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)

In patients with severe alcoholic liver disease (i.e., cirrhosis), a deficiency of S-adenosylmethionine (SAMe) develops as a result of decreased SAMe synthetase activity. Whether a sizeable SAMe depletion occurs already at earlier stages of alcoholic liver disease has been the subject of debate. To address this issue, rats were fed alcohol (or isocaloric carbohydrate) in Lieber-DeCarli liquid diets containing adequate amounts of protein, vitamins, and lipotropic factors, including methionine. Alcohol feeding resulted in hepatic steatosis (without fibrosis) and unchanged SAMe synthetase activity, yet SAMe concentration was already greatly decreased. This most likely resulted from oxidative stress associated with the metabolism of alcohol and the induction of cytochrome P4502E1 (CYP2E1), which generates free radicals. Indeed, the decrease in hepatic SAMe correlated with parameters of oxidative stress, such as increased 4-hydroxynonenal (measured by gas chromatography-mass spectrometry) and diminished glutathione (GSH). Decreased GSH, occurring as a result of excessive GSH consumption caused by the oxidative stress, probably generated by enhanced utilization of SAMe, a precursor of GSH, thereby explaining the depletion of SAMe. In view of the known differences between rodents and primates in the metabolism of lipotropes, my colleagues and I have also studied the interaction between alcohol and SAMe in baboons and found again that, at early stages preceding the development of cirrhosis, there was already a significant lowering of hepatic SAMe concentration, associated with a striking oxidative stress documented by decreased levels and accelerated turnover of GSH. This was associated with increased lipid peroxidation and damage to cellular membranes, including those of the mitochondria, assessed by electron microscopy. Oral administration of SAMe resulted in its hepatic repletion with a corresponding attenuation of the ethanol-induced oxidative stress and liver injury, with significantly less GSH depletion, less increases in plasma aspartate aminotransferase (AST) levels, less leakage of mitochondrial glutamic dehydrogenase into the plasma, and fewer megamitochondria. In conclusion, (1) both in rodents and in non-human primates, significant SAMe depletion occurs already at early stages of alcoholic liver disease, despite the consumption of adequate diets; (2) the decreased hepatic SAMe concentration and the associated liver lesions, including mitochondrial injury, can be corrected with SAMe supplementation; and (3) accordingly, therapeutic administration of SAMe should be the subject of a comprehensive clinical trial to assess its capacity to attenuate early stages of alcoholic liver injury in human beings.
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PMID:S-Adenosyl-L-methionine and alcoholic liver disease in animal models: implications for early intervention in human beings. 1216 46

Nonalcoholic fatty liver disease, an entity that includes nonalcoholic steatohepatitis, is typically a benign, indolent condition. However, in a subset of patients, the clinical course may progress to advanced cirrhosis, end-stage liver disease, or hepatocellular carcinoma. Unfortunately, the pathogenesis, natural history, and potential therapies for these disorders remain poorly understood. Identifying patients who should be targeted for potential treatment remains difficult. Liver biopsy should be considered to assess the degree of hepatic inflammation and fibrosis, because physical examination findings, biochemical parameters, and the results of radiographic studies have been shown to correlate poorly with the severity of steatohepatitis and fibrosis. Although there is some evidence suggesting that obesity, diabetes mellitus, older age, and perhaps an aspartate transaminase:alanine aminotransaminase ratio higher than 1 may be predictors of more advanced fibrosis, histology remains the gold standard. Most patients with simple hepatic steatosis appear to follow a benign course and probably do not require aggressive therapy. Conversely, patients with steatohepatitis with extensive inflammation and fibrosis are the patients who are most likely to benefit from effective therapies. The most commonly recommended treatment is weight loss. Existing data suggest that rapid weight loss may promote hepatic inflammation and fibrosis; therefore, gradual weight loss should be recommended. Large, randomized, controlled trials evaluating the long-term histologic impact and clinical outcomes of weight loss strategies are lacking. Potentially promising pharmacologic therapies include insulin-sensitizing oral hypoglycemic agents such as metformin and the thiazolidenediols, antihyperlipidemic agents such as gemfibrozil or 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, vitamin E and other antioxidants, ursodeoxycholic acid, and betaine. As with weight loss, data regarding the efficacy of these pharmacologic options are limited. In addition, there are no widely accepted guidelines to help direct the clinician in the optimal use of these agents in patients with nonalcoholic fatty liver diseases.
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PMID:Therapeutic Options in Nonalcoholic Fatty Liver Disease. 1240 79

