Progressive Familial Intrahepatic Cholestasis



Progressive Familial Intrahepatic Cholestasis


Joseph Misdraji, MD





Key Facts


Etiology/Pathogenesis



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


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


  • PFIC3 is due to mutations of ABCB4 gene that encodes MDR3, a phospholipid floppase


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



  • Histologic overlap between the 3 types of PFIC and with other causes of intrahepatic cholestasis


  • PFIC1 is characterized by canalicular cholestasis with limited giant cell transformation and compact hepatocytes


  • PFIC2 is characterized by pattern of neonatal giant cell hepatitis


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


Ancillary Tests



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


  • Absence of staining for canalicular proteins by immunohistochemistry can be diagnostic






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)



Definitions



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


  • PFIC type 1 (PFIC1)



    • Familial intrahepatic cholestasis 1 (FIC1) disease


    • Byler disease


    • Greenland familial cholestasis (GFC)


  • PFIC type 2 (PFIC2)



    • Bile salt export pump (BSEP) disease


    • Byler syndrome


  • PFIC type 3 (PFIC3)



    • Multidrug resistance protein 3 (MDR3) disease


  • Benign recurrent intrahepatic cholestasis (BRIC)



    • Caused by mutations in FIC1


ETIOLOGY/PATHOGENESIS


Autosomal Recessive Genetic Disorder



  • PFIC1



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



      • FIC1 is expressed in several tissues including canalicular membrane of hepatocyte, enterocytes, pancreas


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


      • Mechanism of cholestasis unclear but may be related to membrane instability, decreased BSEP function, or downregulation of cystic fibrosis transmembrane conductance regulator (CFTR)


  • PFIC2



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



      • D482G mutation results in abnormal but not absent protein and less severe disease


  • PFIC3



    • Mutation of ABCB4 gene that encodes MDR3 glycoprotein



      • MDR3 is floppase 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 leading 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)



      • Heterozygous mutations identified in some cases of transient neonatal cholestasis and cholestasis of pregnancy


    • PFIC1



      • Presents in neonatal period with intense pruritus and jaundice


      • Extrahepatic manifestations include short stature, pancreatitis, diarrhea, deafness, respiratory issues, and elevated sweat chloride concentration


    • BRIC1



      • Recurrent episodes of cholestasis with intense pruritus, often triggered by a viral infection



      • Episodes resolve spontaneously without histologic progression


  • BSEP disease



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



      • Heterozygous mutations identified in cholestasis of pregnancy, drug-induced cholestasis, and transient neonatal cholestasis


    • 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 may present in infancy, childhood, or even adulthood


    • In infancy, presents with less intense pruritus than PFIC1 or PFIC2 and, in later years, as complications of portal hypertension such as gastrointestinal bleeding


    • Heterozygous mutations identified in patients with intrahepatic lithiasis, cholesterol gallstone disease, cholestasis of pregnancy, transient neonatal cholestasis, cholestatic drug reactions, adult idiopathic cirrhosis, cholangiocarcinoma


Laboratory Tests



  • GGT



    • Normal in PFIC1 and PFIC2, elevated in PFIC3


  • Elevated serum bile acids and normal cholesterol 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



    • BSEP deficiency more likely to progress to cirrhosis


  • Fat malabsorption may result in fat-soluble vitamin deficiencies, with coagulopathy, rickets, or seizures


  • 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



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


    • Liver transplantation



      • May result in intractable diarrhea and steatohepatitis in FIC1 deficiency


      • Recurrence of disease in allograft reported in BSEP deficiency


  • Drugs



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


MICROSCOPIC PATHOLOGY


Histologic Features

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Jul 8, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Progressive Familial Intrahepatic Cholestasis

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