Contribution of variant alleles of ABCB11 to susceptibility to intrahepatic cholestasis of pregnancy.

BACKGROUND: Intrahepatic cholestasis of pregnancy (ICP) has a complex aetiology with a significant genetic component. ABCB11 encodes the bile salt export pump (BSEP); mutations cause a spectrum of cholestatic disease, and are implicated in the aetiology of ICP. METHODS: ABCB11 variation in ICP was investigated by screening for five mutant alleles (E297G, D482G, N591S, D676Y and G855R) and the V444A polymorphism (c.1331T>C, rs2287622) in two ICP cohorts (n = 333 UK, n = 158 continental Europe), and controls (n = 261) for V444A. PCR primers were used to amplify and sequence patient and control DNA. The molecular basis for the observed phenotypes was investigated in silico by analysing the equivalent residues in the structure of the homologous bacterial transporter Sav1866. RESULTS: E297G was observed four times and D482G once. N591S was present in two patients; D676Y and G855R were not observed. The V444A polymorphism was associated with ICP (allelic analysis for C vs T: OR 1.7 (95% CI 1.4 to 2.1, p<0.001)). In addition, CC homozygotes were more likely to have ICP than TT homozygotes: OR 2.8 (95% CI 1.7 to 4.4 p<0.0001). Structural analyses suggest that E297G and D482G destabilize the protein fold of BSEP. The molecular basis of V444A and N591S was not apparent from the Sav1866 structure. CONCLUSIONS: Heterozygosity for the common ABCB11 mutations accounts for 1% of European ICP cases; these two mutants probably reduce the folding efficiency of BSEP. N591S is a recurrent mutation; however, the mechanism may be independent of protein stability or function. The V444A polymorphism is a significant risk factor for ICP in this population.

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.

Bouveret's syndrome presenting as upper gastrointestinal hemorrhage without hematemesis.

A 74-year-old woman with a recent diagnosis of peptic ulcer disease diagnosed by endoscopy after presentation with an episode of upper gastrointestinal bleeding returned 6 1/2 weeks later with a 5-day history of nausea and vomiting without associated symptoms. An ultrasound was nondiagnostic except for a large gallstone and a poorly visualized gallbladder. Repeat endoscopy revealed a hard mass that was presumed to have formed secondarily to an ulcer-induced stricture, and a 6-cm filling defect just proximal to the duodenal bulb was seen on a preoperative upper gastrointestinal series. At laparotomy the mass was actually a large gallstone and two smaller stones, which had eroded into and become impacted in the duodenal bulb creating a gastric outlet obstruction. The stones were extracted via a duodenotomy, and the remaining portion of the gallbladder was removed with repair of the cholecystoduodenal fistula. The patient was discharged home after an uncomplicated postoperative course. Gastric outlet obstruction by a duodenal gallstone is a condition known as Bouveret's syndrome, which is a rare complication of gallstone disease. Upper gastrointestinal hemorrhage is an especially rare form of presentation.

Tissue expanders for abdominal wall reconstruction following severe trauma: technical note and case reports.

A technique of abdominal wall reconstruction without the use of prosthetic materials or myocutaneous flaps following severe abdominal trauma is described. Six weeks before abdominal reconstruction, tissue expanders are inserted on either side of the ventral defect and inflated at weekly intervals to increase the amount of local tissue for coverage. Restoration of the abdominal wall is accomplished by denuding the skin graft covering the ventral defect of its dermal elements and suturing this newly created fascial graft to the existing rectus fascia. The fascial graft is covered with full-thickness skin using local advancement flaps. This procedure has been carried out on two patients in conjunction with closure of a colostomy in one and closure of an enterocutaneous fistula in another. Both patients healed without infection, and follow-up at 3 and 12 months postoperatively demonstrated no evidence of hernia formation.