Conjugated hyperbilirubinemia in infants and children can be caused by obstructive or hepatocellular conditions of the liver or biliary system. The most common causes are extrahepatic biliary atresia, an inflammatory condition affecting the biliary tree which requires early surgery to prevent liver damage; Alagille syndrome, a genetic disorder characterized by bile duct paucity and other organ system abnormalities; and alpha-1-antitrypsin deficiency, a genetic condition where abnormal protein retention in the liver can cause liver disease. Early identification of the underlying cause is important for prognosis and institution of appropriate treatment.

1. Conjugated Hyperbilirubinemia:
Screening and Treatment in Older Infants and
Children
Rula Harb, MD,* Daniel
W. Thomas, MD†
Author Disclosure
Drs Harb and Thomas
did not disclose any
financial relationships
relevant to this
article.
Objectives After completing this article, readers should be able to:
1. Describe the metabolism of bilirubin.
2. Evaluate a child of any age who has conjugated hyperbilirubinemia.
3. Recognize the signs and symptoms of Wilson disease.
Introduction
Jaundice refers to yellow discoloration of the skin, sclera, mucous membranes, and body
fluids. It is a common problem that can be the presenting sign for many disorders. The
challenge for the physician is to identify patients who need additional evaluation. The
differential diagnosis for jaundice is age-specific; this review addresses the causative
conditions in infants beyond the newborn period, older children, and adolescents.
Jaundice is caused by elevated serum bilirubin concentrations. It is apparent in infants
when the serum bilirubin value is greater than 4 to 5 mg/dL (68.4 to 85.5 mcmol/L) and
in older children at values greater than 2 to 3 mg/dL (34.2 to 51.3 mmol/L). Serum total
bilirubin is measured in the laboratory as the sum of two components: unconjugated
(“indirect”) and conjugated (“direct”) fractions. The terms “direct” and conjugated
hyperbilirubinemia often are used interchangeably. However, this usage is not always
accurate because direct bilirubin may include both the conjugated fraction and bilirubin
bound to albumin (delta bilirubin). Delta bilirubin is formed by covalent bonding between
conjugated bilirubin in the serum and albumin; it is metabolized with albumin and has a
similar half-life of 21 days. The presence of delta bilirubin often prolongs direct hyperbi-
lirubinemia while results of the other liver tests are normalizing. Many hospitals continue
to measure direct bilirubin by a method that includes both direct and delta bilirubin.
Clinicians should consider asking for a breakdown of the direct bilirubin fraction if the
jaundice is prolonged or presenting atypically.
Conjugated hyperbilirubinemia is defined as a conjugated bilirubin concentration
greater than 2 mg/dL (34.2 mmol/L) or more than 20% of total bilirubin. It is the
biochemical marker of cholestasis used most commonly and defined as perturbation of bile
flow. Although jaundice is seen commonly in newborns who have physiologic jaundice,
breastfeeding and breast milk jaundice, red blood cell defects, and hemolysis, these are
conditions of unconjugated (indirect) hyperbilirubinemia. Causes of unconjugated hyper-
bilirubinemia in the older infant/child are not reviewed in this article. Conjugated
hyperbilirubinemia is less common, affecting approximately 1 in 2,500 infants. This
condition is never normal at any age, and distinguishing cholestasis from noncholestatic
causes of jaundice is crucial. Prolonged hyperbilirubinemia of greater than 2 to 3 weeks’
duration requires additional investigation.
Bilirubin Metabolism
The liver has many functions, many of which depend on its ability to secrete bile. Bile
secretion is the method by which the liver excretes toxins, modulates cholesterol metab-
olism, and aids in the intestinal digestion and absorption of lipids and fat-soluble
vitamins. Bile is composed of water, bile acids (cholic and chenodeoxycholic acids),
phospholipids, cholesterol, bile pigment (bilirubin), electrolytes, xenobiotics, and
metabolized drugs. Impairment of bile flow or secretion by the liver results in backup
*Children’s Hospital of Los Angeles, Los Angeles, Calif.
†
Editorial Board.
Article gastroenterology
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2. of its constituents within the liver canaliculi and hepa-
tocytes, ultimately creating cholestatic damage to the
liver.
Bilirubin is the product of heme breakdown in the
reticuloendothelial cells of the spleen and liver (Fig. 1).
