Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015695 (fatty liver)
 13,941 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mitochondrial dysfunction has been associated with long-term toxicities of human immunodeficiency virus (HIV) therapy, particularly with the nucleoside analog reverse transcriptase inhibitors (NRTIs). Lactic acidosis, hepatic steatosis, myopathies, cardiomyopathies, neuropathies, and lipodystrophy are frequently attributed to mitochondrial toxicity. Since mitochondrial toxicity could pose a major threat to the long-term success of HIV therapy, the scientific evidence underlying an association between mitochondrial toxicity and antiretroviral therapies, must be carefully examined. There is some data to support the association between NRTIs and mitochondria dysfunction. In this review, we examine human, animal, and in vitro data implicating mitochondrial dysfunction as the causal mechanism of NRTI-associated toxicity in HIV-infected patients.
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PMID:Mitochondrial dysfunction and antiretroviral nucleoside analog toxicities: what is the evidence? 1612 Feb 93

Antiretroviral medications have significantly improved the prognosis of individuals infected with the human immunodeficiency virus (HIV) by maintaining immune integrity and limiting the impact of opportunistic infections. However, these benefits have not come without a price as long-term complications of therapy are increasingly recognized as significant causes of morbidity and mortality. Many of these complications are thought to be mediated through mitochondrial injury, which appears to be the result of nucleoside analogue toxicity. A syndrome of fatty liver (steatosis) with lactic acidosis represents the most fulminant presentation of such antiretroviral toxicity, though milder variants of hepatic steatosis with or without lactate elevations have also been described in HIV-seropositive individuals. The spectrum of hepatic steatosis and hyperlactatemia is likely multifactorial and may share some features with non-alcoholic fatty liver disease (NAFLD), which is the hepatic component of the metabolic syndrome described in the general population. As antiretrovirals are also known to contribute to metabolic syndrome components including insulin resistance, hypertriglyceridemia, and central adiposity, the possibility of common pathophysiologic mechanisms underlying NAFLD and antiretroviral-associated fatty liver seem likely. However, lactate elevations are not a component of NAFLD, suggesting other factors must also be involved. A review follows which details the role of mitochondrial damage in hepatic steatosis among HIV-infected individuals and the general population, as well as the association of this damage to the pathogenesis of hyperlactatemia.
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PMID:Mitochondrial injury in the pathogenesis of antiretroviral-induced hepatic steatosis and lactic acidemia. 1612 Mar 75

Advances in anti-retroviral therapy (ART) has led to improved survival of patients infected with the human immunodeficiency virus (HIV). ART for HIV patients is composed of a combination of nucleoside reverse transcriptase inhibitors (NRTI) and/or a non-nucleoside reverse transcriptase inhibitor (NNRTI), and/or a protease inhibitor (PI). The long-term exposure to ART and HIV are causing mitochondrial toxicities, such as myopathies, neuropathy, myelopoiesis, pancreatitis, lactic acidosis, hepatic steatosis, and lipodystrophy. The mitochondrial pathogenesis has been believed to be due exclusively to NRTI-induced inhibition of DNA polymerase-gamma; it is now apparent that the etiology is far more complex, involving multiple mechanisms as well as an effect by HIV per se. Current therapy for patients includes interruption or change in medications and mitochondrial co-factors.
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PMID:Mitochondrial dysfunction in AIDS and its treatment. 1612 Apr 31

The behavior of hepatitis C in states of immunodeficiency is poorly understood and it is still unclear whether the characteristics of hepatitis C virus (HCV) infection in renal transplant patients differ from those observed in immunocompetent subjects. The aim of this study was to compare the biochemical and histologic characteristics of chronic HCV infection between renal transplant and immunocompetent patients. Forty-one HCV-RNA-positive renal transplant patients and 41 immunocompetent controls matched for gender, age at infection and time of infection were included in the study. The groups were compared regarding laboratory and histologic variables. Renal transplant patients showed lower alanine aminotransferase (ALT) levels (p = 0.005) and higher levels of gamma-glutamyltransferase (p = 0.003), alkaline phosphatase (p < 0.001), and direct bilirubin (p < 0.001) when compared with controls. Histologic analysis revealed less intense portal (p < 0.001) and periportal (p = 0.046) inflammatory infiltrate in renal transplant patients but a larger proportion of cases with confluent necrosis (p = 0.043). No difference in the presence of septal fibrosis, hepatic steatosis, bile duct injury and siderosis was observed. However, there was a difference in the presence of lymphoid aggregates, which were less frequent in the renal transplant group (p < 0.001). In conclusion, the characteristics of hepatitis C in renal transplant patients differ from that observed in immunocompetent patients. In renal transplant patients, HCV infection is biochemically characterized by lower ALT levels and higher frequency of cholestasis. Regarding histology, despite lower frequency of lymphoid aggregates and less intense portal/periportal inflammatory infiltrate, a greater lobular damage was observed. The impact of these differences on the progression of fibrosis remains to be established.
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PMID:Hepatitis C virus infection in renal transplant patients: a comparative study with immunocompetent patients. 1631 22

