Alcohol and liver fibrosis--pathobiochemistry and treatment.
In Western societies roughly 50% of all cases of liver cirrhosis are related to alcohol abuse. The oxidative metabolite of ethanol, acetaldehyde, often in conjunction with viral or metabolic liver disease, is implicated as the major cause for liver fibrogenesis. Acetaldehyde damages cell membranes, initiates lipid peroxidation and forms noxious protein adducts, resulting in the activation of Kupffer cells and perisinusoidal lipocytes/portal fibroblasts. The activation of lipocytes and fibroblasts to a proliferative and collagen-producing myofibroblast-like phenotype is triggered by the release of fibrogenic factors such as platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta) from the activated Kupffer cells. Due to the socioeconomic burden inflicted by cirrhosis, antifibrotic treatment is urgently needed. Strategies to prevent or reverse cirrhosis must interrupt the continuous process of pathological wound healing in the liver. An antifibrotic effect has been demonstrated for the interferons, prostaglandins E and relaxin. Polyunsaturated lecithin, silymarin and ursodeoxycholic acid, agents with a high hepatotropism and a good safety-profile, appear to have antifibrotic properties. Targeted approaches include the specific removal of matrix-bound fibrogenic growth factors and the induction of stress-relaxation of the activated mesenchymal cells by biologically active matrix-peptides and their stable analogues. Since serum tests for the non-invasive assessment of collagen synthesis and degradation in the liver are now available, rapid progress in the development and clinical application of antifibrotic drugs can be anticipated.
Schuppan
D
D
Klinikum Benjamin Franklin, Abteilung für Gastroenterologie und Hepatologie, Freie Universität, Berlin, Germany.
Atkinson
J
J
Ruehl
M
M
Riecken
E O
EO
D000079:Acetaldehyde / Q000493:pharmacokinetics; D000431:Ethanol / Q000493:pharmacokinetics; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008104:Liver Cirrhosis, Alcoholic / Q000188:drug therapy / Q000473:pathology*; D010982:Platelet-Derived Growth Factor / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology
D010982:Platelet-Derived Growth Factor; D016212:Transforming Growth Factor beta; D000431:Ethanol; D000079:Acetaldehyde