Neonatal Cholestasis

Neonatal Cholestasis
Jenny Bergquist, M.D.
August 5, 2005

Definition: Neonatal Cholestasis
Prolonged conjugated hyperbilirubinemia
in the newborn period
Conjugated hyperbilirubinemia
Conjugated bilirubin >1mg/dL if TB < 5mg/dL
>20% Total Bilirubin if TB is >5 mg/dL
Caused by a group of hepatobiliary
diseases occuring within the first 3 months
of life
Occurs in 1:2500 live births

Neonatal Cholestasis
NASPGHAN Recommendations
Evaluate infants with jaundice at the 2
week visit
Up to 15% of infants are jaundiced at 2 weeks,
the majority due to breast milk jaundice
Timely and accurate diagnosis is crucial for
successful treatment and favorable prognosis
Breast-fed infants may have an evaluation
delayed until 3 weeks if:
Normal exam
No h/o dark urine or light stools
Reliably monitored

Differential Diagnosis:
Obstructive Cholestasis
Biliary Atresia
* accounts for 30% of all cases of neonatal
cholestasis
Choledochal cysts
Gallstones
Alagille syndrome
Neonatal sclerosing cholangitis
Cystic fibrosis
Tumor

Differential Diagnosis:
Hepatocellular Cholestasis
Idiopathic neonatal hepatitis
Diagnosis based on liver biopsy findings: “giant cell hepatitis”
Was thought to account for ~40% of neonatal cholestasis
(with new diagnostic techniques, % is probably ~10-20%)
60-70% resolve without sequelae
Infectious
Viral: TORCH, CMV, HIV, viral hepatitis
Bacterial: sepsis, syphilis, UTI
Genetic/metabolic
Alpha-1-antitrysin deficiency, galactosemia, tyrosinemia,
hypothyroid, PFIC, CF
Toxic/secondary causes
TPN associated cholestasis

History
Congenital infections
Prenatal ultrasound
ABO incompatibility
Neonatal infection
UTI
Dietary history
Weight gain
vomiting
Stool pattern
Delayed: CF,
hypothyroid
Diarrhea: infx,
metabolic disease
Stool and urine color
Excessive bleeding
Irritability or lethargy
+family history

Physical Exam
Weight measurement
General appearance
Ill-appearing: infection, metabolic disease
Well-appearing: biliary atresia
Fundoscopic exam (congenital infection)
Cardiac murmur
Abdominal exam
Ascites, abd wall veins, liver, spleen
Stool/urine for color
Skin exam
Bruising, petechiae
Dysmorphic features
Broad nasal bridge, triangular facies, deep set eyes (Alagille)

Laboratory Studies
Total and direct bilirubin
LFTs + GGTP
Detects liver cell or bile duct injury
PT/PTT, glucose, albumin
Assessment of biosynthetic capacity of liver
CBC, urine and blood culture
Viral serologies
(TORCH infections + HBsAg, CMV, HIV if indicated)
UA for reducing substances
TFTs
Alpha-1-antitrypsin
Sweat chloride or mutation analysis for CF gene

NASPGHAN Recommendations:
Imaging Studies
Ultrasound: initial study recommended
for patients with cholestasis of unknown
etiology
Evaluates for anatomic abnormalities
Liver Biopsy
Recommended for most infants with
cholestasis of unknown etiology
Differentiates b/w extra and intrahepatic processes,
disorders of physiology from anatomy and can
determine need for surgical vs. medical intervention
Scintigraphy (HIDA), ERCP, MRCP

Biliary Atresia
1:8,000-15,000 live births
Accounts for 30% of all cases of
cholestasis in infants
Female>Male
Asians>African Americans>Caucasian
Most frequent cause of chronic end-stage
liver disease in children
Leading indication for liver transplantation
in the pediatric population (40-50% of all
liver transplants)

