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)

Hepatic steatosis and the accompanying oxidative stress have been associated with a variety of liver diseases. It is not known if fat accumulation per se plays a direct role in the oxidative stress of the organ. This study tested if steatosis induced by a short-term carbohydrate-rich diet results in an increased hepatic sensitivity to oxidative stress. Antioxidant status was determined in a liver perfusion system and in isolated parenchymal, endothelial and Kupffer cells from rats kept on sucrose-rich diet or on regular diet for 48 h. t-Butyl hydroperoxide addition (2 mM) to the perfusion fluid resulted in a release of alanine aminotransferase (ALT) in livers from controls, whereas no ALT release was observed in fatty livers. After t-butyl hydroperoxide addition, oxidized glutathione release was 40% less in fatty than in control livers, whereas reduced glutathione (GSH) release was not different. Sinusoidal oxidant stress was mimicked by the addition of lipopolysaccharide (LPS) from Escherichia coli (10 microg/ml) followed by the addition of opsonized zymosan (8 mg/ml) to the perfusion medium. LPS plus zymosan treatments resulted in the release of ALT in control but not in fatty livers. At the end of perfusion, liver glutathione content was 3-fold elevated, and the tissue content of lipid peroxidation products was approx. 40% less in fatty livers compared to controls. GSH content was doubled and glucose-6-phosphate dehydrogenase (G6PD) expression was elevated by 3- and 10-fold in sinusoidal endothelial and parenchymal cells form fatty livers compared to cells from control animals. Following H(2)O(2) administration in vitro (0.2-1 mM), GSH remained elevated in endothelial and parenchymal cells from fatty livers compared to cells from controls. In contrast, G6PD activity and GSH content were similar in Kupffer cells isolated from fatty or control livers. The study shows that hepatic fat accumulation caused by a short-term sucrose diet is not accompanied by elevated hepatic lipid peroxidation, and an elevated hepatic antioxidant activity can be manifested in the presence of prominent steatosis. The diet-induced increase in G6PD expression and, thus, the efficient maintenance of reduced glutathione in endothelial and parenchymal cells are a supportive mechanism in the observed hepatic resistance against intracellular or sinusoidal oxidative stress.
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PMID:Augmented resistance to oxidative stress in fatty rat livers induced by a short-term sucrose-rich diet. 1101 71

Cytotoxic T lymphocytes (CTLs) play an important role in the pathogenesis of viral hepatitis. We studied the expression of mRNAs of perforin and Fas ligand (Fas-L) in biopsy specimens from chronic hepatitis B (CHB) (15 cases) and hepatitis C (CHC) patients (13 cases). Both perforin and Fas-L mRNAs were detected in all cases of both CHB and CHC. No messages were detected in the control livers from two cases of fatty liver, a case of Gilbert's syndrome, and a case of Dubin-Johnson syndrome. Semiquantitative analysis revealed a positive correlation between the intensity of perforin and Fas-L mRNAs in both CHB and CHC. In CHB, the intensity of both perforin and Fas-L mRNAs showed a positive correlation with the histological activity and serum alanine aminotransferase level, while the correlation was not apparent in CHC. These results suggest that both perforin and Fas/Fas-L systems are involved in the pathogenesis of liver cell injury of CHB and CHC.
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PMID:Expression of perforin and Fas ligand mRNA in the liver of viral hepatitis. 1105 Dec 76

