971 [MEDLINE 2063453]

Persson 1990 published data only

Persson H Friman S Schersten T Svanvik J Karlberg I

Ursodeoxycholic acid for prevention of acute rejection in liver

transplant recipients Lancet 1990336(8706)52ndash3 [MEDLINE

1973232]

Rafael 1995 published data only

Rafael E Duraj F Rudstrom H Wilczek H Ericzon B Effect of

ursodeoxycholic acid treatment for cholestasis in liver transplant

recipients Transplantation Proceedings 199527(6)3501ndash2

[MEDLINE 8540069]


Sama C Morselli-Labate AM Grazi GL Mastroianni A Danesi G

Pianta P et alUrsodeoxycholic acid in liver transplantation effect

on cholestasis and rejection Gastroenterology 1998114(4 Suppl)

A1332

Additional references

Adams 1990

Adams DH Neuberger JM Patterns of graft rejection following

liver transplantation Journal of Hepatology 199010(1)113ndash9

[MEDLINE 2407770]

Al-Quaiz 1994

Al-Quaiz M OrsquoGrady J Tredger J Williams R Variable effect of

ursodeoxycholic acid on cyclosporin absorption after orthotopic

liver transplantation Transplant International 19947(3)190ndash4

[MEDLINE 8060468]

Armstrong 1982

Armstrong MJ Carey MC The hydrophobic-hydrophilic balance

of bile salt Inverse correlation between reverse phase high

performance liquid chromatographic mobilities and micellar

cholesterol-solubilizing capacities Journal of Lipid Research 1982

23(1)70ndash80 [MEDLINE 7057113]

Ascher 1988

Ascher NL Stock PG Baumgardner GL Payne WD Najarian JS

Infection and rejection of primary hepatic transplant in 93

consecutive patients treated with triple immunosuppressive therapy

Surgery Gynecology amp Obstetrics 1988167(6)474ndash84

[MEDLINE 3055368]

Brok 2008

Brok J Thorlund K Gluud C Wetterslev J Trial sequential

analysis reveals insufficient information size and potentially false

positive results in many meta-analyses Journal of Clinical

Epidemiology 200861(8)763ndash9 [MEDLINE 18411040]

Brok 2009

Brok J Thorlund K Wetterslev J Gluud C Apparently conclusive

meta-analysis may be inconclusive - Trial sequential analysis

adjustment of random error risk due to repetitive testing of

accumulating data in apparently conclusive neonatal meta-analysis

International Journal of Epidemiology 200938(1)298ndash303

[MEDLINE 18824466]

Calmus 1990

Calmus Y Gane P Rouger P Poupon R Hepatic expression of class

I and class II major histocompatibility complex molecules in

primary biliary cirrhosis effect of ursodeoxycholic acid Hepatology

199011(1)12ndash5 [MEDLINE 2403961]

Calmus 1992

Calmus Y Arvieux C Gane P Boucher E Nordlinger B Rouger P

et alCholestasis induces major histocompatibility complex class I

expression in hepatocytes Gastroenterology 1992102(4 Pt 1)


Chen 2003a

Chen W Gluud C Bile acids for primary sclerosing cholangitis

Cochrane Database of Systematic Reviews 2003 Issue 2 [DOI

10100214651858CD003626]

Chen 2007

Chen W Liu J Gluud C Bile acids for viral hepatitis Cochrane

Database of Systematic Reviews 2007 Issue 4 [DOI 101002

14651858CD003181pub2]

Cheng 2002

Cheng K Ashby D Smyth R Ursodeoxycholic acid for cystic

fibrosis-related liver disease Cochrane Database of Systematic

Reviews 2002 Issue 2 [DOI 10100214651858CD000222]

Corbani 2008

Corbani A Burroughs AK Intrahepatic cholestasis after liver

transplantation Clinics in Liver Disease 200812(1)111ndash29

[MEDLINE 18242500]

DeMets 1987

DeMets DL Methods for combining randomised clinical trials

strengths and limitations Statistics in Medicine 19876(3)341ndash50

[MEDLINE 3616287]



DerSimonian 1986

DerSimonian R Laird N Meta-analysis in clinical trials Controlled

Clinical Trials 19867(3)177ndash88 [MEDLINE 3802833]

Egger 1997

Egger M Davey Smith G Schneider M Minder C Bias in meta-

analysis detected by a simple graphical test BMJ (Clinical Research

Ed) 1997315(7109)629ndash34 [MEDLINE 9310563]

Ericzon 1990

Ericzon BG Eusufzai S Kubota K Einarsson K Angelin B

Characteristics of biliary lipid metabolism after liver

transplantation Hepatology 199012(5)1222ndash8 [MEDLINE

2227822]

FK506 1994

The US Multicenter FK506 Liver Study Group A comparison of

tacrolimus (FK506) and cyclosporine for immunosuppression in

liver transplantation New England Journal of Medicine 1994331

(17)1110ndash5 [MEDLINE 7523946]

Friman 1994

Friman S Svanvik J A possible role of ursodeoxycholic acid in liver

transplantation Scandinavian Journal of Gastroenterology 1994204


Fuchs 1999

Fuchs M Stange EF Metabolism of bile acids In Johannes

Bircher Jean-Pierre Benhamou Neil McIntyre Mario Rizzetto

Juan Rodes editor(s) Oxford Textbook of Clinical Hepatology 2

Vol 1 Oxford Oxford University Press 1999223ndash56

Fusai 2006

Fusai G Dhaliwal P Rolando N Sabin CA Patch D Davidson BR

et alIncidence and risk factors for the development of prolonged

and severe intrahepatic cholestasis after liver transplantation Liver

Transplantation 200612(11)1626ndash33 [DOI 101002lt20870]

Gluud 2001

Gluud C Alcoholic hepatitis no glucocorticosteroids In

Leuschner U James OFW Dancygier H editor(s) Steatohepatitis

(NASH and ASH) Falk Symposium 121 Lancaster Kluwer

Academic Publisher 2001322ndash42

Gluud 2010

Gluud C Nikolova D Klingenberg SL Alexakis N Als-Nielsen B

Colli A et alCochrane Hepato-Biliary Group About The

Cochrane Collaboration (Cochrane Review Groups (CRGs))

2010 Issue 1 Art No LIVER

Gong 2008

Gong Y Huang ZB Christiansen E Gluud C Ursodeoxycholic

acid for primary biliary cirrhosis Cochrane Database of Systematic

Reviews 2008 Issue 3 [DOI 101002

14651858CD000551pub2]

Haddad 2006

Haddad EM McAlister VC Renouf E Malthaner R Kjaer MS

Gluud LL Cyclosporin versus tacrolimus for liver transplanted

patients Cochrane Database of Systematic Reviews 2006 Issue 4

[DOI 10100214651858CD005161pub2]

Heuman 1993

Heuman DM Hepatoprotective properties of ursodeoxycholic acid

Gastroenterology 1993104(6)1865ndash9 [MEDLINE 8500748]

Higgins 2008

Higgins PTJ Green S editors Cochrane Handbook for Systematic

Reviews of Interventions West Sussex England Wiley-Blackwell

2008

Hirschfield 2009

Hirschfield GM Gibbs P Griffiths WJH Adult liver

transplantation what non-specialists need to know BMJ (Clinical

Research Ed) 2009338(b1670)1321ndash7 [DOI 101136

bmjb1670]

Hussain 2002

Hussain HK Nghiem HV Imaging of hepatic transplantation

Clinics in Liver Disease 20026(1)247ndash70 [MEDLINE

11933592]

ICH-GCP 1997

International Conference on Harmonisation Expert Working

Group Code of Federal Regulations amp International Conference on

Harmonization Guidelines Media Parexel Barnett 1997

Ioannidis 2001

Ioannidis JPA Lau J Evolution of treatment effects over time

Empirical insight from recursive cumulative meta analyses

Proceedings of the National Academy of Sciences 200198(3)831ndash6

IWP 1995

International Working Party Terminology for hepatic allograft

rejection Hepatology 199522(2)648ndash54 [MEDLINE 7635435]

Kjaergard 2001

Kjaergard LL Villumsen J Gluud C Reported methodological

quality and discrepancies between large and small randomised trials

in meta-analyses Annals of Internal Medicine 2001135(11)982ndash9

[MEDLINE 11730399]

Klintmalm 1989

Klintmalm GB Nery JR Husberg BS Gonwa TA Tillery GW

Rejection in liver transplantation Hepatology 198910(6)978ndash85

[MEDLINE 2583691]

Knechtle 2009

Knechtle SJ Kwun J Unique aspects of rejection and tolerance in

liver transplantation Seminars in Liver Disease 200929(1)91ndash101

[MEDLINE 19235662]

Krams 1993

Krams SM Ascher NL Martinez OM New immunologic insights

into mechanisms of allograft rejection Gastroenterology Clinics of

North America 199318(2)374ndash7 [MEDLINE 8509176]

Lan 1983

Lan KKG DeMets DL Discrete sequential boundaries for clinical

trials Biometrika 198370659ndash63

Merion 1989

Merion RM Gorski DH Burtch GD Turcotte JG Colletti LM

Campbell DA Jr Bile refeeding after liver transplantation and

avoidance of intravenous cyclosporine Surgery 1989106(4)


Moher 1998

Moher D Pham B Jones A Cook DJ Jadad AR Moher M et

alDoes quality of reports of randomised trials affect estimates of

intervention efficacy reported in meta-analyses Lancet 1998352

(9128)609ndash13 [MEDLINE 9746022]



Neuberger 1999

Neuberger J Incidence timing and risk factors for acute and

chronic rejection Liver Transplantation and Surgery 19995(4 Suppl

1)S30ndashS36 [MEDLINE 10431015]

Okolicsanyi 1986

Okolicsanyi L Lirussi F Strazzabosco M Jemmolo RM Orlando R

Nassuato G et alThe effect of drugs on bile flow and composition

An overview Drugs 198631(5)430ndash48 [MEDLINE 2872047]

Palmer 1972

Palmer RH Bile acids liver injury and liver disease Archives of

Internal Medicine 1972130(4)606ndash17 [MEDLINE 4627840]

Perez 2009

Perez MJ Briz O Bile-acid-induced cell injury and protection

World Journal of Gastroenterology 200915(14)1677ndash89

[MEDLINE 19360911]

Pogue 1997

Pogue JM Yusuf S Cumulating evidence from randomized trials

Utilizing sequential monitoring boundaries for cumulative meta-

analysis Controlled Clinical Trials 199718(6)580ndash93

[MEDLINE 9408720]

Pogue 1998

Pogue J Yusuf S Overcoming the limitations of current meta-

analysis of randomised controlled trials Lancet 1998351(9095)


RevMan 2008

The Nordic Cochrane Centre The Cochrane Collaboration

Review Manager (RevMan) 50 Copenhagen The Nordic

Cochrane Centre The Cochrane Collaboration 2008

Royle 2003

Royle P Milne R Literature searching for randomized controlled

trials used in Cochrane reviews rapid versus exhaustive searches

International Journal of Technology Assessment in Health Care 2003

19(4)591ndash603

Schulz 1995

Schulz KF Chalmers I Hayer R Altman D Empirical evidence of

bias JAMA 1995273(5)408ndash12 [MEDLINE 7823387]

Sharara 1995

Sharara AI Camargo CA Clavien PA Ursodeoxycholic acid

prevents steroid resistant rejection in liver transplant recipients

Gastroenterology 1995108A1168

Sholmerich 1984

Sholmerich J Becher MS Schmidt KH Schubert R Kremer B

Felhaus S et alInfluence of hydroxylation and conjugation of bile

salts on their membrane damaging properties Hepatology 19844

(4)661ndash7 [MEDLINE 6745854]

Soderdahl 1998

Soderdahl G Nowak G Duraj F Wang FH Einarsson C Ericzon

BG Ursodeoxycholic acid increased bile flow and affects bile

composition in the early postoperative phase following liver

transplantation Transplantation International 199811(Suppl 1)

S231ndashS238 [MEDLINE 9664985]

Terasaki 1991

Terasaki S Nakanuma Y Ogino H Unoura M Kobayashi K

Hepatocellular and biliary expression of HLA antigens in primary

biliary cirrhosis before and after ursodeoxycholic acid therapy

American Journal of Gastroenterology 199186(9)1194ndash9

[MEDLINE 1882800]

Thalheimer 2002

Thalheimer U Capra F Liver transplantation making the best out

of what we have Digestive Diseases and Sciences 200247(5)


Thorlund 2009

Thorlund K Devereaux PJ Wetterslev J Guyatt G Ioannidis JP

Thabane L et alCan trial sequential monitoring boundaries reduce

spurious inferences from meta-analyses International Journal of


Thuluvath 2003

Thuluvath PJ Yoo HY Thompson RE A model to predict survival

at one month one year and five years after liver transplantation

based on pretransplant clinical characteristics Liver Transplantation

20039(5)527ndash32 [MEDLINE 12740799]

van den Berg 1998

van den Berg AP Twilhaar WN Mesander G van Son WJ van der

Bij W Klompmaker IJ et alQuantitation of immunosuppression

by flow cytometric measurement of the capacity of T cells for

interleukin-2 production Transplantation 199865(8)1066ndash71

[MEDLINE 9583867]

Vierling 1992

Vierling J Immunologic mechanisms of hepatic allograft rejection

Seminars in Liver Disease 199212(1)16ndash27 [MEDLINE

1570548]

Wetterslev 2008

Wetterslev J Thorlund K Brok J Gluud C Trial sequential

analysis may establish when firm evidence is reached in cumulative

meta-analysis Journal of Clinical Epidemiology 200861(1)64ndash75

[MEDLINE 18083463]

Wiesner 1992

Wiesner RH Acute cellular rejection following liver

transplantation incidence risk factors and outcome in the

NIDDK Liver Transplant Database (LTD) study Gastroenterology

1992102A910

Wood 2008

Wood L Egger M Gluud LL Schulz KF Juni P Altman DG et

alEmpirical evidence of bias in treatment effect estimates in

controlled trials with different interventions and outcomes meta-

epidemiological study BMJ (Clinical Research Ed) 2008336

(7644)601ndash5 [MEDLINE 18316340]

Yoshikawa 1998

Yoshikawa M Matsui Y Kawamoto H Toyohara M Matsumura

K Yamao J et alIntragastric administration of ursodeoxycholic

acid suppresses immunoglobulin secretion by lymphocytes from

liver but not from peripheral blood spleen or Peyerrsquos patches in

mice International Journal of Immunopharmacology 199820(1-3)


References to other published versions of this review



Chen 2003b

Chen W Gluud C Bile acids for liver transplanted patients


10100214651858CD005442]lowast Indicates the major publication for the study



C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Angelico 1999

Methods Study design open-label randomised one-year pilot study

Participants Country Italy

Publication language English

Inclusion criteria

- patients who underwent liver transplantation from April 1994 to December 1994

Exclusion criteria

- not mentioned

Participants

Two patients in TUDCA group and two patients in control group were excluded from

the basic information of participants by the study due to withdrawal

- TUDCA group (n = 14)

Mean age (years +- SD)

467 +- 84

Ratio of sex (malefemale) 122

Origins of liver diseases

hepatitis C cirrhosis (9) hepatitis B cirrhosis (2) hepatitis B and C cirrhosis (1) cryp-

togenic cirrhosis (2) alcoholic cirrhosis (0) Wilson cirrhosis (0)

- Control group (n = 15)


474 +- 74





Interventions TUDCA group

- Dose 500 mgday in two divided doses

- Route orally

- Duration the treatment was started on day 5 after transplantation and continued for

one year

Control group

- no treatment

Co-interventions all patients received standard triple-drug regimens (steroids azathio-

prine and cyclosporine or tacrolimus)

Outcomes All cause mortality

Number of patients with rejection after liver transplantation

Notes Letter was sent to the authors in September 2009 A reply with additional information

was received shortly after

Risk of bias



Angelico 1999 (Continued)

Item Authorsrsquo judgement Description

Adequate sequence generation Yes Computer generated table

Allocation concealment Unclear No information provided

Blinding No Not performed

Incomplete outcome data addressed

All outcomes

Yes Withdrawal two patients from the

TUDCA group and two patients from the

placebo group Three of them died due to

transplant non-function in the first postop-

erative week and one patient was regrafted

due to thrombosis of hepatic artery

Free of selective reporting Unclear Post-transplant cholestasis and liver bio-

chemistry specified as outcomes Differ-

ence reported as not significant but no ac-

tual data given

Sample size calculation No Not reported

Intention-to-treat analysis No Not stated and not used

Baseline imbalance Unclear Not enough information provided

Early stopping of trial Unclear Not enough information provided

Barnes 1997

Methods Study design randomised placebo-controlled double-blind trial

Participants Country United States


Inclusion criteria

- patients aged 18 years or older who underwent liver transplantation at the Cleveland

Clinic Foundation from April 1992 through June of 1994

Exclusion criteria

- patients who were found to have cancer at surgically resected margins of the biliary

tree

- patents who underwent retransplantation

Participants

- UDCA group (n = 28)


505 +- 116


Child class A 7



Barnes 1997 (Continued)

B 13

and C 8

Origins of liver diseases Laennecrsquos cirrhosis 4

PBC 3

cryptogenic cirrhosis 6

hepatitis Ccirrhosis 4

hepatitis Bcirrhosis 3

autoimmune hepatitis with cirrhosis 3

PSC 2

other 3

- Placebo group (n = 24)


507 +- 93


Child class A 6

B 14

and C 4


PBC 5





PSC 2

other 4

Interventions UDCA group

- Dose 10-15 mgkg body weightday in divided doses

- Route orally

- Duration immediately after intestinal transit recovery usually between postoperative

days three and five and continue for three months

Placebo group

- identical-appearing capsules administered in the same quantity and manner







Number of days of hospitalisation

Adverse events



Risk of bias







Blinding Yes Quote ldquorandomised to receive either

UDCA or an identical placebo capsulerdquo


All outcomes

Yes Mean follow-up time 18 months Ten pa-

tients withdrawn from study 6 in UDCA

group and 4 in placebo group Reasons

for withdrawal were reported Four patients

died in the placebo group

Free of selective reporting Yes All expected outcomes reported

Sample size calculation Unclear The trial reported the method of sample

size calculation but the actual number of

patients needed was not reported

Intention-to-treat analysis Yes Stated and used


Early stopping of trial Unclear The number of patients needed to gain the

actual power was not reported Whether

the trial was terminated early is not clear

Fleckenstein 1998

Methods Study design prospective randomised double-blind trial



Inclusion criteria

- patients who underwent liver transplantation at the Johns Hopkins Hospital

Exclusion criteria

- patients who were under 18 years old undergoing repeat transplantation had primary

graft nonfunction or refused consent

Participants



443 +- 127


Origins of liver diseases hepatitis C 6

alcohol 2

autoimmune 1

PBC 2



Fleckenstein 1998 (Continued)

PSC 1

autoimmune cholangiopathy 1

hepatitis B 1



496 +- 109



alcohol 3

autoimmune 3

PBC 1

PSC 2

cryptogenic 2

hepatitis B 1

alpha1-antitrypsin deficiency 1


- Dose 15 mgkg body weightday in divided doses

- Route orally



Placebo group

- Identical-appearing capsules administered in the same quantity and manner




Number with retransplantation



Serum bilirubin levels at the end of treatment

Notes Follow-up time nine months

Letter was sent to the authors in September 2009 No reply was received

Risk of bias


Adequate sequence generation Unclear No information provided


Blinding Yes Method of blinding not described but

probably adequate


All outcomes

Yes Withdrawal one patient from the UDCA

group and two patients from the placebo

group because of capsule size




Free of selective reporting Unclear Outcomes were not completely described


Intention-to-treat analysis Yes Quote ldquoThree patients withdrew after in-

clusionThey were included in the statis-

tical analysisrdquo



Keiding 1997

Methods Study design prospective randomised placebo-controlled multicenter study

Participants Country Denmark Finland Norway and Sweden


Inclusion criteria

- patients who underwent liver transplantation in Denmark Finland Norway and Swe-

den from September 1 1992 to May 31 1994

Exclusion criteria

- patients with malignant diseases

Participants

The age of the children ranged from 0 to 13 years (median 15) and the age of adults

ranged from 14 to 59 years old (median 44) MaleFemale ratio was 96 for children and

4344 for adults



paracetamol intoxication 1 hepatitis B 1 autoimmune hepatitis 0 biliary atresia 2

metabolic diseases 7 neonatal hepatitis 2 PBC 13 post hepatitis cirrhosis 8 PSC 3

cryptogenic cirrhosis 7 alcoholic cirrhosis 2 other reasons 8


Origins of liver diseases paracetamol intoxication 1 hepatitis B 0 autoimmune hepatitis

1 biliary atresia 3 metabolic diseases 11 neonatal hepatitis 0 PBC 7 post hepatitis

cirrhosis 5 PSC 7 cryptogenic cirrhosis 2 alcoholic cirrhosis 6 other reasons 5


- Dose 15 mgkg body weightday in two or three divided doses

- Route orally



Placebo group






Keiding 1997 (Continued)


Number of deaths related to rejection




Adverse events

Notes Letter was sent to the authors in September 2009 No reply was received

Risk of bias


Adequate sequence generation Unclear Patients were randomised at a ratio of 11

Allocation concealment Yes Quote ldquo The allocation was performed in

blocks of 10 patients using the sealed serial

envelope methodrdquo

Blinding Yes Quote ldquoThe UDCA and the placebo cap-

sules had identical appearance and tasterdquo


All outcomes

Yes Follow-up time 12 months Five UDCA

patients and five placebo patients withdrew

from study Reasons were reported

Free of selective reporting Unclear Insufficient information

Sample size calculation Yes Performed and allowed for a difference in

the incidence of at least one episode of

acute rejection of 50 between the treat-

ment and placebo groups with 90 statisti-

cal power and a significance level of P value

less than 005 The calculated sample size

was 80 patients


Baseline imbalance Yes The study seems to be free of baseline im-

balance

Early stopping of trial Yes Study attained the pre-specified sample

size



Koneru 1993

Methods Study design randomised controlled trial



Inclusion criteria

- patients who underwent liver transplantation

Exclusion criteria

- not mentioned

Participants



no information

Ratio of sex (malefemale) no information


no information



no information



no information


- Dose 900 mgday

- Route orally



Control group

- no treatment


prine and cyclosporine)

Outcomes Number of patients with retransplantation due to rejection

Number of patients with rejection episodes

Notes Abstract


Risk of bias







Koneru 1993 (Continued)


All outcomes

Unclear The study gives the impression that there

were no withdrawals but this was not ex-

plicitly stated

Free of selective reporting Unclear Insufficient information provided

Sample size calculation No Not performed

Intention-to-treat analysis Unclear No information provided



Pageaux 1995

Methods Study design double-blind randomised study

Participants Country France


Inclusion criteria


Exclusion criteria

- not mentioned

Participants

- UDCA group (n=26)


47 +- 10


Origins of liver diseases alcoholic cirrhosis 14

post-hepatic B cirrhosis 2

post-hepatitis C cirrhosis 4

PBC 2

liver cancer 2

fulminant hepatitis 1

miscellaneous 1



51+- 9




post-hepatic C cirrhosis 6

PBC 3

liver cancer 4


miscellaneous 1



Pageaux 1995 (Continued)


- Dose 600 mgday in three divided doses

- Route orally


days three and five and continue for two months

Placebo group




Outcomes Number of patients with acute cellular rejection



Risk of bias




Blinding Unclear Method of blinding not described


All outcomes

Yes Five patients died from non-immunologi-

cal causes before the end of the first month

and were excluded from the study Reasons

were reported

Free of selective reporting Unclear Not enough information provided





Sama 1991




Inclusion criteria



Sama 1991 (Continued)


Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information



- Route orally


day five and day seven and continue for six months

Control group

- no treatment

Co-interventions all patients received standard immunosuppressive treatment (steroids

and cyclosporine)



Notes Abstract


Risk of bias


Adequate sequence generation Unclear A randomisation list was performed before

patients were admitted to the trial (infor-

mation from principal author)


Blinding Unclear The principle author provided information

that the study was made according to a

single-blind randomised protocol The pri-

mary outcome was the occurrence of biopsy

proven rejection episodes The pathologists

were blind but the patients were not





All outcomes

Unclear Five patients from the UDCA group and

six patients from the placebo group were

excluded Reasons for exclusion were not

fully stated

Free of selective reporting No Data about survival of patients were not

adequately reported



Baseline imbalance Unclear Basic characteristics of patients not re-

ported


UDCA = ursodeoxycholic acid

TUDCA = tauroursodeoxycholic acid

PBC = primary biliary cirrhosis

PSC = primary sclerosing cholangitis

OKT3 = anti-CD3 monoclonal antibody

Characteristics of excluded studies [ordered by study ID]

Assy 2007 A randomised controlled trial that included only recipients of liver transplantation with stable graft function and

no episodes of rejection for at least 2 years that were then offered total immunosuppression withdrawal Fourteen

patients received UDCA (15 mgkg body weightday) and 12 received placebo Rejection occurred in 43 and

75 of patients respectively (no significant difference) None developed chronic rejection After follow-up two

patients were free of immunosuppression 80 were steroid free and 50 were able to reduce their dose of

cyclosporine

Clavien 1996 Case series Fifty consecutive liver-transplanted patients were treated with a standard cyclosporine immunosup-

pressive regimen Twenty three of the 43 survivors developed an episode of rejection and UDCA (10 mgkg

weightday) was initiated Only one patient had a second episode of rejection

Friman 1992 Observational study Thirty-three liver-transplanted patients received 10 mg UDCAkg body weightday for

median of 10 months (range four to 21 months) Eight historical liver-transplanted patients served as control

group The rejection incidence was significantly lower in the patients who received the treatment with UDCA

Biochemistry one month after transplantation demonstrated significantly lower average values of aminotrans-

ferases and alkaline phosphatases in patients treated with UDCA than in the control group



(Continued)

Heathcote 1999 Observational study From 1987 to 1996 37 UDCA treated and 53 placebo treated patients with primary biliary

cirrhosis were referred for transplantation Posttransplantation survival rates at one month were 939 in the

UDCA group and 884 in the placebo group and one year survival rates were 903 and 784 respectively

(no significant differences) However rejection (type not defined - a secondary outcome measure) occurred

significantly less often in the UDCA group (429) than in placebo group (688)

Henriksson 1991 Observational study All patients in this study were given sequential quadruple immunosuppression with anti-

lymphocyte globulin azathioprine steroids and cyclosporine All patients with primary graft function (n = 11)

were treated with 10 mg UDCAkg body weightday starting during the first postoperative week Patients who

received liver transplantation in the first 6 months of 1989 (n = 8) served as controls In the control group one

patient died after 9 months with chronic graft dysfunction and six patients had rejection episodes during the

first postoperative month All patients in the UDCA group were alive without rejection episodes

Persson 1990 Observational study All 11 adult patients transplanted between August 1989 and January 1990 with primary

graft function were treated with 10 mg UDCA kg body weightday Eight patients transplanted during the first

half of 1989 served as control UDCA was started during the first postoperative week and the treatment was

continued for six months All patients in the UDCA treated group survived with satisfactory graft function In

the control group six patients had at least one rejection episode needing treatment during the first postoperative

month

Rafael 1995 Observational study Seventeen patients who underwent liver transplantation between February 1990 and April

1993 and developed biliary complications after transplantation were retrospectively analysed regarding treatment

with UDCA UDCA was given in a dose of 500 to 1000 mgday Ten patients were treated for at least one year while

seven patients were treated for 14 to 250 days UDCA significantly improved gammaglutamyl transpeptidase in

liver graft recipients with biliary complications There was also a trend towards improvement in serum bilirubin

and alanine transaminase values

Sama 1998 Observational study Thirty-four patients who underwent liver transplantation between January 1995 and June

1996 were included in the study Seventeen were treated with UDCA 10 mgkg body weightday during 6

months while 17 served as controls on the basis of having undergone liver transplantation closest to UDCA

patients A significant decrease in serum bilirubin levels was observed in UDCA patients There was a significantly

higher incidence of recurrent hepatitis in the control group

UDCA ursodeoxycholic acid



D A T A A N D A N A L Y S E S

Comparison 1 Bile acids for liver-transplanted patients

Outcome or subgroup titleNo of

studies

No of

participants Statistical method Effect size

1 All-cause mortality at maximum

follow-up

5 257 Risk Ratio (M-H Fixed 95 CI) 085 [053 136]

11 UDCA versus placebo or

no treatment


12 TUDCA versus no

treatment


2 All-cause mortality worst-best

case and best-worst case

scenarios

5 Risk Ratio (M-H Fixed 95 CI) Subtotals only

21 Worst-best case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 130 [086 196]

22 Best-worst case scenario 5 257 Risk Ratio (M-H Fixed 95 CI) 058 [038 090]

3 Subgroup analyses all-cause

mortality at maximum

follow-up according to time of

start of bile acids


31 Less than three days after

transplantation


32 Three days or more after

transplantation


4 Subgroup analyses all cause


follow-up according to

treatment duration


41 Less than six months 3 184 Risk Ratio (M-H Fixed 95 CI) 078 [045 138]

42 Six months or more 2 73 Risk Ratio (M-H Fixed 95 CI) 102 [043 240]

5 Number of deaths related

to rejection at maximum

follow-up


51 UDCA versus placebo 1 102 Risk Ratio (M-H Fixed 95 CI) 030 [001 712]

6 Number of retransplantations at

maximum follow-up


7 Number of patients with acute

cellular rejection at maximum

follow-up



no treatment


72 TUDCA versus no

treatment


8 Subgroup analysis number of

patients with acute cellular

rejection according to time of

start of bile acid





transplantation



liver transplantation


9 Subgroup analysis number

of patients with acute

cellular rejection according to

treatment duration




10 Number of patients with

chronic rejection at maximum

follow-up



steroid-resistant rejection at

maximum follow-up


12 Serum bilirubin (mgdl) at the

end of treatment

1 30 Mean Difference (IV Fixed 95 CI) 26 [-096 616]

13 Number of days of

hospitalisation after liver

transplantation

1 52 Mean Difference (IV Fixed 95 CI) -85 [-1667 -033]

14 Adverse events 3 187 Risk Ratio (M-H Fixed 95 CI) 088 [030 260]

Analysis 11 Comparison 1 Bile acids for liver-transplanted patients Outcome 1 All-cause mortality at

maximum follow-up

Review Bile acids for liver-transplanted patients


Outcome 1 All-cause mortality at maximum follow-up

Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio

nN nN M-HFixed95 CI M-HFixed95 CI

1 UDCA versus placebo or no treatment

Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 116 108 935 080 [ 049 130 ]

Total events 23 (Favours bile acids) 27 (Control)

Heterogeneity Chi2 = 416 df = 3 (P = 025) I2 =28

Test for overall effect Z = 091 (P = 036)

01 02 05 1 2 5 10

Favours bile acids Favours control

(Continued )



( Continued)Study or subgroup Favours bile acids Control Risk Ratio Weight Risk Ratio


2 TUDCA versus no treatment

Angelico 1999 316 217 65 159 [ 030 833 ]

Subtotal (95 CI) 16 17 65 159 [ 030 833 ]


Heterogeneity not applicable


Total (95 CI) 132 125 1000 085 [ 053 136 ]




01 02 05 1 2 5 10


Analysis 12 Comparison 1 Bile acids for liver-transplanted patients Outcome 2 All-cause mortality worst-

best case and best-worst case scenarios



Outcome 2 All-cause mortality worst-best case and best-worst case scenarios

Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio


1 Worst-best case scenario

Angelico 1999 516 217 65 266 [ 060 1180 ]

Barnes 1997 828 724 253 098 [ 042 230 ]

Fleckenstein 1998 314 416 125 086 [ 023 319 ]

Keiding 1997 1954 1048 355 169 [ 087 327 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]

Total events 40 (Bile acids) 29 (Control)



2 Best-worst case scenario

005 02 1 5 20


(Continued )



( Continued)Study or subgroup Bile acids Control Risk Ratio Weight Risk Ratio


Angelico 1999 316 417 90 080 [ 021 302 ]

Barnes 1997 228 1124 274 016 [ 004 063 ]

Fleckenstein 1998 214 616 130 038 [ 009 159 ]

Keiding 1997 1454 1548 368 083 [ 045 154 ]

Sama 1991 520 620 139 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]




005 02 1 5 20


Analysis 13 Comparison 1 Bile acids for liver-transplanted patients Outcome 3 Subgroup analyses all-

cause mortality at maximum follow-up according to time of start of bile acids



Outcome 3 Subgroup analyses all-cause mortality at maximum follow-up according to time of start of bile acids



1 Less than three days after transplantation

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 54 48 355 124 [ 061 254 ]




2 Three days or more after transplantation

Angelico 1999 316 217 65 159 [ 030 833 ]

Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Sama 1991 520 620 201 083 [ 030 229 ]

005 02 1 5 20


(Continued )





Subtotal (95 CI) 78 77 645 063 [ 033 120 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20


Analysis 14 Comparison 1 Bile acids for liver-transplanted patients Outcome 4 Subgroup analyses all

cause mortality at maximum follow-up according to treatment duration



Outcome 4 Subgroup analyses all cause mortality at maximum follow-up according to treatment duration



1 Less than six months

Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 96 88 734 078 [ 045 138 ]




2 Six months or more

Angelico 1999 316 217 65 159 [ 030 833 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 36 37 266 102 [ 043 240 ]



005 02 1 5 20


(Continued )






Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20


Analysis 15 Comparison 1 Bile acids for liver-transplanted patients Outcome 5 Number of deaths related

to rejection at maximum follow-up



Outcome 5 Number of deaths related to rejection at maximum follow-up



1 UDCA versus placebo

Keiding 1997 054 148 1000 030 [ 001 712 ]

Total (95 CI) 54 48 1000 030 [ 001 712 ]




0001 001 01 1 10 100 1000




Analysis 16 Comparison 1 Bile acids for liver-transplanted patients Outcome 6 Number of

retransplantations at maximum follow-up



Outcome 6 Number of retransplantations at maximum follow-up

Study or subgroup Bile acids Placebo Risk Ratio Weight Risk Ratio


Fleckenstein 1998 214 016 100 567 [ 029 10891 ]

Keiding 1997 154 448 900 022 [ 003 192 ]

Total (95 CI) 68 64 1000 076 [ 020 286 ]

Total events 3 (Bile acids) 4 (Placebo)



0001 001 01 1 10 100 1000

Favours bile acids Favours placebo

Analysis 17 Comparison 1 Bile acids for liver-transplanted patients Outcome 7 Number of patients with

acute cellular rejection at maximum follow-up



Outcome 7 Number of patients with acute cellular rejection at maximum follow-up




Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 158 148 905 089 [ 074 108 ]

01 02 05 1 2 5 10


(Continued )









Angelico 1999 816 1017 95 085 [ 045 160 ]

Subtotal (95 CI) 16 17 95 085 [ 045 160 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10


Analysis 18 Comparison 1 Bile acids for liver-transplanted patients Outcome 8 Subgroup analysis

number of patients with acute cellular rejection according to time of start of bile acid



Outcome 8 Subgroup analysis number of patients with acute cellular rejection according to time of start of bile acid




Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Subtotal (95 CI) 70 64 422 084 [ 063 111 ]




2 Three days or more after liver transplantation

Angelico 1999 816 1017 95 085 [ 045 160 ]

01 02 05 1 2 5 10


(Continued )





Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 104 101 578 092 [ 072 117 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10





number of patients with acute cellular rejection according to treatment duration



Outcome 9 Subgroup analysis number of patients with acute cellular rejection according to treatment duration




Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Subtotal (95 CI) 138 128 777 087 [ 071 107 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 36 37 223 094 [ 065 136 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10




Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients

with chronic rejection at maximum follow-up



Outcome 10 Number of patients with chronic rejection at maximum follow-up



Barnes 1997 128 624 611 014 [ 002 110 ]

Fleckenstein 1998 114 116 88 114 [ 008 1663 ]

Keiding 1997 154 348 300 030 [ 003 275 ]

Total (95 CI) 96 88 1000 028 [ 008 095 ]




0001 001 01 1 10 100 1000



with steroid-resistant rejection at maximum follow-up



Outcome 11 Number of patients with steroid-resistant rejection at maximum follow-up



Barnes 1997 328 724 277 037 [ 011 127 ]

Fleckenstein 1998 314 316 103 114 [ 027 478 ]

Keiding 1997 1454 1548 583 083 [ 045 154 ]

Pageaux 1995 226 124 38 185 [ 018 1908 ]

Total (95 CI) 122 112 1000 077 [ 047 127 ]




001 01 1 10 100




Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl)

at the end of treatment



Outcome 12 Serum bilirubin (mgdl) at the end of treatment

Study or subgroup Bile acids Placebo Mean Difference Weight Mean Difference

N Mean(SD) N Mean(SD) IVFixed95 CI IVFixed95 CI

Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]

Total (95 CI) 14 16 1000 260 [ -096 616 ]



-10 -5 0 5 10


Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of

hospitalisation after liver transplantation



Outcome 13 Number of days of hospitalisation after liver transplantation



Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]

Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]



