APPROACH TO THE INFANT

WITH CHOL E S TA S I S
Frederick J. Suchy, M.D.
Cholestasis :
Physiologically : a measurable decrease in bile
flow
Pathologically : the histologic presence of bile
pigment in hepatocytes and bile ducts,
Clinically : the accumulation in blood and
extrahepatic tissues of substances normally
excreted in bile (e.g., bilirubin, bile acids, and
cholesterol).
Neonate: clinical and laboratory features of the many
liver diseases presenting with cholestasis are quite
similar.
INCIDENCE
Cholestasis: 1 in 2500 live births.
Idiopathic neonatal hepatitis : 1 in 4800 - 9000 live
births, the most common in older
Biliary atresia : 1 in 8000 - 21,000 live births,
more frequently in Far Eastern
DIFFERENTIAL DIAGNOSIS
OF NEONATAL CHOLESTASIS

cholestasis
immaturity of hepatic excretory function
infection during the perinatal period
initial effects of congenital malformations
inborn errors of metabolism
Table 9.2.
there is overlap between disorders in their clinical
features
Ex:
injury to the biliary epithelium may be a
prominent finding in neonatal infection with
cytomegalovirus, 1-antitrypsin deficiency, and
some inborn errors of bile acid metabolism.
mechanical obstruction of the common bile duct
liver dysfunction and intra hepatic injury,
include giant cell transformation of hepatocytes
The term neonatal hepatitis refers to the histologic
finding

of extensive giant cell transformation of hepatocytes.

The term should now be designated as neonatal
hepatitis only if an infectious agent can be
documented or suspected on the basis of other
clinical features associated with congenital infection.
An increasing number of infections have been
associated with neonatal hepatitis, including
parvovirus B19, human herpes virus 6, and the HIV.
Spontaneously resolving forms of neonatal
cholestasis may
Result: immaturity of bile secretion and perinatal
disease leading to hepatic hypoxia or ischemia.
Histologic examination: moderate portal and lobular
fibrosis, multinucleated giant hepatocytes, and
hematopoietic foci
Downs syndrome, hemolytic disease of the newborn,
and congenital heart disease, systemic disease (?)
cause hepatitis or cholestasis.
MANIFESTATIONS OF CHOLESTATIC LIVER
DISEASE IN THE NEONATE
Unconjugated hyperbilirubinemia
in older : harmless
in neonate (immature BBB): associated with
deposition of free bilirubin in neuronal tissue and
brain damage.
first appreciated in the head and progresses
caudally to the palms and soles as the serum
bilirubin increases.

Conjugated bilirubin: not toxic

elevated level: present liver disease in the neonate.
Clinically jaundice:
the serum bilirubin concentration
in the older child: 23 mg/dL,
in the neonate: 5 mg/dL.
Cholestasis if: direct billirubin 20 % total billirubin
(DB 1 mg/dl if TB 5 mg/dl)
The initial goal must be to exclude rapidly lifethreatening but potentially treatable disorders such
as gram-negative infection, endocrinopathies (such
as panhypopituitarism), galactosemia, and inborn
errors of bile acid metabolism.
2.4 - 15% of newborns will still be jaundiced at 2
weeks of age; the majority are breast fed.
The incidence of jaundice in breast-fed babies at 4
weeks was
9%, but none had liver disease
The vast majority of infants with biliary atresia
appear entirely well during the first 46 weeks of life
apart from mild jaundice.
Stools of biliary atresia : acholic, but early,
incomplete or evolving obstruction, stools may
appear normally pigmented or only intermittently
pigmented.
Fluctuating levels of serum bilirubin do not rule out
biliary atresia liver disease also must be suspected in
a

jaundiced infant whose urine is dark yellow as

opposed to colorless.
Idiopathic neonatal hepatitis occurs more commonly
in males, especially those born prematurely or with
low birth weight; there is a familial incidence of
approximately 1015%.
Possibly predisposing to liver injury, may present in
up to 40% of patients without affected siblings.
In contrast, biliary atresia is more common in
females of normal birth weight; familial cases are
rare.
Analysis by Alagille
288 patients,
intra hepatic cholestasis > biliary atresia:
male gender (66% vs. 45%),
low birth weight (2680 g vs. 3230 g),
later onset of jaundice (mean, 23 days vs. 11 days),
and later onset of acholic stools (mean, 30 days vs.
16 days).
An enlarged liver (firm or hard) (53% vs. 87%)
Pruritus and xanthomata, cutaneous manifestations
of chronic cholestasis, are not observed in the
neonate.

