Fatty macrovesicular

Antiretroviral nucleoside analogues have been associated with hepatic steatosis and lactic acidosis. These compounds require phosphorylation to active triphosphate derivatives by cellular phosphokinases. The triphosphate nucleotide inhibits the growing proviral DNA chain, but it also inhibits host DNA polymerases, and this can result in compensatory glycolysis and lactic acidosis. Abnormal mitochondrial oxidation of free fatty acids causes the accumulation of neutral fat in liver cells, and this manifests as hepatomegaly with macrovesicular steatosis. Hepatic steatosis and lactic acidosis have been reported previously with zidovudine, didanosine, zalcita-bine, Combivir (zidovudine plus lamivudine), and lamivudine. Of 349 Australian patients studied for 18 months (516 patient-years) taking NRTIs only two had severe lactic acidosis (847). 

Chemicals that damage mitochondrial structure, enzymes, or DNA synthesis can disrupt beta oxidation of hpids and oxidative energy production within hepatocytes. Prolonged interruption of beta oxidation leads to micro-vesicular steatosis which can progress to macrovesicular steatosis. This sequence of events has been noted with alcoholic and nonalcoholic steatohepatitis. The role of mitochondria has been extensively studied with nonalcoholic fatty hver disease, a major issue in human medicine. Alcoholic steatosis and other forms of hepatic steatosis have been linked to impairment of ATP homeostasis and mitochondrial abnormalities have been reported in a growing body of hterature. 

Histologically, non-alcoholic steatohepatitis shows moderate to high-grade, mainly macrovesicular fatty degeneration of the liver cells with inflammatory infiltrates and formation of fibrosis. Cirrhosis frequently develops. Despite the morphological similarity to alcohol-induced fatty liver hepatitis, there is no (noteworthy) alcohol consumption involved in NASH. Viral or autoimmune hepatitis are not detectable either. There are no or only moderate subjective complaints. The transaminases are normal or slightly increased. NASH is mostly associated with obesity and/or type II diabetes, thus NASH is regarded as the hepatic manifestation of a metabolic syndrome. 

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