Komplit Kasus Ingris ES Edit 22 Agusts 2013

8/13/2019 Komplit Kasus Ingris ES Edit 22 Agusts 2013

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CHAPTER I

INTRODUCTION

Drug-induced allergic hepatitis is a liver-specific inflammatory reaction caused by

hypersensitivity to a particular drug. Although less common than other forms of drug-induced

hepatotoxicity, it has more serious clinical implications, the outcome can sometimes be fatal,

and it appears to increase in proportion to the number of prescribed drugs.1

The serious drug-related hepatotoxicity that is disabling or life-threatening or that

requires hospitalization. Although drug-related hepatotoxicity is uncommon for many drugs,

the reported incidence is between 1 in 10,000 and 1 in 100,000 patients, its true incidence is

difficult to determine. The numbers may be much higher, because of under reporting,

difficulties in detection or diagnosis, and incomplete observation of persons exposed. In most

cases, there is no effective treatment other than stopping the drug and providing general

supportive care. In the United States, drug-related hepatotoxicity is now the leading cause of

acute liver failure among patients referred for liver transplantation, most of whom have had

no prior liver disease, because of an intentional or unintentional overdose of acetaminophen,

the drug most often implicated in such cases.2

In contrast, hepatotoxicity associated with most other drugs is idiosyncratic, which

implies by definition that DILI develops in only a small proportion of subjects exposed to a

drug in therapeutic doses, and the risk of acute liver failure associated with idiosyncratic

hepatotoxins is usually less than 1 per 10,000 exposed patients. However, more than 1,000

drugs and herbal products have been associated with idiosyncratic hepatotoxicity, and taken

together idiosyncratic hepatotoxicity is responsible for more than 10% of all cases of acute

liver failure.3, 4

DILI accounts for 7% of reported drug adverse effects, 2% of jaundice in hospitals,

and approximately 30% of fulminant liver failure. DILI has replaced viral hepatitis as the

most apparent cause of acute liver failure. A brief search of commercial pharmacopoeia

databases suggests there are more than 700 drugs with reported hepatotoxicity and approved

for use in the United States. With an estimated background rate of idiopathic liver failure of 1

in 1,000,000, the U.S. Food and Drug Administration (FDA) has withdrawn drugs or

mandated relabeling for severe or fatal liver injury exceeding 1 in 50,000 individuals.5

Antituberculosis drug-induced liver injury (TB DILI) is a leading cause of DILI and

drug-induced acute liver failure (DIALF) in many of the developing world. Single center

registries of DILI continue to highlight the high incidence of DILI and DIALF, much of it


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due to diagnostic errors and inappropriate prescriptions. The clinical spectrum includes

asymptomatic elevation in liver tests to acute hepatitis and acute liver failure. TB DILI can

occur across all age groups including children with significant morbidity and mortality.

Although TB DILI develops more commonly in males, ALF is noted to be commoner in

females with a worse prognosis. Contrasting reports on the role of genetic and environmental

factors continue to be published. The presence of jaundice, hypoalbuminemia, ascites,

encephalopathy and high prothrombin time are poor prognostic markers.6, 7

The incidence has been reported to be higher in developing countries and factors such

as acute or chronic liver disease, indiscriminate use of drugs, malnutrition and more advanced

TB have been implicated. A high incidence of viral hepatitis has been reported to coexist in

patients with TB in developing countries, resulting in misdiagnosis of tuberculosis drugs

induced hepatotoxicity, especially if serological tests are not performed. A study from Nepal

reported the incidence of hepatotoxicity as 8%.7

These include isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA) and ethambutol

(EMB). Although a vast majority of patients tolerate the drugs, some develop adverse effects

of which hepatotoxicity is the most significant. Twenty percent of patients develop

asymptomatic elevation of liver enzymes which is self limiting (as a result of adaptation or

discontinuance) in a majority of patients but the outlook may be less favorable in those with

develop jaundice, ascites, encephalopathy or acute liver failure.5, 8

Furthermore, the ripple effects of hepatotoxicity include disruption of treatment with

potential for prolongation of treatment, genesis of drug resistance and suboptimal cure.

Hepatotoxicity or DILI due to antituberculosis drug-induced liver injury (DILI) encompasses

a wide spectrum of liver injury ranging from asymptomatic minimal elevation of liver

enzymes to acute liver failure, often leading to death or liver transplantation. Indeed, it is a

leading cause of drug-induced liver injury in India and of drug-induced acute liver failure

leading to death (DIALF).5, 9, 10

In this case we described a case of a boy 12 years old with drug induced hepatities

due to anti tuberculosis drugs. With suportive therapy has good result.


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CHAPTER 2

CASE RESUME

An 13 years old boy (MRM, medical record C183381, from Kota Waringin, Pangkalan Bun), body

weight 31,5 kg, height 145 cm was referred to Kariadi Hospital at October 16th 2009 with chief

complain jaundice, three and a half month before admited to the dr Kariadi hospital, the patient

complained cough for 1 week, fever subfebrile, no sputum, no cold, no petechie, no nausea, no

vomite, no diarrhea. The parents took him to Pangkalan Bun Hospital, and from laboratory and

rontgen investigation result the child was diagnosed with pulmonary tuberculosis by a Pediatrician,

and got anti tuberculosis therapy (ATT).

Two and a half month before admited to the dr Kariadi hospital, after consumtion of ATT for

one month, the patient complained sudden high fever for 5 days, continuously, icteric, headache,

myalgia, no gastrocnemius pain, heartburn, nausea, vomite 4-5 times / day, no diarrhea, no cough, no

cold. The child looked weak, loss of appetite, tawny-colored urine with normal volume, urinary

frequency, no dysuria, no urgency, and normal defecation.

The parents took him to the Pangkalan Bun hospital and administered for 9 days, the

laboratory examination revealed anaemia (Hb 6.1 g /dl), leukocytosis (21.000/mm3), AST 199 U/l,

ALT 272 U/l, total bilirubin 24.2 mg/dl, direct bilirubin 15.6 mg/dl, widal O titers of 1/320 and

positive plasmodium vivax. Anti tuberculosis drugs was stop due to the increasing of the liver

enzymes. The parent discharged the child from hospital due to negative improvement and want torefer to Kariadi hospital.

The child was never hepatities, severe illness, alergy history, and no often taken drugs or

herbal medicine, similar like his family. Total scoring TB of this case was 1, from chest x ray. There

was not other family or neighboard with chronic or bleeding cough. He has already full basic

imunization.

The child was administered to emergency room of Kariadi hospital, he was composmentis,

weak, pale, icteric, adequate spontaneous breathing, and sub febrile fever. He had epigastrial pain,

nausea, vomite more than 5 times/days, loss of appetite, tawny-colored urine and normal defecation.Physical examination found pulse, HR 84 x/minute, RR 24 x/minute, 37.5 C, normal BP 100/60

mmgHg. On Inspection, his conjunctiva was anemic, icteric sclera. In auscultation, lungs and the heart

sounds were normal. Abdominal palpation was flat, flexible, epigastrial pain, hypocondriaca dextra

pain, involving intestine sound normal, his liver was palpated 1/3-1/3 BH with a sharp border, elastic

and flat. There were no costovertebral tenderness, suprapubic pain and no gastrocnemius pain. The D5

NS infusion was administered, laboratory tests, and chest x rays, was conduct before the patient

admited to C1L1.

Laboratory examination revealed Hb 6.4 g/dl with normally RDW and erythrocytes index, Ht

18.2%, WBC 9.800/mm3, platelet count 522.000/mm3, Ureum 16 mg/dl, creatinine 0,57 mg/dl,


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calcium 2.29 mmol/L, sodium 138 mmol/L, potassium 3,5 mmol/L, chloride 108 mmol/L, blood

glucose 90 mg/dl, serum cholesterol 456 mg/dl, serum HDL 32 mg/dl, serum LDL 378 mg/dl, serum

trigliserid 229 mg/dl, total protein serum 5,6 g/dl, serum albumin 4,3 g/dl, total protein 6,1 gr/dl, AST

199 U/l, ALT 272 U/l, total bilirubine 22,92 mg/dl, direct bilirubine 16,9 mg/dl. Routine urine

examination showed negative proteinuria, urobilinogen 8, bilirubinurine 6, negative lekosit esterase,

sediment leucocyte 0-2, sediment erythrocyte 37,4/ Ul. The chest x rays impresion no cardiomegaly,

bronchitis acute and thickening of the hilar glands. Assesment was: observation of icteric, with

differential diagnosis were acute hepatities, drug induced hepatities, malaria and leptospirosis. And

normocitic normochromic anaemia.

Patient were treated in C1L1 with intravenous fluid D 10% 960/40/10 gtt/ minute, methicol

3x 1 tablet, urdafalk 2 x 250 mg, vitamin K 1 x 10 mg, vitamin A 1 x 6.000 iu. Program: transfusion

PRC 300 cc. Diet: diet hepatities, 3 x 200 cc hepatosol.