The syndrome of hemolysis, elevated liver enzymes, and low platelet count (HELLP syndrome) and of acute fatty liver of pregnancy (AFLP) do not have an abrupt onset. Thrombocytopenia or reduced antithrombin activity, or both, seen at presentation do not result from these complications. There are a small number of pregnant women who exhibit a gradual antenatal decline in platelet counts or antithrombin activity, or both, irrespective of the presence or absence of preeclampsia. Those who develop a profound decrease in either platelet counts or antithrombin activity are at an increased risk for developing perinatal aspartate aminotransferase (AST) elevation. Thrombocytopenia or reduced antithrombin activity, or both, precede the onset of these diseases. Therefore, monitoring of platelet counts and antithrombin activity during pregnancy is clinically useful for identifying women at an increased risk of the HELLP syndrome and AFLP. Because women with twin pregnancies are likely to exhibit a decrease in platelet counts or antithrombin activity, or both, compared with women with singleton pregnancies, HELLP syndrome and AFLP are more likely to occur in women with twin pregnancies.
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PMID:Gestational thrombocytopenia and pregnancy-induced antithrombin deficiency: progenitors to the development of the HELLP syndrome and acute fatty liver of pregnancy. 1253 42

To determine the difference between alcoholic hepatitis (AH) and non-alcoholic steatohepatitis (NASH) in Japan, six patients with Ah and four patients with NASH, recently treated at our institute, were clinically and pathologically evaluated. Clinical features of the diseases differed: in NASH patients, mean age was higher, mean body mass index much higher, and the prevalence of diabetes mellitus was higher than in AH patients. The patients with NASH presented with unremarkable symptoms and signs. Abnormalities in liver function tests including prothrombin time and choline esterase were mild in NASH patients, except for the indocyanine green test. They had ALT-dominant hypertransaminasemia. AST, ALT and gamma GTP did not normalize as promptly as in AH patients after admission. However, there was no significant difference in the histological grade of fibrosis, inflammation or hepatocytic metamorphosis between NASH and AH patients. Stellate-form fibrosis was characteristic of AH, whereas pericellular and perivenular types were common in NASH patients. Focal cell necrosis was rather intense, and fatty deposits prominent, in NASH patients. However, it was difficult to histopathologically discriminate between NASH and AH patients. If AH is histologically suspected in non-alcoholic patients, the possibility of NASH should always be considered. Furthermore, even in patients with suspected simple fatty liver, a liver biopsy should be performed, especially in cases with prolonged abnormal liver function findings.
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PMID:Clinical and pathological differences between alcoholic hepatitis and non-alcoholic steatohepatitis. 1268 23

As left-displaced abomasum (LDA) often occurs in cows with high contents of fat in the liver (fatty liver), a postpartum fatty liver-inducing regimen was applied to 16 cows. The main interest of the study was whether there were productive or metabolic changes in cows prior to LDA. Therefore, feed intake and milk production were monitored and blood samples were collected from the cows. The LDA occurred in 4 out of 16 dairy cows that were included in the feeding regimen. Compared to cows not developing LDA, LDA-cows had a significantly lower feed intake, 6.5 kg/d less, and milk production, 8 kg/d less, prior to clinical diagnosis of LDA. In the 10-d period preceding clinical diagnosis of LDA, blood concentrations of calcium, glucose, and insulin were significantly lower, whereas blood concentrations of nonesterified fatty acids and beta-hydroxybutyrate, as well as aspartate aminotransferase activities were significantly elevated compared to cows not developing LDA. These preclinical changes may play an important role in the pathogenesis of LDA. It is not certain, however, whether there is a causal association between these parameters and LDA.
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PMID:Feed intake, milk yield, and metabolic parameters prior to left displaced abomasum in dairy cows. 1274 71