Liver biopsy has historically played a central role in the diagnosis and management of a variety of chronic liver diseases. However, as the understanding of disease pathology has progressed, and laboratory diagnostics, imaging technology, and clinical algorithms to determine both the etiology and presence of fibrosis have advanced, the role of liver biopsy has become more circumscribed. In chronic liver disease, liver biopsy is now more often used selectively, rather than routinely, for diagnostic purposes. Newer treatment of chronic hepatitis B and C has become more effective and thus reduced the routine need to acquire tissue. Risk factors for nonalcoholic fatty liver disease are readily identified and suggest the diagnosis after exclusion of alternative considerations, and there is no specific treatment for this condition; thus there is little role for the routine use of liver biopsy to guide treatment. Only in select cases of chronic hepatitis C, especially in patients with genotype 1, an indeterminate stage and grade of disease on noninvasive evaluation, or in those with human immunodeficiency virus coinfection, for whom the risks and benefits of treatment are less clear, is there a role for routine pretreatment biopsy.
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PMID:Role of liver biopsy in the management of chronic liver disease: selective rather than routine. 1636 15

The introduction of highly active antiretroviral therapy (HAART) for treatment of human immunodeficiency virus (HIV) infection has led to substantial reduction in morbidity and near-complete suppression of HIV-1 replication. But since HAART is unlikely to eradicate HIV-1, antiviral therapy may be required a lifelong, leading to an increase in attention on the long-term safety of HAART. A major toxicity of HAART is the mitochondrial toxicity. Mitochondrial toxicity becomes apparent particularly over the medium-term to long-term therapy and is attributed to treatment with nucleoside reverse transcriptase inhibitors (NRTIs), leading to a wide range of severe adverse events in HIV-infected patients. These include lactic acidosis, hepatic steatosis, neuropathy, (cardio-) myopathy, pancreatitis, and probably lipodystrophy. Furthermore, lactic acidosis and encephalopathy have been reported in children exposed in-utero and/or postnatally to NRTIs. Mitochondrial toxicity could pose a major threat to long-term success of HIV-therapy, and is of great concern for children exposed in-utero and/or postnatally to NRTIs. Therefore, investigation of mitochondrial toxicity of new compounds or new combinations is of growing interest for the clinical application of antiretroviral agents. However, at present no standardized and validated screening model system exists for the investigation of NRTI-induced mitochondrial toxicity. There is a need for the generation of a relevant in vitro assay system that can assess the mitochondrial toxicity in early preclinical development. This paper gives an overview of cell culture models currently used for the investigation of NRTI-induced mitochondrial toxicity and discusses the relevance and suitability of these models for prediction of clinical toxicity.
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PMID:Cell culture models for the investigation of NRTI-induced mitochondrial toxicity. Relevance for the prediction of clinical toxicity. 1640 76

The newly developed elastometer, FibroScan((R)), was utilized to evaluate liver fibrosis in hepatitis C virus (HCV)- and human immunodeficiency virus (HIV)-coinfected 33 hemophiliacs and HIV-uninfected 24 patients with chronic hepatitis C. Chronicity in the liver was categorized into 4 stages by abdominal ultrasound (AUS): 1 (normal or fatty liver); 2 (chronic liver disease, mild); 3 (moderate); and 4 (severe). Stiffness of the liver was significantly increased as AUS stages advanced: 5.4+/-2.2 (N=3) versus 7.5+/-2.7 (N=9), in stage 1; 4.9+/-1.7 (N=2) versus 9.9+/-6.0 (N=10), in stage 2, 13.5+/-4.7 (N=5) versus 12.9+/-5.9 (N=6), in stage 3, and 22.0+/-9.5 (N=14) versus 28.1+/-21.3 (N=8), in stage 4, in non-HIV group and in HIV group, respectively (P=0.004 and 0.007). Stiffness was correlated with AUS stages (r=0.740, P<0.001), platelet counts (PLT; r=-0.642, P=0.001) and 7S domain of type IV collagen (IV-coll; r=0.480, P=0.024) in non-HIV group, while in HIV group, with IV-coll (r=0.801, P<0.001), AUS stages (r=-0.603, P<0.001), procollagen type III peptides (P-III-P; r=0.621, P=0.001), PLT (r=-0.480, P=0.005), and hyaluronic acid (r=0.433, P=0.027). FibroScan((R)) is absolutely noninvasive and can be the alternative to liver biopsy, especially in patients with bleeding tendency.
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PMID:Usefulness of elastometry in evaluating the extents of liver fibrosis in hemophiliacs coinfected with hepatitis C virus and human immunodeficiency virus. 1671 34