Nonalcoholic steatohepatitis, along with other forms of nonalcoholic fatty liver disease, is a chronic liver disease that is attracting increasing significance. It is a clinicopathologic syndrome that was originally described in obese, diabetic females who denied alcohol use but in whom the hepatic histology was consistent with alcoholic hepatitis. This typical patient profile has been expanded and is now recognized to occur even in normal weight males without overt abnormalities in carbohydrate metabolism. Although originally believed to be a benign clinical entity, nonalcoholic steatohepatitis is now recognized as a cause of progressive fibrotic liver disease with adverse clinical sequelae. It is important to emphasize that nonalcoholic steatohepatitis is best considered one type of a larger spectrum of nonalcoholic fatty liver disease that is a consequence of insulin resistance and ranges from fat alone to fat plus inflammation, fat plus ballooning degeneration, and nonalcoholic steatohepatitis, the latter being the most serious form. As with any disease, the clinical importance of nonalcoholic steatohepatitis is related to its prevalence and natural history. Recent studies using different methodologies indicate that in the general population the prevalence of fatty liver and nonalcoholic steatohepatitis is approximately 20% and 3%, respectively. These prevalence rates are increased in certain subpopulations such as obesity and type II diabetes. Of greater concern is the recognition that cirrhosis and liver-related deaths occur in approximately 20% and 8% of these patients, respectively, over a 10-year period. Risk factors for these adverse clinical symptoms include patients older than the age of 45, the presence of diabetes or obesity, an aspartate aminotransferase/alanine aminotransferase ratio > 1 and hepatic histology. However, a number of important unresolved issues must be clarified before the true natural history of this disease can be fully understood.
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PMID:Clinical features and natural history of nonalcoholic steatosis syndromes. 1129 93

Fatty livers are sensitive to lipopolysaccharide (LPS) damage. This study tests the hypothesis that this vulnerability occurs because protective, antiapoptotic mechanisms are not upregulated appropriately. Genetically obese, leptin-deficient ob/ob mice, a model for nonalcoholic fatty liver disease, and their lean litter mates were treated with a small dose of LPS. General measures of liver injury, early (i.e., cytochrome c release) and late (i.e., activation of caspase 3) events that occur during hepatocyte apoptosis, and various aspects of the signal transduction pathways that induce nuclear factor-kappaB (NF-kappaB) and several of its antiapoptotic transcriptional targets (e.g., inducible nitric oxide synthase, bfl-1, and bcl-xL) were compared. Within 0.5-6 h after LPS exposure, cytochrome c begins to accumulate in the cytosol of normal livers, and procaspase 3 cleavage increases. Coincident with these events, kinases (e.g., AKT and Erk-1 and -2) that result in the degradation of inhibitor kappa-B are activated; NF-kappaB activity is induced, and NF-kappaB-regulated gene products accumulate. Throughout this period, there is negligible histological evidence of liver damage, and serum alanine aminotransferase values barely increase over baseline values. Although ob/ob livers have significant histological liver injury and 11-fold greater serum alanine aminotransferase values than those of lean mice by 6 h post-LPS, they exhibit greater activation of AKT and Erk, more profound reductions in inhibitor kappa-B, enhanced activation of NF-kappaB, and greater induction of NF-kappaB-regulated genes. Consistent with this heightened antiapoptotic response, increases in cytochrome c and procaspase 3 cleavage products are inhibited. Together with evidence that ob/ob hepatocytes have a reduced ATP content and undergo increased lysis after in vitro exposure to tumor necrosis factor-alpha, these findings suggest that fatty livers are sensitive to LPS damage because of vulnerability to necrosis, rather than because of apoptosis.
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PMID:Fatty liver vulnerability to endotoxin-induced damage despite NF-kappaB induction and inhibited caspase 3 activation. 1144 19

The validity (sensitivity and specificity) of annual liver function tests, determined by assaying blood levels of aspartate aminotransferase, alanine aminotransferase and gammaglutamyl transpeptidase, was evaluated using the results of health checkups of male bank workers. The specificity of each liver function test to detect persons with fatty liver, excess alcohol users, and hepatic virus carriers, diagnosed respectively by ultrasound, detailed inquiry, and virus marker tests, was always higher than 80%, except for alanine aminotransferase in excess alcohol users (63.5%). However, the highest sensitivity to detect virus carriers was alanine aminotransferase to detect HCV antibody-positive workers, but it was only 45.5%. The highest sensitivity of the liver function tests to detect excess alcohol users in obese subjects was only 33.3%. The highest sensitivity by liver function tests to detect fatty liver was 35.7% which was inferior to that of the body mass index. These results indicate that the liver function tests mandated in the workplace periodic health checkups in Japan exhibit very low sensitivity for the detection of any of the proposed target clinical conditions.
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PMID:Test validity of periodic liver function tests in a population of Japanese male bank employees. 1152 Jun 55

