Combined Mutations of Canalicular Transporter Proteins Cause Severe Intrahepatic Cholestasis of Pregnancy
2006; Elsevier BV; Volume: 131; Issue: 2 Linguagem: Inglês
10.1053/j.gastro.2006.05.003
ISSN1528-0012
AutoresVerena Keitel, Christoph Vogt, Dieter Häussinger, Ralf Kubitz,
Tópico(s)Pediatric Hepatobiliary Diseases and Treatments
ResumoIntrahepatic cholestasis of pregnancy (ICP) is a cholestatic disorder that usually develops in the third trimester of pregnancy and persists until delivery. The cause of ICP remains elusive, but there is evidence that mutations in the canalicular ABC transporter phospholipid flippase (MDR3) and in the bile salt export pump (BSEP) can predispose for the development of ICP. MDR3 and BSEP were investigated by gene sequencing and immunofluorescence microscopy in a patient with severe ICP of early onset. ICP was diagnosed in a patient in the first trimester of pregnancy with severe pruritus, elevated levels of bile salts, and 48-fold elevation of transaminase levels. A liver biopsy specimen showed diminished canalicular expression of the bile salt export pump BSEP, while the expression and localization of the phospholipid flippase MDR3 was normal. Gene sequencing revealed a homozygous MDR3 gene mutation (S320F). The patient was also homozygous for the common BSEP polymorphism V444A. Treatment with ursodeoxycholate normalized transaminase levels but could not prevent further elevation of bile salt levels and preterm delivery. The combined homozygous alterations of the canalicular transporters may explain the early onset and severity of ICP in this patient. The common BSEP polymorphism V444A accounts for the reduced canalicular BSEP expression. Reduced bile salt secretion through BSEP may explain the persistence of elevated bile salt levels and incomplete efficacy of ursodeoxycholate treatment. Intrahepatic cholestasis of pregnancy (ICP) is a cholestatic disorder that usually develops in the third trimester of pregnancy and persists until delivery. The cause of ICP remains elusive, but there is evidence that mutations in the canalicular ABC transporter phospholipid flippase (MDR3) and in the bile salt export pump (BSEP) can predispose for the development of ICP. MDR3 and BSEP were investigated by gene sequencing and immunofluorescence microscopy in a patient with severe ICP of early onset. ICP was diagnosed in a patient in the first trimester of pregnancy with severe pruritus, elevated levels of bile salts, and 48-fold elevation of transaminase levels. A liver biopsy specimen showed diminished canalicular expression of the bile salt export pump BSEP, while the expression and localization of the phospholipid flippase MDR3 was normal. Gene sequencing revealed a homozygous MDR3 gene mutation (S320F). The patient was also homozygous for the common BSEP polymorphism V444A. Treatment with ursodeoxycholate normalized transaminase levels but could not prevent further elevation of bile salt levels and preterm delivery. The combined homozygous alterations of the canalicular transporters may explain the early onset and severity of ICP in this patient. The common BSEP polymorphism V444A accounts for the reduced canalicular BSEP expression. Reduced bile salt secretion through BSEP may explain the persistence of elevated bile salt levels and incomplete efficacy of ursodeoxycholate treatment. Intrahepatic cholestasis of pregnancy (ICP) occurs to a varying degree depending on ethnicity. While ICP affects <1% of pregnancies in western Europe, an ICP incidence of 28% was reported in pregnant women of Araucanian Indian origin.1Lammert F. Marschall H.U. Glantz A. Matern S. Intrahepatic cholestasis of pregnancy molecular pathogenesis, diagnosis and management.J Hepatol. 