FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2079040804> ?p ?o ?g. }

• W2079040804 endingPage "328" @default.
• W2079040804 startingPage "326" @default.
• W2079040804 abstract "To the Editor: The recent introduction of highly active antiretroviral therapy (HAART) dramatically reduced HIV-associated morbidity and mortality, but the significant increase in life expectancy has led to the observation of new, frequent, and sometimes severe toxic effects associated with new, potent combination therapies. Hepatotoxicity, lactic acidosis, myopathy, peripheral neuropathy, pancreatitis, lipoatrophy, and bone marrow toxicity with pancytopenia have recently been described as frequent and potentially serious complications of treatment with nucleoside reverse transcriptase inhibitors (NRTIs), which are generally included in all antiretroviral regimens. Particularly, mitochondrial toxicity was proposed as the common pathway of NRTI-related adverse effects, since in vitro studies have shown that all NRTIs may inhibit the activity of DNA polymerase γ and therefore lead to mitochondrial DNA (mtDNA) depletion, and multiple enzyme dysfunction. 1–3 On the other hand, longer survival rates lead to the emergence of hepatitis C virus (HCV) infection and chronic liver disease as an important cause of morbidity and mortality in the setting of HIV infection. Furthermore, the effective administration of HAART in HIV/HCV-coinfected subjects may be limited by hepatotoxicity of these medications in concert with viral liver damage; and interferon-ribavirin anti-HCV therapy may interact unfavorably with some antiretroviral compounds. 4–6 Hepatocellular mitochondrial toxicity is sometimes also observed in HIV-negative patients with chronic hepatitis C infection. In fact, HCV infection is associated with increased lipoperoxidation, which may interfere with mitochondrial enzymatic function, by causing depletion of mtDNA. 7 Therefore, hepatocellular mitochondrial abnormalities may be considered the underlying pathogenetic mechanism of hepatotoxic effects (such as liver steatosis, acute or chronic hepatitis, and liver failure), observed in patients receiving an NRTI-based HAART, mostly in association with HCV coinfection. Thirty-four HIV/HCV-coinfected subjects followed up at our Division of Infectious Diseases underwent liver biopsy between December 2000 and December 2002 for histologic and ultrastructural evaluation. Our series included 21 men and 13 women, with a median age of 38.6 (range 26–53) years. The median CD4+ lymphocyte count and plasma HIV viral load at the time of liver biopsy were 361 (range 130–1023) cells/μL and 4261 (range <50–9500) copies/mL, respectively. The median duration of antiretroviral therapy was 8.7 (range 2.5–14.2) years. At the time of liver biopsy, three patients were treated with 2 NRTIs alone, 21 with 2 NRTIs and 1 PI, eight with 2 NRTIs and 1 NNRTI, one with 2 NRTIs and 2 PIs, and one with 3 NRTIs. To assess the specificity of ultrastructural study, 5 HIV/HCV-coinfected subjects who had never received any antiretroviral treatment were selected as control patients. These 5 individuals were 2 men and 3 women, with a median age of 38.4 (range 36–42) years, median CD4+ lymphocyte count of 492 (range 412–721) cells/μL, and median plasma HIV viral load of 8126 (range 2500–19,200) copies/mL. All the evaluated patients who received antiretroviral treatment had a mild to moderate elevation of serum transaminase levels at the time of liver histologic examination, similarly to all control subjects, but no one was symptomatic, in either studied group. Median serum alanine aminotransferase (ALT) concentration was 94 IU in the treated group and 122 IU in the control group; median serum γ-glutamyltransferase levels were 66 IU and 83 IU, respectively; median total serum bilirubin levels were 0.62 mg/dL and 0.55 mg/dL, respectively. The frequency of HCV genotype 1b infection was 5 of 34 (14.7%) among treated patients and 0 of 5 among antiretroviral-naive subjects. No patient was previously treated with antiviral therapy for chronic hepatitis C, in either observed group. Liver percutaneous needle biopsy specimens were cut into 2 pieces: the first clinical specimen was fixed in 10% buffered formalin for standard histologic examination, and the other in 2.5% glutaraldehyde for electron microscopy evaluation. Histologic and ultrastructural studies were simultaneously performed by 2 independent observers in all the considered cases. Among subjects receiving antiretroviral therapy, histologic assessment