Contribution of metabolic factors to alanine aminotransferase activity in persons with other causes of liver disease

doi:10.1053/j.gastro.2004.12.004

Gastroenterology

Volume 128, Issue 3, March 2005, Pages 627-635

https://doi.org/10.1053/j.gastro.2004.12.004 Get rights and content

Background & Aims: Nonalcoholic fatty liver disease has been defined by the presence of hepatic steatosis in the absence of other chronic liver diseases. We sought to determine whether obesity, insulin resistance, and the metabolic syndrome, which are the main risk factors for nonalcoholic fatty liver disease, are associated with similar elevations in serum alanine aminotransferase activity in persons with and those without other causes of chronic liver disease. Methods: Adult participants of the third National Health and Nutrition Examination Survey were divided into those with causes of chronic liver disease (n = 1037), defined as viral hepatitis, excessive alcohol consumption, or increased transferrin-iron saturation, and those without (n = 8004). Results: Among persons with other causes of chronic liver disease, obesity (adjusted odds ratio, 4.9; 95% confidence interval, 2.5–9.4), insulin resistance (adjusted odds ratio, 6.8; 95% confidence interval, 3.0–15.5, comparing the highest and the lowest quartile), and the metabolic syndrome (adjusted odds ratio, 3.3; 95% confidence interval, 1.4–8.0) were all strongly associated with increased alanine aminotransferase activity (>43 IU/L). Among persons without other causes of chronic liver disease, statistically similar associations were identified. Conclusions: Obesity, insulin resistance, and the metabolic syndrome are strong predictors of increased alanine aminotransferase activity in the US population, both in persons with and in persons without other causes of chronic liver disease. We hypothesize that metabolic fatty liver disease related to these conditions is the cause of the increased alanine aminotransferase activity and may be underrecognized in persons with other causes of chronic liver disease.

Section snippets

Survey design

Data were derived from the Third National Health and Nutrition Examination Survey (NHANES III), a cross-sectional study conducted by the National Center for Health Statistics from 1988 to 1994 to assess the health and nutritional status of the noninstitutionalized US population.¹⁸ Data included laboratory investigation results, physical examination findings, and structured questionnaires conducted in mobile examination centers at 89 locations throughout the United States.

Study sample

Of 18,827 participants

Results

Out of 9041 participants, 1037 had the following causes of chronic liver disease: 184 had viral hepatitis (136 HCV, 46 HBV, and 2 HCV and HBV), 654 had excessive alcohol consumption (in the absence of HBV or HCV), and 199 had increased TS (in the absence of HBV, HCV, or excessive alcohol consumption). The prevalence of increased ALT activity was 10.3% in those with and 3.4% in those without the causes of chronic liver disease listed previously (Table 1). Among persons without these causes of

Discussion

Our study is limited by the fact that liver tissue was not available to determine hepatic steatosis, inflammation, or fibrosis. Instead, increased ALT activity was used as a surrogate measure for the presence of liver disease as in previous population-based studies.3, 14 Therefore, we cannot confirm that the increased ALT activity that was associated with obesity, insulin resistance, or the metabolic syndrome was related to hepatic steatosis. However, previous studies have shown that most (83%)

