Progressive Familial Intrahepatic Cholestasis

Progressive Familial Intrahepatic Cholestasis

Joseph Misdraji, MD

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.



  • Progressive familial intrahepatic cholestasis (PFIC)


  • 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


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


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



  • 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


  • 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


Histologic Features

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

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