Inherited Hyperbilirubinemias

8/8/2019 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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Inherited Hyperbilirubinemias