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The use of conjugated hyperbilirubinemia greater than100 lllmol/L as an indicator of irreversible liver diseasein infants with short bowel syndrome

Ahmed Nasra,d, Yaron Avitzurb, Vicky L. Ngb,c, Nicole De Silvaa,c, Paul W. Walesa,c,d,*

aDivision of General Surgery, Faculty of Medicine, The Hospital for Sick Children, University of Toronto, Toronto, CanadaM5G 1X8bDivision ofGastroenterology, Faculty ofMedicine, TheHospital for SickChildren,University of Toronto, Toronto, CanadaM5G1X8cGroup for The Improvement of Intestinal Function and Treatment (GIFT), Faculty of Medicine,

The Hospital for Sick Children, University of Toronto, Toronto, Canada M5G 1X8dPopulation Health Sciences, Faculty ofMedicine, The Hospital for Sick Children, University of Toronto, Toronto, CanadaM5G1X8

0022-3468/$ – see front matter D 2007

doi:10.1016/j.jpedsurg.2006.10.008

Presented at the British Association o

International Congress, Stockholm, Swe

* Corresponding author. Division

Sick Children, Toronto, Ontario, Canada

Ext 1490; fax: +1 416 813 7477.

E-mail address: paul.wales@sickkid

Index words:Hyperbilirubinemia;

Short bowel syndrome;

Cholestasis;

Parenteral nutrition;

Pediatrics

AbstractBackground: The introduction of parenteral nutrition resulted in improved survival of neonates with

short bowel syndrome. It is unclear why some may deteriorate to end-stage liver disease (ESLD).

Knowledge of when to refer such children for evaluation for transplantation is crucial. A commonly

used criterion is conjugated hyperbilirubinemia greater than 100 lmol/L (CB100).

Objectives: The aim of this study is to evaluate if CB100 is a reliable marker for identifying which

infants with short bowel syndrome will subsequently develop ESLD.

Methods: All neonates from our short bowel registry (1997-2003) were reviewed. Conjugated

hyperbilirubinemia greater than 100 lmol/L was defined as a sustained CB100 for at least 2 weeks with

no concurrent sepsis. The sensitivity, specificity, as well as positive and negative predictive values for

predicting an outcome of ESLD were calculated.

Results: Seventy short gut infants were identified (25 males; mean gestational age of 32.5 F 4.9 weeks

and weight of 1902F 888 g). Twenty-three patients (33%) developed CB100. Seventeen patients (24%)

developed ESLD. Conjugated hyperbilirubinemia greater than 100 lmol/L had a sensitivity of 94% and a

specificity of 87% in determining which patients would advance to ESLD. The positive and negative

predictive values were 70% and 98%, respectively. The median time from CB100 to ESLD was 60 days

(range, 10-365 days).

Conclusion:A positive predictive value of 70% ensures a safe level of over-triage to the transplant service

for assessment; however, the short duration from CB100 to ESLD (60 days) implies a late detection of

advanced liver disease, which raises concern about the use of this test in the clinical setting.

D 2007 Elsevier Inc. All rights reserved.

Elsevier Inc. All rights reserved.

f Paediatric Surgeons 53rd Annual

den, July 18 -22, 2006.

of General Surgery, Hospital for

M5G 1X8. Tel.: +1 416 813 7654,

s.ca (P.W. Wales).

The introduction of intravenous feeding and parenteral

nutrition (PN) in the 1960s revolutionized the management

of children with short bowel syndrome and allowed, for the

first time, long-term survival for these children [1]. This life-

saving therapy, however, has proven to be a double-edged

Journal of Pediatric Surgery (2007) 42, 359–362

Table 2 The predictive validity of CB100 as a marker for

the development of ESLD

ESLD

Present Absent

CB100 Present 16 7 23

Absent 1 46 47

17 53 70

Sensitivity = 94%, specificity = 87%, PPV = 70%, NPV = 98%

PPV indicates positive predictive value; NPV, negative predictive value.

A. Nasr et al.360

sword. Parenteral nutrition–associated cholestasis (PNAC)

remains a significant complication in infants who receive

prolonged PN support. Parenteral nutrition–associated cho-

lestasis occurs in up to 60% of neonates [2,3]. Of those,

10% will develop end-stage liver disease (ESLD) [4].

