Hepatology : official journal of the American Association for the Study of Liver Diseases
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We sought to develop an oral treatment for unconjugated hyperbilirubinemia. In the Gunn rat model of unconjugated hyperbilirubinemia, dietary supplementation with the lipase inhibitor orlistat (Orl) or with calcium phosphate (CaP) decreases plasma unconjugated bilirubin (UCB) levels. We determined whether Orl, CaP, or their combination is superior to phototherapy, the conventional treatment, and whether the effects of Orl and CaP are influenced by dietary fat content. ⋯ In conclusion, plasma UCB concentrations in Gunn rats are negatively related to fecal fat excretion and dietary fat content. Orlistat is equally effective as phototherapy for the treatment of unconjugated hyperbilirubinemia in Gunn rats, and combined oral treatment with Orl + CaP is more effective than phototherapy. The present results support the feasibility of an efficient oral treatment of unconjugated hyperbilirubinemia.
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Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disease associated with poor maternal and fetal outcome. The diagnosis is based on pruritus with abnormal liver function in the absence of other pathological conditions. However, pruritus in pregnancy is common, and it may be the only presenting feature in ICP. ⋯ Significant differences in the ICP compared with control and PG groups were also found for total bile acids, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase and alkaline phosphatase. In conclusion, the measurement of GSTA provides a test of liver dysfunction that distinguishes women with ICP from those with PG. Additionally, on the basis of this study, reference ranges for biochemical markers of liver function require reevaluation in pregnancy.
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Acetaminophen overdose causes massive hepatic failure via mechanisms involving glutathione depletion, oxidative stress, and mitochondrial dysfunction. The ultimate target of acetaminophen causing cell death remains uncertain, and the role of apoptosis in acetaminophen-induced cell killing is still controversial. Our aim was to evaluate the mitochondrial permeability transition (MPT) as a key factor in acetaminophen-induced necrotic and apoptotic killing of primary cultured mouse hepatocytes. ⋯ In the presence of fructose plus glycine, CsA decreased apoptosis and delayed but did not prevent the MPT. In conclusion, after acetaminophen a CsA-sensitive MPT occurred after 3 to 6 hours followed by a CsA-insensitive MPT 9 to 16 hours after acetaminophen. The MPT then induces ATP depletion-dependent necrosis or caspase-dependent apoptosis as determined, in part, by ATP availability from glycolysis.
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The mechanisms underlying alcoholic liver disease are not completely understood, but lipid accumulation seems to be central to the cause of this disease. The peroxisome proliferator-activated receptor alpha (PPARalpha) plays an important role in the control of lipid homeostasis, metabolism of bioactive molecules, and modulation of inflammatory responses. To investigate the roles of PPARalpha in alcoholic liver injury, wild-type and PPARalpha-null mice were continuously fed a diet containing 4% ethanol, and liver injury was analyzed. ⋯ Next, the molecular mechanisms of ethanol-induced liver injury in PPARalpha-null mice were investigated, and changes related to ethanol and acetaldehyde metabolism, oxidative stress, inflammation, hepatocyte proliferation, fibrosis, and mitochondrial permeability transition activation occurred specifically in PPARalpha-null mice as compared with wild-type mice. In conclusion, these studies suggest a protective role for PPARalpha in alcoholic liver disease. Humans may be more susceptible to liver toxicity induced by ethanol as PPARalpha expression in human liver is considerably lower compared to that of rodents.