Linkage between a new splicing site mutation in the MDR3 alias ABCB4 gene and intrahepatic cholestasis of pregnancy

Intrahepatic cholestasis of pregnancy (ICP) is defined as pruritus and elevated bile acid serum concentrations in late pregnancy. Splicing mutations have been described in the multidrug resistance p-glycoprotein 3 (MDR3, ABCB4) gene in up to 20% of ICP women. Pedigrees studied were not large enough for linkage analysis. Ninety-seven family members of a woman with proven ICP were asked about pruritus in earlier pregnancies, birth complications and symptomatic gallstone disease. The familial cholestasis type 1 (FIC1, ATP8B1) gene, bile salt export pump (BSEP, ABCB11) and MDR3 gene were analyzed in 55 relatives. We identified a dominant mode of inheritance with female restricted expression and a new intronic MDR3 mutation c.3486+5G>A resulting in a 54 bp (3465-3518) inframe deletion via cryptic splicing site activation. Linkage analysis of the ICP trait versus this intragenic MDR3 variant yielded a LOD score of 2.48. A Bayesian analysis involving MDR3, BSEP, FIC1 and an unknown locus gave a posterior probability of >0.9966 in favor of MDR3 as causative ICP locus. During the episode of ICP the median gamma-glutamyl transpeptidase (gamma-GT) activity was 10 U/l (95% CI, 6.9 to 14.7 U/l) in the index woman. Four stillbirths were reported in seven heterozygous women (22 pregnancies) and none in five women (14 pregnancies) without MDR3 mutation. Symptomatic gallstone disease was more prevalent in heterozygous relatives (7/21) than in relatives without the mutation (1/34), (P = 0.00341). CONCLUSION: This study demonstrates that splicing mutations in the MDR3 gene can cause ICP with normal gamma-GT and may be associated with stillbirths and gallstone disease.     

Recurrent intrahepatic cholestasis of pregnancy and chain-like choledocholithiasis in a female patient with stop codon in the ABDC4-gene of the hepatobiliary phospholipid transporter

We report the case of a 40-years-old female patient with recurrent cholestatic liver disease who presented twice with severe intrahepatic cholestasis of pregnancy and pronounced choledocholithiasis between pregnancies. Bile duct stones were removed endoscopically and a laparoscopic cholecystectomy was performed after the second pregnancy. Liver histology revealed intrahepatic cholestasis with portal inflammation and fibrosis, resembling progressive familial intrahepatic cholestasis (PFIC). Molecular genetic studies identified the heterozygous mutation c.957C > T in the ABCB4 gene encoding the hepatobiliary phospholipid transporter. This is the first report of this mutation that introduces a stop codon in an index patient with intrahepatic cholestasis of pregnancy and multiple bile duct stones. In addition, we detected the ABCB11 polymorphism V 444A, which is associated with a decreased expression of the bile salt export pump. Whereas homozygous carriers of the ABCB4 mutation develop PFIC type 3, the heterozygous ABC transporter mutations represent genetic risk factors for cholelithiasis and recurrent cholestatic hepatitis upon challenge with oral contraceptives or during pregnancy. Of note, the patient presented with normal serum gamma-glutamyltranspeptidase activities during pregnancy-associated cholestatic episodes but normal liver enzymes after delivery, whereas choledocholithiasis was associated with high gamma-glutamyl transpeptidase levels. It is unknown whether ursodeoxycholic acid prevents cholestasis or gallstones in patients with ABCB4 deficiency.     

Hepatobiliary phospholipid transporter ABCB4, MDR3 gene variants in a large cohort of Italian women with intrahepatic cholestasis of pregnancy