METABOLIC DISORDER:

 Irritability, poor feeding, vomiting, and lethargy

are frequent symptoms (Ex: galactosemia and
tyrosinemia).
Ascites, edema, and coagulopathy may be
present at birth or evolve rapidly during the first
weeks of life after massive loss of hepatocytes
A profound impairment of hepatic synthetic
function, often in excess of that expected for the
degree of cholestasis, may be an early indication
of metabolic liver disease (ex: neonatal iron
storage disease or tyrosinemia).
Neurologic abnormalities may be primary
symptoms (ex: mitochondrial disorders,
Zellwegers syndrome, OR secondary to
hypoglycemia, hyperammonemia, intracranial
hemorrhage).

EVALUATION OF THE
CHOLESTATIC NEONATE
Figure 9.1.

The initial assessment should confirm rapidly that

cholestasis is present, provide a baseline assessment
of the severity of liver dysfunction, and exclude
potentially treatable infectious and metabolic
disorders.
Next, to establish a specific diagnosis, a
comprehensive plan for investigation is outlined,
which should be guided by the initial history and
physical examination. Because of the frequent lack of
specific clinical features and overlap of many
diagnostic studies, most cholestatic infants require a
stepwise, comprehensive evaluation.

Aserologic test or imaging study may establish the

probable cause of the liver disease. Ex: USG : a
choledochal cyst, hypothyroidism, cystic fibrosis, and
galactosemia.
Numerous biochemical and imaging studies have
been used
in an effort to distinguish between infants with
intrahepatic versus
obstructive cholestasis and thus avoid unnecessary
surgical exploration.
Standard liver biochemical tests show nonspecific
and variable elevation of serum direct bilirubin,
aminotransferases,
alkaline phosphatase, 5_-nucleotidase, and lipids
Poor hepatic function at birth, (including
hypoglycemia and coagulopathy unresponsive to vit
K), may reflect the prenatal effects of an inborn error
of metabolism or an intrauterine infection.
Because loss of hepatocyte mass in some metabolic
disorders occurs by apoptosis rather than cell
necrosis,
Serum aminotransferase values may be normal or
only modestly
elevated.
Low or normal serum GGT is found in PFIC (Bylers
disease), some inborn errors of bile acid metabolism,
and benign

recurrent cholestasis compared with other cholestatic

patients.
However, no single biochemical test or imaging study
or combination of non invasive tests has proved to be
of sufficient discriminatory value in excluding
extrahepatic obstruction, because 10% of
intrahepatic cholestasis have clinical and laboratory
studies overlap with biliary atresia.
Aspiration and visual inspection of duodenal
secretions for bile pigment or measurement of
radioactivity in duodenal fluid after scintigraphy have
been used by some workers to distinguish
intrahepatic from extrahepatic cholestasis.
Table 9.3: Evaluation of the Infant with
Cholestasis
USG is the most useful initial imaging modality for
information : liver structure, size, and composition.
A high-frequency can assess gallbladder size, detect
gallstones and sludge in the bile ducts and
gallbladder, ascites, cystic or
obstructive dilatation of the biliary tree, and
extrahepatic anomalies.
Common bile duct dilatation is not a feature of biliary
atresia; either the duct is not visualized or a portion
of the duct appears to be of normal caliber. There
may sometimes be slight dilatation of the
intrahepatic bile ducts, and the gallbladder may be
absent or reduced to a remnant in biliary atresia.
However, these findings cannot be reliably used to
diagnose biliary atresia.

