Semin Liver Dis 2001; 21(4): 535-544
DOI: 10.1055/s-2001-19034
Copyright © 2001 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

FIC1 Disease: A Spectrum of Intrahepatic Cholestatic Disorders

Saskia W. C. van Mil1 , Leo W. J. Klomp2 , Laura N. Bull3 , Roderick H. J. Houwen1
  • 1Pediatric Gastroenterology, University Medical Center, Utrecht, The Netherlands
  • 2Metabolic Diseases, University Medical Center, Utrecht, The Netherlands
  • 3Liver Center Laboratory, San Francisco General Hospital, University of California, San Francisco, California, U.S.A
Further Information

Publication History

Publication Date:
17 December 2001 (online)

ABSTRACT

FIC1 disease collectively refers to a group of autosomal-recessive familial liver disorders characterized by intrahepatic cholestasis due to mutations in the ATP8B1 gene (initially named FIC1). Classically, FIC1 disease comprises two different disorders: progressive familial intrahepatic cholestasis type 1 (PFIC1) and benign recurrent intrahepatic cholestasis (BRIC). However, we now view these two disorders as two ends of a continuum. Current therapeutic strategies for FIC1 disease, both medical and surgical, may relieve symptoms, but are presently insufficiently evaluated. ATP8B1 encodes a protein belonging to a recently defined subfamily of P-type ATPases. The biochemical and cellular functions of its product, FIC1, and the mechanisms by which its absence or dysfunction leads to cholestasis are currently elusive. Further studies to elucidate FIC1's function will be essential to unravel the pathogenesis of FIC1 disease. Such studies will also have a general impact on our understanding of the molecular mechanisms of bile formation and may therefore improve clinical management of both hereditary and acquired forms of cholestasis.

REFERENCES

  • 1 Arrese M, Ananthananarayanan M, Suchy F J. Hepatobiliary transport: molecular mechanisms of development and cholestasis.  Pediatr Res . 1998;  44 141-147
  • 2 Jacquemin E, Hadchouel M. Genetic basis of progressive familial intrahepatic cholestasis.  J Hepatol . 1999;  31 377-381
  • 3 Knisely A S. Progressive familial intrahepatic cholestasis: a personal perspective.  Pediatr Dev Pathol . 2000;  3 113-125
  • 4 Clayton R J, Iber F L, Ruebner B H. Byler disease.  Fatal familial intrahepatic cholestasis in an Amish kindred. Am J Dis Child . 1969;  117 112-124
  • 5 Summerskill W HJ, Walshe J M. Benign recurrent intrahepatic obstructive jaundice.  Lancet . 1959;  2 686-690
  • 6 Nielsen I M, Ornvold K, Jacobsen B B. Fatal familial cholestatic syndrome in Greenland Eskimo children.  Acta Paediatr Scand . 1986;  75 1010-1016
  • 7 Klomp L W, Bull L N, Knisely A S. A missense mutation in FIC1 is associated with Greenland familial cholestasis.  Hepatology . 2000;  32 1337-1341
  • 8 Kullak-Ublick G A, Stieger B. Hepatic transport of bile salts.  Semin Liver Dis . 2000;  20 273-292
  • 9 Jacquemin E, Setchell K D, O'Connell N C. A new cause of progressive intrahepatic cholestasis: 3 beta-hydroxy-C27-steroid dehydrogenase/isomerase deficiency.  J Pediatr . 1994;  125 379-384
  • 10 Setchell K D, Schwarz M, O'Connell N C. Identification of a new inborn error in bile acid synthesis: mutation of the oxysterol 7alpha-hydroxylase gene causes severe neonatal liver disease.  J Clin Invest . 1998;  102 1690-1703
  • 11 de Vree M J, Jacquemin E, Sturm E. Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis.  Proc Natl Acad Sci U S A . 1998;  95 282-287
  • 12 Morton D H, Salen G, Batta A K. Abnormal hepatic sinusoidal bile acid transport in an Amish kindred is not linked to FIC1 and is improved by ursodiol.  Gastroenterology . 2000;  119 188-195
