ABSTRACT
Methods: We included 235 patients with chronic extrahepatic cholestasis due to pancreatic cancer, cholangiocarcinoma, or papillary carcinoma. Results: GGT was significantly higher in patients without pruritus (median 967, IQR 587-1571) compared to patients with pruritus (median 561 IQR 266-1084 IU/l) (p < 0.01). In contrast, median alkaline phosphatase (AP) was 491 U/L (IQR; 353-684) in patients with pruritus and was not significantly different from 518 U/L (IQR; 353-726) in patients without pruritus (p = 0.524). Direct bilirubin was significantly higher in patients with pruritus compared to patients without pruritus (168 µmol/L (IQR; 95-256) vs. 120 µmol/L (IQR; 56.75-185.5)) (p < 0.01). After correcting for the extent of cholestasis via direct bilirubin, the negative association between GGT and pruritus remained significant and became stronger (p < 0.001). Conclusion: Serum GGT activity is inversely associated with the presence of cholestatic itch in patients with chronic extrahepatic cholestasis.
ABSTRACT
BACKGROUND: In chronic liver disease, hepatic stellate cells (HSCs) are activated, highly proliferative and produce excessive amounts of extracellular matrix, leading to liver fibrosis. Elevated levels of toxic reactive oxygen species (ROS) produced during chronic liver injury have been implicated in this activation process. Therefore, activated hepatic stellate cells need to harbor highly effective anti-oxidants to protect against the toxic effects of ROS. AIM: To investigate the protective mechanisms of activated HSCs against ROS-induced toxicity. METHODS: Culture-activated rat HSCs were exposed to hydrogen peroxide. Necrosis and apoptosis were determined by Sytox Green or acridine orange staining, respectively. The hydrogen peroxide detoxifying enzymes catalase and glutathione-peroxidase (GPx) were inhibited using 3-amino-1,2,4-triazole and mercaptosuccinic acid, respectively. The anti-oxidant glutathione was depleted by L-buthionine-sulfoximine and repleted with the GSH-analogue GSH-monoethylester (GSH-MEE). RESULTS: Upon activation, HSCs increase their cellular glutathione content and GPx expression, while MnSOD (both at mRNA and protein level) and catalase (at the protein level, but not at the mRNA level) decreased. Hydrogen peroxide did not induce cell death in activated HSCs. Glutathione depletion increased the sensitivity of HSCs to hydrogen peroxide, resulting in 35% and 75% necrotic cells at 0.2 and 1mmol/L hydrogen peroxide, respectively. The sensitizing effect was abolished by GSH-MEE. Inhibition of catalase or GPx significantly increased hydrogen peroxide-induced apoptosis, which was not reversed by GSH-MEE. CONCLUSION: Activated HSCs have increased ROS-detoxifying capacity compared to quiescent HSCs. Glutathione levels increase during HSC activation and protect against ROS-induced necrosis, whereas hydrogen peroxide-detoxifying enzymes protect against apoptotic cell death.
