Intrahepatic cholestasis involves impaired excretion of bile via the hepatobiliary system as a consequence of one or more lesions within the liver. In humans,
intrahepatic cholestasis most often results as a side-effect of
drug therapy and the clinical manifestation of this condition,
jaundice, has been estimated to account for hospitalization in 2 to 5% of the cases for the general population and approaches as much as 20% in the elderly. With the aging of the population and the common occurrence of poly-
drug therapy in geriatric patients, it is to be expected that
jaundice due to
drug-induced
intrahepatic cholestasis will become even more prevalent, and accordingly the need to understand the basic mechanisms of this disease condition will become more urgent. The list of culprit agents implicated in the induction of
intrahepatic cholestasis in humans is continually expanding. These include various
steroid hormones,
bile acids, drugs and other chemicals. Experimentally, a wide spectrum of agents has been shown to precipitate
intrahepatic cholestasis. Over the years, a number of hypotheses on the biochemical and pathological mechanisms of
intrahepatic cholestasis has emerged, including the following: impaired sinusoidal membrane function; interference with the distribution and binding of cytoplasmic endogenous
carrier proteins; interference with mitochondrial energy supply; defects in the canalicular membrane including altered Na+/K+ -
ATP-ase activity; impairment of microfilament and microtubule functions; interference with bile secretion involving
bile acid dependent and independent fractions, and altered
bile acid metabolism due to "hypoactive hypertrophic smooth endoplasmic reticulum". In partial agreement with the latter hypothesis, our studies indicated that impairment of the endoplasmic reticulum might represent one of the early stages in the development of
intrahepatic cholestasis. Various experimental conditions that induce
intrahepatic cholestasis to different degrees resulted in an interference of the synthesis of microsomal
phospholipids and altered microsomal function. The conditions included the administration of various hepatotoxic compounds or
steroids, pregnancy, delayed development of the endoplasmic reticulum in neonates, and dietary methyl donor or
choline deficiency. This review reports the biochemical-pathological mechanisms postulated to be involved in the genesis of
intrahepatic cholestasis with specific reference to experimental models of
drug-induced
intrahepatic cholestasis. The important practical implications of
cholestasis are also briefly surveyed.