neonatal and infantile cholestasis ying-kit leung, md, faap president, hong kong society of...

Neonatal and Infantile Neonatal and Infantile CholestasisCholestasis

Ying-kit Leung, MD, FAAP

President,

Hong Kong Society of Paediatric Gastroenterology, Hepatology and Nutrition,

Yantai, Shandong, July 2006

DEFINITIONDEFINITION

Neonatal cholestasis is defined as Neonatal cholestasis is defined as conjugated hyperbilirubinemia conjugated hyperbilirubinemia developing within the first 90 days of developing within the first 90 days of extrauterine life.extrauterine life.

Conjugated bilirubin exceeds 1.5 to Conjugated bilirubin exceeds 1.5 to 2.0 mg/dl.2.0 mg/dl.

Conjugated bilirubin generally Conjugated bilirubin generally exceeds 20% of the total bilirubin.exceeds 20% of the total bilirubin.

Bilirubin ProductionBilirubin Production

Biliverdin

Bilirubin

erythrocytehemoglobin

musclemyoglobin cytochromes

catalases

hemeoxygenase

biliverdinreductase

reticulo-endothelial

cell

BilirubinAlbumin liver

CO + Fe

Heme

GST

BilirubinBilirubinUptake, Conjugation, ExcretionUptake, Conjugation, Excretion

BBAlb

G B G

G B

R

UDPG

UDPGLUCURONYLTRANSFERASE

HEPATOCYTESINUSOID DISSE

BILECANALICULUS

2. UPTAKE

3. CONJUGATION

4. EXCRETION

E.R.

B-G

B-G

B-B-G

B-G

B-GBuBgsB

uBg

B-G dark urine

acholic stools

Conjugated Hyperbilirubinemia

Conjugatedhyperbilirubinemia

extrahepatic intrahepatic

Neonatal CholestasisNeonatal Cholestasis

EXTRAHEPATIC ETIOLOGIESEXTRAHEPATIC ETIOLOGIES

Extrahepatic biliary atresiaExtrahepatic biliary atresia Choledochal cystCholedochal cyst Bile duct stenosisBile duct stenosis Spontaneous perforation of the bile Spontaneous perforation of the bile

ductduct CholelithiasisCholelithiasis Inspissated bile/mucus plugInspissated bile/mucus plug Extrinsic compression of the bile ductExtrinsic compression of the bile duct

INTRAHEPATIC ETIOLOGIESINTRAHEPATIC ETIOLOGIES

IdiopathicIdiopathic ToxicToxic Genetic/ChromosomalGenetic/Chromosomal InfectiousInfectious MetabolicMetabolic MiscellaneousMiscellaneous

INTRAHEPATIC ETIOLOGIESINTRAHEPATIC ETIOLOGIES Idiopathic Neonatal HepatitisIdiopathic Neonatal Hepatitis ToxicToxic

TPN-associated cholestasisTPN-associated cholestasis Drug-induced cholestasisDrug-induced cholestasis

Genetic/ChromosomalGenetic/Chromosomal Trisomy 18Trisomy 18 Trisomy 21Trisomy 21


InfectiousInfectious Bacterial sepsis (E. coli, Bacterial sepsis (E. coli,

Listeriosis, Staph. aureus)Listeriosis, Staph. aureus) TORCHESTORCHES Hepatitis B and CHepatitis B and C VaricellaVaricella Coxsackie virusCoxsackie virus Echo virusEcho virus TuberculosisTuberculosis


Metabolic Disorders of Carbohydrate

MetabolismGalactosemiaFructosemiaGlycogen Storage Disease Type IV

Disorders of Amino Acid MetabolismTyrosinemiaHypermethioninemia


Metabolic (cont.) Disorders of Lipid Metabolism

Niemann-Pick diseaseWolman diseaseGaucher diseaseCholesterol ester storage disease

Disorders of Bile Acid Metabolism3B-hydroxysteroid dehydrogenase/isomerase

Trihydroxycoprostanic acidemia


Metabolic (cont.) Peroxisomal Disorders

Zellweger syndromeAdrenoleukodystrophy

Endocrine DisordersHypothyroidismIdiopathic hypopituitarism


Metabolic (cont.) Miscellaneous Metabolic

DisordersAlpha-1-antitrypsin deficiencyCystic fibrosisNeonatal iron storage diseaseNorth American Indian cholestasis