Beta-cyclodextrin is a compound that forms inclusion complexes with a variety of molecules, specially bile acids and sterols. This study examines the effects of beta-cyclodextrin on cholesterol and bile acid metabolism in hypercholesterolaemic rats. Male Wistar rats were divided into 4 groups that received during 7 weeks: control diet, 2% cholesterol diet (A), A+2.5% beta-cyclodextrin (B) and A+5% beta-cyclodextrin (C). The cholesterol-rich diet induced hepatomegaly and fatty liver and significantly reduced cholesterol, bile acid and phospholipid secretion. Addition of beta-cyclodextrin normalised biliary lipid secretion. Moreover, when compared to A, beta-cyclodextrin significantly lowered plasma phospholipid concentration (B: -21%; C: -29%) and the liver free/total cholesterol molar ratio (B: -40%; C: -38%), increased bile acid faecal output (B: +17%; C: +62%) and enhanced cholesterol 7alpha-hydroxylase activity (B:+50%; C : +100%)and mRNA levels (B: + 14%; C: +29%). 5% beta-cyclodextrin also reduced plasma triglycerides concentration (-38%). However, ALT and AST activities were significantly increased (B: +140% and +280%; C: +72% and +135%) and there was a high incidence of cell necrosis with portal inflammatory cell infiltration. Addition of beta-cyclodextrin to a cholesterol-rich diet results in a triglyceride-lowering action, enhancement of bile acid synthesis and excretion, and normalization of biliary lipid secretion, but produces a marked hepatotoxic effect.
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PMID:Effects of dietary beta-cyclodextrin in hypercholesterolaemic rats. 1274 79

In order to determine the effect of ursodeoxycholic acid on nonalcoholic fatty liver disease, 30 patients with body mass indices higher than 25, serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) or gamma-glutamyltransferase (gamma-GT) at least more than 1.5 times the upper limit of normality, and hepatic steatosis demonstrated by ultrasonography were randomized into two groups of 15 patients to receive placebo or 10 mg kg-1 day-1 ursodeoxycholic acid for three months. Abdominal computed tomography was performed to quantify hepatic fat content, which was significantly correlated with histological grading of steatosis (r s = -0.83, P < 0.01). Patient body mass index remained stable for both groups throughout the study, but a significant reduction in mean ( +/- SEM) serum levels of ALT, AST and gamma-GT was observed only in the treated group (ALT = 81.2 +/- 9.7, 44.8 +/- 7.7, 48.1 +/- 7.7 and 52.2 +/- 6.3 IU/l at the beginning and after the first, second and third months, respectively, N = 14, P < 0.05). For the placebo group ALT values were 66.4 +/- 9.8, 54.5 +/- 7, 60 +/- 7.6 and 43.7 5 IU/l, respectively. No alterations in hepatic lipid content were observed in these patients by computed tomography examination (50.2 +/- 4.2 Hounsfield units (HU) at the beginning versus 51.1 +/- 4.1 HU at the third month). These results show that ursodeoxycholic acid is able to reduce serum levels of hepatic enzymes in patients with nonalcoholic fatty liver disease, but this effect is not related to modifications in liver fat content.
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PMID:A randomized double-blind study of the short-time treatment of obese patients with nonalcoholic fatty liver disease with ursodeoxycholic acid. 1279 1

Chronic liver disease is a major cause of morbidity and mortality in the United States. Although often used to detect liver disease, the prevalence and etiology of elevated aminotransferases are unknown. We analyzed data on adults ages 17 yr and older (N = 15,676) from the Third National Health and Nutrition Examination Survey (1988-1994). Participants were classified as having elevated aminotransferase levels if either aspartate aminotransferase or alanine aminotransferase was elevated above normal. Aminotransferase elevation was classified as "explained" if there was laboratory evidence of hepatitis B or C infection, iron overload, or if there was a history of alcohol consumption. Analyses were weighted to provide national estimates. The prevalence of aminotransferase elevation in the United States was 7.9%. Aminotransferase elevation was more common in men compared to women (9.3% vs 6.6%, p = 0.002), in Mexican Americans (14.9%) and non-Hispanic blacks (8.1%) compared to non-Hispanic whites (7.1%, p < 0.001). High alcohol consumption, hepatitis B or C infection and high transferrin saturation were found in only 31.0% of cases. Aminotransferase elevation was unexplained in the majority (69.0%). In both men and women, unexplained aminotransferase elevation was significantly associated with higher body mass index, waist circumference, triglycerides, fasting insulin, and lower HDL; and with type 2 diabetes and hypertension in women (all p < 0.05). Aminotransferase elevation was common in the United States, and the majority could not be unexplained by alcohol consumption, viral hepatitis or hemochromatosis. Unexplained aminotransferase elevation was strongly associated with adiposity and other features of the metabolic syndrome, and thus may represent nonalcoholic fatty liver disease.
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PMID:The prevalence and etiology of elevated aminotransferase levels in the United States. 1280 14