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Citation Excerpt :
More recently, the ALT:AST ratio has been shown to be a better surrogate marker than ALT for predicting insulin resistance in a Japanese cohort.21 In prior epidemiologic studies, elevation in ALT has most frequently been used as a surrogate marker for NAFLD.7,22 It is well-established that NAFLD may be present in those with aminotransferase levels within the normal range.6,12
Serum levels of aminotransferases are used as markers of nonalcoholic fatty liver disease in epidemiology research. However, it is not clear whether they can be used to identify patients with fatty liver. We investigated the accuracy of serum levels of aminotransferases in detection of hepatic steatosis. In addition, we derived a Framingham steatosis index (FSI) and tested its ability to identify patients with hepatic steatosis in an independent cohort.
We performed a cross-sectional study of 1181 members of the Framingham Third Generation Cohort (46.1% women; mean age, 50.3 ± 6.7 years). People with hepatic steatosis were identified by computed tomography that was performed from 2008 through 2011. We compared the abilities of levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and the ratio of ALT:AST to identify people with hepatic steatosis by using c-statistic analyses. We performed a stepwise regression procedure to identify demographic and clinical factors that correlated with hepatic steatosis; we used these, along with biochemical factors associated with steatosis, to develop the FSI. We validated the FSI by using data from the third National Health and Nutrition Examination Survey.
The prevalence of hepatic steatosis in the Framingham Third Generation Cohort was 26.8%. The ratio of ALT:AST identified people with hepatic steatosis with the highest c-statistic value (0.728); the value for only ALT was 0.706, and the value for only AST was 0.589. We derived the FSI on the basis of patient age, sex, body mass index, levels of triglycerides, hypertension, diabetes, and ratio of ALT:AST. The FSI identified patients with hepatic steatosis with a c-statistic value of 0.845. When it was applied to the third National Health and Nutrition Examination Survey cohort, the FSI identified patients with steatosis with a c-statistic value of 0.760 and was well-calibrated.
In an analysis of the Framingham Third Generation Cohort, we found the ratio of ALT:AST to identify people with hepatic steatosis more accurately than either ALT or AST alone. We used data from this cohort to develop and validate the FSI, which identifies patients with steatosis with a c-statistic value of about 0.8.
Impact of increasing alanine aminotransferase levels within normal range on incident diabetes
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Citation Excerpt :
However, directly measuring hepatic fat content using proton magnetic resonance spectroscopy and computed tomography is unlikely in routine clinical practice.9,10,25 Serum ALT appears to be the best indicator of liver fat levels.7,8,20 Elevated ALT levels are also associated with many components of insulin resistance syndrome, such as fasting glucose levels, insulin levels, leptin, adiponectin, triglycerides, cholesterol, and percentage of body fat.12
Abnormal alanine aminotransferase level (ALT) levels might be associated with type 2 diabetes, but whether higher ALT levels within the normal range predict the risk is unknown.
We followed a community-based cohort of 3446 individuals who were ≥35 years old without diabetes and hepatitis B or C in southern Taiwan for 8 years (1997–2004) to study the risk for type 2 diabetes with different normal ALT levels.
Among the 337 incident diabetes cases, 16.0% were from those with ALT levels <10 IU/L, 44.5% with ALT levels 10–19 IU/L, 30.0% with ALT levels 20–39 IU/L, and only 9.5% with ALT levels ≥40 IU/L. A cumulative hazard function test showed that the higher the ALT levels, the greater the cumulative incidence rate of diabetes (p < 0.001, log-rank test). A multiple Cox proportional hazards analysis showed that increasing age, lower educational levels, higher body mass index levels (≥25 vs. <25), and higher ALT levels (vs. the reference group, ALT <10 IU/L), from hazard ratio (HR) = 1.8, for ALT = 10–19, HR = 3.7 for ALT = 20–39, to HR = 4.5 for ALT ≥40, were significant factors for developing diabetes (p < 0.001). The hazard ratios of higher ALT levels in the participants without alcohol consumption were similar to or higher than those in the total cohort.
Higher ALT levels, even within the normal range, are strong predictors of type 2 diabetes independently of body mass index levels with a dose–response relationship.
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Serum alanine aminotransferase (ALT) activity is a commonly used surrogate marker for the evaluation of hepatocellular damage [15]. Several epidemiologic studies have reported that obesity and diabetes are important risk factors for elevated ALT activity in individuals with no apparent underlying cause of liver disease [16-18]. The aim of the present study was to evaluate whether obesity and diabetes as well as other metabolic factors (eg, lipid profile) are associated with serum ALT activity in a population with hepatitis B infection in Taiwan.