Miscellaneous Arteriohepatic dysplasia (Alagille

syndrome) Nonsyndromic paucity of

intrahepatic bile ducts Caroli’s disease Byler’s disease, PFIC Congenital hepatic fibrosis

COMMON ETIOLOGIESCOMMON ETIOLOGIES

Premature infantsPremature infants Sepsis/AcidosisSepsis/Acidosis TPN-associatedTPN-associated Drug-inducedDrug-induced

Idiopathic neonatal hepatitisIdiopathic neonatal hepatitis Extrahepatic biliary atresiaExtrahepatic biliary atresia Alpha-1-antitrypsin deficiencyAlpha-1-antitrypsin deficiency Intrahepatic cholestasis syndromesIntrahepatic cholestasis syndromes

CLINICAL PRESENTATIONCLINICAL PRESENTATION

JaundiceJaundice Scleral icterusScleral icterus HepatomegalyHepatomegaly Acholic stoolsAcholic stools Dark urineDark urine Other signs and symptoms depend Other signs and symptoms depend

on specific disease processon specific disease process

GOALS OF TIMELY GOALS OF TIMELY EVALUATIONEVALUATION

Diagnose and treat known medical Diagnose and treat known medical and/or life-threatening conditions.and/or life-threatening conditions.

Identify disorders amenable to Identify disorders amenable to surgical therapy within an surgical therapy within an appropriate time-frame. appropriate time-frame.

Avoid surgical intervention in Avoid surgical intervention in intrahepatic diseases.intrahepatic diseases.

Bu Bc ± Bu

Bu

•Hemolysis Rh ABO

•Breast Milk

•Physiological

•Hypothyroidism

Bc ± Bu

dark urine

acholic stools

Bc ± Bu

BEWARE!!!

dark urine

acholic stools

• hepatosplenomegaly

• bilirubinuria

• conjugated bilirubin • abnormal LFTs

EVALUATIONEVALUATION

Basic 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


Tests for infectious causesTests for infectious causes Indicated cultures of blood, urine, CSFIndicated cultures of blood, urine, CSF TORCH titers, VDRLTORCH titers, VDRL Urine for CMVUrine for CMV Hepatitis B and C serologyHepatitis B and C serology

Ophthalmologic examinationOphthalmologic examination


Metabolic work-upMetabolic work-up Protein electrophoresis, alpha-1-antitrypsin Protein electrophoresis, alpha-1-antitrypsin

level and phenotypelevel and phenotype Thyroid function testsThyroid function tests Sweat chlorideSweat chloride Urine/serum amino acidsUrine/serum amino acids Review results of newborn metabolic Review results of newborn metabolic

screenscreen Urine reducing substancesUrine reducing substances Urine bile acidsUrine bile acids


Radiological evaluationRadiological evaluation UltrasonographyUltrasonography

Patient should be NPO to increase Patient should be NPO to increase likelihood of visualizing the gallbladder likelihood of visualizing the gallbladder

Feeding with exam may demonstrate a Feeding with exam may demonstrate a functioning gallbladderfunctioning gallbladder

Hepatobiliary scintigraphyHepatobiliary scintigraphyPremedicate with phenobarbital Premedicate with phenobarbital

5mg/kg/d for 3-5 days5mg/kg/d for 3-5 days


Invasive studiesInvasive studies Duodenal intubationDuodenal intubation Percutaneous liver biopsyPercutaneous liver biopsy Percutaneous transhepatic Percutaneous transhepatic

cholangiographycholangiography Endoscopic retrograde Endoscopic retrograde

cholangiopancreatography (ERCP)cholangiopancreatography (ERCP) Exploratory laparotomy with Exploratory laparotomy with

intraoperative cholangiogramintraoperative cholangiogram

ESTIMATED FREQUENCY OF VARIOUSCLINICAL FORMS OF NEONATAL

CHOLESTASIS

PROPOSED SUBTYPES OF INTRAHEPATICCHOLESTASIS

intrahepatic or extrahepatic intrahepatic or extrahepatic ?? treatable disorder treatable disorder ?? liver damage liver damage ?? complications of cholestasis complications of cholestasis ??

