Urinary tract infections in infants: comparison betweenthose with conjugated vs unconjugatedhyperbilirubinaemia

HUNG-CHANG LEE*{, SHIUH-BIN FANG*{1, CHUN-YAN YEUNG* &

JENG-DAW TSAI*{

Departments of Paediatrics, *Mackay Memorial Hospital, {Taipei Medical University and {Taiwan

Adventist Hospital, Taipei, and 1Department of Paediatrics, Chung Shan Medical University, Taichung,

Taiwan

(Accepted September 2005)

Abstract

Aims: The aim was to investigate conjugated and unconjugated hyperbilirubinaemia in association with urinary

tract infection (UTI) in young infants.

Methods: Fifty infants aged ,3 mths who developed prolonged jaundice among 2128 infants with UTI from 1984

to 2004 were enrolled retrospectively. They were divided into conjugated (n522) and unconjugated (n528)

hyperbilirubinaemia groups and the clinical variables between the two were compared.

Results: Compared with the unconjugated group, the conjugated hyperbilirubinaemia group had statistically

significantly lower haemoglobin (1.57 vs 1.80 mmol/L), higher aspartate aminotransferase (96 vs 32.5 U/L) and

alanine aminotransferase (81.5 vs 16 U/L), were older on admission (48.0 vs 32.5 days), had a longer duration of

jaundice before treatment (43.5 vs 30 days) and a higher incidence of E. coli infections (19/22 vs 15/28). The direct/

total bilirubin ratio was linearly correlated with duration of jaundice before treatment (p50.004). The most

significant cut-off value for the duration of jaundice vis-a-vis the type of jaundice was 38 days (p50.007). Patients who

on presentation had had jaundice for.44 days (p50.007) were unlikely to have unconjugated hyperbilirubinaemia.

Conclusions: Infants with UTI may present with unconjugated hyperbilirubinaemia in the early stage. After 6 weeks, it

is always conjugated hyperbilirubinaemia and is frequently associated with anaemia, elevated hepatic amino-

transferases and E. coli infections.

Introduction

Urinary tract infection (UTI) can present

with jaundice in early infancy, but when and

how the types of hyperbilirubinaemia

change is unclear. We analysed the clinical

features of UTI associated with jaundice in

early infancy. The goals of this study were

(i) to compare conjugated and unconjugated

hyperbilirubinaemia in association with UTI,

(ii) to look for a correlation between the

degree of conjugated hyperbilirubinaemia

and the duration of jaundice before treat-

ment, (iii) to determine when conjugated

hyperbilirubinaemia becomes more likely

than unconjugated hyperbilirubinaemia,

and (iv) to seek a reasonable explanation for

the characteristic features of prolonged jaun-

dice in young infants with UTI.

Subjects and methods

We retrospectively reviewed the records of

infants in the 1st 3 months of life admitted

to Mackay Memorial Hospital, Taipei, Taiwan

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Reprint requests to: Dr Shiuh-Bin Fang, Department of

Paediatrics, Taiwan Adventist Hospital 424, Section 2,

Pateh Road, Taipei 105, Taiwan. Fax: z886 2 2777

5623; e-mail: drsbfang@ms3.hinet.net

Annals of Tropical Paediatrics (2005) 25, 277–282

# 2005 The Liverpool School of Tropical Medicine

DOI: 10.1179/146532805X72421

week of life had evidence of pyelonephritis.2

The jaundice was regarded by these authors

as a feature of septicaemia associated with

pyelitis. In 1967, three infants aged from 3

to 7 weeks who presented with jaundice

were reported to have UTI without sepsis,

with or without hepatic dysfunction.3 This

demonstrates the diverse manifestations of

jaundice in young infants with UTI. In our

retrospective study, the type of jaundice

associated with UTI was conjugated hyper-

bilirubinaemia in 22 and unconjugated

hyperbilirubinaemia in 28. Patients with

conjugated hyperbilirubinaemia were older

than those with unconjugated hyperbiliru-

binaemia and had a longer duration of

jaundice before treatment, even though the

total bilirubin levels were not significantly

different.

Previous studies of sepsis and jaundice in

infancy indicate that during the 1st week of

life idiopathic hyperbilirubinaemia with

elevation of the indirect-reacting fraction

might be exacerbated or prolonged by the

sepsis. Beyond the 1st week, the character-

istic pattern of UTI in infants is that of

‘obstructive jaundice’.2,4 In this study, we

found that a number of jaundiced infants

presented with unconjugated hyperbilirubi-

naemia until 38–44 days of age. The

duration of jaundice correlated positively

with the direct/total bilirubin ratio but not

with the direct bilirubin level. This suggests

that the temporal transformation from a

preponderance of unconjugated to conju-

gated hyperbilirubinaemia might result from

a gradual decrease in indirect bilirubin

rather than an increase in direct bilirubin.

However, the levels of hepatic aminotrans-

ferases were higher in infants presenting

with conjugated hyperbilirubinaemia, sug-

gesting there may also have been some

element of hepatic inflammation associated

with cholestasis in an untreated UTI.

