1998 Progressive Familial Intrahepatic Cholestasis Types 1, 2, And 3. GUT
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SCIENCE ALERT Progressive familial intrahepatic cholestasis types 1, 2, and 3 Comment Progressive familial intrahepatic cholestasis (PFIC) is a group of diseases characterised by cholestasis and biliary cirrhosis. Byler disease, the best known member of this group, is now also known as PFIC type 1. Byler disease is named after Jacob Byler, a farmer of Amish ancestry, who settled in Pennsylvania in the late 18th century. Patients have recurrent and later persistent cholestasis. 1 The recur- rent disease pattern is reminiscent of benign recurrent int- rahepatic cholestasis (BRIC). In contrast to BRIC, Byler disease eventually evolves into biliary cirrhosis. Clinically the disease is characterised by jaundice, steatorrhoea, reduced growth, and a relatively low to normal serum ª-glutamyltranspeptidase (ªGT) activity despite an el- evated alkaline phosphatase. Positional cloning studies in a large Byler kindred revealed a mutation in a locus at chro- mosome 18q21-q22, the FIC1 locus. 2–4 In their recent paper in Nature Genetics Bull et al suggest that this mutation aVects a member of a subfamily of P-type ATPases; other members of this subfamily seem to be involved in ATP dependent aminophospholipid transport. FIC1 is ex- pressed in several epithelial tissues and more strongly in the intestine than in the liver. Patients with this disease have high serum bile salt concentrations. Disturbed hepatobil- iary (and perhaps intestinal) transport of bile salts is the most likely cause. How this relates to a P-type ATPase, possibly mediating aminophospholipid transport, is cur- rently unknown. As expected, BRIC is genetically related to Byler disease as FIC1 is also mutated in BRIC patients, confirming earlier reports. 4–6 Another form of PFIC, PFIC type 2, is characterised by persistent neonatal cholestasis with histological features of neonatal hepatitis and later biliary cirrhosis. Serum bile acid concentrations and alkaline phosphatase activities are elevated and the serum ªGT activity is normal. Strautnieks et al suggest that the gene defect for this disease is located in a locus at chromosome 2q24, the FIC2 locus. 7 This dis- ease probably also results from a defect of hepatobiliary bile salt transport. A recently cloned candidate protein for the canalicular bile salt transporter belongs to the P-glycoprotein family and is called “the sister of P-glycoprotein”. Interestingly this protein is encoded by a gene on chromosome 2q24. de Vree and associates have characterised a third type of PFIC, PFIC type 3. This disease presents with recurrent pruritus or jaundice in the first months of life and then progresses to biliary cirrhosis. In contrast to patients with PFIC types 1 or 2, these patients have a high serum ªGT activity. Oude Elferink’s and Borst’s groups have been involved in the development of the mdr2 knockout mouse. 8 In this model there is no phospholipid transport from liver to bile. Mdr2 in rodents, known as MDR3 in humans, has been characterised as a phospholipid translocator, mediat- ing the transfer of phosphatidylcholine from the inner leaf- let of the canalicular membrane to the outer leaflet. 9 A functional bile salt transporter is needed for the transfer of phospholipids from the membrane into the bile as the extraction of phospholipids from the canalicular mem- brane is mediated by bile salts. 10 Mdr2 knockout mice pro- duce bile in which phospholipids are low to absent and the Bull LN, van Eijk MJT, Pawlikowska L, et al. A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis. Nat Genet 1998;18:219–24. Abstract Cholestasis, or impaired bile flow, is an important but poorly understood manifestation of liver disease. Two clinically distinct forms of inherited cholestasis, benign recurrent cholestasis (BRIC) and progressive familial intrahepatic cholestasis type 1 (PFIC1), were previously mapped to 18q21. Haplotype analy- sis narrowed the candidate region for both diseases to the same interval of less than 1 cM, in which we identified a gene mutated in BRIC and PFIC1 patients. This gene (called FIC1) is the first identi- fied human member of a recently described sub- family of P-type ATPases; ATP-dependent amino- phospholipid transport is the previously described function of members of this subfamily. FIC1 is expressed in several epithelial tissues and, surpris- ingly, more strongly in the small intestine than in the liver. Its protein product is likely to play an essential role in enterohepatic circulation of bile acids; further characterization of FIC1 will facilitate understanding of normal bile formation and cholestasis. de Vree JML, Jacquemin E, Strum E, et al. Mutations in the MDR3 gene cause progressive familal intrahepatic cholestasis. Proc Natl Acad Sci 1998;95:282–7. Abstract Class III multidrug resistance (MDR) P-glyco- proteins (P-gp), mdr2 in mice and MDR3 in man, mediate the translocation of phophatidylcholine across the canalicular