Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P17174 (aspartate aminotransferase)
 14,872 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dietary habits are often considered as a pathogenic factor for fatty liver. The impact of dietary intake and steatosis on drug metabolism remains poorly investigated. Our aim was to assess the effect of dietary intake on in vivo cytochrome P450 (CYP) activities in eleven patients with abnormal liver function tests potentially due to fatty liver and associated with a high-sugar diet. Liver function tests, liver volume, aminopyrine breath test (ABT) and chlorzoxazone (CZ) pharmacokinetics (area under the curve, AUC) which are known to reflect CYP2E1 activity were evaluated before and after 2 months restriction of dietary sugar intake. Features at inclusion were an increased BMI (30.3 (SD 3.2) kg/m2), high hepatic volume (1.96 (SD 0.48) litres), hyperechogenic liver parenchyma, elevated liver enzyme activities (alanine aminotransferase (EC 2.6.1.2) 58.6 (SD 17.4) IU/1 with alanine aminotransferase: aspartate aminotransferase (EC 2.6.1.1) ratio > 1), together with a normal ABT value (0.68 (SD 0.21)% specific activity of administered dose of [14C]aminopyrine in breath after 1 h) and a high CYP2E1 activity (CZ AUC 20.3 (SD 7.1) micrograms/ml per h). A dietary sugar restriction was prescribed. On the basis of repeated interviews by the same dietitian, unaware of any clinical and biochemical data, six patients remained complaint to the diet and exhibited reductions in BMI (P < 0.001), serum alanine aminotransferase (P = 0.008), liver volume (P = 0.002) and CYP2E1 activity (P = 0.007), a significant increase in ABT (P < 0.001) together with the disappearance of liver hyperechogenicity at ultrasound. In contrast, the five non-compliant patients did not show any significant change in any of these variables. In conclusion, CYP2E1 activity is induced in patients with perturbations of liver function tests potentially due to fatty liver. In these patients, effective dietary sugar restriction is associated with a reduction in liver volume, a reduction in CYP2E1 activity and an increased aminopyrine metabolism rate.
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PMID:Dietary restriction of energy and sugar results in a reduction in human cytochrome P450 2E1 activity. 1065 74

Nonalcoholic steatohepatitis (NASH) is a histological diagnosis applied to a constellation of liver biopsy findings that develop in the absence of alcohol abuse. Steatosis, a mixed cellular inflammatory infiltrate across the lobule, evidence of hepatocyte injury and fibrosis are the findings that can be seen. This entity is often identified during evaluation of elevated aminotransferases after exclusion of viral, metabolic and other causes of liver disease. Obesity is a major risk factor for NASH. The role of diabetes is less certain, although evidence is accumulating that hyperinsulinism may play an important pathophysiological role. Patients sometimes suffer from right upper quadrant abdominal pain and fatigue; examination may reveal centripetal obesity and hepatomegaly. Although patients are often discovered because of persistent aminotransferase elevations, these enzymes can be normal in NASH. When they are elevated, the alanine aminotransferase level is typically significantly greater than the aspartate aminotransferase level. This can be particularly helpful for excluding occult alcohol abuse. Imaging studies identify hepatic steatosis when the amount of fat in the liver is significant; however, imaging does not distinguish benign steatosis from NASH. Ultimately a liver biopsy is needed to diagnose NASH. The biopsy may be useful for establishing prognosis based on the presence or absence of fibrosis and for excluding other unexpected causes of liver enzyme elevations. Weight loss is the mainstay of treatment for obese patients. About 15% to 40% of NASH patients develop fibrosis; how many of these cases progress to cirrhosis is unknown, but about 1% of liver transplants are performed with a pretransplant diagnosis of NASH.
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PMID:Nonalcoholic steatohepatitis: an evolving diagnosis. 1079 85