Several studies have reported that obesity and diabetes are important risk factors for elevated blood aminotransferase activity in individuals with no underlying causes of liver disease. The aim of this study was to determine whether obesity and fasting glucose level were associated with hepatic dysfunction in patients with hepatitis B infection. A total of 934 patients with hepatitis B infection were enrolled, among whom increased alanine aminotransferase (ALT) activity (≥40 IU/L) was observed in 25.1%. By univariate analysis, factors associated with increased ALT activity among patients with hepatitis B infection included body mass index (BMI), fasting blood glucose level, and blood triglyceride and high-density cholesterol levels. By multivariate logistic regression analysis, BMI and fasting blood glucose level were independent predictors of elevated ALT activity, with odds ratios of 1.73 (95% confidence interval, 1.17-2.56) for subjects with a BMI greater than or equal to 25 kg/m² and 1.88 (95% confidence interval, 1.06-3.33) for subjects with a fasting blood glucose greater than or equal to 126 mg/dL. Even in subjects with ALT activity within the reference range, ALT activity was found to be associated with BMI. In conclusion, a BMI greater than or equal to 25 kg/m² and a fasting blood glucose level greater than or equal to 126 mg/dL were risk factors for increased ALT activity in subjects with hepatitis B infection, suggesting that obesity and diabetic fasting hyperglycemia may aggravate liver injury in this population.
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2010, Annals of Hepatology
Citation Excerpt :
Some factors like chronic hepatitis, fatty liver, cho-lelithiasis, hyperglycemia, hyperlipidemia, obesity, medications, alcohol consumption, hemochromato-sis, Wilson’s disease, and alphal-antitrypsin deficiency may affect ATLs.1-3 Moreover, some previous studies shown that the prevalence of elevated liver enzymes is higher in individuals with metabolic syndrome (MetS).4,5 The causes of elevated ATLs may change according to ethnicity, geographic region, and develop situation of countries.
Introduction. Elevated aminotransferase levels(ATLs) are alert the physicians for liver-affecting disease and may reflect liver injury. We aimed to determine the prevalence of elevated ATLs and the association of elevated ATLs with the metabolic syndrome(MetS) in a northern province of Turkey.
Materials and methods. Elevated ATLs were evaluated among 1,095 individuals of the Tokat Prevalence Study which have been described in detail elsewhere. 1,095 participants had been selected by a simple random sampling method among 530,000 inhabitants in 70 (12 urban and 58 rural) areas in the province of Tokat which is located in the Black Sea Region of Turkey.
Results. The prevalence of elevated serum ALT, AST, and ALT and/ or AST were found as 11%, 7.2%, and 13.3%, respectively. Increased BMI, fatty liver, and MetS were higher in our general population with elevated ATLs. After exclusion of individuals with hepatitis B or hepatitis C infection, 132 individuals with elevated ATLs (91 male and 41 female) were evaluated. MetS was found in 59 participants and its prevalence was markedly higher in females with elevated ATLs (p < 0.0001). When the males with elevated ATLs were evaluated, the ALT levels of the persons who have no risk of MetS (p = 0.007) and the persons who have one risk of MetS (p = 0.001) were lower than the persons with MetS.
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2020, Journal of Clinical and Experimental Hepatology
Although serological markers of disease severity improve after hepatitis C virus (HCV) treatment, it is unclear if all patients experience sustained improvement. We aim to evaluate longitudinal changes in aspartate (AST), alanine (ALT) aminotransferase, platelet count (PLT), and fibrosis-4 (FIB-4) after HCV treatment.
All adult chronic HCV patients who received antiviral therapy from January 2011 to February 2017 at four large urban hospital systems were evaluated to assess changes in AST, ALT, PLT, and FIB-4 from pre-treatment to post-treatment annually up to 4 years after HCV therapy. Comparisons used Student's t-test and analysis of variance, and were stratified by sex, race, ethnicity, age, body mass index (BMI), and diabetes mellitus.
Among 2691 patients (62.2% men, 76.9% aged 45–65 years, 56.5% white), all markers of disease severity demonstrated sustained improvements from pre-treatment to 4 years post-treatment (AST 53 U/L to 27.5 U/L, ALT 53 U/L to 29 U/L, PLT 168 × 10³ to 176 × 10³, FIB-4 2.51 to 1.68). However, Hispanics and patients with BMI >30 kg/m² experienced rebound increases in AST, ALT, and FIB-4 at 4 years post-treatment after experiencing initial improvements in these serological markers in the first-year post-treatment. Sustained improvements in PLT were observed in all groups, including Hispanics and patients with BMI >30 kg/m².
HCV treatment in a large community-based cohort demonstrated sustained improvements in AST, ALT, PLT, and FIB-4. Rebound increases in AST, ALT, and FIB-4 observed in Hispanics and those with BMI >30 kg/m² may reflect persisting nonalcoholic fatty liver disease.

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: Supported by the American College of Gastroenterology, a Junior Faculty Development Award (to G.N.I.), and the General Medical Research Service of the Veterans Affairs Puget Sound Health Care System (to S.P.L. and S.E.K.).

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Clinical-liver, pancreas, and biliary tractContribution of metabolic factors to alanine aminotransferase activity in persons with other causes of liver disease

Section snippets

Survey design

Study sample

Results

Discussion

Clin Liver Dis

Gastroenterology

Am J Gastroenterol

Gastroenterology

Hum Pathol

Gastroenterology

Gastroenterology

Hepatology

Hepatology

Clin Liver Dis

Gastroenterology

Am J Med

Gastroenterology

J Virol Methods

Hepatology

Am J Gastroenterol

Gastroenterology

Gastroenterology

Hepatology

Hepatology

Hepatology

Clin Liver Dis

Mod Pathol

Gastroenterology

Hepatology

Gastroenterology

Clinical-liver, pancreas, and biliary tract
Contribution of metabolic factors to alanine aminotransferase activity in persons with other causes of liver disease