Antiretroviral medications have significantly improved the prognosis of subjects infected by human immunodeficiency virus (HIV). However, long-term complications of these drugs are increasingly recognized as significant causes of morbidity and mortality. Non-alcoholic fatty liver disease (NAFLD), which can evolve into non-alcoholic steato-hepatitis (NASH), cirrhosis and ultimately hepatic failure is one of the more often observed complications in the current clinical practice and the correlation with liver enzyme elevations is controversial. Multiple factors have been considered as possibly correlated to this event in the HIV-infected population, including metabolic abnormalities (such as hyperlipidaemia, hyperglycaemia and being overweight), chronic inflammation, concurrent infection with hepatitis C and B viruses, and treatment with certain nucleoside reverse transcriptase inhibitors (NRTI). HIV-associated syndromes such as lactic acidosis and lypodystrophy are frequently associated with fatty liver disease and a mitochondrial injury has been considered as its possible pathogenetic factor. In particular, treatment containing stavudine and didanosine have proven to be the most commonly implicated in the occurrence of mitochondrial abnormalities. Epidemiologic data to better define the role of predictive factors and drugs associated with the development of NAFLD are still lacking. Furthermore, it remains unclear the better therapeutic management for this condition, even if the current best therapeutic option for NAFLD is the treatment of the underlying disease. Other studies are mandatory to better elucidate the pathogenesis of NAFLD and the optimal therapeutic strategy for the underlying conditions.
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PMID:Steatohepatitis in HIV-infected subjects: pathogenesis, clinical impact and implications in clinical management. 1789 69

Preeclampsia is a multifactorial pregnancy-specific disease. In some cases, severe preeclampsia and related disorders of acute fatty liver of pregnancy and hemolysis, elevated liver enzymes, low platelets syndrome are associated with inherited defects in mitochondrial beta-oxidation of fatty acids, especially a deficiency of long-chain 3-hydroxyacyl coenzyme A dehydrogenase (LCHAD). Recently, an unexplained increase in the incidence of preeclampsia has been documented in human immunodeficiency virus (HIV)-infected pregnant women on treatment with highly active antiretroviral therapy (HAART). We performed this study to determine if antiretroviral drugs affect mitochondrial beta-oxidation fatty acids in vitro. Two normal and 1 heterozygous LCHAD-deficient cell lines were exposed to up to 5 times the therapeutic concentrations of the following antiretroviral drugs: nevirapine, didanosine, lamivudine, and a combination of nelfinavir, zidovudine, and lamivudine. One homozygous LCHAD-deficient cell line served as the positive control. After exposure of the fibroblasts to these drugs for periods ranging from 2 to 10 days, accumulations of even-chain 3-hydroxy fatty acids (3-OH-C6 to 3-OH-C18) in the culture media were measured by stable-isotope dilution gas chromatography/mass spectrometry. Compared to the respective unexposed fibroblasts, there was no significant build-up of 3-hydroxy fatty acids in the culture media of normal or heterozygous LCHAD-deficient fibroblasts exposed to antiretroviral drugs. Our results show that the commonly used antiretroviral drugs do not adversely affect fatty acid oxidation in fibroblasts. Therefore, an altered fatty acid oxidation may not be the mechanism for the reported increased risk of preeclampsia in HIV-infected pregnant women on HAART.
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PMID:Highly active antiretroviral therapy does not affect mitochondrial beta-oxidation of fatty acids: an in vitro study in fibroblasts. 1824 Aug 71

Liver histological improvement after treatment for chronic hepatitis C in patients co-infected with human immunodeficiency virus-1 (HIV-1) has been described. Paired liver biopsies in twenty six HCV/HIV co-infected patients were compared to determine factors possibly associated with histological improvement. The patients were submitted to a liver biopsy before treatment for hepatitis C and 25 months after the end of treatment. Fragments of the liver biopsy obtained before and after treatment were compared regarding the following parameters: histological activity index (HAI) and degree of fibrosis (Knodell); intensity of collagen deposits (Sirius Red staining) and degree of stellate cell activation (alpha-smooth muscle actin labeling). The ratios of the post and pre-treatment variables were related through logistic regression to body mass index (BMI), alcohol ingestion, HCV genotype, HCV viremia, presence of hepatic iron and pre-treatment hepatic steatosis. A negative RNA test in the 24th week of treatment was associated with improvement in fibrosis, collagen deposits and stellate cell numbers. The other variables analyzed did not correlate to an improvement in hepatic histology after hepatitis C treatment. Reduction in HCV viremia during treatment may result in reduced hepatic fibrosis even in patients without a sustained virological response.
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PMID:HCV virological response during treatment of chronic hepatitis C is associated with liver histological improvement in patients with HCV/HIV co-infection. 1883


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