The end product of this metabolic pathway is water-
insoluble unconjugated bilirubin, which is bound to
albumin in the circulation. Unconjugated bilirubin is
taken up and metabolized in the liver to conjugated
bilirubin (Fig. 2). Conjugated bilirubin is secreted into
the biliary system by a specific transporter. Defects in
bilirubin conjugation cause unconjugated hyperbiliru-
binemia (Gilbert syndrome and Crigler-Najjar syn-
dromes I and II). Hepatocellular disease can cause a
mixed unconjugated and conjugated hyperbilirubinemia
due to both impaired bilirubin conjugation and canalic-
ular excretion. Defects in conjugated bilirubin excretion
cause isolated conjugated hyperbilirubinemia without
cholestasis (Rotor and Dubin-Johnson syndromes).
Other mutations in membrane transporters of other or-
ganic anions, such as bile acids, are linked with several
diseases, including cystic fibrosis, adrenoleukodystrophy,
and the familial intrahepatic cholestasis syndromes.
Once bile is excreted from the liver, it is stored in the
gallbladder until a meal activates duodenal cholecystoki-
nin release and expulsion of gallbladder contents into the
intestine. Conjugated bilirubin cannot be reabsorbed by
intestinal epithelial cells and is degraded by intestinal
flora into stercobilin and urobilinogen, which are ex-
creted into stool. A small portion of conjugated bilirubin
is deconjugated by intestinal beta-glucuronidase. The
unconjugated bilirubin can be reabsorbed into the circu-
lation and returned to the liver, which is known as
enterohepatic bilirubin circulation. The amount of bili-
rubin reabsorbed normally is very small, but it can be-
come significant in cases of bowel
obstruction, where relatively more
bilirubin is deconjugated and ab-
sorbed, thereby increasing serum
bilirubin concentrations and wors-
ening jaundice.
Jaundice in the Infant
Prolonged jaundice in the infant
(lasting beyond 2 to 3 weeks after
birth) is abnormal and requires ad-
ditional investigation. It is para-
mount to fractionate the bilirubin
in infants who have abnormal or
prolonged jaundice to identify
those who have conjugated hyper-
bilirubinemia and recognize the disorders that may be
amenable to early medical intervention (eg, galac-
tosemia, urinary tract infection) or surgery (eg, biliary
atresia, choledochal cyst). In addition, early diagnosis
facilitates the institution of necessary nutritional and
medical support to promote optimal growth and devel-
opment.
The causes of cholestatic jaundice in the infant vary
and can be divided into two primary categories: obstruc-
tive and hepatocellular. A detailed classification is listed
in Table 1. The four most common causes of persistent
cholestatic jaundice in infants are discussed.
Extrahepatic Biliary Atresia (EHBA)
EHBA is the most common and serious cause of pro-
longed cholestatic jaundice in infants. It results from a
progressive and destructive inflammatory process that
affects both the extra- and intrahepatic biliary tree. The
cause of EHBA has not been identified clearly. Two
clinical forms have been defined: an embryonic/fetal
form, which constitutes 20% of cases, and a perinatal/
acquired type, which comprises the remaining 80% of
cases. (1) The embryonic type has an earlier onset, has no
jaundice-free interval, and is associated with other non-
hepatic anomalies or syndromic features, such as isolated
cardiovascular and gastrointestinal anomalies (intestinal
malrotation, preduodenal portal vein, abdominal situs
inversus) and splenic anomalies (polysplenia, asplenia).
The acquired type is not associated with other congenital
anomalies, usually occurs in an otherwise healthy term
infant, and has a jaundice-free interval followed by the
development of jaundice in the first few postnatal weeks.
Both forms share the cardinal features of cholestatic
jaundice, hepatomegaly, and acholic stools.
EHBA was universally fatal before the Kasai hepato-
Figure 1. Bilirubin production in the reticuloendothelial system. RBC‫؍‬red blood cell
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3. portoenterostomy was introduced by Dr Morio Kasai in
1959. This procedure establishes bile flow in up to 80%
of patients if performed prior to 60 days after birth. The
success rate decreases as the infant’s age increases, with
bile flow established in up to 45% of infants 60 to 90 days
of age and 10% of infants 90 to 120 days of age. (1) These
results underscore the importance of diagnosing this
condition early. Approximately one third of patients
require liver transplant in the first postnatal year, one
third require it in their teens, and one third live with
some liver function after the Kasai procedure into adult-
hood. (1) It is estimated that approximately 50% of
patients who have good results from the initial Kasai
surgery still become transplant candidates later in life.