-100 -50 0 50 100




Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events



Outcome 14 Adverse events

Study or subgroup Bile acids Placebo Risk Ratio Risk Ratio


Angelico 1999 016 017 00 [ 00 00 ]

Barnes 1997 128 124 086 [ 006 1298 ]

Keiding 1997 554 548 089 [ 027 288 ]

Total (95 CI) 98 89 088 [ 030 260 ]




001 01 1 10 100


A P P E N D I C E S

Appendix 1 Search strategies

Data Base Date of Search Search Strategy

The Cochrane Hepato-Biliary Group Con-

trolled Trials Register

September 2009 1 rsquoliver transplantationrsquo and rsquochenodeoxy-

cholicrsquo

2 rsquoliver transplantationrsquo and rsquocholicrsquo

3 rsquoliver transplantationrsquo and rsquodeoxycholicrsquo

4 rsquoliver transplantationrsquo and rsquoglycochen-

odeoxycholicrsquo

5 rsquoliver transplantationrsquo and rsquoglycocholicrsquo

6 rsquoliver transplantationrsquo and rsquoglycodeoxy-

cholicrsquo

7 rsquoliver transplantationrsquo and rsquoglycolitho-

cholicrsquo

8 rsquoliver transplantationrsquo and rsquohyodeoxy-

cholicrsquo

9 rsquoliver transplantationrsquo and rsquolithocholicrsquo

10 rsquoliver transplantationrsquo and rsquotaurochen-

odeoxycholicrsquo



(Continued)

11 rsquoliver transplantationrsquo and rsquotauro-

cholicrsquo

12 rsquoliver transplantationrsquo and rsquotaurodehy-

drocholicrsquo

13 rsquoliver transplantationrsquo and rsquotau-

rodeoxycholicrsquo

14 rsquoliver transplantationrsquo and rsquotauroglyco-

cholicrsquo

15 rsquoliver transplantationrsquo and rsquotaurolitho-

cholicrsquo

16 rsquoliver transplantationrsquo and rsquotaurosel-

cholicrsquo

17 rsquoliver transplantationrsquo and rsquotaurourso-

cholicrsquo

18 rsquoliver transplantationrsquo and rsquotaurour-

sodeoxycholicrsquo

19 rsquoliver transplantationrsquo and rsquoursocholicrsquo

20 rsquoliver transplantationrsquo and rsquoursodeoxy-

cholicrsquo

The Cochrane Central Register of Con-

trolled Trials in The Cochrane Library

Issue 3 2009 1 LIVER-TRANSPLANTATION

ME

2 LIVER AND TRANSPLANTATION

3 BILE ACID ME

4

CHENODEOXYCHOLIC or CHOLIC

or DEOXYCHOLIC or GLYCOCHEN-

ODEOXYCHOLIC or GLYCOCHOLIC

or GLYCODEOXYCHOLIC or GLY-

COLITHOCHOLIC or HYODEOXY-

CHOLIC or LITHOCHOLIC or TAU-

ROCHENODEOXYCHOLIC or TAU-

ROCHOLIC or TAURODEHYDRO-

CHOLIC or TAURODEOXYCHOLIC

or TAUROGLYCOCHOLIC or TAU-

ROLITHOCHOLIC or TAUROSEL-

CHOLIC or TAUROURSOCHOLIC or

TAUROURSODEOXYCHOLIC or UR-

SOCHOLIC or URSODEOXYCHOLIC

5 1 or 2

6 3 or 4

7 5 and 6

MEDLINE September 2009 1 LIVER-TRANSPLANTATION

ME


3 BILE ACID ME

4





(Continued)













5 1 or 2

6 3 or 4

7 5 and 6

8 RANDOMIZED-CONTROLLED-

TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10

EMBASE September 2009 1 LIVER-TRANSPLANTATION

ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10



(Continued)

Science Citation Index Expanded September 2009 1 LIVER-TRANSPLANTATION

ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10

The Chinese Biomedical Database Searched from January 1980 to April 2002 1 LIVER-TRANSPLANTATION

ME


3 BILE ACID ME

4















5 1 or 2



(Continued)

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10

W H A T rsquo S N E W

Last assessed as up-to-date 8 February 2010

18 September 2009 New citation required but conclusions have not

changed

This review is an updated version of a review that was

published for the first time in Issue 3 2005 of TheCochrane Library by Chen 2003b

18 September 2009 New search has been performed No new studies fulfilled the inclusion criteria

H I S T O R Y

Protocol first published Issue 3 2003

Review first published Issue 3 2005

C O N T R I B U T I O N S O F A U T H O R S

GP and VG independently performed searches of relevant databases GP validated the search selected trials for inclusion contacted

the authors of the trials performed data extraction and data analysis and drafted the systematic review VG revised the review update

CG and DS revised the review update solved discrepancies of data extraction validated data analyses and provided consultation

D E C L A R A T I O N S O F I N T E R E S T

None known



S O U R C E S O F S U P P O R T

Internal sources

bull Copenhagen Trial Unit Denmark

External sources

bull Danish Medical Research Councilrsquos Grant on Getting Research into Practice (GRIP) Denmark

D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W

We assessed the risk of bias in the included studies for another four domains that were added to the review protocol (incomplete

outcome data selective outcome reporting baseline imbalance and early stopping of trial) In general the text of the risk of bias

domains were updated following Higgins 2008 Trials were considered at low risk of bias when judged as adequate in all domains

Quasi-randomised studies observational and case-control studies were included for the report of adverse events

We performed trial sequential analysis for outcomes demonstrating a statistically significant result

I N D E X T E R M S

Medical Subject Headings (MeSH)

lowastLiver Transplantation Cholagogues and Choleretics [lowasttherapeutic use] Graft Rejection [lowastprevention amp control] Randomized Con-

trolled Trials as Topic Taurochenodeoxycholic Acid [lowasttherapeutic use] Ursodeoxycholic Acid [lowasttherapeutic use]

MeSH check words

Humans



T A B L E O F C O N T E N T S

1HEADER

1ABSTRACT

2PLAIN LANGUAGE SUMMARY

2BACKGROUND

3OBJECTIVES

3METHODS

6RESULTS

Figure 1 8

Figure 2 9

Figure 3 12

13DISCUSSION

14AUTHORSrsquo CONCLUSIONS

14ACKNOWLEDGEMENTS

14REFERENCES

18CHARACTERISTICS OF STUDIES

32DATA AND ANALYSES

Analysis 11 Comparison 1 Bile acids for liver-transplanted patients Outcome 1 All-cause mortality at maximum follow-

up 33

Analysis 12 Comparison 1 Bile acids for liver-transplanted patients Outcome 2 All-cause mortality worst-best case and

best-worst case scenarios 34

Analysis 13 Comparison 1 Bile acids for liver-transplanted patients Outcome 3 Subgroup analyses all-cause mortality at

maximum follow-up according to time of start of bile acids 35

Analysis 14 Comparison 1 Bile acids for liver-transplanted patients Outcome 4 Subgroup analyses all cause mortality at

maximum follow-up according to treatment duration 36

Analysis 15 Comparison 1 Bile acids for liver-transplanted patients Outcome 5 Number of deaths related to rejection at

maximum follow-up 37

Analysis 16 Comparison 1 Bile acids for liver-transplanted patients Outcome 6 Number of retransplantations at maximum

follow-up 38

Analysis 17 Comparison 1 Bile acids for liver-transplanted patients Outcome 7 Number of patients with acute cellular



with acute cellular rejection according to time of start of bile acid 39


with acute cellular rejection according to treatment duration 41

Analysis 110 Comparison 1 Bile acids for liver-transplanted patients Outcome 10 Number of patients with chronic


Analysis 111 Comparison 1 Bile acids for liver-transplanted patients Outcome 11 Number of patients with steroid-

resistant rejection at maximum follow-up 42

Analysis 112 Comparison 1 Bile acids for liver-transplanted patients Outcome 12 Serum bilirubin (mgdl) at the end of

treatment 43

Analysis 113 Comparison 1 Bile acids for liver-transplanted patients Outcome 13 Number of days of hospitalisation after

liver transplantation 43

Analysis 114 Comparison 1 Bile acids for liver-transplanted patients Outcome 14 Adverse events 44

44APPENDICES

48WHATrsquoS NEW

48HISTORY

48CONTRIBUTIONS OF AUTHORS

48DECLARATIONS OF INTEREST

48SOURCES OF SUPPORT

49DIFFERENCES BETWEEN PROTOCOL AND REVIEW

49INDEX TERMS

iBile acids for liver-transplanted patients (Review)







Denmark








A B S T R A C T

Background




Objectives


Search strategy


Selection criteria








Main results


































B A C K G R O U N D























































































O B J E C T I V E S




M E T H O D S


Types of studies









group

Patients in control

group

AE in experimental

group




to study medication

were rare






capsules (5 pts)



capsules (5 pts)

No other presumed


fects were observed


tion was well tol-

erated in all pa-

tients and no drug-


were recorded


was required

pt(s) = patient(s)

AE = adverse events


























of rejections













9 Quality of life

































Data extraction




















separate domains









described















Blinding




trial












stated







outcomes


judgement




Baseline imbalance




characteristics





Early stopping














Statistical methods















































Subgroup analyses











plied by duration






1999)



co-interventions



R E S U L T S



studies















unpublished trials










Patients















































Outcome measures


























































All-cause mortality
















(118)



















Subgroup analyses






























1999) (RR 030 95 CI 001 to 712) 098 (0) versus 189





















(I2 = 0)












17)

Subgroup analyses

















95 CI 071 to 107) 72138 (522) versus 76128 (594)






































112 (232) (RR 077 95 CI 047 to 127) (Analysis 111)


Liver biochemistry







Cost-effectiveness







Adverse events


















Quality of life














D I S C U S S I O N




















bias













































































adverse events































R E F E R E N C E S







10575563]















9649640]






[MEDLINE 9197351]









(2)119ndash22 [MEDLINE 7499781]







2)68







17589339]





199610(6 Pt 2)658ndash62 [MEDLINE 8996761]










19995(4)269ndash74 [MEDLINE 10388499]





(3)1971 [MEDLINE 2063453]





1973232]





[MEDLINE 8540069]





A1332


Adams 1990



[MEDLINE 2407770]

Al-Quaiz 1994




[MEDLINE 8060468]

Armstrong 1982





23(1)70ndash80 [MEDLINE 7057113]

Ascher 1988





[MEDLINE 3055368]

Brok 2008





Brok 2009






[MEDLINE 18824466]

Calmus 1990




199011(1)12ndash5 [MEDLINE 2403961]

Calmus 1992





Chen 2003a



10100214651858CD003626]

Chen 2007



14651858CD003181pub2]

Cheng 2002




Corbani 2008



[MEDLINE 18242500]

DeMets 1987



[MEDLINE 3616287]



DerSimonian 1986



Egger 1997



Ed) 1997315(7109)629ndash34 [MEDLINE 9310563]

Ericzon 1990




2227822]

FK506 1994




(17)1110ndash5 [MEDLINE 7523946]

Friman 1994




Fuchs 1999





Fusai 2006





Gluud 2001





Gluud 2010





Gong 2008




14651858CD000551pub2]

Haddad 2006




[DOI 10100214651858CD005161pub2]

Heuman 1993



Higgins 2008



2008

Hirschfield 2009




bmjb1670]

Hussain 2002



11933592]

ICH-GCP 1997




Ioannidis 2001




IWP 1995



Kjaergard 2001




[MEDLINE 11730399]

Klintmalm 1989



[MEDLINE 2583691]

Knechtle 2009



[MEDLINE 19235662]

Krams 1993




Lan 1983



Merion 1989





Moher 1998




(9128)609ndash13 [MEDLINE 9746022]



Neuberger 1999




Okolicsanyi 1986




Palmer 1972



Perez 2009



[MEDLINE 19360911]

Pogue 1997




[MEDLINE 9408720]

Pogue 1998




RevMan 2008




Royle 2003




19(4)591ndash603

Schulz 1995



Sharara 1995




Sholmerich 1984





Soderdahl 1998






Terasaki 1991





[MEDLINE 1882800]

Thalheimer 2002




Thorlund 2009





Thuluvath 2003




20039(5)527ndash32 [MEDLINE 12740799]

van den Berg 1998





[MEDLINE 9583867]

Vierling 1992



1570548]

Wetterslev 2008




[MEDLINE 18083463]

Wiesner 1992




1992102A910

Wood 2008





(7644)601ndash5 [MEDLINE 18316340]

Yoshikawa 1998










Chen 2003b








Angelico 1999




Inclusion criteria


Exclusion criteria

- not mentioned

Participants





467 +- 84







474 +- 74







- Route orally


one year

Control group

- no treatment







Risk of bias









All outcomes










tual data given





Barnes 1997




Inclusion criteria



Exclusion criteria


tree


Participants



505 +- 116


Child class A 7




B 13

and C 8


PBC 3





PSC 2

other 3



507 +- 93


Child class A 6

B 14

and C 4


PBC 5





PSC 2

other 4



- Route orally



Placebo group









Adverse events



Risk of bias










All outcomes















Fleckenstein 1998




Inclusion criteria


Exclusion criteria



Participants



443 +- 127



alcohol 2

autoimmune 1

PBC 2




PSC 1


hepatitis B 1



496 +- 109



alcohol 3

autoimmune 3

PBC 1

PSC 2

cryptogenic 2

hepatitis B 1




- Route orally



Placebo group











Risk of bias





probably adequate


All outcomes











tical analysisrdquo



Keiding 1997




Inclusion criteria



Exclusion criteria


Participants



4344 for adults












- Route orally



Placebo group












Adverse events


Risk of bias









All outcomes











was 80 patients



balance


size



Koneru 1993




Inclusion criteria


Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information


- Dose 900 mgday

- Route orally



Control group

- no treatment





Notes Abstract


Risk of bias









All outcomes



plicitly stated






Pageaux 1995




Inclusion criteria


Exclusion criteria

- not mentioned

Participants

- UDCA group (n=26)


47 +- 10





PBC 2

liver cancer 2


miscellaneous 1



51+- 9





PBC 3

liver cancer 4


miscellaneous 1






- Route orally



Placebo group







Risk of bias






All outcomes




were reported






Sama 1991




Inclusion criteria





Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information



- Route orally



Control group

- no treatment


and cyclosporine)



Notes Abstract


Risk of bias
















All outcomes




fully stated


adequately reported




ported













cyclosporine











(Continued)

















month


















studies

No of



follow-up



no treatment


12 TUDCA versus no

treatment




scenarios







start of bile acids



transplantation



transplantation





treatment duration






follow-up




maximum follow-up




follow-up



no treatment


72 TUDCA versus no

treatment





start of bile acid





transplantation








treatment duration






follow-up




maximum follow-up



end of treatment




transplantation




maximum follow-up







Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 116 108 935 080 [ 049 130 ]




01 02 05 1 2 5 10


(Continued )






Angelico 1999 316 217 65 159 [ 030 833 ]

Subtotal (95 CI) 16 17 65 159 [ 030 833 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




01 02 05 1 2 5 10










Angelico 1999 516 217 65 266 [ 060 1180 ]

Barnes 1997 828 724 253 098 [ 042 230 ]

Fleckenstein 1998 314 416 125 086 [ 023 319 ]

Keiding 1997 1954 1048 355 169 [ 087 327 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]





005 02 1 5 20


(Continued )





Angelico 1999 316 417 90 080 [ 021 302 ]

Barnes 1997 228 1124 274 016 [ 004 063 ]

Fleckenstein 1998 214 616 130 038 [ 009 159 ]

Keiding 1997 1454 1548 368 083 [ 045 154 ]

Sama 1991 520 620 139 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]




005 02 1 5 20










Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 54 48 355 124 [ 061 254 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Sama 1991 520 620 201 083 [ 030 229 ]

005 02 1 5 20


(Continued )





Subtotal (95 CI) 78 77 645 063 [ 033 120 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 96 88 734 078 [ 045 138 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 36 37 266 102 [ 043 240 ]



005 02 1 5 20


(Continued )






Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Keiding 1997 054 148 1000 030 [ 001 712 ]

Total (95 CI) 54 48 1000 030 [ 001 712 ]




0001 001 01 1 10 100 1000











Fleckenstein 1998 214 016 100 567 [ 029 10891 ]

Keiding 1997 154 448 900 022 [ 003 192 ]

Total (95 CI) 68 64 1000 076 [ 020 286 ]




0001 001 01 1 10 100 1000










Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 158 148 905 089 [ 074 108 ]

01 02 05 1 2 5 10


(Continued )









Angelico 1999 816 1017 95 085 [ 045 160 ]

Subtotal (95 CI) 16 17 95 085 [ 045 160 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10










Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Subtotal (95 CI) 70 64 422 084 [ 063 111 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

01 02 05 1 2 5 10


(Continued )





Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 104 101 578 092 [ 072 117 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10












Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Subtotal (95 CI) 138 128 777 087 [ 071 107 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 36 37 223 094 [ 065 136 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10











Barnes 1997 128 624 611 014 [ 002 110 ]

Fleckenstein 1998 114 116 88 114 [ 008 1663 ]

Keiding 1997 154 348 300 030 [ 003 275 ]

Total (95 CI) 96 88 1000 028 [ 008 095 ]




0001 001 01 1 10 100 1000









Barnes 1997 328 724 277 037 [ 011 127 ]

Fleckenstein 1998 314 316 103 114 [ 027 478 ]

Keiding 1997 1454 1548 583 083 [ 045 154 ]

Pageaux 1995 226 124 38 185 [ 018 1908 ]

Total (95 CI) 122 112 1000 077 [ 047 127 ]




001 01 1 10 100











Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]

Total (95 CI) 14 16 1000 260 [ -096 616 ]



-10 -5 0 5 10









Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]

Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]



-100 -50 0 50 100










Angelico 1999 016 017 00 [ 00 00 ]

Barnes 1997 128 124 086 [ 006 1298 ]

Keiding 1997 554 548 089 [ 027 288 ]

Total (95 CI) 98 89 088 [ 030 260 ]




001 01 1 10 100


A P P E N D I C E S






cholicrsquo




odeoxycholicrsquo



cholicrsquo


cholicrsquo


cholicrsquo



odeoxycholicrsquo



(Continued)


cholicrsquo


drocholicrsquo


rodeoxycholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


sodeoxycholicrsquo



cholicrsquo




ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


ME


3 BILE ACID ME

4





(Continued)













5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10



(Continued)


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2



(Continued)

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10




changed




H I S T O R Y








None known




Internal sources


External sources








I N D E X T E R M S




MeSH check words

Humans








Denmark








A B S T R A C T

Background




Objectives


Search strategy


Selection criteria








Main results


































B A C K G R O U N D























































































O B J E C T I V E S




M E T H O D S


Types of studies









group

Patients in control

group

AE in experimental

group




to study medication

were rare






capsules (5 pts)



capsules (5 pts)

No other presumed


fects were observed


tion was well tol-

erated in all pa-

tients and no drug-


were recorded


was required

pt(s) = patient(s)

AE = adverse events


























of rejections













9 Quality of life

































Data extraction




















separate domains









described















Blinding




trial












stated







outcomes


judgement




Baseline imbalance




characteristics





Early stopping














Statistical methods















































Subgroup analyses











plied by duration






1999)



co-interventions



R E S U L T S



studies















unpublished trials










Patients















































Outcome measures


























































All-cause mortality
















(118)



















Subgroup analyses






























1999) (RR 030 95 CI 001 to 712) 098 (0) versus 189





















(I2 = 0)












17)

Subgroup analyses

















95 CI 071 to 107) 72138 (522) versus 76128 (594)






































112 (232) (RR 077 95 CI 047 to 127) (Analysis 111)


Liver biochemistry







Cost-effectiveness







Adverse events


















Quality of life














D I S C U S S I O N




















bias













































































adverse events































R E F E R E N C E S







10575563]















9649640]






[MEDLINE 9197351]









(2)119ndash22 [MEDLINE 7499781]







2)68







17589339]





199610(6 Pt 2)658ndash62 [MEDLINE 8996761]










19995(4)269ndash74 [MEDLINE 10388499]





(3)1971 [MEDLINE 2063453]





1973232]





[MEDLINE 8540069]





A1332


Adams 1990



[MEDLINE 2407770]

Al-Quaiz 1994




[MEDLINE 8060468]

Armstrong 1982





23(1)70ndash80 [MEDLINE 7057113]

Ascher 1988





[MEDLINE 3055368]

Brok 2008





Brok 2009






[MEDLINE 18824466]

Calmus 1990




199011(1)12ndash5 [MEDLINE 2403961]

Calmus 1992





Chen 2003a



10100214651858CD003626]

Chen 2007



14651858CD003181pub2]

Cheng 2002




Corbani 2008



[MEDLINE 18242500]

DeMets 1987



[MEDLINE 3616287]



DerSimonian 1986



Egger 1997



Ed) 1997315(7109)629ndash34 [MEDLINE 9310563]

Ericzon 1990




2227822]

FK506 1994




(17)1110ndash5 [MEDLINE 7523946]

Friman 1994




Fuchs 1999





Fusai 2006





Gluud 2001





Gluud 2010





Gong 2008




14651858CD000551pub2]

Haddad 2006




[DOI 10100214651858CD005161pub2]

Heuman 1993



Higgins 2008



2008

Hirschfield 2009




bmjb1670]

Hussain 2002



11933592]

ICH-GCP 1997




Ioannidis 2001




IWP 1995



Kjaergard 2001




[MEDLINE 11730399]

Klintmalm 1989



[MEDLINE 2583691]

Knechtle 2009



[MEDLINE 19235662]

Krams 1993




Lan 1983



Merion 1989





Moher 1998




(9128)609ndash13 [MEDLINE 9746022]



Neuberger 1999




Okolicsanyi 1986




Palmer 1972



Perez 2009



[MEDLINE 19360911]

Pogue 1997




[MEDLINE 9408720]

Pogue 1998




RevMan 2008




Royle 2003




19(4)591ndash603

Schulz 1995



Sharara 1995




Sholmerich 1984





Soderdahl 1998






Terasaki 1991





[MEDLINE 1882800]

Thalheimer 2002




Thorlund 2009





Thuluvath 2003




20039(5)527ndash32 [MEDLINE 12740799]

van den Berg 1998





[MEDLINE 9583867]

Vierling 1992



1570548]

Wetterslev 2008




[MEDLINE 18083463]

Wiesner 1992




1992102A910

Wood 2008





(7644)601ndash5 [MEDLINE 18316340]

Yoshikawa 1998










Chen 2003b








Angelico 1999




Inclusion criteria


Exclusion criteria

- not mentioned

Participants





467 +- 84







474 +- 74







- Route orally


one year

Control group

- no treatment







Risk of bias









All outcomes










tual data given





Barnes 1997




Inclusion criteria



Exclusion criteria


tree


Participants



505 +- 116


Child class A 7




B 13

and C 8


PBC 3





PSC 2

other 3



507 +- 93


Child class A 6

B 14

and C 4


PBC 5





PSC 2

other 4



- Route orally



Placebo group









Adverse events



Risk of bias










All outcomes















Fleckenstein 1998




Inclusion criteria


Exclusion criteria



Participants



443 +- 127



alcohol 2

autoimmune 1

PBC 2




PSC 1


hepatitis B 1



496 +- 109



alcohol 3

autoimmune 3

PBC 1

PSC 2

cryptogenic 2

hepatitis B 1




- Route orally



Placebo group











Risk of bias





probably adequate


All outcomes











tical analysisrdquo



Keiding 1997




Inclusion criteria



Exclusion criteria


Participants



4344 for adults












- Route orally



Placebo group












Adverse events


Risk of bias









All outcomes











was 80 patients



balance


size



Koneru 1993




Inclusion criteria


Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information


- Dose 900 mgday

- Route orally



Control group

- no treatment





Notes Abstract


Risk of bias









All outcomes



plicitly stated






Pageaux 1995




Inclusion criteria


Exclusion criteria

- not mentioned

Participants

- UDCA group (n=26)


47 +- 10





PBC 2

liver cancer 2


miscellaneous 1



51+- 9





PBC 3

liver cancer 4


miscellaneous 1






- Route orally



Placebo group







Risk of bias






All outcomes




were reported






Sama 1991




Inclusion criteria





Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information



- Route orally



Control group

- no treatment


and cyclosporine)



Notes Abstract


Risk of bias
















All outcomes




fully stated


adequately reported




ported













cyclosporine











(Continued)

















month


















studies

No of



follow-up



no treatment


12 TUDCA versus no

treatment




scenarios







start of bile acids



transplantation



transplantation





treatment duration






follow-up




maximum follow-up




follow-up



no treatment


72 TUDCA versus no

treatment





start of bile acid





transplantation








treatment duration






follow-up




maximum follow-up



end of treatment




transplantation




maximum follow-up







Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 116 108 935 080 [ 049 130 ]




01 02 05 1 2 5 10


(Continued )






Angelico 1999 316 217 65 159 [ 030 833 ]

Subtotal (95 CI) 16 17 65 159 [ 030 833 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




01 02 05 1 2 5 10










Angelico 1999 516 217 65 266 [ 060 1180 ]

Barnes 1997 828 724 253 098 [ 042 230 ]

Fleckenstein 1998 314 416 125 086 [ 023 319 ]

Keiding 1997 1954 1048 355 169 [ 087 327 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]





005 02 1 5 20


(Continued )





Angelico 1999 316 417 90 080 [ 021 302 ]

Barnes 1997 228 1124 274 016 [ 004 063 ]

Fleckenstein 1998 214 616 130 038 [ 009 159 ]

Keiding 1997 1454 1548 368 083 [ 045 154 ]

Sama 1991 520 620 139 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]




005 02 1 5 20










Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 54 48 355 124 [ 061 254 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Sama 1991 520 620 201 083 [ 030 229 ]

005 02 1 5 20


(Continued )





Subtotal (95 CI) 78 77 645 063 [ 033 120 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 96 88 734 078 [ 045 138 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 36 37 266 102 [ 043 240 ]



005 02 1 5 20


(Continued )






Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Keiding 1997 054 148 1000 030 [ 001 712 ]

Total (95 CI) 54 48 1000 030 [ 001 712 ]




0001 001 01 1 10 100 1000











Fleckenstein 1998 214 016 100 567 [ 029 10891 ]

Keiding 1997 154 448 900 022 [ 003 192 ]

Total (95 CI) 68 64 1000 076 [ 020 286 ]




0001 001 01 1 10 100 1000










Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 158 148 905 089 [ 074 108 ]

01 02 05 1 2 5 10


(Continued )









Angelico 1999 816 1017 95 085 [ 045 160 ]

Subtotal (95 CI) 16 17 95 085 [ 045 160 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10










Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Subtotal (95 CI) 70 64 422 084 [ 063 111 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

01 02 05 1 2 5 10


(Continued )





Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 104 101 578 092 [ 072 117 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10












Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Subtotal (95 CI) 138 128 777 087 [ 071 107 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 36 37 223 094 [ 065 136 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10











Barnes 1997 128 624 611 014 [ 002 110 ]

Fleckenstein 1998 114 116 88 114 [ 008 1663 ]

Keiding 1997 154 348 300 030 [ 003 275 ]

Total (95 CI) 96 88 1000 028 [ 008 095 ]




0001 001 01 1 10 100 1000









Barnes 1997 328 724 277 037 [ 011 127 ]

Fleckenstein 1998 314 316 103 114 [ 027 478 ]

Keiding 1997 1454 1548 583 083 [ 045 154 ]

Pageaux 1995 226 124 38 185 [ 018 1908 ]

Total (95 CI) 122 112 1000 077 [ 047 127 ]




001 01 1 10 100











Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]

Total (95 CI) 14 16 1000 260 [ -096 616 ]



-10 -5 0 5 10









Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]

Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]



-100 -50 0 50 100










Angelico 1999 016 017 00 [ 00 00 ]

Barnes 1997 128 124 086 [ 006 1298 ]

Keiding 1997 554 548 089 [ 027 288 ]

Total (95 CI) 98 89 088 [ 030 260 ]




001 01 1 10 100


A P P E N D I C E S






cholicrsquo




odeoxycholicrsquo



cholicrsquo


cholicrsquo


cholicrsquo



odeoxycholicrsquo



(Continued)


cholicrsquo


drocholicrsquo


rodeoxycholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


sodeoxycholicrsquo



cholicrsquo




ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


ME


3 BILE ACID ME

4





(Continued)













5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10



(Continued)


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2



(Continued)

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10




changed




H I S T O R Y








None known




Internal sources


External sources








I N D E X T E R M S




MeSH check words

Humans





























B A C K G R O U N D























































































O B J E C T I V E S




M E T H O D S


Types of studies









group

Patients in control

group

AE in experimental

group




to study medication

were rare






capsules (5 pts)



capsules (5 pts)

No other presumed


fects were observed


tion was well tol-

erated in all pa-

tients and no drug-


were recorded


was required

pt(s) = patient(s)

AE = adverse events


























of rejections













9 Quality of life

































Data extraction




















separate domains









described















Blinding




trial












stated







outcomes


judgement




Baseline imbalance




characteristics





Early stopping














Statistical methods















































Subgroup analyses











plied by duration






1999)



co-interventions



R E S U L T S



studies















unpublished trials










Patients















































Outcome measures


























































All-cause mortality
















(118)



















Subgroup analyses






























1999) (RR 030 95 CI 001 to 712) 098 (0) versus 189





















(I2 = 0)












17)

Subgroup analyses

















95 CI 071 to 107) 72138 (522) versus 76128 (594)






































112 (232) (RR 077 95 CI 047 to 127) (Analysis 111)


Liver biochemistry







Cost-effectiveness







Adverse events


















Quality of life














D I S C U S S I O N




















bias













































































adverse events































R E F E R E N C E S







10575563]















9649640]






[MEDLINE 9197351]









(2)119ndash22 [MEDLINE 7499781]







2)68







17589339]





199610(6 Pt 2)658ndash62 [MEDLINE 8996761]










19995(4)269ndash74 [MEDLINE 10388499]





(3)1971 [MEDLINE 2063453]





1973232]





[MEDLINE 8540069]





A1332


Adams 1990



[MEDLINE 2407770]

Al-Quaiz 1994




[MEDLINE 8060468]

Armstrong 1982





23(1)70ndash80 [MEDLINE 7057113]

Ascher 1988





[MEDLINE 3055368]

Brok 2008





Brok 2009






[MEDLINE 18824466]

Calmus 1990




199011(1)12ndash5 [MEDLINE 2403961]

Calmus 1992





Chen 2003a



10100214651858CD003626]

Chen 2007



14651858CD003181pub2]

Cheng 2002




Corbani 2008



[MEDLINE 18242500]

DeMets 1987



[MEDLINE 3616287]



DerSimonian 1986



Egger 1997



Ed) 1997315(7109)629ndash34 [MEDLINE 9310563]

Ericzon 1990




2227822]

FK506 1994




(17)1110ndash5 [MEDLINE 7523946]

Friman 1994




Fuchs 1999





Fusai 2006





Gluud 2001





Gluud 2010





Gong 2008




14651858CD000551pub2]

Haddad 2006




[DOI 10100214651858CD005161pub2]

Heuman 1993



Higgins 2008



2008

Hirschfield 2009




bmjb1670]

Hussain 2002



11933592]

ICH-GCP 1997




Ioannidis 2001




IWP 1995



Kjaergard 2001




[MEDLINE 11730399]

Klintmalm 1989



[MEDLINE 2583691]

Knechtle 2009



[MEDLINE 19235662]

Krams 1993




Lan 1983



Merion 1989





Moher 1998




(9128)609ndash13 [MEDLINE 9746022]



Neuberger 1999




Okolicsanyi 1986




Palmer 1972



Perez 2009



[MEDLINE 19360911]

Pogue 1997




[MEDLINE 9408720]

Pogue 1998




RevMan 2008




Royle 2003




19(4)591ndash603

Schulz 1995



Sharara 1995




Sholmerich 1984





Soderdahl 1998






Terasaki 1991





[MEDLINE 1882800]

Thalheimer 2002




Thorlund 2009





Thuluvath 2003




20039(5)527ndash32 [MEDLINE 12740799]

van den Berg 1998





[MEDLINE 9583867]

Vierling 1992



1570548]

Wetterslev 2008




[MEDLINE 18083463]

Wiesner 1992




1992102A910

Wood 2008





(7644)601ndash5 [MEDLINE 18316340]

Yoshikawa 1998










Chen 2003b








Angelico 1999




Inclusion criteria


Exclusion criteria

- not mentioned

Participants





467 +- 84







474 +- 74







- Route orally


one year

Control group

- no treatment







Risk of bias









All outcomes










tual data given





Barnes 1997




Inclusion criteria



Exclusion criteria


tree


Participants



505 +- 116


Child class A 7




B 13

and C 8


PBC 3





PSC 2

other 3



507 +- 93


Child class A 6

B 14

and C 4


PBC 5





PSC 2

other 4



- Route orally



Placebo group









Adverse events



Risk of bias










All outcomes















Fleckenstein 1998




Inclusion criteria


Exclusion criteria



Participants



443 +- 127



alcohol 2

autoimmune 1

PBC 2




PSC 1


hepatitis B 1



496 +- 109



alcohol 3

autoimmune 3

PBC 1

PSC 2

cryptogenic 2

hepatitis B 1




- Route orally



Placebo group











Risk of bias





probably adequate


All outcomes











tical analysisrdquo



Keiding 1997




Inclusion criteria



Exclusion criteria


Participants



4344 for adults












- Route orally



Placebo group












Adverse events


Risk of bias









All outcomes











was 80 patients



balance


size



Koneru 1993




Inclusion criteria


Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information


- Dose 900 mgday

- Route orally



Control group

- no treatment





Notes Abstract


Risk of bias









All outcomes



plicitly stated






Pageaux 1995




Inclusion criteria


Exclusion criteria

- not mentioned

Participants

- UDCA group (n=26)


47 +- 10





PBC 2

liver cancer 2


miscellaneous 1



51+- 9





PBC 3

liver cancer 4


miscellaneous 1






- Route orally



Placebo group







Risk of bias






All outcomes




were reported






Sama 1991




Inclusion criteria





Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information



- Route orally



Control group

- no treatment


and cyclosporine)



Notes Abstract


Risk of bias
















All outcomes




fully stated


adequately reported




ported













cyclosporine











(Continued)

















month


















studies

No of



follow-up



no treatment


12 TUDCA versus no

treatment




scenarios







start of bile acids



transplantation



transplantation





treatment duration






follow-up




maximum follow-up




follow-up



no treatment


72 TUDCA versus no

treatment





start of bile acid





transplantation








treatment duration






follow-up




maximum follow-up



end of treatment




transplantation




maximum follow-up







Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 116 108 935 080 [ 049 130 ]




01 02 05 1 2 5 10


(Continued )






Angelico 1999 316 217 65 159 [ 030 833 ]

Subtotal (95 CI) 16 17 65 159 [ 030 833 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




01 02 05 1 2 5 10










Angelico 1999 516 217 65 266 [ 060 1180 ]

Barnes 1997 828 724 253 098 [ 042 230 ]

Fleckenstein 1998 314 416 125 086 [ 023 319 ]

Keiding 1997 1954 1048 355 169 [ 087 327 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]





005 02 1 5 20


(Continued )





Angelico 1999 316 417 90 080 [ 021 302 ]

Barnes 1997 228 1124 274 016 [ 004 063 ]

Fleckenstein 1998 214 616 130 038 [ 009 159 ]

Keiding 1997 1454 1548 368 083 [ 045 154 ]

Sama 1991 520 620 139 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]




005 02 1 5 20










Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 54 48 355 124 [ 061 254 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Sama 1991 520 620 201 083 [ 030 229 ]

005 02 1 5 20


(Continued )





Subtotal (95 CI) 78 77 645 063 [ 033 120 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 96 88 734 078 [ 045 138 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 36 37 266 102 [ 043 240 ]



005 02 1 5 20


(Continued )






Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Keiding 1997 054 148 1000 030 [ 001 712 ]

Total (95 CI) 54 48 1000 030 [ 001 712 ]




0001 001 01 1 10 100 1000











Fleckenstein 1998 214 016 100 567 [ 029 10891 ]

Keiding 1997 154 448 900 022 [ 003 192 ]

Total (95 CI) 68 64 1000 076 [ 020 286 ]




0001 001 01 1 10 100 1000










Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 158 148 905 089 [ 074 108 ]

01 02 05 1 2 5 10


(Continued )









Angelico 1999 816 1017 95 085 [ 045 160 ]

Subtotal (95 CI) 16 17 95 085 [ 045 160 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10










Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Subtotal (95 CI) 70 64 422 084 [ 063 111 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

01 02 05 1 2 5 10


(Continued )





Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 104 101 578 092 [ 072 117 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10












Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Subtotal (95 CI) 138 128 777 087 [ 071 107 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 36 37 223 094 [ 065 136 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10











Barnes 1997 128 624 611 014 [ 002 110 ]

Fleckenstein 1998 114 116 88 114 [ 008 1663 ]

Keiding 1997 154 348 300 030 [ 003 275 ]

Total (95 CI) 96 88 1000 028 [ 008 095 ]




0001 001 01 1 10 100 1000









Barnes 1997 328 724 277 037 [ 011 127 ]

