RESUMO
BACKGROUND: Hepatotoxicity is a major side effect of treatment with bosentan in patients with pulmonary hypertension (PH). Bosentan is metabolized by the cytochrome CYP2C9 and inhibits the bile salt export pump, which is encoded by ABCB11. This suggests that genetic variants of CYP2C9 and/or ABCB11 may predispose patients to bosentan-induced liver injury. MATERIAL AND METHODS: PH patients with (n = 23) or without (n = 25) an increase of alanine aminotransferase (ALT) or aspartate-aminotransferase (AST) during bosentan therapy were included in our analysis. Functionally relevant alleles of CYP2C9 and 16 representative variants of ABCB11 were genotyped. Data were analyzed using logistic regression. RESULTS: Variants of ABCB11 were not associated with bosentan-induced liver injury. In contrast, variant alleles of CYP2C9 were more common in patients with elevated transaminases (allele frequency 52%) compared to controls (allele frequency 24%, P = 0.04, odds ratio 3.5, 95% confidence interval 1.01-11.8). CONCLUSION: Our data indicate hepatotoxicity of bosentan from decreased hepatic metabolism due to common variants of CYP2C9.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Anti-Hipertensivos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/genética , Citocromo P-450 CYP2C9/genética , Hipertensão Pulmonar/tratamento farmacológico , Sulfonamidas/efeitos adversos , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP , Adulto , Idoso , Idoso de 80 Anos ou mais , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Bosentana , Estudos de Casos e Controles , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Feminino , Predisposição Genética para Doença , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-IdadeRESUMO
Alveolar echinococcosis of the liver can be mistaken as a liver tumor. The occurrence of the fox tapeworm echinococcus multilocularis is increasing in formerly unaffected European regions. As a consequence, alveolar echinococcosis is becoming an important differential diagnosis in Eastern and Northern Europe.
Assuntos
Equinococose Hepática/diagnóstico , Equinococose Hepática/epidemiologia , Animais , Biópsia , Diagnóstico Diferencial , Echinococcus/isolamento & purificação , Europa (Continente)/epidemiologia , Feminino , Humanos , Incidência , Fígado/diagnóstico por imagem , Fígado/parasitologia , Fígado/patologia , Neoplasias Hepáticas/diagnóstico , Pessoa de Meia-Idade , UltrassonografiaRESUMO
BACKGROUND/AIMS: From quantitative trait locus mapping in inbred mice, we identified the Nr1h4 gene encoding the nuclear bile salt receptor FXR as a candidate gene for the cholesterol gallstone susceptibility locus Lith7. Here, we investigated further an association of the gene encoding FXR and gallstone susceptibility in mice and humans. METHODS: The Nr1h4 gene was sequenced in inbred mouse strains with susceptible and resistant Lith7 alleles. Quantitative RT-PCR was employed to determine mRNA expression levels. Gallstone carriers and control subjects of three different populations comprising 1004 individuals were genotyped for polymorphisms of the orthologous human gene detected by sequencing. RESULTS: Expression and sequence analyses in inbred mice were consistent with Nr1h4 underlying Lith7. In the human populations, we identified three frequent haplotypes that accounted for > 95% of all haplotypes observed. In a Mexican population, the most common haplotype NR1H4_1 was associated with gallstone prevalence. In contrast, NR1H4_1 displayed no association with gallstone prevalence in a German population, whereas in a Chilean population we observed a trend towards a protective effect of NR1H4_1. CONCLUSIONS: Our study in an inbred mouse model and in three ethnically distinct populations indicates complex interactions of NR1H4 alleles and other risk factors for the development of cholelithiasis.
Assuntos
Proteínas de Ligação a DNA/genética , Cálculos Biliares/epidemiologia , Cálculos Biliares/genética , Receptores Citoplasmáticos e Nucleares/genética , Fatores de Transcrição/genética , Alelos , Animais , Índice de Massa Corporal , Chile/epidemiologia , Mapeamento Cromossômico , Dieta , Etnicidade/estatística & dados numéricos , Feminino , Regulação da Expressão Gênica , Genótipo , Alemanha/epidemiologia , Humanos , Masculino , México/epidemiologia , Camundongos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/biossíntese , RNA Mensageiro/genéticaRESUMO
We describe the case of a 73-year-old woman was admitted to our hospital because of constant abdominal pain in her right upper quadrant and postprandial bloating and fullness for several months. On abdominal x-ray the extrahepatic bile ducts were positive for gas and on ultrasound a gallstone in the duodenum was suspected whereas the gallbladder was not detectable. An upper gastrointestinal endoscopy confirmed a large gallstone that was impacted in the duodenal bulb ("Bouveret's syndrome"). The gallstone was fragmented employing mechanical lithotripsy and removed. Duodenoscopy revealed a cholecystoduodenal fistula and a second gallstone in the gallbladder. The patient underwent open cholecystectomy with closure of the cholecystoduodenal fistula and made a full recovery. We conclude that in patients with upper abdominal pain and pneumobilia on x-ray the unusual complication of cholelithiasis with an impacted gallstone in the duodenal bulb should be suspected. In those rare cases of Bouveret's syndrome endoscopic removal of the gallstone should be attempted to minimize the necessary surgical procedure whenever possible.