“Idiopathic” Neonatal Hepatitis
“Idiopathic” neonatal hepatitis, also known as “giant
cell” hepatitis, used to be considered the most common
cause of neonatal cholestasis. However, its relative occur-
rence has decreased as specific dis-
orders that cause a similar clinical
and histologic picture have been
identified (eg, alpha-1-antitrypsin
deficiency, defective bile acid syn-
thesis and transport). The diagno-
sis is made in infants who have pro-
longed cholestatic jaundice and
typical biopsy findings of disrupted
hepatic architecture, multinucle-
ated “giant” hepatocytes, focal he-
patocyte necrosis, expansion of
portal triads with inflammatory in-
filtrate, and extramedullary hema-
topoiesis in addition to the absence
of another disorder. Electron mi-
croscopy often is useful in diagno-
sis.
The prognosis of “idiopathic”
hepatitis is variable and depends on
whether a metabolic or infectious
cause ultimately is diagnosed.
Jaundice usually resolves by 3 to 4
months of age; persistence of jaun-
dice beyond this age warrants addi-
tional evaluation.
Alagille Syndrome (AGS)
AGS also is known as syndromic
bile duct paucity or arteriohepatic
dysplasia. It is an autosomally
dominant inherited with low pen-
etrance disorder of bile duct paucity that occurs in con-
junction with syndromic extrahepatic findings.
The defect in AGS is a mutation of the Jagged 1 (JAG1)
gene, which is mapped to chromosome 20p12 and en-
codes a ligand for the Notch signaling pathway, which is
important in cell fate determination. The diagnosis can
be made in the patient who has a marked reduction of
intrahepatic bile ducts on liver biopsy in association with
other cardiac, ocular, skeletal, and facial abnormalities.
The bile duct paucity may not be apparent in early
infancy. AGS usually presents in the first 3 postnatal
months and must be distinguished from biliary atresia
and other causes of nonsyndromic paucity. It may be
diagnosed in older children who have persistent choles-
tatic jaundice and in adults after diagnosis in a related
child.
In the original series described by Alagille in 1975, (2)
15 of 30 patients who had cholestatic jaundice and
hepatic ductular hypoplasia with intact extrahepatic bile
Figure 2. Bilirubin conjugation. Movement of bilirubin (B) from the circulation into the
hepatocyte occurs at the hepatocyte basolateral membrane with the help of a membrane
carrier protein. Binding of B to glutathione-S-transferase (GST) facilitates movement into
the rough endoplasmic reticulum (RER), where conjugation with glucuronic acid (GA) is
enabled by bilirubin ceridine diphosphate glucuronosyl transferase 1A1 (UGT1A1). The
conjugated bilirubin is excreted into bile at the hepatocyte canalicular membrane through
a process mediated by the membrane-bound transporter cMOAT (canalicular multispecific
organic anion transporter). Alb‫؍‬albumin, cytosol‫؍‬the fluid within a cell that contains the
cell’s oranelles, B-GA‫؍‬conjugated bilirubin (mono- and di-glucuronides). Adapted from
Gourley GR. Bilirubin metabolism. In: Walker WA, Goulet OJ, Kleinman RE, et al, eds.
Pediatric Gastrointestinal Disease: Pathophysiology, Diagnosis, Management. 4th ed.
Hamilton, Ontario, Canada: BC Decker, Inc; 2004:1344–1362.
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4. ducts had other common features.
These included a characteristic fa-
cies (prominent forehead, deep-set
eyes with mild hypertelorism,
straight nose, and small, pointed
chin), a systolic murmur caused by
peripheral pulmonic stenosis, verte-
bral arch defects, growth retarda-
tion, mild-to-moderate mental re-
tardation, and hypogonadism in
boys. Emerick and associates (3)
studied 92 patients who had AGS
and found cholestasis in 96%, bile
duct paucity in 85%, cardiac mur-
mur in 97%, vertebral anomalies in
51%, characteristic facies in 96%,
eye findings (posterior embryo-
toxon) in 78%, and renal anomalies
in 40%. Minor features included
growth retardation (87%), mental
retardation (2%), developmental
delay (16%), and pancreatic insuffi-
ciency (41%). Alagille and col-
leagues (4) have recommended that
the diagnosis be made by confirm-
ing the existence of cholestasis and
two of the other four abnormalities.
Factors that contribute significantly
to mortality in AGS include cardiac
disease (other cardiac defects be-
sides peripheral pulmonic stenosis
such as tetralogy of Fallot), intra-
cranial hemorrhage, and progres-
sive liver disease.