History of Illness

The boy was stayed in C1L1 of Kariadi Hospital. During hospitalization, his progress of

illness was as follow:

Day two:Body weight 31,5 kg, height 145 cm, HAZ -1,59 SD, BMI -1,94 SD, complain

icteric, fever especially at night until 39 oC, epigastrial pain, abdominal discomfort, vomite and no

gastrocnemius pain. General condition: ill appearance, conscious, adequat spontaneus breathing, and

icteric. Physical examination showed t: 37.5 C, RR 24/min, HR: 92/min. Other physical

examinations same with the previous day. Assesment was: observation of icteric, with differential

diagnosis were acute hepatities, drug induced hepatities, malaria and leptospirosis. And normocitic

normochromic anaemia and well nourised. Programs: haematology analyser tubex TF, blood smear,

blood smear malaria, urinalisis, faeces routine, blood culture, urine culture. Counsultation to

Gastroentero-Hepatology, Haemotology and Nutrition. Therapy: intravenous fluid dextrose 10% with

maintenance sodium and potasium, amoxicillin injection, per oral medication and diet similar with the

previous day.

Day three-eight: complains: icteric, fever especially at night, epigastrial pain, abdominaldiscomfort. General condition: ill appearance, conscious. Physical examination showed: t: 37C, RR

24/min, HR:92 /min, other physical examinations equal with the previous day. Result counsultation

from Gastroentero-Hepatologi: suspect hepatities, sugesstion for hepatities screening,

antituberculosis therapy stop, add urdafalk. From Nutrition: porridge low fiber three times, 200 cc

hepatosol 3 times/ day, extra fruit sirup. Program: haematology analyser, blood smear, SGOT, SGPT,

total bilirubin, direct bilirubin, ICT malaria, hepatities screenings, and abdominal USG. Laboratory

result of IgM leptospirosis was positif but hepatities and malaria were negatif. From abdominal

ultrasonografi impresion hepatomegali, rough liver parenchime was posiblility of drug induced

hepatities with differential diagnose viral hepatities, suspect contracted gall bladder, there were no


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fattering liver or enlargement gall bladder. Assesment was:observation of icteric, with differential

diagnosis were drug induced hepatities and leptospirosis. Additional therapy with amoxicillin 500

mg 4 times/ day and others therapy unchanged. Diet: hepatities diet (porridge low fiber three times,

200 cc hepatosol 3 times/ day, extra fruit sirup.

Day nine-seventeen: complains: abdominal discomfort, no vomite, sometimes still febris.

General condition: conscious, adequately spontaneous breathing, icteric. Physical examination

showed: t: 37 C, RR:20 x/min, HR: 88x /min. Abdominal palpation was flat, flexible, no epigastrial

pain involving intestine sound normal, his liver was palpated - with a sharp border, elastic and

flat. Others physical examinations equal with the previous day. Programs: haematology analyser,

blood smear, SGOT, SGPT, total bilirubin, direct bilirubin, coagulation study, IgM, IgG CMV and

toxoplasmosis. Counsultation to Haematology impresion chronical inflamation. Result of screenig of

CMV and toxoplasmosis were negative. From urine culture revealed urinary tract infection with E.

Coli, abnormal coagulation. Assesment was:observation of icteric, with differential diagnosis was

drug induced hepatities and leptospirosis, urinary tract infection. Therapy: additional therapy with

amicacyn injection 2 x 150 mg, others therapy unchanged. Transfution of FFP 250 cc.

Day eighteen- tweenty eight: no abdominal discomfort, no febris. General condition: well,

conscious, icteric. Physical examination showed t: 37C, RR 20/min, HR: 92/min, conjunctiva was

not anemic, other physical examinations same with the previous day. Program: fine needle biopsi,

haematology analyser, blood smear, SGOT, SGPT, total bilirubin, direct bilirubin, alkalifosfatase,

gamma GT, total protein, albumin, coagulation study, cholesterol, trigliserid, urinalysis, liver biopsy.

Result of liver biopsy revealed hepatic injury due to drug induced hepatotoxic. Assesment was:

observation drug induced hepatities, leptospirosis, urinary tract infection. Therapy: intravenous fluid

medication stop, change with cefixime 2 x 150 mg, others therapy peroral similar.

Day tweenty nine-thirty one: Body weight 29 kg, still icteric. General condition: well

appearance, conscious, icteric. Physical examination showed a t 36,8C, RR 20/min, HR 92/min,

other physical examinations same with the previous day. Assesment was: observation drug induced

hepatities due to OAT, leptospirosis, and urinary tract infection. Program: abdominal USG evaluation.

Result of abdominal USG were impresion hepatomegali, structure of liver parenchime lookednormally, no intra and extra hepatic duct enlargement, and the gall bladder shape looked normally.

Therapy: cefixim stopped, others same with the previous day.

Day thirty two: Body weight 29 kg, still icteric, no abdominal discomfort, no fever. General

condition: well appearance, conscious, icteric. Physical examination showed a t 36,8C, RR 20/min,

HR 92/min, other physical examinations same with the previous day. Therapy: methicol 3 x 1 tablet,

urdafalk 2 x 250 mg, vitamin K 1 x 10 mg, vitamin A 1 x 6.000 iu. The patient discharge from Kariadi

hospital referred back to Pangkalan Bun Hospital with drug induced hepatities, leptospirosis and post

urinary tract infection.


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The icteric released after 8 months since went out from Kariadi Hospital, with haemoglobin

10,7 gr/dl, SGOT 29 U/l, SGPT 52 U/l, total bilirubin 3, the boy was counsulted to pediatrician in

Pangkalan Bun.

Table 1. Laboratory examination result in Kariadi Hospital

Date 16-10-09 17-10-09 21-10-09 26-10-09 2-11-09

Normal limit

Hb (g/dl) >11,5 6,4 10,5 9,4 8,2 9,2

Eritrosit (jt/mm3) 4,2-5,2 juta 3,82 3,97 2,85 3,98

Ht (%) 37-44 18,2 29,3 28,1 22,2 28,6

LED

Leukosit/mm 4.500-13.000 9.800 6.860 13.500 9.320 9.310

Trombosit/mm 150-400rb 522.000 397.000 366.000 460.000 510.000

MCV (fL) 77-101 78,0 76,8 77,7 75,5

MCH (pg) 23-31 27,3 27,4 28,7 28,3

MCHC (g/dl) 29-36 35,0 35,6 37,0 37,3

RDW % 11,6-14,8 21,7 21,0 20,8 19,7

PT 10-15 16,6/10,9 (1,5) 13,7/9,8PTT 23,4-36,8 43,3/31,7 (1,4) 42,9/29,2

TT 10,7-13,7 20,5/20 16,5/16

Fibrinogen mg/dl 180-350 534 619,3

GDS (mg/dl) 74-106 90

Na (mmol/l) 136-145 138

K (mmjol/l) 3,5-5,1 3,5

Cl (mmol/l) 98-107 108

Ca (mmol/l) 2,12-2,52 2,29

SGOT (U/l) 15-37 199(5,38x)

73

SGPT (U/l) 30-65 272

(4,19x)

131

Ureum (mg/dl) 15-39 16 20

Creatinin (mg/dl) 0,6-1,3 0,57 0,58

Bil direk (U/l) 0-0,3 16,9 26,43 16,7

Bil. Total (U/l) 0-1 22,92 33,72 19,13

Albumin g/dl 3,4-5,0 4,3 3,1

Prot g/dl 6,4-8,2 5,6 6,4

Alk fosfat U/I 50-136 1.575 876

Gama GT U/I 5-85 364

Cholesterol

mg/dl

456 402

Trigliserid mg/dl 200 229 210

HDL mg/dl >55 32

LDL mg/dl 150 378ICT malaria neg

Smear blood

malaria

neg

IgM

LeptospirosisPos

HbsAg Neg

Anti HBs Neg

Anti HCV Neg

Anti HAV neg

IgG Toxo Neg

IgM Toxo Neg

IgG CMV NegIgM CMV Neg

ANA 20-60 U 22,4


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Urin Coklat keruh BJ

1,02, pH 6,5,prot 25,

urobilin 8, bilirubin

6, leuko 0-2, eri 37,4,

bakteri 19,4

Faeces Brown, karbohidrat

+, bakteri +, yeast +Kultur darah Steril

Kultur urin E. Coli > 100.000

Sensitif: cefotaxim,

amikacyn, gentamicin

Resisten: ampicilin,

ceftazidim,ciprofloxacincotrimo

xazol

Tabel 2. Blood smear result

17-10-09 21-10-09

Diff count E3/B0/St3/Sg74/L14/M5 E4/B0/St0/Sg76/L14/M6

Eritrosit Slightly anisocytosis(microsit), slightly

poikilositisis (ovalosit)

Slightly anisocytosis (microsit,macrosit), moderate

poikilocytosis (ovalosit, elipsoit,

tear drop, pear shape, target cell,

fragmentosit)

Trombosit Quantity , big shape Quantity , big shape

Lekosit The quantity looks normal The quantity looks normal

Tabel 3. Supporting examination result

20/10/2009 31/10/2009 8/11/2009

USG abdomen Rough liver parenchime there is a posibility for druginduced, differential

diagnosis: hepatitis

Contracted gallbladersuspect

There is no liver fatteningor bile duct enlargement

There is no anomaly on theother intraabdominal

organs sonography

HepatosplenomegaliLiver parenchime

structure still looks

normal

There is no intra andextra hepatal duct

enlargement

The gallblader shapelooks normal,

gallblader lumen was

not filled with liquid/no distension

No ascitesFine needle

Biopsy Liver

Biopsi tissue representativeenough

Shows liver tissue pieceswith 4 portal tract and 4

central vein.

Liver cells architecture isstill in good condition,lobulus structure still can be

interpreted.