BACKGROUND: Intrahepatic cholestasis of pregnancy is a multifactorial disorder of pregnancy associated with a genetic background. AIM: To evaluate the genetic contribution of ABCB4, MDR3 gene in the development of intrahepatic cholestasis of pregnancy in a large cohort of Italian subjects. METHODS: This study represents an extension of a previous multicentre-prospective study including three Italian referral centres. In all, we enrolled 96 women at the 3rd trimester of pregnancy. Genomic DNA was extracted from peripheral venous blood leucocytes by standard procedures. Polymerase chain reaction was used to amplify exon 14, 15 and 16 of MDR3 gene. RESULTS: We found 3 non-synonymous heterozygous mutations in exon 14 (E528D, R549H, G536A), 1 in exon 15 (R590Q) and 2 in exon 16 (R652G, T6671). MDR3 gene variants in exons 14, 15 and 16 occurred in 7/96 of pregnant mothers with intrahepatic cholestasis of pregnancy (7.2%), and in none of 96 pregnant controls matched for age and parity. All seven patients had normal gamma-glutamyl transpeptidase, normal bilirubin, but high levels of both alanine transferase and serum bile acids. One had cholesterol biliary lithiasis. The outcome of pregnancy was normal in four cases (with vaginal delivery), while there was one fetal distress. CONCLUSIONS: MDR3 mutations are responsible for the development of intrahepatic cholestasis of pregnancy in only a small percentage of Italian women. Further genetic studies are warranted, however, to clarify the role of different mutations in intrahepatic cholestasis of pregnancy.     

Cholestasis during pregnancy: rare hepatic diseases unmasked by pregnancy

The occurrence of cholestasis during pregnancy may be due to several disorders. These include pregnancyspecific diseases, like intrahepatic cholestasis of pregnancy(ICP), as well as to other causes such as oligosymptomatic choledocolitiasis, viral hepatitis and other underlying liver disorders like primary biliary cirrhosis. In recent years, the discovery of mutations in hepatobiliary transporters genes responsible of some rare forms of genetic cholestasis have led to the study of this mutations in pregnant women with cholestasis. Thus, mutations in the hepatic phospholipid transporter(MDR3, ABCB4), in the aminophospholipid transporter ATP8B1 and in the bile salt export pump (BSEP, ABCB11) have been found in patients diagnosed as ICP. However, patients included in these studies belong to a heterogeneous population, which may not represent true cases of ICP since some reports include patients diagnosed in the first trimester of pregnancy, with elevated serum levels of gamma-glutamyl transpeptidase and clear evidence of chronic liver disease. Thus, consideration must be given to the possibility of other rare underlying hepatic disorders may be unmasked during pregnancy with cholestasis as its first manifestation.     

The multiple facets of ABCB4 (MDR3) deficiency

Opinion statement ABCB4 (MDR3), a lipid translocator, moves phosphatidylcholine from the inner to the outer leaflet of the canalicular membrane. Genetic mutations of ABCB4 lead to three distinct but related hepatobiliary diseases. Progressive familial intrahepatic cholestasis (PFIC) type 3 is a chronic cholestatic syndrome characterized by a markedly elevated γ-glutamyltranspeptidase. Patients present with jaundice, pruritus, and hepatosplenomegaly. Periportal inflammation progresses to biliary cirrhosis and causes portal hypertension. Ursodeoxycholic acid (UDCA) normalizes liver function tests in approximately one half of treated PFIC type 3 patients. Partial responders or nonresponders eventually will require liver transplantation. Gallstone patients with ABCB4 mutations may have low phospholipid-associated cholelithiasis syndrome, characterized by cholesterol gallstones and intrahepatic microlithiasis, along with recurrent biliary symptoms, despite cholecystectomy. Patients with ABCB4 mutations also may develop intrahepatic brown pigment stones. UDCA may improve biliary symptoms even before the dissolution of stones occurs. Additional therapies such as farnesoid X receptor ligands/agonists and benzfibrates show future therapeutic promise. Intrahepatic cholestasis of pregnancy affects pregnant women with abnormal ABCB4. These women suffer from disabling pruritus and also may experience steatorrhea. Fetuses are at high risk for prematurity and stillbirths. The definitive treatment is delivery of the baby. In the interim, limited fat intake, fat-soluble vitamin supplementation, and UDCA with or without S-adenosylmethionine can provide symptomatic relief. Additional hepatobiliary diseases related to ABCB4 mutations are likely to be identified. This may result in the discovery of additional therapies for PFIC type 3, gallstones, and intrahepatic cholestasis of pregnancy.     