Fleckenstein 1998 314 316 103 114 [ 027 478 ]

Keiding 1997 1454 1548 583 083 [ 045 154 ]

Pageaux 1995 226 124 38 185 [ 018 1908 ]

Total (95 CI) 122 112 1000 077 [ 047 127 ]




001 01 1 10 100











Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]

Total (95 CI) 14 16 1000 260 [ -096 616 ]



-10 -5 0 5 10









Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]

Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]



-100 -50 0 50 100










Angelico 1999 016 017 00 [ 00 00 ]

Barnes 1997 128 124 086 [ 006 1298 ]

Keiding 1997 554 548 089 [ 027 288 ]

Total (95 CI) 98 89 088 [ 030 260 ]




001 01 1 10 100


A P P E N D I C E S






cholicrsquo




odeoxycholicrsquo



cholicrsquo


cholicrsquo


cholicrsquo



odeoxycholicrsquo



(Continued)


cholicrsquo


drocholicrsquo


rodeoxycholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


sodeoxycholicrsquo



cholicrsquo




ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


ME


3 BILE ACID ME

4





(Continued)













5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10



(Continued)


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2



(Continued)

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10




changed




H I S T O R Y








None known




Internal sources


External sources








I N D E X T E R M S




MeSH check words

Humans






























































O B J E C T I V E S




M E T H O D S


Types of studies









group

Patients in control

group

AE in experimental

group




to study medication

were rare






capsules (5 pts)



capsules (5 pts)

No other presumed


fects were observed


tion was well tol-

erated in all pa-

tients and no drug-


were recorded


was required

pt(s) = patient(s)

AE = adverse events


























of rejections













9 Quality of life

































Data extraction




















separate domains









described















Blinding




trial












stated







outcomes


judgement




Baseline imbalance




characteristics





Early stopping














Statistical methods















































Subgroup analyses











plied by duration






1999)



co-interventions



R E S U L T S



studies















unpublished trials










Patients















































Outcome measures


























































All-cause mortality
















(118)



















Subgroup analyses






























1999) (RR 030 95 CI 001 to 712) 098 (0) versus 189





















(I2 = 0)












17)

Subgroup analyses

















95 CI 071 to 107) 72138 (522) versus 76128 (594)






































112 (232) (RR 077 95 CI 047 to 127) (Analysis 111)


Liver biochemistry







Cost-effectiveness







Adverse events


















Quality of life














D I S C U S S I O N




















bias













































































adverse events































R E F E R E N C E S







10575563]















9649640]






[MEDLINE 9197351]









(2)119ndash22 [MEDLINE 7499781]







2)68







17589339]





199610(6 Pt 2)658ndash62 [MEDLINE 8996761]










19995(4)269ndash74 [MEDLINE 10388499]





(3)1971 [MEDLINE 2063453]





1973232]





[MEDLINE 8540069]





A1332


Adams 1990



[MEDLINE 2407770]

Al-Quaiz 1994




[MEDLINE 8060468]

Armstrong 1982





23(1)70ndash80 [MEDLINE 7057113]

Ascher 1988





[MEDLINE 3055368]

Brok 2008





Brok 2009






[MEDLINE 18824466]

Calmus 1990




199011(1)12ndash5 [MEDLINE 2403961]

Calmus 1992





Chen 2003a



10100214651858CD003626]

Chen 2007



14651858CD003181pub2]

Cheng 2002




Corbani 2008



[MEDLINE 18242500]

DeMets 1987



[MEDLINE 3616287]



DerSimonian 1986



Egger 1997



Ed) 1997315(7109)629ndash34 [MEDLINE 9310563]

Ericzon 1990




2227822]

FK506 1994




(17)1110ndash5 [MEDLINE 7523946]

Friman 1994




Fuchs 1999





Fusai 2006





Gluud 2001





Gluud 2010





Gong 2008




14651858CD000551pub2]

Haddad 2006




[DOI 10100214651858CD005161pub2]

Heuman 1993



Higgins 2008



2008

Hirschfield 2009




bmjb1670]

Hussain 2002



11933592]

ICH-GCP 1997




Ioannidis 2001




IWP 1995



Kjaergard 2001




[MEDLINE 11730399]

Klintmalm 1989



[MEDLINE 2583691]

Knechtle 2009



[MEDLINE 19235662]

Krams 1993




Lan 1983



Merion 1989





Moher 1998




(9128)609ndash13 [MEDLINE 9746022]



Neuberger 1999




Okolicsanyi 1986




Palmer 1972



Perez 2009



[MEDLINE 19360911]

Pogue 1997




[MEDLINE 9408720]

Pogue 1998




RevMan 2008




Royle 2003




19(4)591ndash603

Schulz 1995



Sharara 1995




Sholmerich 1984





Soderdahl 1998






Terasaki 1991





[MEDLINE 1882800]

Thalheimer 2002




Thorlund 2009





Thuluvath 2003




20039(5)527ndash32 [MEDLINE 12740799]

van den Berg 1998





[MEDLINE 9583867]

Vierling 1992



1570548]

Wetterslev 2008




[MEDLINE 18083463]

Wiesner 1992




1992102A910

Wood 2008





(7644)601ndash5 [MEDLINE 18316340]

Yoshikawa 1998










Chen 2003b








Angelico 1999




Inclusion criteria


Exclusion criteria

- not mentioned

Participants





467 +- 84







474 +- 74







- Route orally


one year

Control group

- no treatment







Risk of bias









All outcomes










tual data given





Barnes 1997




Inclusion criteria



Exclusion criteria


tree


Participants



505 +- 116


Child class A 7




B 13

and C 8


PBC 3





PSC 2

other 3



507 +- 93


Child class A 6

B 14

and C 4


PBC 5





PSC 2

other 4



- Route orally



Placebo group









Adverse events



Risk of bias










All outcomes















Fleckenstein 1998




Inclusion criteria


Exclusion criteria



Participants



443 +- 127



alcohol 2

autoimmune 1

PBC 2




PSC 1


hepatitis B 1



496 +- 109



alcohol 3

autoimmune 3

PBC 1

PSC 2

cryptogenic 2

hepatitis B 1




- Route orally



Placebo group











Risk of bias





probably adequate


All outcomes











tical analysisrdquo



Keiding 1997




Inclusion criteria



Exclusion criteria


Participants



4344 for adults












- Route orally



Placebo group












Adverse events


Risk of bias









All outcomes











was 80 patients



balance


size



Koneru 1993




Inclusion criteria


Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information


- Dose 900 mgday

- Route orally



Control group

- no treatment





Notes Abstract


Risk of bias









All outcomes



plicitly stated






Pageaux 1995




Inclusion criteria


Exclusion criteria

- not mentioned

Participants

- UDCA group (n=26)


47 +- 10





PBC 2

liver cancer 2


miscellaneous 1



51+- 9





PBC 3

liver cancer 4


miscellaneous 1






- Route orally



Placebo group







Risk of bias






All outcomes




were reported






Sama 1991




Inclusion criteria





Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information



- Route orally



Control group

- no treatment


and cyclosporine)



Notes Abstract


Risk of bias
















All outcomes




fully stated


adequately reported




ported













cyclosporine











(Continued)

















month


















studies

No of



follow-up



no treatment


12 TUDCA versus no

treatment




scenarios







start of bile acids



transplantation



transplantation





treatment duration






follow-up




maximum follow-up




follow-up



no treatment


72 TUDCA versus no

treatment





start of bile acid





transplantation








treatment duration






follow-up




maximum follow-up



end of treatment




transplantation




maximum follow-up







Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 116 108 935 080 [ 049 130 ]




01 02 05 1 2 5 10


(Continued )






Angelico 1999 316 217 65 159 [ 030 833 ]

Subtotal (95 CI) 16 17 65 159 [ 030 833 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




01 02 05 1 2 5 10










Angelico 1999 516 217 65 266 [ 060 1180 ]

Barnes 1997 828 724 253 098 [ 042 230 ]

Fleckenstein 1998 314 416 125 086 [ 023 319 ]

Keiding 1997 1954 1048 355 169 [ 087 327 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]





005 02 1 5 20


(Continued )





Angelico 1999 316 417 90 080 [ 021 302 ]

Barnes 1997 228 1124 274 016 [ 004 063 ]

Fleckenstein 1998 214 616 130 038 [ 009 159 ]

Keiding 1997 1454 1548 368 083 [ 045 154 ]

Sama 1991 520 620 139 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]




005 02 1 5 20










Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 54 48 355 124 [ 061 254 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Sama 1991 520 620 201 083 [ 030 229 ]

005 02 1 5 20


(Continued )





Subtotal (95 CI) 78 77 645 063 [ 033 120 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 96 88 734 078 [ 045 138 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 36 37 266 102 [ 043 240 ]



005 02 1 5 20


(Continued )






Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Keiding 1997 054 148 1000 030 [ 001 712 ]

Total (95 CI) 54 48 1000 030 [ 001 712 ]




0001 001 01 1 10 100 1000











Fleckenstein 1998 214 016 100 567 [ 029 10891 ]

Keiding 1997 154 448 900 022 [ 003 192 ]

Total (95 CI) 68 64 1000 076 [ 020 286 ]




0001 001 01 1 10 100 1000










Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 158 148 905 089 [ 074 108 ]

01 02 05 1 2 5 10


(Continued )









Angelico 1999 816 1017 95 085 [ 045 160 ]

Subtotal (95 CI) 16 17 95 085 [ 045 160 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10










Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Subtotal (95 CI) 70 64 422 084 [ 063 111 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

01 02 05 1 2 5 10


(Continued )





Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 104 101 578 092 [ 072 117 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10












Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Subtotal (95 CI) 138 128 777 087 [ 071 107 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 36 37 223 094 [ 065 136 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10











Barnes 1997 128 624 611 014 [ 002 110 ]

Fleckenstein 1998 114 116 88 114 [ 008 1663 ]

Keiding 1997 154 348 300 030 [ 003 275 ]

Total (95 CI) 96 88 1000 028 [ 008 095 ]




0001 001 01 1 10 100 1000









Barnes 1997 328 724 277 037 [ 011 127 ]

Fleckenstein 1998 314 316 103 114 [ 027 478 ]

Keiding 1997 1454 1548 583 083 [ 045 154 ]

Pageaux 1995 226 124 38 185 [ 018 1908 ]

Total (95 CI) 122 112 1000 077 [ 047 127 ]




001 01 1 10 100











Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]

Total (95 CI) 14 16 1000 260 [ -096 616 ]



-10 -5 0 5 10









Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]

Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]



-100 -50 0 50 100










Angelico 1999 016 017 00 [ 00 00 ]

Barnes 1997 128 124 086 [ 006 1298 ]

Keiding 1997 554 548 089 [ 027 288 ]

Total (95 CI) 98 89 088 [ 030 260 ]




001 01 1 10 100


A P P E N D I C E S






cholicrsquo




odeoxycholicrsquo



cholicrsquo


cholicrsquo


cholicrsquo



odeoxycholicrsquo



(Continued)


cholicrsquo


drocholicrsquo


rodeoxycholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


sodeoxycholicrsquo



cholicrsquo




ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


ME


3 BILE ACID ME

4





(Continued)













5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10



(Continued)


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2



(Continued)

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10




changed




H I S T O R Y








None known




Internal sources


External sources








I N D E X T E R M S




MeSH check words

Humans






capsules (5 pts)



capsules (5 pts)

No other presumed


fects were observed


tion was well tol-

erated in all pa-

tients and no drug-


were recorded


was required

pt(s) = patient(s)

AE = adverse events


























of rejections













9 Quality of life

































Data extraction




















separate domains









described















Blinding




trial












stated







outcomes


judgement




Baseline imbalance




characteristics





Early stopping














Statistical methods















































Subgroup analyses











plied by duration






1999)



co-interventions



R E S U L T S



studies















unpublished trials










Patients















































Outcome measures


























































All-cause mortality
















(118)



















Subgroup analyses






























1999) (RR 030 95 CI 001 to 712) 098 (0) versus 189





















(I2 = 0)












17)

Subgroup analyses

















95 CI 071 to 107) 72138 (522) versus 76128 (594)






































112 (232) (RR 077 95 CI 047 to 127) (Analysis 111)


Liver biochemistry







Cost-effectiveness







Adverse events


















Quality of life














D I S C U S S I O N




















bias













































































adverse events































R E F E R E N C E S







10575563]















9649640]






[MEDLINE 9197351]









(2)119ndash22 [MEDLINE 7499781]







2)68







17589339]





199610(6 Pt 2)658ndash62 [MEDLINE 8996761]










19995(4)269ndash74 [MEDLINE 10388499]





(3)1971 [MEDLINE 2063453]





1973232]





[MEDLINE 8540069]





A1332


Adams 1990



[MEDLINE 2407770]

Al-Quaiz 1994




[MEDLINE 8060468]

Armstrong 1982





23(1)70ndash80 [MEDLINE 7057113]

Ascher 1988





[MEDLINE 3055368]

Brok 2008





Brok 2009






[MEDLINE 18824466]

Calmus 1990




199011(1)12ndash5 [MEDLINE 2403961]

Calmus 1992





Chen 2003a



10100214651858CD003626]

Chen 2007



14651858CD003181pub2]

Cheng 2002




Corbani 2008



[MEDLINE 18242500]

DeMets 1987



[MEDLINE 3616287]



DerSimonian 1986



Egger 1997



Ed) 1997315(7109)629ndash34 [MEDLINE 9310563]

Ericzon 1990




2227822]

FK506 1994




(17)1110ndash5 [MEDLINE 7523946]

Friman 1994




Fuchs 1999





Fusai 2006





Gluud 2001





Gluud 2010





Gong 2008




14651858CD000551pub2]

Haddad 2006




[DOI 10100214651858CD005161pub2]

Heuman 1993



Higgins 2008



2008

Hirschfield 2009




bmjb1670]

Hussain 2002



11933592]

ICH-GCP 1997




Ioannidis 2001




IWP 1995



Kjaergard 2001




[MEDLINE 11730399]

Klintmalm 1989



[MEDLINE 2583691]

Knechtle 2009



[MEDLINE 19235662]

Krams 1993




Lan 1983



Merion 1989





Moher 1998




(9128)609ndash13 [MEDLINE 9746022]



Neuberger 1999




Okolicsanyi 1986




Palmer 1972



Perez 2009



[MEDLINE 19360911]

Pogue 1997




[MEDLINE 9408720]

Pogue 1998




RevMan 2008




Royle 2003




19(4)591ndash603

Schulz 1995



Sharara 1995




Sholmerich 1984





Soderdahl 1998






Terasaki 1991





[MEDLINE 1882800]

Thalheimer 2002




Thorlund 2009





Thuluvath 2003




20039(5)527ndash32 [MEDLINE 12740799]

van den Berg 1998





[MEDLINE 9583867]

Vierling 1992



1570548]

Wetterslev 2008




[MEDLINE 18083463]

Wiesner 1992




1992102A910

Wood 2008





(7644)601ndash5 [MEDLINE 18316340]

Yoshikawa 1998










Chen 2003b








Angelico 1999




Inclusion criteria


Exclusion criteria

- not mentioned

Participants





467 +- 84







474 +- 74







- Route orally


one year

Control group

- no treatment







Risk of bias









All outcomes










tual data given





Barnes 1997




Inclusion criteria



Exclusion criteria


tree


Participants



505 +- 116


Child class A 7




B 13

and C 8


PBC 3





PSC 2

other 3



507 +- 93


Child class A 6

B 14

and C 4


PBC 5





PSC 2

other 4



- Route orally



Placebo group









Adverse events



Risk of bias










All outcomes















Fleckenstein 1998




Inclusion criteria


Exclusion criteria



Participants



443 +- 127



alcohol 2

autoimmune 1

PBC 2




PSC 1


hepatitis B 1



496 +- 109



alcohol 3

autoimmune 3

PBC 1

PSC 2

cryptogenic 2

hepatitis B 1




- Route orally



Placebo group











Risk of bias





probably adequate


All outcomes











tical analysisrdquo



Keiding 1997




Inclusion criteria



Exclusion criteria


Participants



4344 for adults












- Route orally



Placebo group












Adverse events


Risk of bias









All outcomes











was 80 patients



balance


size



Koneru 1993




Inclusion criteria


Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information


- Dose 900 mgday

- Route orally



Control group

- no treatment





Notes Abstract


Risk of bias









All outcomes



plicitly stated






Pageaux 1995




Inclusion criteria


Exclusion criteria

- not mentioned

Participants

- UDCA group (n=26)


47 +- 10





PBC 2

liver cancer 2


miscellaneous 1



51+- 9





PBC 3

liver cancer 4


miscellaneous 1






- Route orally



Placebo group







Risk of bias






All outcomes




were reported






Sama 1991




Inclusion criteria





Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information



- Route orally



Control group

- no treatment


and cyclosporine)



Notes Abstract


Risk of bias
















All outcomes




fully stated


adequately reported




ported













cyclosporine











(Continued)

















month


















studies

No of



follow-up



no treatment


12 TUDCA versus no

treatment




scenarios







start of bile acids



transplantation



transplantation





treatment duration






follow-up




maximum follow-up




follow-up



no treatment


72 TUDCA versus no

treatment





start of bile acid





transplantation








treatment duration






follow-up




maximum follow-up



end of treatment




transplantation




maximum follow-up







Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 116 108 935 080 [ 049 130 ]




01 02 05 1 2 5 10


(Continued )






Angelico 1999 316 217 65 159 [ 030 833 ]

Subtotal (95 CI) 16 17 65 159 [ 030 833 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




01 02 05 1 2 5 10










Angelico 1999 516 217 65 266 [ 060 1180 ]

Barnes 1997 828 724 253 098 [ 042 230 ]

Fleckenstein 1998 314 416 125 086 [ 023 319 ]

Keiding 1997 1954 1048 355 169 [ 087 327 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]





005 02 1 5 20


(Continued )





Angelico 1999 316 417 90 080 [ 021 302 ]

Barnes 1997 228 1124 274 016 [ 004 063 ]

Fleckenstein 1998 214 616 130 038 [ 009 159 ]

Keiding 1997 1454 1548 368 083 [ 045 154 ]

Sama 1991 520 620 139 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]




005 02 1 5 20










Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 54 48 355 124 [ 061 254 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Sama 1991 520 620 201 083 [ 030 229 ]

005 02 1 5 20


(Continued )





Subtotal (95 CI) 78 77 645 063 [ 033 120 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 96 88 734 078 [ 045 138 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 36 37 266 102 [ 043 240 ]



005 02 1 5 20


(Continued )






Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Keiding 1997 054 148 1000 030 [ 001 712 ]

Total (95 CI) 54 48 1000 030 [ 001 712 ]




0001 001 01 1 10 100 1000











Fleckenstein 1998 214 016 100 567 [ 029 10891 ]

Keiding 1997 154 448 900 022 [ 003 192 ]

Total (95 CI) 68 64 1000 076 [ 020 286 ]




0001 001 01 1 10 100 1000










Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 158 148 905 089 [ 074 108 ]

01 02 05 1 2 5 10


(Continued )









Angelico 1999 816 1017 95 085 [ 045 160 ]

Subtotal (95 CI) 16 17 95 085 [ 045 160 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10










Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Subtotal (95 CI) 70 64 422 084 [ 063 111 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

01 02 05 1 2 5 10


(Continued )





Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 104 101 578 092 [ 072 117 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10












Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Subtotal (95 CI) 138 128 777 087 [ 071 107 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 36 37 223 094 [ 065 136 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10











Barnes 1997 128 624 611 014 [ 002 110 ]

Fleckenstein 1998 114 116 88 114 [ 008 1663 ]

Keiding 1997 154 348 300 030 [ 003 275 ]

Total (95 CI) 96 88 1000 028 [ 008 095 ]




0001 001 01 1 10 100 1000









Barnes 1997 328 724 277 037 [ 011 127 ]

Fleckenstein 1998 314 316 103 114 [ 027 478 ]

Keiding 1997 1454 1548 583 083 [ 045 154 ]

Pageaux 1995 226 124 38 185 [ 018 1908 ]

Total (95 CI) 122 112 1000 077 [ 047 127 ]




001 01 1 10 100











Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]

Total (95 CI) 14 16 1000 260 [ -096 616 ]



-10 -5 0 5 10









Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]

Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]



-100 -50 0 50 100










Angelico 1999 016 017 00 [ 00 00 ]

Barnes 1997 128 124 086 [ 006 1298 ]

Keiding 1997 554 548 089 [ 027 288 ]

Total (95 CI) 98 89 088 [ 030 260 ]




001 01 1 10 100


A P P E N D I C E S






cholicrsquo




odeoxycholicrsquo



cholicrsquo


cholicrsquo


cholicrsquo



odeoxycholicrsquo



(Continued)


cholicrsquo


drocholicrsquo


rodeoxycholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


sodeoxycholicrsquo



cholicrsquo




ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


ME


3 BILE ACID ME

4





(Continued)













5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10



(Continued)


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2



(Continued)

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10




changed




H I S T O R Y








None known




Internal sources


External sources








I N D E X T E R M S




MeSH check words

Humans


























Data extraction




















separate domains









described















Blinding




trial












stated







outcomes


judgement




Baseline imbalance




characteristics





Early stopping














Statistical methods















































Subgroup analyses











plied by duration






1999)



co-interventions



R E S U L T S



studies















unpublished trials










Patients















































Outcome measures


























































All-cause mortality
















(118)



















Subgroup analyses






























1999) (RR 030 95 CI 001 to 712) 098 (0) versus 189





















(I2 = 0)












17)

Subgroup analyses

















95 CI 071 to 107) 72138 (522) versus 76128 (594)






































112 (232) (RR 077 95 CI 047 to 127) (Analysis 111)


Liver biochemistry







Cost-effectiveness







Adverse events


















Quality of life














D I S C U S S I O N




















bias













































































adverse events































R E F E R E N C E S







10575563]















9649640]






[MEDLINE 9197351]









(2)119ndash22 [MEDLINE 7499781]







2)68







17589339]





199610(6 Pt 2)658ndash62 [MEDLINE 8996761]










19995(4)269ndash74 [MEDLINE 10388499]





(3)1971 [MEDLINE 2063453]





1973232]





[MEDLINE 8540069]





A1332


Adams 1990



[MEDLINE 2407770]

Al-Quaiz 1994




[MEDLINE 8060468]

Armstrong 1982





23(1)70ndash80 [MEDLINE 7057113]

Ascher 1988





[MEDLINE 3055368]

Brok 2008





Brok 2009






[MEDLINE 18824466]

Calmus 1990




199011(1)12ndash5 [MEDLINE 2403961]

Calmus 1992





Chen 2003a



10100214651858CD003626]

Chen 2007



14651858CD003181pub2]

Cheng 2002




Corbani 2008



[MEDLINE 18242500]

DeMets 1987



[MEDLINE 3616287]



DerSimonian 1986



Egger 1997



Ed) 1997315(7109)629ndash34 [MEDLINE 9310563]

Ericzon 1990




2227822]

FK506 1994




(17)1110ndash5 [MEDLINE 7523946]

Friman 1994




Fuchs 1999





Fusai 2006





Gluud 2001





Gluud 2010





Gong 2008




14651858CD000551pub2]

Haddad 2006




[DOI 10100214651858CD005161pub2]

Heuman 1993



Higgins 2008



2008

Hirschfield 2009




bmjb1670]

Hussain 2002



11933592]

ICH-GCP 1997




Ioannidis 2001




IWP 1995



Kjaergard 2001




[MEDLINE 11730399]

Klintmalm 1989



[MEDLINE 2583691]

Knechtle 2009



[MEDLINE 19235662]

Krams 1993




Lan 1983



Merion 1989





Moher 1998




(9128)609ndash13 [MEDLINE 9746022]



Neuberger 1999




Okolicsanyi 1986




Palmer 1972



Perez 2009



[MEDLINE 19360911]

Pogue 1997




[MEDLINE 9408720]

Pogue 1998




RevMan 2008




Royle 2003




19(4)591ndash603

Schulz 1995



Sharara 1995




Sholmerich 1984





Soderdahl 1998






Terasaki 1991





[MEDLINE 1882800]

Thalheimer 2002




Thorlund 2009





Thuluvath 2003




20039(5)527ndash32 [MEDLINE 12740799]

van den Berg 1998





[MEDLINE 9583867]

Vierling 1992



1570548]

Wetterslev 2008




[MEDLINE 18083463]

Wiesner 1992




1992102A910

Wood 2008





(7644)601ndash5 [MEDLINE 18316340]

Yoshikawa 1998










Chen 2003b








Angelico 1999




Inclusion criteria


Exclusion criteria

- not mentioned

Participants





467 +- 84







474 +- 74







- Route orally


one year

Control group

- no treatment







Risk of bias









All outcomes










tual data given





Barnes 1997




Inclusion criteria



Exclusion criteria


tree


Participants



505 +- 116


Child class A 7




B 13

and C 8


PBC 3





PSC 2

other 3



507 +- 93


Child class A 6

B 14

and C 4


PBC 5





PSC 2

other 4



- Route orally



Placebo group









Adverse events



Risk of bias










All outcomes















Fleckenstein 1998




Inclusion criteria


Exclusion criteria



Participants



443 +- 127



alcohol 2

autoimmune 1

PBC 2




PSC 1


hepatitis B 1



496 +- 109



alcohol 3

autoimmune 3

PBC 1

PSC 2

cryptogenic 2

hepatitis B 1




- Route orally



Placebo group











Risk of bias





probably adequate


All outcomes











tical analysisrdquo



Keiding 1997




Inclusion criteria



Exclusion criteria


Participants



4344 for adults












- Route orally



Placebo group












Adverse events


Risk of bias









All outcomes











was 80 patients



balance


size



Koneru 1993




Inclusion criteria


Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information


- Dose 900 mgday

- Route orally



Control group

- no treatment





Notes Abstract


Risk of bias









All outcomes



plicitly stated






Pageaux 1995




Inclusion criteria


Exclusion criteria

- not mentioned

Participants

- UDCA group (n=26)


47 +- 10





PBC 2

liver cancer 2


miscellaneous 1



51+- 9





PBC 3

liver cancer 4


miscellaneous 1






- Route orally



Placebo group







Risk of bias






All outcomes




were reported






Sama 1991




Inclusion criteria





Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information



- Route orally



Control group

- no treatment


and cyclosporine)



Notes Abstract


Risk of bias
















All outcomes




fully stated


adequately reported




ported













cyclosporine











(Continued)

















month


















studies

No of



follow-up



no treatment


12 TUDCA versus no

treatment




scenarios







start of bile acids



transplantation



transplantation





treatment duration






follow-up




maximum follow-up




follow-up



no treatment


72 TUDCA versus no

treatment





start of bile acid





transplantation








treatment duration






follow-up




maximum follow-up



end of treatment




transplantation




maximum follow-up







Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 116 108 935 080 [ 049 130 ]




01 02 05 1 2 5 10


(Continued )






Angelico 1999 316 217 65 159 [ 030 833 ]

Subtotal (95 CI) 16 17 65 159 [ 030 833 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




01 02 05 1 2 5 10










Angelico 1999 516 217 65 266 [ 060 1180 ]

Barnes 1997 828 724 253 098 [ 042 230 ]

Fleckenstein 1998 314 416 125 086 [ 023 319 ]

Keiding 1997 1954 1048 355 169 [ 087 327 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]





005 02 1 5 20


(Continued )





Angelico 1999 316 417 90 080 [ 021 302 ]

Barnes 1997 228 1124 274 016 [ 004 063 ]

Fleckenstein 1998 214 616 130 038 [ 009 159 ]

Keiding 1997 1454 1548 368 083 [ 045 154 ]

Sama 1991 520 620 139 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]




005 02 1 5 20










Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 54 48 355 124 [ 061 254 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Sama 1991 520 620 201 083 [ 030 229 ]

005 02 1 5 20


(Continued )





Subtotal (95 CI) 78 77 645 063 [ 033 120 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 96 88 734 078 [ 045 138 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 36 37 266 102 [ 043 240 ]



005 02 1 5 20


(Continued )






Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Keiding 1997 054 148 1000 030 [ 001 712 ]

Total (95 CI) 54 48 1000 030 [ 001 712 ]




0001 001 01 1 10 100 1000











Fleckenstein 1998 214 016 100 567 [ 029 10891 ]

Keiding 1997 154 448 900 022 [ 003 192 ]

Total (95 CI) 68 64 1000 076 [ 020 286 ]




0001 001 01 1 10 100 1000










Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 158 148 905 089 [ 074 108 ]

01 02 05 1 2 5 10


(Continued )









Angelico 1999 816 1017 95 085 [ 045 160 ]

Subtotal (95 CI) 16 17 95 085 [ 045 160 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10










Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Subtotal (95 CI) 70 64 422 084 [ 063 111 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

01 02 05 1 2 5 10


(Continued )





Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 104 101 578 092 [ 072 117 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10












Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Subtotal (95 CI) 138 128 777 087 [ 071 107 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 36 37 223 094 [ 065 136 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10











Barnes 1997 128 624 611 014 [ 002 110 ]

Fleckenstein 1998 114 116 88 114 [ 008 1663 ]

Keiding 1997 154 348 300 030 [ 003 275 ]

Total (95 CI) 96 88 1000 028 [ 008 095 ]




0001 001 01 1 10 100 1000









Barnes 1997 328 724 277 037 [ 011 127 ]

Fleckenstein 1998 314 316 103 114 [ 027 478 ]

Keiding 1997 1454 1548 583 083 [ 045 154 ]

Pageaux 1995 226 124 38 185 [ 018 1908 ]

Total (95 CI) 122 112 1000 077 [ 047 127 ]




001 01 1 10 100











Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]

Total (95 CI) 14 16 1000 260 [ -096 616 ]



-10 -5 0 5 10









Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]

Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]



-100 -50 0 50 100










Angelico 1999 016 017 00 [ 00 00 ]

Barnes 1997 128 124 086 [ 006 1298 ]

Keiding 1997 554 548 089 [ 027 288 ]

Total (95 CI) 98 89 088 [ 030 260 ]




001 01 1 10 100


A P P E N D I C E S






cholicrsquo




odeoxycholicrsquo



cholicrsquo


cholicrsquo


cholicrsquo



odeoxycholicrsquo



(Continued)


cholicrsquo


drocholicrsquo


rodeoxycholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


sodeoxycholicrsquo



cholicrsquo




ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


ME


3 BILE ACID ME

4





(Continued)













5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10



(Continued)


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2



(Continued)

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10




changed




H I S T O R Y








None known




Internal sources


External sources








I N D E X T E R M S




MeSH check words

Humans




characteristics





Early stopping














Statistical methods















































Subgroup analyses











plied by duration






1999)



co-interventions



R E S U L T S



studies















unpublished trials










Patients















































Outcome measures


























































All-cause mortality
















(118)



















Subgroup analyses






























1999) (RR 030 95 CI 001 to 712) 098 (0) versus 189





















(I2 = 0)












17)

Subgroup analyses

















95 CI 071 to 107) 72138 (522) versus 76128 (594)






































112 (232) (RR 077 95 CI 047 to 127) (Analysis 111)


Liver biochemistry







Cost-effectiveness







Adverse events


















Quality of life














D I S C U S S I O N




















bias













































































adverse events































R E F E R E N C E S







10575563]















9649640]






[MEDLINE 9197351]









(2)119ndash22 [MEDLINE 7499781]







2)68







17589339]





199610(6 Pt 2)658ndash62 [MEDLINE 8996761]










19995(4)269ndash74 [MEDLINE 10388499]





(3)1971 [MEDLINE 2063453]





1973232]





[MEDLINE 8540069]





A1332


Adams 1990



[MEDLINE 2407770]

Al-Quaiz 1994




[MEDLINE 8060468]

Armstrong 1982





23(1)70ndash80 [MEDLINE 7057113]

Ascher 1988





[MEDLINE 3055368]

Brok 2008





Brok 2009






[MEDLINE 18824466]

Calmus 1990




199011(1)12ndash5 [MEDLINE 2403961]

Calmus 1992





Chen 2003a



10100214651858CD003626]

Chen 2007



14651858CD003181pub2]

Cheng 2002




Corbani 2008



[MEDLINE 18242500]

DeMets 1987



[MEDLINE 3616287]



DerSimonian 1986



Egger 1997



Ed) 1997315(7109)629ndash34 [MEDLINE 9310563]

Ericzon 1990




2227822]

FK506 1994




(17)1110ndash5 [MEDLINE 7523946]

Friman 1994




Fuchs 1999





Fusai 2006





Gluud 2001





Gluud 2010





Gong 2008




14651858CD000551pub2]

Haddad 2006




[DOI 10100214651858CD005161pub2]

Heuman 1993



Higgins 2008



2008

Hirschfield 2009




bmjb1670]

Hussain 2002



11933592]

ICH-GCP 1997




Ioannidis 2001




IWP 1995



Kjaergard 2001




[MEDLINE 11730399]

Klintmalm 1989



[MEDLINE 2583691]

Knechtle 2009



[MEDLINE 19235662]

Krams 1993




Lan 1983



Merion 1989





Moher 1998




(9128)609ndash13 [MEDLINE 9746022]



Neuberger 1999




Okolicsanyi 1986




Palmer 1972



Perez 2009



[MEDLINE 19360911]

Pogue 1997




[MEDLINE 9408720]

Pogue 1998




RevMan 2008




Royle 2003




19(4)591ndash603

Schulz 1995



Sharara 1995




Sholmerich 1984





Soderdahl 1998






Terasaki 1991





[MEDLINE 1882800]

Thalheimer 2002




Thorlund 2009





Thuluvath 2003




20039(5)527ndash32 [MEDLINE 12740799]

van den Berg 1998





[MEDLINE 9583867]

Vierling 1992



1570548]

Wetterslev 2008




[MEDLINE 18083463]

Wiesner 1992




1992102A910

Wood 2008





(7644)601ndash5 [MEDLINE 18316340]

Yoshikawa 1998










Chen 2003b








Angelico 1999




Inclusion criteria


Exclusion criteria

- not mentioned

Participants





467 +- 84







474 +- 74







- Route orally


one year

Control group

- no treatment







Risk of bias









All outcomes










tual data given





Barnes 1997




Inclusion criteria



Exclusion criteria


tree


Participants



505 +- 116


Child class A 7




B 13

and C 8


PBC 3





PSC 2

other 3



507 +- 93


Child class A 6

B 14

and C 4


PBC 5





PSC 2

other 4



- Route orally



Placebo group









Adverse events



Risk of bias










All outcomes















Fleckenstein 1998




Inclusion criteria


Exclusion criteria



Participants



443 +- 127



alcohol 2

autoimmune 1

PBC 2




PSC 1


hepatitis B 1



496 +- 109



alcohol 3

autoimmune 3

PBC 1

PSC 2

cryptogenic 2

hepatitis B 1




- Route orally



Placebo group











Risk of bias





probably adequate


All outcomes











tical analysisrdquo



Keiding 1997




Inclusion criteria



Exclusion criteria


Participants



4344 for adults












- Route orally



Placebo group












Adverse events


Risk of bias









All outcomes











was 80 patients



balance


size



Koneru 1993




Inclusion criteria


Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information


- Dose 900 mgday

- Route orally



Control group

- no treatment





Notes Abstract


Risk of bias









All outcomes



plicitly stated






Pageaux 1995




Inclusion criteria


Exclusion criteria

- not mentioned

Participants

- UDCA group (n=26)


47 +- 10





PBC 2

liver cancer 2


miscellaneous 1



51+- 9





PBC 3

liver cancer 4


miscellaneous 1






- Route orally



Placebo group







Risk of bias






All outcomes




were reported






Sama 1991




Inclusion criteria





Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information



- Route orally



Control group

- no treatment


and cyclosporine)



Notes Abstract


Risk of bias
















All outcomes




fully stated


adequately reported




ported













cyclosporine











(Continued)

















month


















studies

No of



follow-up



no treatment


12 TUDCA versus no

treatment




scenarios







start of bile acids



transplantation



transplantation





treatment duration






follow-up




maximum follow-up




follow-up



no treatment


72 TUDCA versus no

treatment





start of bile acid





transplantation








treatment duration






follow-up




maximum follow-up



end of treatment




transplantation




maximum follow-up







Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 116 108 935 080 [ 049 130 ]




01 02 05 1 2 5 10


(Continued )






Angelico 1999 316 217 65 159 [ 030 833 ]

Subtotal (95 CI) 16 17 65 159 [ 030 833 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




01 02 05 1 2 5 10










Angelico 1999 516 217 65 266 [ 060 1180 ]

Barnes 1997 828 724 253 098 [ 042 230 ]

Fleckenstein 1998 314 416 125 086 [ 023 319 ]

Keiding 1997 1954 1048 355 169 [ 087 327 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]





005 02 1 5 20


(Continued )





Angelico 1999 316 417 90 080 [ 021 302 ]

Barnes 1997 228 1124 274 016 [ 004 063 ]

Fleckenstein 1998 214 616 130 038 [ 009 159 ]

Keiding 1997 1454 1548 368 083 [ 045 154 ]

Sama 1991 520 620 139 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]




005 02 1 5 20










Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 54 48 355 124 [ 061 254 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Sama 1991 520 620 201 083 [ 030 229 ]

005 02 1 5 20


(Continued )





