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)

A girl with partial lipodystrophy is described presenting with muscle weakness and developmental delay several years before lipoatrophy became apparent. The patient subsequently developed epilepsy, fatty liver, secondary amenorrhoea, hirsutism, insulin-resistant diabetes mellitus, hyperlipidaemia, and hypothyroidism. She remains weak with poor exercise tolerance. This case illustrates an atypical presentation of the Barraquer-Simon syndrome.
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PMID:Partial lipodystrophy presenting with myopathy. 1007 99

Frequency-selective chemical shift magnetic resonance (MR) imaging was applied on the calf musculature and the abdomen of a patient with acquired generalized lipoatrophy (AGL; Lawrence syndrome), a very rare syndrome affecting selectively several types of adipose tissue accompanied by alterations in glucose and energy metabolism. In addition, (1)H-MRS was used for assessment of intra- (IMCL) and extramyocellular lipid stores (EMCL) in the skeletal musculature of the calf. Results from the AGL patient were compared with an age-matched group of five healthy volunteers. Fat-selective imaging of the calf revealed a total lack of subcutaneous adipose tissue. No EMCL signal was found in the spectra from the soleus muscle of the AGL patient. IMCL signals were present in the spectra but were clearly lower than in the controls (14% of normal value in the soleus muscle). In abdominal images, subcutaneous fat signal was not detectable, as in the calf, but nearly normal conditions were shown for visceral adipose tissue between abdominal organs. Fat-selective images showed the liver with high signal intensity, indicating hepatic steatosis combined with hepatosplenomegaly. Modern chemical shift-selective MR imaging and localized spectroscopy allow a noninvasive and quantitative assessment of tissue composition in patients with disorders of carbohydrate and lipid metabolism.
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PMID:Acquired generalized lipoatrophy (AGL): highly selective MR lipid imaging and localized (1)H-MRS. 1093 94

Nucleoside analogues represent the cornerstones of antiretroviral regimens. A range of drug- or tissue-specific toxicities, such as peripheral neuropathy, myopathy, pancreatitis and lactic acidosis with hepatic steatosis, has been documented with these agents. The fat atrophy seen on long term antiretroviral therapy may also be related to nucleoside analogues. The mechanisms by which nucleoside analogues cause toxicity are not clearly established. In vitro, the triphosphates of these agents are weak to modest substrates for human DNA polymerases, showing the greatest affinity for mitochondrial DNA polymerase gamma. Short term exposure in vitro to some nucleoside analogues has been demonstrated to cause increased lactate production or falls in mitochondrial DNA suggestive of mitochondrial toxicity. However, stavudine and to a lesser extent zidovudine are poor substrates for mitochondrial thymidine kinase type 2, the predominant form in cells that are not actively mitotic such as neurons, myocytes and adipocytes. These are the cell types where the proposed mitochondrial toxicities neuropathy, myopathy and lipoatrophy are observed. Thus, active concentrations of phosphorylated products of stavudine and zidovudine may not be present in mitochondria. The familial mitochondrial diseases do not have identical presentations to nucleoside analogue toxicities. These disorders most commonly involve the CNS, typically with seizures or dementia, and occasionally the kidneys. Although nucleoside analogues are known to penetrate the CNS and are commonly renally excreted unchanged, mitochondrial toxicities at these sites have not been documented. Furthermore, toxicity caused by nucleoside or nucleotide analogues does not always appear to arise through the mitochondrial route. Cidofovir appears to cause renal tubular dysfunction via a toxic intracellular metabolite, and zidovudine-related anaemia appears to be related to decreased globin RNA synthesis. In vitro or animal models suggest that zidovudine myopathy, stavudine-related (but not zalcitabine- or didanosine-related) neuropathy and didanosine-related pancreatitis may all be not related, or not exclusively related, to mitochondrial dysfunction. The integration of nucleoside analogues into nuclear DNA, best documented with zidovudine but likely to occur with other agents, represents an alternative but potentially delayed pathway to cytotoxicity and cell apoptosis. This is the mechanism of cell death during therapy with antineoplastic nucleoside analogues, and may have contributed to the multisystem toxicities observed with the anti-hepatitis B drug fialuridine. New research evaluating the effects of long term exposure of cell lines is required to address the possibility that nuclear genotoxicity plays a role in long term nucleoside analogue toxicity.
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PMID:Toxicity of antiretroviral nucleoside and nucleotide analogues: is mitochondrial toxicity the only mechanism? 1114 57