Intrahepatic cholestasis of pregnancy: the severe form is associated with common variants of the hepatobiliary phospholipid transporter ABCB4 gene

BACKGROUND: Intrahepatic cholestasis of pregnancy (ICP) is characterised by troublesome maternal pruritus, raised serum bile acid levels and increased fetal risk. Mutations of the ABCB4 gene encoding the hepatobiliary phospholipid transporter have been identified in a small proportion of patients with cholestasis of pregnancy. In a recent prospective study on 693 patients with cholestasis of pregnancy, a cut-off level for serum bile acid (> or =40 micromol/l) was determined for increased risk of fetal complications. OBJECTIVES: To investigate whether common combinations of polymorphic alleles (haplotypes) of the genes encoding the hepatobiliary ATP-binding cassette (ABC) transporters for phospholipids (ABCB4) and bile acids (ABCB11) were associated with this severe form of cholestasis of pregnancy. METHODS: For genetic analysis, 52 women with bile acid levels > or =40 micromol/l (called cases) and 52 unaffected women (called controls) matched for age, parity and geographical residence were studied. Gene variants tagging common ABCB4 and ABCB11 haplotypes were genotyped and haplotype distributions were compared between cases and controls by permutation testing. RESULTS: In contrast with ABCB11 haplotypes, ABCB4 haplotypes differed between the two groups (p = 0.019), showing that the severe form of cholestasis of pregnancy is associated with the ABCB4 gene variants. Specifically, haplotype ABCB4_5 occurred more often in cases, whereas haplotypes ABCB4_3 and ABCB4_7 were more common in controls. These associations were reflected by different frequencies of at-risk alleles of the two tagging polymorphisms (c.711A: odds ratio (OR) 2.27, p = 0.04; deletion intron 5: OR 14.68, p = 0.012). CONCLUSION: Variants of ABCB4 represent genetic risk factors for the severe form of ICP in Sweden.     

A study of exons 14, 15, and 24 of the ABCB11 gene in Egyptian children with normal GGT cholestasis

Background and study aimsProgressive familial intrahepatic cholestasis type 2 (PFIC2) is a rare inherited disorder caused by mutation in the ATP-binding cassette subfamily B member 11 gene (ABCB11) that encodes the bile salt export pump (BSEP), which is the main transporter of bile acids from hepatocytes to the canalicular lumen. Defects in BSEP synthesis and/or function lead to reduced bile salt secretion followed by accumulation of bile salts in hepatocytes and hepatocellular damage. This study aimed to detect variations in exons 14, 15, and 24 of the ABCB11 gene in patients with suspected PFIC2 among a group of Egyptian infants and children with normal gamma-glutamyl transpeptidase (GGT) cholestasis.Patients and methodsThis observational case-control study was conducted on 13 children with suspected PFIC2 and 13 healthy subjects as controls. Genotyping of the ABCB11 gene was performed via DNA extraction followed by PCR amplification, purification, and then sequencing analysis of exons 14, 15, and 24 of the ABCB11 gene.ResultsThe study detected two single nucleotide variations, c.1638+ 32T > C (rs2241340) in exon 14 and c.3084A > G (p.Ala1028 = ) (rs497692) in exon 24 of the ABCB11 gene. No variations were identified in exon 15.ConclusionThe study revealed two benign variants involving exons 14 and 24 of the ABCB11 gene. Exons 14, 15, and 24 are not hot spots for common mutations in Egyptian PFIC2 patients. Further study of other exons of the ABCB11 gene is necessary to confirm the diagnosis of PFIC2.     

Mechanism of gamma-glutamyl transpeptidase release in serum during intrahepatic and extrahepatic cholestasis in the rat: a histochemical, biochemical and molecular approach