Subtotal (95 CI) 78 77 645 063 [ 033 120 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 96 88 734 078 [ 045 138 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 36 37 266 102 [ 043 240 ]



005 02 1 5 20


(Continued )






Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Keiding 1997 054 148 1000 030 [ 001 712 ]

Total (95 CI) 54 48 1000 030 [ 001 712 ]




0001 001 01 1 10 100 1000











Fleckenstein 1998 214 016 100 567 [ 029 10891 ]

Keiding 1997 154 448 900 022 [ 003 192 ]

Total (95 CI) 68 64 1000 076 [ 020 286 ]




0001 001 01 1 10 100 1000










Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 158 148 905 089 [ 074 108 ]

01 02 05 1 2 5 10


(Continued )









Angelico 1999 816 1017 95 085 [ 045 160 ]

Subtotal (95 CI) 16 17 95 085 [ 045 160 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10










Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Subtotal (95 CI) 70 64 422 084 [ 063 111 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

01 02 05 1 2 5 10


(Continued )





Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 104 101 578 092 [ 072 117 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10












Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Subtotal (95 CI) 138 128 777 087 [ 071 107 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 36 37 223 094 [ 065 136 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10











Barnes 1997 128 624 611 014 [ 002 110 ]

Fleckenstein 1998 114 116 88 114 [ 008 1663 ]

Keiding 1997 154 348 300 030 [ 003 275 ]

Total (95 CI) 96 88 1000 028 [ 008 095 ]




0001 001 01 1 10 100 1000









Barnes 1997 328 724 277 037 [ 011 127 ]

Fleckenstein 1998 314 316 103 114 [ 027 478 ]

Keiding 1997 1454 1548 583 083 [ 045 154 ]

Pageaux 1995 226 124 38 185 [ 018 1908 ]

Total (95 CI) 122 112 1000 077 [ 047 127 ]




001 01 1 10 100











Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]

Total (95 CI) 14 16 1000 260 [ -096 616 ]



-10 -5 0 5 10









Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]

Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]



-100 -50 0 50 100










Angelico 1999 016 017 00 [ 00 00 ]

Barnes 1997 128 124 086 [ 006 1298 ]

Keiding 1997 554 548 089 [ 027 288 ]

Total (95 CI) 98 89 088 [ 030 260 ]




001 01 1 10 100


A P P E N D I C E S






cholicrsquo




odeoxycholicrsquo



cholicrsquo


cholicrsquo


cholicrsquo



odeoxycholicrsquo



(Continued)


cholicrsquo


drocholicrsquo


rodeoxycholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


sodeoxycholicrsquo



cholicrsquo




ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


ME


3 BILE ACID ME

4





(Continued)













5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10



(Continued)


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2



(Continued)

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10




changed




H I S T O R Y








None known




Internal sources


External sources








I N D E X T E R M S




MeSH check words

Humans











unpublished trials










Patients















































Outcome measures


























































All-cause mortality
















(118)



















Subgroup analyses






























1999) (RR 030 95 CI 001 to 712) 098 (0) versus 189





















(I2 = 0)












17)

Subgroup analyses

















95 CI 071 to 107) 72138 (522) versus 76128 (594)






































112 (232) (RR 077 95 CI 047 to 127) (Analysis 111)


Liver biochemistry







Cost-effectiveness







Adverse events


















Quality of life














D I S C U S S I O N




















bias













































































adverse events































R E F E R E N C E S







10575563]















9649640]






[MEDLINE 9197351]









(2)119ndash22 [MEDLINE 7499781]







2)68







17589339]





199610(6 Pt 2)658ndash62 [MEDLINE 8996761]










19995(4)269ndash74 [MEDLINE 10388499]





(3)1971 [MEDLINE 2063453]





1973232]





[MEDLINE 8540069]





A1332


Adams 1990



[MEDLINE 2407770]

Al-Quaiz 1994




[MEDLINE 8060468]

Armstrong 1982





23(1)70ndash80 [MEDLINE 7057113]

Ascher 1988





[MEDLINE 3055368]

Brok 2008





Brok 2009






[MEDLINE 18824466]

Calmus 1990




199011(1)12ndash5 [MEDLINE 2403961]

Calmus 1992





Chen 2003a



10100214651858CD003626]

Chen 2007



14651858CD003181pub2]

Cheng 2002




Corbani 2008



[MEDLINE 18242500]

DeMets 1987



[MEDLINE 3616287]



DerSimonian 1986



Egger 1997



Ed) 1997315(7109)629ndash34 [MEDLINE 9310563]

Ericzon 1990




2227822]

FK506 1994




(17)1110ndash5 [MEDLINE 7523946]

Friman 1994




Fuchs 1999





Fusai 2006





Gluud 2001





Gluud 2010





Gong 2008




14651858CD000551pub2]

Haddad 2006




[DOI 10100214651858CD005161pub2]

Heuman 1993



Higgins 2008



2008

Hirschfield 2009




bmjb1670]

Hussain 2002



11933592]

ICH-GCP 1997




Ioannidis 2001




IWP 1995



Kjaergard 2001




[MEDLINE 11730399]

Klintmalm 1989



[MEDLINE 2583691]

Knechtle 2009



[MEDLINE 19235662]

Krams 1993




Lan 1983



Merion 1989





Moher 1998




(9128)609ndash13 [MEDLINE 9746022]



Neuberger 1999




Okolicsanyi 1986




Palmer 1972



Perez 2009



[MEDLINE 19360911]

Pogue 1997




[MEDLINE 9408720]

Pogue 1998




RevMan 2008




Royle 2003




19(4)591ndash603

Schulz 1995



Sharara 1995




Sholmerich 1984





Soderdahl 1998






Terasaki 1991





[MEDLINE 1882800]

Thalheimer 2002




Thorlund 2009





Thuluvath 2003




20039(5)527ndash32 [MEDLINE 12740799]

van den Berg 1998





[MEDLINE 9583867]

Vierling 1992



1570548]

Wetterslev 2008




[MEDLINE 18083463]

Wiesner 1992




1992102A910

Wood 2008





(7644)601ndash5 [MEDLINE 18316340]

Yoshikawa 1998










Chen 2003b








Angelico 1999




Inclusion criteria


Exclusion criteria

- not mentioned

Participants





467 +- 84







474 +- 74







- Route orally


one year

Control group

- no treatment







Risk of bias









All outcomes










tual data given





Barnes 1997




Inclusion criteria



Exclusion criteria


tree


Participants



505 +- 116


Child class A 7




B 13

and C 8


PBC 3





PSC 2

other 3



507 +- 93


Child class A 6

B 14

and C 4


PBC 5





PSC 2

other 4



- Route orally



Placebo group









Adverse events



Risk of bias










All outcomes















Fleckenstein 1998




Inclusion criteria


Exclusion criteria



Participants



443 +- 127



alcohol 2

autoimmune 1

PBC 2




PSC 1


hepatitis B 1



496 +- 109



alcohol 3

autoimmune 3

PBC 1

PSC 2

cryptogenic 2

hepatitis B 1




- Route orally



Placebo group











Risk of bias





probably adequate


All outcomes











tical analysisrdquo



Keiding 1997




Inclusion criteria



Exclusion criteria


Participants



4344 for adults












- Route orally



Placebo group












Adverse events


Risk of bias









All outcomes











was 80 patients



balance


size



Koneru 1993




Inclusion criteria


Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information


- Dose 900 mgday

- Route orally



Control group

- no treatment





Notes Abstract


Risk of bias









All outcomes



plicitly stated






Pageaux 1995




Inclusion criteria


Exclusion criteria

- not mentioned

Participants

- UDCA group (n=26)


47 +- 10





PBC 2

liver cancer 2


miscellaneous 1



51+- 9





PBC 3

liver cancer 4


miscellaneous 1






- Route orally



Placebo group







Risk of bias






All outcomes




were reported






Sama 1991




Inclusion criteria





Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information



- Route orally



Control group

- no treatment


and cyclosporine)



Notes Abstract


Risk of bias
















All outcomes




fully stated


adequately reported




ported













cyclosporine











(Continued)

















month


















studies

No of



follow-up



no treatment


12 TUDCA versus no

treatment




scenarios







start of bile acids



transplantation



transplantation





treatment duration






follow-up




maximum follow-up




follow-up



no treatment


72 TUDCA versus no

treatment





start of bile acid





transplantation








treatment duration






follow-up




maximum follow-up



end of treatment




transplantation




maximum follow-up







Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 116 108 935 080 [ 049 130 ]




01 02 05 1 2 5 10


(Continued )






Angelico 1999 316 217 65 159 [ 030 833 ]

Subtotal (95 CI) 16 17 65 159 [ 030 833 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




01 02 05 1 2 5 10










Angelico 1999 516 217 65 266 [ 060 1180 ]

Barnes 1997 828 724 253 098 [ 042 230 ]

Fleckenstein 1998 314 416 125 086 [ 023 319 ]

Keiding 1997 1954 1048 355 169 [ 087 327 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]





005 02 1 5 20


(Continued )





Angelico 1999 316 417 90 080 [ 021 302 ]

Barnes 1997 228 1124 274 016 [ 004 063 ]

Fleckenstein 1998 214 616 130 038 [ 009 159 ]

Keiding 1997 1454 1548 368 083 [ 045 154 ]

Sama 1991 520 620 139 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]




005 02 1 5 20










Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 54 48 355 124 [ 061 254 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Sama 1991 520 620 201 083 [ 030 229 ]

005 02 1 5 20


(Continued )





Subtotal (95 CI) 78 77 645 063 [ 033 120 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 96 88 734 078 [ 045 138 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 36 37 266 102 [ 043 240 ]



005 02 1 5 20


(Continued )






Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Keiding 1997 054 148 1000 030 [ 001 712 ]

Total (95 CI) 54 48 1000 030 [ 001 712 ]




0001 001 01 1 10 100 1000











Fleckenstein 1998 214 016 100 567 [ 029 10891 ]

Keiding 1997 154 448 900 022 [ 003 192 ]

Total (95 CI) 68 64 1000 076 [ 020 286 ]




0001 001 01 1 10 100 1000










Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 158 148 905 089 [ 074 108 ]

01 02 05 1 2 5 10


(Continued )









Angelico 1999 816 1017 95 085 [ 045 160 ]

Subtotal (95 CI) 16 17 95 085 [ 045 160 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10










Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Subtotal (95 CI) 70 64 422 084 [ 063 111 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

01 02 05 1 2 5 10


(Continued )





Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 104 101 578 092 [ 072 117 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10












Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Subtotal (95 CI) 138 128 777 087 [ 071 107 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 36 37 223 094 [ 065 136 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10











Barnes 1997 128 624 611 014 [ 002 110 ]

Fleckenstein 1998 114 116 88 114 [ 008 1663 ]

Keiding 1997 154 348 300 030 [ 003 275 ]

Total (95 CI) 96 88 1000 028 [ 008 095 ]




0001 001 01 1 10 100 1000









Barnes 1997 328 724 277 037 [ 011 127 ]

Fleckenstein 1998 314 316 103 114 [ 027 478 ]

Keiding 1997 1454 1548 583 083 [ 045 154 ]

Pageaux 1995 226 124 38 185 [ 018 1908 ]

Total (95 CI) 122 112 1000 077 [ 047 127 ]




001 01 1 10 100











Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]

Total (95 CI) 14 16 1000 260 [ -096 616 ]



-10 -5 0 5 10









Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]

Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]



-100 -50 0 50 100










Angelico 1999 016 017 00 [ 00 00 ]

Barnes 1997 128 124 086 [ 006 1298 ]

Keiding 1997 554 548 089 [ 027 288 ]

Total (95 CI) 98 89 088 [ 030 260 ]




001 01 1 10 100


A P P E N D I C E S






cholicrsquo




odeoxycholicrsquo



cholicrsquo


cholicrsquo


cholicrsquo



odeoxycholicrsquo



(Continued)


cholicrsquo


drocholicrsquo


rodeoxycholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


sodeoxycholicrsquo



cholicrsquo




ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


ME


3 BILE ACID ME

4





(Continued)













5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10



(Continued)


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2



(Continued)

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10




changed




H I S T O R Y








None known




Internal sources


External sources








I N D E X T E R M S




MeSH check words

Humans
























All-cause mortality
















(118)



















Subgroup analyses






























1999) (RR 030 95 CI 001 to 712) 098 (0) versus 189





















(I2 = 0)












17)

Subgroup analyses

















95 CI 071 to 107) 72138 (522) versus 76128 (594)






































112 (232) (RR 077 95 CI 047 to 127) (Analysis 111)


Liver biochemistry







Cost-effectiveness







Adverse events


















Quality of life














D I S C U S S I O N




















bias













































































adverse events































R E F E R E N C E S







10575563]















9649640]






[MEDLINE 9197351]









(2)119ndash22 [MEDLINE 7499781]







2)68







17589339]





199610(6 Pt 2)658ndash62 [MEDLINE 8996761]










19995(4)269ndash74 [MEDLINE 10388499]





(3)1971 [MEDLINE 2063453]





1973232]





[MEDLINE 8540069]





A1332


Adams 1990



[MEDLINE 2407770]

Al-Quaiz 1994




[MEDLINE 8060468]

Armstrong 1982





23(1)70ndash80 [MEDLINE 7057113]

Ascher 1988





[MEDLINE 3055368]

Brok 2008





Brok 2009






[MEDLINE 18824466]

Calmus 1990




199011(1)12ndash5 [MEDLINE 2403961]

Calmus 1992





Chen 2003a



10100214651858CD003626]

Chen 2007



14651858CD003181pub2]

Cheng 2002




Corbani 2008



[MEDLINE 18242500]

DeMets 1987



[MEDLINE 3616287]



DerSimonian 1986



Egger 1997



Ed) 1997315(7109)629ndash34 [MEDLINE 9310563]

Ericzon 1990




2227822]

FK506 1994




(17)1110ndash5 [MEDLINE 7523946]

Friman 1994




Fuchs 1999





Fusai 2006





Gluud 2001





Gluud 2010





Gong 2008




14651858CD000551pub2]

Haddad 2006




[DOI 10100214651858CD005161pub2]

Heuman 1993



Higgins 2008



2008

Hirschfield 2009




bmjb1670]

Hussain 2002



11933592]

ICH-GCP 1997




Ioannidis 2001




IWP 1995



Kjaergard 2001




[MEDLINE 11730399]

Klintmalm 1989



[MEDLINE 2583691]

Knechtle 2009



[MEDLINE 19235662]

Krams 1993




Lan 1983



Merion 1989





Moher 1998




(9128)609ndash13 [MEDLINE 9746022]



Neuberger 1999




Okolicsanyi 1986




Palmer 1972



Perez 2009



[MEDLINE 19360911]

Pogue 1997




[MEDLINE 9408720]

Pogue 1998




RevMan 2008




Royle 2003




19(4)591ndash603

Schulz 1995



Sharara 1995




Sholmerich 1984





Soderdahl 1998






Terasaki 1991





[MEDLINE 1882800]

Thalheimer 2002




Thorlund 2009





Thuluvath 2003




20039(5)527ndash32 [MEDLINE 12740799]

van den Berg 1998





[MEDLINE 9583867]

Vierling 1992



1570548]

Wetterslev 2008




[MEDLINE 18083463]

Wiesner 1992




1992102A910

Wood 2008





(7644)601ndash5 [MEDLINE 18316340]

Yoshikawa 1998










Chen 2003b








Angelico 1999




Inclusion criteria


Exclusion criteria

- not mentioned

Participants





467 +- 84







474 +- 74







- Route orally


one year

Control group

- no treatment







Risk of bias









All outcomes










tual data given





Barnes 1997




Inclusion criteria



Exclusion criteria


tree


Participants



505 +- 116


Child class A 7




B 13

and C 8


PBC 3





PSC 2

other 3



507 +- 93


Child class A 6

B 14

and C 4


PBC 5





PSC 2

other 4



- Route orally



Placebo group









Adverse events



Risk of bias










All outcomes















Fleckenstein 1998




Inclusion criteria


Exclusion criteria



Participants



443 +- 127



alcohol 2

autoimmune 1

PBC 2




PSC 1


hepatitis B 1



496 +- 109



alcohol 3

autoimmune 3

PBC 1

PSC 2

cryptogenic 2

hepatitis B 1




- Route orally



Placebo group











Risk of bias





probably adequate


All outcomes











tical analysisrdquo



Keiding 1997




Inclusion criteria



Exclusion criteria


Participants



4344 for adults












- Route orally



Placebo group












Adverse events


Risk of bias









All outcomes











was 80 patients



balance


size



Koneru 1993




Inclusion criteria


Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information


- Dose 900 mgday

- Route orally



Control group

- no treatment





Notes Abstract


Risk of bias









All outcomes



plicitly stated






Pageaux 1995




Inclusion criteria


Exclusion criteria

- not mentioned

Participants

- UDCA group (n=26)


47 +- 10





PBC 2

liver cancer 2


miscellaneous 1



51+- 9





PBC 3

liver cancer 4


miscellaneous 1






- Route orally



Placebo group







Risk of bias






All outcomes




were reported






Sama 1991




Inclusion criteria





Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information



- Route orally



Control group

- no treatment


and cyclosporine)



Notes Abstract


Risk of bias
















All outcomes




fully stated


adequately reported




ported













cyclosporine











(Continued)

















month


















studies

No of



follow-up



no treatment


12 TUDCA versus no

treatment




scenarios







start of bile acids



transplantation



transplantation





treatment duration






follow-up




maximum follow-up




follow-up



no treatment


72 TUDCA versus no

treatment





start of bile acid





transplantation








treatment duration






follow-up




maximum follow-up



end of treatment




transplantation




maximum follow-up







Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 116 108 935 080 [ 049 130 ]




01 02 05 1 2 5 10


(Continued )






Angelico 1999 316 217 65 159 [ 030 833 ]

Subtotal (95 CI) 16 17 65 159 [ 030 833 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




01 02 05 1 2 5 10










Angelico 1999 516 217 65 266 [ 060 1180 ]

Barnes 1997 828 724 253 098 [ 042 230 ]

Fleckenstein 1998 314 416 125 086 [ 023 319 ]

Keiding 1997 1954 1048 355 169 [ 087 327 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]





005 02 1 5 20


(Continued )





Angelico 1999 316 417 90 080 [ 021 302 ]

Barnes 1997 228 1124 274 016 [ 004 063 ]

Fleckenstein 1998 214 616 130 038 [ 009 159 ]

Keiding 1997 1454 1548 368 083 [ 045 154 ]

Sama 1991 520 620 139 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]




005 02 1 5 20










Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 54 48 355 124 [ 061 254 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Sama 1991 520 620 201 083 [ 030 229 ]

005 02 1 5 20


(Continued )





Subtotal (95 CI) 78 77 645 063 [ 033 120 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 96 88 734 078 [ 045 138 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 36 37 266 102 [ 043 240 ]



005 02 1 5 20


(Continued )






Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Keiding 1997 054 148 1000 030 [ 001 712 ]

Total (95 CI) 54 48 1000 030 [ 001 712 ]




0001 001 01 1 10 100 1000











Fleckenstein 1998 214 016 100 567 [ 029 10891 ]

Keiding 1997 154 448 900 022 [ 003 192 ]

Total (95 CI) 68 64 1000 076 [ 020 286 ]




0001 001 01 1 10 100 1000










Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 158 148 905 089 [ 074 108 ]

01 02 05 1 2 5 10


(Continued )









Angelico 1999 816 1017 95 085 [ 045 160 ]

Subtotal (95 CI) 16 17 95 085 [ 045 160 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10










Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Subtotal (95 CI) 70 64 422 084 [ 063 111 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

01 02 05 1 2 5 10


(Continued )





Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 104 101 578 092 [ 072 117 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10












Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Subtotal (95 CI) 138 128 777 087 [ 071 107 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 36 37 223 094 [ 065 136 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10











Barnes 1997 128 624 611 014 [ 002 110 ]

Fleckenstein 1998 114 116 88 114 [ 008 1663 ]

Keiding 1997 154 348 300 030 [ 003 275 ]

Total (95 CI) 96 88 1000 028 [ 008 095 ]




0001 001 01 1 10 100 1000









Barnes 1997 328 724 277 037 [ 011 127 ]

Fleckenstein 1998 314 316 103 114 [ 027 478 ]

Keiding 1997 1454 1548 583 083 [ 045 154 ]

Pageaux 1995 226 124 38 185 [ 018 1908 ]

Total (95 CI) 122 112 1000 077 [ 047 127 ]




001 01 1 10 100











Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]

Total (95 CI) 14 16 1000 260 [ -096 616 ]



-10 -5 0 5 10









Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]

Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]



-100 -50 0 50 100










Angelico 1999 016 017 00 [ 00 00 ]

Barnes 1997 128 124 086 [ 006 1298 ]

Keiding 1997 554 548 089 [ 027 288 ]

Total (95 CI) 98 89 088 [ 030 260 ]




001 01 1 10 100


A P P E N D I C E S






cholicrsquo




odeoxycholicrsquo



cholicrsquo


cholicrsquo


cholicrsquo



odeoxycholicrsquo



(Continued)


cholicrsquo


drocholicrsquo


rodeoxycholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


sodeoxycholicrsquo



cholicrsquo




ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


ME


3 BILE ACID ME

4





(Continued)













5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10



(Continued)


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2



(Continued)

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10




changed




H I S T O R Y








None known




Internal sources


External sources








I N D E X T E R M S




MeSH check words

Humans











17)

Subgroup analyses

















95 CI 071 to 107) 72138 (522) versus 76128 (594)






































112 (232) (RR 077 95 CI 047 to 127) (Analysis 111)


Liver biochemistry







Cost-effectiveness







Adverse events


















Quality of life














D I S C U S S I O N




















bias













































































adverse events































R E F E R E N C E S







10575563]















9649640]






[MEDLINE 9197351]









(2)119ndash22 [MEDLINE 7499781]







2)68







17589339]





199610(6 Pt 2)658ndash62 [MEDLINE 8996761]










19995(4)269ndash74 [MEDLINE 10388499]





(3)1971 [MEDLINE 2063453]





1973232]





[MEDLINE 8540069]





A1332


Adams 1990



[MEDLINE 2407770]

Al-Quaiz 1994




[MEDLINE 8060468]

Armstrong 1982





23(1)70ndash80 [MEDLINE 7057113]

Ascher 1988





[MEDLINE 3055368]

Brok 2008





Brok 2009






[MEDLINE 18824466]

Calmus 1990




199011(1)12ndash5 [MEDLINE 2403961]

Calmus 1992





Chen 2003a



10100214651858CD003626]

Chen 2007



14651858CD003181pub2]

Cheng 2002




Corbani 2008



[MEDLINE 18242500]

DeMets 1987



[MEDLINE 3616287]



DerSimonian 1986



Egger 1997



Ed) 1997315(7109)629ndash34 [MEDLINE 9310563]

Ericzon 1990




2227822]

FK506 1994




(17)1110ndash5 [MEDLINE 7523946]

Friman 1994




Fuchs 1999





Fusai 2006





Gluud 2001





Gluud 2010





Gong 2008




14651858CD000551pub2]

Haddad 2006




[DOI 10100214651858CD005161pub2]

Heuman 1993



Higgins 2008



2008

Hirschfield 2009




bmjb1670]

Hussain 2002



11933592]

ICH-GCP 1997




Ioannidis 2001




IWP 1995



Kjaergard 2001




[MEDLINE 11730399]

Klintmalm 1989



[MEDLINE 2583691]

Knechtle 2009



[MEDLINE 19235662]

Krams 1993




Lan 1983



Merion 1989





Moher 1998




(9128)609ndash13 [MEDLINE 9746022]



Neuberger 1999




Okolicsanyi 1986




Palmer 1972



Perez 2009



[MEDLINE 19360911]

Pogue 1997




[MEDLINE 9408720]

Pogue 1998




RevMan 2008




Royle 2003




19(4)591ndash603

Schulz 1995



Sharara 1995




Sholmerich 1984





Soderdahl 1998






Terasaki 1991





[MEDLINE 1882800]

Thalheimer 2002




Thorlund 2009





Thuluvath 2003




20039(5)527ndash32 [MEDLINE 12740799]

van den Berg 1998





[MEDLINE 9583867]

Vierling 1992



1570548]

Wetterslev 2008




[MEDLINE 18083463]

Wiesner 1992




1992102A910

Wood 2008





(7644)601ndash5 [MEDLINE 18316340]

Yoshikawa 1998










Chen 2003b








Angelico 1999




Inclusion criteria


Exclusion criteria

- not mentioned

Participants





467 +- 84







474 +- 74







- Route orally


one year

Control group

- no treatment







Risk of bias









All outcomes










tual data given





Barnes 1997




Inclusion criteria



Exclusion criteria


tree


Participants



505 +- 116


Child class A 7




B 13

and C 8


PBC 3





PSC 2

other 3



507 +- 93


Child class A 6

B 14

and C 4


PBC 5





PSC 2

other 4



- Route orally



Placebo group









Adverse events



Risk of bias










All outcomes















Fleckenstein 1998




Inclusion criteria


Exclusion criteria



Participants



443 +- 127



alcohol 2

autoimmune 1

PBC 2




PSC 1


hepatitis B 1



496 +- 109



alcohol 3

autoimmune 3

PBC 1

PSC 2

cryptogenic 2

hepatitis B 1




- Route orally



Placebo group











Risk of bias





probably adequate


All outcomes











tical analysisrdquo



Keiding 1997




Inclusion criteria



Exclusion criteria


Participants



4344 for adults












- Route orally



Placebo group












Adverse events


Risk of bias









All outcomes











was 80 patients



balance


size



Koneru 1993




Inclusion criteria


Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information


- Dose 900 mgday

- Route orally



Control group

- no treatment





Notes Abstract


Risk of bias









All outcomes



plicitly stated






Pageaux 1995




Inclusion criteria


Exclusion criteria

- not mentioned

Participants

- UDCA group (n=26)


47 +- 10





PBC 2

liver cancer 2


miscellaneous 1



51+- 9





PBC 3

liver cancer 4


miscellaneous 1






- Route orally



Placebo group







Risk of bias






All outcomes




were reported






Sama 1991




Inclusion criteria





Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information



- Route orally



Control group

- no treatment


and cyclosporine)



Notes Abstract


Risk of bias
















All outcomes




fully stated


adequately reported




ported













cyclosporine











(Continued)

















month


















studies

No of



follow-up



no treatment


12 TUDCA versus no

treatment




scenarios







start of bile acids



transplantation



transplantation





treatment duration






follow-up




maximum follow-up




follow-up



no treatment


72 TUDCA versus no

treatment





start of bile acid





transplantation








treatment duration






follow-up




maximum follow-up



end of treatment




transplantation




maximum follow-up







Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 116 108 935 080 [ 049 130 ]




01 02 05 1 2 5 10


(Continued )






Angelico 1999 316 217 65 159 [ 030 833 ]

Subtotal (95 CI) 16 17 65 159 [ 030 833 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




01 02 05 1 2 5 10










Angelico 1999 516 217 65 266 [ 060 1180 ]

Barnes 1997 828 724 253 098 [ 042 230 ]

Fleckenstein 1998 314 416 125 086 [ 023 319 ]

Keiding 1997 1954 1048 355 169 [ 087 327 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]





005 02 1 5 20


(Continued )





Angelico 1999 316 417 90 080 [ 021 302 ]

Barnes 1997 228 1124 274 016 [ 004 063 ]

Fleckenstein 1998 214 616 130 038 [ 009 159 ]

Keiding 1997 1454 1548 368 083 [ 045 154 ]

Sama 1991 520 620 139 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]




005 02 1 5 20










Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 54 48 355 124 [ 061 254 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Sama 1991 520 620 201 083 [ 030 229 ]

005 02 1 5 20


(Continued )





Subtotal (95 CI) 78 77 645 063 [ 033 120 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 96 88 734 078 [ 045 138 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 36 37 266 102 [ 043 240 ]



005 02 1 5 20


(Continued )






Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Keiding 1997 054 148 1000 030 [ 001 712 ]

Total (95 CI) 54 48 1000 030 [ 001 712 ]




0001 001 01 1 10 100 1000











Fleckenstein 1998 214 016 100 567 [ 029 10891 ]

Keiding 1997 154 448 900 022 [ 003 192 ]

Total (95 CI) 68 64 1000 076 [ 020 286 ]




0001 001 01 1 10 100 1000










Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 158 148 905 089 [ 074 108 ]

01 02 05 1 2 5 10


(Continued )









Angelico 1999 816 1017 95 085 [ 045 160 ]

Subtotal (95 CI) 16 17 95 085 [ 045 160 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10










Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Subtotal (95 CI) 70 64 422 084 [ 063 111 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

01 02 05 1 2 5 10


(Continued )





Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 104 101 578 092 [ 072 117 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10












Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Subtotal (95 CI) 138 128 777 087 [ 071 107 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 36 37 223 094 [ 065 136 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10











Barnes 1997 128 624 611 014 [ 002 110 ]

Fleckenstein 1998 114 116 88 114 [ 008 1663 ]

Keiding 1997 154 348 300 030 [ 003 275 ]

Total (95 CI) 96 88 1000 028 [ 008 095 ]




0001 001 01 1 10 100 1000









Barnes 1997 328 724 277 037 [ 011 127 ]

Fleckenstein 1998 314 316 103 114 [ 027 478 ]

Keiding 1997 1454 1548 583 083 [ 045 154 ]

Pageaux 1995 226 124 38 185 [ 018 1908 ]

Total (95 CI) 122 112 1000 077 [ 047 127 ]




001 01 1 10 100











Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]

Total (95 CI) 14 16 1000 260 [ -096 616 ]



-10 -5 0 5 10









Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]

Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]



-100 -50 0 50 100










Angelico 1999 016 017 00 [ 00 00 ]

Barnes 1997 128 124 086 [ 006 1298 ]

Keiding 1997 554 548 089 [ 027 288 ]

Total (95 CI) 98 89 088 [ 030 260 ]




001 01 1 10 100


A P P E N D I C E S






cholicrsquo




odeoxycholicrsquo



cholicrsquo


cholicrsquo


cholicrsquo



odeoxycholicrsquo



(Continued)


cholicrsquo


drocholicrsquo


rodeoxycholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


sodeoxycholicrsquo



cholicrsquo




ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


ME


3 BILE ACID ME

4





(Continued)













5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10



(Continued)


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2



(Continued)

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10




changed




H I S T O R Y








None known




Internal sources


External sources








I N D E X T E R M S




MeSH check words

Humans















112 (232) (RR 077 95 CI 047 to 127) (Analysis 111)


Liver biochemistry







Cost-effectiveness







Adverse events


















Quality of life














D I S C U S S I O N




















bias













































































adverse events































R E F E R E N C E S







10575563]















9649640]






[MEDLINE 9197351]









(2)119ndash22 [MEDLINE 7499781]







2)68







17589339]





199610(6 Pt 2)658ndash62 [MEDLINE 8996761]










19995(4)269ndash74 [MEDLINE 10388499]





(3)1971 [MEDLINE 2063453]





1973232]





[MEDLINE 8540069]





A1332


Adams 1990



[MEDLINE 2407770]

Al-Quaiz 1994




[MEDLINE 8060468]

Armstrong 1982





23(1)70ndash80 [MEDLINE 7057113]

Ascher 1988





[MEDLINE 3055368]

Brok 2008





Brok 2009






[MEDLINE 18824466]

Calmus 1990




199011(1)12ndash5 [MEDLINE 2403961]

Calmus 1992





Chen 2003a



10100214651858CD003626]

Chen 2007



14651858CD003181pub2]

Cheng 2002




Corbani 2008



[MEDLINE 18242500]

DeMets 1987



[MEDLINE 3616287]



DerSimonian 1986



Egger 1997



Ed) 1997315(7109)629ndash34 [MEDLINE 9310563]

Ericzon 1990




2227822]

FK506 1994




(17)1110ndash5 [MEDLINE 7523946]

Friman 1994




Fuchs 1999





Fusai 2006





Gluud 2001





Gluud 2010





Gong 2008




14651858CD000551pub2]

Haddad 2006




[DOI 10100214651858CD005161pub2]

Heuman 1993



Higgins 2008



2008

Hirschfield 2009




bmjb1670]

Hussain 2002



11933592]

ICH-GCP 1997




Ioannidis 2001




IWP 1995



Kjaergard 2001




[MEDLINE 11730399]

Klintmalm 1989



[MEDLINE 2583691]

Knechtle 2009



[MEDLINE 19235662]

Krams 1993




Lan 1983



Merion 1989





Moher 1998




(9128)609ndash13 [MEDLINE 9746022]



Neuberger 1999




Okolicsanyi 1986




Palmer 1972



Perez 2009



[MEDLINE 19360911]

Pogue 1997




[MEDLINE 9408720]

Pogue 1998




RevMan 2008




Royle 2003




19(4)591ndash603

Schulz 1995



Sharara 1995




Sholmerich 1984





Soderdahl 1998






Terasaki 1991





[MEDLINE 1882800]

Thalheimer 2002




Thorlund 2009





Thuluvath 2003




20039(5)527ndash32 [MEDLINE 12740799]

van den Berg 1998





[MEDLINE 9583867]

Vierling 1992



1570548]

Wetterslev 2008




[MEDLINE 18083463]

Wiesner 1992




1992102A910

Wood 2008





(7644)601ndash5 [MEDLINE 18316340]

Yoshikawa 1998










Chen 2003b








Angelico 1999




Inclusion criteria


Exclusion criteria

- not mentioned

Participants





467 +- 84







474 +- 74







- Route orally


one year

Control group

- no treatment







Risk of bias









All outcomes










tual data given





Barnes 1997




Inclusion criteria



Exclusion criteria


tree


Participants



505 +- 116


Child class A 7




B 13

and C 8


PBC 3





PSC 2

other 3



507 +- 93


Child class A 6

B 14

and C 4


PBC 5





PSC 2

other 4



- Route orally



Placebo group









Adverse events



Risk of bias










All outcomes















Fleckenstein 1998




Inclusion criteria


Exclusion criteria



Participants



443 +- 127



alcohol 2

autoimmune 1

PBC 2




PSC 1


hepatitis B 1



496 +- 109



alcohol 3

autoimmune 3

PBC 1

PSC 2

cryptogenic 2

hepatitis B 1




- Route orally



Placebo group











Risk of bias





probably adequate


All outcomes











tical analysisrdquo



Keiding 1997




Inclusion criteria



Exclusion criteria


Participants



4344 for adults












- Route orally



Placebo group












Adverse events


Risk of bias









All outcomes











was 80 patients



balance


size



Koneru 1993




Inclusion criteria


Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information


- Dose 900 mgday

- Route orally



Control group

- no treatment





Notes Abstract


Risk of bias









All outcomes



plicitly stated






Pageaux 1995




Inclusion criteria


Exclusion criteria

- not mentioned

Participants

- UDCA group (n=26)


47 +- 10





PBC 2

liver cancer 2


miscellaneous 1



51+- 9





PBC 3

liver cancer 4


miscellaneous 1






- Route orally



Placebo group







Risk of bias






All outcomes




were reported






Sama 1991




Inclusion criteria





Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information



- Route orally



Control group

- no treatment


and cyclosporine)



Notes Abstract


Risk of bias
















All outcomes




fully stated


adequately reported




ported













cyclosporine











(Continued)

















month


















studies

No of



follow-up



no treatment


12 TUDCA versus no

treatment




scenarios







start of bile acids



transplantation



transplantation





treatment duration






follow-up




maximum follow-up




follow-up



no treatment


72 TUDCA versus no

treatment





start of bile acid





transplantation








treatment duration






follow-up




maximum follow-up



end of treatment




transplantation




maximum follow-up







Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 116 108 935 080 [ 049 130 ]




01 02 05 1 2 5 10


(Continued )






Angelico 1999 316 217 65 159 [ 030 833 ]

Subtotal (95 CI) 16 17 65 159 [ 030 833 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




01 02 05 1 2 5 10










Angelico 1999 516 217 65 266 [ 060 1180 ]

Barnes 1997 828 724 253 098 [ 042 230 ]

Fleckenstein 1998 314 416 125 086 [ 023 319 ]

Keiding 1997 1954 1048 355 169 [ 087 327 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]





005 02 1 5 20


(Continued )





Angelico 1999 316 417 90 080 [ 021 302 ]

Barnes 1997 228 1124 274 016 [ 004 063 ]

Fleckenstein 1998 214 616 130 038 [ 009 159 ]

Keiding 1997 1454 1548 368 083 [ 045 154 ]

Sama 1991 520 620 139 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]




005 02 1 5 20










Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 54 48 355 124 [ 061 254 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Sama 1991 520 620 201 083 [ 030 229 ]

005 02 1 5 20


(Continued )





Subtotal (95 CI) 78 77 645 063 [ 033 120 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 96 88 734 078 [ 045 138 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 36 37 266 102 [ 043 240 ]



005 02 1 5 20


(Continued )






Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Keiding 1997 054 148 1000 030 [ 001 712 ]

Total (95 CI) 54 48 1000 030 [ 001 712 ]




0001 001 01 1 10 100 1000











Fleckenstein 1998 214 016 100 567 [ 029 10891 ]

Keiding 1997 154 448 900 022 [ 003 192 ]

Total (95 CI) 68 64 1000 076 [ 020 286 ]