There were necrotic livercells foccuses (degenerationof hepatocytes) and bile


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pigment on several liver cell

citoplasm (hepatocellular

cholestasis).

Several double nucleus livercell (regenerative)

Kupfer cells is notproliferated

No specific sign foundNo mallignant cells foundConclussion:

Liver, biopsi: hepatic injurydue to drugs induced (

OAT)

Fig.1. Result of liver biopsy

Hepatoceluler colestasis Perivenulae necrosis


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CHAPTER III

DISCUSSION

Drug-induced allergic hepatitis is a liver-specific inflammatory reaction caused by

hypersensitivity to a particular drug. Although less common than other forms of drug-induced

hepatotoxicity, it has more serious clinical implications, the outcome can sometimes be fatal,

and it appears to increase in proportion to the number of prescribed drugs. There is

convincing experimental evidence to implicate the immune system in the pathogenesis of

many drug hypersensitivity reactions. The onset of a hypersensitivity reaction frequently

involves covalent binding of the drug to proteins (or more often as a result of its metabolism

and bioactivation) to form immunogenic conjugates, followed by antigen uptake, processing,

presentation and T-cell proliferation.1, 11

Hepatocytes, because of their capability to metabolize drugs, usually form drug

protein adducts, for which the immune system normally shows tolerance. Hypersensitivity

reactions occur when this tolerance is impaired. Additional signals, likely a concomitant

inflammatory reaction, may eventually be needed to break this tolerance. The allergic

hepatitis induced by drugs is generally a type IV hypersensitivity reaction involving CD4,

CD8 cytotoxic lymphocytes as well natural killer cells. Antibodies directed to the drug are

much less common. Antibodies against cellular components may also occur when the

sensitization process evolves towards an autoimmune reaction.1, 12

Allergic hepatitis is frequently associated with fever, rash and liver cell infiltration

(drug rash with eosinophilia and systemic symptoms (DRESS) syndrome). Clinically, both

hepatocellular injury and cholestasis can occur, and most episodes have good clinical

prognoses upon drug discontinuation. In few cases the damage to liver cells may continue,

even upon drug withdrawal, in the form of an autoimmune hepatitis. The available diagnostic

tools to confirm the involvement of a given drug in an immunomediated hepatic injury are

rather limited, and this is largely due to a still incomplete understanding of the pathogenesis

of drug allergy in the liver. Better understanding the molecular and cellular events will

definitively help to identify risk factors, and facilitate the prediction and prevention

strategies.1, 11Most cases of DILI resolve on discontinuation of the drug, but recovery can

take months or rarely the disease can progress despite drug withdrawal. Drugs such as

methotrexate may lead to chronic hepatitis and cirrhosis, while others such as minocycline,

nitrofurantoin and methyldopa are implicated in autoimune hepatitis.3, 4


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Table 4. Drugs that have caused acute fulminant hepatic failure (Medical Economics, 2000

Anesthetic

Enflurane

Halothane

Isoflurane

Antimicrobials

Dapsone

Isoniazid

Ketoconazole

Pyrazinamide

Rifampisine

Sulfonamides

Trovafloxacin

Anticonvulsants

Carbamazepine

Felbamate

Phenytoin

Valproic acid

HalothaneIsoflurane

NSAIDs and analgesics

Acetaminophen

Bromfenac

Diclofenac

Etodolac

Indomethacin

Oxaprozin

Piroxicam

Sulindac

Miscellaneous agents

Disulfiram

Flutamide

Labetolol

Nefazodone

Nicotinic acid

Pemoline

Propythiouracil

TolcaponeTroglitazone

Source: Ansari JA.3

Earlier definitions were plagued by inconsistencies in elevation of numerical levels of

transaminases needed for a diagnosis of DILI. Presently, there is a fair amount of consistency

in the criteria used for diagnosing DILI including TB DILI. In the absence of symptoms,

elevation of transaminases up to 5 times the upper limit of normal (ULN) and in the presence

of symptoms up to three times the ULN or twice the ULN of bilirubin constitutes DILI.

7

Drug-induced liver injury (DILI) is common and nearly all classes of medications can

cause liver disease. Most cases of DILI are benign, and improve after drug withdrawal. It is

important to recognize and remove the offending agent as quickly as possible to prevent the

progression to chronic liver disease and/or acute liver failure. There are no definite risk

factors for DILI, but pre-existing liver disease and genetic susceptibility may predispose

certain individuals. Although most patients have clinical symptoms that are identical to other

liver diseases, some patients may present with symptoms of systemic hypersensitivity.

Adverse drug reactions is an important cause of liver injury that may require discontinuation

of the offending agent, hospitalization, or even liver transplantation.6

Drug-induced liver injury (DILI) is ultimately a clinical diagnosis of exclusion.

Histologic specimens of the liver are often not obtained. Other causes of liver injury, such as

acute viral hepatitis, should be methodically sought, and their absence makes the diagnosis

plausible. Usually, the time of onset to acute injury is within months of initiating a drug.

Rechallenge with the suspected offending agent with more than twofold serum alanine

aminotransferase (ALT) elevation, and discontinuation leading to a fall in ALT, is the


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strongest confirmation of the diagnosis.5 Increases in the levels of the liver enzymes alanine

aminotransferase (ALT) and aspartate aminotransferase (AST) in serum, in combination with

increased bilirubin levels, are actually considered to be the most relevant indication of liver

toxicity.8

Because the liver is responsible for concentrating and metabolizing a majority of

medications, it is a prime target for medication-induced damage. However, a broad range of

different pharmacological agents can induce liver damage, including anesthetics, anticancer

drugs, antibiotics, antituberculosis agents, antiretrovirals, and cardiac medications.

Depending on the duration of injury and the histological location of damage, drug-induced

liver injury (DILI) is categorized as acute or chronic, and either as hepatitis, cholestatic, or a

mixed pattern of injury.8

Tuberculosis is a major health burden worldwide. Although better drugs are available

for managing tuberculosis, treatment failure is one of the common problems encountered.

Among the various causes which can cause treatment interuption, drug induced

hepatotoxicity is a common cause. Isoniazid and pyrazinamide are the common drugs causing

hepatotoxicity. Upon occurrence of hepatotoxicity, the hepatotoxic drugs should be stopped

and reintroduced as per the available guidelines. The healthcare professional should also

counsel the patients for recognizing the early symptoms due to hepatotoxicity which could

prevent morbidity.13

The clinical presentation of tuberculosis drugs associated hepatitis is similar to that of

acute viral hepatitis. Tuberculosis drugs can cause varied degree of hepatotoxicity from a

transitory asymptomatic rise in transaminases to acute liver failure and the frequency of

hepatotoxicity in different countries varies widely from 2-39%.6 The occurrence of drug

induced hepatotoxicity is unpredictable but it is observed that certain patients are at a

relatively higher risk than other populations.13

Fatality due to tuberculosis drugs induced hepatotoxicity was more likely when

jaundice occurred over 6 weeks after the start of therapy, serum bilirubin levels were higher

or where treatment was continued despite jaundice. It has been observed in several studies

that patients with pre-existing hepatic diseases due to chronic viral infection with Hepatitis B,

Hepatitis C, HIV, alcoholics, the elderly, and the malnourished are at a higher risk of

developing drug induced hepatitis compared to the general population. In some studies

highest incidence of hepatotoxicity was observed in those who were given empirical anti

tuberculosis therapy (ATT) without a definitive diagnosis of TB.13, 14


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I n th is case, from anamnesis and physical examination lead to icteric observation

with differential diagnosis hepatities viral infections, leptospirosis, malaria, drug induced

hepatities. We suspected drug induced hepatities based on data from anamnesis with history

of taken anti tuberculosis therapy for 1 month, then the patient complained joundice, fever,

nausea, vomitte, but there was not rash. From the laboratory result, we found increased of

liver function tests more than 5 times from ULN for AST and 4 times for ALT, increased of

total bilirubin and direct bilirubin, then negative result of hepatities and malaria screening.

Serological result of IgM leptospirosis was positif. Ultrasound impreased rough liver

parenchime was posibility for drugs induced hepatities. From liver showed liver cells

architecture still good condition, there were necrotic liver cells foccuses (degeneration of

hepatocytes) and bile pigment on several lever citoplasma cells (hepatocelluler cholestasis)

with conclusion hepatic injury due to drugs induced hepatities, but limitation of this case we

didnot stain with immunohistochemical staining, so we couldnt find immuno complex, and

we didnt investigation of content of drugs in the bloodtoo. We still differential diagnosis of

jaundice was drugs-induced hepatitis and leptospirosis. It was posible drugs-induced

hepatities combination with leptospirosis and urinary tract infections, made clinical

manifestation worse.

General Mechanisms of Hepatotoxicity

DILI is commonly classified into intrinsic vs. Idiosyncratic hepatotoxicity, and the

latter further into allergic vs. non-allergic. Intrinsic hepatotoxicity is regarded as dose

dependent and predictable above an approximate threshold dose, whereas idiosyncratic

hepatotoxicity occurs without obvious dose-dependency and in an unpredictable fashion.

