Neonatal Cholestasis

1. NEONATAL CHOLESTASIS
lGregory J. Semancik, M.D.
lMajor, Medical Corps, U.S. Army
lFellow, Pediatric Gastroenterology and
Nutrition
lWalter Reed Army Medical Center

2. OBJECTIVES
lKnow the differential diagnosis for neonatal
cholestasis.
lUnderstand how to evaluate the neonate
with conjugated hyperbilirubinemia.
lKnow the therapeutic management of
neonates with cholestasis.

3. DEFINITION
lNeonatal cholestasis is defined as
conjugated hyperbilirubinemia developing
within the first 90 days of extrauterine life.
lConjugated bilirubin exceeds 1.5 to 2.0
mg/dl.
lConjugated bilirubin generally exceeds 20%
of the total bilirubin.

4. ETIOLOGIES
lBasic distinction is between:
–Extrahepatic etiologies
–Intrahepatic etiologies

5. EXTRAHEPATIC ETIOLOGIES
lExtrahepatic biliary atresia
lCholedochal cyst
lBile duct stenosis
lSpontaneous perforation of the bile duct
lCholelithiasis
lInspissated bile/mucus plug
lExtrinsic compression of the bile duct

6. INTRAHEPATIC ETIOLOGIES
lIdiopathic
lToxic
lGenetic/Chromosomal
lInfectious
lMetabolic
lMiscellaneous

7. INTRAHEPATIC ETIOLOGIES
lIdiopathic Neonatal Hepatitis
lToxic
–TPN-associated cholestasis
–Drug-induced cholestasis
lGenetic/Chromosomal
–Trisomy 18
–Trisomy 21

8. INTRAHEPATIC ETIOLOGIES
lInfectious
–Bacterial sepsis (E. coli, Listeriosis, Staph. aureus)
–TORCHES
–Hepatitis B and C
–Varicella
–Coxsackie virus
–Echo virus
–Tuberculosis

9. INTRAHEPATIC ETIOLOGIES
lMetabolic
–Disorders of Carbohydrate Metabolism
•Galactosemia
•Fructosemia
•Glycogen Storage Disease Type IV
–Disorders of Amino Acid Metabolism
•Tyrosinemia
•Hypermethioninemia

10. INTRAHEPATIC ETIOLOGIES
lMetabolic (cont.)
–Disorders of Lipid Metabolism
•Niemann-Pick disease
•Wolman disease
•Gaucher disease
•Cholesterol ester storage disease
–Disorders of Bile Acid Metabolism
•3B-hydroxysteroid dehydrogenase/isomerase
•Trihydroxycoprostanic acidemia

11. INTRAHEPATIC ETIOLOGIES
lMetabolic (cont.)
–Peroxisomal Disorders
•Zellweger syndrome
•Adrenoleukodystrophy
–Endocrine Disorders
•Hypothyroidism
•Idiopathic hypopituitarism

12. INTRAHEPATIC ETIOLOGIES
lMetabolic (cont.)
–Miscellaneous Metabolic Disorders
•Alpha-1-antitrypsin deficiency
•Cystic fibrosis
•Neonatal iron storage disease
•North American Indian cholestasis

13. INTRAHEPATIC ETIOLOGIES
lMiscellaneous
–Arteriohepatic dysplasia (Alagille syndrome)
–Nonsyndromic paucity of intrahepatic bile ducts
–Caroli’s disease
–Byler’s disease
–Congenital hepatic fibrosis

14. INTRAHEPATIC ETIOLOGIES
lMiscellaneous (cont.)
–Familial benign recurrent intrahepatic cholestasis
–Hereditary cholestasis with lymphedema (Aagenaes)
–Histiocytosis X
–Shock
–Neonatal lupus

15. COMMON ETIOLOGIES
lPremature infants
–Sepsis/Acidosis
–TPN-associated
–Drug-induced
lIdiopathic neonatal hepatitis
lExtrahepatic biliary atresia
lAlpha-1-antitrypsin deficiency
lIntrahepatic cholestasis syndromes

16. CLINICAL PRESENTATION
lJaundice
lScleral icterus
lHepatomegaly
lAcholic stools
lDark urine
lOther signs and symptoms depend on
specific disease process

17. GOALS OF TIMELY EVALUATION
lDiagnose and treat known medical and/or
life-threatening conditions.
lIdentify disorders amenable to surgical
therapy within an appropriate time-frame.
lAvoid surgical intervention in intrahepatic
diseases.

18. EVALUATION
lBasic evaluation
–History and physical examination (includes exam of stool
color)
–CBC and reticulocyte count
–Electrolytes, BUN, creatinine, calcium, phosphate
–SGOT, SGPT, GGT, alkaline phosphatase
–Total and direct bilirubin
–Total protein, albumin, cholesterol, PT/PTT

19. EVALUATION
lTests for infectious causes
–Indicated cultures of blood, urine, CSF
–TORCH titers, RPR/VDRL
–Urine for CMV
–Hepatitis B and C serology
lOphthalmologic examination

20. EVALUATION
lMetabolic work-up
–Protein electrophoresis, alpha-1-antitrypsin level and
phenotype
–Thyroid function tests
–Sweat chloride
–Urine/serum amino acids
–Review results of newborn metabolic screen
–Urine reducing substances
–Urine bile acids