The mechanism of the elevation of serum gamma-glutamyl transpeptidase activity in cholestasis is not clear. We therefore analyzed rat gamma-glutamyl transpeptidase activities in liver, bile and serum during intrahepatic cholestasis induced by a single dose of alpha-naphthyl isothiocyanate (20 mg/100 gm body weight) and during extrahepatic cholestasis after bile duct ligation. At days 1 and 2 after alpha-naphthyl isothiocyanate ingestion, we saw a fivefold and a 60-fold increase in serum and bile gamma-glutamyl transpeptidase activities, respectively. These increases were associated with a decrease in hepatic gamma-glutamyl transpeptidase activity and of corresponding mRNA. Simultaneously, necrosis of the biliary epithelium appeared in portal tracts. From day 2 to day 14, gamma-glutamyl transpeptidase activity in bile and serum progressively returned to basal levels; in the liver, cholangiolar proliferation was mild and was associated with moderate elevation of the gamma-glutamyl transpeptidase activity and of its corresponding mRNA. In extrahepatic cholestasis, a 10-fold increase in serum gamma-glutamyl transpeptidase activity was detected between day 0 and day 14. This increase was associated with major cholangiolar proliferation and with a progressive rise in hepatic gamma-glutamyl transpeptidase activity and in specific mRNA; in bile, gamma-glutamyl transpeptidase activity was slightly elevated. In these two models of cholestasis, histochemically detected gamma-glutamyl transpeptidase activity was largely predominant in biliary cells. We found no significant induction of gamma-glutamyl transpeptidase activity in hepatocytes. These results suggest that in these two models of cholestasis, the increase in serum gamma-glutamyl transpeptidase activity is of biliary cell origin and does not originate from hepatocytes.(ABSTRACT TRUNCATED AT 250 WORDS)     

ABCB4 and ABCB11 mutations in intrahepatic cholestasis of pregnancy in an Italian population

BackgroundGenetic alterations in the ATP-binding cassette subfamily B member 4 (ABCB4) and ATP-binding cassette subfamily B member 11 (ABCB11) have been associated to the onset of intrahepatic cholestasis of pregnancy (ICP) in predisposed women.AimsTo identify new and/or frequent ABCB4 and ABCB11 genes variants in a cohort of Italian patients with ICP and to evaluate the possible pathogenetic role for the novel mutations identified.MethodsDNA of 33 unrelated Italian women with obstetric cholestasis were screened for mutations in the entire coding sequence of ABCB4 and ABCB11 genes. Polymerase chain reaction and automated sequencing was performed on the 27 coding exons of both genes.ResultsGenotyping revealed 11 mutations, 5 of whom were novel variants: 2 localized on ABCB4 (p.I587DfsX603, p.I738LfsX744) and 3 on ABCB11 (p.V284D, p.Q558H, p.P731S). The most severe phenotypes were associated with the variants p.I587DfsX603, p.I738LfsX744 and p.V284D. Moreover, the already described mutation p.N510S found in ABCB4 seems to be strictly involved in the onset of ICP in that particular patient.ConclusionsOur data support the hypothesis of a significant involvement of ABCB4 mutations in the onset of ICP, but also confirm an important role for ABCB11 mutations in increasing the susceptibility to cholestasis of pregnancy.     

Antisense oligonucleotides rescue an intronic splicing variant in the ABCB11 gene that causes progressive familial intrahepatic cholestasis type 2

BackgroundProgressive familial intrahepatic cholestasis type 2 (PFIC2) is a rare disorder caused by variants in the ABCB11 gene encoding the bile salt export pump (BSEP). We investigated the molecular defect in a PFIC2 infant and rescued the splicing defect with antisense oligonucleotides (ASOs).MethodsWhole-exome sequencing (WES) revealed compound heterozygous variants in the ABCB11 gene in a PFIC2 patient. Liver biopsy was immunostained for BSEP. The splicing effect of the candidate variants was investigated by minigene assay. ASOs were designed to rescue aberrant splicing.ResultsA Chinese girl of two nonconsanguineous healthy parents suffered from low glutamyl transpeptidase cholestasis and showed no response to the ursodeoxycholic acid. WES revealed that the patient was compound heterozygous for two novel variants in the ABCB11 gene: c.76+29T>G and c.390–2A>G. Liver immunohistochemistry showed the absence of BSEP. The variant c.76+29T>G was confirmed to retain 42 bp in the mature mRNA. The variant c.390–2A>G was confirmed to cause exon 6 skipping. We designed two ASOs and identified one of them that efficiently induced pseudoexon exclusion.ConclusionWe reported two novel variants of the ABCB11 gene, c.76+29T>G and c.390-2A>G, in a PFIC2 infant, thereby expanding the genotype of PFIC2. Our findings provide evidence for ASOs as a therapeutic approach for PFIC2 patients carrying intronic variants.     

