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.


TERMINOLOGY




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



MICROSCOPIC PATHOLOGY

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