NEONATAL CHOLESTASISGregory J. Semancik, M.D.Major, Medical Corps, U.S. ArmyFellow, Pediatric Gastroenterology and NutritionWalter Reed Army Medical Center

OBJECTIVESKnow the differential diagnosis for neonatal cholestasis.Understand how to evaluate the neonate with conjugated hyperbilirubinemia.Know the therapeutic management of neonates with cholestasis.

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

ETIOLOGIESBasic distinction is between:Extrahepatic etiologiesIntrahepatic etiologies

EXTRAHEPATIC ETIOLOGIESExtrahepatic biliary atresiaCholedochal cystBile duct stenosisSpontaneous perforation of the bile ductCholelithiasisInspissated bile/mucus plugExtrinsic compression of the bile duct

INTRAHEPATIC ETIOLOGIESIdiopathicToxicGenetic/ChromosomalInfectiousMetabolicMiscellaneous

INTRAHEPATIC ETIOLOGIESIdiopathic Neonatal HepatitisToxicTPN-associated cholestasisDrug-induced cholestasisGenetic/ChromosomalTrisomy 18Trisomy 21

INTRAHEPATIC ETIOLOGIESInfectiousBacterial sepsis (E. coli, Listeriosis, Staph. aureus)TORCHESHepatitis B and CVaricellaCoxsackie virusEcho virusTuberculosis

INTRAHEPATIC ETIOLOGIESMetabolicDisorders of Carbohydrate MetabolismGalactosemiaFructosemiaGlycogen Storage Disease Type IVDisorders of Amino Acid MetabolismTyrosinemiaHypermethioninemia

INTRAHEPATIC ETIOLOGIESMetabolic (cont.)Disorders of Lipid MetabolismNiemann-Pick diseaseWolman diseaseGaucher diseaseCholesterol ester storage diseaseDisorders of Bile Acid Metabolism3B-hydroxysteroid dehydrogenase/isomeraseTrihydroxycoprostanic acidemia

INTRAHEPATIC ETIOLOGIESMetabolic (cont.)Peroxisomal DisordersZellweger syndromeAdrenoleukodystrophyEndocrine DisordersHypothyroidismIdiopathic hypopituitarism

INTRAHEPATIC ETIOLOGIESMetabolic (cont.)Miscellaneous Metabolic DisordersAlpha-1-antitrypsin deficiencyCystic fibrosisNeonatal iron storage diseaseNorth American Indian cholestasis

INTRAHEPATIC ETIOLOGIESMiscellaneousArteriohepatic dysplasia (Alagille syndrome)Nonsyndromic paucity of intrahepatic bile ductsCarolis diseaseBylers diseaseCongenital hepatic fibrosis

INTRAHEPATIC ETIOLOGIESMiscellaneous (cont.)Familial benign recurrent intrahepatic cholestasisHereditary cholestasis with lymphedema (Aagenaes)Histiocytosis XShockNeonatal lupus

COMMON ETIOLOGIESPremature infantsSepsis/AcidosisTPN-associatedDrug-inducedIdiopathic neonatal hepatitisExtrahepatic biliary atresiaAlpha-1-antitrypsin deficiencyIntrahepatic cholestasis syndromes

CLINICAL PRESENTATIONJaundiceScleral icterusHepatomegalyAcholic stoolsDark urineOther signs and symptoms depend on specific disease process

GOALS OF TIMELY EVALUATIONDiagnose and treat known medical and/or life-threatening conditions.Identify disorders amenable to surgical therapy within an appropriate time-frame. Avoid surgical intervention in intrahepatic diseases.