  • 13 Betard C, Rasquin-Weber A, Brewer C. Localization of a recessive gene for North American Indian childhood cirrhosis to chromosome region 16q22 and identification of a shared haplotype.  Am J Hum Genet . 2000;  67 222-228
  • 14 Bull L N, Roche E, Song E J. Mapping of the locus for cholestasis-lymphedema syndrome (Aegenaes syndrome) to a 6.6-cM interval on chromosome 15q.  Am J Hum Genet . 2000;  67 994-999
  • 15 Sinke R J, Carlton V E, Juijn J A. Benign recurrent intrahepatic cholestasis (BRIC): evidence of genetic heterogeneity and delimitation of the BRIC locus to a 7-cM interval between D18S69 and D18S64.  Hum Genet . 1997;  100 382-387
  • 16 Floreani A, Molaro M, Mottes M. Autosomal dominant benign recurrent intrahepatic cholestasis (BRIC) unlinked to 18q21 and 2q24.  Am J Med Genet . 2000;  95 450-453
  • 17 Lee J, Boyer J L. Molecular alterations in hepatocyte transport mechanisms in acquired cholestatic liver disorders.  Semin Liver Dis . 2000;  20 373-384
  • 18 Rotthauwe H W, Beseler W D, Kowalewski S. Benign recurrent intrahepatic cholestasis.  Klin Wochenschr . 1969;  47 140-149
  • 19 Whitington P F, Freese D K, Alonso E M. Clinical and biochemical findings in progressive familial intrahepatic cholestasis.  J Pediatr Gastroenterol Nutr . 1994;  18 134-141
  • 20 Tygstrup N, Steig B A, Juijn J A. Recurrent familial intrahepatic cholestasis in the Faeroe Islands. Phenotypic heterogeneity but genetic homogeneity.  Hepatology . 1999;  29 506-508
  • 21 De Koning J T, Sandkuijl L A, De Schryver E J. Autosomal-recessive inheritance of benign recurrent intrahepatic cholestasis.  Am J Med Genet . 1995;  57 479-482
  • 22 Brenard R, Geubel A P, Benhamou J P. Benign recurrent intrahepatic cholestasis. A report of 26 cases.  J Clin Gastroenterol . 1989;  11 546-551
  • 23 Bijleveld C M, Vonk R J, Kuipers F. Benign recurrent intrahepatic cholestasis: altered bile acid metabolism.  Gastroenterology . 1989;  97 427-432
  • 24 de Pagter G A, Berge Henegouwen P G, Bokkel Huinink A J, Brandt K H. Familial benign recurrent intrahepatic cholestasis. Interrelation with intrahepatic cholestasis of pregnancy and from oral contraceptives?.  Gastroenterology . 1976;  71 202-207
  • 25 Bull L N, Carlton V E, Stricker N L. Genetic and morphological findings in progressive familial intrahepatic cholestasis (Byler disease [PFIC-1] and Byler syndrome): evidence for heterogeneity.  Hepatology . 1997;  26 155-164
  • 26 Ornvold K, Nielsen I M, Poulsen H. Fatal familial cholestatic syndrome in Greenland Eskimo children. A histomorphological analysis of 16 cases.  Virchows Arch [A] . 1989;  415 275-281
  • 27 Catano da Silva L, De Brito T. Benign recurrent intrahepatic cholestasis in two brothers.  Ann Intern Med . 1966;  65 330-341
  • 28 Cissarek T, Schumacher B, Schwobel H. Follow-up of benign recurrent intrahepatic cholestasis (Summerskill-Walshe-Tygstrup syndrome) over 46 years.  Z Gastroenterol . 1998;  36 379-383
  • 29 Alonso E M, Snover D C, Montag A. Histologic pathology of the liver in progressive familial intrahepatic cholestasis.  J Pediatr Gastroenterol Nutr . 1994;  18 128-133
  • 30 Williams, Carter M A, Sherlock S. Ideopathic recurrent cholestasis: a study of the functional and pathological lesions in four cases.  Q J Med . 1964;  131 387-399
  • 31 Bircher J. Treatment of patients with benign recurrent intrahepatic cholestasis.  Hepatology . 1989;  10 1030-1032
  • 32 Crosignani A, Podda M, Bertolini E. Failure of ursodeoxycholic acid to prevent a cholestatic episode in a patient with benign recurrent intrahepatic cholestasis: a study of bile acid metabolism.  Hepatology . 1991;  13 1076-1083
  • 33 Jacquemin E. Progressive familial intrahepatic cholestasis.  J Gastroenterol Hepatol . 1999;  14 594-599