2000; 33: 1012-1021Abstract Full Text Full Text PDF PubMed Scopus (353) Google Scholar ICP usually develops during the third trimester of pregnancy. The most common symptom of ICP is pruritus, which is accompanied by jaundice in up to 20%. Rarely, the mother’s peripartum morbidity increases due to ICP-associated coagulopathy. Otherwise, symptoms of ICP resolve spontaneously within 2 days to 2 weeks after delivery. However, ICP is associated with an increased fetal risk, such as meconium-stained amniotic fluid in 25%,2Rioseco A.J. Ivankovic M.B. Manzur A. Hamed F. Kato S.R. Parer J.T. Germain A.M. Intrahepatic cholestasis of pregnancy a retrospective case-control study of perinatal outcome.Am J Obstet Gynecol. 1994; 170: 890-895Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar prematurity in 12%,2Rioseco A.J. Ivankovic M.B. Manzur A. Hamed F. Kato S.R. Parer J.T. Germain A.M. Intrahepatic cholestasis of pregnancy a retrospective case-control study of perinatal outcome.Am J Obstet Gynecol. 1994; 170: 890-895Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar and intrauterine fetal death in up to 7%.3Williamson C. Hems L.M. Goulis D.G. Walker I. Chambers J. Donaldson O. Swiet M. Johnston D.G. Clinical outcome in a series of cases of obstetric cholestasis identified via a patient support group.BJOG. 2004; 111: 676-681Crossref PubMed Scopus (152) Google Scholar Increased bile salt concentrations are found in 90% of patients with ICP and represent the most sensitive parameter in the diagnosis of ICP. Liver enzyme levels typically increase moderately but may increase more than 10-fold in 40% of cases in selected groups.4Bacq Y. Sapey T. Brechot M.C. Pierre F. Fignon A. Dubois F. Intrahepatic cholestasis of pregnancy a French prospective study.Hepatology. 1997; 26: 358-364Crossref PubMed Scopus (226) Google Scholar An increase of 20-fold in a single case was the highest value reported so far.5Gendrot C. Bacq Y. Brechot M.C. Lansac J. Andres C. A second heterozygous MDR3 nonsense mutation associated with intrahepatic cholestasis of pregnancy.J Med Genet. 2003; 40: e32Crossref PubMed Scopus (71) Google Scholar Here we describe a woman with exceptionally high transaminase levels due to ICP.Case ReportA 26-year-old woman of Moroccan descent developed severe pruritus in the ninth week of her first pregnancy. Pruritus was also induced 3 years earlier by the contraceptive pill, necessitating immediate discontinuation. The patient had no history of abdominal pain, gallstone disease, abdominal surgery, fever, or infections.Her mother gave birth to 4 children and had pruritus during the third trimester of 3 pregnancies; one birth was preterm. The patient’s aunt (sister of the mother) has one child and also had a history of third-trimester pruritus and premature birth.At first presentation (ninth week of gestation), laboratory test results were as follows (normal values in parentheses): total serum bilirubin level, 2.25 mg/dL (<1.1 mg/dL), aspartate aminotransferase level, 70 U/L (<31 U/L), alanine aminotransferase level, 236 U/L (<35 U/L); γ-glutamyltransferase level, 60 U/L (<38 U/L); total serum bile salt concentration, 98 μmol/L (<8 μmol/L). The peak increase of alanine aminotransferase level was 48 times greater than normal (1704 U/L) at gestational week 13, which is the uppermost increase in a patient with ICP reported so far. Toward the end of pregnancy, the maximum concentration of bile salts was 202 μmol/L, which is a 25-fold increase in the upper normal value (Figure 1).All other common serologic parameters associated with liver diseases were normal (ferritin, transferrin, α1-antitrypsin, ceruloplasmin, cytoplasmic antineutrophilic cytoplasmic antibody, perinuclear antineutrophilic cytoplasmic