0001 001 01 1 10 100 1000










Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 158 148 905 089 [ 074 108 ]

01 02 05 1 2 5 10


(Continued )









Angelico 1999 816 1017 95 085 [ 045 160 ]

Subtotal (95 CI) 16 17 95 085 [ 045 160 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10










Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Subtotal (95 CI) 70 64 422 084 [ 063 111 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

01 02 05 1 2 5 10


(Continued )





Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 104 101 578 092 [ 072 117 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10












Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Subtotal (95 CI) 138 128 777 087 [ 071 107 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 36 37 223 094 [ 065 136 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10











Barnes 1997 128 624 611 014 [ 002 110 ]

Fleckenstein 1998 114 116 88 114 [ 008 1663 ]

Keiding 1997 154 348 300 030 [ 003 275 ]

Total (95 CI) 96 88 1000 028 [ 008 095 ]




0001 001 01 1 10 100 1000









Barnes 1997 328 724 277 037 [ 011 127 ]

Fleckenstein 1998 314 316 103 114 [ 027 478 ]

Keiding 1997 1454 1548 583 083 [ 045 154 ]

Pageaux 1995 226 124 38 185 [ 018 1908 ]

Total (95 CI) 122 112 1000 077 [ 047 127 ]




001 01 1 10 100











Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]

Total (95 CI) 14 16 1000 260 [ -096 616 ]



-10 -5 0 5 10









Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]

Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]



-100 -50 0 50 100










Angelico 1999 016 017 00 [ 00 00 ]

Barnes 1997 128 124 086 [ 006 1298 ]

Keiding 1997 554 548 089 [ 027 288 ]

Total (95 CI) 98 89 088 [ 030 260 ]




001 01 1 10 100


A P P E N D I C E S






cholicrsquo




odeoxycholicrsquo



cholicrsquo


cholicrsquo


cholicrsquo



odeoxycholicrsquo



(Continued)


cholicrsquo


drocholicrsquo


rodeoxycholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


sodeoxycholicrsquo



cholicrsquo




ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


ME


3 BILE ACID ME

4





(Continued)













5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10



(Continued)


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2



(Continued)

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10




changed




H I S T O R Y








None known




Internal sources


External sources








I N D E X T E R M S




MeSH check words

Humans





Quality of life














D I S C U S S I O N




















bias













































































adverse events































R E F E R E N C E S







10575563]















9649640]






[MEDLINE 9197351]









(2)119ndash22 [MEDLINE 7499781]







2)68







17589339]





199610(6 Pt 2)658ndash62 [MEDLINE 8996761]










19995(4)269ndash74 [MEDLINE 10388499]





(3)1971 [MEDLINE 2063453]





1973232]





[MEDLINE 8540069]





A1332


Adams 1990



[MEDLINE 2407770]

Al-Quaiz 1994




[MEDLINE 8060468]

Armstrong 1982





23(1)70ndash80 [MEDLINE 7057113]

Ascher 1988





[MEDLINE 3055368]

Brok 2008





Brok 2009






[MEDLINE 18824466]

Calmus 1990




199011(1)12ndash5 [MEDLINE 2403961]

Calmus 1992





Chen 2003a



10100214651858CD003626]

Chen 2007



14651858CD003181pub2]

Cheng 2002




Corbani 2008



[MEDLINE 18242500]

DeMets 1987



[MEDLINE 3616287]



DerSimonian 1986



Egger 1997



Ed) 1997315(7109)629ndash34 [MEDLINE 9310563]

Ericzon 1990




2227822]

FK506 1994




(17)1110ndash5 [MEDLINE 7523946]

Friman 1994




Fuchs 1999





Fusai 2006





Gluud 2001





Gluud 2010





Gong 2008




14651858CD000551pub2]

Haddad 2006




[DOI 10100214651858CD005161pub2]

Heuman 1993



Higgins 2008



2008

Hirschfield 2009




bmjb1670]

Hussain 2002



11933592]

ICH-GCP 1997




Ioannidis 2001




IWP 1995



Kjaergard 2001




[MEDLINE 11730399]

Klintmalm 1989



[MEDLINE 2583691]

Knechtle 2009



[MEDLINE 19235662]

Krams 1993




Lan 1983



Merion 1989





Moher 1998




(9128)609ndash13 [MEDLINE 9746022]



Neuberger 1999




Okolicsanyi 1986




Palmer 1972



Perez 2009



[MEDLINE 19360911]

Pogue 1997




[MEDLINE 9408720]

Pogue 1998




RevMan 2008




Royle 2003




19(4)591ndash603

Schulz 1995



Sharara 1995




Sholmerich 1984





Soderdahl 1998






Terasaki 1991





[MEDLINE 1882800]

Thalheimer 2002




Thorlund 2009





Thuluvath 2003




20039(5)527ndash32 [MEDLINE 12740799]

van den Berg 1998





[MEDLINE 9583867]

Vierling 1992



1570548]

Wetterslev 2008




[MEDLINE 18083463]

Wiesner 1992




1992102A910

Wood 2008





(7644)601ndash5 [MEDLINE 18316340]

Yoshikawa 1998










Chen 2003b








Angelico 1999




Inclusion criteria


Exclusion criteria

- not mentioned

Participants





467 +- 84







474 +- 74







- Route orally


one year

Control group

- no treatment







Risk of bias









All outcomes










tual data given





Barnes 1997




Inclusion criteria



Exclusion criteria


tree


Participants



505 +- 116


Child class A 7




B 13

and C 8


PBC 3





PSC 2

other 3



507 +- 93


Child class A 6

B 14

and C 4


PBC 5





PSC 2

other 4



- Route orally



Placebo group









Adverse events



Risk of bias










All outcomes















Fleckenstein 1998




Inclusion criteria


Exclusion criteria



Participants



443 +- 127



alcohol 2

autoimmune 1

PBC 2




PSC 1


hepatitis B 1



496 +- 109



alcohol 3

autoimmune 3

PBC 1

PSC 2

cryptogenic 2

hepatitis B 1




- Route orally



Placebo group











Risk of bias





probably adequate


All outcomes











tical analysisrdquo



Keiding 1997




Inclusion criteria



Exclusion criteria


Participants



4344 for adults












- Route orally



Placebo group












Adverse events


Risk of bias









All outcomes











was 80 patients



balance


size



Koneru 1993




Inclusion criteria


Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information


- Dose 900 mgday

- Route orally



Control group

- no treatment





Notes Abstract


Risk of bias









All outcomes



plicitly stated






Pageaux 1995




Inclusion criteria


Exclusion criteria

- not mentioned

Participants

- UDCA group (n=26)


47 +- 10





PBC 2

liver cancer 2


miscellaneous 1



51+- 9





PBC 3

liver cancer 4


miscellaneous 1






- Route orally



Placebo group







Risk of bias






All outcomes




were reported






Sama 1991




Inclusion criteria





Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information



- Route orally



Control group

- no treatment


and cyclosporine)



Notes Abstract


Risk of bias
















All outcomes




fully stated


adequately reported




ported













cyclosporine











(Continued)

















month


















studies

No of



follow-up



no treatment


12 TUDCA versus no

treatment




scenarios







start of bile acids



transplantation



transplantation





treatment duration






follow-up




maximum follow-up




follow-up



no treatment


72 TUDCA versus no

treatment





start of bile acid





transplantation








treatment duration






follow-up




maximum follow-up



end of treatment




transplantation




maximum follow-up







Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 116 108 935 080 [ 049 130 ]




01 02 05 1 2 5 10


(Continued )






Angelico 1999 316 217 65 159 [ 030 833 ]

Subtotal (95 CI) 16 17 65 159 [ 030 833 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




01 02 05 1 2 5 10










Angelico 1999 516 217 65 266 [ 060 1180 ]

Barnes 1997 828 724 253 098 [ 042 230 ]

Fleckenstein 1998 314 416 125 086 [ 023 319 ]

Keiding 1997 1954 1048 355 169 [ 087 327 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]





005 02 1 5 20


(Continued )





Angelico 1999 316 417 90 080 [ 021 302 ]

Barnes 1997 228 1124 274 016 [ 004 063 ]

Fleckenstein 1998 214 616 130 038 [ 009 159 ]

Keiding 1997 1454 1548 368 083 [ 045 154 ]

Sama 1991 520 620 139 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]




005 02 1 5 20










Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 54 48 355 124 [ 061 254 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Sama 1991 520 620 201 083 [ 030 229 ]

005 02 1 5 20


(Continued )





Subtotal (95 CI) 78 77 645 063 [ 033 120 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 96 88 734 078 [ 045 138 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 36 37 266 102 [ 043 240 ]



005 02 1 5 20


(Continued )






Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Keiding 1997 054 148 1000 030 [ 001 712 ]

Total (95 CI) 54 48 1000 030 [ 001 712 ]




0001 001 01 1 10 100 1000











Fleckenstein 1998 214 016 100 567 [ 029 10891 ]

Keiding 1997 154 448 900 022 [ 003 192 ]

Total (95 CI) 68 64 1000 076 [ 020 286 ]




0001 001 01 1 10 100 1000










Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 158 148 905 089 [ 074 108 ]

01 02 05 1 2 5 10


(Continued )









Angelico 1999 816 1017 95 085 [ 045 160 ]

Subtotal (95 CI) 16 17 95 085 [ 045 160 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10










Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Subtotal (95 CI) 70 64 422 084 [ 063 111 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

01 02 05 1 2 5 10


(Continued )





Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 104 101 578 092 [ 072 117 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10












Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Subtotal (95 CI) 138 128 777 087 [ 071 107 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 36 37 223 094 [ 065 136 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10











Barnes 1997 128 624 611 014 [ 002 110 ]

Fleckenstein 1998 114 116 88 114 [ 008 1663 ]

Keiding 1997 154 348 300 030 [ 003 275 ]

Total (95 CI) 96 88 1000 028 [ 008 095 ]




0001 001 01 1 10 100 1000









Barnes 1997 328 724 277 037 [ 011 127 ]

Fleckenstein 1998 314 316 103 114 [ 027 478 ]

Keiding 1997 1454 1548 583 083 [ 045 154 ]

Pageaux 1995 226 124 38 185 [ 018 1908 ]

Total (95 CI) 122 112 1000 077 [ 047 127 ]




001 01 1 10 100











Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]

Total (95 CI) 14 16 1000 260 [ -096 616 ]



-10 -5 0 5 10









Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]

Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]



-100 -50 0 50 100










Angelico 1999 016 017 00 [ 00 00 ]

Barnes 1997 128 124 086 [ 006 1298 ]

Keiding 1997 554 548 089 [ 027 288 ]

Total (95 CI) 98 89 088 [ 030 260 ]




001 01 1 10 100


A P P E N D I C E S






cholicrsquo




odeoxycholicrsquo



cholicrsquo


cholicrsquo


cholicrsquo



odeoxycholicrsquo



(Continued)


cholicrsquo


drocholicrsquo


rodeoxycholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


sodeoxycholicrsquo



cholicrsquo




ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


ME


3 BILE ACID ME

4





(Continued)













5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10



(Continued)


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2



(Continued)

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10




changed




H I S T O R Y








None known




Internal sources


External sources








I N D E X T E R M S




MeSH check words

Humans















adverse events































R E F E R E N C E S







10575563]















9649640]






[MEDLINE 9197351]









(2)119ndash22 [MEDLINE 7499781]







2)68







17589339]





199610(6 Pt 2)658ndash62 [MEDLINE 8996761]










19995(4)269ndash74 [MEDLINE 10388499]





(3)1971 [MEDLINE 2063453]





1973232]





[MEDLINE 8540069]





A1332


Adams 1990



[MEDLINE 2407770]

Al-Quaiz 1994




[MEDLINE 8060468]

Armstrong 1982





23(1)70ndash80 [MEDLINE 7057113]

Ascher 1988





[MEDLINE 3055368]

Brok 2008





Brok 2009






[MEDLINE 18824466]

Calmus 1990




199011(1)12ndash5 [MEDLINE 2403961]

Calmus 1992





Chen 2003a



10100214651858CD003626]

Chen 2007



14651858CD003181pub2]

Cheng 2002




Corbani 2008



[MEDLINE 18242500]

DeMets 1987



[MEDLINE 3616287]



DerSimonian 1986



Egger 1997



Ed) 1997315(7109)629ndash34 [MEDLINE 9310563]

Ericzon 1990




2227822]

FK506 1994




(17)1110ndash5 [MEDLINE 7523946]

Friman 1994




Fuchs 1999





Fusai 2006





Gluud 2001





Gluud 2010





Gong 2008




14651858CD000551pub2]

Haddad 2006




[DOI 10100214651858CD005161pub2]

Heuman 1993



Higgins 2008



2008

Hirschfield 2009




bmjb1670]

Hussain 2002



11933592]

ICH-GCP 1997




Ioannidis 2001




IWP 1995



Kjaergard 2001




[MEDLINE 11730399]

Klintmalm 1989



[MEDLINE 2583691]

Knechtle 2009



[MEDLINE 19235662]

Krams 1993




Lan 1983



Merion 1989





Moher 1998




(9128)609ndash13 [MEDLINE 9746022]



Neuberger 1999




Okolicsanyi 1986




Palmer 1972



Perez 2009



[MEDLINE 19360911]

Pogue 1997




[MEDLINE 9408720]

Pogue 1998




RevMan 2008




Royle 2003




19(4)591ndash603

Schulz 1995



Sharara 1995




Sholmerich 1984





Soderdahl 1998






Terasaki 1991





[MEDLINE 1882800]

Thalheimer 2002




Thorlund 2009





Thuluvath 2003




20039(5)527ndash32 [MEDLINE 12740799]

van den Berg 1998





[MEDLINE 9583867]

Vierling 1992



1570548]

Wetterslev 2008




[MEDLINE 18083463]

Wiesner 1992




1992102A910

Wood 2008





(7644)601ndash5 [MEDLINE 18316340]

Yoshikawa 1998










Chen 2003b








Angelico 1999




Inclusion criteria


Exclusion criteria

- not mentioned

Participants





467 +- 84







474 +- 74







- Route orally


one year

Control group

- no treatment







Risk of bias









All outcomes










tual data given





Barnes 1997




Inclusion criteria



Exclusion criteria


tree


Participants



505 +- 116


Child class A 7




B 13

and C 8


PBC 3





PSC 2

other 3



507 +- 93


Child class A 6

B 14

and C 4


PBC 5





PSC 2

other 4



- Route orally



Placebo group









Adverse events



Risk of bias










All outcomes















Fleckenstein 1998




Inclusion criteria


Exclusion criteria



Participants



443 +- 127



alcohol 2

autoimmune 1

PBC 2




PSC 1


hepatitis B 1



496 +- 109



alcohol 3

autoimmune 3

PBC 1

PSC 2

cryptogenic 2

hepatitis B 1




- Route orally



Placebo group











Risk of bias





probably adequate


All outcomes











tical analysisrdquo



Keiding 1997




Inclusion criteria



Exclusion criteria


Participants



4344 for adults












- Route orally



Placebo group












Adverse events


Risk of bias









All outcomes











was 80 patients



balance


size



Koneru 1993




Inclusion criteria


Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information


- Dose 900 mgday

- Route orally



Control group

- no treatment





Notes Abstract


Risk of bias









All outcomes



plicitly stated






Pageaux 1995




Inclusion criteria


Exclusion criteria

- not mentioned

Participants

- UDCA group (n=26)


47 +- 10





PBC 2

liver cancer 2


miscellaneous 1



51+- 9





PBC 3

liver cancer 4


miscellaneous 1






- Route orally



Placebo group







Risk of bias






All outcomes




were reported






Sama 1991




Inclusion criteria





Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information



- Route orally



Control group

- no treatment


and cyclosporine)



Notes Abstract


Risk of bias
















All outcomes




fully stated


adequately reported




ported













cyclosporine











(Continued)

















month


















studies

No of



follow-up



no treatment


12 TUDCA versus no

treatment




scenarios







start of bile acids



transplantation



transplantation





treatment duration






follow-up




maximum follow-up




follow-up



no treatment


72 TUDCA versus no

treatment





start of bile acid





transplantation








treatment duration






follow-up




maximum follow-up



end of treatment




transplantation




maximum follow-up







Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 116 108 935 080 [ 049 130 ]




01 02 05 1 2 5 10


(Continued )






Angelico 1999 316 217 65 159 [ 030 833 ]

Subtotal (95 CI) 16 17 65 159 [ 030 833 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




01 02 05 1 2 5 10










Angelico 1999 516 217 65 266 [ 060 1180 ]

Barnes 1997 828 724 253 098 [ 042 230 ]

Fleckenstein 1998 314 416 125 086 [ 023 319 ]

Keiding 1997 1954 1048 355 169 [ 087 327 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]





005 02 1 5 20


(Continued )





Angelico 1999 316 417 90 080 [ 021 302 ]

Barnes 1997 228 1124 274 016 [ 004 063 ]

Fleckenstein 1998 214 616 130 038 [ 009 159 ]

Keiding 1997 1454 1548 368 083 [ 045 154 ]

Sama 1991 520 620 139 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]




005 02 1 5 20










Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 54 48 355 124 [ 061 254 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Sama 1991 520 620 201 083 [ 030 229 ]

005 02 1 5 20


(Continued )





Subtotal (95 CI) 78 77 645 063 [ 033 120 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 96 88 734 078 [ 045 138 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 36 37 266 102 [ 043 240 ]



005 02 1 5 20


(Continued )






Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Keiding 1997 054 148 1000 030 [ 001 712 ]

Total (95 CI) 54 48 1000 030 [ 001 712 ]




0001 001 01 1 10 100 1000











Fleckenstein 1998 214 016 100 567 [ 029 10891 ]

Keiding 1997 154 448 900 022 [ 003 192 ]

Total (95 CI) 68 64 1000 076 [ 020 286 ]




0001 001 01 1 10 100 1000










Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 158 148 905 089 [ 074 108 ]

01 02 05 1 2 5 10


(Continued )









Angelico 1999 816 1017 95 085 [ 045 160 ]

Subtotal (95 CI) 16 17 95 085 [ 045 160 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10










Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Subtotal (95 CI) 70 64 422 084 [ 063 111 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

01 02 05 1 2 5 10


(Continued )





Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 104 101 578 092 [ 072 117 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10












Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Subtotal (95 CI) 138 128 777 087 [ 071 107 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 36 37 223 094 [ 065 136 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10











Barnes 1997 128 624 611 014 [ 002 110 ]

Fleckenstein 1998 114 116 88 114 [ 008 1663 ]

Keiding 1997 154 348 300 030 [ 003 275 ]

Total (95 CI) 96 88 1000 028 [ 008 095 ]




0001 001 01 1 10 100 1000









Barnes 1997 328 724 277 037 [ 011 127 ]

Fleckenstein 1998 314 316 103 114 [ 027 478 ]

Keiding 1997 1454 1548 583 083 [ 045 154 ]

Pageaux 1995 226 124 38 185 [ 018 1908 ]

Total (95 CI) 122 112 1000 077 [ 047 127 ]




001 01 1 10 100











Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]

Total (95 CI) 14 16 1000 260 [ -096 616 ]



-10 -5 0 5 10









Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]

Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]



-100 -50 0 50 100










Angelico 1999 016 017 00 [ 00 00 ]

Barnes 1997 128 124 086 [ 006 1298 ]

Keiding 1997 554 548 089 [ 027 288 ]

Total (95 CI) 98 89 088 [ 030 260 ]




001 01 1 10 100


A P P E N D I C E S






cholicrsquo




odeoxycholicrsquo



cholicrsquo


cholicrsquo


cholicrsquo



odeoxycholicrsquo



(Continued)


cholicrsquo


drocholicrsquo


rodeoxycholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


sodeoxycholicrsquo



cholicrsquo




ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


ME


3 BILE ACID ME

4





(Continued)













5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10



(Continued)


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2



(Continued)

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10




changed




H I S T O R Y








None known




Internal sources


External sources








I N D E X T E R M S




MeSH check words

Humans




2)68







17589339]





199610(6 Pt 2)658ndash62 [MEDLINE 8996761]










19995(4)269ndash74 [MEDLINE 10388499]





(3)1971 [MEDLINE 2063453]





1973232]





[MEDLINE 8540069]





A1332


Adams 1990



[MEDLINE 2407770]

Al-Quaiz 1994




[MEDLINE 8060468]

Armstrong 1982





23(1)70ndash80 [MEDLINE 7057113]

Ascher 1988





[MEDLINE 3055368]

Brok 2008





Brok 2009






[MEDLINE 18824466]

Calmus 1990




199011(1)12ndash5 [MEDLINE 2403961]

Calmus 1992





Chen 2003a



10100214651858CD003626]

Chen 2007



14651858CD003181pub2]

Cheng 2002




Corbani 2008



[MEDLINE 18242500]

DeMets 1987



[MEDLINE 3616287]



DerSimonian 1986



Egger 1997



Ed) 1997315(7109)629ndash34 [MEDLINE 9310563]

Ericzon 1990




2227822]

FK506 1994




(17)1110ndash5 [MEDLINE 7523946]

Friman 1994




Fuchs 1999





Fusai 2006





Gluud 2001





Gluud 2010





Gong 2008




14651858CD000551pub2]

Haddad 2006




[DOI 10100214651858CD005161pub2]

Heuman 1993



Higgins 2008



2008

Hirschfield 2009




bmjb1670]

Hussain 2002



11933592]

ICH-GCP 1997




Ioannidis 2001




IWP 1995



Kjaergard 2001




[MEDLINE 11730399]

Klintmalm 1989



[MEDLINE 2583691]

Knechtle 2009



[MEDLINE 19235662]

Krams 1993




Lan 1983



Merion 1989





Moher 1998




(9128)609ndash13 [MEDLINE 9746022]



Neuberger 1999




Okolicsanyi 1986




Palmer 1972



Perez 2009



[MEDLINE 19360911]

Pogue 1997




[MEDLINE 9408720]

Pogue 1998




RevMan 2008




Royle 2003




19(4)591ndash603

Schulz 1995



Sharara 1995




Sholmerich 1984





Soderdahl 1998






Terasaki 1991





[MEDLINE 1882800]

Thalheimer 2002




Thorlund 2009





Thuluvath 2003




20039(5)527ndash32 [MEDLINE 12740799]

van den Berg 1998





[MEDLINE 9583867]

Vierling 1992



1570548]

Wetterslev 2008




[MEDLINE 18083463]

Wiesner 1992




1992102A910

Wood 2008





(7644)601ndash5 [MEDLINE 18316340]

Yoshikawa 1998










Chen 2003b








Angelico 1999




Inclusion criteria


Exclusion criteria

- not mentioned

Participants





467 +- 84







474 +- 74







- Route orally


one year

Control group

- no treatment







Risk of bias









All outcomes










tual data given





Barnes 1997




Inclusion criteria



Exclusion criteria


tree


Participants



505 +- 116


Child class A 7




B 13

and C 8


PBC 3





PSC 2

other 3



507 +- 93


Child class A 6

B 14

and C 4


PBC 5





PSC 2

other 4



- Route orally



Placebo group









Adverse events



Risk of bias










All outcomes















Fleckenstein 1998




Inclusion criteria


Exclusion criteria



Participants



443 +- 127



alcohol 2

autoimmune 1

PBC 2




PSC 1


hepatitis B 1



496 +- 109



alcohol 3

autoimmune 3

PBC 1

PSC 2

cryptogenic 2

hepatitis B 1




- Route orally



Placebo group











Risk of bias





probably adequate


All outcomes











tical analysisrdquo



Keiding 1997




Inclusion criteria



Exclusion criteria


Participants



4344 for adults












- Route orally



Placebo group












Adverse events


Risk of bias









All outcomes











was 80 patients



balance


size



Koneru 1993




Inclusion criteria


Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information


- Dose 900 mgday

- Route orally



Control group

- no treatment





Notes Abstract


Risk of bias









All outcomes



plicitly stated






Pageaux 1995




Inclusion criteria


Exclusion criteria

- not mentioned

Participants

- UDCA group (n=26)


47 +- 10





PBC 2

liver cancer 2


miscellaneous 1



51+- 9





PBC 3

liver cancer 4


miscellaneous 1






- Route orally



Placebo group







Risk of bias






All outcomes




were reported






Sama 1991




Inclusion criteria





Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information



- Route orally



Control group

- no treatment


and cyclosporine)



Notes Abstract


Risk of bias
















All outcomes




fully stated


adequately reported




ported













cyclosporine











(Continued)

















month


















studies

No of



follow-up



no treatment


12 TUDCA versus no

treatment




scenarios







start of bile acids



transplantation



transplantation





treatment duration






follow-up




maximum follow-up




follow-up



no treatment


72 TUDCA versus no

treatment





start of bile acid





transplantation








treatment duration






follow-up




maximum follow-up



end of treatment




transplantation




maximum follow-up







Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 116 108 935 080 [ 049 130 ]




01 02 05 1 2 5 10


(Continued )






Angelico 1999 316 217 65 159 [ 030 833 ]

Subtotal (95 CI) 16 17 65 159 [ 030 833 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




01 02 05 1 2 5 10










Angelico 1999 516 217 65 266 [ 060 1180 ]

Barnes 1997 828 724 253 098 [ 042 230 ]

Fleckenstein 1998 314 416 125 086 [ 023 319 ]

Keiding 1997 1954 1048 355 169 [ 087 327 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]





005 02 1 5 20


(Continued )





Angelico 1999 316 417 90 080 [ 021 302 ]

Barnes 1997 228 1124 274 016 [ 004 063 ]

Fleckenstein 1998 214 616 130 038 [ 009 159 ]

Keiding 1997 1454 1548 368 083 [ 045 154 ]

Sama 1991 520 620 139 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]




005 02 1 5 20










Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 54 48 355 124 [ 061 254 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Sama 1991 520 620 201 083 [ 030 229 ]

005 02 1 5 20


(Continued )





Subtotal (95 CI) 78 77 645 063 [ 033 120 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 96 88 734 078 [ 045 138 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 36 37 266 102 [ 043 240 ]



005 02 1 5 20


(Continued )






Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Keiding 1997 054 148 1000 030 [ 001 712 ]

Total (95 CI) 54 48 1000 030 [ 001 712 ]




0001 001 01 1 10 100 1000











Fleckenstein 1998 214 016 100 567 [ 029 10891 ]

Keiding 1997 154 448 900 022 [ 003 192 ]

Total (95 CI) 68 64 1000 076 [ 020 286 ]




0001 001 01 1 10 100 1000










Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 158 148 905 089 [ 074 108 ]

01 02 05 1 2 5 10


(Continued )









Angelico 1999 816 1017 95 085 [ 045 160 ]

Subtotal (95 CI) 16 17 95 085 [ 045 160 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10










Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Subtotal (95 CI) 70 64 422 084 [ 063 111 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

01 02 05 1 2 5 10


(Continued )





Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 104 101 578 092 [ 072 117 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10












Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Subtotal (95 CI) 138 128 777 087 [ 071 107 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 36 37 223 094 [ 065 136 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10











Barnes 1997 128 624 611 014 [ 002 110 ]

Fleckenstein 1998 114 116 88 114 [ 008 1663 ]

Keiding 1997 154 348 300 030 [ 003 275 ]

Total (95 CI) 96 88 1000 028 [ 008 095 ]




0001 001 01 1 10 100 1000









Barnes 1997 328 724 277 037 [ 011 127 ]

Fleckenstein 1998 314 316 103 114 [ 027 478 ]

Keiding 1997 1454 1548 583 083 [ 045 154 ]

Pageaux 1995 226 124 38 185 [ 018 1908 ]

Total (95 CI) 122 112 1000 077 [ 047 127 ]




001 01 1 10 100











Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]

Total (95 CI) 14 16 1000 260 [ -096 616 ]



-10 -5 0 5 10









Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]

Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]



-100 -50 0 50 100










Angelico 1999 016 017 00 [ 00 00 ]

Barnes 1997 128 124 086 [ 006 1298 ]

Keiding 1997 554 548 089 [ 027 288 ]

Total (95 CI) 98 89 088 [ 030 260 ]




001 01 1 10 100


A P P E N D I C E S






cholicrsquo




odeoxycholicrsquo



cholicrsquo


cholicrsquo


cholicrsquo



odeoxycholicrsquo



(Continued)


cholicrsquo


drocholicrsquo


rodeoxycholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


sodeoxycholicrsquo



cholicrsquo




ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


ME


3 BILE ACID ME

4





(Continued)













5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10



(Continued)


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2



(Continued)

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10




changed




H I S T O R Y








None known




Internal sources


External sources








I N D E X T E R M S




MeSH check words

Humans



DerSimonian 1986



Egger 1997



Ed) 1997315(7109)629ndash34 [MEDLINE 9310563]

Ericzon 1990




2227822]

FK506 1994




(17)1110ndash5 [MEDLINE 7523946]

Friman 1994




Fuchs 1999





Fusai 2006





Gluud 2001





Gluud 2010





Gong 2008




14651858CD000551pub2]

Haddad 2006




[DOI 10100214651858CD005161pub2]

Heuman 1993



Higgins 2008



2008

Hirschfield 2009




bmjb1670]

Hussain 2002



11933592]

ICH-GCP 1997




Ioannidis 2001




IWP 1995



Kjaergard 2001




[MEDLINE 11730399]

Klintmalm 1989



[MEDLINE 2583691]

Knechtle 2009



[MEDLINE 19235662]

Krams 1993




Lan 1983



Merion 1989





Moher 1998




(9128)609ndash13 [MEDLINE 9746022]



Neuberger 1999




Okolicsanyi 1986




Palmer 1972



Perez 2009



[MEDLINE 19360911]

Pogue 1997




[MEDLINE 9408720]

Pogue 1998




RevMan 2008




Royle 2003




19(4)591ndash603

Schulz 1995



Sharara 1995




Sholmerich 1984





Soderdahl 1998






Terasaki 1991





[MEDLINE 1882800]

Thalheimer 2002




Thorlund 2009





Thuluvath 2003




20039(5)527ndash32 [MEDLINE 12740799]

van den Berg 1998





[MEDLINE 9583867]

Vierling 1992



1570548]

Wetterslev 2008




[MEDLINE 18083463]

Wiesner 1992




1992102A910

Wood 2008





(7644)601ndash5 [MEDLINE 18316340]

Yoshikawa 1998










Chen 2003b








Angelico 1999




Inclusion criteria


Exclusion criteria

- not mentioned

Participants





467 +- 84







474 +- 74







- Route orally


one year

Control group

- no treatment







Risk of bias









All outcomes










tual data given





Barnes 1997




Inclusion criteria



Exclusion criteria


tree


Participants



505 +- 116


Child class A 7




B 13

and C 8


PBC 3





PSC 2

other 3



507 +- 93


Child class A 6

B 14

and C 4


PBC 5





PSC 2

other 4



- Route orally



Placebo group









Adverse events



Risk of bias










All outcomes















Fleckenstein 1998




Inclusion criteria


Exclusion criteria



Participants



443 +- 127



alcohol 2

autoimmune 1

PBC 2




PSC 1


hepatitis B 1



496 +- 109



alcohol 3

autoimmune 3

PBC 1

PSC 2

cryptogenic 2

hepatitis B 1




- Route orally



Placebo group











Risk of bias





probably adequate


All outcomes











tical analysisrdquo



Keiding 1997




Inclusion criteria



Exclusion criteria


Participants



4344 for adults












- Route orally



Placebo group












Adverse events


Risk of bias









All outcomes











was 80 patients



balance


size



Koneru 1993




Inclusion criteria


Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information


- Dose 900 mgday

- Route orally



Control group

- no treatment





Notes Abstract


Risk of bias









All outcomes



plicitly stated






Pageaux 1995




Inclusion criteria


Exclusion criteria

- not mentioned

Participants

- UDCA group (n=26)


47 +- 10





PBC 2

liver cancer 2


miscellaneous 1



51+- 9





PBC 3

liver cancer 4


miscellaneous 1






- Route orally



Placebo group







Risk of bias






All outcomes




were reported






Sama 1991




Inclusion criteria





Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information



- Route orally



Control group

- no treatment


and cyclosporine)



Notes Abstract


Risk of bias
















All outcomes




fully stated


adequately reported




ported













cyclosporine











(Continued)

















month


















studies

No of



follow-up



no treatment


12 TUDCA versus no

treatment




scenarios







start of bile acids



transplantation



transplantation





treatment duration






follow-up




maximum follow-up




follow-up



no treatment


72 TUDCA versus no

treatment





start of bile acid





transplantation








treatment duration






follow-up




maximum follow-up



end of treatment




transplantation




maximum follow-up







Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 116 108 935 080 [ 049 130 ]




01 02 05 1 2 5 10


(Continued )






Angelico 1999 316 217 65 159 [ 030 833 ]

Subtotal (95 CI) 16 17 65 159 [ 030 833 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




01 02 05 1 2 5 10










Angelico 1999 516 217 65 266 [ 060 1180 ]

Barnes 1997 828 724 253 098 [ 042 230 ]

Fleckenstein 1998 314 416 125 086 [ 023 319 ]

Keiding 1997 1954 1048 355 169 [ 087 327 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]





005 02 1 5 20


(Continued )





Angelico 1999 316 417 90 080 [ 021 302 ]

Barnes 1997 228 1124 274 016 [ 004 063 ]

Fleckenstein 1998 214 616 130 038 [ 009 159 ]

Keiding 1997 1454 1548 368 083 [ 045 154 ]

Sama 1991 520 620 139 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]




005 02 1 5 20










Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 54 48 355 124 [ 061 254 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Sama 1991 520 620 201 083 [ 030 229 ]

005 02 1 5 20


(Continued )





Subtotal (95 CI) 78 77 645 063 [ 033 120 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 96 88 734 078 [ 045 138 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 36 37 266 102 [ 043 240 ]



005 02 1 5 20


(Continued )






Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Keiding 1997 054 148 1000 030 [ 001 712 ]

Total (95 CI) 54 48 1000 030 [ 001 712 ]




0001 001 01 1 10 100 1000











Fleckenstein 1998 214 016 100 567 [ 029 10891 ]

Keiding 1997 154 448 900 022 [ 003 192 ]

Total (95 CI) 68 64 1000 076 [ 020 286 ]




0001 001 01 1 10 100 1000










Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 158 148 905 089 [ 074 108 ]

01 02 05 1 2 5 10


(Continued )









Angelico 1999 816 1017 95 085 [ 045 160 ]

Subtotal (95 CI) 16 17 95 085 [ 045 160 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10










Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Subtotal (95 CI) 70 64 422 084 [ 063 111 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

01 02 05 1 2 5 10


(Continued )





Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 104 101 578 092 [ 072 117 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10












Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Subtotal (95 CI) 138 128 777 087 [ 071 107 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 36 37 223 094 [ 065 136 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10











Barnes 1997 128 624 611 014 [ 002 110 ]

Fleckenstein 1998 114 116 88 114 [ 008 1663 ]

Keiding 1997 154 348 300 030 [ 003 275 ]

Total (95 CI) 96 88 1000 028 [ 008 095 ]




0001 001 01 1 10 100 1000









Barnes 1997 328 724 277 037 [ 011 127 ]

Fleckenstein 1998 314 316 103 114 [ 027 478 ]

Keiding 1997 1454 1548 583 083 [ 045 154 ]

Pageaux 1995 226 124 38 185 [ 018 1908 ]

Total (95 CI) 122 112 1000 077 [ 047 127 ]




001 01 1 10 100











Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]

Total (95 CI) 14 16 1000 260 [ -096 616 ]



-10 -5 0 5 10









Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]

Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]



-100 -50 0 50 100










Angelico 1999 016 017 00 [ 00 00 ]

Barnes 1997 128 124 086 [ 006 1298 ]

Keiding 1997 554 548 089 [ 027 288 ]

Total (95 CI) 98 89 088 [ 030 260 ]




001 01 1 10 100


A P P E N D I C E S






cholicrsquo




odeoxycholicrsquo



cholicrsquo


cholicrsquo


cholicrsquo



odeoxycholicrsquo



(Continued)


cholicrsquo


drocholicrsquo


rodeoxycholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


sodeoxycholicrsquo



cholicrsquo




ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


ME


3 BILE ACID ME

4





(Continued)













5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10



(Continued)


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2



(Continued)

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10




changed




H I S T O R Y








None known




Internal sources


External sources








I N D E X T E R M S




MeSH check words

Humans



Neuberger 1999




Okolicsanyi 1986




Palmer 1972



Perez 2009



[MEDLINE 19360911]

Pogue 1997




[MEDLINE 9408720]

Pogue 1998




RevMan 2008




Royle 2003




19(4)591ndash603

Schulz 1995



Sharara 1995




Sholmerich 1984





Soderdahl 1998






Terasaki 1991





[MEDLINE 1882800]

Thalheimer 2002




Thorlund 2009





Thuluvath 2003




20039(5)527ndash32 [MEDLINE 12740799]

van den Berg 1998





[MEDLINE 9583867]

Vierling 1992



1570548]

Wetterslev 2008




[MEDLINE 18083463]

Wiesner 1992




1992102A910

Wood 2008





(7644)601ndash5 [MEDLINE 18316340]

