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however, because newborns appear healthy and start developing Department of Pediatrics, and bDepartment of Pathology, Baylor
College of Medicine and Texas Children’s Hospital, Houston,
disease at an unknown time.
Texas
WHAT THIS STUDY ADDS: Patients with BA have elevated direct/ KEY WORDS
biliary atresia, direct bilirubin, conjugated bilirubin, total
conjugated bilirubin (DB/CB) levels at birth. BA could be detected bilirubin, newborn bilirubin screening
earlier if: (1) all newborns have DB/CB levels measured, including
ABBREVIATIONS
those not jaundiced; and (2) all elevated DB/CB levels are BA—biliary atresia
followed, independent of total bilirubin measurements. LT—liver transplantation
DB—direct bilirubin
CB—conjugated bilirubin
HoL—hour(s) of life
TB—total bilirubin
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ARTICLES
Biliary atresia (BA), a disease of un- would be unaffected as newborns and Data Acquisition
known etiology, causes significant have normal direct bilirubin/conju- For subjects with BA and controls, bili-
morbidity in pediatric populations. BA gated bilirubin (DB/CB) levels shortly rubin measurements from 0 to 96 HoL
is thought to be acquired by otherwise after birth. were obtained retrospectively from
healthy infants who develop bile duct birth hospitals. In addition, birth times
obstruction weeks after birth and PATIENTS AND METHODS (or, if unavailable, times of cord-blood
progress to end-stage liver disease collection) were recorded to calculate
Patient Selection
over the next 6 to 9 months. If affected time of bilirubin measurements, and
infants are identified with BA within This study was approved by the insti-
laboratory methodologies were re-
the first months, they undergo the Ka- tutional review board at Baylor Col-
corded to determine whether DB or CB
sai hepatoportoenterostomy (HPE) in lege of Medicine. Eligible subjects
measurements were made. For sub-
an attempt to restore bile flow and de- with BA were born between January
jects with BA, demographic data and
lay cirrhosis. If BA is diagnosed later, 1, 2007, and December 31, 2010, and
clinical course were also obtained
infants have advanced liver damage, cared for at Texas Children’s Hospi-
retrospectively.
rarely benefit from the Kasai opera- tal, a tertiary care center in Houston,
Texas. BA diagnoses were made by Subjects included in this study had ei-
tion, and proceed with liver transplan-
liver biopsy and/or intraoperative ther DB/TB or CB/unconjugated biliru-
tation (LT) evaluation because no other
cholangiogram. Eligible control sub- bin measured. As previously reported,
therapies exist. Unfortunately, be-
jects were the first 75 term infants DB and CB levels are similar but not
cause of unsuccessful Kasai opera-
equivalent. DB assays are chemical re-
tions and/or delayed diagnoses, ⬃ half born at the beginning of each season
(April 2010, July 2010, October 2010, actions (diazo reactions) that detect
of the patients with BA ultimately re-
some unconjugated bilirubin in addi-
quire LT, making BA the leading indica- and January 2011) at Ben Taub Gen-
tion to CB, whereas CB assays measure
tion for pediatric LT worldwide.1–3 eral Hospital, a large county hospital
CB directly by using direct spectropho-
Results of recent studies suggest that in Houston. All newborns in this hos-
tometry.6 Seventy-one DB levels were
LT can be delayed and even avoided if pital have DB and total bilirubin (TB)
obtained from 23 hospitals using Ab-
the Kasai hepatoportoenterostomy is measurements at 24 to 48 hours of
bott (Abbott Park, IL), Beckman Coulter
performed early, before significant life (HoL) regardless of clinical con-
(Brea, CA), Roche (Indianapolis, IN), or
liver damage develops (ie, before 8 dition. No control subjects later de-
Siemens (Deerfield, IL) machines. Most
weeks).4 However, making such an veloped liver disease.
hospitals reported a normal DB range
early diagnosis is difficult. One delay Excluded subjects had BA splenic of 0.0 to 0.3 mg/dL; however, 1 hospital
arises because there are no validated malformation (BASM) syndrome or reported a DB range of 0.0 to 0.5 mg/
early markers to screen for BA The were born prematurely. Subjects dL, which was used in this study. Thir-
earliest clinical marker–jaundice, is with BASM syndrome were defined teen CB levels were obtained from 6
accompanied by a number of patho- as those with who had either absent, hospitals using Vitros machines (Or-
logic changes in the liver, including or ⬎1 spleen on abdominal ultra- tho Clinical Diagnostics, Rochester,
bile duct proliferation and fibrosis. An- sound and were excluded because NY). A normal CB range of 0.0 to 0.3
other delay arises because BA is rela- they would be predicted to have con- mg/dL was used, consistent with find-
tively rare. BA occurs in 1 in 8000 to 1 in genital disease and elevated DB/CB ings from a recent large population
12 000 infants and a result, infants levels at birth.5 Premature subjects study.7
with BA are often mistaken initially for were defined as those born before 37
infants with more common forms of weeks’ gestation and were excluded Statistical Analysis
neonatal jaundice such as breastfeed- because this population lacks well- For analysis of demographic data,
ing jaundice or prolonged newborn accepted bilirubin ranges. In addi- Fisher’s exact test was used. For DB/TB
“physiologic” jaundice.1 tion, premature subjects have a analysis, levels were first grouped ac-
To help clinicians make earlier diagno- number of comorbidities that could cording to when they were collected
ses, we aimed to determine the earli- elevate DB/CB levels shortly after (0 –24, 24 – 48, 48 –72, or 72–96 HoL).