It is unclear why some patients have minimal morbidity,

whereas others deteriorate to ESLD. Progressive hepatic

dysfunction mandates referral for combined small bowel

and liver or isolated liver transplant assessment. Accord-

ingly, the knowledge of when to refer and list such

children for transplantation is crucial. A commonly used

criterion is sustained conjugated hyperbilirubinemia greater

than 100 lmol/L (CB100) [5]. There is, however, a

lack of evidence in the literature to support this widely

used criterion.

The goal of this study was to evaluate if CB100 should

be used as a reliable marker for identifying infants with

short bowel syndrome that will ultimately develop ESLD

and will require liver transplantation.

1. Methods

1.1. Study design

This is a retrospective cohort study.

1.2. Patient selection and definitions

All neonates with short bowel syndrome admitted to our

tertiary center were identified through our short bowel

registry (1997-2003). The observation period continued

until December 31, 2005. The neonates were either

monitored in-hospital or followed in our Intestinal Rehabil-

itation Clinic.

Short bowel syndrome was defined as the need for PN

for 6 weeks or more after intestinal resection, or patients

having less than 25% of bowel length as expected by gesta-

tional age [6,7]. Conjugated hyperbilirubinemia greater than

100 lmol/L was defined as a sustained hyperbilirubinemia

greater than 100 lmol/L for at least 2 weeks with no

Table 1 Patients demographics

Mean gestational

age (wk)

32.5 F 4.9

Sex, male/female 25/45

Mean weight (g) 1902 F 888

Diagnosis (%) ! Necrotizing enterocolitis 21 (30.0)

! Hirschsprung 4 (5.7)

! Abdominal wall defects 12 (17.1)

! Volvulus 5 (7.1)

! Meconium ileus 10 (14.2)

! Atresia 8 (11.4)

! Spontaneous perforation 6 (8.6)

! Other 4 (5.7)

The short bowel cohort (N = 70 infants).

concurrent sepsis [5]. End-stage liver disease was defined as

Conjugated hyperbilirubinemia greater than 200 mmol/L for

more than 2 weeks not associated with sepsis, plus an

international normalization ratio greater than 1.5, albumin

less than 20g/L, platelets less than 100,000, or evidence of

portal hypertension or bridging fibrosis in a liver biopsy.

1.3. Data analysis

The predictive validity of CB100 as a marker for

the development of ESLD was calculated using a standard

2 � 2 table.

This study was approved by the Hospital Research

Ethics Board.

2. Results

Seventy short gut infants were identified over a period of 6

years (1997-2003). There were 25 males and 45 females. The

mean gestational age of infants in this cohort was 32.5F 4.9

weeks, and the mean weight was 1902 F 888 g (Table 1).

Thirty seven (54%) patients developed cholestasis

(defined as a conjugated hyperbilirubinemia N2 weeks and

not associated with sepsis). Twenty-three patients (33%)

developed CB100, whereas 17 patients (24%) deve-

loped ESLD.

Conjugated hyperbilirubinemia greater than 100 lmol/L

used as a marker for ESLD had a sensitivity of 94%

(16/17) and a specificity of 87% (46/53). The positive and

the negative predictive values were 70% (16/23) and 98%

(46/47), respectively (Table 2).

The median time from CB100 to ESLD was 60 days

(interquartile range, 22-120 days). The median time between

cholestasis to ESLD was 148 days (interquartile range, 64-

170 days).

3. Discussion

Parenteral nutrition–associated cholestasis is the most

common complication in infants with short bowel syndrome

occurring in at least 67% of patients [7]. The etiology of

PNAC is multifactorial, and hence, strategies to prevent

it are limited [8]. Fortunately for most children, the

Hyperbilirubinemia and liver failure 361

cholestasis is temporary and resolves with gut adaptation

and subsequent weaning of the PN. However, 17% to 35%

[6,7] of children with short bowel syndrome will progress to

end-stage liver failure.

The development of irreversible liver failure during gut

adaptation poses a significant challenge that can only be

addressed through transplantation [9-11]. Despite the

promise of transplantation, our efforts are hampered by

the difficulty of differentiating severe but reversible

PNAC from irreversible liver failure. This leads to late

referral for transplantation and subsequently contributes to

the high mortality rate of children with short bowel

syndrome [4,11]. To address this issue, we have adopted a

policy of early referral and listing for transplantation.