Investigation of CholestasisInvestigation of Cholestasis

Objectives

X-rayX-ray spine: butterfly vertebrae (Alagille)spine: butterfly vertebrae (Alagille) skull, long bones (intrauterine infection)skull, long bones (intrauterine infection)

sweat test sweat test (cystic fibrosis)(cystic fibrosis)

ophthalmological examinationophthalmological examination cataract (galactosemia, intrauterine infection)cataract (galactosemia, intrauterine infection) retinopathy (intrauterine infection)retinopathy (intrauterine infection) posterior embryotoxon (Alagille)posterior embryotoxon (Alagille)

othersothers bone marrow (Niemann Pick disease type C)bone marrow (Niemann Pick disease type C) bile acidsbile acids


Special TestsSpecial Tests

ultrasoundultrasound choledochal cyst etc.choledochal cyst etc. post-prandial contraction of gall bladderpost-prandial contraction of gall bladder

hepatobiliary scan (hepatobiliary scan (99m99mTc - H / B / DIS / PIP / - IDA) Tc - H / B / DIS / PIP / - IDA) after pre-treatment with phenobarb or cholestyramineafter pre-treatment with phenobarb or cholestyramine


Special Tests (cont)Special Tests (cont)

ultrasoundultrasound choledochal cyst etc.choledochal cyst etc. post-prandial contraction of gall bladderpost-prandial contraction of gall bladder

hepatobiliary scan (hepatobiliary scan (99m99mTc - H / B / DIS / PIP / - IDA) Tc - H / B / DIS / PIP / - IDA) after pre-treatment with phenobarb or cholestyramineafter pre-treatment with phenobarb or cholestyramine

ERCPERCP ((eendoscopic ndoscopic rretrograde etrograde ccholangioholangioppancreatography)ancreatography)



Endoscopic Retrograde Cholangio-Pancreatography



liver histology (needle biopsy)liver histology (needle biopsy) biliary atresia: portal ductal proliferationbiliary atresia: portal ductal proliferation neonatal hepatitis: giant cellsneonatal hepatitis: giant cells specific disorder e.g specific disorder e.g 11-antitrypsin -antitrypsin

Biliary AtresiaBiliary Atresia

DefinitionDefinition - Progressive scarring of - Progressive scarring of bile ducts outside and inside of the bile ducts outside and inside of the liver that leads to complete blockage liver that leads to complete blockage of bile flow in the first three months of of bile flow in the first three months of life.life.

BileBile is the yellow fluid made in the is the yellow fluid made in the liver that liver that helps digest food helps digest food (fat) in the intestine(fat) in the intestine

Anatomy in Biliary AtresiaAnatomy in Biliary Atresia

Kasai ProcedureKasai Procedure

KASAI PROCEDUREKASAI PROCEDURE

Performed for biliary atresia that is Performed for biliary atresia that is not surgically correctable with not surgically correctable with excision of a distal atretic segment.excision of a distal atretic segment.

Roux-en-Y portoenterostomyRoux-en-Y portoenterostomy Bile flow re-established in 80-90% if Bile flow re-established in 80-90% if

performed prior to 8 weeks-old.performed prior to 8 weeks-old. Bile flow re-established in less than Bile flow re-established in less than

20% if performed after 12 weeks-old20% if performed after 12 weeks-old

KASAI PROCEDUREKASAI PROCEDURE

Success of the operation is Success of the operation is dependent on the presence and size dependent on the presence and size of ductal remnants, the extent of the of ductal remnants, the extent of the intrahepatic disease, and the intrahepatic disease, and the experience of the surgeon.experience of the surgeon.

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

LIVER TRANSPLANTATIONLIVER TRANSPLANTATION

Survival rates approach 80% at 1 Survival rates approach 80% at 1 year and 70% at 5 years.year and 70% at 5 years.

Biliary atresia is the most common Biliary atresia is the most common indication for transplant and may be indication for transplant and may be the initial treatment when detected the initial treatment when detected late or may be used as a salvage late or may be used as a salvage procedure for a failed Kasai.procedure for a failed Kasai.

Used early in cases of tyrosinemia.Used early in cases of tyrosinemia.

