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Selected Pediatric Hepatobiliary DiseasesSelected Pediatric Hepatobiliary Diseases

John HicksJohn HicksTexas ChildrenTexas Children’’s Hospitals Hospital

Baylor College of MedicineBaylor College of MedicineHouston, TxHouston, Tx

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Normal Portal Tract & Duct Plate Normal Portal Tract & Duct Plate Malformation Associated with Malformation Associated with Developmental Syndromes and Developmental Syndromes and

Congenital Hepatic FibrosisCongenital Hepatic Fibrosis

Ductal Plate Malformation & Syndromes

MeckelMeckel--GruberGruber

Jeune Jeune

IvemarkIvemark

BardetBardet--BiedelBiedel

Tuberous SclerosisTuberous Sclerosis

SmithSmith--LemliLemli--OpitzOpitz

EllisEllis--van Creveldvan Creveld

ElejaldeElejalde

Trisomy 9 & 13Trisomy 9 & 13MeckelMeckel--GruberGruber

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Hepatorenal Hepatorenal Fibropolycystic Fibropolycystic

DiseaseDisease

ARPKDARPKD

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Cholestatic DisordersCholestatic Disorders Neonatal CholestasisNeonatal Cholestasis Idiopathic Neonatal Cholestasis Idiopathic Neonatal Cholestasis

(15%)(15%) Viral Neonatal CholestasisViral Neonatal Cholestasis

(CMV 3(CMV 3--5%)5%) Bacterial & ParasiticBacterial & Parasitic Bile Duct Obstruction & Bile Duct Obstruction &

CholangiopathiesCholangiopathies EHBA (25EHBA (25--30%)30%) Choledochal CystsCholedochal Cysts Caroli DiseaseCaroli Disease Congenital Hepatic FibrosisCongenital Hepatic Fibrosis Sclerosing CholangitisSclerosing Cholangitis Bile Duct StenosisBile Duct Stenosis

Cholestatic DisordersCholestatic Disorders Cholestatic Syndromes (20%)Cholestatic Syndromes (20%)

AlagilleAlagille

PFICPFIC

Dubin JohnsonDubin Johnson

RotorRotor

MetabolicMetabolic

AlphaAlpha--11--Antitrypsin (7Antitrypsin (7--10%)10%)

Cystic FibrosisCystic Fibrosis

Iron Storage DiseaseIron Storage Disease

EndocrinopathiesEndocrinopathies

Amino Acid DisordersAmino Acid Disorders

Lipid DisordersLipid Disorders

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Cholestatic DisordersCholestatic Disorders

Metabolic DisordersMetabolic Disorders Urea Cycle Urea Cycle Carbohydrate (Galactosemia 1%, Carbohydrate (Galactosemia 1%,

GSD Type IV)GSD Type IV) Mitochondrial DisordersMitochondrial Disorders Peroxisomal DisordersPeroxisomal Disorders

Bile Acid Synthetic Disorders Bile Acid Synthetic Disorders (2%)(2%)

CholelithiasesCholelithiases InsipissatedInsipissated Bile/MucusBile/Mucus Tumors/MassesTumors/Masses ToxicToxic MiscellaneousMiscellaneous

Choledochal CystCholedochal Cyst

Segmental Dilatation of Bile Segmental Dilatation of Bile Duct SystemDuct System

1:15,000 Live Births1:15,000 Live Births Gender Ratio 4F:1MGender Ratio 4F:1M Present with Jaundice, Present with Jaundice,

Abdominal Mass, & Vomiting Abdominal Mass, & Vomiting in Infancyin Infancy

Distinguishing From EHBA Distinguishing From EHBA DifficultDifficult

CaroliCaroli’’s Disease (Type V)s Disease (Type V) Cholangiocarcinoma Risk Cholangiocarcinoma Risk

(10%, > over 20 yrs of age)(10%, > over 20 yrs of age)

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Neonatal CholestasisNeonatal Cholestasis

Steatosis, fibrosis or cirrhosis;Steatosis, fibrosis or cirrhosis;

Storage products in liver cells and/or Storage products in liver cells and/or Kupffer cellsKupffer cells

Metabolic disordersMetabolic disorders

Bile ductule proliferationBile ductule proliferation

Portal fibrosis or cirrhosisPortal fibrosis or cirrhosisParenteral nutritionParenteral nutrition

Portal and acinar lymphocyte Portal and acinar lymphocyte inflammation; Apoptotic bodiesinflammation; Apoptotic bodies