antibody, antinuclear antibodies, anti-smooth muscle antibodies, LKM1 antibody, antimitochondrial antibody M2, and gliadin antibodies). Virologic and bacteriologic tests were negative (hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis E virus, adenovirus, Epstein-Barr virus, herpes simplex type 1 virus, herpes simplex type 2 virus, cytomegalovirus, varicella zoster virus, measles, mumps, rubella, parvovirus B19, human immunodeficiency virus, Brucella, Coxiella, and Leptospira).On abdominal ultrasound (11th week of pregnancy), the liver was of normal size and consistency. There were no gallstones, dilation of extrahepatic or intrahepatic bile ducts, signs of portal hypertension, or other vascular abnormalities.Genetic AnalysisSequencing of all coding exons and exon-intron boundaries of MDR3 and BSEP revealed a nonsynonymous homozygous mutation in each gene (compared with the reference sequences NM_000443 for MDR3 and AF091582 for BSEP). A single nucleotide exchange from cytidine to thymidine at position 959 in exon 9 of MDR3 (959C→T) led to a change from serine to phenylalanine (S320F) (Figure 2A), which has been described to be ICP specific.6Pauli-Magnus C. Lang T. Meier Y. Zodan-Marin T. Jung D. Breymann C. Zimmermann R. Kenngott S. Beuers U. Reichel C. Kerb R. Penger A. Meier P.J. Kullak-Ublick G.A. Sequence analysis of bile salt export pump (ABCB11) and multidrug resistance p-glycoprotein 3 (ABCB4, MDR3) in patients with intrahepatic cholestasis of pregnancy.Pharmacogenetics. 2004; 14: 91-102Crossref PubMed Scopus (231) Google Scholar The second homozygous polymorphism was detected in the BSEP gene at the complementary DNA position 1331 with a thymidine replaced by a cytidine (1331T→C), leading to an exchange of valine to alanine (V444A) (Figure 2B). This polymorphism is very frequent in the white population.6Pauli-Magnus C. Lang T. Meier Y. Zodan-Marin T. Jung D. Breymann C. Zimmermann R. Kenngott S. Beuers U. Reichel C. Kerb R. Penger A. Meier P.J. Kullak-Ublick G.A. Sequence analysis of bile salt export pump (ABCB11) and multidrug resistance p-glycoprotein 3 (ABCB4, MDR3) in patients with intrahepatic cholestasis of pregnancy.Pharmacogenetics. 2004; 14: 91-102Crossref PubMed Scopus (231) Google Scholar It has also been detected in the Japanese population7Saito S. Iida A. Sekine A. Miura Y. Ogawa C. Kawauchi S. Higuchi S. Nakamura Y. Three hundred twenty-six genetic variations in genes encoding nine members of ATP-binding cassette, subfamily B (ABCB/MDR/TAP), in the Japanese population.J Hum Genet. 2002; 47: 38-50Crossref PubMed Scopus (82) Google Scholar and was found in a patient with benign recurrent intrahepatic cholestasis (BRIC).8Kubitz R. Keitel V. Scheuring S. Köhrer K. Häussinger D. Benign recurrent intrahepatic cholestasis associated with mutations of the bile salt export pump (BSEP).J Clin Gastroenterol. 2006; 40: 171-175Crossref PubMed Scopus (74) Google ScholarFigure 2Topology models of MDR3 and BSEP. Amino acid sequences were derived from NP_000434.1 (MDR3) and NP_003733.1 (BSEP). Transmembrane domains were estimated according to Tusnády (http://www.enzim.hu/hmmtop/index.html). Topology models were drawn by the use of the transmembrane protein display software TOPO2 by S. J. Johns (http://www.sacs.ucsf.edu/TOPO/topo.html). The mutations found in this patient are within the fifth transmembrane domain (MDR3, S320F) and in the nucleotide binding fold (BSEP, V444A). The relevant sequences from the patient, her mother, and aunt are shown.View Large Image Figure ViewerDownload (PPT)Furthermore, 2 synonymous single nucleotide polymorphisms (SNPs) within the BSEP gene were detected in our patient. The SNP 3084A→G (A1028A) was found on one allele and has been reported recently,6Pauli-Magnus C. Lang T. Meier Y. Zodan-Marin T. Jung D. Breymann C. Zimmermann R. Kenngott S. Beuers U. Reichel C. Kerb R. Penger A. Meier P.J. Kullak-Ublick G.A. Sequence analysis of bile salt export pump (ABCB11) and multidrug resistance p-glycoprotein 3 (ABCB4, MDR3) in patients with intrahepatic cholestasis of pregnancy.Pharmacogenetics. 