Allergic idiosyncratic hepatotoxicity is characterized by the presence of typical symptoms

and signs of adaptive immune reactions, including fever, skin reactions, eosinophilia,

formation of autoantibodies, and a short latency time particularly after re-exposure. Other

clinical classifications differentiate e.g. between hepatocellular, cholestatic or mixed liver

enzyme patterns, histological criteria, acute vs. chronic onset, or severity. These

classifications are useful in clinical practice because they describe typical clinical signatures

of DILI for specific drugs, and they can also give useful hints regarding the involved

mechanisms. Nevertheless, one must realize that these classifications are descriptive and

based on clinical or histopathological criteria. They can therefore be misleading if mixed with

mechanistic concepts and may indeed be the foundation of some classic paradigms that are

now challenged by recent advances in mechanistic hepatotoxicity. For example, common


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misconceptions are that specific substances can be clearly classified as either intrinsic or

idiosyncratic hepatotoxins, and that dose or direct cell injury play no role in idiosyncratic

hepatotoxicity. However, unpredictable rare severe DILI often develops on a background of

frequent and dose-dependent mild increases in transaminases. 8

A general 3-step model for drug induced liver injury

Such a general mechanistic model is presented in Fig. (2). According to this model DILI

involves three subsequent main steps. It also includes details on the intrinsic and extrinsic

pathways emphasizing the central role of mitochondria for the mechanisms leading to

apoptosis vs. necrosis. Fig. (3) additionally demonstrates the important role of risk factors in

DILI.8

1. Initial Mechanisms of Toxicity: Direct Cell Stress, Direct Mitochondrial Impairment,

and Specific Immune Reactions

First, drug metabolites or less frequently also parent drugs cause direct cell stress,

target mitochondrial function, or trigger specific immune reactions. The most important drug

metabolizing enzyme system for the creation of hepatotoxic reactive metabolites is the

polymorphic cytochrome P450 (CYP450) family that mediates oxidative phase-I drug

metabolism. However, conjugative phase-II metabolism may also result in hepatotoxic

metabolites, e.g. acyl glucuronides are well known to cause DILI. Reactive metabolites can

exert initial cell stress through a wide range of mechanisms including depletion of glutathione

(GSH), or binding to enzymes, lipids, nucleic acids and other cell structures. Furthermore

reactive metabolites or parent drugs may specifically inhibit other hepatocellular functions

such as the apical (canalicular) bile salt efflux pump (BSEP, ABCB11 gene), in which case

the subsequent intracellular accumulation of its substrates may cause secondary toxic

hepatocyte damage. In case of initial targeting of mitochondria, reactive metabolites or parent

drugs uncouple or inhibit the mitochondrial respiratory chain causing ATP depletion and

increased concentrations of reactive oxygen species (ROS), inhibit - oxidation leading to

steatosis (e.g. after intramitochondrial accumulation of amiodarone), damage mitochondrial

DNA or interfere with its replication, or directly cause mitochondrial permeability transition

(MPT), i.e. opening of the MPT pore located in their inner membrane. There is probably an

injury threshold that involves inhibition of mitochondrial electron transport below a critical

threshold and an increase in cytosolic ROS and JNK activation above a critical threshold for


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liver injury to take place. The inhibition of mitochondrial electron transport in the early

stages will not be reflected by elevated ALT values, indicating the requirement for earlier

markers of impending mitochondrial damage. Functional tests such as the 13C-methionine

breath test or the use of NMR spectra for metabonomics may prove to be useful here.8

Specific immune responses involving cytotoxic T-cells with concomitant release of

inflammatory cytokines can be evoked by reactive metabolites that covalently bind to

proteins and are subsequently recognized as neo-antigens (hapten formation). Their

subsequent major histocompatibility complex (MHC)-dependent presentation on antigen

presenting cells may then activate formation of antibodies against haptens or autoantibodies

against cell structures such as CYP450 enzymes.8

In some instances initial injury also targets nonparenchymal liver cells. Examples

include toxicity against biliary epithelial cells by reactive flucloxacillin metabolites, direct

activation of stellate cells by methotrexate leading to fibrosis, or sinusoidal toxicity by herbal

pyrrolizidine alkaloids or chemotherapy used for hematopoietic stem cell transplantation

causing sinusoidal obstruction syndrome (venoocclusive disease). Further discussion of such

nonparenchymal hepatotoxicity is beyond the scope of this review, but if the resulting

damage is sufficiently severe it may eventually also extend to hepatocytes and lead to acute

or chronic liver failure. Different hepatotoxins are typically associated with specific patterns

regarding their initial mechanism of injury. However, one should be aware of the fact that a

single drug may concomitantly act through several of these initial mechanisms, and that for

many drugs at least some of the involved mechanisms currently remain unknown. These

initial specific injurious mechanisms can also be referred to as upstream events. In the next

step they lead to subsequent rather unspecific downstream events that involve the innate

immune system, which balances pro- and anti-inflammatory responses and therefore

determines the further progress to severe injury or recovery.8

2. Direct and Death Receptor-Mediated Pathways Leading to Mitochondrial

Permeability Transition

Second, initial cell stress and/or initial specific immune reactions lead to MPT. If the

initial mechanism does not directly target and impair mitochondrial function, this occurs in

two principle ways, i.e. either via a direct pathway initiated by severe cell stress (intrinsic

pathway), or via an indirect death receptor-amplified pathway that is triggered by mild cell

stress and/or specific immune reactions (extrinsic pathway).8


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In the intrinsic pathway severe intracellular stress activates the endoplasmic reticulum

pathway, lysosomal permeabilization, or c-jun N-terminal kinase (JNK). Subsequent

activation of pro-apoptotic (e.g. Bax, Bak, Bad) and inhibition of anti-apoptotic (e.g. Bcl-2,

Bcl-xL) proteins of the Bcl-2 family then activates MPT. 8

In the extrinsic pathway an initial mild injury may be amplified if inflammatory

responses due to mild stress and/or additional factors have modulated the innate immune

system, where signaling cytokines that promote (e.g. IL-12) or prevent (e.g. IL-4, IL-10, IL-

13, MCP-1) injury are usually well balanced. As a consequence, sensitized liver cells become

more susceptible to lethal effects of tumor necrosis factor alpha (TNF), Fas ligand (FasL)

and interferon gamma (IF). This is particularly important if one considers that the liver as

the central organ of detoxification is constantly exposed to cell stress that can activate TNF

and FasL. If the initial event is a specific immune reaction, MHC-dependent antigen

presentation will activate the release of TNF and FasL from Kupffer cells (hepaticmacrophages) and cytotoxic T-cells. According to the danger hypothesis for autoimmune

diseases, haptenization alone may be insufficient to trigger the development of frank allergic

hepatotoxicity, which requires an additional stimulation, a so-called danger-signal. If reactive

metabolites cause concomitant mild direct cell stress or if other concomitant inflammatory

diseases are present, the accompanying release of injurious cytokines may constitute such a

danger signal that promotes MHCII-dependent antigen presentation, renders hepatocytes

more susceptible to injury, and therefore promotes autoimmune hepatotoxicity. Regardless of

how the extrinsic pathway is initiated, eventually TNFand FasL bind to intracellular death

receptors, and TNF and Fas receptor- associated death domain proteins (TRADD/FADD)

will subsequently activate initiator caspase 8. The activating death-receptor complex is also

called the death-inducing signaling complex (DISC). Although initiator caspase 8 can start

apoptosis through a direct activation of effector caspases 3, 6 and 7, this direct path appears

to be too weak in hepatocytes to mediate apoptosis . Therefore an amplification mechanism is

required: caspase 8 can activate proapoptotic Bcl-2 proteins (e.g. Bid), as well as signaling

ceramides. Like in the intrinsic pathway this leads to MPT, which therefore plays a key role

and is a common step that mediates further cell death in both, intrinsic as well as extrinsic

pathways.8

3. Apoptosis and Necrosis

Third, impaired mitochondrial function and energy production leads to apoptotic or

necrotic cell death. MPT allows massive influx of protons through the inner mitochondrial


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membrane, which stops mitochondrial ATP synthesis. Mitochondrial ATP depletion resulting

from MPT (or other direct mechanisms of mitochondrial damage mentioned above) causes

matrix expansion and mitochondrial outer membrane permeabilization and rupture with

release of cytochrome c and other pro-apoptotic mitochondrial proteins from the

intermembrane space into the cytosol.8

In the case of apoptosis, cytochrome C then binds to a cytoplasmic scaffold (apaf-1)

and pro-caspase 9, forming a complex called apoptosome, which activates signaling

procaspase 9. This, however, is an active process that requires ATP and can therefore only

start if MPT did not rapidly and simultaneously occur in all mitochondria. Only if some

mitochondria are left intact and continue to synthesize ATP, activated pro-caspase 9 and

possibly also other pro-apoptotic mitochondrial proteins subsequently activate executioner

caspase 3. Caspase 3 will then cleave specific cell proteins and further activate pro-caspases

6,7 and 2, which have their own target proteins. These processes eventually result in

programmed apoptotic cell death, which is characterized by cytoplasmic and nuclear

condensation and fragmentation without loss of membrane integrity. Histologically these

remaining fragments are referred to as Councilman bodies. Apoptosis equals a silent cell

death, where apoptotic fragments are removed by phagocytosis with little accompanying

inflammation and therefore also only little secondary damage. Necrosis, in contrast, develops

if the initial injury is so severe that MPT quickly occurs in all mitochondria, or if other

mechanisms cause rapid severe mitochondrial ATP depletion, preventing the apoptotic

pathway. This is typical for hepatotoxins that directly cause profound initial cell stress.