membrane of the hepatocyte. Mice with a disrupted mdr2 gene completely lack biliary phopholipid excretion and develop progres- sive liver disease, characterized histologically by portal inflammation, proliferation of the bile duct epithelium, and fibrosis. The disease phenotype is very similar to a subtype of progressive familial int- rahepatic cholestasis, hallmarked by a high serum ª-glutamyltransferase (ª-GT) activity. We report immunohistochemistry for MDR3 P-gp, reverse transcription-coupled PCR sequence analysis, and genomic DNA analysis of MDR3 from two progres- sive familial intrahepatic cholestasis patients with high serum ª-GT. Canalicular staining for MDR3 P-gp was negative in the liver tissue of both patients. Reverse transcription-coupled PCR sequencing of the first patient’s sequence demonstrated a ho- mozygous 7-bp deletion, starting at codon 132, which results in a frameshift and introduces a stop codon 29 codons downstream. The second patient is ho- mozygous for a nonsense mutation in codon 957 (C → T) that introduces a stop codon (TGA). Our results demonstrate that mutations in the human MDR3 gene lead to progressive familial intrahepatic cholestasis with high serum ª-GT. The histopatho- logical picture in these patients is very similar to that in the corresponding mdr2(-/-) mouse, in which mdr2 P-gp deficiency induces complete absence of phospholipid in bile. 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Transcript of 1998 Progressive Familial Intrahepatic Cholestasis Types 1, 2, And 3. GUT
SCIENCE ALERT
Progressive familial intrahepatic cholestasis types 1, 2, and 3
CommentProgressive familial intrahepatic cholestasis (PFIC) is agroup of diseases characterised by cholestasis and biliarycirrhosis. Byler disease, the best known member of thisgroup, is now also known as PFIC type 1. Byler disease isnamed after Jacob Byler, a farmer of Amish ancestry, whosettled in Pennsylvania in the late 18th century. Patientshave recurrent and later persistent cholestasis.1 The recur-rent disease pattern is reminiscent of benign recurrent int-rahepatic cholestasis (BRIC). In contrast to BRIC, Bylerdisease eventually evolves into biliary cirrhosis. Clinicallythe disease is characterised by jaundice, steatorrhoea,reduced growth, and a relatively low to normal serumã-glutamyltranspeptidase (ãGT) activity despite an el-evated alkaline phosphatase. Positional cloning studies in alarge Byler kindred revealed a mutation in a locus at chro-mosome 18q21-q22, the FIC1 locus.2–4 In their recentpaper inNature Genetics Bull et al suggest that this mutationaVects a member of a subfamily of P-type ATPases; othermembers of this subfamily seem to be involved in ATPdependent aminophospholipid transport. FIC1 is ex-pressed in several epithelial tissues and more strongly in theintestine than in the liver. Patients with this disease havehigh serum bile salt concentrations. Disturbed hepatobil-iary (and perhaps intestinal) transport of bile salts is themost likely cause. How this relates to a P-type ATPase,possibly mediating aminophospholipid transport, is cur-rently unknown. As expected, BRIC is genetically relatedto Byler disease as FIC1 is also mutated in BRIC patients,confirming earlier reports.4–6
Another form of PFIC, PFIC type 2, is characterised bypersistent neonatal cholestasis with histological features ofneonatal hepatitis and later biliary cirrhosis. Serum bileacid concentrations and alkaline phosphatase activities areelevated and the serum ãGT activity is normal. Strautniekset al suggest that the gene defect for this disease is locatedin a locus at chromosome 2q24, the FIC2 locus.7 This dis-ease probably also results from a defect of hepatobiliarybile salt transport. A recently cloned candidate protein forthe canalicular bile salt transporter belongs to theP-glycoprotein family and is called “the sister ofP-glycoprotein”. Interestingly this protein is encoded by agene on chromosome 2q24.de Vree and associates have characterised a third type of
PFIC, PFIC type 3. This disease presents with recurrentpruritus or jaundice in the first months of life and thenprogresses to biliary cirrhosis. In contrast to patients withPFIC types 1 or 2, these patients have a high serum ãGTactivity. Oude Elferink’s and Borst’s groups have beeninvolved in the development of the mdr2 knockout mouse.8
In this model there is no phospholipid transport from liverto bile. Mdr2 in rodents, known as MDR3 in humans, hasbeen characterised as a phospholipid translocator, mediat-ing the transfer of phosphatidylcholine from the inner leaf-let of the canalicular membrane to the outer leaflet.9 Afunctional bile salt transporter is needed for the transfer ofphospholipids from the membrane into the bile as theextraction of phospholipids from the canalicular mem-brane is mediated by bile salts.10 Mdr2 knockout mice pro-duce bile in which phospholipids are low to absent and the
Bull LN, van Eijk MJT, Pawlikowska L, et al. A geneencoding a P-type ATPase mutated in two forms ofhereditary cholestasis.Nat Genet 1998;18:219–24.