Yoshikawa 1998










Chen 2003b








Angelico 1999




Inclusion criteria


Exclusion criteria

- not mentioned

Participants





467 +- 84







474 +- 74







- Route orally


one year

Control group

- no treatment







Risk of bias









All outcomes










tual data given





Barnes 1997




Inclusion criteria



Exclusion criteria


tree


Participants



505 +- 116


Child class A 7




B 13

and C 8


PBC 3





PSC 2

other 3



507 +- 93


Child class A 6

B 14

and C 4


PBC 5





PSC 2

other 4



- Route orally



Placebo group









Adverse events



Risk of bias










All outcomes















Fleckenstein 1998




Inclusion criteria


Exclusion criteria



Participants



443 +- 127



alcohol 2

autoimmune 1

PBC 2




PSC 1


hepatitis B 1



496 +- 109



alcohol 3

autoimmune 3

PBC 1

PSC 2

cryptogenic 2

hepatitis B 1




- Route orally



Placebo group











Risk of bias





probably adequate


All outcomes











tical analysisrdquo



Keiding 1997




Inclusion criteria



Exclusion criteria


Participants



4344 for adults












- Route orally



Placebo group












Adverse events


Risk of bias









All outcomes











was 80 patients



balance


size



Koneru 1993




Inclusion criteria


Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information


- Dose 900 mgday

- Route orally



Control group

- no treatment





Notes Abstract


Risk of bias









All outcomes



plicitly stated






Pageaux 1995




Inclusion criteria


Exclusion criteria

- not mentioned

Participants

- UDCA group (n=26)


47 +- 10





PBC 2

liver cancer 2


miscellaneous 1



51+- 9





PBC 3

liver cancer 4


miscellaneous 1






- Route orally



Placebo group







Risk of bias






All outcomes




were reported






Sama 1991




Inclusion criteria





Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information



- Route orally



Control group

- no treatment


and cyclosporine)



Notes Abstract


Risk of bias
















All outcomes




fully stated


adequately reported




ported













cyclosporine











(Continued)

















month


















studies

No of



follow-up



no treatment


12 TUDCA versus no

treatment




scenarios







start of bile acids



transplantation



transplantation





treatment duration






follow-up




maximum follow-up




follow-up



no treatment


72 TUDCA versus no

treatment





start of bile acid





transplantation








treatment duration






follow-up




maximum follow-up



end of treatment




transplantation




maximum follow-up







Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 116 108 935 080 [ 049 130 ]




01 02 05 1 2 5 10


(Continued )






Angelico 1999 316 217 65 159 [ 030 833 ]

Subtotal (95 CI) 16 17 65 159 [ 030 833 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




01 02 05 1 2 5 10










Angelico 1999 516 217 65 266 [ 060 1180 ]

Barnes 1997 828 724 253 098 [ 042 230 ]

Fleckenstein 1998 314 416 125 086 [ 023 319 ]

Keiding 1997 1954 1048 355 169 [ 087 327 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]





005 02 1 5 20


(Continued )





Angelico 1999 316 417 90 080 [ 021 302 ]

Barnes 1997 228 1124 274 016 [ 004 063 ]

Fleckenstein 1998 214 616 130 038 [ 009 159 ]

Keiding 1997 1454 1548 368 083 [ 045 154 ]

Sama 1991 520 620 139 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]




005 02 1 5 20










Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 54 48 355 124 [ 061 254 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Sama 1991 520 620 201 083 [ 030 229 ]

005 02 1 5 20


(Continued )





Subtotal (95 CI) 78 77 645 063 [ 033 120 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 96 88 734 078 [ 045 138 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 36 37 266 102 [ 043 240 ]



005 02 1 5 20


(Continued )






Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Keiding 1997 054 148 1000 030 [ 001 712 ]

Total (95 CI) 54 48 1000 030 [ 001 712 ]




0001 001 01 1 10 100 1000











Fleckenstein 1998 214 016 100 567 [ 029 10891 ]

Keiding 1997 154 448 900 022 [ 003 192 ]

Total (95 CI) 68 64 1000 076 [ 020 286 ]




0001 001 01 1 10 100 1000










Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 158 148 905 089 [ 074 108 ]

01 02 05 1 2 5 10


(Continued )









Angelico 1999 816 1017 95 085 [ 045 160 ]

Subtotal (95 CI) 16 17 95 085 [ 045 160 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10










Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Subtotal (95 CI) 70 64 422 084 [ 063 111 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

01 02 05 1 2 5 10


(Continued )





Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 104 101 578 092 [ 072 117 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10












Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Subtotal (95 CI) 138 128 777 087 [ 071 107 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 36 37 223 094 [ 065 136 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10











Barnes 1997 128 624 611 014 [ 002 110 ]

Fleckenstein 1998 114 116 88 114 [ 008 1663 ]

Keiding 1997 154 348 300 030 [ 003 275 ]

Total (95 CI) 96 88 1000 028 [ 008 095 ]




0001 001 01 1 10 100 1000









Barnes 1997 328 724 277 037 [ 011 127 ]

Fleckenstein 1998 314 316 103 114 [ 027 478 ]

Keiding 1997 1454 1548 583 083 [ 045 154 ]

Pageaux 1995 226 124 38 185 [ 018 1908 ]

Total (95 CI) 122 112 1000 077 [ 047 127 ]




001 01 1 10 100











Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]

Total (95 CI) 14 16 1000 260 [ -096 616 ]



-10 -5 0 5 10









Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]

Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]



-100 -50 0 50 100










Angelico 1999 016 017 00 [ 00 00 ]

Barnes 1997 128 124 086 [ 006 1298 ]

Keiding 1997 554 548 089 [ 027 288 ]

Total (95 CI) 98 89 088 [ 030 260 ]




001 01 1 10 100


A P P E N D I C E S






cholicrsquo




odeoxycholicrsquo



cholicrsquo


cholicrsquo


cholicrsquo



odeoxycholicrsquo



(Continued)


cholicrsquo


drocholicrsquo


rodeoxycholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


sodeoxycholicrsquo



cholicrsquo




ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


ME


3 BILE ACID ME

4





(Continued)













5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10



(Continued)


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2



(Continued)

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10




changed




H I S T O R Y








None known




Internal sources


External sources








I N D E X T E R M S




MeSH check words

Humans



Chen 2003b








Angelico 1999




Inclusion criteria


Exclusion criteria

- not mentioned

Participants





467 +- 84







474 +- 74







- Route orally


one year

Control group

- no treatment







Risk of bias









All outcomes










tual data given





Barnes 1997




Inclusion criteria



Exclusion criteria


tree


Participants



505 +- 116


Child class A 7




B 13

and C 8


PBC 3





PSC 2

other 3



507 +- 93


Child class A 6

B 14

and C 4


PBC 5





PSC 2

other 4



- Route orally



Placebo group









Adverse events



Risk of bias










All outcomes















Fleckenstein 1998




Inclusion criteria


Exclusion criteria



Participants



443 +- 127



alcohol 2

autoimmune 1

PBC 2




PSC 1


hepatitis B 1



496 +- 109



alcohol 3

autoimmune 3

PBC 1

PSC 2

cryptogenic 2

hepatitis B 1




- Route orally



Placebo group











Risk of bias





probably adequate


All outcomes











tical analysisrdquo



Keiding 1997




Inclusion criteria



Exclusion criteria


Participants



4344 for adults












- Route orally



Placebo group












Adverse events


Risk of bias









All outcomes











was 80 patients



balance


size



Koneru 1993




Inclusion criteria


Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information


- Dose 900 mgday

- Route orally



Control group

- no treatment





Notes Abstract


Risk of bias









All outcomes



plicitly stated






Pageaux 1995




Inclusion criteria


Exclusion criteria

- not mentioned

Participants

- UDCA group (n=26)


47 +- 10





PBC 2

liver cancer 2


miscellaneous 1



51+- 9





PBC 3

liver cancer 4


miscellaneous 1






- Route orally



Placebo group







Risk of bias






All outcomes




were reported






Sama 1991




Inclusion criteria





Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information



- Route orally



Control group

- no treatment


and cyclosporine)



Notes Abstract


Risk of bias
















All outcomes




fully stated


adequately reported




ported













cyclosporine











(Continued)

















month


















studies

No of



follow-up



no treatment


12 TUDCA versus no

treatment




scenarios







start of bile acids



transplantation



transplantation





treatment duration






follow-up




maximum follow-up




follow-up



no treatment


72 TUDCA versus no

treatment





start of bile acid





transplantation








treatment duration






follow-up




maximum follow-up



end of treatment




transplantation




maximum follow-up







Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 116 108 935 080 [ 049 130 ]




01 02 05 1 2 5 10


(Continued )






Angelico 1999 316 217 65 159 [ 030 833 ]

Subtotal (95 CI) 16 17 65 159 [ 030 833 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




01 02 05 1 2 5 10










Angelico 1999 516 217 65 266 [ 060 1180 ]

Barnes 1997 828 724 253 098 [ 042 230 ]

Fleckenstein 1998 314 416 125 086 [ 023 319 ]

Keiding 1997 1954 1048 355 169 [ 087 327 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]





005 02 1 5 20


(Continued )





Angelico 1999 316 417 90 080 [ 021 302 ]

Barnes 1997 228 1124 274 016 [ 004 063 ]

Fleckenstein 1998 214 616 130 038 [ 009 159 ]

Keiding 1997 1454 1548 368 083 [ 045 154 ]

Sama 1991 520 620 139 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]




005 02 1 5 20










Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 54 48 355 124 [ 061 254 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Sama 1991 520 620 201 083 [ 030 229 ]

005 02 1 5 20


(Continued )





Subtotal (95 CI) 78 77 645 063 [ 033 120 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 96 88 734 078 [ 045 138 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 36 37 266 102 [ 043 240 ]



005 02 1 5 20


(Continued )






Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Keiding 1997 054 148 1000 030 [ 001 712 ]

Total (95 CI) 54 48 1000 030 [ 001 712 ]




0001 001 01 1 10 100 1000











Fleckenstein 1998 214 016 100 567 [ 029 10891 ]

Keiding 1997 154 448 900 022 [ 003 192 ]

Total (95 CI) 68 64 1000 076 [ 020 286 ]




0001 001 01 1 10 100 1000










Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 158 148 905 089 [ 074 108 ]

01 02 05 1 2 5 10


(Continued )









Angelico 1999 816 1017 95 085 [ 045 160 ]

Subtotal (95 CI) 16 17 95 085 [ 045 160 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10










Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Subtotal (95 CI) 70 64 422 084 [ 063 111 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

01 02 05 1 2 5 10


(Continued )





Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 104 101 578 092 [ 072 117 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10












Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Subtotal (95 CI) 138 128 777 087 [ 071 107 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 36 37 223 094 [ 065 136 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10











Barnes 1997 128 624 611 014 [ 002 110 ]

Fleckenstein 1998 114 116 88 114 [ 008 1663 ]

Keiding 1997 154 348 300 030 [ 003 275 ]

Total (95 CI) 96 88 1000 028 [ 008 095 ]




0001 001 01 1 10 100 1000









Barnes 1997 328 724 277 037 [ 011 127 ]

Fleckenstein 1998 314 316 103 114 [ 027 478 ]

Keiding 1997 1454 1548 583 083 [ 045 154 ]

Pageaux 1995 226 124 38 185 [ 018 1908 ]

Total (95 CI) 122 112 1000 077 [ 047 127 ]




001 01 1 10 100











Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]

Total (95 CI) 14 16 1000 260 [ -096 616 ]



-10 -5 0 5 10









Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]

Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]



-100 -50 0 50 100










Angelico 1999 016 017 00 [ 00 00 ]

Barnes 1997 128 124 086 [ 006 1298 ]

Keiding 1997 554 548 089 [ 027 288 ]

Total (95 CI) 98 89 088 [ 030 260 ]




001 01 1 10 100


A P P E N D I C E S






cholicrsquo




odeoxycholicrsquo



cholicrsquo


cholicrsquo


cholicrsquo



odeoxycholicrsquo



(Continued)


cholicrsquo


drocholicrsquo


rodeoxycholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


sodeoxycholicrsquo



cholicrsquo




ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


ME


3 BILE ACID ME

4





(Continued)













5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10



(Continued)


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2



(Continued)

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10




changed




H I S T O R Y








None known




Internal sources


External sources








I N D E X T E R M S




MeSH check words

Humans





Angelico 1999




Inclusion criteria


Exclusion criteria

- not mentioned

Participants





467 +- 84







474 +- 74







- Route orally


one year

Control group

- no treatment







Risk of bias









All outcomes










tual data given





Barnes 1997




Inclusion criteria



Exclusion criteria


tree


Participants



505 +- 116


Child class A 7




B 13

and C 8


PBC 3





PSC 2

other 3



507 +- 93


Child class A 6

B 14

and C 4


PBC 5





PSC 2

other 4



- Route orally



Placebo group









Adverse events



Risk of bias










All outcomes















Fleckenstein 1998




Inclusion criteria


Exclusion criteria



Participants



443 +- 127



alcohol 2

autoimmune 1

PBC 2




PSC 1


hepatitis B 1



496 +- 109



alcohol 3

autoimmune 3

PBC 1

PSC 2

cryptogenic 2

hepatitis B 1




- Route orally



Placebo group











Risk of bias





probably adequate


All outcomes











tical analysisrdquo



Keiding 1997




Inclusion criteria



Exclusion criteria


Participants



4344 for adults












- Route orally



Placebo group












Adverse events


Risk of bias









All outcomes











was 80 patients



balance


size



Koneru 1993




Inclusion criteria


Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information


- Dose 900 mgday

- Route orally



Control group

- no treatment





Notes Abstract


Risk of bias









All outcomes



plicitly stated






Pageaux 1995




Inclusion criteria


Exclusion criteria

- not mentioned

Participants

- UDCA group (n=26)


47 +- 10





PBC 2

liver cancer 2


miscellaneous 1



51+- 9





PBC 3

liver cancer 4


miscellaneous 1






- Route orally



Placebo group







Risk of bias






All outcomes




were reported






Sama 1991




Inclusion criteria





Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information



- Route orally



Control group

- no treatment


and cyclosporine)



Notes Abstract


Risk of bias
















All outcomes




fully stated


adequately reported




ported













cyclosporine











(Continued)

















month


















studies

No of



follow-up



no treatment


12 TUDCA versus no

treatment




scenarios







start of bile acids



transplantation



transplantation





treatment duration






follow-up




maximum follow-up




follow-up



no treatment


72 TUDCA versus no

treatment





start of bile acid





transplantation








treatment duration






follow-up




maximum follow-up



end of treatment




transplantation




maximum follow-up







Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 116 108 935 080 [ 049 130 ]




01 02 05 1 2 5 10


(Continued )






Angelico 1999 316 217 65 159 [ 030 833 ]

Subtotal (95 CI) 16 17 65 159 [ 030 833 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




01 02 05 1 2 5 10










Angelico 1999 516 217 65 266 [ 060 1180 ]

Barnes 1997 828 724 253 098 [ 042 230 ]

Fleckenstein 1998 314 416 125 086 [ 023 319 ]

Keiding 1997 1954 1048 355 169 [ 087 327 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]





005 02 1 5 20


(Continued )





Angelico 1999 316 417 90 080 [ 021 302 ]

Barnes 1997 228 1124 274 016 [ 004 063 ]

Fleckenstein 1998 214 616 130 038 [ 009 159 ]

Keiding 1997 1454 1548 368 083 [ 045 154 ]

Sama 1991 520 620 139 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]




005 02 1 5 20










Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 54 48 355 124 [ 061 254 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Sama 1991 520 620 201 083 [ 030 229 ]

005 02 1 5 20


(Continued )





Subtotal (95 CI) 78 77 645 063 [ 033 120 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 96 88 734 078 [ 045 138 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 36 37 266 102 [ 043 240 ]



005 02 1 5 20


(Continued )






Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Keiding 1997 054 148 1000 030 [ 001 712 ]

Total (95 CI) 54 48 1000 030 [ 001 712 ]




0001 001 01 1 10 100 1000











Fleckenstein 1998 214 016 100 567 [ 029 10891 ]

Keiding 1997 154 448 900 022 [ 003 192 ]

Total (95 CI) 68 64 1000 076 [ 020 286 ]




0001 001 01 1 10 100 1000










Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 158 148 905 089 [ 074 108 ]

01 02 05 1 2 5 10


(Continued )









Angelico 1999 816 1017 95 085 [ 045 160 ]

Subtotal (95 CI) 16 17 95 085 [ 045 160 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10










Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Subtotal (95 CI) 70 64 422 084 [ 063 111 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

01 02 05 1 2 5 10


(Continued )





Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 104 101 578 092 [ 072 117 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10












Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Subtotal (95 CI) 138 128 777 087 [ 071 107 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 36 37 223 094 [ 065 136 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10











Barnes 1997 128 624 611 014 [ 002 110 ]

Fleckenstein 1998 114 116 88 114 [ 008 1663 ]

Keiding 1997 154 348 300 030 [ 003 275 ]

Total (95 CI) 96 88 1000 028 [ 008 095 ]




0001 001 01 1 10 100 1000









Barnes 1997 328 724 277 037 [ 011 127 ]

Fleckenstein 1998 314 316 103 114 [ 027 478 ]

Keiding 1997 1454 1548 583 083 [ 045 154 ]

Pageaux 1995 226 124 38 185 [ 018 1908 ]

Total (95 CI) 122 112 1000 077 [ 047 127 ]




001 01 1 10 100











Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]

Total (95 CI) 14 16 1000 260 [ -096 616 ]



-10 -5 0 5 10









Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]

Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]



-100 -50 0 50 100










Angelico 1999 016 017 00 [ 00 00 ]

Barnes 1997 128 124 086 [ 006 1298 ]

Keiding 1997 554 548 089 [ 027 288 ]

Total (95 CI) 98 89 088 [ 030 260 ]




001 01 1 10 100


A P P E N D I C E S






cholicrsquo




odeoxycholicrsquo



cholicrsquo


cholicrsquo


cholicrsquo



odeoxycholicrsquo



(Continued)


cholicrsquo


drocholicrsquo


rodeoxycholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


sodeoxycholicrsquo



cholicrsquo




ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


ME


3 BILE ACID ME

4





(Continued)













5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10



(Continued)


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2



(Continued)

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10




changed




H I S T O R Y








None known




Internal sources


External sources








I N D E X T E R M S




MeSH check words

Humans









All outcomes










tual data given





Barnes 1997




Inclusion criteria



Exclusion criteria


tree


Participants



505 +- 116


Child class A 7




B 13

and C 8


PBC 3





PSC 2

other 3



507 +- 93


Child class A 6

B 14

and C 4


PBC 5





PSC 2

other 4



- Route orally



Placebo group









Adverse events



Risk of bias










All outcomes















Fleckenstein 1998




Inclusion criteria


Exclusion criteria



Participants



443 +- 127



alcohol 2

autoimmune 1

PBC 2




PSC 1


hepatitis B 1



496 +- 109



alcohol 3

autoimmune 3

PBC 1

PSC 2

cryptogenic 2

hepatitis B 1




- Route orally



Placebo group











Risk of bias





probably adequate


All outcomes











tical analysisrdquo



Keiding 1997




Inclusion criteria



Exclusion criteria


Participants



4344 for adults












- Route orally



Placebo group












Adverse events


Risk of bias









All outcomes











was 80 patients



balance


size



Koneru 1993




Inclusion criteria


Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information


- Dose 900 mgday

- Route orally



Control group

- no treatment





Notes Abstract


Risk of bias









All outcomes



plicitly stated






Pageaux 1995




Inclusion criteria


Exclusion criteria

- not mentioned

Participants

- UDCA group (n=26)


47 +- 10





PBC 2

liver cancer 2


miscellaneous 1



51+- 9





PBC 3

liver cancer 4


miscellaneous 1






- Route orally



Placebo group







Risk of bias






All outcomes




were reported






Sama 1991




Inclusion criteria





Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information



- Route orally



Control group

- no treatment


and cyclosporine)



Notes Abstract


Risk of bias
















All outcomes




fully stated


adequately reported




ported













cyclosporine











(Continued)

















month


















studies

No of



follow-up



no treatment


12 TUDCA versus no

treatment




scenarios







start of bile acids



transplantation



transplantation





treatment duration






follow-up




maximum follow-up




follow-up



no treatment


72 TUDCA versus no

treatment





start of bile acid





transplantation








treatment duration






follow-up




maximum follow-up



end of treatment




transplantation




maximum follow-up







Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 116 108 935 080 [ 049 130 ]




01 02 05 1 2 5 10


(Continued )






Angelico 1999 316 217 65 159 [ 030 833 ]

Subtotal (95 CI) 16 17 65 159 [ 030 833 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




01 02 05 1 2 5 10










Angelico 1999 516 217 65 266 [ 060 1180 ]

Barnes 1997 828 724 253 098 [ 042 230 ]

Fleckenstein 1998 314 416 125 086 [ 023 319 ]

Keiding 1997 1954 1048 355 169 [ 087 327 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]





005 02 1 5 20


(Continued )





Angelico 1999 316 417 90 080 [ 021 302 ]

Barnes 1997 228 1124 274 016 [ 004 063 ]

Fleckenstein 1998 214 616 130 038 [ 009 159 ]

Keiding 1997 1454 1548 368 083 [ 045 154 ]

Sama 1991 520 620 139 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]




005 02 1 5 20










Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 54 48 355 124 [ 061 254 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Sama 1991 520 620 201 083 [ 030 229 ]

005 02 1 5 20


(Continued )





Subtotal (95 CI) 78 77 645 063 [ 033 120 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 96 88 734 078 [ 045 138 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 36 37 266 102 [ 043 240 ]



005 02 1 5 20


(Continued )






Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Keiding 1997 054 148 1000 030 [ 001 712 ]

Total (95 CI) 54 48 1000 030 [ 001 712 ]




0001 001 01 1 10 100 1000











Fleckenstein 1998 214 016 100 567 [ 029 10891 ]

Keiding 1997 154 448 900 022 [ 003 192 ]

Total (95 CI) 68 64 1000 076 [ 020 286 ]




0001 001 01 1 10 100 1000










Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 158 148 905 089 [ 074 108 ]

01 02 05 1 2 5 10


(Continued )









Angelico 1999 816 1017 95 085 [ 045 160 ]

Subtotal (95 CI) 16 17 95 085 [ 045 160 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10










Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Subtotal (95 CI) 70 64 422 084 [ 063 111 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

01 02 05 1 2 5 10


(Continued )





Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 104 101 578 092 [ 072 117 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10












Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Subtotal (95 CI) 138 128 777 087 [ 071 107 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 36 37 223 094 [ 065 136 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10











Barnes 1997 128 624 611 014 [ 002 110 ]

Fleckenstein 1998 114 116 88 114 [ 008 1663 ]

Keiding 1997 154 348 300 030 [ 003 275 ]

Total (95 CI) 96 88 1000 028 [ 008 095 ]




0001 001 01 1 10 100 1000









Barnes 1997 328 724 277 037 [ 011 127 ]

Fleckenstein 1998 314 316 103 114 [ 027 478 ]

Keiding 1997 1454 1548 583 083 [ 045 154 ]

Pageaux 1995 226 124 38 185 [ 018 1908 ]

Total (95 CI) 122 112 1000 077 [ 047 127 ]




001 01 1 10 100











Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]

Total (95 CI) 14 16 1000 260 [ -096 616 ]



-10 -5 0 5 10









Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]

Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]



-100 -50 0 50 100










Angelico 1999 016 017 00 [ 00 00 ]

Barnes 1997 128 124 086 [ 006 1298 ]

Keiding 1997 554 548 089 [ 027 288 ]

Total (95 CI) 98 89 088 [ 030 260 ]




001 01 1 10 100


A P P E N D I C E S






cholicrsquo




odeoxycholicrsquo



cholicrsquo


cholicrsquo


cholicrsquo



odeoxycholicrsquo



(Continued)


cholicrsquo


drocholicrsquo


rodeoxycholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


sodeoxycholicrsquo



cholicrsquo




ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


ME


3 BILE ACID ME

4





(Continued)













5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10



(Continued)


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2



(Continued)

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10




changed




H I S T O R Y








None known




Internal sources


External sources








I N D E X T E R M S




MeSH check words

Humans




B 13

and C 8


PBC 3





PSC 2

other 3



507 +- 93


Child class A 6

B 14

and C 4


PBC 5





PSC 2

other 4



- Route orally



Placebo group









Adverse events



Risk of bias










All outcomes















Fleckenstein 1998




Inclusion criteria


Exclusion criteria



Participants



443 +- 127



alcohol 2

autoimmune 1

PBC 2




PSC 1


hepatitis B 1



496 +- 109



alcohol 3

autoimmune 3

PBC 1

PSC 2

cryptogenic 2

hepatitis B 1




- Route orally



Placebo group











Risk of bias





probably adequate


All outcomes











tical analysisrdquo



Keiding 1997




Inclusion criteria



Exclusion criteria


Participants



4344 for adults












- Route orally



Placebo group












Adverse events


Risk of bias









All outcomes











was 80 patients



balance


size



Koneru 1993




Inclusion criteria


Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information


- Dose 900 mgday

- Route orally



Control group

- no treatment





Notes Abstract


Risk of bias









All outcomes



plicitly stated






Pageaux 1995




Inclusion criteria


Exclusion criteria

- not mentioned

Participants

- UDCA group (n=26)


47 +- 10





PBC 2

liver cancer 2


miscellaneous 1



51+- 9





PBC 3

liver cancer 4


miscellaneous 1






- Route orally



Placebo group







Risk of bias






All outcomes




were reported






Sama 1991




Inclusion criteria





Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information



- Route orally



Control group

- no treatment


and cyclosporine)



Notes Abstract


Risk of bias
















All outcomes




fully stated


adequately reported




ported













cyclosporine











(Continued)

















month


















studies

No of



follow-up



no treatment


12 TUDCA versus no

treatment




scenarios







start of bile acids



transplantation



transplantation





treatment duration






follow-up




maximum follow-up




follow-up



no treatment


72 TUDCA versus no

treatment





start of bile acid





transplantation








treatment duration






follow-up




maximum follow-up



end of treatment




transplantation




maximum follow-up







Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 116 108 935 080 [ 049 130 ]




01 02 05 1 2 5 10


(Continued )






Angelico 1999 316 217 65 159 [ 030 833 ]

Subtotal (95 CI) 16 17 65 159 [ 030 833 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




01 02 05 1 2 5 10










Angelico 1999 516 217 65 266 [ 060 1180 ]

Barnes 1997 828 724 253 098 [ 042 230 ]

Fleckenstein 1998 314 416 125 086 [ 023 319 ]

Keiding 1997 1954 1048 355 169 [ 087 327 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]





005 02 1 5 20


(Continued )





Angelico 1999 316 417 90 080 [ 021 302 ]

Barnes 1997 228 1124 274 016 [ 004 063 ]

Fleckenstein 1998 214 616 130 038 [ 009 159 ]

Keiding 1997 1454 1548 368 083 [ 045 154 ]

Sama 1991 520 620 139 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]




005 02 1 5 20










Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 54 48 355 124 [ 061 254 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Sama 1991 520 620 201 083 [ 030 229 ]

005 02 1 5 20


(Continued )





Subtotal (95 CI) 78 77 645 063 [ 033 120 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 96 88 734 078 [ 045 138 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 36 37 266 102 [ 043 240 ]



005 02 1 5 20


(Continued )






Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Keiding 1997 054 148 1000 030 [ 001 712 ]

Total (95 CI) 54 48 1000 030 [ 001 712 ]




0001 001 01 1 10 100 1000











Fleckenstein 1998 214 016 100 567 [ 029 10891 ]

Keiding 1997 154 448 900 022 [ 003 192 ]

Total (95 CI) 68 64 1000 076 [ 020 286 ]




0001 001 01 1 10 100 1000










Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 158 148 905 089 [ 074 108 ]

01 02 05 1 2 5 10


(Continued )









Angelico 1999 816 1017 95 085 [ 045 160 ]

Subtotal (95 CI) 16 17 95 085 [ 045 160 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10










Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Subtotal (95 CI) 70 64 422 084 [ 063 111 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

01 02 05 1 2 5 10


(Continued )





Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 104 101 578 092 [ 072 117 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10












Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Subtotal (95 CI) 138 128 777 087 [ 071 107 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 36 37 223 094 [ 065 136 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10











Barnes 1997 128 624 611 014 [ 002 110 ]

Fleckenstein 1998 114 116 88 114 [ 008 1663 ]

Keiding 1997 154 348 300 030 [ 003 275 ]

Total (95 CI) 96 88 1000 028 [ 008 095 ]




0001 001 01 1 10 100 1000









Barnes 1997 328 724 277 037 [ 011 127 ]

Fleckenstein 1998 314 316 103 114 [ 027 478 ]

Keiding 1997 1454 1548 583 083 [ 045 154 ]

Pageaux 1995 226 124 38 185 [ 018 1908 ]

Total (95 CI) 122 112 1000 077 [ 047 127 ]




001 01 1 10 100











Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]

Total (95 CI) 14 16 1000 260 [ -096 616 ]



-10 -5 0 5 10









Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]

Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]



-100 -50 0 50 100










Angelico 1999 016 017 00 [ 00 00 ]

Barnes 1997 128 124 086 [ 006 1298 ]

Keiding 1997 554 548 089 [ 027 288 ]

Total (95 CI) 98 89 088 [ 030 260 ]




001 01 1 10 100


A P P E N D I C E S






cholicrsquo




odeoxycholicrsquo



cholicrsquo


cholicrsquo


cholicrsquo



odeoxycholicrsquo



(Continued)


cholicrsquo


drocholicrsquo


rodeoxycholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


sodeoxycholicrsquo



cholicrsquo




ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


ME


3 BILE ACID ME

4





(Continued)













5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10



(Continued)


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2



(Continued)

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10




changed




H I S T O R Y








None known




Internal sources


External sources








I N D E X T E R M S




MeSH check words

Humans









All outcomes















Fleckenstein 1998




Inclusion criteria


Exclusion criteria



Participants



443 +- 127



alcohol 2

autoimmune 1

PBC 2




PSC 1


hepatitis B 1



496 +- 109



alcohol 3

autoimmune 3

PBC 1

PSC 2

cryptogenic 2

hepatitis B 1




- Route orally



Placebo group











Risk of bias





probably adequate


All outcomes











tical analysisrdquo



Keiding 1997




Inclusion criteria



Exclusion criteria


Participants



4344 for adults












- Route orally



Placebo group












Adverse events


Risk of bias









All outcomes











was 80 patients



balance


size



Koneru 1993




Inclusion criteria


Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information


- Dose 900 mgday

- Route orally



Control group

- no treatment





Notes Abstract


Risk of bias









All outcomes



plicitly stated






Pageaux 1995




Inclusion criteria


Exclusion criteria

- not mentioned

Participants

- UDCA group (n=26)


47 +- 10





PBC 2

liver cancer 2


miscellaneous 1



51+- 9





PBC 3

liver cancer 4


miscellaneous 1






- Route orally



Placebo group







Risk of bias






All outcomes




were reported






Sama 1991




Inclusion criteria





Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information



- Route orally



Control group

- no treatment


and cyclosporine)



Notes Abstract


Risk of bias
















All outcomes




fully stated


adequately reported




ported













cyclosporine











(Continued)

















month


















studies

No of



follow-up



no treatment


12 TUDCA versus no

treatment




scenarios







start of bile acids



transplantation



transplantation





treatment duration






follow-up




maximum follow-up




follow-up



no treatment


72 TUDCA versus no

treatment





start of bile acid





transplantation








treatment duration






follow-up




maximum follow-up



end of treatment




transplantation




maximum follow-up







Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 116 108 935 080 [ 049 130 ]




01 02 05 1 2 5 10


(Continued )






Angelico 1999 316 217 65 159 [ 030 833 ]

Subtotal (95 CI) 16 17 65 159 [ 030 833 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




01 02 05 1 2 5 10










Angelico 1999 516 217 65 266 [ 060 1180 ]

Barnes 1997 828 724 253 098 [ 042 230 ]

Fleckenstein 1998 314 416 125 086 [ 023 319 ]

Keiding 1997 1954 1048 355 169 [ 087 327 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]





005 02 1 5 20


(Continued )





Angelico 1999 316 417 90 080 [ 021 302 ]

Barnes 1997 228 1124 274 016 [ 004 063 ]

Fleckenstein 1998 214 616 130 038 [ 009 159 ]

Keiding 1997 1454 1548 368 083 [ 045 154 ]

Sama 1991 520 620 139 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]




005 02 1 5 20










Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 54 48 355 124 [ 061 254 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Sama 1991 520 620 201 083 [ 030 229 ]

005 02 1 5 20


(Continued )





Subtotal (95 CI) 78 77 645 063 [ 033 120 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 96 88 734 078 [ 045 138 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 36 37 266 102 [ 043 240 ]



005 02 1 5 20


(Continued )






Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Keiding 1997 054 148 1000 030 [ 001 712 ]

Total (95 CI) 54 48 1000 030 [ 001 712 ]




0001 001 01 1 10 100 1000











Fleckenstein 1998 214 016 100 567 [ 029 10891 ]

Keiding 1997 154 448 900 022 [ 003 192 ]

Total (95 CI) 68 64 1000 076 [ 020 286 ]




0001 001 01 1 10 100 1000










Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 158 148 905 089 [ 074 108 ]

01 02 05 1 2 5 10


(Continued )









Angelico 1999 816 1017 95 085 [ 045 160 ]

Subtotal (95 CI) 16 17 95 085 [ 045 160 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10










Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Subtotal (95 CI) 70 64 422 084 [ 063 111 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

01 02 05 1 2 5 10


(Continued )





Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 104 101 578 092 [ 072 117 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10












Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Subtotal (95 CI) 138 128 777 087 [ 071 107 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 36 37 223 094 [ 065 136 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10











Barnes 1997 128 624 611 014 [ 002 110 ]

Fleckenstein 1998 114 116 88 114 [ 008 1663 ]

Keiding 1997 154 348 300 030 [ 003 275 ]

Total (95 CI) 96 88 1000 028 [ 008 095 ]




0001 001 01 1 10 100 1000









Barnes 1997 328 724 277 037 [ 011 127 ]

Fleckenstein 1998 314 316 103 114 [ 027 478 ]

Keiding 1997 1454 1548 583 083 [ 045 154 ]

Pageaux 1995 226 124 38 185 [ 018 1908 ]

Total (95 CI) 122 112 1000 077 [ 047 127 ]




001 01 1 10 100











Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]

Total (95 CI) 14 16 1000 260 [ -096 616 ]



-10 -5 0 5 10









Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]

Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]



-100 -50 0 50 100










Angelico 1999 016 017 00 [ 00 00 ]

Barnes 1997 128 124 086 [ 006 1298 ]

Keiding 1997 554 548 089 [ 027 288 ]

Total (95 CI) 98 89 088 [ 030 260 ]




001 01 1 10 100


A P P E N D I C E S






cholicrsquo




odeoxycholicrsquo



cholicrsquo


cholicrsquo


cholicrsquo



odeoxycholicrsquo



(Continued)


cholicrsquo


drocholicrsquo


rodeoxycholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


sodeoxycholicrsquo



cholicrsquo




ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


ME


3 BILE ACID ME

4





(Continued)













5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10



(Continued)


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2



(Continued)

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10




changed




H I S T O R Y








None known




Internal sources


External sources








I N D E X T E R M S




MeSH check words

Humans




PSC 1


hepatitis B 1



496 +- 109



alcohol 3

autoimmune 3

PBC 1

PSC 2

cryptogenic 2

hepatitis B 1




- Route orally



Placebo group











Risk of bias





probably adequate


All outcomes











tical analysisrdquo



Keiding 1997




Inclusion criteria



Exclusion criteria


Participants



4344 for adults












- Route orally



Placebo group












Adverse events


Risk of bias









All outcomes











was 80 patients



balance


size



Koneru 1993




Inclusion criteria


Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information


- Dose 900 mgday

- Route orally



Control group

- no treatment





Notes Abstract


Risk of bias









All outcomes



plicitly stated






Pageaux 1995




Inclusion criteria


Exclusion criteria

- not mentioned

Participants

- UDCA group (n=26)


47 +- 10





PBC 2

liver cancer 2


miscellaneous 1



51+- 9





PBC 3

liver cancer 4


miscellaneous 1






- Route orally



Placebo group







Risk of bias






All outcomes




were reported






Sama 1991




Inclusion criteria





Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information



- Route orally



Control group

- no treatment


and cyclosporine)



Notes Abstract


Risk of bias
















All outcomes




fully stated


adequately reported




ported













cyclosporine











(Continued)

















month


















studies

No of



follow-up



no treatment


12 TUDCA versus no

treatment




scenarios







start of bile acids



transplantation



transplantation





treatment duration






follow-up




maximum follow-up




follow-up



no treatment


72 TUDCA versus no

treatment





start of bile acid





transplantation








treatment duration






follow-up




maximum follow-up



end of treatment




transplantation




maximum follow-up







Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 116 108 935 080 [ 049 130 ]




01 02 05 1 2 5 10


(Continued )






Angelico 1999 316 217 65 159 [ 030 833 ]

Subtotal (95 CI) 16 17 65 159 [ 030 833 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




01 02 05 1 2 5 10










Angelico 1999 516 217 65 266 [ 060 1180 ]

Barnes 1997 828 724 253 098 [ 042 230 ]