However, in the absence of ATP also activation of the extrinsic pathway may lead to necrotic

cell death. Cell swelling and lysis that follow severe disturbance of cell functions characterize

necrosis. Necrotic cell lysis induces inflammatory responses including release of cytokines,

which is important because these may amplify initial injury through a sensitization of

surrounding hepatocytes and therefore cause further collateral damage. Finally it should be

mentioned that the distinction between apoptosis and necrosis is not always clear-cut. Mixed

phenomena have been described, and the same hepatotoxin may cause one or the other, or

even the concomitant occurrence of both, depending on the circumstances including dose and

preexisting vulnerability of hepatocytes.8

Apoptosis and necrosis may therefore also be regarded as a continuous spectrum.

Furthermore some controversy exists around the exact mechanisms and triggers for

hepatotoxic apoptosis including the role of MPT. In conclusion one can state that

mitochondria stand in the center of life and death in hepatotoxicity: they can be targets of


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initial direct toxicity, MPT plays a key role in the further signaling of extrinsic and intrinsic

pathways, and because mitochondria generate most of the cells ATP supply and are also the

main intracellular source of oxygen and nitrogen free radicals, the extent of mitochondrial

impairment finally determines whether hepatocytes die by apoptosis or necrosis.8

Fig. (2). A 3-step mechanistic working model of hepatotoxicity. First, initial injury is exerted through direct cell

stress, direct mitochondrial inhibition and/or specific immune reactions. Second, initial injury can lead to

mitochondrial permeability transition (MPT). Direct cell stress causes MPT via the intrinsic pathway. Theintrinsic pathway involves activation of intracellular stressor cascades and pro-apoptotic proteins including Bax.

Alternatively MPT can be initiated through the death receptor-mediated extrinsic pathway that is activated by

immune reactions and/or after sensitization to TNFand FasL binding to death receptors. Cytokines modulate

the sensitivity of its activation. Third, MPT leads to necrosis or apoptosis depending on the availability of ATP.

In hepatocytes activation of initiator caspase 8 through the extrinsic pathway is not sufficient to directly activate

apoptosis, but amplification through pro-apoptotic factors including Bid and ceramides lead to MPT, which will

then lead to the apoptotic pathway that is activated in the presence of sufficient remaining ATP production.

Necrosis occurs if there is no ATP available, which is required for energy-consuming apoptotic pathways.

Several highlighted amplification mechanisms (A) may play an important role at different levels for the

idiosyncratic occurrence of hepatotoxicity.

Source: Russmann.8


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A mechanistic view on risk factors

From a mechanistic point of view risk factors for hepatotoxicity are of particular interest,

because they are the very explanation for the rare occurrence that defines idiosyncratic DILI.

Severe idiosyncratic DILI typically occurs in less than 1 in 10000 exposed patients, whereas

most risk factors that have been associated with DILI have a much higher prevalence in the

exposed population. In particular this is true for genetic polymorphisms, which, by definition,

have a prevalence of at least 1%. Furthermore, even statistically significant relative risk

estimates for such associations tend to be weak and therefore do not allow a reliable

prediction of DILI in clinical practice. In perfect accordance with a complex multi-step

mechanistic model of hepatotoxicity, this indicates that the presence of one single risk factor

is usually not sufficient to explain the occurrence of idiosyncratic DILI, but that complex

interactions of different mechanisms with several risk factors must be assumed in most cases.

As mentioned above, incident environmental factors can function as triggering risk factors for

DILI, particularly if they tip the balance of injurious vs. protective processes in the presence

of other prevalent risk factors. Several clinical risk factors for DILI such as high age, female

gender and concomitant diseases or drugs have been described. Many of those may actually

be associated with altered pharmacokinetics, which are an obvious risk factor whenever

toxicity is dose-dependent and altered pharmacokinetics result in elevated concentrations of

parent drugs and/or their toxic metabolites. However, from a current mechanistic point of

view, it is most interesting to ask where risk factors exert their effect based on a multi-step

model of hepatotoxicity that differentiates specific upstream vs. Nonspecific downstream

mechanisms. In addition, risk factors can also be classified as either genetic or environmental.

Such a view on risk factors superimposed on the 3-stepmodel is shown in Fig. (2).8


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Fig. (3). Risk factors for hepatotoxicity. First, risk factors can be classified into environmental vs. genetic

factors. From a mechanistic point of view risk factors can further affect all different levels of events leading to

the final outcome of drug-induced liver injury, which is mostly dichotomous, i.e. full recovery vs. acute liver

failure. Note that risk factors affecting events downstream of initial injury are rather unspecific regarding

different hepatotoxins. The figure presents a selection of well-described risk factors, but one must assume that

other factors also play a role, of which many currently remain unknown.

Source: Russmann.8

Hepatocyte injury in the course of an allergic hepatitis: drug-induced liverautoimmunity

The immune response to foreign antigens in the liver is generally associated with a

strong and sustained CD4 and CD8 T-cell response. Immune-mediated killing of hepatocytes

is mainly achieved by cytotoxic T cells. Activated CD8 T cells are recruited to or trapped in

the liver irrespective of their antigen specificity. Only upon recognition of their cognate

antigen, however, do these CD8 T cells undergo rapid proliferation. Proliferation presumably

occurs directly in the liver in this scenario, as increased numbers of antigen-specific T cells

are not detectable in draining lymph nodes during the early days after adoptive transfer. The


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lytic activity of cytotoxic T lymphocytes (CTLs) can occur by at least two pathways. In the

perforin/ granzyme-mediated pathway the pore-forming agent perforin, probably in

conjunction with granzymes, induces apoptosis in target cells. In the Fas-mediated pathway,

engagement of Fas and Fas ligand triggers apoptosis of the CTL-bound target cell by a death

domain-initiated caspase cascade. Regardless of the initiating pathway, the downstream

events that lead to apoptosis appear to be similar.1, 16

Natural killer cells and natural killer T (NKT) cells are effector cells in the liver.

Natural killer cells are bone marrow-derived mononuclear cells that have markers of both T

lymphocytes and macrophages. The cytoplasmic granules contain perforin and granzymes,

which are involved in cell membrane attack and induction of apoptosis in target cells. As

opposed to target recognition by cytotoxic T lymphocytes, recognition of target cells by

natural killer cells is not restricted to MHC-antigen presentation and their major role is the

defence of the liver against invading tumour cells acting by the Fas/ Fas ligand pathway,

resulting in activation of the caspases cascade and apoptosis.1, 16

NKTcells are considered to be separate from natural killer cells and pit cell

populations. In addition to natural killer phenotype, they present surface expression of TCR.

The TCR on NKT cells interacts with CD1, as opposed to the MHC-1 or MHC-2 interaction

with the TCR on T lymphocytes, and can interact with target cells without restrictions. This

liver-resident, locally regenerating pool of rapid response killing cells has a significant role in

defending the liver from invading tumour cells.1

Natural killer and NKT cells are likely to play a role in the progression of drug-

induced liver injury by secreting interferon-g, and provoking a concomitant inflammatory

response (chemokine production, accumulation of neutrophils, and upregulating Fas ligand

expression in the liver), thus contributing to the severity and progression of liver injury

downstream of the metabolism of the drug hepatotoxicity. Nevertheless, natural killer and

NKT cells have been reported to dramatically diminish in a case of fulminant drug hepatitis,

suggesting that both may be involved in hepatic injury in fulminant hepatic failure.1

The role of Kupffer cells in drug hepatotoxicity is contradictory and likely to be

indirect. These cells can be activated by different stimuli resulting in the release of mediators

acting on hepatocytes (tumour necrosis factor a, nitric oxide, reactive oxygen species) that

exert important catabolic effects on hepatocytes. Activation of Kupffer cells seems to be one

of the early events in acetaminophen toxicity, yet a protective effect has also been described.1

Autoimmune hepatitis can be one of the consequences of a drug-mediated

hypersensitivity reaction, in which damage to liver continues once the use of the drug has


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been discontinued. The symptoms of drug-induced autoimmunity can resemble typical

systemic autoimmune diseases (i.e. systemic lupus erythematosus) or be organ-specific

autoimmune reactions (i.e. liver). If not recognized promptly, they can give rise to chronic

hepatitis (resembling viral hepatitis, i.e. a-methyldopa, halothane, hydralazine and other

hydrazine-containing drugs, minocycline, nitrofurantoin, and oxyphenisatin) or cholangitis

(resembling primary biliary cirrhosis, i.e. chlorpromazine). Several antibiotics, notably

penicillins, cephalosporins, and macrolides, may cause severe cholestasic hepatitis, but

rarely, if ever, cause self-perpetuating autoimmune liver disease.1

A conceptual framework for the pathogenesis of autoimmune hepatitis points at

environmental agents triggering a cascade of T-cell-mediated events directed at liver antigens

in a host genetically predisposed to the disease. A T-cell-mediated immune response is

thought to play a major role in the causation of autoimmune liver damage. In addition to CD4

