Microvesicular steatosis

Dutertre, J.P., Bastides, F., JonviDe, A.P., De Muret, A., Sormeville, A. Larrey D. and Autret, E. (1991) Microvesicular steatosis after ketoprofen administration. European Journal of Gastroenterology and Hepatology, 3, 953—954. 

Therefore, the metabolite interferes with mitochondrial function and decreases the production of ATP and other important cofactors such as NADH and FADH. Therefore, after repeated use of the drug, mitochondrial integrity is reduced and cellular and overall liver fat oxidation is inhibited. Consequently, fat accumulates, seen as microvesicular steatosis. Electron microscopy shows swollen mitochondria and damaged mitochondrial structures. The accumulated lipid may encourage lipid peroxidation and oxidative stress to occur, causing further damage. 

Fromenty B, Pessayre D. Impaired mitochondrial unction in microvesicular steatosis. J Hepatol 1997 26 43-53. 

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. 

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)... 

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 defect in argininosuccinate synthetase coincides with markedly elevated citrulline values in the blood. Neither citrullinaemia nor a carbamylphosphate synthetase defect cause liver damage. By contrast, an argininosuc-cinase defect leads to microvesicular steatosis and megamitochondria with dilatation of the ER. 

Autosomal recessive cystinosis is caused by an enzyme-induced blockage of cystine degradation, particularly in the RES lysosomes of the bone marrow, liver, spleen and kidneys. Especially in the stellate cells of the spleen and to a lesser extent of the hepatic lobule centres, hexagonal and rectangular cystine crystals are found, pointing at an early stage to cystinosis. There is evidence of hepatosplenomegaly and microvesicular steatosis. The clinical picture of the infantile type presents as a Fan-coni syndrome, (s. pp 593, 597) The children affected die in the first five years of life. 

Hautekeete, M.L., Degott, C., Benhamou, J.-R Microvesicular steatosis of the liver. Acta Clin. Belg. 1990 45 311-326... 

Compound-specific effects vs. class effects or Microvesicular steatosis Cyclopropane carboxylic acid (CPCA) Butyrate, structurally similar to CPCA, but does not cause microvesicular steatosis Jolly et al.23... 

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. 

At present oral doses, tetracycline and its derivatives produce mild hepatic steatosis in humans at worst. However, fatal cases of microvesicular steatosis have occurred in the past, usually after 4—10 days of intravenous administration of high doses of either tetracycline or diverse tetracycline derivatives (Zimmerman 1978). Predisposing conditions (Zimmerman 1978) included preexisting renal failure, which decreases tetracycline elimination, or pregnancy, which can impair mitochondrial function. 

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). 

One in 13,000 pregnant women develop microvesicular steatosis during the last trimester of pregnancy (Kaplan 1985). Untreated, the disease progresses to coma, kidney failure, and hemorrhage, and leads to the death of the mother and child in 75-85% of cases. In contrast, if the pregnancy is terminated rapidly, a healthy child is usually bom and the mother rapidly recovers (Ebert et al. 1984). 

Dutertre JP, Bastides F, Jonville AP, De Muret A, Sonneville A, Larrey D, Autret E (1991) Microvesicular steatosis after ketoprofen administration. Eur J Gastroenterol Hepatol 3 953-954 Ebel RE, Lardy HA (1975) Influence of aurovertin on mitochondrial ATPase activity. J Biol Chem 250 4992 995... 

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... 

Fromenty B, Grimbert S, Mansouri A, Beaugrand M, Erlinger S, Rotig A, Pessayre D (1995) Hepatic mitochondrial DNA deletion in alcoholics association with microvesicular steatosis. Gastroenterology 108 193-200... 

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. 

Church, R.J., Wu, H., Mosedale, M., Sumner, S.J., Pathmasiri, W., Kurtz, C.L., Fletcher, M.T., Eaddy, J.S., Pandher, K., Singer, M., Batheja, A., Watkins, P.B., Adkins, K., Harrill, A.H., 2014. A systems biology approach utilizing a mouse diversity panel identifies genetic differences influencing isoniazid-induced microvesicular steatosis. Toxicol Sci 140,481-492. 

Su G, Seflon RM, Murray M (1999) Down-regulation of rat hepatic microsomal cytochromes P-450 in microvesicular steatosis induced by orotic acid. J Pharmacol Exp Ther 291 953-959... 

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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