2004; 14: 91-102Crossref PubMed Scopus (231) Google Scholar, 7Saito S. Iida A. Sekine A. Miura Y. Ogawa C. Kawauchi S. Higuchi S. Nakamura Y. Three hundred twenty-six genetic variations in genes encoding nine members of ATP-binding cassette, subfamily B (ABCB/MDR/TAP), in the Japanese population.J Hum Genet. 2002; 47: 38-50Crossref PubMed Scopus (82) Google Scholar, 8Kubitz R. Keitel V. Scheuring S. Köhrer K. Häussinger D. Benign recurrent intrahepatic cholestasis associated with mutations of the bile salt export pump (BSEP).J Clin Gastroenterol. 2006; 40: 171-175Crossref PubMed Scopus (74) Google Scholar while the SNP 2907G→A (K969K) was homozygous and has not been described before.The patient’s mother and aunt (the mother’s sister) were heterozygous for the MDR3 mutation S320F. The mother was heterozygous for the BSEP polymorphism V444A, while the aunt was homozygous for V444A (Figure 2).Liver BiopsyStandard histologic analysis of a liver needle biopsy specimen (taken in the 11th week of pregnancy) revealed mild cholestasis, minimal portal inflammation, and single cell necrosis in zone 3. No Mallory or Councilman bodies, siderosis, steatosis, fibrosis, cirrhosis, or signs of viral hepatitis were found.Two anti-human BSEP antibodies, K249Noe J. Stieger B. Meier P.J. Functional expression of the canalicular bile salt export pump of human liver.Gastroenterology. 2002; 123: 1659-1666Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar and K168,10Keitel V. Burdelski M. Warskulat U. Kühlkamp T. Keppler D. Häussinger D. Kubitz R. Expression and localization of hepatobiliary transport proteins in progressive familial intrahepatic cholestasis.Hepatology. 2005; 41: 1160-1172Crossref PubMed Scopus (204) Google Scholar directed against the C-terminus and the linker regions of BSEP, respectively, showed a very weak canalicular staining (as compared with normal human liver tissue) despite a normal canalicular staining pattern of other canalicular transporter proteins such as MRP2 (Figure 3). Despite the homozygous MDR3 mutation, the anti-MDR3 antibody P3II26 (Alexis) revealed a normal canalicular expression pattern (Figure 3).Figure 3Immunofluorescence staining of BSEP in liver slices. In control livers, BSEP (A, K24; B, K168; red), MDR3 (green), and the multidrug resistance-related protein 2 (MRP2, green) were all strongly expressed and colocalized at the canalicular membrane. In the patient’s liver MDR3 immunofluorescence (green) was normal, while BSEP immunoreactivity (K24 and K168; red) was markedly reduced. Bars = 10 μm.View Large Image Figure ViewerDownload (PPT)In the course of the disease, the patient was treated with cholestyramine 2 g three times daily and ursodeoxycholate 500 mg twice daily. Transaminases decreased to normal values (Figure 1), while bile salt concentrations increased gradually to ∼200 μmol/L. Pruritus was only transiently alleviated. It persisted until delivery despite treatment.In the 35th week of pregnancy, the patient had a preterm rupture of membranes, followed by a spontaneous delivery of a healthy, well-developed female infant with an Apgar score of 8/8/9. Ursodeoxycholate treatment was discontinued immediately after birth, and a transient increase in liver enzyme levels was observed (Figure 1). However, serum bile salt and bilirubin levels returned to normal within 4 weeks and pruritus ceased, thus corroborating