Hepatic steatosis is associated with significant morbidity and mortality after liver resection and transplantation. Although apoptosis is a key mechanism of reperfusion injury in the normal liver, the pathway leading to cell death in steatotic hepatocytes is unknown. A model of hepatic ischemia and reperfusion injury in fatty and lean Zucker rats was used. Fatty animals had increased aspartate aminotransferase (AST) release and decreased survival after 60 minutes of ischemia compared with lean animals. Apoptosis was the predominant form of cell death in the lean rats (82%), whereas necrosis was minimal. In contrast, fatty animals developed only moderate amounts of apoptosis but showed massive necrosis (73%) after 24 hours of reperfusion. Intracellular mediators of apoptosis, such as caspase 8, caspase 3, and cytochrome c, were significantly lower in the steatotic than in the lean liver indicating dysfunction in activation of the apoptotic pathway. The high percentage of necrosis in the steatotic rats was associated with renal acute tubular necrosis after 24 hours of reperfusion in the fatty, but not in lean rats. Caspase inhibition significantly decreased reperfusion injury in lean animals, but was ineffective in fatty animals. The results indicate that the increased susceptibility of fatty livers to reperfusion injury is associated with a change from an apoptotic form of cell death to necrosis. We conclude that new therapeutic strategies are necessary in the fatty liver.
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PMID:Mechanisms of ischemic injury are different in the steatotic and normal rat liver. 1109 35

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

N,N-Dimethylformamide (DMF) has excellent solvent properties and is used intensively in the production of synthetic leather and resins. It has caused hepatoxicity in human and animal studies. Hepatitis B virus (HBV) and hepatitis C virus infections are reported to be the major causes of chronic liver diseases (including liver cirrhosis and liver cancer) in Taiwan. This study examined the dose-response relationship of the observed abnormal liver function among the DMF-exposed workers and the interactions among DMF, other chemical exposures, HBV infection, and potential confounders on liver abnormalities. The average DMF exposure concentration was 11.6 ppm (median, 5.9 ppm; range, 0.1 to 86.6 ppm); 65 of 176 workers (36.9%) had high (> 10 ppm) DMF exposure, 37 (21%) had middle (> 5 ppm, < or = 10 ppm) exposure, and 74 (42%) had low (< or = 5 ppm) exposure. There were 24 of 65 abnormal liver function test results (LFTs) (36.9%) (elevations of either glutamate oxaloacetate transaminase, glutamate pyruvate transaminase, or gamma-glutamyl transpeptidase) among the workers with high DMF exposure, 10 of 37 abnormal LFTs (27%) among workers with middle DMF exposure, and 11 of 74 abnormal LFTs (22%) among workers with low DMF exposure. Compared with the workers having low DMF exposure, the HBV, drinking, body mass index (BMI), sex, duration of employment, epichlorohydrin, and toluene exposure adjusted odds ratios (ORs) (and 95% confidence intervals [CIs]) for abnormal LFTs were 1.62 (0.61, 4.28) for workers with middle DMF exposure and 2.93 (1.27, 6.8) for those with high DMF exposure, and there was a significant dose response between DMF exposure and the prevalence of abnormal LFTs (P = 0.006). There were significant associations between abnormal LFTs and HBV carriers (adjusted OR: 3.11; 95% CI: 1.29, 7.5; P = 0.01) and between abnormal LFTs and increased BMI (adjusted OR: 2.2; 95% CI: 1.02, 4.72; P = 0.041). Ultrasonography showed significant associations between chronic liver diseases and HBV carrier status, increased BMI, and high cumulative (> 100 ppm-years) DMF exposure (respectively, adjusted OR: 9.58, 95% CI: 1.79, 51.4, P = 0.007; adjusted OR: 13.2, 95% CI: 1.32, 132, P = 0.025; and adjusted OR: 6.2, 95% CI: 1.14, 34.1, P = 0.032). Drinking and BMI were significantly associated with fatty liver (respectively, adjusted OR: 4.9, 95% CI: 1.39, 17.3, P = 0.012; and adjusted OR: 7.93, 95% CI: 1.6, 39.3, P = 0.01). In conclusion, this study demonstrated that (1) a significant dose-response relationship existed between liver function abnormalities and DMF exposure among workers in Taiwan, (2) HBV carrier status or increased BMI had synergistic effects with DMF in causing liver abnormalities (abnormal LFTs and clinical chronic liver diseases).
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PMID:Abnormal liver function associated with occupational exposure to dimethylformamide and hepatitis B virus. 1138 83

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

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

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


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