Fleckenstein 1998 314 416 125 086 [ 023 319 ]

Keiding 1997 1954 1048 355 169 [ 087 327 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]





005 02 1 5 20


(Continued )





Angelico 1999 316 417 90 080 [ 021 302 ]

Barnes 1997 228 1124 274 016 [ 004 063 ]

Fleckenstein 1998 214 616 130 038 [ 009 159 ]

Keiding 1997 1454 1548 368 083 [ 045 154 ]

Sama 1991 520 620 139 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]




005 02 1 5 20










Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 54 48 355 124 [ 061 254 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Sama 1991 520 620 201 083 [ 030 229 ]

005 02 1 5 20


(Continued )





Subtotal (95 CI) 78 77 645 063 [ 033 120 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 96 88 734 078 [ 045 138 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 36 37 266 102 [ 043 240 ]



005 02 1 5 20


(Continued )






Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Keiding 1997 054 148 1000 030 [ 001 712 ]

Total (95 CI) 54 48 1000 030 [ 001 712 ]




0001 001 01 1 10 100 1000











Fleckenstein 1998 214 016 100 567 [ 029 10891 ]

Keiding 1997 154 448 900 022 [ 003 192 ]

Total (95 CI) 68 64 1000 076 [ 020 286 ]




0001 001 01 1 10 100 1000










Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 158 148 905 089 [ 074 108 ]

01 02 05 1 2 5 10


(Continued )









Angelico 1999 816 1017 95 085 [ 045 160 ]

Subtotal (95 CI) 16 17 95 085 [ 045 160 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10










Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Subtotal (95 CI) 70 64 422 084 [ 063 111 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

01 02 05 1 2 5 10


(Continued )





Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 104 101 578 092 [ 072 117 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10












Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Subtotal (95 CI) 138 128 777 087 [ 071 107 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 36 37 223 094 [ 065 136 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10











Barnes 1997 128 624 611 014 [ 002 110 ]

Fleckenstein 1998 114 116 88 114 [ 008 1663 ]

Keiding 1997 154 348 300 030 [ 003 275 ]

Total (95 CI) 96 88 1000 028 [ 008 095 ]




0001 001 01 1 10 100 1000









Barnes 1997 328 724 277 037 [ 011 127 ]

Fleckenstein 1998 314 316 103 114 [ 027 478 ]

Keiding 1997 1454 1548 583 083 [ 045 154 ]

Pageaux 1995 226 124 38 185 [ 018 1908 ]

Total (95 CI) 122 112 1000 077 [ 047 127 ]




001 01 1 10 100











Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]

Total (95 CI) 14 16 1000 260 [ -096 616 ]



-10 -5 0 5 10









Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]

Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]



-100 -50 0 50 100










Angelico 1999 016 017 00 [ 00 00 ]

Barnes 1997 128 124 086 [ 006 1298 ]

Keiding 1997 554 548 089 [ 027 288 ]

Total (95 CI) 98 89 088 [ 030 260 ]




001 01 1 10 100


A P P E N D I C E S






cholicrsquo




odeoxycholicrsquo



cholicrsquo


cholicrsquo


cholicrsquo



odeoxycholicrsquo



(Continued)


cholicrsquo


drocholicrsquo


rodeoxycholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


sodeoxycholicrsquo



cholicrsquo




ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


ME


3 BILE ACID ME

4





(Continued)













5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10



(Continued)


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2



(Continued)

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10




changed




H I S T O R Y








None known




Internal sources


External sources








I N D E X T E R M S




MeSH check words

Humans








tical analysisrdquo



Keiding 1997




Inclusion criteria



Exclusion criteria


Participants



4344 for adults












- Route orally



Placebo group












Adverse events


Risk of bias









All outcomes











was 80 patients



balance


size



Koneru 1993




Inclusion criteria


Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information


- Dose 900 mgday

- Route orally



Control group

- no treatment





Notes Abstract


Risk of bias









All outcomes



plicitly stated






Pageaux 1995




Inclusion criteria


Exclusion criteria

- not mentioned

Participants

- UDCA group (n=26)


47 +- 10





PBC 2

liver cancer 2


miscellaneous 1



51+- 9





PBC 3

liver cancer 4


miscellaneous 1






- Route orally



Placebo group







Risk of bias






All outcomes




were reported






Sama 1991




Inclusion criteria





Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information



- Route orally



Control group

- no treatment


and cyclosporine)



Notes Abstract


Risk of bias
















All outcomes




fully stated


adequately reported




ported













cyclosporine











(Continued)

















month


















studies

No of



follow-up



no treatment


12 TUDCA versus no

treatment




scenarios







start of bile acids



transplantation



transplantation





treatment duration






follow-up




maximum follow-up




follow-up



no treatment


72 TUDCA versus no

treatment





start of bile acid





transplantation








treatment duration






follow-up




maximum follow-up



end of treatment




transplantation




maximum follow-up







Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 116 108 935 080 [ 049 130 ]




01 02 05 1 2 5 10


(Continued )






Angelico 1999 316 217 65 159 [ 030 833 ]

Subtotal (95 CI) 16 17 65 159 [ 030 833 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




01 02 05 1 2 5 10










Angelico 1999 516 217 65 266 [ 060 1180 ]

Barnes 1997 828 724 253 098 [ 042 230 ]

Fleckenstein 1998 314 416 125 086 [ 023 319 ]

Keiding 1997 1954 1048 355 169 [ 087 327 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]





005 02 1 5 20


(Continued )





Angelico 1999 316 417 90 080 [ 021 302 ]

Barnes 1997 228 1124 274 016 [ 004 063 ]

Fleckenstein 1998 214 616 130 038 [ 009 159 ]

Keiding 1997 1454 1548 368 083 [ 045 154 ]

Sama 1991 520 620 139 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]




005 02 1 5 20










Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 54 48 355 124 [ 061 254 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Sama 1991 520 620 201 083 [ 030 229 ]

005 02 1 5 20


(Continued )





Subtotal (95 CI) 78 77 645 063 [ 033 120 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 96 88 734 078 [ 045 138 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 36 37 266 102 [ 043 240 ]



005 02 1 5 20


(Continued )






Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Keiding 1997 054 148 1000 030 [ 001 712 ]

Total (95 CI) 54 48 1000 030 [ 001 712 ]




0001 001 01 1 10 100 1000











Fleckenstein 1998 214 016 100 567 [ 029 10891 ]

Keiding 1997 154 448 900 022 [ 003 192 ]

Total (95 CI) 68 64 1000 076 [ 020 286 ]




0001 001 01 1 10 100 1000










Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 158 148 905 089 [ 074 108 ]

01 02 05 1 2 5 10


(Continued )









Angelico 1999 816 1017 95 085 [ 045 160 ]

Subtotal (95 CI) 16 17 95 085 [ 045 160 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10










Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Subtotal (95 CI) 70 64 422 084 [ 063 111 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

01 02 05 1 2 5 10


(Continued )





Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 104 101 578 092 [ 072 117 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10












Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Subtotal (95 CI) 138 128 777 087 [ 071 107 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 36 37 223 094 [ 065 136 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10











Barnes 1997 128 624 611 014 [ 002 110 ]

Fleckenstein 1998 114 116 88 114 [ 008 1663 ]

Keiding 1997 154 348 300 030 [ 003 275 ]

Total (95 CI) 96 88 1000 028 [ 008 095 ]




0001 001 01 1 10 100 1000









Barnes 1997 328 724 277 037 [ 011 127 ]

Fleckenstein 1998 314 316 103 114 [ 027 478 ]

Keiding 1997 1454 1548 583 083 [ 045 154 ]

Pageaux 1995 226 124 38 185 [ 018 1908 ]

Total (95 CI) 122 112 1000 077 [ 047 127 ]




001 01 1 10 100











Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]

Total (95 CI) 14 16 1000 260 [ -096 616 ]



-10 -5 0 5 10









Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]

Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]



-100 -50 0 50 100










Angelico 1999 016 017 00 [ 00 00 ]

Barnes 1997 128 124 086 [ 006 1298 ]

Keiding 1997 554 548 089 [ 027 288 ]

Total (95 CI) 98 89 088 [ 030 260 ]




001 01 1 10 100


A P P E N D I C E S






cholicrsquo




odeoxycholicrsquo



cholicrsquo


cholicrsquo


cholicrsquo



odeoxycholicrsquo



(Continued)


cholicrsquo


drocholicrsquo


rodeoxycholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


sodeoxycholicrsquo



cholicrsquo




ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


ME


3 BILE ACID ME

4





(Continued)













5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10



(Continued)


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2



(Continued)

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10




changed




H I S T O R Y








None known




Internal sources


External sources








I N D E X T E R M S




MeSH check words

Humans









Adverse events


Risk of bias









All outcomes











was 80 patients



balance


size



Koneru 1993




Inclusion criteria


Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information


- Dose 900 mgday

- Route orally



Control group

- no treatment





Notes Abstract


Risk of bias









All outcomes



plicitly stated






Pageaux 1995




Inclusion criteria


Exclusion criteria

- not mentioned

Participants

- UDCA group (n=26)


47 +- 10





PBC 2

liver cancer 2


miscellaneous 1



51+- 9





PBC 3

liver cancer 4


miscellaneous 1






- Route orally



Placebo group







Risk of bias






All outcomes




were reported






Sama 1991




Inclusion criteria





Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information



- Route orally



Control group

- no treatment


and cyclosporine)



Notes Abstract


Risk of bias
















All outcomes




fully stated


adequately reported




ported













cyclosporine











(Continued)

















month


















studies

No of



follow-up



no treatment


12 TUDCA versus no

treatment




scenarios







start of bile acids



transplantation



transplantation





treatment duration






follow-up




maximum follow-up




follow-up



no treatment


72 TUDCA versus no

treatment





start of bile acid





transplantation








treatment duration






follow-up




maximum follow-up



end of treatment




transplantation




maximum follow-up







Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 116 108 935 080 [ 049 130 ]




01 02 05 1 2 5 10


(Continued )






Angelico 1999 316 217 65 159 [ 030 833 ]

Subtotal (95 CI) 16 17 65 159 [ 030 833 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




01 02 05 1 2 5 10










Angelico 1999 516 217 65 266 [ 060 1180 ]

Barnes 1997 828 724 253 098 [ 042 230 ]

Fleckenstein 1998 314 416 125 086 [ 023 319 ]

Keiding 1997 1954 1048 355 169 [ 087 327 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]





005 02 1 5 20


(Continued )





Angelico 1999 316 417 90 080 [ 021 302 ]

Barnes 1997 228 1124 274 016 [ 004 063 ]

Fleckenstein 1998 214 616 130 038 [ 009 159 ]

Keiding 1997 1454 1548 368 083 [ 045 154 ]

Sama 1991 520 620 139 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]




005 02 1 5 20










Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 54 48 355 124 [ 061 254 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Sama 1991 520 620 201 083 [ 030 229 ]

005 02 1 5 20


(Continued )





Subtotal (95 CI) 78 77 645 063 [ 033 120 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 96 88 734 078 [ 045 138 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 36 37 266 102 [ 043 240 ]



005 02 1 5 20


(Continued )






Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Keiding 1997 054 148 1000 030 [ 001 712 ]

Total (95 CI) 54 48 1000 030 [ 001 712 ]




0001 001 01 1 10 100 1000











Fleckenstein 1998 214 016 100 567 [ 029 10891 ]

Keiding 1997 154 448 900 022 [ 003 192 ]

Total (95 CI) 68 64 1000 076 [ 020 286 ]




0001 001 01 1 10 100 1000










Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 158 148 905 089 [ 074 108 ]

01 02 05 1 2 5 10


(Continued )









Angelico 1999 816 1017 95 085 [ 045 160 ]

Subtotal (95 CI) 16 17 95 085 [ 045 160 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10










Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Subtotal (95 CI) 70 64 422 084 [ 063 111 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

01 02 05 1 2 5 10


(Continued )





Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 104 101 578 092 [ 072 117 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10












Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Subtotal (95 CI) 138 128 777 087 [ 071 107 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 36 37 223 094 [ 065 136 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10











Barnes 1997 128 624 611 014 [ 002 110 ]

Fleckenstein 1998 114 116 88 114 [ 008 1663 ]

Keiding 1997 154 348 300 030 [ 003 275 ]

Total (95 CI) 96 88 1000 028 [ 008 095 ]




0001 001 01 1 10 100 1000









Barnes 1997 328 724 277 037 [ 011 127 ]

Fleckenstein 1998 314 316 103 114 [ 027 478 ]

Keiding 1997 1454 1548 583 083 [ 045 154 ]

Pageaux 1995 226 124 38 185 [ 018 1908 ]

Total (95 CI) 122 112 1000 077 [ 047 127 ]




001 01 1 10 100











Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]

Total (95 CI) 14 16 1000 260 [ -096 616 ]



-10 -5 0 5 10









Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]

Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]



-100 -50 0 50 100










Angelico 1999 016 017 00 [ 00 00 ]

Barnes 1997 128 124 086 [ 006 1298 ]

Keiding 1997 554 548 089 [ 027 288 ]

Total (95 CI) 98 89 088 [ 030 260 ]




001 01 1 10 100


A P P E N D I C E S






cholicrsquo




odeoxycholicrsquo



cholicrsquo


cholicrsquo


cholicrsquo



odeoxycholicrsquo



(Continued)


cholicrsquo


drocholicrsquo


rodeoxycholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


sodeoxycholicrsquo



cholicrsquo




ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


ME


3 BILE ACID ME

4





(Continued)













5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10



(Continued)


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2



(Continued)

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10




changed




H I S T O R Y








None known




Internal sources


External sources








I N D E X T E R M S




MeSH check words

Humans



Koneru 1993




Inclusion criteria


Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information


- Dose 900 mgday

- Route orally



Control group

- no treatment





Notes Abstract


Risk of bias









All outcomes



plicitly stated






Pageaux 1995




Inclusion criteria


Exclusion criteria

- not mentioned

Participants

- UDCA group (n=26)


47 +- 10





PBC 2

liver cancer 2


miscellaneous 1



51+- 9





PBC 3

liver cancer 4


miscellaneous 1






- Route orally



Placebo group







Risk of bias






All outcomes




were reported






Sama 1991




Inclusion criteria





Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information



- Route orally



Control group

- no treatment


and cyclosporine)



Notes Abstract


Risk of bias
















All outcomes




fully stated


adequately reported




ported













cyclosporine











(Continued)

















month


















studies

No of



follow-up



no treatment


12 TUDCA versus no

treatment




scenarios







start of bile acids



transplantation



transplantation





treatment duration






follow-up




maximum follow-up




follow-up



no treatment


72 TUDCA versus no

treatment





start of bile acid





transplantation








treatment duration






follow-up




maximum follow-up



end of treatment




transplantation




maximum follow-up







Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 116 108 935 080 [ 049 130 ]




01 02 05 1 2 5 10


(Continued )






Angelico 1999 316 217 65 159 [ 030 833 ]

Subtotal (95 CI) 16 17 65 159 [ 030 833 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




01 02 05 1 2 5 10










Angelico 1999 516 217 65 266 [ 060 1180 ]

Barnes 1997 828 724 253 098 [ 042 230 ]

Fleckenstein 1998 314 416 125 086 [ 023 319 ]

Keiding 1997 1954 1048 355 169 [ 087 327 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]





005 02 1 5 20


(Continued )





Angelico 1999 316 417 90 080 [ 021 302 ]

Barnes 1997 228 1124 274 016 [ 004 063 ]

Fleckenstein 1998 214 616 130 038 [ 009 159 ]

Keiding 1997 1454 1548 368 083 [ 045 154 ]

Sama 1991 520 620 139 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]




005 02 1 5 20










Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 54 48 355 124 [ 061 254 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Sama 1991 520 620 201 083 [ 030 229 ]

005 02 1 5 20


(Continued )





Subtotal (95 CI) 78 77 645 063 [ 033 120 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 96 88 734 078 [ 045 138 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 36 37 266 102 [ 043 240 ]



005 02 1 5 20


(Continued )






Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Keiding 1997 054 148 1000 030 [ 001 712 ]

Total (95 CI) 54 48 1000 030 [ 001 712 ]




0001 001 01 1 10 100 1000











Fleckenstein 1998 214 016 100 567 [ 029 10891 ]

Keiding 1997 154 448 900 022 [ 003 192 ]

Total (95 CI) 68 64 1000 076 [ 020 286 ]




0001 001 01 1 10 100 1000










Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 158 148 905 089 [ 074 108 ]

01 02 05 1 2 5 10


(Continued )









Angelico 1999 816 1017 95 085 [ 045 160 ]

Subtotal (95 CI) 16 17 95 085 [ 045 160 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10










Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Subtotal (95 CI) 70 64 422 084 [ 063 111 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

01 02 05 1 2 5 10


(Continued )





Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 104 101 578 092 [ 072 117 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10












Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Subtotal (95 CI) 138 128 777 087 [ 071 107 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 36 37 223 094 [ 065 136 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10











Barnes 1997 128 624 611 014 [ 002 110 ]

Fleckenstein 1998 114 116 88 114 [ 008 1663 ]

Keiding 1997 154 348 300 030 [ 003 275 ]

Total (95 CI) 96 88 1000 028 [ 008 095 ]




0001 001 01 1 10 100 1000









Barnes 1997 328 724 277 037 [ 011 127 ]

Fleckenstein 1998 314 316 103 114 [ 027 478 ]

Keiding 1997 1454 1548 583 083 [ 045 154 ]

Pageaux 1995 226 124 38 185 [ 018 1908 ]

Total (95 CI) 122 112 1000 077 [ 047 127 ]




001 01 1 10 100











Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]

Total (95 CI) 14 16 1000 260 [ -096 616 ]



-10 -5 0 5 10









Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]

Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]



-100 -50 0 50 100










Angelico 1999 016 017 00 [ 00 00 ]

Barnes 1997 128 124 086 [ 006 1298 ]

Keiding 1997 554 548 089 [ 027 288 ]

Total (95 CI) 98 89 088 [ 030 260 ]




001 01 1 10 100


A P P E N D I C E S






cholicrsquo




odeoxycholicrsquo



cholicrsquo


cholicrsquo


cholicrsquo



odeoxycholicrsquo



(Continued)


cholicrsquo


drocholicrsquo


rodeoxycholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


sodeoxycholicrsquo



cholicrsquo




ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


ME


3 BILE ACID ME

4





(Continued)













5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10



(Continued)


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2



(Continued)

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10




changed




H I S T O R Y








None known




Internal sources


External sources








I N D E X T E R M S




MeSH check words

Humans





All outcomes



plicitly stated






Pageaux 1995




Inclusion criteria


Exclusion criteria

- not mentioned

Participants

- UDCA group (n=26)


47 +- 10





PBC 2

liver cancer 2


miscellaneous 1



51+- 9





PBC 3

liver cancer 4


miscellaneous 1






- Route orally



Placebo group







Risk of bias






All outcomes




were reported






Sama 1991




Inclusion criteria





Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information



- Route orally



Control group

- no treatment


and cyclosporine)



Notes Abstract


Risk of bias
















All outcomes




fully stated


adequately reported




ported













cyclosporine











(Continued)

















month


















studies

No of



follow-up



no treatment


12 TUDCA versus no

treatment




scenarios







start of bile acids



transplantation



transplantation





treatment duration






follow-up




maximum follow-up




follow-up



no treatment


72 TUDCA versus no

treatment





start of bile acid





transplantation








treatment duration






follow-up




maximum follow-up



end of treatment




transplantation




maximum follow-up







Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 116 108 935 080 [ 049 130 ]




01 02 05 1 2 5 10


(Continued )






Angelico 1999 316 217 65 159 [ 030 833 ]

Subtotal (95 CI) 16 17 65 159 [ 030 833 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




01 02 05 1 2 5 10










Angelico 1999 516 217 65 266 [ 060 1180 ]

Barnes 1997 828 724 253 098 [ 042 230 ]

Fleckenstein 1998 314 416 125 086 [ 023 319 ]

Keiding 1997 1954 1048 355 169 [ 087 327 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]





005 02 1 5 20


(Continued )





Angelico 1999 316 417 90 080 [ 021 302 ]

Barnes 1997 228 1124 274 016 [ 004 063 ]

Fleckenstein 1998 214 616 130 038 [ 009 159 ]

Keiding 1997 1454 1548 368 083 [ 045 154 ]

Sama 1991 520 620 139 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]




005 02 1 5 20










Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 54 48 355 124 [ 061 254 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Sama 1991 520 620 201 083 [ 030 229 ]

005 02 1 5 20


(Continued )





Subtotal (95 CI) 78 77 645 063 [ 033 120 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 96 88 734 078 [ 045 138 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 36 37 266 102 [ 043 240 ]



005 02 1 5 20


(Continued )






Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Keiding 1997 054 148 1000 030 [ 001 712 ]

Total (95 CI) 54 48 1000 030 [ 001 712 ]




0001 001 01 1 10 100 1000











Fleckenstein 1998 214 016 100 567 [ 029 10891 ]

Keiding 1997 154 448 900 022 [ 003 192 ]

Total (95 CI) 68 64 1000 076 [ 020 286 ]




0001 001 01 1 10 100 1000










Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 158 148 905 089 [ 074 108 ]

01 02 05 1 2 5 10


(Continued )









Angelico 1999 816 1017 95 085 [ 045 160 ]

Subtotal (95 CI) 16 17 95 085 [ 045 160 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10










Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Subtotal (95 CI) 70 64 422 084 [ 063 111 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

01 02 05 1 2 5 10


(Continued )





Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 104 101 578 092 [ 072 117 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10












Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Subtotal (95 CI) 138 128 777 087 [ 071 107 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 36 37 223 094 [ 065 136 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10











Barnes 1997 128 624 611 014 [ 002 110 ]

Fleckenstein 1998 114 116 88 114 [ 008 1663 ]

Keiding 1997 154 348 300 030 [ 003 275 ]

Total (95 CI) 96 88 1000 028 [ 008 095 ]




0001 001 01 1 10 100 1000









Barnes 1997 328 724 277 037 [ 011 127 ]

Fleckenstein 1998 314 316 103 114 [ 027 478 ]

Keiding 1997 1454 1548 583 083 [ 045 154 ]

Pageaux 1995 226 124 38 185 [ 018 1908 ]

Total (95 CI) 122 112 1000 077 [ 047 127 ]




001 01 1 10 100











Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]

Total (95 CI) 14 16 1000 260 [ -096 616 ]



-10 -5 0 5 10









Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]

Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]



-100 -50 0 50 100










Angelico 1999 016 017 00 [ 00 00 ]

Barnes 1997 128 124 086 [ 006 1298 ]

Keiding 1997 554 548 089 [ 027 288 ]

Total (95 CI) 98 89 088 [ 030 260 ]




001 01 1 10 100


A P P E N D I C E S






cholicrsquo




odeoxycholicrsquo



cholicrsquo


cholicrsquo


cholicrsquo



odeoxycholicrsquo



(Continued)


cholicrsquo


drocholicrsquo


rodeoxycholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


sodeoxycholicrsquo



cholicrsquo




ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


ME


3 BILE ACID ME

4





(Continued)













5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10



(Continued)


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2



(Continued)

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10




changed




H I S T O R Y








None known




Internal sources


External sources








I N D E X T E R M S




MeSH check words

Humans






- Route orally



Placebo group







Risk of bias






All outcomes




were reported






Sama 1991




Inclusion criteria





Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information



- Route orally



Control group

- no treatment


and cyclosporine)



Notes Abstract


Risk of bias
















All outcomes




fully stated


adequately reported




ported













cyclosporine











(Continued)

















month


















studies

No of



follow-up



no treatment


12 TUDCA versus no

treatment




scenarios







start of bile acids



transplantation



transplantation





treatment duration






follow-up




maximum follow-up




follow-up



no treatment


72 TUDCA versus no

treatment





start of bile acid





transplantation








treatment duration






follow-up




maximum follow-up



end of treatment




transplantation




maximum follow-up







Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 116 108 935 080 [ 049 130 ]




01 02 05 1 2 5 10


(Continued )






Angelico 1999 316 217 65 159 [ 030 833 ]

Subtotal (95 CI) 16 17 65 159 [ 030 833 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




01 02 05 1 2 5 10










Angelico 1999 516 217 65 266 [ 060 1180 ]

Barnes 1997 828 724 253 098 [ 042 230 ]

Fleckenstein 1998 314 416 125 086 [ 023 319 ]

Keiding 1997 1954 1048 355 169 [ 087 327 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]





005 02 1 5 20


(Continued )





Angelico 1999 316 417 90 080 [ 021 302 ]

Barnes 1997 228 1124 274 016 [ 004 063 ]

Fleckenstein 1998 214 616 130 038 [ 009 159 ]

Keiding 1997 1454 1548 368 083 [ 045 154 ]

Sama 1991 520 620 139 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]




005 02 1 5 20










Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 54 48 355 124 [ 061 254 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Sama 1991 520 620 201 083 [ 030 229 ]

005 02 1 5 20


(Continued )





Subtotal (95 CI) 78 77 645 063 [ 033 120 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 96 88 734 078 [ 045 138 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 36 37 266 102 [ 043 240 ]



005 02 1 5 20


(Continued )






Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Keiding 1997 054 148 1000 030 [ 001 712 ]

Total (95 CI) 54 48 1000 030 [ 001 712 ]




0001 001 01 1 10 100 1000











Fleckenstein 1998 214 016 100 567 [ 029 10891 ]

Keiding 1997 154 448 900 022 [ 003 192 ]

Total (95 CI) 68 64 1000 076 [ 020 286 ]




0001 001 01 1 10 100 1000










Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 158 148 905 089 [ 074 108 ]

01 02 05 1 2 5 10


(Continued )









Angelico 1999 816 1017 95 085 [ 045 160 ]

Subtotal (95 CI) 16 17 95 085 [ 045 160 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10










Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Subtotal (95 CI) 70 64 422 084 [ 063 111 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

01 02 05 1 2 5 10


(Continued )





Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 104 101 578 092 [ 072 117 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10












Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Subtotal (95 CI) 138 128 777 087 [ 071 107 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 36 37 223 094 [ 065 136 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10











Barnes 1997 128 624 611 014 [ 002 110 ]

Fleckenstein 1998 114 116 88 114 [ 008 1663 ]

Keiding 1997 154 348 300 030 [ 003 275 ]

Total (95 CI) 96 88 1000 028 [ 008 095 ]




0001 001 01 1 10 100 1000









Barnes 1997 328 724 277 037 [ 011 127 ]

Fleckenstein 1998 314 316 103 114 [ 027 478 ]

Keiding 1997 1454 1548 583 083 [ 045 154 ]

Pageaux 1995 226 124 38 185 [ 018 1908 ]

Total (95 CI) 122 112 1000 077 [ 047 127 ]




001 01 1 10 100











Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]

Total (95 CI) 14 16 1000 260 [ -096 616 ]



-10 -5 0 5 10









Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]

Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]



-100 -50 0 50 100










Angelico 1999 016 017 00 [ 00 00 ]

Barnes 1997 128 124 086 [ 006 1298 ]

Keiding 1997 554 548 089 [ 027 288 ]

Total (95 CI) 98 89 088 [ 030 260 ]




001 01 1 10 100


A P P E N D I C E S






cholicrsquo




odeoxycholicrsquo



cholicrsquo


cholicrsquo


cholicrsquo



odeoxycholicrsquo



(Continued)


cholicrsquo


drocholicrsquo


rodeoxycholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


sodeoxycholicrsquo



cholicrsquo




ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


ME


3 BILE ACID ME

4





(Continued)













5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10



(Continued)


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2



(Continued)

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10




changed




H I S T O R Y








None known




Internal sources


External sources








I N D E X T E R M S




MeSH check words

Humans





Exclusion criteria

- not mentioned

Participants



no information



no information



no information



no information



- Route orally



Control group

- no treatment


and cyclosporine)



Notes Abstract


Risk of bias
















All outcomes




fully stated


adequately reported




ported













cyclosporine











(Continued)

















month


















studies

No of



follow-up



no treatment


12 TUDCA versus no

treatment




scenarios







start of bile acids



transplantation



transplantation





treatment duration






follow-up




maximum follow-up




follow-up



no treatment


72 TUDCA versus no

treatment





start of bile acid





transplantation








treatment duration






follow-up




maximum follow-up



end of treatment




transplantation




maximum follow-up







Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 116 108 935 080 [ 049 130 ]




01 02 05 1 2 5 10


(Continued )






Angelico 1999 316 217 65 159 [ 030 833 ]

Subtotal (95 CI) 16 17 65 159 [ 030 833 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




01 02 05 1 2 5 10










Angelico 1999 516 217 65 266 [ 060 1180 ]

Barnes 1997 828 724 253 098 [ 042 230 ]

Fleckenstein 1998 314 416 125 086 [ 023 319 ]

Keiding 1997 1954 1048 355 169 [ 087 327 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]





005 02 1 5 20


(Continued )





Angelico 1999 316 417 90 080 [ 021 302 ]

Barnes 1997 228 1124 274 016 [ 004 063 ]

Fleckenstein 1998 214 616 130 038 [ 009 159 ]

Keiding 1997 1454 1548 368 083 [ 045 154 ]

Sama 1991 520 620 139 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]




005 02 1 5 20










Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 54 48 355 124 [ 061 254 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Sama 1991 520 620 201 083 [ 030 229 ]

005 02 1 5 20


(Continued )





Subtotal (95 CI) 78 77 645 063 [ 033 120 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 96 88 734 078 [ 045 138 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 36 37 266 102 [ 043 240 ]



005 02 1 5 20


(Continued )






Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Keiding 1997 054 148 1000 030 [ 001 712 ]

Total (95 CI) 54 48 1000 030 [ 001 712 ]




0001 001 01 1 10 100 1000











Fleckenstein 1998 214 016 100 567 [ 029 10891 ]

Keiding 1997 154 448 900 022 [ 003 192 ]

Total (95 CI) 68 64 1000 076 [ 020 286 ]




0001 001 01 1 10 100 1000










Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 158 148 905 089 [ 074 108 ]

01 02 05 1 2 5 10


(Continued )









Angelico 1999 816 1017 95 085 [ 045 160 ]

Subtotal (95 CI) 16 17 95 085 [ 045 160 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10










Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Subtotal (95 CI) 70 64 422 084 [ 063 111 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

01 02 05 1 2 5 10


(Continued )





Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 104 101 578 092 [ 072 117 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10












Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Subtotal (95 CI) 138 128 777 087 [ 071 107 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 36 37 223 094 [ 065 136 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10











Barnes 1997 128 624 611 014 [ 002 110 ]

Fleckenstein 1998 114 116 88 114 [ 008 1663 ]

Keiding 1997 154 348 300 030 [ 003 275 ]

Total (95 CI) 96 88 1000 028 [ 008 095 ]




0001 001 01 1 10 100 1000









Barnes 1997 328 724 277 037 [ 011 127 ]

Fleckenstein 1998 314 316 103 114 [ 027 478 ]

Keiding 1997 1454 1548 583 083 [ 045 154 ]

Pageaux 1995 226 124 38 185 [ 018 1908 ]

Total (95 CI) 122 112 1000 077 [ 047 127 ]




001 01 1 10 100











Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]

Total (95 CI) 14 16 1000 260 [ -096 616 ]



-10 -5 0 5 10









Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]

Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]



-100 -50 0 50 100










Angelico 1999 016 017 00 [ 00 00 ]

Barnes 1997 128 124 086 [ 006 1298 ]

Keiding 1997 554 548 089 [ 027 288 ]

Total (95 CI) 98 89 088 [ 030 260 ]




001 01 1 10 100


A P P E N D I C E S






cholicrsquo




odeoxycholicrsquo



cholicrsquo


cholicrsquo


cholicrsquo



odeoxycholicrsquo



(Continued)


cholicrsquo


drocholicrsquo


rodeoxycholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


sodeoxycholicrsquo



cholicrsquo




ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


ME


3 BILE ACID ME

4





(Continued)













5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10



(Continued)


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2



(Continued)

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10




changed




H I S T O R Y








None known




Internal sources


External sources








I N D E X T E R M S




MeSH check words

Humans





All outcomes




fully stated


adequately reported




ported













cyclosporine











(Continued)

















month


















studies

No of



follow-up



no treatment


12 TUDCA versus no

treatment




scenarios







start of bile acids



transplantation



transplantation





treatment duration






follow-up




maximum follow-up




follow-up



no treatment


72 TUDCA versus no

treatment





start of bile acid





transplantation








treatment duration






follow-up




maximum follow-up



end of treatment




transplantation




maximum follow-up







Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 116 108 935 080 [ 049 130 ]




01 02 05 1 2 5 10


(Continued )






Angelico 1999 316 217 65 159 [ 030 833 ]

Subtotal (95 CI) 16 17 65 159 [ 030 833 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




01 02 05 1 2 5 10










Angelico 1999 516 217 65 266 [ 060 1180 ]

Barnes 1997 828 724 253 098 [ 042 230 ]

Fleckenstein 1998 314 416 125 086 [ 023 319 ]

Keiding 1997 1954 1048 355 169 [ 087 327 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]





005 02 1 5 20


(Continued )





Angelico 1999 316 417 90 080 [ 021 302 ]

Barnes 1997 228 1124 274 016 [ 004 063 ]

Fleckenstein 1998 214 616 130 038 [ 009 159 ]

Keiding 1997 1454 1548 368 083 [ 045 154 ]

Sama 1991 520 620 139 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]




005 02 1 5 20










Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 54 48 355 124 [ 061 254 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Sama 1991 520 620 201 083 [ 030 229 ]

005 02 1 5 20


(Continued )





Subtotal (95 CI) 78 77 645 063 [ 033 120 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 96 88 734 078 [ 045 138 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 36 37 266 102 [ 043 240 ]



005 02 1 5 20


(Continued )






Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Keiding 1997 054 148 1000 030 [ 001 712 ]

Total (95 CI) 54 48 1000 030 [ 001 712 ]




0001 001 01 1 10 100 1000











Fleckenstein 1998 214 016 100 567 [ 029 10891 ]

Keiding 1997 154 448 900 022 [ 003 192 ]

Total (95 CI) 68 64 1000 076 [ 020 286 ]




0001 001 01 1 10 100 1000










Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 158 148 905 089 [ 074 108 ]

01 02 05 1 2 5 10


(Continued )









Angelico 1999 816 1017 95 085 [ 045 160 ]

Subtotal (95 CI) 16 17 95 085 [ 045 160 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10










Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Subtotal (95 CI) 70 64 422 084 [ 063 111 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

01 02 05 1 2 5 10


(Continued )





Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 104 101 578 092 [ 072 117 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10












Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Subtotal (95 CI) 138 128 777 087 [ 071 107 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 36 37 223 094 [ 065 136 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10











Barnes 1997 128 624 611 014 [ 002 110 ]

Fleckenstein 1998 114 116 88 114 [ 008 1663 ]

Keiding 1997 154 348 300 030 [ 003 275 ]

Total (95 CI) 96 88 1000 028 [ 008 095 ]




0001 001 01 1 10 100 1000









Barnes 1997 328 724 277 037 [ 011 127 ]

Fleckenstein 1998 314 316 103 114 [ 027 478 ]

Keiding 1997 1454 1548 583 083 [ 045 154 ]

Pageaux 1995 226 124 38 185 [ 018 1908 ]

Total (95 CI) 122 112 1000 077 [ 047 127 ]




001 01 1 10 100











Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]

Total (95 CI) 14 16 1000 260 [ -096 616 ]



-10 -5 0 5 10









Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]

Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]



-100 -50 0 50 100










Angelico 1999 016 017 00 [ 00 00 ]

Barnes 1997 128 124 086 [ 006 1298 ]

Keiding 1997 554 548 089 [ 027 288 ]

Total (95 CI) 98 89 088 [ 030 260 ]




001 01 1 10 100


A P P E N D I C E S






cholicrsquo




odeoxycholicrsquo



cholicrsquo


cholicrsquo


cholicrsquo



odeoxycholicrsquo



(Continued)


cholicrsquo


drocholicrsquo


rodeoxycholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


sodeoxycholicrsquo



cholicrsquo




ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


ME


3 BILE ACID ME

4





(Continued)













5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10



(Continued)


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2



(Continued)

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10




changed




H I S T O R Y








None known




Internal sources


External sources








I N D E X T E R M S




MeSH check words

Humans



(Continued)

















month


















studies

No of



follow-up



no treatment


12 TUDCA versus no

treatment




scenarios







start of bile acids



transplantation



transplantation





treatment duration






follow-up




maximum follow-up




follow-up



no treatment


72 TUDCA versus no

treatment





start of bile acid





transplantation








treatment duration






follow-up




maximum follow-up



end of treatment




transplantation




maximum follow-up







Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 116 108 935 080 [ 049 130 ]




01 02 05 1 2 5 10


(Continued )






Angelico 1999 316 217 65 159 [ 030 833 ]

Subtotal (95 CI) 16 17 65 159 [ 030 833 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




01 02 05 1 2 5 10










Angelico 1999 516 217 65 266 [ 060 1180 ]

Barnes 1997 828 724 253 098 [ 042 230 ]

Fleckenstein 1998 314 416 125 086 [ 023 319 ]

Keiding 1997 1954 1048 355 169 [ 087 327 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]





005 02 1 5 20


(Continued )





Angelico 1999 316 417 90 080 [ 021 302 ]