Neonatal hepatitisNeonatal hepatitis

Loss of interlobular bile ducts Loss of interlobular bile ducts

(bile duct to hepatic artery ratio <0.8)(bile duct to hepatic artery ratio <0.8)Paucity of intrahepatic bile Paucity of intrahepatic bile ductsducts

Bile ductule proliferationBile ductule proliferation

Portal fibrosisPortal fibrosis

Ductular and canalicular cholestasisDuctular and canalicular cholestasis

Extrahepatic biliary atresiaExtrahepatic biliary atresia

Neonatal HepatitisNeonatal Hepatitis Distinction From Obstruction Distinction From Obstruction

Based Upon Clinical, Laboratory Based Upon Clinical, Laboratory and Radiologic Findingsand Radiologic Findings

ObstructionObstruction Intralobular Ducts Bile PlugsIntralobular Ducts Bile Plugs Bile Duct ProliferationBile Duct Proliferation Portal InflammationPortal Inflammation

Neonatal HepatitisNeonatal Hepatitis Inflammation, Increased Inflammation, Increased

HematopoiesisHematopoiesis Hepatocyte Ballooning, Giant Hepatocyte Ballooning, Giant

Cell Transformation, NecrosisCell Transformation, Necrosis Variable Degree of CholestasisVariable Degree of Cholestasis

Overlap with ObstructionOverlap with Obstruction Idiopathic Hepatitis Idiopathic Hepatitis –– Higher Higher

Morbidity and MortalityMorbidity and Mortality

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S03-7275 neonatal hepatitis he4

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ExtraExtra--Hepatic Hepatic Biliary AtresiaBiliary Atresia

Obliterative CholangiopathyObliterative Cholangiopathy Progressive Cirrhosis with Death Progressive Cirrhosis with Death

by Age 2 Years if Not Treatedby Age 2 Years if Not Treated 11--8 per 15,000 Live Births in USA8 per 15,000 Live Births in USA Perinatal Form (most common)Perinatal Form (most common) Embryonic/Fetal Form (10Embryonic/Fetal Form (10--35%) with 35%) with

Congenital AnomaliesCongenital Anomalies Other Associations: Maternal Other Associations: Maternal

Diabetes, Trisomy 21 & 18, Primary Diabetes, Trisomy 21 & 18, Primary Ciliary Dyskinesia (Situs) SyndromeCiliary Dyskinesia (Situs) Syndrome

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Biliary Atresia & Splenic Biliary Atresia & Splenic Malformation Syndrome (BASM)Malformation Syndrome (BASM)

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A1AT

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Ductal Plate Malformation-Like in Several Portal Tracts in BA

No Proliferation in 4 week old with later proven BA

S05-6783 Gross (1)

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Alagille SyndromeAlagille Syndrome(arteriohepatic dysplasia, (arteriohepatic dysplasia,

syndromic bile duct paucity)syndromic bile duct paucity) Autosomal Dominant Complex Autosomal Dominant Complex

Multisystem Disorder (liver, Multisystem Disorder (liver, heart, eyes, face, skeleton)heart, eyes, face, skeleton)

Diagnostic Features (3 of 5)Diagnostic Features (3 of 5) CholestasisCholestasis

Cardiac Defect (Pulmonary Artery Cardiac Defect (Pulmonary Artery & Branches Stenosis & Branches Stenosis -- Common)Common)

Skeletal (Butterfly Vertebra)Skeletal (Butterfly Vertebra)

Characteristic Facial FeaturesCharacteristic Facial Features

Eye (Posterior Embryotoxon)Eye (Posterior Embryotoxon)

Bile Duct Paucity (<0.8 ratio)Bile Duct Paucity (<0.8 ratio) Develops Over TimeDevelops Over Time

Bile Duct Paucity in 90%Bile Duct Paucity in 90%

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Alagille SyndromeAlagille Syndrome Skeletal Manifestations: Asymptomatic Butterfly Vertebrae (VerteSkeletal Manifestations: Asymptomatic Butterfly Vertebrae (Vertebral bral

Body Clefting) in 33Body Clefting) in 33--87%87% Facial Features (All): Prominent Forehead, DeepFacial Features (All): Prominent Forehead, Deep--Set Eyes, Moderate Set Eyes, Moderate

Hypertelorism, Pointed Chin, Saddle or Straight Nose with BulbouHypertelorism, Pointed Chin, Saddle or Straight Nose with Bulbous s Tip, Inverted Triangle Form to FaceTip, Inverted Triangle Form to Face