  • 34 Yerushalmi B, Sokol R J, Narkewicz M R. Use of rifampin for severe pruritus in children with chronic cholestasis.  J Pediatr Gastroenterol Nutr . 1999;  29 442-447
  • 35 Cancado E L, Leitao R M, Carrilho F J. Unexpected clinical remission of cholestasis after rifampicin therapy in patients with normal or slightly increased levels of gamma-glutamyl transpeptidase.  Am J Gastroenterol . 1998;  93 1510-1517
  • 36 Melter M, Rodeck B, Kardorff R. Progressive familial intrahepatic cholestasis: partial biliary diversion normalizes serum lipids and improves growth in noncirrhotic patients.  Am J Gastroenterol . 2000;  95 3522-3528
  • 37 Emond J C, Whitington P F. Selective surgical management of progressive familial intrahepatic cholestasis (Byler's disease).  J Pediatr Surg . 1995;  30 1635-1641
  • 38 Ismail H, Kalicinski P, Markiewicz M. Treatment of progressive familial intrahepatic cholestasis: liver transplantation or partial external biliary diversion.  Pediatr Transplant . 1999;  3 219-224
  • 39 Hollands C M, Rivera-Pedrogo F J, Gonzalez-Vallina R. Ileal exclusion for Byler's disease: an alternative surgical approach with promising early results for pruritus.  J Pediatr Surg . 1998;  33 220-224
  • 40 Soubrane O, Gauthier F, DeVictor D. Orthotopic liver transplantation for Byler disease.  Transplantation . 1990;  50 804-806
  • 41 Houwen R H, Baharloo S, Blankenship K. Genome screening by searching for shared segments: mapping a gene for benign recurrent intrahepatic cholestasis.  Nat Genet . 1994;  8 380-386
  • 42 Carlton V E, Knisely A S, Freimer N B. Mapping of a locus for progressive familial intrahepatic cholestasis (Byler disease) to 18q21-q22, the benign recurrent intrahepatic cholestasis region.  Hum Mol Genet . 1995;  4 1049-1053
  • 43 Kagalwalla A F, Al Amir R A, Khalifa A. Progressive familial intrahepatic cholestasis (Byler's disease) in Arab children.  Ann Trop Paediatr . 1995;  15 321-327
  • 44 Strautnieks S S, Kagalwalla A F, Tanner M S. Identification of a locus for progressive familial intrahepatic cholestasis PFIC2 on chromosome 2q24.  Am J Hum Genet . 1997;  61 630-633
  • 45 Bull L N, van Eijk J M, Pawlikowska L. A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis.  Nat Genet . 1998;  18 219-224
  • 46 Bull L N, Juijn J A, Liao M. Fine-resolution mapping by haplotype evaluation: the examples of PFIC1 and BRIC.  Hum Genet . 1999;  104 241-248
  • 47 Klomp L W, Bull L N, Juijn J A. Characterization of multiple different mutations in FIC1 associated with hereditary cholestasis.  Hepatology . 1999;  30 (Abst) 407
  • 48 Strautnieks S S, Bull L N, Knisely A S. A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis.  Nat Genet . 1998;  20 233-238
  • 49 Lutsenko S, Kaplan J H. Organization of P-type ATPases: significance of structural diversity.  Biochemistry . 1995;  34 15607-15613
  • 50 Scarborough G A. Structure and function of the P-type ATPases.  Curr Opin Cell Biol . 1999;  11 517-522
  • 51 Sudbrak R, Brown J, Dobson-Stone C. Hailey-Hailey disease is caused by mutations in ATP2C1 encoding a novel Ca(2+) pump.  Hum Mol Genet . 2000;  9 1131-1140
  • 52 Sakuntabhai A, Ruiz-Perez V, Carter S. Mutations in ATP2A2, encoding a Ca2+ pump, cause Darier disease.  Nat Genet . 1999;  21 271-277
  • 53 Yamaguchi Y, Heiny M E, Gitlin J D. Isolation and characterization of a human liver cDNA as a candidate gene for Wilson disease.  Biochem Biophys Res Commun . 1993;  197 271-277
  • 54 Bull P C, Thomas G R, Rommens J M. The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene.  Nat Genet . 1993;  5 327-337
  • 55 Petrukhin K, Fischer S G, Pirastu M. Mapping, cloning and genetic characterization of the region containing the Wilson disease gene.  Nat Genet . 1993;  5 338-343