Outcome after Kasai procedureOutcome after Kasai procedure

Short-termShort-term - bile flow dependent on age at - bile flow dependent on age at KasaiKasai < 60 days < 60 days 80% 80%

60 - 90 days60 - 90 days 50% 50%> 90 days > 90 days 10-20% 10-20%

Long-termLong-term - 10 yr. survival (no transplant) - 10 yr. survival (no transplant)20 - 40% 20 - 40% US,FranceUS,France

50% 50% JapanJapan

Liver transplantationLiver transplantation - required for ~80% - required for ~80%

extrahepatic biliary atresiaextrahepatic biliary atresia

Extrahepatic Neonatal CholestasisExtrahepatic Neonatal Cholestasis

choledochal cystcholedochal cyst

inspissated bile syndromeinspissated bile syndrome

bile duct stenosisbile duct stenosis

spontaneous perforation of bile duct spontaneous perforation of bile duct

cholelithiasischolelithiasis

tumors, massestumors, masses

Persistent Familial Intrahepatic Cholestasis

normal GT high GT

PFIC 1PFIC 1Byler DiseaseByler Disease

AmishAmish

PFIC 2PFIC 2Byler SyndromeByler Syndrome

Middle EasternMiddle Eastern

PFIC 3PFIC 3

18q21-22 2q24

BBenignenignRRecurrentecurrentIIntrahepaticntrahepaticCCholestasisholestasis

IIntrahepaticntrahepatic

CCholestasisholestasis

PPregnancyregnancy

7q21

basolateral membrane

junctional complex

apical membrane

hepatocytehepatocyte

canaliculussinusoid sinusoid

rate-limitingrate-limiting against concentration gradient against concentration gradient

(x1000 for bile salts)(x1000 for bile salts) energy requiringenergy requiring

basolateral membrane

apical membrane

[BS][BS]

H2O

bile salt-dependent

bile flow

bile salt-independent

bile flow

NTCPNa+

BS-

Na+/K+ ATPaseK+

Na+

Na+

TaurocholateCotransporting Polypeptide

Bile Salt Uptake

Na+-dependent Na+-independent

OATPsA-

BS-,OA-

drugs

OrganicAnionTransportingPolypeptides

NTCPNa+

BS-

Na+/K+ ATPaseK+

Na+

Na+

TaurocholateCotransporting Polypeptide

Bile Salt Uptake

Na+-independentNa+-dependent

OATPsA-

BS-,OA-

drugs

OCT1

OrganicCationTransporter

OC+

NTCPNa+

BS-

Na+/K+ ATPaseK+

Na+

OATPsA-

BS-,OA-

drugs

OCT1

OrganicAnionTransporting Polypeptides

Na+ Taurocholate Cotransporting Polypeptide

OrganicCationTransporter

OC+

NTCPNa+

BS-

Na+/K+ ATPaseK+

Na+

OATPsA-

BS-,OA-

drugs

OCT1

OrganicAnionTransporting Polypeptides

Na+ Taurocholate Cotransporting Polypeptide

OC+

MRP

Multi-drugResistanceProtein

1 3 6

ABCTRANSPORTERS

ATPBindingCassette

BSEP

BS-BileSaltExportPump(SGPC)(cBAT)

BSEP

BS-

MRP2

AnionicConjugates

canalicularMulti-specificOrganicAcidTransporter

Multi-drugResistanceProtein 2

•bilirubin-G•BA-G, BA-S•glutathione-S

•leukotriene C4•drugs•17-estradiol-G

BSEP

BS-

Phospholipids

MDR3

MRP2

AnionicConjugates

MultiDrugResistancegene product

BSEP

BS-

Phospholipids

MDR3

MRP2

AnionicConjugates

hydrophobic cationsphysiological??

anti-cancer drugs

MDR1

NTCP

Na+/K+

ATPaseOCT1

OATPsBSEP

MDR3

MRP2

AE2Cl-

channel

GSH transporter

MDR1

canaliculus

cholangiocyte

Cl-CFTR

AE2Cl-

HC0-

FIC1

P-type ATPaseAminophospholipids

11b

CysticFibrosisTransmembraneRegulator


normal GT



2q24

high GT


AmishAmish

PFIC 3PFIC 3

18q21-22




PPregnancyregnancy

7q21


Middle Eastern +Middle Eastern + neonatal hepatitisneonatal hepatitis jaundicejaundice prurituspruritus normal normal GTGT bile saltsbile salts in bilein bile

in in plasmaplasma

persistent, progressivepersistent, progressive liver failure 2-10 yrliver failure 2-10 yr

BSEP

BSBileSaltExportPump(SGPC)(cBAT)