Alpha-1-Antitrypsin
Deficiency
Alpha-1-antitrypsin is a member of
the serine protease inhibitor family
(the serpins) that protects the con-
nective tissue from degradation by
inhibition of neutrophil elastase,
cathepsin G, and proteinase 3. Al-
though lung disease associated with
alpha-1-antitrypsin deficiency is at-
tributed to markedly reduced con-
centrations, liver disease results
from retention of the abnormally
folded protein in the endoplasmic
reticulum (ER) of the hepatocyte
(the site of synthesis of most alpha-
Table 1. Differential Diagnosis of Cholestatic
Jaundice in the Infant
Obstructive
● Extrahepatic biliary atresia
● Choledochal cyst
● Spontaneous perforation of the bile duct
● Inspissated bile
● Mass: stone, tumor
Hepatocellular
● Idiopathic neonatal hepatitis
● Disorders of the intrahepatic bile ducts
– Alagille syndrome (arteriohepatic dysplasia/syndromic paucity of the
intrahepatic bile ducts)
– Nonsyndromic paucity of the intrahepatic bile ducts
– Congenital hepatic fibrosis with bile duct cysts (Caroli disease)
● Metabolic disorders
– Disorders of amino acid metabolism
Ⅲ Tyrosinemia
– Disorders of lipid metabolism
Ⅲ Gaucher disease
Ⅲ Niemann-Pick disease
Ⅲ Cholesterol ester storage disease (Wolman syndrome)
– Disorders of carbohydrate metabolism
Ⅲ Galactosemia
Ⅲ Hereditary fructose intolerance
Ⅲ Glycogen storage disease
– Disorders of bile acid metabolism and transport excretion
– Zellweger syndrome and other disorders of peroxisomal metabolism
– Disorders of bilirubin transport (do not cause cholestatic liver injury)
Ⅲ Dubin-Johnson syndrome
Ⅲ Rotor syndrome
– Mitochondrial disorders
– Alpha-1-antitrypsin deficiency
– Cystic fibrosis
– Neonatal iron storage disease
● Endocrine disorders
– Hypothyroidism
– Hypopituitarism and septo-optic dysplasia
● Infectious
– Sepsis (urinary tract infection, endotoxemia, enterocolitis)
– TORCH infections (toxoplasmosis, cytomegalovirus, herpesvirus, rubella, syphilis)
– Hepatitis B, non-typeable hepatitis
– Human immunodeficiency virus
● Drugs and Toxins
– Total parenteral nutrition
– Medications
– Fetal alcohol syndrome
● Other
– Vascular anomalies
Ⅲ Budd-Chiari syndrome
Ⅲ Hepatoendothelioma/hemangioma
– Cardiac insufficiency and hypoperfusion
– Chromosomal abnormalities
Ⅲ Trisomy 21
Ⅲ Trisomy 18
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5. 1-antitrypsin). Alpha-1-antitrypsin is a polymorphic pro-
tein that has allelic variants defined by isoelectric focusing
of the plasma and classified according to the protease
inhibitor (Pi) phenotype. Structural variants that have
normal plasma concentrations or functional activity are
known as PiM alpha-1-antitrypsin. Variants in which
alpha-1-antitrypsin is not detected are known as null
allelic variants and when inherited with another null
variant, are associated with early development of emphy-
sema but no liver disease. Variants that have reduced
alpha-1-antitrypsin activity include the PiZ and PiS. The
PiZ homozygote is the condition associated most com-
monly with liver and lung disease.
Alpha-1-antitrypsin deficiency is the most common
genetic cause of acute and chronic liver disease in chil-
dren and the most common genetically caused disorder
necessitating liver transplantation in children. Presenta-
tion of liver disease in ZZ homozygotes is variable. In a
review of 44 patients, Volpert and colleagues (5) re-
ported that the age of diagnosis of alpha-1-antitrypsin
deficiency-associated liver disease was younger than 1
month in 10 patients, 1 month to 1 year in 21 patients,
and older than 1 year in 13 patients. One of every 10
patients has prolonged jaundice in infancy, and 1 of 100
develops cirrhosis and requires transplantation. (6)
Other clinical presentations include neonatal hepatitis
syndrome, mild elevation of transaminase values in the
toddler, portal hypertension and cirrhosis in the child or
adolescent, chronic hepatitis in the adult, and hepatocel-
lular carcinoma in the adult. Diagnosis is made by dem-
onstrating an abnormal Pi phenotype (PiZZ) and peri-
odic acid-Schiff-positive, diastase-resistant globules in
the ER of hepatocytes.
Jaundice in the Older Child/Adolescent
New-onset cholestatic jaundice in the older child and
adolescent always requires additional investigation. It is
essential to fractionate the bilirubin to differentiate cho-
lestatic jaundice from unconjugated hyperbilirubinemia
due to hemolysis or defective bilirubin conjugation, as
occurs in Gilbert syndrome.
