C S Lieber

..DLPC, an innocuous phospholipid, may be considered for prevention and treatment of liver fibrosis...

..Our aims were to determine the effectiveness of PPC in preventing or reversing liver fibrosis in heavy drinkers and to assess the extent of liver injury associated with the reduced drinking achieved in these patients...

..Our aim was to determine whether this could be overcome by using dilinoleoylphosphatidylcholine (DLPC), an innocuous antioxidant extracted from soybeans...

..An additional system, containing cytochromes P-450 inducible by chronic alcohol feeding, was demonstrated in liver microsomes and found to be a major cause of hepatotoxicity...

..Finally, abstinence from excessive drinking is always indicated; it is difficult to achieve but agents that oppose alcohol craving are becoming available and they should be used more extensively...

..Progress in the understanding of the pathogenesis of alcoholic fatty liver and its progression to inflammation and fibrosis has resulted in prospects for their better prevention and treatment...

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..Obesity and diabetes are frequently associated with nonalcoholic steatohepatitis (NASH), but studies have been hampered by the absence of a suitable experimental model...

..The anti-inflammatory corticosteroids and colchicine yielded mixed results. Finally, replacing long-chain with medium-chain triglycerides opposed the fatty liver experimentally and clinically...

..Thus, in view of the innocuity of silymarin, it might be advisable in future clinical studies to insure the controlled administration of sufficient amounts of silymarin...

..This was shown in alcohol-fed baboons and in other experimental models of liver injury and in clinical trials, some of which are reviewed in other articles in this issue...

..This symposium reviewed the biological and corresponding molecular aspects of SAMe metabolism and the clinical consequences of its deficiency or supplementation in various tissues...

..An overall substantial and sustained reduction in drinking was observed. Hepatic histological and other findings are described in a companion article...

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..Similarly dilinoleoylphosphatidylcholine (DLPC), PPC's main component, also partially opposes the increase in CYP2E1 by ethanol. Hence, therapy with SAMe +DLPC is now being considered...

..Available antiviral agents are contraindicated in the alcoholic. Anti-inflammatory agents, such as steroids, may be selectively useful. Finally, anticraving agents, such as naltrexone or acamprosate, should be part of therapy...

..Moreover, a diagnostic algorithm including 3 serum markers (TIMP1, PIIINP, HA) and age has been proposed to accurately detect fibrosis with acceptable levels of sensitivity/specificity in a chronic hepatitis C subgroup...

..Since there is a pathophysiological link between SIRT1 and PGC-1alpha and mitochondrial energy, the implication of the study is that mitochondrial dysfunction due to alcohol abuse can be treated by dietary modifications...

..Because of the similarity of the pathogenesis of alcohol-induced liver damage and non-alcoholic steatohepatitis (NASH), our aim was to assess whether MCT is also beneficial in NASH...

..We now wondered whether the induction of mitochondrial CYP2E1 plays a role and whether liver injury could be avoided through mitochondrial intervention...

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..PPC (and its active component dilinoleoylphosphatidylcholine) also oppose hepatic oxidative stress and fibrosis. PPC is now being tested clinically for the prevention and treatment of liver disease in the alcoholic...

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..Thus, alcohol consumption disrupts nuclear-mitochondrial interactions by post-translation protein modifications, which contribute to alteration of mitochondrial biogenesis through the newly discovered reduction of SIRT5...

..Corresponding clinical trials are ongoing...

..DLPC decreases ethanol-induced CYP2E1 and should be considered for the prevention of alcoholic liver disease...

..As a consequence, administration of ethanol (an exogenous source of acetaldehyde) resulted in striking elevations in the levels of acetaldehyde in carbon tetrachloride-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)..

..Therefore, azide should be avoided when measuring the MEOS activity because it may lead to underestimation, especially of CYP1A2- and CYP3A4-dependent ethanol oxidation...

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..These data are consistent with the view that Class IV ADH is a member of the ADH family and is phylogenetically close to the other ADHs...

..CONCLUSIONS: Beta-carotene potentiates the CYP2E1 induction by ethanol in rat liver and also increases CYP4A1, which may, at least in part, explain the associated hepatotoxicity...

..CONCLUSIONS: In alcohol-fed baboons, cytokeratin 7 staining of hepatocytes (but not cytokeratin 19, nor fat deposition) predicts with a high degree of sensitivity and specificity progression to more severe liver disease...

..The parallelism between these effects suggests a causal link. Furthermore, these beneficial effects and the innocuity of lycopene now justify an in vivo trial...

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..In conclusion, this preliminary study indicates that beta-carotene is toxic to hepatocytes, especially when combined with acetaldehyde, the metabolite of ethanol...

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..The concentration-dependency of these effects may explain earlier discrepancies. The combined pharmacokinetic differences may increase the vulnerability of women to the effects of ethanol...

..This process appears to be mediated by the JAK/STAT pathway via the leptin receptor long form and the H2O2-dependent p38 and ERK1/2 pathways via activated JAK...

..CONCLUSION: As decreased TIMP-1 production may enhance collagen deposition, the combined administration of DLPC+SAMe should be considered for the prevention of H2O2-mediated signaling and the resulting fibrosis...

