Cholestasis: pathophysiology and pathobiochemistry

Clinical and morphological diagnosis of cholestasis involves a variety of different parameters, but bile fluid formation and composition of bile are usually not accessible in patients. In contrast, a pathophysiological definition of cholestasis can be based on current knowledge on the mechanisms of bile formation. Hence, causes of cholestasis may be localized in each step of the process of bile formation. 1. Inhibition of fluid formation reduces maximal secretory capacity. 2. Inhibition of the transcellular hepatobiliary transport may involve transport carriers, binding proteins, and the systems of biotransformation. 3. Mechanical obstruction or regurgitation of bile constituents due to increased permeability of the bile tract may inhibit the biliary elimination of cholephilic compounds. Consequences of the inhibition of biliary elimination are retention in the liver and the whole organism of potentially toxic compounds. Among these are endogenous compounds such as bile acids and cysteinyl-leukotrienes, but xenobiotics as well may become more toxic in cholestasis. The composition of bile and portal venous blood is altered. In experimental animals, changes in secretory function can already be observed before clinically used indicator enzymes of cholestasis increase. This functional inhibition of biliary elimination can be characterized as "subclinical" cholestasis that may, nevertheless, inhibit the elimination and potentiate the toxicity of cholephilic endo- and xenobiotics.