Fatty microvesicular

The antipsychotic chlorpromazine is a prototype heptotoxicant for production of cholestasis. Pleiotropic effects of chlorpromazine on membrane permeability and associated ion gradients and microfilament-mediated canalicular contraction have been attributed to detergent effects. Valproic acid, an anticonvulsant, is associated with microvesicular steatosis. Inhibition of mitochondial fatty acid (S-oxidation is an important component of this toxic effect and is apparently related to carnitine availability as evidenced by the protection afforded by L-carnitine supplements. The hypolipidemic drugs clofibrate, fenofibrate, and gemfibrozil are peroxisome prolif-erators in rodent liver, but not in humans. Isoniazid, an antibiotic used to treat tuberculosis, exhibits an approximately 1 % incidence of hepatotoxicity. Although toxicity is known to be metabolism-dependent and protein adduction has been well-... 

The authors suggested that this patient had a defect in lipid metabolism, based on the muscle biopsy. Muscle mitochondria are a principle site for beta-oxidation of fatty acids. Microvesicular steatosis can progress to liver failure with severe and prolonged impairment of beta-oxidation. This metabolic defect may have exacerbated the direct toxic effects of cocaine. 

The liver is the principal organ of fat metabolism and, as a result, damage to the hepatocytes can disrupt normal fat metabolism and lead to steatosis the accmnnlation of fat within the hepatocytes. Steatosis or fatty liver can be classified into two categories based on the size of the fat droplets deposited within the hepatocyte microvesicular or... 

Hepatic lesions in the case of yellow fever are more likely to correspond to those of hepatosis, (s. p. 404) There is also evidence of distinct acidophilic hepatocellular necrosis as well as microvesicular fatty degeneration of the hepatocytes. Hyaline, eosinophilic inclusions in the cytoplasm of degenerated hepatic cells (so-called Councilman bodies) are characteristic and were first identified by w.T. Councilman in 1890 in yellow fever (s. p. 396). Acidophilic inclusion bodies in the hepatocellular nuclei which are arranged concentrically around the nucleolus (so-called Torres corpuscles) correspond to the yellow fever virus (C.M. Torres, 1928). The liver does not present any significant signs of inflammation. The reticular fibre structure is maintained, so that the liver architecture is usually completely restored-provided the outcome of the disease is favourable, (s. fig. 23.4)... 

Alcoholic foamy degeneration is considered to be a variant of alcoholic fatty liver (T. Uchida et al., 1983). There is evidence of microvesicular steatosis, giant mitochondria, focal cell necrosis (with elevation of GPT, GOT and GDH) and cholestasis (with increase of AP and sometimes of bilirubin), whereas inflammatory alterations are rare and Mallory bodies totally absent. Likewise, there is no sign of fever or leucocytosis. (133)... 

Tab. 31.3 Causes of microvesicular fatty degeneration (with some references)...

Liver biopsy may be required for diagnosis - unless there are any contraindications, (s. tab. 7.4) In order to detect the characteristic microvesicular (mainly centroacinar) fatty changes, fixation without alcohol and examination of the biopsy material in the form of a frozen section are necessary. (108) The hepatocytes are swollen and resemble so-called foam cells. The nucleus is pyknotic. The mitochondria are deformed, (s. fig. 31.9)... 

Fig. 31.9 Microvesicular fatty changes of liver cells in acute fatty liver of pregnancy (Sudan red)...

Sherlock, S. Acute fatty liver of pregnancy and the microvesicular fat diseases. Gut 1983 24 265-269... 

Fatal multisystem toxicity including both renal and hepatic failure, with microvesicular fatty change in the liver, has been reported with tolmetin in a young woman (12). 

Shaw GR, Anderson WR. Multisystem failure and hepatic microvesicular fatty metamorphosis associated with tolmetin ingestion. Arch Pathol Lab Med 1991 115(8) 818-21. 

Accumulation of microvesicular lipid droplets between myofibrils adjacent to mitochondria was found in muscle biopsies from seven children taking valproate (SEDA-22, 92). Ultrastructural abnormalities in the mitochondria suggested that these could have resulted from impaired mitochondrial fatty acid oxidation. 

Jolly, RA, Ciurlionis R, Morfitt D, et al. Microvesicular steatosis induced by a short chain fatty acid effects on mitochondrial function and correlation with gene expression. Toxicol Pathol. 2004 32(Suppl. 2),19-25. 

Alcohol is the drug that most commonly produces steatonecrotic changes in the liver. When alcohol is converted into acetaldehyde, the synthesis of fatty acids is increased. When the hepatocyte has become completely engorged with microvesicular fat, it often breaks open, spilling into the blood. If enough hepatocytes break open, an... 