B-GBSBS

BSEP MRP2BA-GBA-S

BSBS

GT

bile saltsbile salts in bilein bile in plasma in plasma

normal normal GTGT prurituspruritus

jaundicejaundice

hepatitishepatitis

B-G

BileSalts

• 2q24• ABC B11• liver-specific

normal GT



2q24


AmishAmish

18q21-22



high GT

PFIC 3PFIC 3



PPregnancyregnancy

7q21

Phospholipids

MDR3

MultiDrugResistancegene product

PFIC 3PFIC 3 elevated elevated GTGT neonatal hepatitisneonatal hepatitis jaundice milderjaundice milder prurituspruritus PL : BA ratio PL : BA ratio in bilein bile persistent, progressivepersistent, progressive liver failure 2-10 yrliver failure 2-10 yr

• 7q 21• ABC B4• phospholipid flippase/translocase• liver-specific

PHOSPHATIDYLCHOLINE

flippase

Phospholipids

BS

PLmixed

micelles

MDR3

chol

BSEP

Phospholipids

BS

PLmixed

micelles

MDR3

chol

BSEP

PL

Phospholipids

BS

PL

mixed micelles

MDR3

chol

BSEP

Phospholipids

MDR3

BS

PL

MDR3

chol

BSEP

cholangiopathycholangiopathy bile duct proliferationbile duct proliferation portal inflammationportal inflammation fibrosisfibrosis

Phospholipids

MDR3PL

MDR3

BSEP

cholangiopathycholangiopathy bile duct proliferationbile duct proliferation portal inflammationportal inflammation fibrosisfibrosis

GT

BS

GTGT high high GTGT

UPTAKE

CONJUGATIONEXCRETION

PRODUCTION

G

B

B-G

B

Bu Bc

Bc

Dubin-Johnson

Rotor

Conjugated HyperbilirubinemiaConjugated Hyperbilirubinemia

MRP2

AnionicConjugates

canalicularMulti-specificOrganicAcidTransporter•bilirubin-G

•BA-G, BA-S•glutathione-S

Multi-drugResistanceProtein 2

Dubin JohnsonDubin Johnson conjugated conjugated

hyperbilirubinemiahyperbilirubinemia no liver diseaseno liver disease normal liver enzymesnormal liver enzymes brown-black pigment brown-black pigment

in hepatocytesin hepatocytes

MRP2

B-G

B-G

MRP3

conjugated hyperbilirubinemiaconjugated hyperbilirubinemia

B-G

B-G

B-B-G

Bc

B-GBuBgsB

uBg

uBgB-Gdark urine

acholic stools

MRP3

BSEP

BS

MRP2

B-G

B-G

MRP3

conjugated hyperbilirubinemiaconjugated hyperbilirubinemia

no cholestasisno cholestasis

pigmentpigment

• multi-specific organic anion conjugate transporter• ABC C2• liver, kidney, intestine

OrganicAnion

Conjugates

high GT



PFIC 3PFIC 3

2q24



PPregnancyregnancy

7q21


normal GT


AmishAmish

18q21-22


FIC1

P-type ATPaseAminophospholipids


AmishAmish intermittent intermittent persistent persistent progressive liver diseaseprogressive liver disease ± diarrhea, pancreatitis, ± diarrhea, pancreatitis,

hearing losshearing loss

PFIC1• P-type ATPase family (ion transport pumps)• 18q21-22 • bovine homologue -aminophospholipid transport• function - maintenance of membrane lipid composition?• expressed in cholangiocyte, hepatocyte?, intestine, pancreas,

PHOSPHATIDYLSERINE

BRICmutations

P motif

FIC1

FIC1

diarrheadiarrhea

pancreatitispancreatitis

ALPHA-1-ANTITRYPSIN ALPHA-1-ANTITRYPSIN DEFICIENCYDEFICIENCY

Alpha-1-antitrypsin makes up 90% of Alpha-1-antitrypsin makes up 90% of alpha-1-globulin fractionalpha-1-globulin fraction

Associated with PiZZ (about 10-20% Associated with PiZZ (about 10-20% will have liver disease) and rarely will have liver disease) and rarely with PiSZ and PiZ-null phenotypeswith PiSZ and PiZ-null phenotypes

Biopsy shows hepatocellular edema, Biopsy shows hepatocellular edema, giant cell transformation, necrosis, giant cell transformation, necrosis, and pseudoacinar transformation.and pseudoacinar transformation.

