Current concepts in intrahepatic cholestasis.

The investigations on experimental intrahepatic cholestasis of the last 10 years suggest that any of several different functional alterations may lead to cholestasis. In most studies very high doses of cholestatic compounds have been used. The relevance of these studies to clinical syndroms of cholestasis which usually are observed at much lower doses, is unclear. One target of cholestatic compounds may be the lipid phase of several cell structures such as the sinusoidal and canalicular membrane, the endoplasmic reticulum and the mitochondria. By their capacity to interact with the lipid layer and proteins of membranes these compounds impair specific cellular functions: the activity of carrier proteins, the activity of the hydroxylating system and the energy supply. Another target may be the binding proteins in the cytoplasma and possibly the microfilaments. One may suggest that other factors such as interference with regulatory processes in the cell may be of interest in the future. So far the primary event of drug-induced intrahepatic cholestasis is still unknown and it is not even clear whether the increased bile acid levels are cause or consequence of the cholestatic condition.