AbstractCholestasis, or impaired bile flow, is an importantbut poorly understood manifestation of liver disease.Two clinically distinct forms of inherited cholestasis,benign recurrent cholestasis (BRIC) and progressivefamilial intrahepatic cholestasis type 1 (PFIC1),were previously mapped to 18q21. Haplotype analy-sis narrowed the candidate region for both diseasesto the same interval of less than 1 cM, in which weidentified a gene mutated in BRIC and PFIC1patients. This gene (called FIC1) is the first identi-fied human member of a recently described sub-family of P-type ATPases; ATP-dependent amino-phospholipid transport is the previously describedfunction of members of this subfamily. FIC1 isexpressed in several epithelial tissues and, surpris-ingly, more strongly in the small intestine than in theliver. Its protein product is likely to play an essentialrole in enterohepatic circulation of bile acids;further characterization of FIC1 will facilitateunderstanding of normal bile formation andcholestasis.
de Vree JML, Jacquemin E, Strum E, et al. Mutations inthe MDR3 gene cause progressive familal intrahepaticcholestasis. Proc Natl Acad Sci 1998;95:282–7.
AbstractClass III multidrug resistance (MDR) P-glyco-proteins (P-gp), mdr2 in mice and MDR3 in man,mediate the translocation of phophatidylcholineacross the canalicular membrane of the hepatocyte.Mice with a disrupted mdr2 gene completely lackbiliary phopholipid excretion and develop progres-sive liver disease, characterized histologically byportal inflammation, proliferation of the bile ductepithelium, and fibrosis. The disease phenotype isvery similar to a subtype of progressive familial int-rahepatic cholestasis, hallmarked by a high serumã-glutamyltransferase (ã-GT) activity. We reportimmunohistochemistry for MDR3 P-gp, reversetranscription-coupled PCR sequence analysis, andgenomic DNA analysis of MDR3 from two progres-sive familial intrahepatic cholestasis patients withhigh serum ã-GT. Canalicular staining for MDR3P-gp was negative in the liver tissue of both patients.Reverse transcription-coupled PCR sequencing ofthe first patient’s sequence demonstrated a ho-mozygous 7-bp deletion, starting at codon 132, whichresults in a frameshift and introduces a stop codon 29codons downstream. The second patient is ho-mozygous for a nonsensemutation in codon 957 (C→T) that introduces a stop codon (TGA). Our resultsdemonstrate that mutations in the human MDR3gene lead to progressive familial intrahepaticcholestasis with high serum ã-GT. The histopatho-logical picture in these patients is very similar to thatin the corresponding mdr2(−/−) mouse, in whichmdr2 P-gp deficiency induces complete absence ofphospholipid in bile.