Barnes 1997 228 1124 274 016 [ 004 063 ]

Fleckenstein 1998 214 616 130 038 [ 009 159 ]

Keiding 1997 1454 1548 368 083 [ 045 154 ]

Sama 1991 520 620 139 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]




005 02 1 5 20










Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 54 48 355 124 [ 061 254 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Sama 1991 520 620 201 083 [ 030 229 ]

005 02 1 5 20


(Continued )





Subtotal (95 CI) 78 77 645 063 [ 033 120 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 96 88 734 078 [ 045 138 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 36 37 266 102 [ 043 240 ]



005 02 1 5 20


(Continued )






Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Keiding 1997 054 148 1000 030 [ 001 712 ]

Total (95 CI) 54 48 1000 030 [ 001 712 ]




0001 001 01 1 10 100 1000











Fleckenstein 1998 214 016 100 567 [ 029 10891 ]

Keiding 1997 154 448 900 022 [ 003 192 ]

Total (95 CI) 68 64 1000 076 [ 020 286 ]




0001 001 01 1 10 100 1000










Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 158 148 905 089 [ 074 108 ]

01 02 05 1 2 5 10


(Continued )









Angelico 1999 816 1017 95 085 [ 045 160 ]

Subtotal (95 CI) 16 17 95 085 [ 045 160 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10










Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Subtotal (95 CI) 70 64 422 084 [ 063 111 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

01 02 05 1 2 5 10


(Continued )





Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 104 101 578 092 [ 072 117 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10












Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Subtotal (95 CI) 138 128 777 087 [ 071 107 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 36 37 223 094 [ 065 136 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10











Barnes 1997 128 624 611 014 [ 002 110 ]

Fleckenstein 1998 114 116 88 114 [ 008 1663 ]

Keiding 1997 154 348 300 030 [ 003 275 ]

Total (95 CI) 96 88 1000 028 [ 008 095 ]




0001 001 01 1 10 100 1000









Barnes 1997 328 724 277 037 [ 011 127 ]

Fleckenstein 1998 314 316 103 114 [ 027 478 ]

Keiding 1997 1454 1548 583 083 [ 045 154 ]

Pageaux 1995 226 124 38 185 [ 018 1908 ]

Total (95 CI) 122 112 1000 077 [ 047 127 ]




001 01 1 10 100











Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]

Total (95 CI) 14 16 1000 260 [ -096 616 ]



-10 -5 0 5 10









Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]

Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]



-100 -50 0 50 100










Angelico 1999 016 017 00 [ 00 00 ]

Barnes 1997 128 124 086 [ 006 1298 ]

Keiding 1997 554 548 089 [ 027 288 ]

Total (95 CI) 98 89 088 [ 030 260 ]




001 01 1 10 100


A P P E N D I C E S






cholicrsquo




odeoxycholicrsquo



cholicrsquo


cholicrsquo


cholicrsquo



odeoxycholicrsquo



(Continued)


cholicrsquo


drocholicrsquo


rodeoxycholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


sodeoxycholicrsquo



cholicrsquo




ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


ME


3 BILE ACID ME

4





(Continued)













5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10



(Continued)


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2



(Continued)

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10




changed




H I S T O R Y








None known




Internal sources


External sources








I N D E X T E R M S




MeSH check words

Humans






studies

No of



follow-up



no treatment


12 TUDCA versus no

treatment




scenarios







start of bile acids



transplantation



transplantation





treatment duration






follow-up




maximum follow-up




follow-up



no treatment


72 TUDCA versus no

treatment





start of bile acid





transplantation








treatment duration






follow-up




maximum follow-up



end of treatment




transplantation




maximum follow-up







Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 116 108 935 080 [ 049 130 ]




01 02 05 1 2 5 10


(Continued )






Angelico 1999 316 217 65 159 [ 030 833 ]

Subtotal (95 CI) 16 17 65 159 [ 030 833 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




01 02 05 1 2 5 10










Angelico 1999 516 217 65 266 [ 060 1180 ]

Barnes 1997 828 724 253 098 [ 042 230 ]

Fleckenstein 1998 314 416 125 086 [ 023 319 ]

Keiding 1997 1954 1048 355 169 [ 087 327 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]





005 02 1 5 20


(Continued )





Angelico 1999 316 417 90 080 [ 021 302 ]

Barnes 1997 228 1124 274 016 [ 004 063 ]

Fleckenstein 1998 214 616 130 038 [ 009 159 ]

Keiding 1997 1454 1548 368 083 [ 045 154 ]

Sama 1991 520 620 139 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]




005 02 1 5 20










Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 54 48 355 124 [ 061 254 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Sama 1991 520 620 201 083 [ 030 229 ]

005 02 1 5 20


(Continued )





Subtotal (95 CI) 78 77 645 063 [ 033 120 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 96 88 734 078 [ 045 138 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 36 37 266 102 [ 043 240 ]



005 02 1 5 20


(Continued )






Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Keiding 1997 054 148 1000 030 [ 001 712 ]

Total (95 CI) 54 48 1000 030 [ 001 712 ]




0001 001 01 1 10 100 1000











Fleckenstein 1998 214 016 100 567 [ 029 10891 ]

Keiding 1997 154 448 900 022 [ 003 192 ]

Total (95 CI) 68 64 1000 076 [ 020 286 ]




0001 001 01 1 10 100 1000










Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 158 148 905 089 [ 074 108 ]

01 02 05 1 2 5 10


(Continued )









Angelico 1999 816 1017 95 085 [ 045 160 ]

Subtotal (95 CI) 16 17 95 085 [ 045 160 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10










Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Subtotal (95 CI) 70 64 422 084 [ 063 111 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

01 02 05 1 2 5 10


(Continued )





Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 104 101 578 092 [ 072 117 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10












Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Subtotal (95 CI) 138 128 777 087 [ 071 107 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 36 37 223 094 [ 065 136 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10











Barnes 1997 128 624 611 014 [ 002 110 ]

Fleckenstein 1998 114 116 88 114 [ 008 1663 ]

Keiding 1997 154 348 300 030 [ 003 275 ]

Total (95 CI) 96 88 1000 028 [ 008 095 ]




0001 001 01 1 10 100 1000









Barnes 1997 328 724 277 037 [ 011 127 ]

Fleckenstein 1998 314 316 103 114 [ 027 478 ]

Keiding 1997 1454 1548 583 083 [ 045 154 ]

Pageaux 1995 226 124 38 185 [ 018 1908 ]

Total (95 CI) 122 112 1000 077 [ 047 127 ]




001 01 1 10 100











Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]

Total (95 CI) 14 16 1000 260 [ -096 616 ]



-10 -5 0 5 10









Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]

Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]



-100 -50 0 50 100










Angelico 1999 016 017 00 [ 00 00 ]

Barnes 1997 128 124 086 [ 006 1298 ]

Keiding 1997 554 548 089 [ 027 288 ]

Total (95 CI) 98 89 088 [ 030 260 ]




001 01 1 10 100


A P P E N D I C E S






cholicrsquo




odeoxycholicrsquo



cholicrsquo


cholicrsquo


cholicrsquo



odeoxycholicrsquo



(Continued)


cholicrsquo


drocholicrsquo


rodeoxycholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


sodeoxycholicrsquo



cholicrsquo




ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


ME


3 BILE ACID ME

4





(Continued)













5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10



(Continued)


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2



(Continued)

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10




changed




H I S T O R Y








None known




Internal sources


External sources








I N D E X T E R M S




MeSH check words

Humans




transplantation








treatment duration






follow-up




maximum follow-up



end of treatment




transplantation




maximum follow-up







Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 116 108 935 080 [ 049 130 ]




01 02 05 1 2 5 10


(Continued )






Angelico 1999 316 217 65 159 [ 030 833 ]

Subtotal (95 CI) 16 17 65 159 [ 030 833 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




01 02 05 1 2 5 10










Angelico 1999 516 217 65 266 [ 060 1180 ]

Barnes 1997 828 724 253 098 [ 042 230 ]

Fleckenstein 1998 314 416 125 086 [ 023 319 ]

Keiding 1997 1954 1048 355 169 [ 087 327 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]





005 02 1 5 20


(Continued )





Angelico 1999 316 417 90 080 [ 021 302 ]

Barnes 1997 228 1124 274 016 [ 004 063 ]

Fleckenstein 1998 214 616 130 038 [ 009 159 ]

Keiding 1997 1454 1548 368 083 [ 045 154 ]

Sama 1991 520 620 139 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]




005 02 1 5 20










Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 54 48 355 124 [ 061 254 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Sama 1991 520 620 201 083 [ 030 229 ]

005 02 1 5 20


(Continued )





Subtotal (95 CI) 78 77 645 063 [ 033 120 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 96 88 734 078 [ 045 138 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 36 37 266 102 [ 043 240 ]



005 02 1 5 20


(Continued )






Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Keiding 1997 054 148 1000 030 [ 001 712 ]

Total (95 CI) 54 48 1000 030 [ 001 712 ]




0001 001 01 1 10 100 1000











Fleckenstein 1998 214 016 100 567 [ 029 10891 ]

Keiding 1997 154 448 900 022 [ 003 192 ]

Total (95 CI) 68 64 1000 076 [ 020 286 ]




0001 001 01 1 10 100 1000










Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 158 148 905 089 [ 074 108 ]

01 02 05 1 2 5 10


(Continued )









Angelico 1999 816 1017 95 085 [ 045 160 ]

Subtotal (95 CI) 16 17 95 085 [ 045 160 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10










Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Subtotal (95 CI) 70 64 422 084 [ 063 111 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

01 02 05 1 2 5 10


(Continued )





Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 104 101 578 092 [ 072 117 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10












Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Subtotal (95 CI) 138 128 777 087 [ 071 107 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 36 37 223 094 [ 065 136 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10











Barnes 1997 128 624 611 014 [ 002 110 ]

Fleckenstein 1998 114 116 88 114 [ 008 1663 ]

Keiding 1997 154 348 300 030 [ 003 275 ]

Total (95 CI) 96 88 1000 028 [ 008 095 ]




0001 001 01 1 10 100 1000









Barnes 1997 328 724 277 037 [ 011 127 ]

Fleckenstein 1998 314 316 103 114 [ 027 478 ]

Keiding 1997 1454 1548 583 083 [ 045 154 ]

Pageaux 1995 226 124 38 185 [ 018 1908 ]

Total (95 CI) 122 112 1000 077 [ 047 127 ]




001 01 1 10 100











Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]

Total (95 CI) 14 16 1000 260 [ -096 616 ]



-10 -5 0 5 10









Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]

Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]



-100 -50 0 50 100










Angelico 1999 016 017 00 [ 00 00 ]

Barnes 1997 128 124 086 [ 006 1298 ]

Keiding 1997 554 548 089 [ 027 288 ]

Total (95 CI) 98 89 088 [ 030 260 ]




001 01 1 10 100


A P P E N D I C E S






cholicrsquo




odeoxycholicrsquo



cholicrsquo


cholicrsquo


cholicrsquo



odeoxycholicrsquo



(Continued)


cholicrsquo


drocholicrsquo


rodeoxycholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


sodeoxycholicrsquo



cholicrsquo




ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


ME


3 BILE ACID ME

4





(Continued)













5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10



(Continued)


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2



(Continued)

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10




changed




H I S T O R Y








None known




Internal sources


External sources








I N D E X T E R M S




MeSH check words

Humans






Angelico 1999 316 217 65 159 [ 030 833 ]

Subtotal (95 CI) 16 17 65 159 [ 030 833 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




01 02 05 1 2 5 10










Angelico 1999 516 217 65 266 [ 060 1180 ]

Barnes 1997 828 724 253 098 [ 042 230 ]

Fleckenstein 1998 314 416 125 086 [ 023 319 ]

Keiding 1997 1954 1048 355 169 [ 087 327 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 130 [ 086 196 ]





005 02 1 5 20


(Continued )





Angelico 1999 316 417 90 080 [ 021 302 ]

Barnes 1997 228 1124 274 016 [ 004 063 ]

Fleckenstein 1998 214 616 130 038 [ 009 159 ]

Keiding 1997 1454 1548 368 083 [ 045 154 ]

Sama 1991 520 620 139 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]




005 02 1 5 20










Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 54 48 355 124 [ 061 254 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Sama 1991 520 620 201 083 [ 030 229 ]

005 02 1 5 20


(Continued )





Subtotal (95 CI) 78 77 645 063 [ 033 120 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 96 88 734 078 [ 045 138 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 36 37 266 102 [ 043 240 ]



005 02 1 5 20


(Continued )






Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Keiding 1997 054 148 1000 030 [ 001 712 ]

Total (95 CI) 54 48 1000 030 [ 001 712 ]




0001 001 01 1 10 100 1000











Fleckenstein 1998 214 016 100 567 [ 029 10891 ]

Keiding 1997 154 448 900 022 [ 003 192 ]

Total (95 CI) 68 64 1000 076 [ 020 286 ]




0001 001 01 1 10 100 1000










Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 158 148 905 089 [ 074 108 ]

01 02 05 1 2 5 10


(Continued )









Angelico 1999 816 1017 95 085 [ 045 160 ]

Subtotal (95 CI) 16 17 95 085 [ 045 160 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10










Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Subtotal (95 CI) 70 64 422 084 [ 063 111 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

01 02 05 1 2 5 10


(Continued )





Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 104 101 578 092 [ 072 117 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10












Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Subtotal (95 CI) 138 128 777 087 [ 071 107 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 36 37 223 094 [ 065 136 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10











Barnes 1997 128 624 611 014 [ 002 110 ]

Fleckenstein 1998 114 116 88 114 [ 008 1663 ]

Keiding 1997 154 348 300 030 [ 003 275 ]

Total (95 CI) 96 88 1000 028 [ 008 095 ]




0001 001 01 1 10 100 1000









Barnes 1997 328 724 277 037 [ 011 127 ]

Fleckenstein 1998 314 316 103 114 [ 027 478 ]

Keiding 1997 1454 1548 583 083 [ 045 154 ]

Pageaux 1995 226 124 38 185 [ 018 1908 ]

Total (95 CI) 122 112 1000 077 [ 047 127 ]




001 01 1 10 100











Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]

Total (95 CI) 14 16 1000 260 [ -096 616 ]



-10 -5 0 5 10









Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]

Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]



-100 -50 0 50 100










Angelico 1999 016 017 00 [ 00 00 ]

Barnes 1997 128 124 086 [ 006 1298 ]

Keiding 1997 554 548 089 [ 027 288 ]

Total (95 CI) 98 89 088 [ 030 260 ]




001 01 1 10 100


A P P E N D I C E S






cholicrsquo




odeoxycholicrsquo



cholicrsquo


cholicrsquo


cholicrsquo



odeoxycholicrsquo



(Continued)


cholicrsquo


drocholicrsquo


rodeoxycholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


sodeoxycholicrsquo



cholicrsquo




ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


ME


3 BILE ACID ME

4





(Continued)













5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10



(Continued)


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2



(Continued)

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10




changed




H I S T O R Y








None known




Internal sources


External sources








I N D E X T E R M S




MeSH check words

Humans





Angelico 1999 316 417 90 080 [ 021 302 ]

Barnes 1997 228 1124 274 016 [ 004 063 ]

Fleckenstein 1998 214 616 130 038 [ 009 159 ]

Keiding 1997 1454 1548 368 083 [ 045 154 ]

Sama 1991 520 620 139 083 [ 030 229 ]

Subtotal (95 CI) 132 125 1000 058 [ 038 090 ]




005 02 1 5 20










Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 54 48 355 124 [ 061 254 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Sama 1991 520 620 201 083 [ 030 229 ]

005 02 1 5 20


(Continued )





Subtotal (95 CI) 78 77 645 063 [ 033 120 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 96 88 734 078 [ 045 138 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 36 37 266 102 [ 043 240 ]



005 02 1 5 20


(Continued )






Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Keiding 1997 054 148 1000 030 [ 001 712 ]

Total (95 CI) 54 48 1000 030 [ 001 712 ]




0001 001 01 1 10 100 1000











Fleckenstein 1998 214 016 100 567 [ 029 10891 ]

Keiding 1997 154 448 900 022 [ 003 192 ]

Total (95 CI) 68 64 1000 076 [ 020 286 ]




0001 001 01 1 10 100 1000










Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 158 148 905 089 [ 074 108 ]

01 02 05 1 2 5 10


(Continued )









Angelico 1999 816 1017 95 085 [ 045 160 ]

Subtotal (95 CI) 16 17 95 085 [ 045 160 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10










Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Subtotal (95 CI) 70 64 422 084 [ 063 111 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

01 02 05 1 2 5 10


(Continued )





Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 104 101 578 092 [ 072 117 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10












Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Subtotal (95 CI) 138 128 777 087 [ 071 107 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 36 37 223 094 [ 065 136 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10











Barnes 1997 128 624 611 014 [ 002 110 ]

Fleckenstein 1998 114 116 88 114 [ 008 1663 ]

Keiding 1997 154 348 300 030 [ 003 275 ]

Total (95 CI) 96 88 1000 028 [ 008 095 ]




0001 001 01 1 10 100 1000









Barnes 1997 328 724 277 037 [ 011 127 ]

Fleckenstein 1998 314 316 103 114 [ 027 478 ]

Keiding 1997 1454 1548 583 083 [ 045 154 ]

Pageaux 1995 226 124 38 185 [ 018 1908 ]

Total (95 CI) 122 112 1000 077 [ 047 127 ]




001 01 1 10 100











Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]

Total (95 CI) 14 16 1000 260 [ -096 616 ]



-10 -5 0 5 10









Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]

Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]



-100 -50 0 50 100










Angelico 1999 016 017 00 [ 00 00 ]

Barnes 1997 128 124 086 [ 006 1298 ]

Keiding 1997 554 548 089 [ 027 288 ]

Total (95 CI) 98 89 088 [ 030 260 ]




001 01 1 10 100


A P P E N D I C E S






cholicrsquo




odeoxycholicrsquo



cholicrsquo


cholicrsquo


cholicrsquo



odeoxycholicrsquo



(Continued)


cholicrsquo


drocholicrsquo


rodeoxycholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


sodeoxycholicrsquo



cholicrsquo




ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


ME


3 BILE ACID ME

4





(Continued)













5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10



(Continued)


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2



(Continued)

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10




changed




H I S T O R Y








None known




Internal sources


External sources








I N D E X T E R M S




MeSH check words

Humans





Subtotal (95 CI) 78 77 645 063 [ 033 120 ]




Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Barnes 1997 228 724 253 024 [ 006 107 ]

Fleckenstein 1998 214 416 125 057 [ 012 266 ]

Keiding 1997 1454 1048 355 124 [ 061 254 ]

Subtotal (95 CI) 96 88 734 078 [ 045 138 ]





Angelico 1999 316 217 65 159 [ 030 833 ]

Sama 1991 520 620 201 083 [ 030 229 ]

Subtotal (95 CI) 36 37 266 102 [ 043 240 ]



005 02 1 5 20


(Continued )






Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Keiding 1997 054 148 1000 030 [ 001 712 ]

Total (95 CI) 54 48 1000 030 [ 001 712 ]




0001 001 01 1 10 100 1000











Fleckenstein 1998 214 016 100 567 [ 029 10891 ]

Keiding 1997 154 448 900 022 [ 003 192 ]

Total (95 CI) 68 64 1000 076 [ 020 286 ]




0001 001 01 1 10 100 1000










Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 158 148 905 089 [ 074 108 ]

01 02 05 1 2 5 10


(Continued )









Angelico 1999 816 1017 95 085 [ 045 160 ]

Subtotal (95 CI) 16 17 95 085 [ 045 160 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10










Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Subtotal (95 CI) 70 64 422 084 [ 063 111 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

01 02 05 1 2 5 10


(Continued )





Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 104 101 578 092 [ 072 117 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10












Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Subtotal (95 CI) 138 128 777 087 [ 071 107 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 36 37 223 094 [ 065 136 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10











Barnes 1997 128 624 611 014 [ 002 110 ]

Fleckenstein 1998 114 116 88 114 [ 008 1663 ]

Keiding 1997 154 348 300 030 [ 003 275 ]

Total (95 CI) 96 88 1000 028 [ 008 095 ]




0001 001 01 1 10 100 1000









Barnes 1997 328 724 277 037 [ 011 127 ]

Fleckenstein 1998 314 316 103 114 [ 027 478 ]

Keiding 1997 1454 1548 583 083 [ 045 154 ]

Pageaux 1995 226 124 38 185 [ 018 1908 ]

Total (95 CI) 122 112 1000 077 [ 047 127 ]




001 01 1 10 100











Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]

Total (95 CI) 14 16 1000 260 [ -096 616 ]



-10 -5 0 5 10









Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]

Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]



-100 -50 0 50 100










Angelico 1999 016 017 00 [ 00 00 ]

Barnes 1997 128 124 086 [ 006 1298 ]

Keiding 1997 554 548 089 [ 027 288 ]

Total (95 CI) 98 89 088 [ 030 260 ]




001 01 1 10 100


A P P E N D I C E S






cholicrsquo




odeoxycholicrsquo



cholicrsquo


cholicrsquo


cholicrsquo



odeoxycholicrsquo



(Continued)


cholicrsquo


drocholicrsquo


rodeoxycholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


sodeoxycholicrsquo



cholicrsquo




ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


ME


3 BILE ACID ME

4





(Continued)













5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10



(Continued)


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2



(Continued)

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10




changed




H I S T O R Y








None known




Internal sources


External sources








I N D E X T E R M S




MeSH check words

Humans






Total (95 CI) 132 125 1000 085 [ 053 136 ]




005 02 1 5 20










Keiding 1997 054 148 1000 030 [ 001 712 ]

Total (95 CI) 54 48 1000 030 [ 001 712 ]




0001 001 01 1 10 100 1000











Fleckenstein 1998 214 016 100 567 [ 029 10891 ]

Keiding 1997 154 448 900 022 [ 003 192 ]

Total (95 CI) 68 64 1000 076 [ 020 286 ]




0001 001 01 1 10 100 1000










Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 158 148 905 089 [ 074 108 ]

01 02 05 1 2 5 10


(Continued )









Angelico 1999 816 1017 95 085 [ 045 160 ]

Subtotal (95 CI) 16 17 95 085 [ 045 160 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10










Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Subtotal (95 CI) 70 64 422 084 [ 063 111 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

01 02 05 1 2 5 10


(Continued )





Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 104 101 578 092 [ 072 117 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10












Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Subtotal (95 CI) 138 128 777 087 [ 071 107 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 36 37 223 094 [ 065 136 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10











Barnes 1997 128 624 611 014 [ 002 110 ]

Fleckenstein 1998 114 116 88 114 [ 008 1663 ]

Keiding 1997 154 348 300 030 [ 003 275 ]

Total (95 CI) 96 88 1000 028 [ 008 095 ]




0001 001 01 1 10 100 1000









Barnes 1997 328 724 277 037 [ 011 127 ]

Fleckenstein 1998 314 316 103 114 [ 027 478 ]

Keiding 1997 1454 1548 583 083 [ 045 154 ]

Pageaux 1995 226 124 38 185 [ 018 1908 ]

Total (95 CI) 122 112 1000 077 [ 047 127 ]




001 01 1 10 100











Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]

Total (95 CI) 14 16 1000 260 [ -096 616 ]



-10 -5 0 5 10









Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]

Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]



-100 -50 0 50 100










Angelico 1999 016 017 00 [ 00 00 ]

Barnes 1997 128 124 086 [ 006 1298 ]

Keiding 1997 554 548 089 [ 027 288 ]

Total (95 CI) 98 89 088 [ 030 260 ]




001 01 1 10 100


A P P E N D I C E S






cholicrsquo




odeoxycholicrsquo



cholicrsquo


cholicrsquo


cholicrsquo



odeoxycholicrsquo



(Continued)


cholicrsquo


drocholicrsquo


rodeoxycholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


sodeoxycholicrsquo



cholicrsquo




ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


ME


3 BILE ACID ME

4





(Continued)













5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10



(Continued)


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2



(Continued)

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10




changed




H I S T O R Y








None known




Internal sources


External sources








I N D E X T E R M S




MeSH check words

Humans










Fleckenstein 1998 214 016 100 567 [ 029 10891 ]

Keiding 1997 154 448 900 022 [ 003 192 ]

Total (95 CI) 68 64 1000 076 [ 020 286 ]




0001 001 01 1 10 100 1000










Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 158 148 905 089 [ 074 108 ]

01 02 05 1 2 5 10


(Continued )









Angelico 1999 816 1017 95 085 [ 045 160 ]

Subtotal (95 CI) 16 17 95 085 [ 045 160 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10










Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Subtotal (95 CI) 70 64 422 084 [ 063 111 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

01 02 05 1 2 5 10


(Continued )





Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 104 101 578 092 [ 072 117 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10












Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Subtotal (95 CI) 138 128 777 087 [ 071 107 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 36 37 223 094 [ 065 136 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10











Barnes 1997 128 624 611 014 [ 002 110 ]

Fleckenstein 1998 114 116 88 114 [ 008 1663 ]

Keiding 1997 154 348 300 030 [ 003 275 ]

Total (95 CI) 96 88 1000 028 [ 008 095 ]




0001 001 01 1 10 100 1000









Barnes 1997 328 724 277 037 [ 011 127 ]

Fleckenstein 1998 314 316 103 114 [ 027 478 ]

Keiding 1997 1454 1548 583 083 [ 045 154 ]

Pageaux 1995 226 124 38 185 [ 018 1908 ]

Total (95 CI) 122 112 1000 077 [ 047 127 ]




001 01 1 10 100











Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]

Total (95 CI) 14 16 1000 260 [ -096 616 ]



-10 -5 0 5 10









Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]

Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]



-100 -50 0 50 100










Angelico 1999 016 017 00 [ 00 00 ]

Barnes 1997 128 124 086 [ 006 1298 ]

Keiding 1997 554 548 089 [ 027 288 ]

Total (95 CI) 98 89 088 [ 030 260 ]




001 01 1 10 100


A P P E N D I C E S






cholicrsquo




odeoxycholicrsquo



cholicrsquo


cholicrsquo


cholicrsquo



odeoxycholicrsquo



(Continued)


cholicrsquo


drocholicrsquo


rodeoxycholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


sodeoxycholicrsquo



cholicrsquo




ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


ME


3 BILE ACID ME

4





(Continued)













5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10



(Continued)


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2



(Continued)

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10




changed




H I S T O R Y








None known




Internal sources


External sources








I N D E X T E R M S




MeSH check words

Humans









Angelico 1999 816 1017 95 085 [ 045 160 ]

Subtotal (95 CI) 16 17 95 085 [ 045 160 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10










Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Subtotal (95 CI) 70 64 422 084 [ 063 111 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

01 02 05 1 2 5 10


(Continued )





Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 104 101 578 092 [ 072 117 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10












Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Subtotal (95 CI) 138 128 777 087 [ 071 107 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 36 37 223 094 [ 065 136 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10











Barnes 1997 128 624 611 014 [ 002 110 ]

Fleckenstein 1998 114 116 88 114 [ 008 1663 ]

Keiding 1997 154 348 300 030 [ 003 275 ]

Total (95 CI) 96 88 1000 028 [ 008 095 ]




0001 001 01 1 10 100 1000









Barnes 1997 328 724 277 037 [ 011 127 ]

Fleckenstein 1998 314 316 103 114 [ 027 478 ]

Keiding 1997 1454 1548 583 083 [ 045 154 ]

Pageaux 1995 226 124 38 185 [ 018 1908 ]

Total (95 CI) 122 112 1000 077 [ 047 127 ]




001 01 1 10 100











Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]

Total (95 CI) 14 16 1000 260 [ -096 616 ]



-10 -5 0 5 10









Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]

Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]



-100 -50 0 50 100










Angelico 1999 016 017 00 [ 00 00 ]

Barnes 1997 128 124 086 [ 006 1298 ]

Keiding 1997 554 548 089 [ 027 288 ]

Total (95 CI) 98 89 088 [ 030 260 ]




001 01 1 10 100


A P P E N D I C E S






cholicrsquo




odeoxycholicrsquo



cholicrsquo


cholicrsquo


cholicrsquo



odeoxycholicrsquo



(Continued)


cholicrsquo


drocholicrsquo


rodeoxycholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


sodeoxycholicrsquo



cholicrsquo




ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


ME


3 BILE ACID ME

4





(Continued)













5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10



(Continued)


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2



(Continued)

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10




changed




H I S T O R Y








None known




Internal sources


External sources








I N D E X T E R M S




MeSH check words

Humans





Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 104 101 578 092 [ 072 117 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10












Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Subtotal (95 CI) 138 128 777 087 [ 071 107 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 36 37 223 094 [ 065 136 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10











Barnes 1997 128 624 611 014 [ 002 110 ]

Fleckenstein 1998 114 116 88 114 [ 008 1663 ]

Keiding 1997 154 348 300 030 [ 003 275 ]

Total (95 CI) 96 88 1000 028 [ 008 095 ]




0001 001 01 1 10 100 1000









Barnes 1997 328 724 277 037 [ 011 127 ]

Fleckenstein 1998 314 316 103 114 [ 027 478 ]

Keiding 1997 1454 1548 583 083 [ 045 154 ]

Pageaux 1995 226 124 38 185 [ 018 1908 ]

Total (95 CI) 122 112 1000 077 [ 047 127 ]




001 01 1 10 100











Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]

Total (95 CI) 14 16 1000 260 [ -096 616 ]



-10 -5 0 5 10









Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]

Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]



-100 -50 0 50 100










Angelico 1999 016 017 00 [ 00 00 ]

Barnes 1997 128 124 086 [ 006 1298 ]

Keiding 1997 554 548 089 [ 027 288 ]

Total (95 CI) 98 89 088 [ 030 260 ]




001 01 1 10 100


A P P E N D I C E S






cholicrsquo




odeoxycholicrsquo



cholicrsquo


cholicrsquo


cholicrsquo



odeoxycholicrsquo



(Continued)


cholicrsquo


drocholicrsquo


rodeoxycholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


sodeoxycholicrsquo



cholicrsquo




ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


ME


3 BILE ACID ME

4





(Continued)













5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10



(Continued)


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2



(Continued)

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10




changed




H I S T O R Y








None known




Internal sources


External sources








I N D E X T E R M S




MeSH check words

Humans











Barnes 1997 1728 1724 180 086 [ 058 127 ]

Fleckenstein 1998 814 916 83 102 [ 054 190 ]

Keiding 1997 3554 3248 333 097 [ 073 129 ]

Koneru 1993 316 916 89 033 [ 011 101 ]

Pageaux 1995 926 924 92 092 [ 044 193 ]

Subtotal (95 CI) 138 128 777 087 [ 071 107 ]





Angelico 1999 816 1017 95 085 [ 045 160 ]

Sama 1991 1320 1320 128 100 [ 063 158 ]

Subtotal (95 CI) 36 37 223 094 [ 065 136 ]




Total (95 CI) 174 165 1000 089 [ 074 106 ]




01 02 05 1 2 5 10











Barnes 1997 128 624 611 014 [ 002 110 ]

Fleckenstein 1998 114 116 88 114 [ 008 1663 ]

Keiding 1997 154 348 300 030 [ 003 275 ]

Total (95 CI) 96 88 1000 028 [ 008 095 ]




0001 001 01 1 10 100 1000









Barnes 1997 328 724 277 037 [ 011 127 ]

Fleckenstein 1998 314 316 103 114 [ 027 478 ]

Keiding 1997 1454 1548 583 083 [ 045 154 ]

Pageaux 1995 226 124 38 185 [ 018 1908 ]

Total (95 CI) 122 112 1000 077 [ 047 127 ]




001 01 1 10 100











Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]

Total (95 CI) 14 16 1000 260 [ -096 616 ]



-10 -5 0 5 10









Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]

Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]



-100 -50 0 50 100










Angelico 1999 016 017 00 [ 00 00 ]

Barnes 1997 128 124 086 [ 006 1298 ]

Keiding 1997 554 548 089 [ 027 288 ]

Total (95 CI) 98 89 088 [ 030 260 ]




001 01 1 10 100


A P P E N D I C E S






cholicrsquo




odeoxycholicrsquo



cholicrsquo


cholicrsquo


cholicrsquo



odeoxycholicrsquo



(Continued)


cholicrsquo


drocholicrsquo


rodeoxycholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


sodeoxycholicrsquo



cholicrsquo




ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


ME


3 BILE ACID ME

4





(Continued)













5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10



(Continued)


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2



(Continued)

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10




changed




H I S T O R Y








None known




Internal sources


External sources








I N D E X T E R M S




MeSH check words

Humans










Barnes 1997 128 624 611 014 [ 002 110 ]

Fleckenstein 1998 114 116 88 114 [ 008 1663 ]

Keiding 1997 154 348 300 030 [ 003 275 ]

Total (95 CI) 96 88 1000 028 [ 008 095 ]




0001 001 01 1 10 100 1000









Barnes 1997 328 724 277 037 [ 011 127 ]

Fleckenstein 1998 314 316 103 114 [ 027 478 ]

Keiding 1997 1454 1548 583 083 [ 045 154 ]

Pageaux 1995 226 124 38 185 [ 018 1908 ]

Total (95 CI) 122 112 1000 077 [ 047 127 ]




001 01 1 10 100











Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]

Total (95 CI) 14 16 1000 260 [ -096 616 ]



-10 -5 0 5 10









Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]

Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]



-100 -50 0 50 100










Angelico 1999 016 017 00 [ 00 00 ]

Barnes 1997 128 124 086 [ 006 1298 ]

Keiding 1997 554 548 089 [ 027 288 ]

Total (95 CI) 98 89 088 [ 030 260 ]




001 01 1 10 100


A P P E N D I C E S






cholicrsquo




odeoxycholicrsquo



cholicrsquo


cholicrsquo


cholicrsquo



odeoxycholicrsquo



(Continued)


cholicrsquo


drocholicrsquo


rodeoxycholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


sodeoxycholicrsquo



cholicrsquo




ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


ME


3 BILE ACID ME

4





(Continued)













5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10



(Continued)


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2



(Continued)

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10




changed




H I S T O R Y








None known




Internal sources


External sources








I N D E X T E R M S




MeSH check words

Humans










Fleckenstein 1998 14 319 (68) 16 059 (022) 1000 260 [ -096 616 ]

Total (95 CI) 14 16 1000 260 [ -096 616 ]



-10 -5 0 5 10









Barnes 1997 28 25 (17) 24 335 (13) 1000 -850 [ -1667 -033 ]

Total (95 CI) 28 24 1000 -850 [ -1667 -033 ]



-100 -50 0 50 100










Angelico 1999 016 017 00 [ 00 00 ]

Barnes 1997 128 124 086 [ 006 1298 ]

Keiding 1997 554 548 089 [ 027 288 ]

Total (95 CI) 98 89 088 [ 030 260 ]




001 01 1 10 100


A P P E N D I C E S






cholicrsquo




odeoxycholicrsquo



cholicrsquo


cholicrsquo


cholicrsquo



odeoxycholicrsquo



(Continued)


cholicrsquo


drocholicrsquo


rodeoxycholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


sodeoxycholicrsquo



cholicrsquo




ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


ME


3 BILE ACID ME

4





(Continued)













5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10



(Continued)


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2



(Continued)

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10




changed




H I S T O R Y








None known




Internal sources


External sources








I N D E X T E R M S




MeSH check words

Humans









Angelico 1999 016 017 00 [ 00 00 ]

Barnes 1997 128 124 086 [ 006 1298 ]

Keiding 1997 554 548 089 [ 027 288 ]

Total (95 CI) 98 89 088 [ 030 260 ]




001 01 1 10 100


A P P E N D I C E S






cholicrsquo




odeoxycholicrsquo



cholicrsquo


cholicrsquo


cholicrsquo



odeoxycholicrsquo



(Continued)


cholicrsquo


drocholicrsquo


rodeoxycholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


sodeoxycholicrsquo



cholicrsquo




ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


ME


3 BILE ACID ME

4





(Continued)













5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10



(Continued)


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2



(Continued)

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10




changed




H I S T O R Y








None known




Internal sources


External sources








I N D E X T E R M S




MeSH check words

Humans



(Continued)


cholicrsquo


drocholicrsquo


rodeoxycholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


cholicrsquo


sodeoxycholicrsquo



cholicrsquo




ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


ME


3 BILE ACID ME

4





(Continued)













5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10



(Continued)


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2



(Continued)

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10




changed




H I S T O R Y








None known




Internal sources


External sources








I N D E X T E R M S




MeSH check words

Humans



(Continued)













5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10



(Continued)


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2



(Continued)

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10




changed




H I S T O R Y








None known




Internal sources


External sources








I N D E X T E R M S




MeSH check words

Humans



(Continued)


ME


3 BILE ACID ME

4















5 1 or 2

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10


ME


3 BILE ACID ME

4















5 1 or 2



(Continued)

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10




changed




H I S T O R Y








None known




Internal sources


External sources








I N D E X T E R M S




MeSH check words

Humans



(Continued)

6 3 or 4

7 5 and 6


TRIAL ME

9 RANDOM

10 8 or 9

11 7 and 10




changed




H I S T O R Y








None known




Internal sources


External sources








I N D E X T E R M S




MeSH check words

Humans




Internal sources


External sources








I N D E X T E R M S




MeSH check words

Humans



Bile acids for liver-transplanted patients

Documents

Transcript of Bile acids for liver-transplanted patients