est time at which BA can be detected. birth, including sepsis, antibiotic When more than 1 DB/TB level was re-
We started by examining the newborn use, and parenteral nutrition. No eli- corded for a particular time interval,
period. Assuming that BA is acquired, gible subjects in this study were ⬎42 only the earliest measured level was
we hypothesized that infants with BA weeks’ gestation. used for calculations and graphs.
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ARTICLES
A 4 A * 0.4 *
3
3 0.3
DB, mg/dL
DB, mg/dL
DB/TB
2 0.2
1
1 0.1
0 0.0
0–24 24–48 48–72 72–96 0 Control BA
Control BA
HoL
FIGURE 4
B 5 B 15
* The majority of patients with BA have a DB/TB
Patient 1 ratio of ⱕ0.2. Shown are the mean DB/TB ratios
Patient 2 for controls (n ⫽ 242) versus patients with BA
4 Patient 3 (n ⫽ 24). Only subjects with a TB level of ⬎5
Patient 4 mg/dL were used for analysis. The dashed line
10
Patient 5 indicates the recommended normal limit (0.2).
CB, mg/dL
TB, mg/dL
3 a P ⬍ .0001.
Patient 6
Patient 7
2
5 peared healthy at birth, similar to pa-
tients with BA in general. They would
1
not have been distinctively jaundiced,
0
because they had TB levels below pho-
0
0 20 40 60 80
Control BA totherapy limits (Fig 3B). Hence, given
HoL FIGURE 3 that our subjects with BA were indis-
FIGURE 2 Patients with BA have elevated DB, but not TB, tinguishable from other patients with
Patients with BA have elevated DB and CB levels levels at 24 to 48 HoL. Shown are the mean DB
(A) and TB (B) levels for controls (n ⫽ 300; col- BA, the results from this study should
immediately after birth. A, Mean DB levels at 0 to
24 HoL (n ⫽ 6), 24 to 48 HoL (n ⫽ 24), 48 to 72 lection time: 39 ⫾ 5.6 HoL) versus patients with be broadly applicable to other infants
HoL (n ⫽ 11), and 72 to 96 HoL (n ⫽ 12). Each BA (n ⫽ 24; collection time: 34 ⫾ 6.2 HoL). The
dashed lines indicate the upper limits of normal
with the disease.
subject’s earliest measurement per interval
was used. B, CB levels. The dashed lines indicate (A, 0.5 mg/dL), or the approximate phototherapy As the first study to examine newborn
the upper limits of normal: 0.5 mg/dL (A) and 0.3 level at 34 HoL (B, 11.2 mg/dL). a P ⬍ .0001.
DB/CB levels in infants with BA, this
mg/dL (B).
study has limitations that can be ad-
dressed in future investigations. First,
however, suggest that BA is already have BA shortly after birth, which in the study had only 73 subjects, al-
present in the immediate newborn pe- turn has the potential to improve their though the subjects came from a
riod. All subjects with BA in this study outcomes. broad geographical area spanning 9
had elevated DB/CB levels throughout Because these results disagree with states and Mexico. Second, the study
the first 4 days of life and starting as expectations of BA as an acquired dis- included more DB levels than CB levels.
early as 1 HoL. Furthermore, at 24 to 48 ease, we questioned whether subjects DB measurements can differ between
HoL, subjects with BA had significantly with DB/CB levels collected in the first instruments, and their ranges may
higher mean DB levels compared to 4 days were representative of the gen- vary among hospitals.6,7 Third, we ex-
controls, even though their mean TB eral population of infants with BA. Two amined infants with BA rather than all
level was below phototherapy limits sets of findings suggest that they are infants) in a particular period and, as a
and their mean DB:TB ratio was consid- representative. First, subjects with result, provide information on sensitiv-
ered normal. Thus, rather than being and without measurements had simi- ity but not specificity. However, based
unaffected at birth, and acquiring the lar courses and outcomes (Table 1). upon previous studies, the specificity
disease later, it appears that new- Both groups underwent the Kasai of elevated DB/CB levels for BA would
borns with BA have abnormalities that hepatoportoenterostomy and LT in the likely be low, because more common
are readily detected by common labo- same proportions, and both had equiv- conditions such as sepsis also cause
ratory tests. The findings raise the pos- alent mortality rates. Second, subjects elevated DB/CB levels in the newborn
sibility of identifying infants who may with DB/CB levels would have ap- period.7
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ARTICLES
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