Progressive Familial Intrahepatic Cholestasis (PFIC) Type 1, 2, and 3: A Review of the Liver Pathology Findings

ABSTRACT

Progressive familial intrahepatic cholestatic diseases encompass a group of autosomal recessive hereditary diseases, which usually present in infancy or childhood, with cholestasis of hepatocellular origin. The currently preferred nomenclature for the three PFIC disorders that have been characterized to date is FIC1 deficiency, BSEP deficiency, and MDR3 deficiency, relating to mutations in the specific genes involved in bile acid formation and transport. Since the first description of these diseases, extensive clinical, biochemical, and molecular studies have increased our understanding of the features specific to each one of them. This review focuses mainly on the liver histology, summarizing their characteristic pathologic features, the correlation to specific genotypes, and complications arising with disease progression.

KEYWORDS

Progressive familial intrahepatic cholestasis - pediatric liver disease - Byler disease - FIC1 deficiency - BSEP deficiency - MDR3 deficiency

REFERENCES

• 1 Clayton R J, Iber F L, Ruebner B H, McKusick V A. Byler disease. Fatal familial intrahepatic cholestasis in an Amish kindred.  Am J Dis Child. 1969;  117 (1) 112-124
• 2 Linarelli L G, Williams C N, Phillips M J. Byler's disease: fatal intrahepatic cholestasis.  J Pediatr. 1972;  81 (3) 484-492
• 3 Alissa F T, Jaffe R, Shneider B L. Update on progressive familial intrahepatic cholestasis.  J Pediatr Gastroenterol Nutr. 2008;  46 (3) 241-252
• 4 Alonso E M, Snover D C, Montag A, Freese D K, Whitington P F. Histologic pathology of the liver in progressive familial intrahepatic cholestasis.  J Pediatr Gastroenterol Nutr. 1994;  18 (2) 128-133
• 5 Keitel V, Burdelski M, Vojnisek Z, Schmitt L, Häussinger D, Kubitz R. De novo bile salt transporter antibodies as a possible cause of recurrent graft failure after liver transplantation: a novel mechanism of cholestasis.  Hepatology. 2009;  50 (2) 510-517
• 6 Byrne J A, Meara N J, Rayner A C, Thompson R J, Knisely A S. Lack of hepatocellular CD10 along bile canaliculi is physiologic in early childhood and persistent in Alagille syndrome.  Lab Invest. 2007;  87 (11) 1138-1148
• 7 Liu L U, Qin L, Knisely A S. A patient with persistent pruritus.  Semin Liver Dis. 2010;  30 (2) 205-209
• 8 Miyagawa-Hayashino A, Egawa H, Yorifuji T et al.. Allograft steatohepatitis in progressive familial intrahepatic cholestasis type 1 after living donor liver transplantation.  Liver Transpl. 2009;  15 (6) 610-618
• 9 Demeilliers C, Jacquemin E, Barbu V et al.. Altered hepatobiliary gene expressions in PFIC1: ATP8B1 gene defect is associated with CFTR downregulation.  Hepatology. 2006;  43 (5) 1125-1134
• 10 Bull L N, Carlton V E, Stricker N L et al.. Genetic and morphological findings in progressive familial intrahepatic cholestasis (Byler disease [PFIC-1] and Byler syndrome): evidence for heterogeneity.  Hepatology. 1997;  26 (1) 155-164
• 11 Pawlikowska L, Strautnieks S, Jankowska I et al.. Differences in presentation and progression between severe FIC1 and BSEP deficiencies.  J Hepatol. 2010;  53 (1) 170-178
• 12 Strautnieks S S, Byrne J A, Pawlikowska L et al.. Severe bile salt export pump deficiency: 82 different ABCB11 mutations in 109 families.  Gastroenterology. 2008;  134 (4) 1203-1214
• 13 Davit-Spraul A, Fabre M, Branchereau S et al.. ATP8B1 and ABCB11 analysis in 62 children with normal gamma-glutamyl transferase progressive familial intrahepatic cholestasis (PFIC): phenotypic differences between PFIC1 and PFIC2 and natural history.  Hepatology. 2010;  51 (5) 1645-1655
• 14 Ernst L M, Spinner N B, Piccoli D A, Mauger J, Russo P. Interlobular bile duct loss in pediatric cholestatic disease is associated with aberrant cytokeratin 7 expression by hepatocytes.  Pediatr Dev Pathol. 2007;  10 (5) 383-390
• 15 Knisely A S, Strautnieks S S, Meier Y et al.. Hepatocellular carcinoma in ten children under five years of age with bile salt export pump deficiency.  Hepatology. 2006;  44 (2) 478-486
• 16 Scheimann A O, Strautnieks S S, Knisely A S, Byrne J A, Thompson R J, Finegold M J. Mutations in bile salt export pump (ABCB11) in two children with progressive familial intrahepatic cholestasis and cholangiocarcinoma.  J Pediatr. 2007;  150 (5) 556-559
• 17 Bass L M, Patil D, Rao M S, Green R M, Whitington P F. Pancreatic adenocarcinoma in type 2 progressive familial intrahepatic cholestasis.  BMC Gastroenterol. 2010;  10 30
• 18 Arnell H, Bergdahl S, Papadogiannakis N, Nemeth A, Fischler B. Preoperative observations and short-term outcome after partial external biliary diversion in 13 patients with progressive familial intrahepatic cholestasis.  J Pediatr Surg. 2008;  43 (7) 1312-1320
• 19 Jara P, Hierro L, Martínez-Fernández P et al.. Recurrence of bile salt export pump deficiency after liver transplantation.  N Engl J Med. 2009;  361 (14) 1359-1367
• 20 Siebold L, Dick A A, Thompson R et al.. Recurrent low gamma-glutamyl transpeptidase cholestasis following liver transplantation for bile salt export pump (BSEP) disease (posttransplant recurrent BSEP disease).  Liver Transpl. 2010;  16 (7) 856-863
• 21 Smit J J, Schinkel A H, Oude Elferink R P et al.. Homozygous disruption of the murine mdr2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease.  Cell. 1993;  75 (3) 451-462
• 22 Davit-Spraul A, Gonzales E, Baussan C, Jacquemin E. Progressive familial intrahepatic cholestasis.  Orphanet J Rare Dis. 2009;  4 1
• 23 Jacquemin E, De Vree J M, Cresteil D et al.. The wide spectrum of multidrug resistance 3 deficiency: from neonatal cholestasis to cirrhosis of adulthood.  Gastroenterology. 2001;  120 (6) 1448-1458
• 24 Jacquemin E. Role of multidrug resistance 3 deficiency in pediatric and adult liver disease: one gene for three diseases.  Semin Liver Dis. 2001;  21 (4) 551-562
• 25 Wagner B E, Strautnieks S S, Devlin J et al.. ABCB4 mutation and intrahepatic cholestasis: cholesterol crystals in bile canaliculi.  (abstract) Mod Pathol. 2008;  21 (1 Suppl) 317A