Hereditäre Defekte hepatobiliärer Transportproteine

Defects in transport proteins that are expressed at the hepatocyte canalicular membrane can cause severe impairment of hepatobiliary transport processes. Progressive familial intrahepatic cholestasis (PFIC) typically manifests in early childhood. Genetic variants in the aminophospholipid transporter FIC1 (ATP8B1 gene) cause PFIC1, characterized by elevated serum bile acids but normal or only mildly elevated gamma-GT levels. Benign recurrent intrahepatic cholestasis type 1 (BRIC1) is also caused by ATP8B1 mutations. Defects in the function of the bile salt efflux pump (BSEP; ABCB11) cause PFIC2 or BRIC2, depending on the degree of BSEP impairment. A common BSEP variant, the V444A polymorphism, is commonly found in various types of cholestatic liver injury, including drug-induced liver injury. Finally, dysfunction of the multidrug resistance gene product MDR3 (ABCB4) leads to PFIC3, characterized by low biliary phospholipids and high gamma-GT levels in serum due to bile duct injury. All three transporter genes are also associated with intrahepatic cholestasis of pregnancy. Treatment options include ursodeoxycholic acid for milder forms and liver transplantation for severe pediatric cases.     

Ursodeoxycholic acid therapy in intrahepatic cholestasis of pregnancy: Results in real-world conditions and factors predictive of response to treatment

BackgroundUrsodeoxycholic acid (UDCA) therapy is commonly used in intrahepatic cholestasis of pregnancy (ICP).AimTo evaluate the efficacy and tolerance of UDCA in real-world conditions and to search for factors predictive of response to treatment.MethodsThis observational study included 98 consecutive patients suffering from pruritus during pregnancy associated with increased ALT levels or total bile acid (TBA) concentrations, without other causes of cholestasis. The entire ABCB4 gene coding sequence was analyzed by DNA sequencing.ResultsUDCA was prescribed until delivery in all patients (mean dose 14.0 mg/kg/day; mean duration 30.4 days). Pruritus improved in 75/98 (76.5%) patients, and totally disappeared before delivery in 25/98 (25.5%). After 2–3 weeks of treatment, ALT levels decreased by more than 50% of base line in 67/86 (77.9%) patients and normalized in 34/86 (39.5%), and TBA concentrations decreased in 28/81 (34.6%). Only one patient stopped the treatment before delivery. On multivariate analysis, ALT >175 IU/l before treatment was associated with improvement of pruritus (OR 2.97, 95% CI 1.12–7.89, P = 0.029) and with decreased ALT (OR 18.61, 95% CI 3.94–87.99, P = 0.0002). ABCB4 gene mutation was not associated with response to treatment.ConclusionThis study supports the use of UDCA as first line therapy in ICP.     

Excessive bilirubin elevation in a patient with hereditary spherocytosis and intrahepatic cholestasis

Hereditary spherocytosis is a common hemolytic anemia with an estimated incidence of 1?/?2500 births. It is caused by a molecular defect in one or more of the proteins of the red blood cell cytoskeleton. Mutations in the ABCB11 gene, encoding the bile salt export pump, can entail progressive familial intrahepatic cholestasis and benign recurred intrahepatic cholestasis. A?18 year old Turkish patient with hereditary spherocytosis was admitted to hospital with pruritus and severe jaundice. Ultrasound examination presented stones in gallbladder and bile duct. After endoscopic retrograde cholangiography with extraction of small bile duct stones abdominal pain resolved and liver enzymes normalized within a few days, but bilirubin and bile acids remained highly elevated. Liver biopsy revealed a severe canalicular cholestasis. Genetic analysis showed the compound heterozygous variants ABCB11 A?444V and 3084A?>?G. Treatment with ursodesoxycholic acid and intermittent therapy with prednisone reduced pruritus and jaundice with concomitant improvement of blood test. Here we report the first case of a patient with combined hereditary spherocytosis and compound heterozygous ABCB11 gene variants predisposing to intrahepatic cholestasis. Therefore, patients with hemolytic disorders should be investigated for bile acid transporter diseases in case of hyperbilirubinemia and severe cholestasis.     