EVALUATIONBasic evaluationHistory and physical examination (includes exam of stool color)CBC and reticulocyte countElectrolytes, BUN, creatinine, calcium, phosphateSGOT, SGPT, GGT, alkaline phosphataseTotal and direct bilirubinTotal protein, albumin, cholesterol, PT/PTT

EVALUATIONTests for infectious causesIndicated cultures of blood, urine, CSFTORCH titers, RPR/VDRLUrine for CMVHepatitis B and C serologyOphthalmologic examination

EVALUATIONMetabolic work-upProtein electrophoresis, alpha-1-antitrypsin level and phenotypeThyroid function testsSweat chlorideUrine/serum amino acidsReview results of newborn metabolic screenUrine reducing substancesUrine bile acids

EVALUATIONRadiological evaluationUltrasonographyPatient should be NPO to increase likelihood of visualizing the gallbladder Feeding with exam may demonstrate a functioning gallbladderHepatobiliary scintigraphyPremedicate with phenobarbital 5mg/kg/d for 3-5 days

EVALUATIONInvasive studiesDuodenal intubationPercutaneous liver biopsyPercutaneous transhepatic cholangiographyEndoscopic retrograde cholangiopancreatography (ERCP)Exploratory laparotomy with intraoperative cholangiogram

EXTRAHEPATIC BILIARY ATRESIAGenerally acholic stools with onset at about 2 weeks-oldAverage birth weightHepatomegaly with firm to hard consistencyFemale predominanceNo well-documented familial cases

EXTRAHEPATIC BILIARY ATRESIAIncreased incidence of polysplenia syndrome and intra-abdominal vascular anomaliesNormal uptake on radionucleotide scan with absent excretionBiopsy shows bile duct proliferation, bile plugs, portal or perilobular fibrosis and edema, and intact lobular structure

IDIOPATHIC NEONATAL HEPATITISGenerally normal stools or acholic stools with onset at one month-oldLow birth weightNormal liver on exam or hepatomegaly with normal to firm consistencyMale predominanceFamilial cases (15-20%)

IDIOPATHIC NEONATAL HEPATITISImpaired uptake on radionucleotide scan with normal excretionBiopsy 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.

ALPHA-1-ANTITRYPSIN DEFICIENCYAlpha-1-antitrypsin makes up 90% of alpha-1-globulin fractionAssociated with PiZZ (about 10-20% will have liver disease) and rarely with PiSZ and PiZ-null phenotypesBiopsy shows hepatocellular edema, giant cell transformation, necrosis, and pseudoacinar transformation.

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

INTRAHEPATIC CHOLESTASIS SYNDROMESIncludes several diagnostic entities.Biopsies show cholestasis. May show paucity of intrahepatic bile ducts, giant cell transformation, and/or fibrosis.

TREATMENTSurgicalKasai procedure for biliary atresiaLimited bile duct resection and re-anastomosisCholedochal cyst excisionCholecystectomyLiver transplantation

KASAI PROCEDUREPerformed for biliary atresia that is not surgically correctable with excision of a distal atretic segment.Roux-en-Y portoenterostomyBile flow re-established in 80-90% if performed prior to 8 weeks-old.Bile flow re-established in less than 20% if performed after 12 weeks-old

KASAI PROCEDURESuccess 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.Complications are ascending cholangitis and reobstruction as well as failure to re-establish bile flow.

LIVER TRANSPLANTATIONSurvival rates approach 80% at 1 year and 70% at 5 years.Biliary 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.Used early in cases of tyrosinemia.

TREATMENTMedical managementNutritional supportTreatment of pruritusCholeretics and bile acid-bindersManagement of portal hypertension and its consequences

TREATMENTNutritional supportAdequate calories and proteinSupplement calories with medium chain triglyceridesMaintain levels of essential long-chain fatty acidsTreatment and/or prophylaxis for fat-soluble vitamin deficiencies (vitamins A, D, E, and K)

TREATMENTNutritional support (cont.)Supplemental calcium and phosphate when bone disease is presentProphylaxis for zinc deficiencyLow-copper diet as poorly excretedSodium restriction when ascites present

TREATMENTTreatment of pruritusBile acid-binders: cholestyramine, cholestipolUrsodeoxycholic acidPhenobarbital as a cholereticNaloxoneRifampin

TREATMENTManagement of portal hypertension and its consequencesVariceal bleedingFluid rescuscitationBlood productsSclerotherapyBalloon tamponadePortovenous shuntingPropanolol

TREATMENTManagement of portal hypertension and its consequences (cont.)AscitesSodium restrictionDiuretics: spironolactone, furosemideAlbuminParacentesisThrombocytopoenia managed with platelet infusions when clinically indicated