inherited hyperbilirubinemias
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INHERITEDHYPERBILIRUBINEMIAS
Tawhida Yassin Abdel Ghaffar
Prof of pediatric Hepatology
Ain Shams University
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Indirect hyperbilirubinemia
Gilbert
Crigler Najjar: Type 1, Type II
Direct hyperbilirubinemia
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Levels of bile stasis
Hepatocyte : failure of excretion egPFIC,Dubin Johnson
Bile canaliculus: hepatocyte swelling eghepatitis, storage
Interlobular bile ducts: paucity egsyndromic,non syndromic, VBDS, GVHD
Extrahepatic bil system: eg EHBA,choledochal cyst, spontaneous perforation,inspissated bile
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Inherited Intrahepatic
cholestasis Membrane transport: PFIC, DJS, Rotor
Tight junction sructure/function: NISCH, HC
Signaling during development: Alagille Intracellular vesicular protein trafficking: ARC
BA synthesis: ICP
Nuclear receptor Unknown:
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Direct Hyperbilirubinemia
Dubin Johnson
Rotor
PFIC : 1, 2, 3 BRIC
Alagille
BA synthetic defects ( 3 B-OH steroiddehydrogenase)
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Dubin Johnson Syndrome
AR inheritence with reduced penetrance infemales (but jaundice may manifest during
pregnancy or intake of oral contraceptive pills)
Gene is on ch 10 and its product is cMOAT
Described mainly in Iranian Jews
Onset: late teens ,early 20s ( 10m-56y)
Clinically : recurrent jaundice, no pruritis, abd
pain, +/- hepatomegaly
Commonly associated with coagulopathy dtinherited factor VII def
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Recently, increased urinary excretion of
leukortriens has been found to be of
diagnostic importance.
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Nt p DJSRotor
Gene defect MDR2 ( CMOAT)Iranian jews
Unknown
phillipines
Direct bilirubin high high
Symptoms/Onset Recurrent Jaun +/- Abdpain+/-hepatomegaly.
adolescence
chronic jaundice+/- abdpain +/- episodes of fever
E
arly infancy
Liver biopsy Black pigment no pigment
Urinary coproporphyrinsCopro 1/copro 111
Increased>90%
Increased
Oralcholecystography
HIDA
Failure of visualization ofGB/ v delayed or absent GB
picture
N
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Progressive Familial
Intrahepatic Cholestasis The spectrum of disease ranges from BRIC (1,2)
to PFIC (1,2) depending on the type of mutation
In all types there is absence of lippoprotein Xwhich only contains free cholestrol(ratio of freecholestrol/esterified cholestrol is reduced)
PFIC 3 is reponsible for some cases ofICP(pruritis in 3rd timester that resolves after
delivery), LPAC(cholesterol gall stones that recurafter cholecystectomy) , adult biliary cirrhosis ,PSC(small duct type), TPN cholestasis andpostLTx bile duct injury.
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In all types there is jaundice, pruritis ( minimal
inMDR3), fat sol vit deficiencies, growth
failure In FIC 1 there are extrahepatic manifestations
(watery diarrhoea, chest infections, hearing
loss)
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FIC1 (PFIC 1+BRIC1) PFIC 2 (BSEP) PFIC 3 (MDR3)
Gene defect ATB8B1 ( ch 18) ABCB11( ch 2 ) ABCB4 ( ch 7)
GGT N N high
Onset/course J in 1st y,thenrecurrent j, by 4y it is
persistent.ESLD
Late neonatal,rapidly
progressive,severe
Neon chol/ Cir inyoung adults
Prognosis Liver failure cirrhosis
Biopsy Canal choles/coarse
bile
Canal choles/GCH
cirrhosis
Ductular prolif/ bil
cirrhosis
Extra hepaticmanifestations
Intestine/ chestpancreas/growth/
hearing
No No
ALT/AFP/ Mild rise/ N Marked rise/ high
Gall stones/HCC no Yes/ yes (15%-35%) Yes/yes
LTX Post tx Fatty liver/diarrhoea/ no
improved growth
Good results Good results
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Alagille Syndrome
Inheritance: AD with variable expression
adults who carry the mutated gene are may
not have cholestasis but are at increased riskof vascular anomalies ( cerebral hge/ aorticaneurism or coarctation), renal disease and
HCC
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BAS defect
(3 B OH steroid reductase) Commonest form of BAS defect
presents later in childhood
Jaundice Low GGT
No pruritis
LB: variable (GCH-chronic hepatitis)
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In medical knowledge , Egypt leavesthe rest of the world behind(the Odessy, Homer)
Ibn Sina
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