Biliary Atresia: pathogenesis
Bile duct obstruction due to inflammation
and fibrous obliteration
Perinatal or “classic” type (70-85%):
obstruction begins after birth. Signs/symptoms
develop within ~2-4 weeks of age. No
associated abnormalities
Embryonic type (15-30%): obstructive
process begins in utero. Cholestatic symptoms
present at birth. Associated with congenital
anomalies:
Situs inversus, polysplenia, malrotation, cardiac
anomalies
Unknown etiology: genetic, viral and host
immune factors have been postulated

Variations in Biliary Atresia

Clinical Features
History: Variable degrees of persistent jaundice,
dark urine, light colored stools, +/-poor appetite
* Usually Well-Appearing*
Physical:
Hepatomegaly, +/- splenomegaly
“appear” well-nourised
Usually with decreased fat stores and lean body mass
Enlarged abdomen from HSM may give impression of
“normal weight for age”
Scleral icterus, abdominal wall veins (caput medusa)
Labs:
Total bilirubin rarely is >12mg/dL; CB is usually

Imaging Studies
Ultrasound
Absent gallbladder, “triangular cord” sign
Low sensitivity; operator dependent
Evaluates for other anatomic abnormalities
Hepatobiliary scintigraphy (HIDA)
High sensitivity: normal uptake, but no excretion of
radionuclide tracer into biliary system or bowel in virtually all
patients with BA (exceptions in very early disease)
However, failure of excretion may be seen in both BA and
neonatal hepatitis
Sensitivity and Specificity increase with phenobarbital
administration
ERCP
Invasive, not readily available, technically difficult in infants
Intraoperative use is most common to confirm diagnosis and
document site of obstruction
MRCP
May become an important tool for diagnosis
Further studies are required

“Triangular Cord” Sign

Diagnosis
Percutaneous Liver Biopsy: most reliable test
for diagnosing biliary atresia
Biopsy interpretation is pathologist dependent
Accurate diagnosis made in 90-95% of cases
Liver biopsies made early in the course of disease (

Surgical Management
Kasai Procedure: resection of the
obliterated bile duct w/ creation of a
Roux-n-Y hepatoportoenterostomy
Timing of procedure predicts the
prognosis
90 days- bile flow returned in ~20% cases
Usually require a liver transplant within one year
The experience of the center
performing the Kasai if one of the most
important factors determinig surgical
outcome

Post-operative Management
Prophylactic Abx to prevent cholangitis
Ursodiol: enhance bile flow
No special diet needed unless concern
with poor bile drainageMCT formula
(ie… Alimentum, Pregestimil)
Fat-soluble vitamins: A, D, E, K
+/- short term, high dose steroid therapy

If Kasai Fails?
+/- support for revision of Kasai procedure if fails
Despite clinical improvement after a Kasai, 70-80% pts will
eventually require liver transplantation
Indications for Liver Transplant:
operation not successful in restoring bile flow initially
(~20%)
late referrals (generally >120 days)
develop end-stage liver dz despite bile drainage (ie
portal htn, recurrent cholangitis, ascites, growth failure)
Liver Transplant results:
one-yr survival rates >90% b/c reduced size allografts
and living-related donors

Post-Kasai Complications
Early: Ascending Cholangitis (50%) can lead to
ongoing bile duct injury & re-obstruction
fever, dec. bile secretion, worsening jaundice,
leukocytosis
Late: Portal Hypertension
bleeding esophageal varices, ascites, hypoalbuminemia,
fat-soluble vit def., malabsorbtion of long-chain
triglycerides, encephalopathy
Long term, malignancies screened for
Hepatoblastoma, hepatocarcinoma, cholangiocarcinoma

What happened to our patient?
Kasai Procedure on 8/16/04
Complicated by cholangitis x 2 wks
Portal hypertension
Esophogeal varicessclerotherapy x 2
1/05: TB 32.3/ conjugated bilirubin 18.6
Now on the transplant list awaiting a
liver…

Take-Home Message!
Any Jaundice>2 weeks requires
investigation
ALWAYS ask for fractionated bilirubin
(Total + Direct bilirubin)
Early diagnosis and referral (