the diagnosis of ICP.DiscussionICP is a frequent disorder with low maternal morbidity but increased fetal risk. Pruritus during pregnancy is the leading symptom in the diagnosis of ICP, which can be confirmed by increased serum bile salt levels in the absence of other hepatobiliary diseases.The observation that mothers from patients with progressive familial intrahepatic cholestasis type 3 (PFIC-3, a severe form of inherited cholestasis) experienced ICP11De Vree J.M. Jacquemin E. Sturm E. Cresteil D. Bosma P.J. Aten J. Deleuze J.F. Desrochers M. Burdelski M. Bernard O. Oude Elferink R.P. Hadchouel M. Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis.Proc Natl Acad Sci U S A. 1998; 95: 282-287Crossref PubMed Scopus (627) Google Scholar led to the assumption of a genetic background of ICP. Apart from the MDR3 gene, the BSEP gene has also been associated with ICP.12Eloranta M.L. Hakli T. Hiltunen M. Helisalmi S. Punnonen K. Heinonen S. Association of single nucleotide polymorphisms of the bile salt export pump gene with intrahepatic cholestasis of pregnancy.Scand J Gastroenterol. 2003; 38: 648-652Crossref PubMed Scopus (80) Google Scholar In a recent study, 21 women with ICP were screened for MDR3 and BSEP mutations and were compared with 40 women with normal pregnancies. Two ICP-specific nonsynonymous SNPs were detected in the MDR3 gene (S320F and G762E).6Pauli-Magnus C. Lang T. Meier Y. Zodan-Marin T. Jung D. Breymann C. Zimmermann R. Kenngott S. Beuers U. Reichel C. Kerb R. Penger A. Meier P.J. Kullak-Ublick G.A. Sequence analysis of bile salt export pump (ABCB11) and multidrug resistance p-glycoprotein 3 (ABCB4, MDR3) in patients with intrahepatic cholestasis of pregnancy.Pharmacogenetics. 2004; 14: 91-102Crossref PubMed Scopus (231) Google Scholar In the BSEP gene, one ICP-specific SNP was found (N591S).6Pauli-Magnus C. Lang T. Meier Y. Zodan-Marin T. Jung D. Breymann C. Zimmermann R. Kenngott S. Beuers U. Reichel C. Kerb R. Penger A. Meier P.J. Kullak-Ublick G.A. Sequence analysis of bile salt export pump (ABCB11) and multidrug resistance p-glycoprotein 3 (ABCB4, MDR3) in patients with intrahepatic cholestasis of pregnancy.Pharmacogenetics. 2004; 14: 91-102Crossref PubMed Scopus (231) Google Scholar Another nucleotide exchange from T to C at position 1331 of the BSEP complementary DNA results in an exchange from valine to alanine (V444A). This exchange is detected in 51.3% of alleles of healthy women, while it was found in 83.3% of alleles of patients with ICP.6Pauli-Magnus C. Lang T. Meier Y. Zodan-Marin T. Jung D. Breymann C. Zimmermann R. Kenngott S. Beuers U. Reichel C. Kerb R. Penger A. Meier P.J. Kullak-Ublick G.A. Sequence analysis of bile salt export pump (ABCB11) and multidrug resistance p-glycoprotein 3 (ABCB4, MDR3) in patients with intrahepatic cholestasis of pregnancy.Pharmacogenetics. 2004; 14: 91-102Crossref PubMed Scopus (231) Google Scholar This difference in allele frequency was not statistically significant; however, the association of V444A with ICP suggests that this mutation may become disease relevant under certain conditions such as pregnancy.The patient described in this report was homozygous for V444A. The reduced amount of canalicular BSEP implies that homozygous V444A has a major impact on bile formation despite its frequent occurrence in the healthy population. Loss of BSEP from the canalicular membrane may contribute to increased plasma bile salt concentrations, which result in pruritus and elevated liver enzyme levels due to bile salt toxicity.We have recently described a 16-year-old male patient8Kubitz R. Keitel V. Scheuring S. Köhrer K. Häussinger D. Benign recurrent intrahepatic cholestasis associated with mutations of the bile salt export pump (BSEP).J Clin Gastroenterol. 