Alcoholic liver disease: new insights in pathogenesis lead to new treatments

Much progress has been made in the understanding of the pathogenesis of alc oholic liver disease, resulting in improvement of prevention and therapy, w ith promising prospects for even more effective treatments. The most succes sful approaches that one can expect to evolve are those that deal with the fundamental cellular disturbances resulting from excessive alcohol consumpt ion. Two pathologic concepts are emerging as particularly useful therapeuti cally. Whereas it continues to be important to replenish nutritional defici encies, when present, it is crucial to recognize that because of the alcoho l-induced disease process, some of the nutritional requirements change. Thi s is exemplified by methionine, which normally is one of the essential amin o acids for humans, but needs to be activated to S-adenosylmethionine (SAMe ), a process impaired by the disease. Thus, SAMe rather than methionine is the compound that must be supplemented in the presence of significant liver disease. Indeed, SAMe was found to attenuate mitochondrial lesions in babo ons, replenish glutathione, and significantly reduce mortality in patients with Child A or B cirrhosis. Similarly, polyenylphosphatidylcholine (PPC) c orrects the ethanol-induced hepatic phospholipid depletion as well as the d ecreased phosphatidylethanolamine methyltransferase activity and opposes ox idative stress. It also deactivates hepatic stellate cells, whereas its dil inoleoyl species (DLPC) increases collagenase activity, resulting in preven tion of ethanol-induced septal fibrosis and cirrhosis in the baboon. Clinic al trials with PPC are ongoing in patients with alcoholic liver disease. Fu rthermore, enzymes useful for detoxification, such as CYP2E1, when excessiv ely induced, become harmful and should be downregulated. PPC is one of the substances with anti-CYP2E1 properties that is now emerging. Another import ant aspect is the association of alcoholic liver disease with hepatitis C: a quarter of all patients with alcoholic Liver disease also have markers of HCV infection, with are even higher incidence in some urban areas but, at present, no specific therapy is available since interferon is contraindicat ed in that population. However, in addition to antiviral medications, agent s that oppose oxidative stress and fibrosis should also be tested for hepat itis C treatment since these two processes contribute much to the pathology and mortality associated with the virus. In addition to antioxidants (such as PPC, silymarin, alpha-tocopherol and selenium), anti-inflammatory medic ations (corticosteroids, colchicine, anticytokines) are also being tested a s antifibrotics. Transplantation is now accepted treatment in alcoholics wh o have brought their alcoholism under control and who benefit from adequate social support but organ availability is still the major limiting factor a nd should be expanded more aggressively. Finally, abstinence from excessive drinking is always indicated; it is difficult to achieve but agents that o ppose alcohol craving are becoming available and they should be used more e xtensively.