Abstract:

Several epidemiological studies suggest that coffee drinking is associated with a slower progression of fibrogenesis in patients with chronic, particularly alcoholic, liver disease. However, a causal, mechanistic explanation was pending. New results indicate that the methylxanthine caffeine, major component of coffee and the most widely consumed pharmacologically active substance in the world, might be responsible for this phenomenon as it inhibits the synthesis of Connective Tissue Growth Factor (CTGF/CCN2) in liver parenchymal and non-parenchymal cells, primarily by inducing degradation of Smad2 (and to a much lesser extent Smad3). In particular paraxanthine has been identified as the most potent inhibitor of CTGF synthesis among the three primary metabolites of caffeine, i.e. paraxanthine, theophylline, and theobromine. CTGF plays a crucial role in the fibrotic remodeling of various organs which has therefore frequently been proposed as therapeutic target in the management of fibrotic disorders. This article summarizes the clinicalepidemiological observations as well as the pathophysiological background and provides suggestions for the therapeutic use of methylxanthine derivatives in the management of fibrotic liver diseases.