  • 56 Vulpe C, Levinson B, Whitney S. Isolation of a candidate gene for Menkes disease and evidence that it encodes a copper-transporting ATPase.  Nat Genet . 1993;  3 7-13
  • 57 Mercer J F, Livingston J, Hall B. Isolation of a partial candidate gene for Menkes disease by positional cloning.  Nat Genet . 1993;  3 20-25
  • 58 Chelly J, Monaco A P. Cloning the Wilson disease gene.  Nat Genet . 1993;  5 317-318
  • 59 Tanzi R E, Petrukhin K, Chernov I. The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene.  Nat Genet . 1993;  5 344-350
  • 60 Palmgren M G, Axelsen K B. Evolution of P-type ATPases.  Biochim Biophys Acta . 1998;  1365 37-45
  • 61 Catty P, de Kerchove d'Exarde A, Goffeau A. The complete inventory of the yeast Saccharomyces cerevisiae P-type transport ATPases.  FEBS Lett . 1997;  409 325-332
  • 62 Halleck M S, Lawler Jr F J, Blackshaw S. Differential expression of putative transbilayer amphipath transporters.  Physiol Genomics . 1999;  1 139-150
  • 63 Halleck M S, Pradhan D, Blackman C. Multiple members of a third subfamily of P-type ATPases identified by genomic sequences and ESTs.  Genome Res . 1998;  8 354-361
  • 64 Chen C Y, Ingram M F, Rosal P H. Role for Drs2p, a P-type ATPase and potential aminophospholipid translocase, in yeast late Golgi function.  J Cell Biol . 1999;  147 1223-1236
  • 65 Tang X, Halleck M S, Schlegel R A. A subfamily of P-type ATPases with aminophospholipid transporting activity.  Science . 1996;  272 1495-1497
  • 66 Futerman A H, Ghidoni R, van Meer G. Lipids: regulatory functions in membrane traffic and cell development.  EMBO J . 1998;  17 6772-6775
  • 67 Bevers E M, Comfurius P, Dekkers D W. Regulatory mechanisms of transmembrane phospholipid distributions and pathophysiological implications of transbilayer lipid scrambling.  Lupus . 1998 (suppl 2);  7 (S126-S131)
  • 68 Verkleij A J, Post J A. Membrane phospholipid asymmetry and signal transduction.  J Membr Biol . 2000;  178 1-10
  • 69 Siegmund A, Grant A, Angeletti C. Loss of Drs2p does not abolish transfer of fluorescence-labeled phospholipids across the plasma membrane of Saccharomyces cerevisiae J Biol Chem .  1998;  273 34399-34405
  • 70 Mouro I, Halleck M S, Schlegel R A. Cloning, expression, and chromosomal mapping of a human ATPase II gene, member of the third subfamily of P-type ATPases and orthologous to the presumed bovine and murine aminophospholipid translocase.  Biochem Biophys Res Commun . 1999;  257 333-339
  • 71 Gomes E, Jakobsen M K, Axelsen K B. Chilling tolerance in Arabidopsis involves ALA1, a member of a new family of putative aminophospholipid translocases.  Plant Cell . 2000;  12 2441-2454
  • 72 Dhar M, Webb L S, Smith L. A novel ATPase on mouse chromosome 7 is a candidate gene for increased body fat.  Physiol Genomics . 2000;  4 93-100
  • 73 Mansharamani M, Hewetson A, Chilton B S. Cloning and characterization of an atypical type IV P-type ATPase that binds to the RING motif of RUSH transcription factors.  J Biol Chem . 2000;  276 3641-3649
  • 74 Muteru A, Bull L, Pawlikowska L. Cloning and tissue distribution of the rat homologue of the human gene involved in familial intrahepatic cholestasis type 1.  Hepatology . 1998;  28 (Abst) 530
  • 75 Ujhazy P, Ortiz D F, Misra S. ATP-dependent aminophospholipid translocase activity in rat canalicular membrane vesicles and its relationship to FIC1.  Hepatology . 1999;  30 (Abst) 462
  • 76 van Helvoort A, Smith A J, Sprong H. MDR1 P-glycoprotein is a lipid translocase of broad specificity, while MDR3 P-glycoprotein specifically translocates phosphatidylcholine.  Cell . 1996;  87 507-517