Renal Abnormalities (23Renal Abnormalities (23--74%): Small Hyperechoic Kidney, UPJ 74%): Small Hyperechoic Kidney, UPJ Obstruction, Renal Cysts, Renal Tubular AcidosisObstruction, Renal Cysts, Renal Tubular Acidosis

Pancreatic InsufficiencyPancreatic Insufficiency Growth Failure (50Growth Failure (50--90%)90%) Gross Motor Skill Delays (2%) & Cognitive Delay (16%)Gross Motor Skill Delays (2%) & Cognitive Delay (16%) Vascular Anomalies: Renovascular, Middle Aortic Syndrome, Vascular Anomalies: Renovascular, Middle Aortic Syndrome,

Moyamoya Syndrome, CVA (15%, basilar, carotid, middle cerebral):Moyamoya Syndrome, CVA (15%, basilar, carotid, middle cerebral):Accounts for 34% MortalityAccounts for 34% Mortality

Delayed Puberty with HighDelayed Puberty with High--Pitched VoicePitched Voice Extra Digital Flexion CreaseExtra Digital Flexion Crease CraniosynostosisCraniosynostosis Lower Extremity Fractures Lower Extremity Fractures

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Alagille Syndrome: EndAlagille Syndrome: End--StageStage

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Alagille SyndromeAlagille Syndrome

Autosomal Dominant InheritanceAutosomal Dominant Inheritance Incidence 1: 70,000 Live Births (under estimated)Incidence 1: 70,000 Live Births (under estimated)

JAG1 Mutation (20p12) in 89% with Jagged 1 Protein JAG1 Mutation (20p12) in 89% with Jagged 1 Protein

NOTCH2 (1p13NOTCH2 (1p13--p11) in 1% with Neurogenic Locus p11) in 1% with Neurogenic Locus Notch Homolog Protein 2Notch Homolog Protein 2

Inherited Mutation in 30Inherited Mutation in 30--50%50%

De Novo Mutation in 50De Novo Mutation in 50--70%70%

Phenotype in JAG1 and NOTCH2 Mutations Phenotype in JAG1 and NOTCH2 Mutations IndistinguishableIndistinguishable

Alagille Syndrome: Alagille Syndrome: TreatmentTreatment

Pruritus and Xanthoma: Ursodeoxycholic Acid, Pruritus and Xanthoma: Ursodeoxycholic Acid, Partial External Biliary Diversion, Cholestyramine, Partial External Biliary Diversion, Cholestyramine, Rifampin & NaltrexoneRifampin & Naltrexone

Liver Transplantation for EndLiver Transplantation for End--Stage Disease (20Stage Disease (20--50%)50%) 80% 580% 5--Yr SurvivalYr Survival

Growth & Development: Optimize Nutrition, Fat Growth & Development: Optimize Nutrition, Fat Soluble Vitamin SupplementsSoluble Vitamin Supplements

Cardiac, Renal & Neurologic Involvement: Standard Cardiac, Renal & Neurologic Involvement: Standard Treatment of DiseaseTreatment of Disease

Avoid Contact Sports if Splenomegaly (Spleen Guard)Avoid Contact Sports if Splenomegaly (Spleen Guard) Avoid AlcoholAvoid Alcohol Risk for Hepatocellular CarcinomaRisk for Hepatocellular Carcinoma

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Disorders With Bile Disorders With Bile Duct PaucityDuct Paucity

Syndromic: AlagilleSyndromic: Alagille

Metabolic & GeneticMetabolic & Genetic

AIATAIAT

Cystic FibrosisCystic Fibrosis

Peroxisomal DisordersPeroxisomal Disorders

Trisomy 21Trisomy 21

Prune Belly SyndromePrune Belly Syndrome

Congenital InfectionsCongenital Infections

CMVCMV

RubellaRubella

SyphilisSyphilis

Inflammatory & ImmuneInflammatory & Immune

Graft vs Host DiseaseGraft vs Host Disease

Chronic RejectionChronic Rejection

Sclerosing CholangitisSclerosing Cholangitis

SarcoidosisSarcoidosis

OtherOther

Drugs/Antibiotics Drugs/Antibiotics Associated with Vanishing Associated with Vanishing Bile Duct SyndromeBile Duct Syndrome

EHBA (late)EHBA (late)

PanhypopituitarismPanhypopituitarism

Idiopathic Idiopathic

Familial Intrahepatic Cholestatic DisordersFamilial Intrahepatic Cholestatic Disorders

PFIC 1 (18q21, PFIC 1 (18q21, BylersBylers): Low GGT ): Low GGT -- Presents as HepatitisPresents as Hepatitis