2006; 40: 171-175Crossref PubMed Scopus (74) Google Scholar with BRIC-2.13van Mil S.W. van der Woerd W.L. van der Brugge G. Sturm E. Jansen P.L. Bull L.N. van den Berg I. Berger R. Houwen R.H. Klomp L.W. Benign recurrent intrahepatic cholestasis type 2 is caused by mutations in ABCB11.Gastroenterology. 2004; 127: 379-384Abstract Full Text Full Text PDF PubMed Scopus (282) Google Scholar He was compound heterozygous for the BSEP mutations E186G and V444A. This patient also had reduced canalicular BSEP expression, emphasizing the association between the common variant V444A and a decrease in canalicular BSEP.In the patient described in this study, BSEP messenger RNA was not determined due to lack of material and it cannot be excluded that decreased BSEP messenger RNA accounts for the decrease in protein amounts. However, in the patient with BRIC-2 described previously8Kubitz R. Keitel V. Scheuring S. Köhrer K. Häussinger D. Benign recurrent intrahepatic cholestasis associated with mutations of the bile salt export pump (BSEP).J Clin Gastroenterol. 2006; 40: 171-175Crossref PubMed Scopus (74) Google Scholar with the E186G/V444A genotype, the amount of BSEP messenger RNA was normal despite reduced canalicular BSEP expression. Furthermore, in a study of 5 patients with PFIC-2, BSEP protein was absent from the canaliculi despite normal BSEP messenger RNA levels.10Keitel V. Burdelski M. Warskulat U. Kühlkamp T. Keppler D. Häussinger D. Kubitz R. Expression and localization of hepatobiliary transport proteins in progressive familial intrahepatic cholestasis.Hepatology. 2005; 41: 1160-1172Crossref PubMed Scopus (204) Google Scholar Therefore, possibilities other than transcriptional down-regulation must be considered as the underlying reason for reduced amounts of BSEP protein in our patient. These possibilities include impaired protein maturation leading to increased ER-associated degradation as shown for some frequent BSEP mutations underlying PFIC-2.14Hayashi H. Takada T. Suzuki H. Akita H. Sugiyama Y. Two common PFIC2 mutations are associated with the impaired membrane trafficking of BSEP/ABCB11.Hepatology. 2005; 41: 916-924Crossref PubMed Scopus (110) Google Scholar Furthermore, an increased retention of BSEP within the secretory pathway15Kubitz R. Sütfels G. Kühlkamp T. Kölling R. Häussinger D. Trafficking of the bile salt export pump from the Golgi to the canalicular membrane is regulated by the p38 MAP kinase.Gastroenterology. 2004; 126: 541-553Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar or reduced accessibility of BSEP from intracellular pools16Kipp H. Pichetshote N. Arias I.M. Transporters on demand. Intrahepatic pools of canalicular ATP binding cassette transporters in rat liver.J Biol Chem. 2001; 276: 7218-7224Crossref PubMed Scopus (164) Google Scholar may be the result of the V444A polymorphism. Moreover, an increased vesicular retrieval as described in animal models of cholestasis17Kubitz R. Saha N. Kühlkamp T. Dutta S. vom Dahl S. Wettstein M. Häussinger D. Ca2+-dependent protein kinase C isoforms induce cholestasis in rat liver.J Biol Chem. 2004; 279: 10323-10330Crossref PubMed Scopus (60) Google Scholar could reduce the amount of canalicular BSEP. This mechanism was also identified in estradiol-induced cholestasis in the rat,18Crocenzi F.A. Mottino A.D. Cao J. Veggi L.M. Pozzi E.J. Vore M. Coleman R. Roma M.G. Estradiol-17beta-D-glucuronide induces endocytic internalization of Bsep in rats.Am J Physiol Gastrointest Liver Physiol. 