..PPC also opposes hepatic oxidative stress and fibrosis. It is now being tested clinically...

..Since increased TNF-alpha generation plays a pathogenic role in alcoholic liver disease, the DLPC action on Kupffer cells may explain, in part, its beneficial effects on liver cell injury after ethanol consumption...

..This effect of DLPC may explain, at least in part, the antifibrogenic action of PPC against alcoholic and other fibrotic disorders of the liver...

..Because acarbose attenuates many of the hepatic alterations associated with experimental NASH, it is now indicated to determine whether it exerts similar beneficial effects in patients afflicted by this disease...

..Because medium-chain triglycerides (MCT) reduce alcoholic hepatosteatosis, their effects on ADRP were also evaluated...

..By contrast, TIMP-1, collagen VI, PIIINP, HA and MMP-2 did not significantly change. The mode of action of alcohol on these tests is unknown. These differences must be considered when using those measurements to assess liver fibrosis...

..New agents currently are being studied as promising nutritional supplements for alcoholics with liver disease...

..ERK1/2 stimulates alpha1(I) collagen promoter activity, whereas p38 stabilizes its mRNA. Accordingly, interference with leptin-induced oxidative stress by antioxidants provides an opportunity for the prevention of liver fibrosis...

..These effects were equally prevented by either PPC or DLPC. In conclusion, DLPC fully reproduced PPC's protective action and may be effective in the prevention or delay of more severe liver damage...

..Given the frequent history of alcohol use in patients with hepatitis C, APRI may be of limited usefulness in the diagnosis of fibrosis in many patients...

..Because alcohol potentiates the fibrosis- and cancer-inducing actions of HCV, alcoholics are particularly vulnerable to HCV infection and most in need of treatment...

..Because DLPC is a pure and well defined compound, it may be more suitable than PPC for intervention against alcohol-induced apoptosis...

..CONCLUSIONS: Chronic, but not acute, ethanol administration increases peroxynitrite hepatotoxicity by enhancing concomitant production of nitric oxide and superoxide, both of which are prevented by polyenylphosphatidylcholine...

..LX-2 hepatic stellate cells produce increased amounts of collagen and tissue inhibitor of metalloproteinase (TIMP)-1 in response to leptin. The effect of leptin on MMP-1 production has not been reported...

..This was due, at least in part, to inhibition of hydrogen peroxide production and of the resulting lipid peroxidation, confirming the potent anti-oxidant properties of lycopene and its suitability for clinical studies...

..Both inhibitors reduced TNF-alpha generation. Thus, DLPC diminishes LPS-dependent TNF-alpha generation by inhibiting p38 and ERK1/2 activation; the latter leads to decreased NF-kappaB activation...

..Accordingly, CYP2E1 priming could explain the sensitization of Kupffer cells to LPS activation by ethanol, a critical early step in alcoholic liver disease...

..Northern hybridization analysis with the specific probe for the mRNA of this protein showed that it is expressed in the human stomach but not in the liver. These data indicate that the cDNA we cloned is that of human class IV ADH...

..Broader studies and clinical applications of these earlier findings are now warranted...

..Those who are healthy and whose drinking history shows little risk of developing alcohol dependency may continue to drink moderate amounts. Heavy drinkers should be advised to quit...

..It is concluded that a ST approach is more helpful than MT in treating severely alcohol-dependent individuals who have not been able to cut down drinking on their own. Those already drinking less appeared to be helped by MT...

..RSA committees are active in presenting the most recent findings to the public and to elected representatives, and in making recommendations on areas of research that need funding...

..All the stimulatory effects of ethanol on flow, as well as the rise in NO levels, were prevented by L-NMMA, incriminating NO as the mediator of the hemodynamic effects of ethanol oxidation, acting probably via acetate and adenosine...

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..This review will also aim to describe the importance of IFN-alpha-based therapies in HCV infection, ways of monitoring them, and associated complications...

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..Lieber (USA) discussed the development of the understanding of the pathophysiology of alcoholic liver disease in the last 50 years. He emphasized the role of pathophysiology as an important prerequisite for better treatment strategies...

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..The gene expression profile of ALD is dominated by alcohol metabolism and inflammation and differs from other liver diseases. Annexins may play a role in the progression of fibrosis in ALD...

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..Funds are requested for special laboratory tests, study nurses, travel to meetings, patient monitoring expenses and a core office. ..

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..Accordingly, support is requested for the completion of this novel approach for the treatment of HCV+ patients who become abstinent or who continue to consume alcohol moderately. ..

..Our ultimate goal is to define in molecular terms some of the most far-reaching changes brought about by chronic ethanol consumption in the internal milieu of the body and the resulting response to the environment...

..If successful, the proposed studies will establish DLPC as the first safe and chemically defined agent capable of preventing the progression (and possibly of promoting the regression) of hepatic and pulmonary fibrosis. ..

..Such information is aimed at elucidating key aspects of alcohol mediated pathology in a way which may eventually affect alcohol related medical complications, their prevention and treatment. ..

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