Nonalcoholic fatty liver disease (NAFLD), a prevalent condition associated with obesity, has the potential of evolving into end-stage liver disease. The biochemical mechanisms that define the progression of NAFLD are not well known, but reactive oxygen species (ROS) have been implicated in this process. Uncoupling protein (UCP) 2 is a mitochondrial inner-membrane protein that mediates proton leak, uncouples adenosine triphosphate (ATP) synthesis, and negatively regulates ROS production. UCP2 expression is increased in various animal models of NAFLD. Up-regulation of UCP2 may compromise cellular ATP levels and worsen liver damage, or it may be protective by ROS reduction in NAFLD. This study aimed to obtain a definitive answer as to whether increased UCP2 expression contributes to NAFLD. UCP2-/- mice were exposed to obesity by crossbreeding with ob/ob mice and by long-term high-fat feeding to study the effect of UCP2 deficiency on the outcome of NAFLD. Steatohepatitis score of crossbred mice (ob/ob/ko) was similar to that of ob/ob mice at 25 weeks. No compensatory increase was observed in the expression of UCP5 in ob/ob/ko livers. To unmask the effects of absent leptin and its potential proinflammatory actions, steatosis was also induced in UCP2-/- mice by a high-fat diet continued for 6 months. Serum alanine aminotransferase (ALT) levels remained normal, and the steatohepatitis score in UCP2-/- mice was the same as in wild-type controls. We conclude that increased expression of UCP2 in the livers of mice with genetically or diet-induced obesity exerts neither protective nor deleterious effects on the severity of fatty liver disease.
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PMID:Obesity-related fatty liver is unchanged in mice deficient for mitochondrial uncoupling protein 2. 1191 20

Hepatic steatosis and steatohepatitis are encountered with great frequency in people who consume large amounts of ethanol (more than 6 drinks per day). Ethanol causes steatosis by altering several steps in the hepatic processing of fatty acids, including their uptake from plasma, their use as fuel substrates, and their export as triglyceride. When clinically mild, alcoholic steatosis and steatohepatitis can be difficult to distinguish from nonalcoholic fatty liver disease. This is particularly true among individuals at high risk of accelerated alcoholic liver injury, such as women, the obese, and those with hepatitis C. In the outpatient setting, history and aspartate aminotransferase:alanine aminotransferase ratio offer the best clues to diagnosis. Liver biopsy cannot determine the cause of steatohepatitis, but can show the extent of disease. The etiology of disease is important to prognosis, as alcoholic fatty liver carries a much higher risk of progression and mortality than nonalcoholic fatty liver disease. Patients with moderate to severe alcoholic steatohepatitis are typically hospitalized. Derangements in white blood cell count, prothrombin time, and bilirubin identify those with the highest early mortality. Survival in this severely ill subgroup is improved with the short-term use of corticosteroids; patients who have contraindications to steroids may benefit from other forms of therapy, either pharmacologic, nutritional, or both.
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PMID:Alcoholic steatosis and steatohepatitis. 1194 32