To investigate the associations between obesity and serum hepatic enzyme activities, we measured total body fat (TBF), body mass index (BMI), and hepatic biochemical parameters in 732 apparently healthy adults. TBF was assessed using a body fat analyzer. Serum activities of alanine and aspartate aminotransferase (ALT and AST), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), and lactate dehydrogenase (LD) were determined by standard spectrophotometric methods. Mean activities (+/- SD) of serum ALT and AST in men with high fatness were 51.2 +/- 12.6 U/L and 32.9 +/- 9.2 U/L, which were significantly higher than those in men with low fatness (23.5 +/- 7.4 U/L and 22.5 +/- 7.8 U/L, p < 0.01). Of 147 men with high fatness, 56 (38.1%) had serum ALT levels above the upper limit of normal, whereas only 9.5% (31/328) of men with low or desirable fatness showed elevated serum ALT activities (p < 0.01). Serum ALT, AST, and GGT activities correlated significantly with TBF in both overweight men and women. Among subjects having high TBF, those with fatty liver showed significantly higher incidence of elevated hepatic enzymes, compared to those without fatty liver. In short, elevated serum hepatic enzyme activities are associated with TBF and a high prevalence of fatty liver is observed in subjects with elevated TBF.
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PMID:Association between elevated serum hepatic enzyme activity and total body fat in obese humans. 1295 39

Hypercreatinuria is a well-known feature of liver and testicular toxicity and we have recently proposed that hepatotoxin-induced hypercreatinuria would arise as a consequence of increased cysteine synthesis associated with the provision of protective substances (glutathione and/or taurine). Here a direct relationship between hepatotoxin-induced hypercreatinaemia and hypercreatinuria is shown and the possible relationships of hepatotoxin-induced hypercreatinaemia and hypercreatinuria to hepatic damage and to weakened nutritional status are examined. Male Sprague-Dawley rats were dosed with a variety of model hepatotoxins at two dose levels per toxin. Blood plasma samples taken at 24 h post-dosing and urine samples collected from 24-31 h post-dosing were analysed by (1)H NMR spectroscopy. Both hypercreatinaemia and hypercreatinuria were found in rats dosed with allyl formate (75 mg/kg), chlorpromazine (30 and 60 mg/kg), alpha-naphthylisothiocyanate (ANIT, 100 mg/kg) and thioacetamide (200 mg/kg), whilst significant hypercreatinuria, but not hypercreatinaemia, was found after dosing with thioacetamide (50 mg/kg). Neither hypercreatinaemia nor hypercreatinuria were found after dosing with allyl formate (25 mg/kg), ethionine (300 and 1000 mg/kg) or ANIT (30 mg/kg). Reduced feeding is known to cause hypercreatinuria in rats and, of the four hepatotoxins that induced hypercreatinaemia and hypercreatinuria at the given time-points, two, chlorpromazine and ANIT, also affected nutritional status with ketosis being clearly identifiable from the plasma (1)H NMR spectra. Thus, the creatine changes induced by ANIT and chlorpromazine are potentially attributable, in whole or in part, to reduced feeding rather than to liver effects alone and, consequently, the results were examined with and without inclusion of the ANIT and chlorpromazine data. With all of the data included, there were eight out of ten points of correspondence between the incidence of hypercreatinaemia and/or hypercreatinuria and the incidence of increases in plasma alanine aminotransferase (ALT) activity. At the same time there were nine out of ten points of correspondence between the incidence of hypercreatinaemia and/or hypercreatinuria and the incidence of increases in plasma aspartate aminotransferase (AST) activity. However, with the ANIT and chlorpromazine data excluded there was complete (six out of six points) correspondence between the incidence of hypercreatinaemia and/or hypercreatinuria and the incidence of increases in plasma AST and ALT in the remaining data. Likewise, with all of the data included, there was some apparent correlation (correlation coefficient, r=0.80) between the group mean levels of plasma AST and plasma creatine when expressed relative to the mean values for controls sampled at the same time-point. However, with the ANIT and chlorpromazine data excluded, that correlation coefficient was increased to 0.95. The findings of these studies suggest that the ANIT- and chlorpromazine-induced creatine changes may have been caused by reduced feeding rather than by liver toxicity. The allyl formate and thioacetamide data indicate that hepatocellular necrosis is accompanied by increases in plasma and urinary creatine, and suggest the possibility of a quantitative relationship between the increases in plasma AST and the increases in plasma creatine that are associated with hepatocellular necrosis. The ethionine and ANIT data suggest that fatty liver (steatosis) and cholestatic damage may not be associated with hypercreatinaemia and hypercreatinuria.
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PMID:Hepatotoxin-induced hypercreatinaemia and hypercreatinuria: their relationship to one another, to liver damage and to weakened nutritional status. 1452 May 8


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