T cells, there is growing evidence to suggest a role for CD8 T cells. The syndrome differs

from typical drug hypersensitivity reactions in that drug-specific T cells or antibodies are not

involved, and may even not result in immune sensitization to the drug. Certain drugs are

already known to induce autoimmune hepatitis(e.g. diclofenac, methyldopa, nitrofurantoin,

minocycline clometacin, and interferon) while others (rifampicin, atorvastatin/ ezetimibe)

have recently been claimed to cause autoimmune hepatitis as well as other systemic

manifestations, such as lupus.Many severe forms of drug-induced cholestasis persist after the

drug has been discontinued, and a small number of patients who develop drug-associated

cholestatic hepatitis develop progressive self-destruction of cholangiocytes. There are no

clear mechanisms to explain the phenomenon by which drugs may disrupt immune tolerance

to self antigens. CD4 T lymphocytes expressing the IL-2 receptor chain (CD25) appear to be

central to self-tolerance maintenance, preventing the proliferation and effector function of

autoreactiveTcells.1

Source: Russmann.10


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Source: Russmann.10

This case presumtively from anamnesis, physical examination and laboratory result

drug allergic hepatities due to by immune mediated reaction, base on data history taking anti

tuberculosis drugs, fever, anorexia, nausea, vomitte, abdominal pain,and jaundice. From

laboratory result was found eosinofilia, increased of liver funtions tests, total and direct

bilirubin, ANA was normal. Liver biopsy showed liver cells was still good condition, there

were necrotic liver cells foccuses (degeneration of hepatocytes) and bile pigment on several

liver citoplasma cells (hepatocelluler cholestasis), there was no increased of inflamatory

cells with conclusion hepatic injury due to drugs induced. Limitations of this case we didnt

stain with immunohistostaining, so we couldnt find immune complex. Certain drugs are

already known to hepatitis drug induced by immune-mediated (e.g. diclofenac, methyldopa,

nitrofurantoin, minocycline clometacin, and interferon) while others (rifampicin,atorvastatin/

ezetimibe) have recently been claimed to cause hepatitis as well as other systemic

manifestations, such as lupus.Many severe forms of drug-induced cholestasis persist after the

drug has been discontinued. Base on this data, we conclude this case was drugs-induced

hepatities immune mediated type.

Diagnosis and treatment of drug reactions

It is difficult to identify a drug reaction with certainty. However, the possibility of a

drug reaction must be considered in any patient with liver dysfunction. A careful drug history

should be taken, which includes the patients use of prescription, over-thecounter, herbal, or

alternative medications. Injury induced by complementary and alternative medications has

become more common as the use of these medications has increased. Other causes of liver

dysfunction, such as viral hepatitis, biliary tract or liver disease, must be excluded by a

thorough medical history taking, ultrasonography, and appropriate serologic tests.


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Assessment of causality can be difficult; often, many agents are used simultaneously, and

questions about other potential causes may be inadvertently omitted. Causality-assessment

methods provide a uniform approach to determine the likelihood of drug involvement in a

suspected episode of hepatitis.

Included among the standard factors that should be considered are the temporal

relation (whether the onset of the symptoms was between 5 and 90 days after the initial

exposure); the course after the patient stopped taking the drug (improvement within weeks);

the concomitant use of drugs; the exclusion of causes other than drugs (e.g. viral hepatitis);

patients history with regard to previous toxic effects of the particular agent; andthe response

to rechallenge, if performed. In many instances, data are incomplete. Cautious rechallenge

should be considered only if the diagnosis of drug-induced toxicity was highly questionable

and only if no other drug is available to treat a serious problem.9

The most frequent hepatotoxic drug reactions evoke moderate-to-severe injury to

hepatocytes with a clinical picture that resembles viral hepatitis, characterized by a rapid

onset of malaise, anorexia, nausea, abdominal pain and jaundice in association with elevated

aminotransferase levels. Each drug has its own pattern of injury. If hepatocyte injury

predominates, aminotransferase levels may be at least five times as high as normal.

Elevations of alkaline phosphatase and bilirubin levels predominate in cholestatic syndromes.

Signs of allergic reaction are absent in most patients. Acute liver failure may develop after a

week or more of illness, particularly if the patient has continued the drug after the onset of

symptoms. Death is not uncommon; elderly persons seem to be at particular risk, but specific

data supporting this pattern are sparse.9

Important and specific agents with their effects on the liver. Most drugs have a

signature effect, which is a specific patters of liver injury, although some drugs such as

rifampicin can cause all kinds of liver injury, including hepatocellular injury, cholestasis, or

even isolated hyperbilirubinemia. However, knowledge of the most commonly implicated

agents and high index of suspicion are very essential in diagnosis.13, 17

Ethambutol, there are fewer reports of hepatic dysfunction with ethambutol in the

treatment of tuberculosis. Abnormal liver function tests have been reported in some patients

taking ethambutol; however, these patients were also taking other anti tuberculosis drugs

knowns to cause liver dysfunction.10

Isoniazid, around 10-20% of patients during the first 4-6 months of therapy have a

mild hepatic dysfunction shown by mild and transient increase in serum AST, ALT and

bilirubin concentration. But in some patients the hepatic damage can be progressive and


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cause fatal hepatitis. Acetyl hydrazine, a metabolite of Isoniazid is responsible for liver

damage. Isoniazid should be stopped if the AST increases to over 5 times the normal value. A

prospective cohort study of 11,141 patients receiving isoniazid preventive therapy reported a

rate of hepatitis lower than that previously reported. Of these, 11 patients (0.10% of those

starting and 0.15% of completing therapy) developed clinical hepatitis.3

Pyrazinamide, the well known adverse effect of this drug is hepatotoxicity.

Hepatotoxicity is dose related and may occur any time during therapy. In the Centre for

Diseases Control (CDC) update, 48 cases of hepatotoxicity were reported in association with

a 2 months regimen of Rifampicin- pyrazinamide for the treatment of latent tuberculosis.

Thirty-seven patients recovered and 11 died of liver failure. Of the 48 reported cases, 33

(69%) occurred in the second month of therapy.3

Rifampicin, transient abnormalities in liver function are common in the initial stages

of therapy. But in some cases it may cause severe hepatotoxicity, more so in those with pre-

existing liver disease, forcing the physician to change tretment and opt for liver friendly

treatment. Rifampicin causes transient elevations in hepatic enzymes usually within the first 8

weeks of therapy in 10 to 15% of patients, demonstrating overt rifampicin-induced

hepatotoxicity. The occurence of mortality associated with hepatotoxicity has been reported

to be 16 in 500,000 patients receiving rifampicin. A higher incidence of hepatotoxicity has

been reported in patients receiving rifampicin with other anti tubercular agents and is

estimated to be fewer than 4%.3

Patients were taking combination of anti-TB drugs. Due to this reason, it is difficult

to conclude which drug was the main culprit for causing hepatitis. Although, INH is the

major drug incriminated to induce hepatic injury, role of other possible hepatotoxic drugs

(RMP and PZA) can also be speculated. Previous studies conducted have proven that the risk

is in the order of INH + RMP>INH>PZA>RMP>E. Steele et al. also reported in their, meta-

analysis that INH and RMP given together produce hepatotoxicity more than INH without

RMP. Since INH, RMP and PZA are always given in combination, it is difficult to diagnose

the drug causing hepatotoxicity. Hepatotoxicity can cause permanent injury and death. Early

recognition of DIH with immediate withdrawal of offending agent is very important to arrest

its development and allow liver to heal.18

British Thoracic Society suggests that if there is a rise in ALT and/or AST to greater

than 3 times normal, or a rise in bilirubin, or if the patient showed clinical symptoms of

hepatitis then drugs should be stopped and reintroduced sequentially when these parameters

falls to previous levels. Within few days of cessation of drugs, liver enzymes returned to the


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normal level. This normalization of the liver enzymes levels once the administration of the

regimen has been halted proves that all signs and symptoms shown by the patient are related

to the administration of anti-TB drugs. 18 Current American Thoracic Society center for

disease control recommends adequate monitoring (clinical as well as biochemical) of

individuals in order to avoid unnecessary morbidity and mortality, hence decreasing the cost

of illness. TB patients usually belong to poor socioeconomic status and they cannot afford

regular LFTs. Close monitoring of the patients physical condition can be done in such

situations. 18

I n this case there was history taken anti tuberculosis drugs, specially rifampicin,

isoniazid and pyrazinamid, fever, anorexia, nausea, vomitte, abdominal pain, ,from physical

examination found jaundice, fever, abdominal pain, liver enlargement. From laboratory

result found eosinofilia, elevation of hepatic enzymes serum AST and ALT increased until 5

and 4 times upper normal limit, and then total bilirubin concentration was 22,9 gr/dl, with

direct bilirubin was 16,9 gr/dl. Screening for leptospirosis found positif of IgM leptospirosis.

Screening of hepatities viral, malaria, TORCH were negative result. From liver biopsy

showed liver cells architecture still good condition, there were necrotic liver cells foccuses

(degeneration of hepatocytes) and bile pigment on several lever citoplasma cells

(hepatocelluler cholestasis) with conclusion hepatic injury due to drugs induced hepatities,

but limitation of this case we didnot stain with imunohistostaining, so we couldnt find

immuno complex, and we didnt investigation of content of drugs in the blood too.

Combination of leptospirosis, urinary tract infection and drug allergic presumtively

increased of severity of clinical manifestasion jaundice and liver function tests from drug

induced hepatities.

Therapeutic approaches

Early diagnosis of drug-induced liver reactions is essential to minimizing toxicity.

