Progressive Familial Intrahepatic Cholestasis



Progressive Familial Intrahepatic Cholestasis


Joseph Misdraji, MD





Key Facts


Etiology/Pathogenesis



  • PFIC1 (FIC1 disease) is due to mutations of ATP8B1 (FIC1 gene)


  • PFIC2 (BSEP disease) is due to mutations of ABCB11 gene that encodes bile salt export pump


  • PFIC3 is due to mutation of ABCB4 gene that encodes MDR3, a phospholipid flippase


Clinical Issues



  • PFIC presents in 1st year of life with intense pruritus and jaundice


  • PFIC1 and PFIC2 are characterized by normal serum GGT, whereas PFIC3 is associated with elevated GGT


  • Progressive forms lead to liver failure, cirrhosis, and death before adulthood


  • Partial external biliary diversion or ileal exclusion may be used with some success, but most patients require liver transplantation


Microscopic Pathology



  • PFIC1 is characterized by relatively bland canalicular cholestasis


  • PFIC2 is characterized by pattern of neonatal giant cell hepatitis


  • PFIC3 is characterized by duct proliferation and bile plugs in ductules


Ancillary Tests



  • FIC1 disease reveals coarse, granular bile, referred to as Byler bile


  • Immunohistochemistry for canalicular proteins can be used for diagnosis






Hematoxylin & eosin stained section of a liver biopsy in a child with PFIC shows giant cell transformation of perivenular hepatocytes, typical of childhood cholestasis syndromes.






Hematoxylin & eosin stained section of a liver biopsy in an adult patient with BRIC shows bland canalicular cholestasis with mild lobular architectural disarray but minimal inflammation.


TERMINOLOGY


Abbreviations



  • Progressive familial intrahepatic cholestasis (PFIC)


Synonyms



  • PFIC type 1



    • Familial intrahepatic cholestasis 1 (FIC1) disease


    • Byler disease, Byler syndrome


    • Greenland familial cholestasis (GFC)


  • PFIC type 2



    • Bile salt export pump (BSEP) disease


  • PFIC type 3



    • Multidrug resistance protein 3 (MDR3) disease


Definitions



  • Heterogeneous group of autosomal recessive disorders characterized by chronic cholestasis and progression to cirrhosis and liver failure


ETIOLOGY/PATHOGENESIS


Autosomal Recessive Genetic Disorder



  • PFIC1



    • Mutation of ATP8B1 (FIC1 gene), located on chromosome 18q21-q22



      • FIC1 is expressed on variety of tissues including liver, intestine, pancreas


      • Functions as aminophospholipid flippase, flipping phosphatidylserine from outer to inner lipid layer of cell membrane


      • Mechanism of cholestasis unclear


  • PFIC2



    • Mutations of ABCB11 gene on chromosome 2q24 that encodes BSEP, an ATP-dependent bile acid transporter on canalicular membrane


  • PFIC3



    • Mutation of ABCB4 gene that encodes MDR3 glycoprotein



      • MDR3 is flippase that flips phosphatidylcholine from inner to outer lipid leaflet of canalicular membrane


      • Phosphatidylcholine in bile reduces its detergent action, and MDR3 deficiency results in bile with more detergent properties


      • Absence of phospholipids destabilizes micelles, promoting lithogenicity of bile with crystallization of cholesterol and leads to small bile duct obstruction


CLINICAL ISSUES


Presentation



  • FIC1 deficiency disease



    • Depending on nature of mutation, may present as benign recurrent intrahepatic cholestasis (BRIC1) or progressive and severe form (PFIC1)


    • PFIC1



      • Presents in 1st year of life with intense pruritus and jaundice


      • Systemic disorder with extrahepatic manifestations including pancreatitis, diarrhea, respiratory symptoms, failure to thrive, delayed sexual development, hearing loss


    • BRIC1



      • Recurrent episodes of cholestasis with intense pruritus


      • Episodes resolve spontaneously without histologic progression


  • BSEP disease



    • Depending on nature of mutation, may present as BRIC2 or PFIC2


    • PFIC2



      • Presents as severe intrahepatic cholestasis in infancy


    • BRIC2




      • Presents as recurrent episodes of pruritus, steatorrhea, nausea, vomiting, anorexia, right upper quadrant abdominal pain, and weight loss


      • Frequently complicated by cholesterol cholelithiasis


  • MDR3 disease



    • PFIC3 presents during infancy with pruritus, jaundice, pale stools, hepatomegaly, or complications of portal hypertension, such as splenomegaly or gastrointestinal bleeding


    • MDR3 mutations also seen in patients with intrahepatic lithiasis, cholesterol gallstone disease, intrahepatic cholestasis of pregnancy, transient neonatal cholestasis, cholestatic drug reactions


Laboratory Tests



  • GGT



    • Normal in PFIC1 and PFIC2


    • Elevated in PFIC3


  • Elevated serum bile acids in all 3 types


  • PFIC3 is characterized by low concentrations of phospholipids in bile analysis


Natural History



  • Progressive forms can result in worsening hepatic function, liver failure, cirrhosis, and death before adulthood



    • Chronic cholestasis leads to complications of fat malabsorption such as deficiencies of fat-soluble vitamins and weight loss


  • BSEP disease is associated with development of hepatocellular carcinoma


Treatment



  • Surgical approaches



    • Partial external biliary diversion or cholecystojejunocutaneostomy



      • Short jejunal segment is anastomosed to the dome of gallbladder and terminates as stoma, allowing bile to be discarded


    • Ileal exclusion



      • Approximately 15% of terminal ileum is bypassed, which reduces bile acid reabsorption


    • Liver transplantation



      • May result in intractable diarrhea and steatohepatitis in FIC1 patients


  • Drugs



    • Ursodeoxycholic acid (UDCA), rifampin, cholestyramine, and phenobarbital have been used to treat pruritus


MICROSCOPIC PATHOLOGY


Histologic Features

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Jul 7, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Progressive Familial Intrahepatic Cholestasis

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