A multidrug resistance 3 gene mutation causing cholelithiasis,cholestasis of pregnancy,and adulthood biliary cirrhosis

We describe a 47-year-old patient who developed cholelithiasis in adolescence, followed by recurrent intrahepatic cholestasis of pregnancy, and finally biliary cirrhosis in adulthood. In our patient, the consecutive presentation of the 3 mentioned disorders raised the suspicion of a defect of MDR3, the canalicular protein involved in the transport of phospatidylcholine to bile. Mutational analysis in our patient showed a heterozygous missense mutation of the MDR3 gene that has not been described previously, which occurs in exon 14 at codon 535, and results in the substitution of glycine for aspartic acid. Further analysis of 7 members of the family showed the same mutation in her daughter who, on follow-up, developed cholestasis of pregnancy and persisting high serum levels of gamma-glutamyl transpeptidase and alkaline phosphatase after delivery. Although biliary cirrhosis associated with MDR3 deficiency typically appears before the age of 25 years, in our case, the relatively mild MDR3 dysfunction allowed for a slower progression of the disease with established, well-advanced cirrhosis in the fifth decade of life. The present case, which accumulates the 3 clinical disorders assocaited with MDR3 deficiency, shows that this condition should be suspected not only in children or young people with high gamma-glutamyl transpeptidase cholestasis but also in middle-aged or older patients with chronic idiopathic cholestasis, especially when there is a previous history of cholestasis of pregnancy or juvenile cholelithiasis.     

ABCB4 disease: Many faces of one gene deficiency

ATP-binding cassette (ABC) subfamily B member 4 (ABCB4), also known as multidrug resistance protein 3 (MDR3), encoded by ABCB4, is involved in biliary phospholipid secretion, protecting hepatobiliary system from deleterious detergent and lithogenic properties of the bile. ABCB4 mutations altering canalicular ABCB4 protein function and expression may have variable clinical presentation and predispose to several human liver diseases. Well-established phenotypes of ABCB4 deficit are: progressive familial intrahepatic cholestasis type 3, gallbladder disease 1 (syn. low phospholipid associated cholelithiasis syndrome), high ɣ-glutamyl transferase intrahepatic cholestasis of pregnancy, chronic cholangiopathy, and adult biliary fibrosis/cirrhosis. Moreover, ABCB4 aberrations may be involved in some cases of drug induced cholestasis, transient neonatal cholestasis, and parenteral nutrition-associated liver disease. Recently, genome-wide association studies have documented occurrence of malignant tumours, predominantly hepatobiliary malignancies, in patients with ABCB4/MDR3 deficit.The patient's age at the time of the first presentation of cholestatic disease, as well as the severity of liver disorder and response to treatment are related to the ABCB4 allelic status. Mutational analysis of ABCB4 in patients and their families should be considered in all individuals with cholestasis of unknown aetiology, regardless of age and/or time of onset of the first symptoms.     

ABCB11 gene mutations in Chinese children with progressive intrahepatic cholestasis and low γ glutamyltransferase

Background: Progressive familial intrahepatic cholestasis type 2 (PFIC2) is a severe autosomal recessive liver disorder of childhood that can cause cholestasis and progress to end‐stage liver disease. ABCB11 gene mutations causing PFIC2 have been reported in some population groups, but not in mainland Chinese. Aims: To elucidate the existence of and characterize ABCB11 gene mutations in mainland Chinese with progressive intrahepatic cholestasis and low γ glutamyltransferase (GGT). Methods: Twenty‐four children presenting with progressive intrahepatic cholestasis and low GGT were admitted to a tertiary paediatric hospital in eastern China from January 2004 to July 2007. All encoding exons and flanking areas of the ABCB11 gene were sequenced. Hepatic histopathology results were obtained by review of the medical record. Results: Twelve novel mutations of ABCB11 gene were found in seven patients: three nonsense mutations, six missense mutations, two splicing mutations and one intronic mutation. Giant cell transformation of hepatocytes was demonstrated in all the four patients with ABCB11 mutations and four of 12 patients without mutations in coding sequences of ABCB11 gene who received liver needle biopsy. Conclusions: ABCB11 gene mutations play an important role in Chinese patients with progressive intrahepatic cholestasis and low GGT. The characteristics of ABCB11 gene mutations in Chinese are different from other population groups. Histological examination may be helpful in diagnosis of PFIC2.     