A triangular or tubular echogenic density or

triangular cord (TC) representing a fibrous cone of
tissue at the porta hepatis on a transverse or
longitudinal scan has been proposed as a specific
USG finding for biliary atresia. The TC sign was
present in 80% biliary atresia and 1/66 neonatal
hepatitis.
Use of 4-mm thickness for TC sign: sensitivity of 80%,
specificity of 98%, and positive and negative
predictive values of 94%for the diagnosis of biliary
atresia.
Gallbladder in biliary atresia:
Absence or small: 67-100%
irregular shape or wall

CT information similar to USG, usually unnessery

Magnetic resonance cholangiography (MRC),
accuracy was

82% (19 of 23); sensitivity, 90% (9 of 10); and

specificity, 77%
(10 of 13) for the detection of extrahepatic biliary
atresia, with
a positive predictive value of 75% (9 of 12) and a
negative predictive value of 91% (10 of 11)
Hepatobiliary scintigraphy, differentiate biliary
atresia from other causes of neonatal cholestasis.
useful for assessing cystic
duct patency in a patient with a hydropic gallbladder
or with
cholelithiasis.
Percutaneous transhepatic cholangiography (PTC) or
cholecystocholangiography may be required to
visualize the biliary tract in selected patients. These
techniques are more difficult to perform in infants
because of the small size of the intrahepatic bile
ducts and because disorders do not result in
dilatation of the intrahepatic bile ducts.
Endoscopic retrograde cholangiography (ERCP) may
be useful in
the evaluation of selected infants with obstructive
cholestasis
ERCP successfully in 86% prolonged cholestasis.

Percutaneous liver biopsy important diagnostic steps

in evaluating the cholestatic infant
Diagnosis of biliary atresia : 9095% of cases.
Biopsy: 100% sensitive, 76% specific in biliary
atresia.
The characteristic: large duct obstruction, include
bile duct
proliferation, bile plugs in small bile ducts, and portal
tract edema and fibrosis. The basic lobular
architecture is usually intact.
These findings require time to develop and may not
all be present in biopsy in the first weeks of life. A
repeat liver biopsy, may be required
In intrahepatic disease:
Common : diffuse cellular swelling and giant cell
transformation of hepatocytes, variable
inflammation, and focal hepatocellular necrosis.
May be present: fibrosis, bile ductular injury, bile
duct paucity
Suggest metabolic liver disease: pseudoacinar
arrangement of hepatocytes and steatosis.

Abnormal storage of material in hepatocytes or

Kupffer cells and viral inclusions also maybe found.
Electron microscopy and immunohistochemical
methods may
aid in the identification and localization of these
abnormalities.
Liver tissue also may be frozen for later biochemical
or molecular analysis.
Lai et al. accuracy of liver histology, 96.8%; color of
duodenal juice, 91.6%; peak radioisotope count in
duodenal juice, 84.2%; USG of the hepatobiliary
system,80.2%; and persistence of clay-colored stool,
80.2%.
Logistic regression, the diagnostic methods of
significance
were liver biopsy, color of duodenal juice, abdominal
USG, and stool color. With this protocol, an overall
diagnostic accuracy of 96.8% was attained. No cases
of biliary atresia were missed, although four cases of
neonatal hepatitis were misdiagnosed, resulting in
unnecessary laparotomy.
In cases consistent with a diagnosis of biliary atresia
or in the
small number of cases in which doubt persists about
the diagnosis
after review of the imaging studies and liver biopsy,
the
patency of the biliary tree should be directly
examined at the
time of a mini laparotomy and intra operative
cholangiogram. The adverse effects of a diagnostic
laparotomy are minimal.

High-risk patients with liver failure: uncorrectable

coagulopathy, hepatic encephalopathy, and ascites.
The surgeon should avoid transecting a biliary tree
that is patent but small in diameter because of biliary
hypoplasia
or a low rate of bile flow associated with severe
intrahepatic
cholestasis.
Moreover, the dynamic nature of the neonatal
obstructive cholangiopathies is exemplified by rare
cases in
which the patency of the extrahepatic bile ducts was
initially
proved on cholangiopathy but evolution to biliary
atresia was
later documented at autopsy or laparotomy.