Cause of hypoglycemia Decreased hver glycogen after hver undergoes fatty infiltration and subsequent liver failure. Histology reveals swollen hepatocytes in which the cytoplasm is filled with microvesicular fat. 

In experimental animals, tetracycline and the various tetracycline derivatives lead to extensive microvesicular steatosis of the liver (Freneaux et al. 1988 Labbe et al. 1991). This marked steatogenic effect is due to the dual effects of the tetracyclines, which inhibit both the mitochondrial B-oxidation of fatty acids (Freneaux et al. 1988 Labbe et al. 1991) and also MTP activity, thus decreasing the hepatic secretion of very low-density lipoproteins (Letteron et al. 2003). 

Nonsteroidal antiinflammatory drugs. Pirprofen, naproxen, ibuprofen, and keto-profen can occasionally cause microvesicular steatosis in humans (Bravo et al. 1997 Victorino et al. 1980 Danan et al. 1985 Dutertre et al. 1991). These NSAIDS have a 2-arylpropionate structure, with an asymmetric carbon, and exist as either the S(+)- or the R(—)-enantiomers. Only the S(+)-enantiomer inhibits prostaglandin synthesis, whereas only the R( )-enantiomer is converted into the acyl-CoA derivative. However, both the S(+)-enantiomer and the R( )-enantiomer of ibuprofen inhibit the p-oxidation of medium- and short-chain fatty acids (Freneaux et al. 1990). Pirprofen, tiaprofenic acid, and flurbiprofen also inhibit mitochondrial p-oxidation (Geneve et al. 1987a). 

Freneaux E, Labbe G, Letteron P, Le Dinh T, Degott C, Geneve J, Larrey D, Pessayre D (1988) Inhibition of the mitochondrial oxidation of fatty acids by tetracycline in mice and in man possible role in microvesicular steatosis induced by this antibiotic. Hepatology 8 1056-1062... 

Fromenty B, Fisch C, Labbe G, Degott C, Deschamps D, Berson A, Letteron P, Pessayre D (1990a) Amiodarone inhibits the mitochondrial P-oxidation of fatty acids and produces microvesicular steatosis of the liver in mice. J Pharmacol Exp Ther 255 1371-1376... 

Le Dinh T, Freneaux E, Labbe G, Letteron P, Degott C, Geneve J, Berson A, Larrey D, Pessayre D (1988) Amineptine, a tricyclic antidepressant, inhibits the mitochondrial oxidation of fatty acids and produces microvesicular steatosis of the liver in mice. J Pharmacol Exp Ther 247 745-750 Le Roy F, Bisbal C, Silhol M, Martinand C, Lebleu B, Salehzada T (2001) The 2-5A/RNase L/RNase inhibitor (RLl) pathway regulates mitochondrial mRNAs stability in interferon-a-treated H9 cells. J Biol Chem 276 48473 8482 Le Roy F, Silhol M, Salehzada T, Bisbal C (2007) Regulation of mitochondrial mRNA stability by RNase L is translation-dependent and controls IFNalpha-induced apoptosis. Cell Death Differ 14 1406-1413... 

Geneve, J. Hayat-Bonan, B. Labbe, G. Degott, C. Letteron, P. Freneaux, E. Dinh, T.L. Larrey, D. Pessayre, D. Inhibition of mitochondrial beta-oxidation of fatty adds by pirprofen. Role in microvesicular steatosis due to this nonsteroidal anti-inflammatory drug. J. Pharmacol. Exp. Ther. 1987, 242, 1133-1137. 

VPA. Histologically, microvesicular steatosis induced by 4-en-VPA is accompanied by ultrastructural changes characterized by myeloid bodies, hpid vacuoles and mitochondrial abnormalities. An enhanced excretion of Cg to Cio dicarboxylic acids by patients and rats indicates an interference with mitochondrial P-oxidation as an important pathogenesis. If the normal pathway of fatty acid oxidation is disrupted by VPA, it results in reduced ketone body formation and decrease of free coenzyme-A (CoA) in the liver. Especially, decreased CoA would limit the activities of one or more enzymes in the pathway of fatty acid oxidation. 

A 55-year-old woman developed severe cholestatic liver injury and lactic acidosis after receiving linezolid for 50 days for an infected prosthetic hip [92" ]. Liver biopsy showed Effuse microvesicular steatosis, a mononuclear infiltrate, and bile duct damage. The hepatotoxicity resolved over 14 weeks. Microvesicular steatosis relates to impaired mitochondrial P-oxidation of fatty acids and the authors suggested that UnezoUd may have inhibited mitochondrial protein synthesis. 

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