Gut 1998;42:766–767766
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bile salt concentration is normal. As reported earlier by DeLeuze et al, patients with PFIC type 3 also produce bile saltcontaining bile without phospholipids.11 The histologicalabnormalities of these patients and the knockout mice areremarkably similar. They consist of periportal inflamma-tion, extensive bile duct proliferation, feathery degenera-tion of hepatocytes, fibrosis and, in the knockout mice, livermalignancy. The hypothesis is that this histological pictureresults from the cytotoxicity of bile salts which in normalbile is antagonised by phospholipids.The two patients described by de Vree et al lack MDR3
in the liver. RT-PCR revealed homozygous mutations intheMDR3mRNA.Genomic DNA analysis of their parentsshowed that they are heterozygous for this mutation. A sis-ter of one of the patients is homozygous normal and sodoes not have the disease. It is interesting that the motherof one of these patients had recurrent episodes of cholesta-sis during pregnancy, suggesting that the heterozygousstate may be associated with this condition. Neither of thepatients responded to treatment with ursodeoxycholic acid(UDCA). The authors speculate that patients with thecomplete MDR3 defect do not respond to UDCA whereasthose who do (about 50% with this disease) have a partialdefect.Will the patients or their families benefit from these
findings? One positive outcome is that prenatal diagnosis infamilies with an aVected child is now potentially possible.As for gene therapy, it is too early to speculate but areasonable idea is that diseases which have with a recurrentdisease pattern, such as PFIC-1 and PFIC-3, may be ame-nable to gene therapy if the functional gene can be givenbefore the liver becomes too cirrhotic. Finally, PFIC-2 andPFIC-3 are probably true liver diseases as the proposedmolecular defects aVect proteins which are expressed pre-
dominantly in the liver. PFIC-1 is thought to be caused bya defective protein which resides in the liver and which iseven more highly expressed in the intestine. Livertransplantation in patients with PFIC-1 may only be partlycorrective; persistent diarrhoea has indeed been reportedin transplanted children with this disease.
P L M JANSENMMMÜLLER
Department of Hepatology and Gastroenterology,University Hospital Groningen,PO Box 30.001,9700 RB Groninigen, The Netherlands
1 Clayton RJ, Iber FL, Ruebner BH, et al. Byler disease. Fatal familial intrahe-patic cholestasis in an Amish kindred. Am J Dis Child 1969;117:112–24.
2 Bull LN,Carlton VE, Stricker NL, et al. Genetic and morphological findingsin progressive familial intrahepatic cholestasis (Byler disease [PFIC-1] andByler syndrome): evidence for heterogeneity.Hepatology 1997;26:155–64.
3 Strautnieks SS, Kagalwalla AF, Tanner MS, et al. Locus heterogeneity inprogressive familial intrahepatic cholestasis. J Med Genet 1996;33:833–6.
4 Carlton VE, Knisely AS, Freimer NB. Mapping of a locus for progressivefamilial intrahepatic cholestasis (Byler disease) to 18q21-q22, the benignrecurrent intrahepatic cholestasis region.Hum Mol Genet 1995;4:1049–53.
5 Houwen RHJ, Baharloo S, Blankenship K, et al. Genome screening bysearching for shared segments: mapping a gene for benign recurrent intra-hepatic cholestasis. Nat Genet 1994;8:380–6.
6 Sinke RJ, Carlton VEH, Juijn JA, et al. Benign recurrent intrahepaticcholestasis (BRIC): evidence of genetic heterogeneity and delimitation ofthe BRIC locus to a 7-cM interval between D18S69 and D18S64. HumGenet 1997;100:382–7.
7 Strautnieks SS, Kagalwalla AF, Tanner MS, et al. Identification of a locus forprogressive familial intrahepatic cholestasis PFIC2 on chromosome 2q24.Am J Hum Genet 1997;61:630–3.
8 Smit JJ, Schinkel AH, Oude Elferink RPJ, et al. Homozygous disruption ofthe murine mdr2 P-glycoprotein gene leads to a complete absence of phos-pholipid from bile and to liver disease. Cell 1993;75:451–62.
9 Crawford AR, Smith AJ, Hatch VC, et al. Hepatic secretion of phospholipidvesicles in the mouse critically depends on mdr2 or MDR3 P-glycoproteinexpression. Visualization by electron microscopy. J Clin Invest 1997;100:2562–7.
10 Frijters CM, OttenhoV R, van Wijland MJ, et al. Regulation of mdr2P-glycoprotein expression by bile salts. Biochem J 1997;321:389–95.
11 Deleuze JF, Jacquemin E,Dubuisson C, et al. Defect of multidrug-resistance3 gene expression in a subtype of progressive familial intrahepatic cholesta-sis.Hepatology 1996;23:904–8.
Progressive familial intrahepatic cholestasis types 1, 2, and 3 767
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doi: 10.1136/gut.42.6.766 1998 42: 766-767Gut
P L M JANSEN and M M MÜLLER types 1, 2, and 3Progressive familial intrahepatic cholestasis
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