disclosed a mild to moderate chronic hepatitis (Knodell score < 6) in 19 cases, a moderate disease (Knodell score 6–0) in 9, and a severe disease (Knodell score > 10) in 6 cases; 3 patients had a diagnosis of an initial cirrhotic liver evolution. In the control group, there were 3 cases of mild chronic hepatitis and 2 of moderate disease. Macrovesicular steatosis was observed in 15 of 34 treated patients (44.1%), and in 1 subject only belonging to the control group. Electron microscopy evaluation showed mitochondrial abnormalities in all 34 treated patients and in 3 of the control subjects. The most commonly observed morphologic alterations of the hepatocellular mitochondria in treated patients were polymorphism, crystalline inclusions, glycogen accumulation, reduction or loss of cristae, reduction of matrix density, and hyperplasia. The most relevant ultrastructural findings reported in control patients were polymorphism, crystalline inclusions, and hyperplasia. The frequency of these mitochondrial abnormalities is reported in Table 1. No statistically significant correlations between some patterns of ultrastructural alterations and use of specific antiretroviral agents were found in our study.TABLE 1: Frequency of Ultrastructural Mitochondrial Alterations of Liver Biopsy Specimens Found in 34 HIV/HCV-Coinfected Patients Receiving Antiretroviral Therapy and in 5 HIV/HCV-Coinfected Control Subjects, Who Were Naive to Antiretroviral TreatmentLiver toxicity is a common complication in HIV-infected patients undergoing antiretroviral therapy, reported in 6–30% of treated subjects. 8–10 Mitochondrial dysfunction has been supposed to represent the main pathogenetic mechanism of liver damage induced by NRTI-based therapies, since nucleoside analogues (particularly stavudine, zalcitabine, and didanosine) may inhibit the human DNA polymerase γ, leading to a severe depletion of mtDNA and dysfunction of cellular respiratory chain. A recent histologic and ultrastructural study has demonstrated that NRTI-induced toxic effect in the liver may occur as indolent, nonspecific gastrointestinal disease with variable histologic features, including mild or diffuse steatosis, mild lobular inflammation, and necrosis. However, electron microscopy examination always revealed ultrastructural mitochondrial abnormalities, mostly represented by megamitochondria, loss of cristae, autophagic vacuoles, and electron-dense and crystalline inclusions, which were not present in antiretroviral-naive patients. 11 Conversely, liver mitochondrial alterations have been frequently observed also in HCV-monoinfected subjects. The principal ultrastructural findings described in HCV-positive individuals were irregular shapes of mitochondria and paracrystalline inclusions, which appeared more frequently associated with genotype 1b. 12 HCV infection is usually associated with reduced glutathione levels in both plasma and peripheral lymphocytes, and this depletion seems related to the activity of the liver disease. Consequently, the increased production of free radicals may lead to interference with mitochondrial function, possible depletion of mtDNA, impairment of immunologic mechanisms involved in the HCV clearance, and development of resistance to interferon therapy. 13–15 Therefore, liver damage in HIV/HCV-coinfected patients receiving HAART may result from a synergistic effect of HCV and antiretroviral agents, leading to morphologic and functional mitochondrial abnormalities. In our study, all HIV/HCV-positive patients receiving antiretroviral treatment showed mitochondrial alterations. The main ultrastructural abnormalities of mitochondria probably related to NRTI-based therapy were reduction or loss of cristae, decrease in matrix density, and glycogen accumulation. Conversely, polymorphism, crystalline inclusions, and hyperplasia were also present in control subjects and probably associated with chronic HCV infection, as described in previous reports. This is the first study evaluating ultrastructural mitochondrial alterations of the liver in HIV/HCV-coinfected persons, to the best of our knowledge. Gabriella Verucchi, MD Leonardo Calza, MD Carlo Biagetti, MD Luciano Attard, MD Paolo Costigliola, MD Roberto Manfredi, MD Gianandrea Pasquinelli, MD Francesco Chiodo, MD" @default.
• W2079040804 created "2016-06-24" @default.
• W2079040804 creator A5006204124 @default.
• W2079040804 creator A5009174128 @default.
• W2079040804 creator A5042900908 @default.
• W2079040804 creator A5046270633 @default.
• W2079040804 creator A5049042544 @default.