  • 77 Smit J J, Schinkel A H, Oude Elferink P R. Homozygous disruption of the murine mdr2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease.  Cell . 1993;  75 451-462
  • 78 Jansen P L, Muller M. The molecular genetics of familial intrahepatic cholestasis.  Gut . 2000;  47 1-5
  • 79 Keppler D, Konig J, Buchler M. The canalicular multidrug resistance protein, cMRP/MRP2, a novel conjugate export pump expressed in the apical membrane of hepatocytes.  Adv Enzyme Regul . 1997;  37 321-333
  • 80 Meier P J, Eckhardt U, Schroeder A. Substrate specificity of sinusoidal bile acid and organic anion uptake systems in rat and human liver.  Hepatology . 1997;  26 1667-1677
  • 81 Wang R, Salem M, Yousef I M. Targeted inactivation of sister of P-glycoprotein gene (spgp) in mice results in nonprogressive but persistent intrahepatic cholestasis.  Proc Natl Acad Sci USA . 2001;  98 2011-2016
  • 82 Gerloff T, Stieger B, Hagenbuch B. The sister of P- glycoprotein represents the canalicular bile salt export pump of mammalian liver.  J Biol Chem . 1998;  273 10046-10050
  • 83 Green R M, Hoda F, Ward K L. Molecular cloning and characterization of the murine bile salt export pump.  Gene . 2000;  241 117-123
  • 84 Chiang J Y, Kimmel R, Weinberger C. Farnesoid X receptor responds to bile acids and represses cholesterol 7alpha-hydroxylase gene (CYP7A1) transcription.  J Biol Chem . 2000;  275 10918-10924
  • 85 Lu T T, Makishima M, Repa J J. Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors.  Mol Cell . 2000;  6 507-515
  • 86 Repa J J, Mangelsdorf D J. The role of orphan nuclear receptors in the regulation of cholesterol homeostasis.  Annu Rev Cell Dev Biol . 2000;  16 459-481
  • 87 Parks D J, Blanchard S G, Bledsoe R K. Bile acids: natural ligands for an orphan nuclear receptor.  Science . 1999;  284 1365-1368
  • 88 Makishima M, Okamoto A Y, Repa J J. Identification of a nuclear receptor for bile acids.  Science . 1999;  284 1362-1365
  • 89 Sinal C J, Tohkin M, Miyata M. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis.  Cell . 2000;  102 731-744
  • 90 Xie W, Radominska-Pandya A, Shi Y. An essential role for nuclear receptors SXR/PXR in detoxification of cholestatic bile acids.  Proc Natl Acad Sci USA . 2001;  98 3375-3380
  • 91 Knisely A S, Boyle J T, Naylor E W. Pancreatic disfunction in Byler disease [Abstract].  J Pediatr Gastroenterol Nutr . 1995;  21 328
  • 92 Staudinger J L, Goodwin B, Jones S A. The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity.  Proc Natl Acad Sci U S A . 2001;  98 3369-3374
  • 93 Muller M. Transcriptional control of hepatocanalicular transporter gene expression.  Semin Liver Dis . 2000;  20 323-337
  • 94 Goodwin B, Jones S A, Price R R. A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis.  Mol Cell . 2000;  6 517-526
  • 95 Castillo-Olivares A, Gil G. Role of FXR and FTF in bile acid-mediated suppression of cholesterol 7alpha-hydroxylase transcription.  Nucl Acids Res . 2000;  28 3587-3593
  • 96 Endo T, Uchida K, Amuro Y. Bile acid metabolism in benign recurrent intrahepatic cholestasis. Comparative studies on the icteric and anicteric phases of a single case.  Gastroenterology . 1979;  76 1002-1006
  • 97 Bourke B, Goggin N, Walsh D. Byler-like familial cholestasis in an extended kindred.  Arch Dis Child . 1996;  75 223-227
  • 98 Grompe M. Therapeutic liver repopulation for the treatment of metabolic liver diseases.  Hum Cell . 1999;  12 171-180
  • 99 Sundback C A, Vacanti J P. Alternatives to liver transplantation: from hepatocyte transplantation to tissue-engineered organs.  Gastroenterology . 2000;  118 438-442
  • 100 Kren B T, Metz R, Kumar R, Steer C J. Gene repair using chimeric RNA/DNA oligonucleotides.  Semin Liver Dis . 1999;  19 93-104
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