ALPHA-1-ANTITRYPSIN ALPHA-1-ANTITRYPSIN DEFICIENCYDEFICIENCY

Biopsy also shows accumulation of Biopsy also shows accumulation of PAS-positive, diastase-resistant PAS-positive, diastase-resistant globules in the cytoplasm of globules in the cytoplasm of periportal hepatocytes.periportal hepatocytes.

Varying degrees of fibrosis correlate Varying degrees of fibrosis correlate with disease prognosis.with disease prognosis.

INTRAHEPATIC CHOLESTASIS INTRAHEPATIC CHOLESTASIS SYNDROMESSYNDROMES

Includes several diagnostic entities.Includes several diagnostic entities. Biopsies show cholestasis. May Biopsies show cholestasis. May

show paucity of intrahepatic bile show paucity of intrahepatic bile ducts, giant cell transformation, ducts, giant cell transformation, and/or fibrosis.and/or fibrosis.

Paucity of intrahepatic bile ductsPaucity of intrahepatic bile ducts

Intrahepatic Neonatal CholestasisIntrahepatic Neonatal Cholestasis

Alagille SyndromeAlagille Syndrome


1969-1969-Alagille et al., first reported patients Alagille et al., first reported patients with idiopathic bile duct paucity and with idiopathic bile duct paucity and similar clinical features including similar clinical features including congenital heart diseasecongenital heart disease

1973-Watson & Miller recognized a 1973-Watson & Miller recognized a syndrome that included pulmonary artery syndrome that included pulmonary artery abnormalities, neonatal liver disease, abnormalities, neonatal liver disease, somatic anomalies and a familial tendency somatic anomalies and a familial tendency Coined term arteriohepatic dysplasiaCoined term arteriohepatic dysplasia

Paucity of Bile DuctsPaucity of Bile Ducts


1975-1975-Alagille et al., published Alagille et al., published extended observations in 15 patients extended observations in 15 patients

Chronic liver diseaseChronic liver disease Characteristic faciesCharacteristic facies Systolic murmurSystolic murmur Vertebral arch defectsVertebral arch defects Mental retardation, hypgonadism,Mental retardation, hypgonadism, Family historyFamily history

Paucity of intrahepatic bile ductsPaucity of intrahepatic bile ducts Alagille syndromeAlagille syndrome non-syndromicnon-syndromic

Intrahepatic Neonatal CholestasisIntrahepatic Neonatal Cholestasis

Clinical Features: HepaticClinical Features: Hepatic

HepatomegalyHepatomegaly Neonatal hepatitisNeonatal hepatitis SplenomegalySplenomegaly Portal hypertensionPortal hypertension CirrhosisCirrhosis Synthetic liver Synthetic liver

failurefailure

Clinical Features: HepaticClinical Features: Hepatic

CholestasisCholestasis JaundiceJaundice

Conjugated Conjugated hyperbilirubinehyperbilirubinemia in neonatal mia in neonatal periodperiod

PruritisPruritis XanthomasXanthomas Biochemical Biochemical

abnormalitiesabnormalities

Clinical Features: CardiovascularClinical Features: Cardiovascular

MurmurMurmur Most common Most common

cardiac cardiac manifestation of manifestation of AGSAGS

Due to stenosis at Due to stenosis at some level in the some level in the pulmonary tree with pulmonary tree with or without structural or without structural cardiac diseasecardiac disease

Clinical Features: SkeletalClinical Features: Skeletal

““ Butterfly Butterfly vertebrae”vertebrae”

Shortened Shortened interpedicular interpedicular distancedistance

Shortened distal Shortened distal phalangesphalanges

Shortened distal Shortened distal radius and ulna radius and ulna

Spina bifida occultaSpina bifida occulta

Fusion of adjacent Fusion of adjacent vertebraevertebrae

ClubbingClubbing Pathologic Pathologic

fracturesfractures OsteopeniaOsteopenia RicketsRickets Absent 12Absent 12thth rib rib

Clinical Features: SkeletalClinical Features: SkeletalButterfly VertebrateButterfly Vertebrate

Clinical Features: OcularClinical Features: Ocular

Posterior Posterior embryotoxonembryotoxon An abnormal An abnormal

prominence of prominence of Schwalbe’s lineSchwalbe’s line

Present in 56-95% Present in 56-95% of AGS patientsof AGS patients

Seen in 8-15% of Seen in 8-15% of general populationgeneral population

Clinical Features: OcularClinical Features: OcularPosterior EmbryotoxonPosterior Embryotoxon

Posterior Embryotoxon: prominent Schwalbe's line is visible just inside the temporal limbus.