Conjugated hyperbilirubinemia results from obstruc-
tive or hepatocellular causes. Biliary stones and sludge
can obstruct the common bile duct and cause subsequent
jaundice. Other causes of obstructive jaundice in this age
group include parasitic infestations (ascaris, liver flukes),
primary sclerosing cholangitis, choledochal cyst, and tu-
mors. Hepatocellular causes of conjugated hyperbiliru-
binemia, such as viral or medication-related hepatitis, can
result in jaundice. Clinically apparent liver disease from
chronic hepatitis B infection has decreased markedly due
to the effective implementation of the vaccine for this
disorder. Signs of active hepatitis C usually occur in
adults and are not discussed in detail in this article.
Wilson disease and autoimmune hepatitis are relatively
uncommon causes of hyperbilirubinemia but are two
important entities for the
pediatrician to recognize
early because treatment
that may prevent progres-
sion is available. Other
hepatocellular disorders
are detailed in Table 2.
Wilson Disease
Wilson disease is an auto-
somal recessive disorder of copper homeostasis. The
affected gene is on chromosome 13 and encodes a highly
conserved copper-transporting P-type adenosine
triphosphatase (ATP7b) that excretes copper into bile.
Copper is an essential trace element that participates in
cellular respiration, iron oxidation, pigment formation,
and antioxidant defense. It is absorbed from copper-rich
foods from the stomach and duodenum, bound to ceru-
loplasmin in the circulation, and excreted by the liver
into bile.
The prevalence of Wilson disease is 1 in 30,000 and is
equal among all ethnic groups. The condition presents in
most patients as either hepatic or central nervous system
involvement. Liver disease occurs at an average age of
10 to 13 years in 45% of patients and rarely is seen before
3 years of age. Some 35% of patients present with neuro-
logic signs (tremor, rigidity, dysarthria) a decade older
than patients who have hepatic involvement; 10% present
with psychiatric disturbances (depression, new-onset
school problems, impulsive behavior); and 10% present
with other manifestations, including hemolytic anemia,
Fanconi syndrome (glycosuria, aminoaciduria), and car-
diomyopathy. Thus, patients who have Wilson disease
can have a mixed conjugated and unconjugated hyperbi-
lirubinemia, depending on which disease manifestations
are present.
Alpha-1-antitrypsin deficiency is the
most common genetic cause of acute and chronic
liver disease in children.
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6. Hepatic involvement ranges from asymptomatic
transaminitis to acute liver failure with jaundice, cirrho-
sis, hepatic necrosis, and encephalopathy. Liver biopsy
can show nonspecific findings of steatosis and glycogen
deposition. Micronodular cirrhosis and piecemeal necro-
sis also can be seen. Kaiser-Fleischer (KF) rings, repre-
senting copper deposition in Descemet’s membrane, are
visible on a slitlamp examination of the eye. Neurologic
symptoms are attributed to copper deposition in the
basal ganglia and include parkinsonian symptoms. KF
rings often are present in patients who have neurologic
symptoms, but may be absent in patients who have liver
disease.
Wilson disease is diagnosed in the patient who has
signs and symptoms consistent with the disease in addi-
tion to laboratory findings of impaired hepatic copper
metabolism. The serum ceruloplasmin concentration is
decreased because copper is not conjugated to the apo-
ceruloplasmin synthesized by the hepatocyte. The un-
conjugated apoceruloplasmin is degraded rapidly. Mea-
surement of urinary copper in a 24-hour collection is
increased. A liver biopsy quantitating hepatic copper
content is a helpful diagnostic tool, and a liver that has
normal copper content excludes the diagnosis. A slitlamp
examination can be performed to evaluate for KF rings.
Definitive genetic testing is now available for Wilson
disease.
Therapy is geared toward attaining and maintaining
normal copper homeostasis. Oral D-penicillamine and
trientine are copper chelators. Zinc acetate prevents the
absorption of copper from the gastrointestinal tract. Pa-
tients are counseled to avoid copper-rich foods such as
shellfish, legumes, nuts, chocolate, and liver. Liver trans-
plantation is the treatment of choice for selected patients
who have either advanced liver disease or fulminant liver
failure.
Autoimmune Hepatitis (AIH)
AIH is an inflammatory hepatitis characterized by the
development of pathologic autoantibodies to normal
host proteins and a dense mononuclear infiltrate in the
portal tracts in the absence of another cause. AIH can be
subdivided into two general categories classified by the
type of autoantibodies produced: anti-nuclear antibody/
anti-smooth muscle antibody (ANA/SMA) AIH, and
anti-liver kidney microsomal antibody 1 (LKM1) AIH.
