pituitrin and Liver-Diseases--Alcoholic

Bleeding from esophageal varices remains a difficult clinical problem, carrying a high likelihood both of rebleeding and of mortality. The initial approach requires adequate but not overly vigorous volume replacement with blood and other fluids. Once the patient is resuscitated, upper gastrointestinal endoscopy should be performed to establish the source of bleeding. Both endoscopic variceal sclerotherapy and balloon tamponade appear to be effective in achieving temporary control of acute ongoing hemorrhage from esophageal varices. The value of intravenous vasopressin remains controversial. Rebleeding can be prevented in most patients by shunt surgery. However, surgery carries both considerable early morbidity and mortality (related mainly to the severity of the underlying liver disease) and substantial longer-term morbidity and mortality from hepatic encephalopathy and liver failure. The role of pharmacologic agents (eg, propranolol) intended to prevent variceal hemorrhage by reducing portal pressure remains to be established. At present, we recommend use of endoscopic variceal sclerotherapy for the control of active variceal bleeding, with employment of balloon tamponade and intravenous vasopressin if sclerotherapy is successful. Emergency shunt surgery should be reserved only for those patients whose bleeding cannot be controlled by these other means. For prevention of rebleeding in Child class C patients, we attempt to obliterate the varices by repeated endoscopic sclerotherapy. Patients who have two to three episodes of rebleeding despite this approach are considered for shunt surgery. For better-risk patients who do not have ascites, which is difficult to control, we are currently recommending a distal splenorenal shunt. Alternatively, repeated endoscopic variceal sclerotherapy is used for these better-risk patients (Child class A or B) in some centers, with shunt surgery reserved for patients who continue to rebleed. Which approach to preventing rebleeding in the better-risk patient is more effective, as well as the role of pharmacologic therapy with propranolol or other agents, remains to be settled by well-controlled randomized clinical trials.

Topics: Airway Obstruction; Catheterization; Esophageal and Gastric Varices; Fluid Therapy; Gastrointestinal Hemorrhage; Hemostatic Techniques; Humans; Hypertension, Portal; Liver Diseases, Alcoholic; Propranolol; Sclerosing Solutions; Vasopressins

Hepatocyte growth factor (HGF) is involved in many cellular responses, such as mitogenesis and apoptosis protection; however, its effect against oxidative injury induced by ethanol metabolism is not well understood. The aim of this work was to address the mechanism of HGF-induced protection against ethanol-generated oxidative stress damage in the human cell line VL-17A (cytochrome P450 2E1/alcohol dehydrogenase-transfected HepG2 cells). Cells were pretreated with 50 ng/ml HGF for 12 h and then treated with 100 mM ethanol for 0-48 h. Some parameters of oxidative damage were evaluated. We found that ethanol induced peroxide formation (3.3-fold) and oxidative damage as judged by lipid peroxidation (5.4-fold). Damage was prevented by HGF. To address the mechanisms of HGF-induced protection we investigated the cellular antioxidant system. We found that HGF increased the GSH/GSSG ratio, as well as SOD1, catalase, and gamma-glutamylcysteine synthetase expression. To explore the signaling pathways involved in this process, VL-17A cells were pretreated with inhibitors against PI3K, Akt, and NF-kappaB. We found that all treatments decreased the expression of the antioxidant enzymes, thus abrogating the HGF-induced protection against oxidative stress. Our results demonstrate that HGF protects cells from the oxidative damage induced by ethanol metabolism by a mechanism driven by NF-kappaB and PI3K/Akt signaling.

Topics: Androstadienes; Catalase; Cell Extracts; Cell Line; Cytochrome P-450 Enzyme System; Cytochrome P450 Family 2; Cytoprotection; Ethanol; Gene Expression Regulation, Enzymologic; Glutamate-Cysteine Ligase; Glutathione; Hepatocyte Growth Factor; Hepatocytes; Humans; Lipid Peroxidation; Liver Diseases, Alcoholic; Neurophysins; NF-kappa B; Oxidative Stress; Peptides; Protein Precursors; Proto-Oncogene Proteins c-akt; Signal Transduction; Superoxide Dismutase; Superoxide Dismutase-1; Transfection; Transgenes; Vasopressins; Wortmannin