• W2079040804 creator A5051980640 @default.
• W2079040804 creator A5084048495 @default.
• W2079040804 creator A5088756048 @default.
• W2079040804 date "2004-03-01" @default.
• W2079040804 modified "2023-10-09" @default.
• W2079040804 title "Ultrastructural Liver Mitochondrial Abnormalities in HIV/HCV-Coinfected Patients Receiving Antiretroviral Therapy" @default.
• W2079040804 cites W1978724449 @default.
• W2079040804 cites W1978902758 @default.
• W2079040804 cites W1986859702 @default.
• W2079040804 cites W2004602615 @default.
• W2079040804 cites W2011616562 @default.
• W2079040804 cites W2023757890 @default.
• W2079040804 cites W2034482023 @default.
• W2079040804 cites W2041841997 @default.
• W2079040804 cites W2078232141 @default.
• W2079040804 cites W2115956200 @default.
• W2079040804 cites W2123663982 @default.
• W2079040804 doi "https://doi.org/10.1097/00126334-200403010-00018" @default.
• W2079040804 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/15076252" @default.
• W2079040804 hasPublicationYear "2004" @default.
• W2079040804 type Work @default.
• W2079040804 sameAs 2079040804 @default.
• W2079040804 citedByCount "17" @default.
• W2079040804 countsByYear W20790408042012 @default.
• W2079040804 countsByYear W20790408042014 @default.
• W2079040804 countsByYear W20790408042015 @default.
• W2079040804 countsByYear W20790408042018 @default.
• W2079040804 crossrefType "journal-article" @default.
• W2079040804 hasAuthorship W2079040804A5006204124 @default.
• W2079040804 hasAuthorship W2079040804A5009174128 @default.
• W2079040804 hasAuthorship W2079040804A5042900908 @default.
• W2079040804 hasAuthorship W2079040804A5046270633 @default.
• W2079040804 hasAuthorship W2079040804A5049042544 @default.
• W2079040804 hasAuthorship W2079040804A5051980640 @default.
• W2079040804 hasAuthorship W2079040804A5084048495 @default.
• W2079040804 hasAuthorship W2079040804A5088756048 @default.
• W2079040804 hasBestOaLocation W20790408041 @default.
• W2079040804 hasConcept C142462285 @default.
• W2079040804 hasConcept C159047783 @default.
• W2079040804 hasConcept C203014093 @default.
• W2079040804 hasConcept C2777071529 @default.
• W2079040804 hasConcept C2993143319 @default.
• W2079040804 hasConcept C3013748606 @default.
• W2079040804 hasConcept C71924100 @default.
• W2079040804 hasConceptScore W2079040804C142462285 @default.
• W2079040804 hasConceptScore W2079040804C159047783 @default.
• W2079040804 hasConceptScore W2079040804C203014093 @default.
• W2079040804 hasConceptScore W2079040804C2777071529 @default.
• W2079040804 hasConceptScore W2079040804C2993143319 @default.
• W2079040804 hasConceptScore W2079040804C3013748606 @default.
• W2079040804 hasConceptScore W2079040804C71924100 @default.
• W2079040804 hasIssue "3" @default.
• W2079040804 hasLocation W20790408041 @default.
• W2079040804 hasLocation W20790408042 @default.
• W2079040804 hasLocation W20790408043 @default.
• W2079040804 hasOpenAccess W2079040804 @default.
• W2079040804 hasPrimaryLocation W20790408041 @default.
• W2079040804 hasRelatedWork W2036827172 @default.
• W2079040804 hasRelatedWork W2055280854 @default.
• W2079040804 hasRelatedWork W2070873543 @default.
• W2079040804 hasRelatedWork W2087771447 @default.
• W2079040804 hasRelatedWork W2298250249 @default.
• W2079040804 hasRelatedWork W2614902832 @default.
• W2079040804 hasRelatedWork W2973584526 @default.
• W2079040804 hasRelatedWork W4230957370 @default.
• W2079040804 hasRelatedWork W4288713694 @default.
• W2079040804 hasRelatedWork W4322484426 @default.
• W2079040804 hasVolume "35" @default.
• W2079040804 isParatext "false" @default.
• W2079040804 isRetracted "false" @default.
• W2079040804 magId "2079040804" @default.
• W2079040804 workType "article" @default.