21. EVALUATION
lRadiological evaluation
–Ultrasonography
•Patient should be NPO to increase likelihood of visualizing the
gallbladder
•Feeding with exam may demonstrate a functioning gallbladder
–Hepatobiliary scintigraphy
•Premedicate with phenobarbital 5mg/kg/d for 3-5 days

22. EVALUATION
lInvasive studies
–Duodenal intubation
–Percutaneous liver biopsy
–Percutaneous transhepatic cholangiography
–Endoscopic retrograde
cholangiopancreatography (ERCP)
–Exploratory laparotomy with intraoperative
cholangiogram

23. EXTRAHEPATIC BILIARY
ATRESIA
lGenerally acholic stools with onset at about
2 weeks-old
lAverage birth weight
lHepatomegaly with firm to hard consistency
lFemale predominance
lNo well-documented familial cases

24. EXTRAHEPATIC BILIARY
ATRESIA
lIncreased incidence of polysplenia
syndrome and intra-abdominal vascular
anomalies
lNormal uptake on radionucleotide scan with
absent excretion
lBiopsy shows bile duct proliferation, bile
plugs, portal or perilobular fibrosis and
edema, and intact lobular structure

25. IDIOPATHIC NEONATAL
HEPATITIS
lGenerally normal stools or acholic stools
with onset at one month-old
lLow birth weight
lNormal liver on exam or hepatomegaly with
normal to firm consistency
lMale predominance
lFamilial cases (15-20%)

26. IDIOPATHIC NEONATAL
HEPATITIS
lImpaired uptake on radionucleotide scan
with normal excretion
lBiopsy shows intralobular inflammation with
focal hepatocellular necrosis and disruption
of the hepatic architecture. No alteration of
the bile ducts. Giant cell transformation
occurs but is non-specific.

27. ALPHA-1-ANTITRYPSIN
DEFICIENCY
lAlpha-1-antitrypsin makes up 90% of
alpha-1-globulin fraction
lAssociated with PiZZ (about 10-20% will
have liver disease) and rarely with PiSZ and
PiZ-null phenotypes
lBiopsy shows hepatocellular edema, giant
cell transformation, necrosis, and
pseudoacinar transformation.

28. ALPHA-1-ANTITRYPSIN
DEFICIENCY
lBiopsy also shows accumulation of PAS-
positive, diastase-resistant globules in the
cytoplasm of periportal hepatocytes.
lVarying degrees of fibrosis correlate with
disease prognosis.

29. INTRAHEPATIC CHOLESTASIS
SYNDROMES
lIncludes several diagnostic entities.
lBiopsies show cholestasis. May show
paucity of intrahepatic bile ducts, giant cell
transformation, and/or fibrosis.

30. TREATMENT
lSurgical
–Kasai procedure for biliary atresia
–Limited bile duct resection and re-anastomosis
–Choledochal cyst excision
–Cholecystectomy
–Liver transplantation

31. KASAI PROCEDURE
lPerformed for biliary atresia that is not
surgically correctable with excision of a
distal atretic segment.
lRoux-en-Y portoenterostomy
lBile flow re-established in 80-90% if
performed prior to 8 weeks-old.
lBile flow re-established in less than 20% if
performed after 12 weeks-old

32. KASAI PROCEDURE
lSuccess of the operation is dependent on
the presence and size of ductal remnants,
the extent of the intrahepatic disease, and
the experience of the surgeon.
lComplications are ascending cholangitis and
reobstruction as well as failure to re-
establish bile flow.

33. LIVER TRANSPLANTATION
lSurvival rates approach 80% at 1 year and
70% at 5 years.
lBiliary atresia is the most common indication
for transplant and may be the initial
treatment when detected late or may be
used as a salvage procedure for a failed
Kasai.
lUsed early in cases of tyrosinemia.

34. TREATMENT
lMedical management
–Nutritional support
–Treatment of pruritus
–Choleretics and bile acid-binders
–Management of portal hypertension and its
consequences

35. TREATMENT
lNutritional support
–Adequate calories and protein
–Supplement calories with medium chain
triglycerides
–Maintain levels of essential long-chain fatty
acids
–Treatment and/or prophylaxis for fat-soluble
vitamin deficiencies (vitamins A, D, E, and K)

36. TREATMENT
lNutritional support (cont.)
–Supplemental calcium and phosphate when
bone disease is present
–Prophylaxis for zinc deficiency
–Low-copper diet as poorly excreted
–Sodium restriction when ascites present

37. TREATMENT
lTreatment of pruritus
–Bile acid-binders: cholestyramine, cholestipol
–Ursodeoxycholic acid
–Phenobarbital as a choleretic
–Naloxone
–Rifampin

38. TREATMENT
lManagement of portal hypertension and its
consequences
–Variceal bleeding
•Fluid rescuscitation
•Blood products
•Sclerotherapy
•Balloon tamponade
•Portovenous shunting
•Propanolol

39. TREATMENT
lManagement of portal hypertension and its
consequences (cont.)
–Ascites
•Sodium restriction
•Diuretics: spironolactone, furosemide
•Albumin
•Paracentesis
–Thrombocytopoenia managed with platelet
infusions when clinically indicated