Relationship between pruritus and autotaxin in intrahepatic cholestasis of pregnancy

ObjectiveIntrahepatic cholestasis of pregnancy is a temporary, pregnancy-specific disease that resolves with delivery, characterized by itching (pruritus), as well as high transaminase and serum bile acid levels in the third trimester of pregnancy. Due to the effects of Autotaxin on the physiology of pregnancy, we aimed to investigate Autotaxin activity in patients with intrahepatic cholestasis of pregnancy.Patients and methodsSixty-nine patients diagnosed with intrahepatic cholestasis of pregnancy and 20 healthy pregnant women were enrolled in the study. Fasting serum bile acid, pruritus intensity, serum parameters, gestational week of the patients at the time of diagnosis were recorded, and birth week and birth weight were monitored. Autotaxin serum level was measured enzymatically.ResultsThe mean serum bile acid level (n = 69; 38.74 ± 35.92 μmol/L) in patients with intrahepatic cholestasis of pregnancy (n = 69) was detected to be higher than healthy pregnant women (n = 20; 5.05 ± 1.88 μmol/L) (p < 0.001). Weak correlation was detected between serum bile acid level and itch intensity (p = 0.014, r = 0.295), while no relation was detected between Autotaxin and itch intensity (p = 0.446, r = 0.09). Although mean Autotaxin (intrahepatic cholestasis of pregnancy: 678.10 ± 424.42 pg/mL, control: 535.16 ± 256.47 pg/mL) levels were high in patients with intrahepatic cholestasis of pregnancy, it was not statistically significant (p = 0.157).ConclusionIn our study, we observed that the serum Autotaxin level did not make a significant difference in patients with intrahepatic cholestasis of pregnancy compared to healthy pregnant women. These findings suggest that larger clinical studies are required to reveal the physio-pathological effects of Autotaxin on pregnancy.     

Benign recurrent intrahepatic cholestasis

Benign recurrent intrahepatic cholestasis is a rare autosomal recessive disorder characterized by repeated episodes of intense pruritus, profound elevations in serum alkaline phosphatase and bilirubin, with normal or nearly normal values for serum gamma-glutamyl transferase. Attack lasts from several weeks to months and resolve spontaneously. Between attacks patients remain asymptomatic for months to years. The disorder does not lead to progressive liver injury and is not fatal. Genetic studies have demonstrated that the disorder is the result of a mutation in ATP8BI, a gene that codes for the FIC1 (familial intrahepatic cholestasis) protein, which is also affected in other forms of familial intrahepatic cholestasis. It is believed this protein plays a role in bile acid secretion, in aminophospholid transport, and in maintaining fluidity of the cell membrane. Therapy is supportive and aimed at relieving pruritus and other complications of severe cholestasis until the episode resolves spontaneously.     

Novel ATP8B1 mutation in an adult male with progressive familial intrahepatic cholestasis

Progressive familial intrahepatic cholestasis type 1 is a rare disease that is characterized by low serum γ-glutamyltransferase levels due to mutation in ATP8B1. We present a 23-year-old male who experienced persistent marked pruritus for eighteen years and recurrent jaundice for thirteen years, in addition to cholestasis that eventually became fatal. Genetic sequencing studies of the entire coding (exon) sequences of ATP8B1 and ABCB11 uncovered a novel heterozygous missense 3035G>T mutation (S1012I) and a synonymous 696T>C mutation in ATP8B1. The patient’s progression was associated with not only impaired familial intrahepatic cholestasis 1 (FIC1) function but also impaired bile salt export pump expression due to the impaired FIC1 function. Our findings show that patients with intermittent cholestasis can develop progressive liver disease even after several decades and require regular follow up.