Macrovesicular steatosis

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). 

A 33-year-old chronic alcoholic with hepatitis C developed acute liver and renal insufficiency with grade III encephalopathy. Hemodialysis was begun and emergency liver transplantation was performed. The explanted liver showed marked diffuse macrovesicular steatosis with massive coagulative-type necrosis. The postoperative course included a persistently raised gamma-glutamyltransferase, but he recovered fully after 60 days. 

Macrovesicular steatosis can be attributed to alcohol or cocaine, but massive liver necrosis is more probably due to cocaine. The mechanisms of cocaine hepatotoxicity, such as increased lipid peroxidation, free radical activity, and impaired calcium sequestration, may be potentiated by alcohol. 

This occurs typically in alcoholic steatosis. Macrovesicular steatosis has less effect on the function of the hepatocyte and liver function tests are usually only minimally abnormal. The accumulation of fat within the hepatocyte may trigger an inflammatory response this inflammation within the hepatocyte, or hepatitis related to steatosis, is termed steatohepatitis. Continued inflammatory responses further damage hepatocytes, and the liver disease may then progress to fibrosis and cirrhosis. 

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. 

Microvesicular steatosis (s. p. 582) presents as deposits of tiny lipid particles in the cisterns of the endoplasmic reticulum. The lipid particles are thus surrounded by a membrane. The nucleus remains at the centre of the cell. Macrovesicular steatosis (s. p. 580) often develops further into necrosis if the intake of a foreign substance is continued, (s. tab. 29.10) PhosphoHpidosis is regarded as a special type of steatosis. The hepatocytes are enlarged and display a foamy cytoplasm resulting from a marked increase in phospholip)-... 

A middle-aged woman who had taken germanium lactate-citrate for at least a year (with an estimated cumulative dose of 32.1 g of germanium) developed renal insufficiency with a creatinine clearance of 10 ml/minute, raised creatine kinase activity, and moderately raised hver enzymes. Biopsy showed highly vacuolated cytoplasm in the epithelial cells of the distal renal tubules and microvesicular and macrovesicular steatosis of centrilobular hepatocytes. After withdrawal of the germanium the laboratory values normalized but moderately severe renal impairment persisted (SEDA-16, 231). 

Interferon alfa-associated macrovesicular steatosis has been reported (258). 

Castera L, Kahnsky E, Bedossa P, Tertian G, Buffet C. Macrovesicular steatosis induced by interferon aha therapy for chronic myelogenous leukaemia. Liver 1999 19(3) 259-60. 

In another study, the pathological lesions found in liver biopsies from patients treated with methotrexate were non-specific, consisting usually of macrovesicular steatosis, nuclear pleomorphism, chronic inflammatory infiltrates in the portal tracts, focal liver cell necrosis, fibrosis, and cirrhosis (52). 

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