Alagille Syndrome: GeneticsAlagille Syndrome: Genetics

JAG1: StructureJAG1: Structure Extracellular Extracellular

domaindomain 21 amino acid signal 21 amino acid signal

peptidepeptide 40 amino acide DSL 40 amino acide DSL

regionregion 16 EGF-like regions16 EGF-like regions Cysteine rich regionCysteine rich region

Transmembrane Transmembrane domaindomain

Intracellular Intracellular domaindomain

Defects of Bile Acid Synthesis

1. 7α-hydroxylation of sterol precursors

CTX

2. ring structure modification

3. side chain oxidation and shortening

4. conjugation of the bile acid with an amino acid

Specific TherapySpecific Therapy

MalabsorptionMalabsorption MCT MCT Vitamins A, D, E, KVitamins A, D, E, K

Cholestasis/Pruritus/HyperlipidemiaCholestasis/Pruritus/Hyperlipidemia cholestyramine 250-500 mg/kg/daycholestyramine 250-500 mg/kg/day phenobarbitone 3-10 mg/kg/dayphenobarbitone 3-10 mg/kg/day ursodeoxycholic acid 10-20 mg/kg/dayursodeoxycholic acid 10-20 mg/kg/day rifampicin 10 mg/kg/dayrifampicin 10 mg/kg/day

Therapy of Neonatal CholestasisTherapy of Neonatal Cholestasis

TREATMENTTREATMENT

Medical managementMedical management Nutritional supportNutritional support Treatment of pruritusTreatment of pruritus Choleretics and bile acid-bindersCholeretics and bile acid-binders Management of portal hypertension and Management of portal hypertension and

its consequencesits consequences

TREATMENTTREATMENT

Nutritional supportNutritional support Adequate calories and proteinAdequate calories and protein Supplement calories with medium chain Supplement calories with medium chain

triglyceridestriglycerides Maintain levels of essential long-chain Maintain levels of essential long-chain

fatty acidsfatty acids Treatment and/or prophylaxis for fat-Treatment and/or prophylaxis for fat-

soluble vitamin deficiencies (vitamins A, soluble vitamin deficiencies (vitamins A, D, E, and K)D, E, and K)

TREATMENTTREATMENT

Nutritional support (cont.)Nutritional support (cont.) Supplemental calcium and phosphate Supplemental calcium and phosphate

when bone disease is presentwhen bone disease is present Prophylaxis for zinc deficiencyProphylaxis for zinc deficiency Low-copper diet as poorly excretedLow-copper diet as poorly excreted Sodium restriction when ascites presentSodium restriction when ascites present

TREATMENTTREATMENT

Treatment of pruritusTreatment of pruritus Bile acid-binders: cholestyramine, Bile acid-binders: cholestyramine,

cholestipolcholestipol Ursodeoxycholic acidUrsodeoxycholic acid Phenobarbital as a cholereticPhenobarbital as a choleretic NaloxoneNaloxone RifampinRifampin

TREATMENTTREATMENT

Management of portal hypertension Management of portal hypertension and its consequencesand its consequences Variceal bleedingVariceal bleeding

Fluid rescuscitationFluid rescuscitation Blood productsBlood products SclerotherapySclerotherapy Balloon tamponadeBalloon tamponade Portovenous shuntingPortovenous shunting PropanololPropanolol

TREATMENTTREATMENT

Management of portal hypertension Management of portal hypertension and its consequences (cont.)and its consequences (cont.) AscitesAscites

Sodium restrictionSodium restriction Diuretics: spironolactone, furosemideDiuretics: spironolactone, furosemide AlbuminAlbumin ParacentesisParacentesis

Thrombocytopoenia managed with Thrombocytopoenia managed with platelet infusions when clinically platelet infusions when clinically indicatedindicated

Conjugated HyperbilirubinemiaConjugated Hyperbilirubinemia

REFERURGENTL

Y

Neonatal CholestasisNeonatal Cholestasis

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neonatal and infantile cholestasis ying-kit leung, md, faap president, hong kong society of...

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