A number of possible mechanisms for

UTI-related jaundice or hepatic injury have

been documented, including (i) haemoly-

sis,5–8 (ii) direct invasion of the liver

parenchyma by blood-borne or lymph-

borne micro-organisms,1,2,4 (iii) hepatocel-

lular injury by circulating endotoxins,9–13

(iv) serum bactericidal activity14,15 and (v)

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FIG. 1. The cut-off value for duration of jaundice before treatment and the number (%) of patients with jaundice

longer than the cut-off value in conjugated and unconjugated hyperbilirubinaemia [–N– p-value, * p,0.01,{ 0.00675smallest p-value; –&– (duration of jaundice) patient no./total no. (%) of patients in group A; –m–

(duration of jaundice) patient no./total no. (%) of patients in group B].

280 Hung-Chang Lee et al.

non-specific injury to the liver related to

hyperpyrexia, malnutrition and anoxaemia.

Some cases of haemolysis (a diagnosis

based on the presence of anaemia and

elevated reticulocyte counts) have been

reported to contribute to jaundice in

patients with infections caused by E. coli,

Paracolobacterium, Enterobacter aerogeens and

Enterococcus.5–8 Certain strains of E. coli

produce a haemolysin demonstrated by a

high titre of anti-a-haemolytic antibodies in

a patient’s serum5 and by haemolytic zones

on a blood agar plate.6 Increased red cell

fragility in E. coli sepsis is also reported to be

a common factor of haemolysis.16 However,

haemolysis is not thought to be the major

cause of UTI-related jaundice, although

even mild haemolysis can overload the

immature liver conjugating mechanism,

leading to an increase in serum bilirubin

levels.17 Direct bacterial invasion of the liver

parenchyma leading to toxic hepatitis and

jaundice might explain some cases of UTI-

related prolonged jaundice. In our series,

however, only two of 34 infants who had

blood cultures drawn had E. coli bacterae-

mia. Therefore, direct invasion and haemo-

lysis resulting from bacteraemia would not

explain the jaundice in most of our cases. In

cases without bacteraemia, other mechan-

isms have been implicated. Bacterial

endotoxin may impair the hepatocyte

excretory mechanism,11,13 cause cholesta-

sis12 and damage hepatocytes indirectly.18

Conversely, unconjugated bilirubin, present

as prolonged physiological jaundice, might

be toxic to cells of the immune system,

altering cell-mediated immunity or causing

a functional defect of the complement

system.14 Therefore, the hyperbilirubinae-

mia seen in young infants might not be the

consequence of a UTI but rather contribute

to infection by partially suppressing the

normal bactericidal properties of the

immune system. This latter mechanism

might explain why we found unconjugated

hyperbilirubinaemia to be more common in

young infants with UTI. Overloading of

an immature conjugating mechanism with

products of even mild haemolysis in the 1st

week of life might cause a rise in the indirect

bilirubin level. When the conjugating capa-

city is more mature, liver cell damage

affecting bilirubin excretion from the cell

might then cause elevation of direct bilir-

ubin, as we saw in the older babies.18

Regardless of the type of bilirubin eleva-

tion, our study found a male predominance,

similar to previous reports.7,8,17,19 Seeler &

Hahn cited eight reported series totalling 88

cases with a male predominance of 3:1. This

contrasts with the usual pattern of female

preponderance in the incidence of UTI in

older children who have demonstrable

anomalies of their urinary tracts.8

With regard to the type of pathogen, an

infant infected with E. coli is more likely to

develop jaundice associated with sepsis than

are those infected with other agents. Our

study showed that E. coli was more likely to

be associated with conjugated hyperbilirubi-

naemia than was Klebsiella pneumoniae. A

reversal of the expected frequencies of A and

B blood groups has been observed in

jaundiced infants with urosepsis owing to

haemolytic E. coli but in our study and

another there was no discernible clinical

difference in the degree of haemolysis related

to blood groups.6 A shift to the left in the

differential white cell count, a common sign

of sepsis or severe bacterial infection,

occurred in only six of 22 infants with direct

hyperbilirubinaemia. Early administration of

antibiotics seemingly prevented the develop-

ment of sepsis. Our study clearly demon-

strates that young infants with mild UTI may

develop conjugated hyperbilirubinaemia.

The question remains as to whether less

virulent strains of urinary tract pathogens

predispose to afebrile jaundice and whether a

prolonged occult UTI is more likely to cause

hepatic injury. Mixed urinary infections with

more than one organism are reported spor-

adically3,7 and account for more than 10% of

UTI in infants under 2 mths of age.20

However, polymicrobial infections were not

significantly correlated with conjugated

hyperbilirubinaemia in our study.

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Hyperbilirubinaemia in UTI 281

On the basis of the findings in this study

and others, we propose a dynamic model of

jaundice in young infants with UTI. Urinary

pathogens, mainly E. coli but possibly some

others, might simultaneously induce

increased levels of both indirect bilirubin

and direct bilirubin by way of haemolysis,

endotoxins, immune-mediated responses or

direct hepatocyte damage in the early stages.

With time, the indirect bilirubin level

progressively decreases, but the direct bilir-

ubin level does not fall proportionately.

Ongoing hepatocyte damage might impair

the excretion of conjugated bilirubin, lead-

ing to cholestasis mimicking hepatitis.

Acknowledgments

We are grateful to Dr Mary Jeanne Buttrey

for revising the English in this paper and to

Dr Shyh-Jye Chen for assistance with data

collection.

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