In a study of 52 patients who had AIH, investigators
found that the median age at presentation of ANA/SMA
AIH was 10.5 years and that for LKM1 AIH was 7.4
years. (7) Some 75% of patients were female. Three
patterns of presentation were noted:
1) Acute hepatitis was the pattern in most patients
having both types, with nausea, vomiting, anorexia, fa-
tigue, and abdominal pain, followed by jaundice, dark
urine, and pale stools. Duration of illness varied from
2 weeks to 2 months in this group.
2) Another group (30%) had the insidious onset of
disease of longer duration (6 mo to 2 yr), with relapsing
jaundice, progressive fatigue, headache, anorexia, and
weight loss.
Table 2. Differential Diagnosis of
Cholestatic Jaundice in the
Older Child and Adolescent
Obstructive
● Choledochal cyst
● Mass: stone, tumor, parasite
Hepatocellular
● Autoimmune
– Autoimmune hepatitis
– Primary sclerosing cholangitis
– Primary biliary cirrhosis
● Disorders of the intrahepatic bile ducts
– Alagille syndrome (arteriohepatic dysplasia/
syndromic paucity of the intrahepatic bile ducts)
– Nonsyndromic paucity of the intrahepatic bile
ducts
– Congenital hepatic fibrosis/Caroli disease
● Metabolic disorders
– Wilson Disease
– Disorders of bilirubin transport
– Dubin-Johnson syndrome
– Rotor syndrome
– Mitochondrial disorders
– Alpha-1-antitrypsin deficiency
– Cystic fibrosis
– Hemochromatosis
● Endocrine disorders
– Hypothyroidism
● Infectious
– Sepsis (endotoxemia, enterocolitis)
– Hepatitis A, B, C, E, non-typeable hepatitis
– Human immunodeficiency virus
● Drugs and toxins
– Total parenteral nutrition
– Medications
● Other
– Vascular anomalies
– Budd-Chiari syndrome
– Hemangioma
– Cardiac insufficiency and hypoperfusion
– Chromosomal abnormalities
– Trisomy 21
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7. 3) A small percent of patients, who had no prior
history of jaundice, had complications of portal hyper-
tension.
AIH is suspected on the basis of clinical characteristics
and demonstration of the autoantibodies, as well as an
elevated immunoglobulin G value. Definitive diagnosis is
made on liver biopsy, where the typical histologic picture
is a dense mononuclear infiltrate invading the hepatic
parenchyma (periportal hepatitis), with periportal necro-
sis. In most cases, the disease responds well to immuno-
suppressive therapy. Urgent liver transplantation is indi-
cated if the patient presents in acute fulminant hepatic
failure.
Evaluation of the Jaundiced Patient
Although jaundice is relatively common in the first
2 weeks after birth and is observed frequently in new-
borns, jaundice in the older infant and child always is
abnormal and requires more investigation. Additional
evaluation of children who have conjugated hyperbiliru-
binemia and chronic liver disease should involve looking
for the complications of cholestasis, such as coagulopathy,
fat malabsorption, ascites, and encephalopathy, to initiate
appropriate therapy. Finally, a child who has conjugated
hyperbilirubinemia or evidence of chronic liver disease
should be referred to a pediatric gastroenterologist.
History
The age of the patient and history of presentation give
important clues to the cause of the jaundice. Some
conditions of infantile cholestasis and conjugated hyper-
bilirubinemia present early in life, such as biliary atresia,
AGS, and inherited metabolic disorders. Others often
manifest beyond infancy, such as AIH and Wilson dis-
ease. Diseases such as cystic fibrosis and alpha-1-
antitrypsin deficiency can present as either neonatal cho-
lestasis or later in life as chronic liver disease.
Signs such as poor feeding, irritability, and vomiting
may be associated with a metabolic condition, such as
galactosemia, or suggest encephalopathy. The presence
of acholic stools suggests an obstructive process such as
biliary atresia, choledochal cyst, or gallstone disease.
Additionally, the birth and perinatal histories, past med-
ical and surgical histories, family history (including con-
sanguinity), medication and dietary histories, social ac-
tivity and school performance histories, and travel history
should be sought.