Monitoring hepatic enzyme level is appropriate and necessary with number of agents,

especially with those that lead to overt toxicity. For drugs that produce hepatotoxicity

unpredictably, biochemical monitoring is less useful. ALT (alanin aminotransferase) values

are more specific than AST (aspartate aminotransferase) values. ALT values that are within

the reference range at baseline and rise 2 to 3 fold should lead to enhanced vigilance in terms

of more frequent monitoring. ALT values 4-5 times higher than the reference range should

lead to prompt discontinuation of the drug.3, 14, 15, 19


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Diagnosis of drug-induced hepatitis was made based on the presence of all the

following criteria:20

1. Clinical features of icteric hepatitis (anorexia, nausea and jaundice).2. Elevation of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT)

above 200U/l (five times the upper limit of normal value) at the time of admission.

3. Serum total bilirubin of more than 34.2 micromol/l.4. Absence of serological evidence of an acute infection with hepatitis A, B or C. IgM anti-

hepatitis A virus (HAV) antibody for acute hepatitis A infection was done using enzyme

linked immunosorbent assay at a local private laboratory (

No specific treatment is indicated for drug induced liver disease. Treatment is

generally supportive and based on symptomatology. Other than different synthetic

compounds several hundred plants have been examined for use in a wide variety of liver

disorders. The first step of management of hepatotoxicity is to discontinue the suspected

drug. In general, corticosteroids have no definitive role in tretment. They may suppress the

systemic features associated with hypersensitivity or allergic reactions. Management of

protracted drug induced cholestasis is similar to that for primary biliary cirrhosis.

Cholestyramine may be used for alleviation of pruritus. Ursodeoxycholic acid may be used.

Lastly, consulting a hepatologist is always helpful.3, 21

Prevention and treatment of acute hepatotoxicity caused by unpredictable

(idiosyncratic) hepatotoxins: because no specific antidotal treatments exist for the forms of

toxicity that are caused by drug allergy or metabolic idiosyncrasy, prevention is paramount.

Severe immunologically mediated or allergic hepatitis is generally considered an indication

for steroid therapy, but only anecdotal reports support its use and there is scarce evidence of

its benefits. Management of acute non-immunologic hepatic injury consists of supportive and

symptomatic treatment, the nature of which depends on the form injury.3, 14, 15, 19, 21


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Treatment of idiosyncratic acute hepatocellular injury; drug-induced hepatocellular

jaundice has a potential case fatality rate of 10% or more. Accordingly, it warrants careful

observation for evidence of impending hepatic failure. In the patient whose jaundice is not

severe, whose prothrombine time is normal or negligibly prolonged and who has no clinical

evidence of impending encephalopathy or coagulopathy, medical management can be simply

supportive and the individual can be followed on an outpatient basis. Unless there is

evidence of impending hepatic failure, a standard diet is appropriate, with no need to modify

the protein or other components. Persistent anorexia may be managed by multiple small

feedings and by providing fruits, vegetables and dairy foods rather than meat. Carbonated

drinks, fruits juice and hard candy are usually well tolerated even when nausea is marked.

There is no need to restrict physical activity, although patients should be advised to stay

within limits of fatigability. The patient with measurable prolongation of protrombin time andelevated bilirubin levels should be hospitalized (or observed very closely as an outpatient),

particularly if there is persistent nausea and anorexia after the drug has been withdrawn.3, 14

Treatment of acute cholestatic injury, acute drug-induced cholestatic jaundice is rarely

fatal. Over 99% of patients with cholestatic jaundice caused by erythromycin, chlorpro-

mazine, amoxicillin-clavulanate, or anabolic steroids have survived the episode. There is no

firm evidence that any therapeutic measure affect the rate of disapperance of drug-induced

cholestasis. However, several anecdotal observations suggest that treatment with

ursodeoxycholic acid increases the rate or retrun to normal status and in our view the effort is

Fig 2. Protocol for anti-tuberculosis drugs and possible hepatotoxicity. LFTs: liver function tests; ALT: L-alanine

aminotransferase. Source : Saukkonen3


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waranted. The most important aspects of treatment of cholestatic jaundice relate to the

treatment of pruritus. Cholestyramine, which can offer relief, presumably traps elements

involved in the itching. Other potentially useful agents include hydroxyzine, rifampin and

narcotic antagonists. There is no evidence that glucocorticoids provide symtomatic or other

benefit in drug-induced cholestasis. Perhaps most important is an awareness that certain drug-

induced cholestatic reactions can be mistaken for syndromes of anatomic biliary obstruction

calling for surgical intervention, as has been seen with erythromycin and amoxicillin-

calvulanate.3, 14

Management of chronic drug-induced hepatic disease; treatment of the various

syndromes of chronic hepatic disease that may be drug-induced mainly involves recognition

of symptoms and withdrawal of the responsible agent. The lesion and syndrome of chronic

hepatitis may be caused by a number of agents and by different mechanisms. Chronic

autoimun hepatitis; drug-induced chronic autoimune hepatitis may resemble, to a striking

degree, the form of chronic necroinflammatory disease dubbed autoimmune in origin. This

type of injury has been reported following use several agents, including nitrofurantoin,

minocycline, methyldopa, diclofenac, rifampicyn and pamoline, among others. Indeed, in any

form of non viral chronic hepatitis, especially with autoimmune features, a drug should be

suspected as the cause. Following withdrawal, improvement should become noticeable within

1 to 4 weeks. 3

Chronic cholestasis; drug induced chronic cholestasis is usually a sequel to acute

cholestatic injury with loss of portal area bile ducts Vanishing bile duct syndrome, (VBDS).

Currently, there is no accepted therapy for the cholestatic process in patients with VBDS,

however ursodiol has been used successfully in a few reported patients who had received

amoxicillin calvulanate, chlorpromazine, prochlorpromazine (improving pruritus and liver

function tess) androgens, anabolic steroids and tetracycline. This syndrome usually resolves

spontaneus, although it may take several months to years and only minority of these patients

develop secondary biliary cirrhosis.3

Referral to liver transplantation centre/ surgical care; no specific antidote is available

for the vast majority of hepatotoxicity agents. Emergency liver transplantation has increasing

utility in the setting of drug-induced fulminant hepatotoxicity. Considering early liver

transplantation is important. The Model for End Stage Liver Disease score can be used to

evaluate short term survival in an adult with end stage liver disease. This can help stratify

candidates for liver transplantation. The parameters used are serum creatinine, total bilirubin,

international normalized ratio and the cause of the cirrhosis.1


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I n th is case,management for hepatities drug- induced due to anti tuberculosis drugs

stopped all drugs suspected, and given urdafalk (ursodeoksikolat acid) for hepatoprotector.

Icteric and elevated of liver function test in this case due to of hepatities drug-induced, made

serious with comorbidity were leptospirosis and urinary tract infections. The clinis condition

of patient were more better with treatment of leptospirosis and urinary tract infections , and

also stopped of suspected drugs made allergy. When discharge from hospital condition of

patient was more better, no fever, no nausea, no vomitted but still icteric when discharged

from hospital.

Leptospirosis

Leptospirosis is a zoonotic disease caused by pathogenic spirochetes of the genus

Leptospira. Leptospirosis is an infectious disease of worldwide distribution. Human infection

can occur either through direct contact with infected animals or much more commonly

through indirect contact with water or soil contaminated by urine of infected rodents or

animals.22, 23

Person-to-person transmission is extremely rare since man is a dead-end host for

leptospiral dissemination. In contrast, leptospires can survive for long periods in the renal

tubules of infected animals without causing illness. Most human infections occur in young

adult men and children and result from occupational or environmental exposure.22, 23

The clinical manifestations is mild form leptospirosis may present as an influenza-like

illness with headache and myalgia. Severe leptospirosis, characterized by jaundice, renal

dysfunction, and hemorrhagic diathesis, is referred to as Weils syndrome. Incubation

Period: 2-26 days (usually 7-12 days) In general, clinical manifestation can be divided into

two distinct clinical syndromes. 90% of patients present with mild anicteric febrile illness;

10% are severely ill with jaundice and other manifestations (Weils disease). 22, 24

Anicteric leptospirosis is the more common and milder form of the disease, and is

often biphasic. In the first or septicemic phase, patients usually present with an abrupt onset

of fever, chills, headache, myalgia, skin rash, nausea, vomiting, conjunctival suffusion, and

prostration. Leptospires can be isolated from blood, cerebrospinal fluid (CSF), and tissues.

The fever may be high and remittent reaching a peak of 40C before defervescence.

Conjunctival suffusion is characteristic and usually appears on the third or fourth day.

Myalgias usually involve the muscles in the calf, abdomen, and paraspinal region and can be

severe. When present in the neck, myalgias may cause nuchal rigidity reminiscent of

meningitis. In the abdomen, myalgia may mimic acute abdomen, leading to confusion with


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surgical intra-abdominal emergencies. The skin manifestations seen in mild leptospirosis

include transient urticarial, macular or maculopapular, erythematous or purpuric rash. The

first phase lasts 3- 9 days followed by 2-3 days of defervescence, after which the second or

immune phase develops. The immune phase, is characterized by leptospiruria and

correlates with the appearance of IgM antibodies in the serum. Leptospira now settle in

glomeruli and are eliminated from all sites in the host except eye and perhaps brain, where

they may persist for weeks or months. Fever and earlier constitutional symptoms recur in

some patients, and signs of meningitis, such as headache, photophobia, and nuchal rigidity

may develop. Central nervous system (CNS) involvement in leptospirosis most commonly

occurs as aseptic meningitis. Complications such as optic neuritis, uveitis, iridocyclitis,

chorioretinitis, and peripheral neuropathy occur more frequently in the immune phase.