2003; 285: G449-G459PubMed Google Scholar which may serve as a model of ICP. Increased internalization may eventually result in degradation of BSEP. In addition to changes in protein localization, V444A may alter transport activity as described recently for 2 BRIC-associated BSEP mutations (R432T and E297G).19Noe J. Kullak-Ublick G.A. Jochum W. Stieger B. Kerb R. Haberl M. Mullhaupt B. Meier P.J. Pauli-Magnus C. Impaired expression and function of the bile salt export pump due to three novel ABCB11 mutations in intrahepatic cholestasis.J Hepatol. 2005; 43: 536-543Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar Another possibility of reduced transporter activity includes an increased susceptibility of V444A toward the inhibitory effect of estrogens.20Stieger B. Fattinger K. Madon J. Kullak-Ublick G.A. Meier P.J. Drug- and estrogen-induced cholestasis through inhibition of the hepatocellular bile salt export pump (Bsep) of rat liver.Gastroenterology. 2000; 118: 422-430Abstract Full Text Full Text PDF PubMed Scopus (491) Google ScholarHomozygous V444A can be expected in 25% of the population, but homozygous V444A alone cannot explain the severity of ICP in our patient. Indeed, our patient presented another homozygous mutation in a second canalicular transporter. The MDR3 mutation S320F has been shown to be specific for ICP.6Pauli-Magnus C. Lang T. Meier Y. Zodan-Marin T. Jung D. Breymann C. Zimmermann R. Kenngott S. Beuers U. Reichel C. Kerb R. Penger A. Meier P.J. Kullak-Ublick G.A. Sequence analysis of bile salt export pump (ABCB11) and multidrug resistance p-glycoprotein 3 (ABCB4, MDR3) in patients with intrahepatic cholestasis of pregnancy.Pharmacogenetics. 2004; 14: 91-102Crossref PubMed Scopus (231) Google Scholar Strikingly, S320F does not result in an obvious decrease in MDR3 immunoreactivity as compared with BSEP. This is in line with recent observations that at least 4 of the 18 published severe, PFIC-3–associated, MDR3 mutations do not alter MDR3 localization.10Keitel V. Burdelski M. Warskulat U. Kühlkamp T. Keppler D. Häussinger D. Kubitz R. Expression and localization of hepatobiliary transport proteins in progressive familial intrahepatic cholestasis.Hepatology. 2005; 41: 1160-1172Crossref PubMed Scopus (204) Google Scholar, 21Jacquemin E. Role of multidrug resistance 3 deficiency in pediatric and adult liver disease one gene for three diseases.Semin Liver Dis. 2001; 21: 551-562Crossref PubMed Scopus (150) Google Scholar, 22Jacquemin E. De Vree J.M. Cresteil D. Sokal E.M. Sturm E. Dumont M. Scheffer G.L. Paul M. Burdelski M. Bosma P.J. Bernard O. Hadchouel M. Elferink R.P. The wide spectrum of multidrug resistance 3 deficiency from neonatal cholestasis to cirrhosis of adulthood.Gastroenterology. 2001; 120: 1448-1458Abstract Full Text Full Text PDF PubMed Scopus (408) Google Scholar In conclusion, the ICP-relevant mutation S320F probably alters the activity but not the localization of MDR3. It may be speculated that reduced activity of mutated MDR3 induces changes in the lipid composition of the canalicular membrane, which consecutively causes altered BSEP expression when the V444A polymorphism is present.Elevated γ-glutamyltransferase levels are a common feature of PFIC-3.11De Vree J.M. Jacquemin E. Sturm E. Cresteil D. Bosma P.J. Aten J. Deleuze J.F. Desrochers M. Burdelski M. Bernard O. Oude Elferink R.P. Hadchouel M. Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis.Proc Natl Acad Sci U S A. 1998; 95: 282-287Crossref PubMed Scopus (627) Google Scholar It was proposed that this is due to the toxic effect of bile salts on cholangiocytes, which are not protected by phospholipids, the main substrates of MDR3.21Jacquemin E. Role of multidrug resistance 3 deficiency in pediatric and adult liver disease one gene for three diseases.Semin Liver Dis. 2001; 21: 551-562Crossref PubMed Scopus (150) Google Scholar Elevated γ-glutamyltransferase levels are also typical for MDR3-associated ICP.5Gendrot C. Bacq Y. Brechot M.C. Lansac J. Andres C. A second heterozygous MDR3 nonsense mutation associated with intrahepatic cholestasis of pregnancy.J Med Genet. 