Since the adoption of highly active antiretroviral therapy (HAART) in the mid-1990s, certain metabolic toxicities have been increasingly recognized. These include a fat redistribution syndrome (lipohypertrophy, lipoatrophy), hyperlipidaemia, altered glucose metabolism and insulin resistance, mitochondrial toxicity (presenting as anaemia, myopathy, pancreatitis, neuropathy, hepatic steatosis and lactic acidosis), and bone density abnormalities (osteoporosis and osteonecrosis). Metabolic complications are principally reported with protease inhibitors and nucleoside reverse transcriptase inhibitors, but may be seen with all classes of antiretroviral therapy. In this review, we summarize the epidemiology, pathogenesis and management of these various toxicities.
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PMID:The metabolic toxicities of antiretroviral therapy. 1151 63

Three categories of highly active antiretroviral therapy (HAART)-associated major toxic effects have been identified: nucleoside-related toxic effects (e.g., neuropathy, myopathy, pancreatitis, hepatic steatosis, lactic acidosis, and possibly lipoatrophy), metabolic complications (e.g., fat redistribution, insulin resistance, and hyperlipidemia), and bone disease (e.g., osteopenia and/or osteoporosis). The toxic effects caused by nucleosides are hypothesized to be a result of mitochondrial injury and include myopathy, pancreatitis, liver failure, and lactic acidosis. Alterations in lactic acid metabolism range from common instances of asymptomatic lactic acidemia to rare occurrences of life-threatening lactic acidosis with hepatic steatosis. A metabolic syndrome consisting of lipodystrophy (i.e., fat redistribution), hyperlipidemia and insulin resistance has been observed, particularly with protease inhibitor treatment. Some additive interaction between protease inhibitors and nucleosides has also been described. The potential relationship of these metabolic abnormalities to increased risk of cardiovascular disease and diabetes has broad implications on long-term patient management. Lipodystrophy associated with HAART is generally accompanied by potentially serious abnormalities, including dyslipidemia (i.e., hypercholesterolemia and hypertriglyceridemia) and altered glucose metabolism (i.e., insulin resistance). Regimens of HAART may have adverse effects on bone metabolism, as indicated by emerging reports of osteopenia, osteoporosis, and avascular necrosis.
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PMID:Long-term exposure to lifelong therapies. 1183 99

Conjugated linoleic acids (CLA) are a class of positional, geometric, conjugated dienoic isomers of linoleic acid (LA). Dietary CLA supplementation results in a dramatic decrease in body fat mass in mice, but also causes considerable liver steatosis. However, little is known of the molecular mechanisms leading to hepatomegaly. Although c9,t11- and t10,c12-CLA isomers are found in similar proportions in commercial preparations, the respective roles of these two molecules in liver enlargement has not been studied. We show here that mice fed a diet enriched in t10,c12-CLA (0.4% w/w) for 4 weeks developed lipoatrophy, hyperinsulinemia, and fatty liver, whereas diets enriched in c9,t11-CLA and LA had no significant effect. In the liver, dietary t10,c12-CLA triggered the ectopic production of peroxisome proliferator-activated receptor gamma (PPARgamma), adipocyte lipid-binding protein and fatty acid transporter mRNAs and induced expression of the sterol responsive element-binding protein-1a and fatty acid synthase genes. In vitro transactivation assays demonstrated that t10,c12- and c9,t11-CLA were equally efficient at activating PPARalpha, beta/delta, and gamma and inhibiting liver-X-receptor. Thus, the specific effect of t10,c12-CLA is unlikely to result from direct interaction with these nuclear receptors. Instead, t10,c12-CLA-induced hyperinsulinemia may trigger liver steatosis, by inducing both fatty acid uptake and lipogenesis.
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PMID:Dietary trans-10,cis-12 conjugated linoleic acid induces hyperinsulinemia and fatty liver in the mouse. 1223 71