Nonalcoholic steatohepatitis (NASH) is a disorder characterized by hepatic steatosis, inflammation, and fibrosis. Leptin is an adipocyte-derived antiobesity hormone that in rodents prevents "lipotoxicity" by limiting triglyceride accumulation and also regulates matrix deposition (fibrosis) during wound healing. We therefore determined serum leptin levels in patients with NASH to determine whether relationships existed between leptin levels and severity of hepatic steatosis or fibrosis. We used a radioimmunoassay to determine serum [total] leptin concentrations in 27 men and 20 women with NASH and 47 controls matched for gender and body mass index (BMI; and partly for age). Serum leptin values were correlated with hepatic steatosis, fibrosis, and inflammation (each categorized semiquantitatively on liver histology), and with anthropometric indices, serum lipids, glucose, insulin, c-peptide, and alanine aminotransferase (ALT) levels. Compared with the controls, mean serum leptin levels were raised in both men and women with NASH (men 14 +/- 11 ng/mL vs. 7.2 +/- 4.1 ng/mL, P =.003; women 35 +/- 16 ng/mL vs. 15 +/- 8.2 ng/mL, P <.001). Leptin values correlated with serum c-peptide levels but not with BMI. In a multivariate analysis, serum leptin (P =.027), serum c-peptide (P =.001), and age (P =.027) were selected as independent predictors of the severity of hepatic steatosis. However, serum leptin was not an independent predictor of hepatic inflammation or fibrotic severity. In conclusion, hyperleptinemia occurs in NASH and is not explained simply by gender, obesity, or the presence of type 2 diabetes. Furthermore, leptin levels correlate directly with the severity of hepatic steatosis but not with inflammation or fibrosis. We propose that the relationship between leptin and steatosis reflects a pathogenic role of leptin in hepatic insulin resistance and/or a failure of the antisteatotic actions of leptin ("peripheral leptin resistance").
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PMID:Serum leptin in NASH correlates with hepatic steatosis but not fibrosis: a manifestation of lipotoxicity? 1214 49

The progression of fibrosis in chronic hepatitis C determines the ultimate prognosis and thus the need and urgency of therapy. Fibrogenesis is a complex dynamic process, which is mediated by necroinflammation and activation of stellate cells. The liver biopsy remains the gold standard to assess fibrosis. Scoring systems allow a semiquantitative assessment and are useful for cross-sectional and cohort studies and in treatment trials. The rate at which fibrosis progresses varies markedly between patients. The major factors known to be associated with fibrosis progression are older age at infection, male gender, and excessive alcohol consumption. Viral load and genotype do not seem to influence significantly the progression rate. Progression of fibrosis is more rapid in immunocompromised patients. Hepatic steatosis, obesity, and diabetes may also contribute to more rapid progression of fibrosis. There are no tests that reliably predict the rate of progression of fibrosis in an individual patient. High serum alanine aminotransferase (ALT) levels are associated with a higher risk of fibrosis progression, and worsening of fibrosis is uncommon in patients with persistently normal serum aminotransferase levels. Serum markers for fibrosis are not reliable and need to be improved and validated. Liver biopsy provides the most accurate information on the stage of fibrosis and grade of necroinflammation, both of which have prognostic significance. Repeating the liver biopsy, 3 to 5 years after an initial biopsy is the most accurate means of assessing the progression of fibrosis.
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PMID:Fibrosis and disease progression in hepatitis C. 1240 76

Previously regarded as an obscure disorder, nonalcoholic steatohepatitis (NASH) has recently emerged as an important chronic liver disease. NASH is within a spectrum of disorders characterized by excessive accumulation of fat in the liver, including simple hepatic steatosis (fatty liver), inflammation and necrosis (steatohepatitis), and fibrosis. Collectively, the disorders are called nonalcoholic fatty liver disease (NAFLD). Estimates of the prevalence of these individual conditions are suspect because liver biopsy is required for definitive diagnosis and is not generally performed. Although these conditions have traditionally been thought of as diseases of obese women, and are frequently associated with diabetes mellitus and hypertriglyceridemia, they have also been identified in lean men. Insulin resistance appears to be a common factor. These conditions are difficult to distinguish from each other clinically, and no biochemical or radiological test reliably establishes the diagnosis. A ratio of serum aspartate to alanine aminotransferase levels of less than one can distinguish NAFLD from alcoholic liver disease, but this is a nonspecific finding. Fatty infiltration imparts a diffuse echogenicity to the liver at ultrasonography, but this test cannot easily distinguish fat from fibrous tissue or identify cases of NASH. Only histological examination can establish the diagnosis of NASH, grade its severity, determine the prognosis and guide treatment.
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PMID:Motion - all patients with NASH need to have a liver biopsy: arguments for the motion. 1242 34


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