2003; 40: e32Crossref PubMed Scopus (71) Google Scholar, 23Lucena J.F. Herrero J.I. Quiroga J. Sangro B. Garcia-Foncillas J. Zabalegui N. Sola J. Herraiz M. Medina J.F. Prieto J. A multidrug resistance 3 gene mutation causing cholelithiasis, cholestasis of pregnancy, and adulthood biliary cirrhosis.Gastroenterology. 2003; 124: 1037-1042Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar In our patient, a moderate increase in γ-glutamyltransferase levels was only observed at the beginning of the disease. The reason for the temporal increase may be the low amount of canalicular BSEP, resulting in a low biliary bile salt concentration. In the later course of the disease, the low γ-glutamyltransferase levels may be attributed to the beneficial effect of ursodeoxycholate.Treatment options for patients with ICP include cholestyramine and ursodeoxycholate.24Kondrackiene J. Beuers U. Kupcinskas L. Efficacy and safety of ursodeoxycholic acid versus cholestyramine in intrahepatic cholestasis of pregnancy.Gastroenterology. 2005; 129: 894-901Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar To date, ursodeoxycholate seems to represent the most effective therapy, which has a beneficial effect on pruritus and liver enzyme levels.24Kondrackiene J. Beuers U. Kupcinskas L. Efficacy and safety of ursodeoxycholic acid versus cholestyramine in intrahepatic cholestasis of pregnancy.Gastroenterology. 2005; 129: 894-901Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar, 25Riely C.A. Bacq Y. Intrahepatic cholestasis of pregnancy.Clin Liver Dis. 2004; 8: 167-176Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, 26Zapata R. Sandoval L. Palma J. Hernandez I. Ribalta J. Reyes H. Sedano M. Toha D. Silva J.J. Ursodeoxycholic acid in the treatment of intrahepatic cholestasis of pregnancy. A 12-year experience.Liver Int. 2005; 25: 548-554Crossref PubMed Scopus (110) Google Scholar Ursodeoxycholate may also improve fetal outcome by reducing the risk of preterm delivery.26Zapata R. Sandoval L. Palma J. Hernandez I. Ribalta J. Reyes H. Sedano M. Toha D. Silva J.J. Ursodeoxycholic acid in the treatment of intrahepatic cholestasis of pregnancy. A 12-year experience.Liver Int. 2005; 25: 548-554Crossref PubMed Scopus (110) Google Scholar Typically, the total amount of serum bile salts (including ursodeoxycholate) is not significantly affected by ursodeoxycholate treatment.24Kondrackiene J. Beuers U. Kupcinskas L. Efficacy and safety of ursodeoxycholic acid versus cholestyramine in intrahepatic cholestasis of pregnancy.Gastroenterology. 2005; 129: 894-901Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar However, ursodeoxycholate replaces endogenous bile salts (by about 45%), thereby reducing the absolute (and relative) amount of endogenous bile salts by almost 60%.24Kondrackiene J. Beuers U. Kupcinskas L. Efficacy and safety of ursodeoxycholic acid versus cholestyramine in intrahepatic cholestasis of pregnancy.Gastroenterology. 2005; 129: 894-901Abstract Full Text Full Text PDF PubMed Scopus (200) Google ScholarIn patients with PFIC-3 with severe MDR3 mutations, residual MDR3 activity was shown to be essential for a response to ursodeoxycholate treatment.22Jacquemin E. De Vree J.M. Cresteil D. Sokal E.M. Sturm E. Dumont M. Scheffer G.L. Paul M. Burdelski M. Bosma P.J. Bernard O. Hadchouel M. Elferink R.P. The wide spectrum of multidrug resistance 3 deficiency from neonatal cholestasis to cirrhosis of adulthood.Gastroenterology. 2001; 120: 1448-1458Abstract Full Text Full Text
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