Physical Examination
The clinician should note if the patient is well- or ill-
appearing as well as irritable or drowsy. Both signs may
indicate encephalopathy, infection, or metabolic de-
rangement. Microcephaly in the infant may indicate con-
genital infection. Recognition of dysmorphism is valu-
able. Eyes should be examined for posterior embryotoxon
or KF rings. The systolic murmur of peripheral pulmonic
stenosis, usually heard in the back as well as the front,
suggests AGS. Hepatomegaly typically is present, but a
small liver may indicate cirrhosis and end-stage liver
disease. Splenomegaly, ascites, and prominent vascula-
ture such as caput medusa suggest portal hypertension
and chronic liver disease.
An infant’s diaper should
be examined for pale
stools and dark urine.
Neurologic evaluation
should be undertaken for
ataxia and asterixis.
Laboratory Tests
The key laboratory test to
obtain when evaluating jaundice is fractionation of the
bilirubin. Indirect or unconjugated hyperbilirubinemia
usually indicates excessive red blood cell destruction at
any age. Direct or conjugated hyperbilirubinemia indi-
cates a hepatobiliary disorder. Hepatic transaminase con-
centrations are elevated in the presence of hepatocellular
injury. The alkaline phosphatase and gamma glutamyl
transferase values often are increased with obstructive
conditions. Liver function, including prothrombin time,
albumin, and cholesterol, should be measured. The remain-
der of the evaluation should be tailored to the specific
patient. Hemolytic anemia can be seen in patients who have
Wilson disease. Thyroid function tests can be obtained if
hypothyroidism is suspected. Other age-specific tests may
be considered, including TORCH (toxoplasmosis, rubella,
cytomegalovirus, herpes simplex) titers, blood and urine
cultures, alpha-1-antitrypsin Pi phenotype, iron profile,
chloride sweat test, urine-reducing substances (galac-
tosemia), and a metabolic screen in young infants. Testing
for Wilson disease (ceruloplasmin) or for AIH is appropriate
in older children.
Thekey laboratory test to obtain when
evaluating jaundice is fractionation of the
bilirubin.
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8. Imaging
Real-time ultrasonography is an important diagnostic
tool in the evaluation of the jaundiced patient. The
absence of a gallbladder on a fasting examination in an
infant is suggestive but not diagnostic of biliary atresia.
Ultrasonography may demonstrate gallstones, chole-
dochal cyst, or ascites. A Doppler ultrasonographic study
of the portal circulation may identify portal hypertension
or portal vein thrombosis. Hepatobiliary scintigraphy
with technetium-labeled iminodiacetic acid analogs may
help differentiate obstructive jaundice from nonobstruc-
tive causes. In the case of obstructive jaundice, the he-
patic uptake of tracer is normal, but there is no intestinal
excretion. In cases of severe hepatocellular disease, up-
take into the liver is delayed, but tracer eventually is
excreted into the intestine. Premedication with pheno-
barbital for 3 to 5 days prior to the study enhances biliary
excretion and imaging of the isotope.
Liver Biopsy
Ultimately, many patients require a liver biopsy for de-
finitive and reliable diagnosis. The liver biopsy can be
performed percutaneously, with or without ultrasono-
graphic guidance, or surgically. In addition to evaluation
by an experienced pathologist for specific histologic fea-
tures, liver tissue can be used to quantify iron and copper
content and for electron microscopy to detect certain
metabolic conditions.
Management of Jaundice
Treatment is directed at the specific underlying disorder,
although persistent cholestasis generally can cause reten-
tion of bile acids, bilirubin, and cholesterol; decreased
excretion of bile acids into the intestine with resulting fat
malabsorption; and hepatocellular damage that eventu-
ally causes portal hypertension and end-stage liver dis-
ease. Some general principles apply to the management
of these consequences independent of the specific cause.
These principles include optimizing nutrition by em-
ploying the use of medium-chain triglyceride-containing
formula or supplements and monitoring fat-soluble vita-
min concentrations with supplementation. Management
of the complications of chronic liver disease and portal
hypertension in conjunction with a pediatric gastroenterol-
ogist is essential. All children, particularly those who have
chronic liver disease, should be immunized, including both
hepatitis A and B, using the guidelines of the American
Academy of Pediatrics. It is appropriate to refer any child
who evidences acute, severe liver disease or a chronic liver
condition to a pediatric transplant center for evaluation.
References
1. Balistreri WF, Grand R, Hoofhagle JH, et al. Biliary atresia:
current concepts and research directions. Hepatology. 1996;23:
1682–1692
2. Alagille D, Odie`vre M, Gautier M, et al. Hepatic ductular
hypoplasia associated with characteristic facies, vertebral malforma-
tions, retarded physical growth, mental and sexual development,
and cardiac murmur. J Pediatr. 1975;86:63–71
3. Emerick KM, Rand EB, Goldmuntz E, et al. Features of Alagille
syndrome in 92 patients: frequency and relation to prognosis.
