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home - Liver - Bilirubin Metabolism - Bilirubin Metabolism 3 Written by Dr Sebastian Zeki

Bilirubin Metabolism 3

Inherited conjugated hyperbilirubinemia and cholestasis Familial hepatocellular cholestasis:Progressive familial intrahepaticcholestasis —It is present during infancy or childhood, and is associated with growth failure and progressive liver disease (except BRIC).Coagulopathy (vit K malabsorption) can occur.Intractable pruritis is a dominant feature in the early stages of PFIC I and II. ATP Clinical presentation: Adolescence or early adultwith recurrent cholestatsis and weight lossLabs: Cholestasis without severe hepatocellular injury.Last for weeks to months followed by normalization.In a given patient, recurrent attacks resemble each other in symptoms, signs, and duration.Assoc: Intrahepatic cholestasis of pregnancy and OCP assoc cholestasis.Histology: Noninflammatory intrahepatic cholestasis without fibrosis, regardless of the number and severity of attacks. Becomes normal in remissionGenetics:(AR)Associated with mutations of ATP8B1 (FIC-I- in PFIC I) and ABCB11 (BSEP- in PFICII).Pancreatitis is a known extrahepatic manifestation in BRIC caused by the ATPB1 mutations but not in BRIC patients with mutations in ABCB11.Similarly, cholelithiasis has been described in patients with the ABCB11 mutation but not in those with the ATP8B1 mutation.Treatment —There is no specific treatment for BRIC.No need to liver transplantShort-term nasobiliary drainage improves BRIC pruritus by normalizing [serum bile salt] Progressive familial intrahe-patic cholestasis type II —Progressive familial intrahepatic cholestasis type II (PFIC II) resembles Byler disease clinically but occurs in non-Byler families, mainly in the Middle East and Europe.It is caused by defects in the gene that codes for the sister P-glycoprotein (SPGP=BSEP) , which is an ATP-dependent transporter of bile acids from the hepatocytes into the bile canaliculus.The SPGP gene (ABCB11) has been localized to chromosome 2q24. Treatment —Fat-soluble vitamin supplementationPruritis usually severe and may need surgical procedures to prevent bile acid circulation eg diversion of bile flow to external fistulaLiver transplantation curative for PFIC II and IIIPFIC I may have ongoing disease due to the extrahepatic expression of FIC-I.Gallstone removal in ABCB4 mutations +/- ursodeoxycholic acid (endogenous lithogenic bile acids replace hydrophilic bile acids.) Progressive familial intrahepatic cholestasis type I (=Byler disease or Greenland familial cholestasis).Caused by a mutation in the P-type ATPase gene (ATP8B1),FIC-1-in the canalicular membrane and in cholangiocytes and couples the hydrolysis of ATP to the translocation of acidic phospholipids. MOAT PFIC I and PFIC II are both associated with life-threatening cholestasis.GGT levels are normalPFICII (ABCBII) can predispose to hepatocellular carcinoma (HCC) in young childrenLiver transplantation amelio-rates all manifestations of PFIC II, specifically hepatic expre-sion of SPGP, which is consistent. Progressive familial intrahepatic cholestasis type III —This is due to a mutated ABCB4 gene (=multidrug resistance protein-3 P-glycoprotein).The ABCB4 gene product replenishes phosphatidylcholine(PPC), which protects vs bile damage,in the outer lipid membrane of the bile canaliculus by translocating it from inner lipid layer- the bile salt secretion remains normal. No PPC=Small bile duct damage.It is distinguished from PFIC I, BRIC, and PFIC II by the markedly elevated [GGT].Low phospholipid-associated cholestasis (LPAC))= Heterozygous ABCB4 mutations can reduce biliary phospholipid concentration, with an increased risk for cholesterol stones, microlithiasis, or sludge.Suspect if cholelithiasis < 40, recurrence after cholecystectomy, and intrahepatic sludge or microlithiasis.1/3rd with unexplained cholestasis have mutations at least one ABCB4 allele.ABCB4 mutations also cause acute recurrent biliary pancreatitis, biliary cirrhosis, and fibrosing cholestatic liver disease in adults with or without biliary symptoms. Alagille syndrome(AD) Features: Paucity of interlobular bile ducts.Chronic cholestasis (91 %).Cardiac anomalies, esp. peripheral pulmonic stenosis (85 %).Butterfly vertebrae (87 %).Posterior embryotoxon (prominent Schwalbe line) of the eye (88 %).Dysmorphic facies( broad nasal bridge, triangular facies, and deep set eyes (95 %).Growth and mental retardation, developmental delay, renal disease, and pancreatic insufficiency.Gene= (JAG-1) chromosome 20- usually present <6m with failure to thrive/ jaundice/ CVS problems.Lecithin cholesterol acyltransferase activity is reduced in many. Benign recurrent intrahepatic cholestasis — Bile canalicular and structural anomalies of known genetic basis : Treatment:Liver transplantation may be requiredOccasionally ursodeoxycholic acid is useful Abnormal villin expression —It involves a biliary atresia-like presentation with special ultrastructural features.Patients develop cirrhosis early (2-5 years old).Histology shows a paucity or absence of bile ducts with moderate portal fibrosis at 3m old, which distinguishes these cases from classic biliary atresia.Electron microscopy reveals disordered canalicular microvilli, which are often inverted (ie, projected into the cytoplasm, rather than the canalicular lumen).Villin binds actin and arranges actin fibres in bundles, which are necessary for generating and maintaining anatomically normal microvilli.The gene is mapped to chromosome 2q35-36.The protein is expressed in the microvilli of brush-border surfaces in the GI tract. Written by Dr Sebastian Zeki

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