Symposium 10 Monday Sept. 24th 9 am–10.30 am; Room: Lecture Hall 2
ESBRA-ISBRA joint meeting: Alcohol and organ damage: Chairpersons: Seitz HK (Germany), Saito SJ (Japan)
; |
Abstract |
|---|
Presentation S10-1
Alcohol and Organ Damage Alcohol and the Liver-Alcoholic Liver Disease -Current Status, Pathogenesis and Therapy
Ishii H, Horie Y, Yamagishi Y, Kato S, Hibi T (Japan)
Aims. Alcoholic liver disease (ALD) has continued to be one of the major causes of liver diseases in Western world and Japan. Indeed, the incidence of ALD has kept increasing in Japan; associated with an increase in alcohol consumption. Although alcohol-induced steatosis is clinically benign, treatment at an earlier stage is important in order to prevent further development of steatohepatitis, hepatic fibrosis and cirrhosis.
Although the pathogenesis of ALD has been extensively investigated, newer insights into the pathogenesis have been advocated including the key roles of excessive production of TNF-
, TGF-β and reactive oxygen species associated with bacterial translocation and gut-derived endotoxin. More recently, chronic alcohol feeding has been shown to reduce adiponectin production closely associated with a profound effect on fatty acid oxidation. Indeed, adiponectin has been found to attenuate alcoholic steatosis and steatohepatitis. Furthermore, we have previously reported that leptin deficiency enhances sensitivity of rats to alcohol-induced steatohepatitis through hepatocyte-specific interaction of antioxidant proteins, such as metallothionein –1 and –2, and resultant exaggeration of oxidative stress in hepatocytes. Thus, leptin appears to play one of the key roles in the pathogenesis of ALD. Concerning for treatment of ALD, the most important target of treatment is alcoholic hepatitis, especially severe-type alcoholic hepatitis (SAH). Multiple organ failures are frequently observed in patients with SAH, most of who have a poor prognosis similar to fulminant hepatitis. Although the prognosis of fulminant hepatitis in Japan, majority of them being HBV origin, has been improved by intensive treatments such as plasma exchange (PE), mortality of patients with SAH has remained high. We have carried out nation-wide survey on current status of patients with SAH since 1998.
The ratio of female patients with SAH (24%) was higher than that for other type of ALD (approximately 10%). Mortality of patients with SAH has remained high (66.4%), while that was markedly improved (33.4%) in 2003. PE appears to have been effective in reducing mortality of patients with SAH. White blood cell (WBC) counts were much higher, red blood cell counts were lower and prothrombin time (PT) was prolonged in patients who had died, when compared with the patients who had survived. SAH patients with markedly elevated WBC counts, prolonged PT, or anemia should be treated at an earlier stage with an intensive treatment such as PE. Recently, we have succeeded in the treatment of several patients with SAH who were cured by granulocyte and monocyte adsorption apheresis (GCAP) or leUkocytapheresis (LCAP). Eighteen cases of SAH treated with GCAP or LCAP were reported in Japan, and 13 cases (73%) were successfully treated. Thus, GCAP and LCAP are potential therapeutic strategies for patients with SAH.
Presentation S10-2
Alcohol and the pancreas
Apte M (Australia)
Alcoholic pancreatitis is a major complication of alcohol abuse. Since only a minority of alcoholics develop pancreatitis, there has been a keen interest in identifying the factors that may confer individual susceptibility to the disease. Diet, drinking patterns and a range of inherited factors including polymorphisms of ethanol metabolising enzymes have been evaluated. With respect to the non-oxidative pathway of ethanol metabolism, the polymorphism of CEL [cholesteryl ester lipase, an enzyme that catalyses the conversion of ethanol to fatty acid ethyl ester (FAEE)] is of interest, but the functional significance of this polymorphism is not yet defined. Thus, at present, no susceptibility factor has been unequivocally identified. In contrast, considerable progress has been made with respect to the direct toxic effects of alcohol on the pancreas. It is now known that the acinar cell can metabolise alcohol and that the deleterious effects of alcohol and its metabolites on subcellular organelles may predispose the gland to autodigestive injury in the presence of an appropriate trigger factor. Recent experimental studies provide evidence in support of bacterial endotoxin as one such trigger factor. Another major development in recent years has been the characterization of pancreatic stellate cells (PSCs) as the primary drivers of pancreatic fibrosis. PSCs are activated directly by ethanol and its metabolites and by factors such as cytokines and oxidant stress (known to be upregulated in pancreatic injury). Signalling pathways that may mediate this activation have also been identified. These important advances provide a platform for the development of targeted treatments to prevent/reverse pancreatic fibrosis in alcoholic chronic pancreatitis.