Although this might facilitate survival to transplant, it

may result in transplantation of children who have

potential for hepatic recovery. This highlights the need

to examine approaches that not only allow one to

distinguish irreversible from reversible liver failure but

also to identify those with irreversible liver failure earlier

in the course of their disease. This would allow for earlier

listing of those who require transplant, while avoiding the

risks of transplantation for those who still have potential

for hepatic recovery.

The challenge of determining optimal timing for listing

for isolated liver or combined liver and small bowel

transplantation in children with short bowel syndrome

relates to the limitations of current clinical and laboratory

measures in identifying the severity of ESLD. Although

there are a number of clinical scores to determine the

severity of liver disease (eg, Child [12], Pugh [13], and

Paediatric End-Stage Liver Disease [PELD] [14]), none

absolutely differentiates irreversible from reversible liver

disease [15]. Although both the Child and Pugh scores

were developed for adults and have not been specifically

validated in the pediatric population, they are widely used

in children [16]. Furthermore, most conventional tests of

liver function (eg, bilirubin, transaminases) do not reflect

hepatic reserve [15,17]. Other measures of liver synthetic

function, such as the prothrombin time and serum albumin,

have been studied in this regard but have been found to be

insensitive to the degree of liver dysfunction [17-19]. As

well, although liver biopsy is useful in the diagnosis of

cirrhosis, it has a limited role in the assessment of function

because findings such as fibrosis occur late in the course

of the disease, and heterogeneity of sampling may under-

or overestimate the degree of liver damage [20].

In this study, we examined the sensitivity and specific-

ity of serum bilirubin greater than 100 lmol/L as a marker

for irreversible liver failure in short bowel syndrome.

Beath et al [5] suggested it was wise to consider transplant

referral in patients whose conjugated bilirubin was

consistently greater than 100 lmol/L. In their series of

37 pediatric patients with intestinal failure and liver

dysfunction, only 19% of patients with CB100 survived

more than 6 months [5]. In this study, the measure had a

sensitivity of 94% and a specificity of 87%, with positive

and the negative predictive values of 70% and 98%,

respectively. However, the median time from bilirubin

greater than 100 lmol/L to ESLD was 60 days. Despite

the high sensitivity and specificity of the marker, the time

course for this measure from listing to ESLD does not

allow for sufficiently early identification of irreversible

liver failure to improve outcome in the short bowel

population. This highlights the need for an improved early

marker of irreversible liver failure.

In contrast to conventional tests of liver function,

including those that measure synthetic capacity, dynamic

tests based on metabolism of a probe drug have shown

promise in quantifying the degree of liver dysfunction

[21,22]. Despite this, many of these tests have proved

problematic in the pediatric population in that many require

intravenous administration of the probe drug and may require

infusion of radioactive isotopes [23,24]. In addition, because

of cytochrome P450 interactions with medications common-

ly used in patients with liver failure, metabolism of the probe

drug may be affected [23-25], which impacts the interpret-

ability of the test result.

In summary, liver failure remains the main contributing

factor to the death of children with short bowel syndrome.

Although a rare disease, death from complications of short

bowel syndrome results in 1.4% of all deaths of children

less than 4 years of age [4]. By identifying children with

short bowel syndrome and liver failure earlier in the course

of their disease and ensuring earlier referral for transplan-

tation, we have an opportunity to decrease the proportion of

children who die as a result of this disease.

We have shown that CB100 does discriminate patients

who will eventually develop ESLD and will require liver

transplantation; however, it appears to be a late marker. A

test that permits earlier discrimination of irreversible liver

failure may improve outcome in this population by allowing

earlier listing for transplantation.

4. Q&A

Fitzgerald, Dublin, Ireland

May I ask that in other patient groups where prolonged

intravenous nutrition causes liver damage, you can come off

the nutrition and expect improvement. Is there a point of no

return, so to speak?

A.

It depends on the cholestases and whether these are

irreversible. So you watch these and get to the point where it

is liver or small bowel only. It depends on how the bowel

will adapt. If feeding is more than 50% of the requirement

that means they will adapt. And there is another criteria for

the liver transplant when you refer to liver transplant

isolated or liver and small bowel transplant. Then you need

to take into account the criteria of venous access and the

quality of life etc.

A. Nasr et al.362

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