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Transcript of 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
INTRAHEPATIC ETIOLOGIESINTRAHEPATIC ETIOLOGIES
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
INTRAHEPATIC ETIOLOGIESINTRAHEPATIC ETIOLOGIES
Metabolic Disorders of Carbohydrate
MetabolismGalactosemiaFructosemiaGlycogen Storage Disease Type IV
Disorders of Amino Acid MetabolismTyrosinemiaHypermethioninemia
INTRAHEPATIC ETIOLOGIESINTRAHEPATIC ETIOLOGIES
Metabolic (cont.) Disorders of Lipid Metabolism
Niemann-Pick diseaseWolman diseaseGaucher diseaseCholesterol ester storage disease
Disorders of Bile Acid Metabolism3B-hydroxysteroid dehydrogenase/isomerase
Trihydroxycoprostanic acidemia
INTRAHEPATIC ETIOLOGIESINTRAHEPATIC ETIOLOGIES
Metabolic (cont.) Peroxisomal Disorders
Zellweger syndromeAdrenoleukodystrophy
Endocrine DisordersHypothyroidismIdiopathic hypopituitarism
INTRAHEPATIC ETIOLOGIESINTRAHEPATIC ETIOLOGIES
Metabolic (cont.) Miscellaneous Metabolic
DisordersAlpha-1-antitrypsin deficiencyCystic fibrosisNeonatal iron storage diseaseNorth American Indian cholestasis
INTRAHEPATIC ETIOLOGIESINTRAHEPATIC ETIOLOGIES
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
EVALUATIONEVALUATION
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
EVALUATIONEVALUATION
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
EVALUATIONEVALUATION
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
EVALUATIONEVALUATION
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
Investigation of CholestasisInvestigation of Cholestasis
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
Investigation of CholestasisInvestigation of Cholestasis
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)
Investigation of CholestasisInvestigation of Cholestasis
Special Tests (cont)Special Tests (cont)
Endoscopic Retrograde Cholangio-Pancreatography
Investigation of CholestasisInvestigation of Cholestasis
Special Tests (cont)Special Tests (cont)
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
Persistent Familial Intrahepatic Cholestasis
normal GT
PFIC 2PFIC 2Byler SyndromeByler Syndrome
Middle EasternMiddle Eastern
2q24
high GT
PFIC 1PFIC 1Byler DiseaseByler Disease
AmishAmish
PFIC 3PFIC 3
18q21-22
BBenignenignRRecurrentecurrentIIntrahepaticntrahepaticCCholestasisholestasis
IIntrahepaticntrahepatic
CCholestasisholestasis
PPregnancyregnancy
7q21
PFIC 2PFIC 2Byler SyndromeByler Syndrome
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
PFIC 2PFIC 2Byler SyndromeByler Syndrome
Middle EasternMiddle Eastern
2q24
PFIC 1PFIC 1Byler DiseaseByler Disease
AmishAmish
18q21-22
BBenignenignRRecurrentecurrentIIntrahepaticntrahepaticCCholestasisholestasis
Persistent Familial Intrahepatic Cholestasis
high GT
PFIC 3PFIC 3
IIntrahepaticntrahepatic
CCholestasisholestasis
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 2PFIC 2Byler SyndromeByler Syndrome
Middle EasternMiddle Eastern
PFIC 3PFIC 3
2q24
IIntrahepaticntrahepatic
CCholestasisholestasis
PPregnancyregnancy
7q21
Persistent Familial Intrahepatic Cholestasis
normal GT
PFIC 1PFIC 1Byler DiseaseByler Disease
AmishAmish
18q21-22
BBenignenignRRecurrentecurrentIIntrahepaticntrahepaticCCholestasisholestasis
FIC1
P-type ATPaseAminophospholipids
PFIC 1PFIC 1Byler DiseaseByler Disease
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
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
Alagille SyndromeAlagille Syndrome
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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