Presentation S10-3
Ethanol-induced brain injury: Therapeutic potential of neurogenesis for recovery from ethanol-induced damage of neuronal network
Hashimoto E, Yoshinaga T, Ishii T, Tateno M, Ukai W, Saito S, Saito T (Japan)
Aims. Recent studies have described the possible relevance of disruption of neural stem cell (NSC) functions to the pathophysiology of alcoholism. To understand how ethanol affects neurogenesis, we investigated the effect of ethanol on differentiation from NSCs into neurons. Next, we transplanted NSCs into a model of fetal alcohol effects (FAE) to investigate the possibility of regenerative therapy for FAE.
Methods. We prepared NSCs from E13 rat embryos. The function of NSCs differentiation was assessed by MAP2-ELISA and detected the cellular events in NSCs by Western blot analysis for signal transduction molecule and DNA binding assay for transcriptional factors. We transplanted NSCs labeled with fluorescent dye and radioisotope into a FAE model rat intravenously. Behavioral performance was evaluated by elevated plus maze after transplantation following quantification and localization analysis of NSCs in the brain.
Results. Our in vitro study demonstrated that ethanol suppressed neuronal differentiation at concentrations that did not affect the survival of NSCs. The binding activity of NRSF to its target consensus sequence of NRSE was enhanced after the treatment of NSCs with ethanol. The transplanted cells were detected in wide areas of brain and were greater in number in the brains of the FAE group compared to the control group. Furthermore NSC transplantation attenuated behavioral abnormalities in FAE animals.
Conclusions. These results suggest that differentiation is the most sensitive target of ethanol in the process of neurogenesis. Furthermore, the intravenous NSC transplantation might be a possible approach to recover the ethanol-induced damage of neuronal network.
Presentation S10-4
Alcohol and skeletal muscle
Preedy VR, Fegredo JA, Nakahara T, Hashimoto K, Hirano M (UK)
Aims. Muscle damage (i.e. alcoholic myopathy) will occur in about 40–60% of chronic alcoholics. Thus, this disease entity is about 4–6 times more common than cirrhosis. Alcoholic myopathy is characterised by muscle weakness and loss of muscle bulk. This is due to the selective atrophy of Type II (anaerobic, glycolytic, fast twitch) fibres: Type I fibres (aerobic, oxidative, slow twitch) are relatively protected. The pathogenic mechanisms are unknown.
Methods. In rat models of acute and chronic ethanol toxicity, anatomically-distinct muscles were taken to represent different fibre types. Thus, Type-II fibres were represented by the plantaris or gastrocnemius muscles whilst Type-I fibres were represented by the soleus.
Results. We showed that alcohol increases oxidative stress-related products within the membrane domain of muscle. However, measures of global antioxidant status in muscle appear to be refectory in acute studies whilst chronic studies show impaired antioxidant status. A number of other processes are also involved in the genesis of alcoholic myopathy. For example, myofibrillary protein composition and myosin isoforms are reduced. The level of mRNA encoding myosin is also reduced, albeit for the slow myosin isoform (1-β). Indeed the expression of many hundreds of genes are altered in alcohol-exposed muscle (for example, c-myc, heat shock protein-27 etc), whilst the formation of acetaldehyde protein adduct offers a chemicophysiological basis for this disease.
Conclusions. Alcoholic myopathy is a multifaceted disease process and its study is important as other muscle pathologies are also characterised by selective damage to Type-II fibres.
Presentation S10-5
Alcohol and cancer
Homann N
Alcohol intake is the major cause for cancer of the esophagus, the oral cavity and the pharynx and important risk factors for laryngeal and hepatocellular cancer. The increased risk attributable to alcohol of cancer in the large intestine and in the breast is much smaller, whereas other organ cancers show no significant association to alcohol intake.
Experimental studies have elucidated some of the mechanisms behind these findings. Alcohol associated malnutrition and the fundamental changes of alcohol in the metabolism of other nutrients such as carbohydrates, lipids, vitamins and trace elements may explain a part of alcohol associated carcinogenesis. Other pathomechanisms of alcohol include the increased activation of procarcinogens via alcohol induced cytochrom P450 2E1, an increased solubility and mucosal transfer of carcinogens by alcohol, an altered hormonal status, a suppressed immune function, carcinogenic congeners in alcoholic beverages and an abnormal induced cell proliferation by alcohol. Ethanol-induced cytochrome P-450 2E1 produces various reactive oxygen species, leading to the formation of lipid peroxides such as 4-hydroxy-nonenal. Furthermore, alcohol impairs the antioxidant defense system, resulting in mitochondrial damage and apoptosis.
The metabolism of ethanol leads to the generation of acetaldehyde, a substance which is predominantly responsible for alcohol associated carcinogenesis. Genetic linkage studies could show that certain polymorphisms and/or mutations in the genes coding for enzymes responsible for acetaldehyde accumulation and detoxification are associated with an increased cancer risk. This has been shown for Asians with low acetaldehyde dehydrogenase 2 and for Caucasians with alcohol dehydrogenase 1C*1/1. In addition also bacterial metabolism may lead to very high acetaldehyde levels. Alcohol and alcoholism also influences the treatment of cancer. Alcoholics are at a higher risk of perioperative morbidity and surgical complications.