Benign Recurrent Cholestasis (BRIC, 18q21): Benign Recurrent Cholestasis (BRIC, 18q21):

Episodes of Cholestasis with Pruritus and FibrosisEpisodes of Cholestasis with Pruritus and Fibrosis

PFIC 2 (2q24): Low GGT PFIC 2 (2q24): Low GGT -- Presents as HepatitisPresents as Hepatitis

PFIC 3 (7q21): High GGT PFIC 3 (7q21): High GGT -- Presents as HepatitisPresents as Hepatitis

DubinDubin--Johnson (10q24): Pigment Accumulation in HepatocytesJohnson (10q24): Pigment Accumulation in Hepatocytes

Intrahepatic Cholestasis of Pregnancy (7q21): Intrahepatic Cholestasis of Pregnancy (7q21):

33rdrd Trimester Cholestasis with High Fetal LossTrimester Cholestasis with High Fetal Loss

Aagenaes Syndrome (15q): Aagenaes Syndrome (15q): Cholestasis & LymphedemaCholestasis & Lymphedema

North American Indian Childhood Cirrhosis (16q22): North American Indian Childhood Cirrhosis (16q22): Progressive Cholestasis, Mimics EHBA, Progressive Cholestasis, Mimics EHBA, CirrhinCirrhin MutationMutation

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Progressive Familial Progressive Familial Intrahepatic CholestasisIntrahepatic Cholestasis

Autosomal Recessive Disorders Autosomal Recessive Disorders –– Disrupt Bile Disrupt Bile Formation & Presents with Cholestasis in ChildhoodFormation & Presents with Cholestasis in Childhood

3 Types (PFIC1, PFIC2, PFIC3) with Mutations in 3 Types (PFIC1, PFIC2, PFIC3) with Mutations in Hepatocellular Transport System GenesHepatocellular Transport System Genes

PFIC1 & PFIC2 Present in 1PFIC1 & PFIC2 Present in 1stst Few Months of LifeFew Months of Life PFC3 PFC3 –– Later in Infancy, Childhood or Young AdultLater in Infancy, Childhood or Young Adult Cholestasis, Jaundice & PruritusCholestasis, Jaundice & Pruritus Develop EndDevelop End--Stage Liver Disease Before AdulthoodStage Liver Disease Before Adulthood Diagnosis: Clinical Phenotype, Liver Ultrasound, Diagnosis: Clinical Phenotype, Liver Ultrasound,

Cholangiogram, Liver Biopsy & Genetic TestingCholangiogram, Liver Biopsy & Genetic Testing

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PFIC: FeaturesPFIC: Features

PFIC1: Canalicular Cholestasis, Absence of Bile PFIC1: Canalicular Cholestasis, Absence of Bile Ductular Proliferation, Cholangiole IncreaseDuctular Proliferation, Cholangiole Increase

PFIC2: Lobular Architecture Disruption, PFIC2: Lobular Architecture Disruption, Lobular and Portal Fibrosis and Inflammation, Lobular and Portal Fibrosis and Inflammation, Canalicular Cholestasis, Absence of Bile Canalicular Cholestasis, Absence of Bile Ductular Proliferation, Cholangiole IncreaseDuctular Proliferation, Cholangiole Increase

PFIC3: Portal Fibrosis, Bile Duct Proliferation, PFIC3: Portal Fibrosis, Bile Duct Proliferation, Inflammation, Possible Giant Cell Inflammation, Possible Giant Cell Transformation, Occasional Cholestasis with Transformation, Occasional Cholestasis with Bile Plugs, Progresses to Biliary Cirrhosis Bile Plugs, Progresses to Biliary Cirrhosis

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PFIC ManagementPFIC Management Pruritus: Ursodeoxycholic Acid, Nasobiliary Drainage, Pruritus: Ursodeoxycholic Acid, Nasobiliary Drainage,

Partial External Biliary DiversionPartial External Biliary Diversion Liver Transplantation for EndLiver Transplantation for End--Stage Disease (portal Stage Disease (portal

hypertension, cirrhosis, liver failure)hypertension, cirrhosis, liver failure) Extrahepatic Complications (diarrhea, liver steatosis, Extrahepatic Complications (diarrhea, liver steatosis,

short stature) Do Not Improve & May be Aggravated short stature) Do Not Improve & May be Aggravated with Biliary Diversion or Liver Transplantationwith Biliary Diversion or Liver Transplantation

