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.



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



  • 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


Histologic Features

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

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