A-Type lamins, arising from the LMNA gene, are intermediate filaments proteins that belong to the lamina, a ubiquitous nuclear network. Naturally occurring mutations in these proteins have been shown to be responsible for several distinct diseases that display skeletal and/or cardiac muscle or peripheral nerve involvement. These include familial partial lipodystrophy of the Dunnigan type and the mandibuloacral dysplasia syndrome. The pathophysiology of this group of diseases, often referred to as laminopathies, remains elusive. We report a new condition in a 30-yr-old man exhibiting a previously undescribed heterozygous R133L LMNA mutation. His phenotype associated generalized acquired lipoatrophy with insulin-resistant diabetes, hypertriglyceridemia, hepatic steatosis, hypertrophic cardiomyopathy with valvular involvement, and disseminated whitish papules. Immunofluorescence microscopic analysis of the patient's cultured skin fibroblasts revealed nuclear disorganization and abnormal distribution of A-type lamins, similar to that observed in patients harboring other LMNA mutations. This observation broadens the clinical spectrum of laminopathies, pointing out the clinical variability of lipodystrophy and the unreported possibility of hypertrophic cardiomyopathy and skin involvement. It emphasizes the fact that the diagnosis of genetic alterations in A-type lamins requires careful and complete clinical and morphological investigations in patients regardless of the presenting signs.
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PMID:A new clinical condition linked to a novel mutation in lamins A and C with generalized lipoatrophy, insulin-resistant diabetes, disseminated leukomelanodermic papules, liver steatosis, and cardiomyopathy. 1262 77

HAART has resulted in dramatic declines in morbidity and mortality among patients infected with HIV. Increased experience with HAART has led to the detection of drug related toxicities that may compromise adherence and necessitate discontinuation of treatment and alteration of otherwise effective regimens. This article considers the major long-term complications associated with nucleoside reverse transcriptase inhibitor (NRTI) use--hyperlactatemia and lactic acidosis/hepatic steatosis, other hepatotoxicities, pancreatitis, lipodystrophy, lipoatrophy, neuropathy, and hematologic toxicities. Mechanisms by which NRTIs may produce these effects are discussed, as are differential effects of agents in this class and management options.
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PMID:Long-term complications of nucleoside reverse transcriptase inhibitor therapy. 1274 68

Mitochondrial toxicity has been implicated in the development of a variety of nucleoside reverse transcriptase inhibitor-associated syndromes. Mitochondrial damage and decreases in mitochondrial DNA levels have been demonstrated in various tissues of patients treated with NRTIs, especially in conjunction with exposure to stavudine. Clinical syndromes that may be mediated by mitochondrial toxicity include hyperlactatemia and lactic acidosis, hepatic steatosis, lipoatrophy, peripheral neuropathy, HIV-associated neuromuscular weakness syndrome, pancreatitis, skeletal myopathies, and cardiomyopathy. Early recognition of these syndromes in their mild forms involves close monitoring and a high index of suspicion. This may allow prompt discontinuation of the causative agent(s) and initiation of appropriate therapeutic measures, thereby increasing the chances of reversibility of the syndrome.
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PMID:Mitochondrial dysfunction: patient monitoring and toxicity management. 1531 67

This study explores the mechanisms responsible for the fatty liver setup in mice fed trans-10,cis-12 conjugated linoleic acid (t10c12 CLA), hypothesizing that an induction of low density lipoprotein receptor (LDLR) expression is associated with lipid accumulation. To this end, the effects of t10c12 CLA treatment on lipid parameters, serum lipoproteins, and expression of liver lipid receptors were measured in LDLR(-/-) apoB(100/100) mice as a model of human familial hypercholesterolemia itself depleted of LDLR. Mice were fed t10c12 CLA over 2 or 4 weeks. We first observed that the treatment induced liver steatosis, even in the absence of LDLR. Mice treated for 2 weeks exhibited hypertriglyceridemia with high levels of VLDL and HDL, whereas a 4 week treatment inversely induced a reduction of serum triglycerides (TGs), essentially through a decrease in VLDL levels. In the absence of LDLR, the mRNA levels of other proteins, such as VLDL receptor, lipoprotein lipase, and fatty acid translocase, usually not expressed in the liver, were upregulated, suggesting their involvement in the steatosis setup and lipoprotein clearance. The data also suggest that the TG-lowering effect induced by t10c12 CLA treatment was attributable to both the reduction of circulating free fatty acids in response to the severe lipoatrophy and the high capacity of liver to clear off plasma lipids.
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PMID:Upregulation of liver VLDL receptor and FAT/CD36 expression in LDLR-/- apoB100/100 mice fed trans-10,cis-12 conjugated linoleic acid. 1695 81


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