Chronic Diarrhea May Become Intractable When Bile Chronic Diarrhea May Become Intractable When Bile Salt Secretions Restored with Liver TransplantationSalt Secretions Restored with Liver Transplantation Associated with Severe Steatosis & Steatohepatitis Leading to Associated with Severe Steatosis & Steatohepatitis Leading to

Cirrhosis and ReCirrhosis and Re--Transplantation (may recur with new Transplantation (may recur with new transplant)transplant)

Risk for Hepatocellular Carcinoma & Risk for Hepatocellular Carcinoma & Cholangiocarcinoma (Especially PFIC2 Cholangiocarcinoma (Especially PFIC2 -- 15%)15%)

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AlphaAlpha--11--Antitrypsin DeficiencyAntitrypsin Deficiency Autosomal Recessive Metabolic Disorder Autosomal Recessive Metabolic Disorder

((serpineserpine protease inhibitor [AIAT], 14q31protease inhibitor [AIAT], 14q31--3) 3) with Codominant Expression by Each Allelewith Codominant Expression by Each Allele

Prevalence of 1 in 2,500 to 5,000 live birthsPrevalence of 1 in 2,500 to 5,000 live births

Normal Allele: Normal Allele: PiMPiM

Most Common Alleles (Caucasians): 95% M, Most Common Alleles (Caucasians): 95% M,

22--3% S & 1% Z3% S & 1% Z

AIAT Expression:AIAT Expression:

PiMMPiMM 100%100%

PiSSPiSS 5050--60%60%

PiZZ PiZZ 1010--20%20%

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AIAT in InfancyAIAT in Infancy Neonatal Cholestasis (hepatitis)Neonatal Cholestasis (hepatitis)

Jaundice, Pruritus, Abdominal DistentionJaundice, Pruritus, Abdominal Distention Poor Feeding and Weight GainPoor Feeding and Weight Gain Hepatomegaly and SplenomegalyHepatomegaly and Splenomegaly Elevated Total and Conjugated BilirubinElevated Total and Conjugated Bilirubin Elevated AST, ALT, Hypoalbuminemia, Elevated AST, ALT, Hypoalbuminemia,

Coagulopathy (Vitamin K Deficiency)Coagulopathy (Vitamin K Deficiency)

Liver Biopsy: Highly Variable Findings in Liver Biopsy: Highly Variable Findings in Infancy Infancy –– Mimics Neonatal Cholestasis, Mimics Neonatal Cholestasis, Neonatal Hepatitis, Biliary Atresia & Neonatal Hepatitis, Biliary Atresia & Metabolic Diseases of InfancyMetabolic Diseases of Infancy

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Metabolic Diseases with Cytoplasmic InclusionsMetabolic Diseases with Cytoplasmic Inclusions Globular InclusionsGlobular Inclusions

AlphaAlpha--11--AntitryspsinAntitryspsin Fibrinogen Storage DiseaseFibrinogen Storage Disease

Granular InclusionsGranular Inclusions AlphaAlpha--11--Antichymotrypsin Antichymotrypsin

DeficiencyDeficiency

Mallory BodiesMallory Bodies Wilson DiseaseWilson Disease Endemic Tyrolean CirrhosisEndemic Tyrolean Cirrhosis

StriationsStriations Gaucher DiseaseGaucher Disease

Ground Glass InclusionsGround Glass Inclusions GSD, Type IVGSD, Type IV LaFora DiseaseLaFora Disease

CrystalsCrystals CystinosisCystinosis Wolman Disease Wolman Disease Cholesterol Storage DiseaseCholesterol Storage Disease ProtoporphyriaProtoporphyria

PigmentPigment NPC Type C NPC Type C –– lipofuscinlipofuscin DubinDubin--Johnson Johnson –– lipomelaninlipomelanin Hemochromatosis Hemochromatosis –– ironiron Wilson Disease Wilson Disease -- coppercopper

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Cystic FibrosisCystic Fibrosis Autosomal Recessive (cyclic AMP Autosomal Recessive (cyclic AMP

dependent chloride channel defect)dependent chloride channel defect) Mutation in CFTR Gene (7q31.2) in Mutation in CFTR Gene (7q31.2) in

Cholangiolar EpitheliumCholangiolar Epithelium Steatosis (60%) & Focal Biliary Steatosis (60%) & Focal Biliary

Cirrhosis (10% Infants , 27% 1Cirrhosis (10% Infants , 27% 1stst Yr, Yr, 70% Adults)70% Adults)

Multilobular Cirrhosis in 4Multilobular Cirrhosis in 4--10%10% Rarely, Neonatal CholestasisRarely, Neonatal Cholestasis

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