title: Alteration of cytochrome oxidase subunit I labeling is associated with severe mitochondriopathy in NRTI-related hepatotoxicity in HIV patients.
abstract: Liver mitochondrial toxicity induced by nucleoside reverse transcriptase inhibitors (NRTI) in human immunodeficiency virus (HIV) patients has been associated with a wide range of liver involvement ranging from low-grade hepatotoxicity, asymptomatic lactacidemia to severe liver insufficiency, with massive steatosis and life-threatening lactic acidosis. Considerable efforts have been made in the last few years to establish clinical guidelines to avoid life-threatening NRTI-associated lactic acidosis. However, the important issue of low-grade NRTI-associated hepatotoxicity still needs to be unravelled since its natural history is largely unknown. We have recently reported a series of 13 monoinfected HIV patients with low-grade NRTI-associated toxicity. Our results outlined the heterogeneity of NRTI-induced hepatotoxicity and raised the question of its diagnosis. The present study evaluates the expression of cytochrome oxidase (COX) subunits I and IV, encoded by mitochondrial and nuclear DNA, respectively, in NRTI hepatotoxicity. The aim of our study was to compare the detection rate of mitochondrial abnormalities of immunohistochemistry for COX subunit I with electron microscopy. COX subunit I and IV labeling was performed together with light microscopy and ultrastructural analysis in a series of 55 liver biopsies from HIV monoinfected and HIV-hepatitis C virus coinfected patients. Clinical data were also recorded. Our major findings were: (i) decreased COX subunit I labeling is associated with severe ultrastructural mitochondrial alterations and may represent overt NRTI-induced mitochondrial cytopathy; (ii) mild ultrastructural damage associated with normal COX subunit I labeling is of unknown clinical significance. The results of the study suggest that COX subunit I labeling may be a valuable tool for the diagnosis of mitochondrial liver disease in HIV patients.
authors.affiliation: Department of Pathology, Hôpital Européen Georges Pompidou, Université Paris V René Descartes, Paris, France. jean-paul.duong-van-huyen@hop.egp.ap-hop-paris.fr
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Duong Van Huyen
authors.forename: Dominique
authors.initials: D
authors.lastname: Batisse
authors.forename: Didier
authors.initials: D
authors.lastname: Heudes
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Belair
authors.forename: Christophe
authors.initials: C
authors.lastname: Piketty
authors.forename: Gustavo
authors.initials: G
authors.lastname: Gonzalez-Canali
authors.forename: Laurence
authors.initials: L
authors.lastname: Weiss
authors.forename: Michel D
authors.initials: MD
authors.lastname: Kazatchkine
authors.forename: Patrick
authors.initials: P
authors.lastname: Bruneval
mesh_terms: D000328:Adult; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000209:etiology; D003576:Electron Transport Complex IV / Q000378:metabolism*; D005234:Fatty Liver / Q000139:chemically induced / Q000201:enzymology; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D007150:Immunohistochemistry; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000201:enzymology; D008297:Male; D008854:Microscopy, Electron; D008875:Middle Aged; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000201:enzymology* / Q000648:ultrastructure; D028361:Mitochondrial Diseases / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D021122:Protein Subunits / Q000378:metabolism; D012189:Retrospective Studies; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects*
chemical_list: D021122:Protein Subunits; D018894:Reverse Transcriptase Inhibitors; D003576:Electron Transport Complex IV