Hepatology. 1999;29:822–829
4. Alagille D, Estrada A, Hadchouel M, et al. Syndromic paucity of
interlobular bile ducts (Alagille syndrome or arteriohepatic dyspla-
sia): review of 80 cases. J Pediatr. 1987;110:195–200
5. Volpert D, Molleston JP, Perlmutter DH. Alpha-1-antitrypsin
deficiency-associated liver disease progresses slowly in some chil-
dren. J Pediatr Gastroenterol Nutr. 2000;31:258–263
6. Carrell RW, Lomas DA. Alpha1-antitrypsin deficiency: a model
for conformational diseases. N Engl J Med. 2002;346:45–53
7. Mieli-Vergani G, Vergani D. Immunological liver diseases in
children. Semin Liver Dis. 1998;18:271–279
Suggested Reading
Gitlin JD. Wilson disease. Gastroenterology. 2003;125:1868–1877
McLin VA, Balistreri WF. Approach to neonatal cholestasis. In:
Walker WA, Goulet OJ, Kleinman RE, et al, eds. Pediatric
Gastrointestinal Disease: Pathophysiology, Diagnosis, Manage-
ment. 4th ed. Hamilton, Ontario, Canada: BC Decker Inc;
2004:1079–1091
Moyer V, Freese DK, Whitington PF, et al. Guideline for the
evaluation of cholestatic jaundice in infants: recommendations
of the North American Society for Pediatric Gastroenterology,
Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 2004;
39:115–128
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9. PIR Quiz
Quiz also available online at www.pedsinreview.org.
1. Conjugated hyperbilirubinemia is:
A. A marker of accelerated hemoglobin breakdown.
B. A normal finding in otherwise healthy adolescents.
C. Always linked with cholestasis.
D. Less common than unconjugated hyperbilirubinemia.
E. Synonymous with direct hyperbilirubinemia.
2. A 4-week-old breastfeeding boy is jaundiced and has a total bilirubin concentration of 13 mg/dL
(222.3 mmol/L). The laboratory test that maximizes diagnostic efficiency is:
A. A complete blood count.
B. A reticulocyte count.
C. Bilirubin fractionation.
D. Gamma glutamyl transferase.
E. Hepatic transaminase.
3. A 4-week-old breastfeeding boy has become increasingly jaundiced. The pregnancy was unremarkable.
Delivery was at term, and the infant was appropriate for gestational age. The jaundice was not noted in the
hospital. Findings on the physical examination, other than jaundice, are unremarkable. Today, the total
bilirubin concentration is 13 mg/dL (222.3 mmol/L), with a direct fraction of 6 mg/dL (102.6 mmol/L). Of
the following, the condition that is most likely ruled out by these findings is:
A. Alagille syndrome.
B. Alpha-1-antitrypsin deficiency.
C. Extrahepatic biliary atresia.
D. Neonatal hepatitis.
E. Physiologic jaundice.
4. A previously healthy 15-year-old girl develops jaundice and fatigue. She does not complain of colicky
abdominal pain associated with meals. She has had no known exposure to hepatotoxins. Aside from
jaundice and appearing mildly ill, findings on her physical examination are unremarkable. Initial laboratory
evaluation reveals a bilirubin concentration of 11 mg/dL (188.1 mmol/L) with a direct fraction of 4 mg/dL
(68.4 mmol/L), and elevated hepatic transaminases, but no evidence of Epstein-Barr or hepatitis A, B, or C
virus. As suspected from the history, ultrasonography reveals a normal gallbladder and biliary tree. Serum
ceruloplasmin and autoantibody results are inconclusive. Pi typing reveals PiMM, and the patient proceeds
to liver biopsy. Copper content of the sample is normal. Of the following, the patient is most likely to have:
A. Alpha-1-antitrypsin deficiency.
B. Autoimmune hepatitis.
C. Choledochal cyst.
D. Gilbert syndrome.
E. Wilson disease.
5. Wilson disease is diagnosed definitively through:
A. Genetic testing.
B. Liver biopsy.
C. Serum ceruloplasmin concentrations.
D. Slitlamp examination.
E. Urinary copper excretion.
gastroenterology conjugated hyperbilirubinemia
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10. DOI: 10.1542/pir.28-3-83
2007;28;83Pediatrics in Review
Rula Harb and Daniel W. Thomas
Children
Conjugated Hyperbilirubinemia: Screening and Treatment in Older Infants and
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Rula Harb and Daniel W. Thomas
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