Prolonged or recurrent uveitis was demonstrated in 2% of patients with onset several months

after symptoms of clinical leptospirosis. A rare but severe manifestation is hemorrhagic

pneumonia. The illness in anicteric leptospirosis may be self-limited, lasting 4-30 days, with

complete recovery as a rule. 22-24

In icteric leptospirosis (Weils syndrome) (usually caused by L. icterohaemorrhagiae),

persistent high fever and jaundice may obscure the two phases. This is usually associated

with hepatic dysfunction, renal insufficiency, hemorrhage and multi-organ failure (MOF).

Hemorrhage can occur as petechiae, purpura, conjunctival hemorrhage and gastrointestinal

hemorrhage. MOF is associated with a very high mortality. Myocarditis and hemorrhagic

pulmonary infiltration are other complications, which may prove fatal. 22, 23

Source: Dutta22

The investigations with most of the routine laboratory tests show nonspecific findings.

The leucocyte count can be low, normal or elevated, but is usually associated with a shift to

left. Mild anemia and thrombocytopenia are common; hemolytic anemia and disseminated

intravascular coagulopathy (DIC) have been described in severe cases. Thrombocytopenia is

found in more than 50% of patients and is significantly associated with renal failure. Liver,


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kidney and central nervous system involvement may be present in any combination. Liver

involvement may be mild, or severe with bilirubin levels reaching very high. Serum alkaline

phosphatase, lactate dehydrogenase, aspartate aminotransferase (AST) and alanine

aminotransferase (ALT) may all be elevated, but serum AST is only mildly or moderately

elevated (unlike in viral hepatitis). Hyperamylasemia occurs frequently in severe disease, but

pancreatitis is rare. Serum creatinine phosphokinase (CPK) is usually raised due to muscular

involvement.22, 23

Proteinuria, pyuria, hematuria, and hyaline or granular casts are common findings on

urine analysis even in the absence of renal dysfunction. Renal functional impairment is

primarily a result of tubular damage; however, hypovolemia may play a critical role in the

subsequent development of renal insufficiency. In the cerebrospinal fluid (CSF), features are

those of aseptic meningitis. The CSF protein level may be normal or elevated upto 300 mg/dl,

while the glucose concentration is normal. Although abnormal CSF findings are reported in

as many as 80% of leptospirosis cases, only half of the patients are symptomatic. Various

electrocardiographic and chest x-ray abnormalities are observed in patients with leptospirosis.

Arrhythmias due to significant cardiac irritability have been documented. The arrhythmias

observed were atrial fibrillation, atrial flutter, atrial tachycardia and premature ventricular

contractions. Echocardiograms may reveal pericarditis and small pericardial effusion, in few

cases. The chest radiographic abnormalities can include pulmonary edema, diffuse

pneumonitis, nonsegmental or basal linear opacities and pleural effusions.22, 23

Specific Diagnosis:

Definitive diagnosis of leptospirosis depends on:22

(i) Isolation of organism

(ii) Serological tests

(iii) Detection of specific DNA

Isolation of organism, with:

a) Blood : The organism may be identified by dark field examination of the patients bloodor by culture on a semisolid medium (eg. Fletchers EMJH), if taken before the tenth day

of illness. Cultures take 1-6 weeks to become positive.

b) Urine : The organism may be isolated from the urine on darkground microscopy tenth dayonwards, and in untreated patient, may be recovered on urine culture for several months.

Diagnosis is usually made by means ofserologic tests, of which several are available.

a) Agglutination tests (microscopic, using live organisms; and macroscopic, using killedantigen) become positive after 7-10 days of illness, peak at 3- 4 weeks, and may persist at


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high levels for many years. Thus, to make a diagnosis, a fourfold or greater rise in titer

must be documented. The agglutination tests are cumbersome to perform and require

trained personnel.

b) ELISA IgM and slide agglutination tests (SAT) are also available. As ELISA IgM andSlide agglutination tests (SAT) are simple, sensitive tests which measure IgM antibodies,

they are used to diagnose current leptospirosis at a very early stage and a single sample

is adequate. The IgM ELISA test is particularly useful in making an early diagnosis, as it

is positive as early as 2 days into illness,a time when the clinical manifestation may be

nonspecific. It was found to be 100% sensitive and 93% specific in one study. Dot-ELISA

and dip-stick methods for detecting IgM antibodies are newer screening methods.

PCR methods (presently investigational)appear to be sensitive, specific, positive early in

disease, and able to detect leptospiral DNA in blood, urine, cerebrospinal fluid (CSF) and

aqueous humor. Currently major disadvantage with these tests is that these are genusspecific,

not serovar specific.

Specific Serovar, the investigations of choice to identify specific serovar is microscopic

agglutination test (MAT) and culture isolation. However, culture growth may take several

weeks.

In this case, from anamnesis we found history of fever, jaoundice, headache, mialgia,

heartburn, nausea, vomitte, loss of appetite, tawny-colored urine, no atralgia, no

gastrocnemius pain. From physical examination founded jaundice, sclera icteric, no

conjungtiva sufficion, no gastrocnemius pain. From laboratory results founded anemia,

leucosyte and trobocyte were normally, IgM leptospira positif, increased of liver function

tests, urinalisys and renal function were normally.

Treatment of leptospirosis with various antimicrobial drugs, including penicillin and

tetracyclines, show antileptospiral activity. Penicillin (e.g. 6 million units daily intravenously)

is the drug of choice in severe leptospirosis and is especially effective if started within first

four days of illness. Total duration of therapy should be 10-14 days. Amoxycillin and

erythromycin have also been found effective in severe leptospirosis. Patient should be

observed for evidence of renal failure, and treated, if necessary, with hemodialysis. Patients

with Weils disease having hemorrhagic manifestation may require whole blood or platelet

transfusion. Patients with MOF require to be observed in intensive care unit.22


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Besides penicillin, doxycycline in a dosage of 100 mg twice daily for 7 days is

effective in treatment of mild and moderate leptospirosis. Effective prophylaxis consists of

doxycycline, 200 mg orally once weekly, during the risk of exposure.23

Source: Kobayashi Y 23

The treatment of this case, we gave amoxicillin 500 mg three times a day. The clinical

manifestasion more better, but there was urynary tract infection made worse condition, and

then we changed antibiotic appropriate urine culture result.

The prognosis of leptospirosis depends on the severity of the disease and the

associated complications. Anicteric leptospirosis usually has a good prognosis. Without

jaundice the disease is almost never fatal; however, fatal pulmonary hemorrhage and

myocarditis have been reported occasionally in anicteric cases. The case fatality rate for

Weils disease is 15-40%, and is higher for patients over 60 years of age.

22

Urinary Tract Infection

Urinary tract infection was estimated that 8% of girls and 2% of boys will acquired

UTIs in childhood. Girls olders than age 6 months have UTIs far more commonly than boys,

whereas uncircumcised boys younger than 3 months of age have more UTIs than girls.

Circumcision reduces the risk of UTI in boys. The density of distal urethral and periurethral

bacterial colonization with uropathogenic bacteria correlates with the risk of UTI in children.

Most UTIs are ascending infections. Specific adhesins present on fimbria of uropathogenic

bacteria allow colonization of the uroepithelium in the urethra and bladder and increase th

likelihood of UTI.25, 26

Pathogenesis of urinary tract infection was dysfunctional voiding, which in

uncoordinated relaxation of the urethral sphincter during voiding, leads to incomplete

emptying of the bladder, increasing the risk of bacterial colonization. Similarly, any condition

that interferon with complete emptying of the bladder, such as constipation or neurogenic

bladder, increase the risk of UTI. Poor perineal hygiene, structural abnormalities of the


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urinary tract, catheterization, instrumentation of the urinary tract, and sexual activity increase

the risk as well.25-27

The inflammatory response the pyelonephritis may produce renal parenchymal scars.

Such scars in infancy and childhood were contribute to hypertension, renal disease, and renal

failure later in life. The organism most commonly responsible for UTI are fecal flora, most

commonly E Coli (>85%), Klebsiella, Proteus, other gram-negative bacteria, and less

frequently Enterococcus or coagulase-negative staphylococci.25-27

The clinical manifestations UTI in newborn and infants have nonspecific signs,

including fever, hypothermia, jaundice, poor feeding, irritability, vomiting, failure to thrive,

and sepsis. Strong, foul smelling or cloudy urine may be noted. Preschool children may have

abdominal or flank pain, vomiting, fever, urinary frequency, dysuria, urgency or enuresis.

School-aged children commonly have classic sign of cystitis (frequency, dysuria and

urgency) or pyelonephritis (fever, vomiting and flank pain). Costovertebral tenderness is

unusual in young children, but may be demonstrated by school-aged children. Physical

examination should include attention to blood pressure determination. Urethritis, poor

perineal hygiene, herpes simplex virus, or other genitourinary infections may be apparent on

examination.25, 26, 28

Laboratory finding, from collections of urine for urinalysis and culture is difficult in

children due to frequent contamination of the sample. In toilet-trained, cooperative, older

children, a midstream, clean-catch method is satisfactory. Although cleaning of the peri

Komplit Kasus Ingris ES Edit 22 Agusts 2013

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