Nonalcoholic fatty liver disease with elevated alanine aminotransferase levels is negatively associated with bone mineral density: Cross-sectional study in U.S. adults.
ABSTRACT: BACKGROUND:Nonalcoholic fatty liver disease (NAFLD) has been reported to have a negative effect on bone mineral density (BMD) in Asian populations. Whether such an association exists in Western populations is less clear. METHODS:This cross-sectional analysis of data from NHANES III, a United States national health survey conducted from 1988 to 1994, included 6089 participants aged 40-75 years, selected after excluding people with hepatitis virus serology, elevated alcohol consumption, decreased renal function, or steroid use, and pregnant females. The main outcome, BMD at the femoral neck, was measured using dual-energy X-ray absorptiometry. The primary exposure, NAFLD, was defined as moderate or severe hepatic steatosis diagnosed using abdominal ultrasonography. RESULT:After controlling for gender and menopausal status, race/ethnicity, age and body mass index, NAFLD was not significantly associated with BMD (beta coefficient: -0.006, 95%CI: -0.016, 0.003). A secondary analysis categorized participants with NAFLD according to their serum alanine aminotransferase (ALT) levels into high and normal ALT NAFLD groups, and compared these with the non-NAFLD group. NAFLD with higher levels of ALT was associated with lower levels of BMD (beta coefficient: -0.023, 95% CI: -0.044, -0.002). CONCLUSION:This study showed a relationship between NAFLD with high ALT and lower BMD in the general U.S. population.
Project description:The appropriate alanine aminotransferase (ALT) threshold value to use for diagnosis of chronic liver disease in children is unknown. We sought to develop gender-specific, biology-based, pediatric ALT thresholds.The Screening ALT for Elevation in Today's Youth (SAFETY) study collected observational data from acute care children's hospitals, the National Health and Nutrition Examination Survey (NHANES, 1999-2006), overweight children with and without non-alcoholic fatty liver disease (NAFLD), and children with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infections. The study compared the sensitivity and specificity of ALT thresholds currently used by children's hospitals vs study-derived, gender-specific, biology-based, ALT thresholds for detecting children with NAFLD, HCV, or HBV.The median upper limit of ALT at children's hospitals was 53 U/L (range, 30-90 U/L). The 95th percentile levels for ALT in healthy weight, metabolically normal, liver disease-free, NHANES pediatric participants were 25.8 U/L (boys) and 22.1 U/L (girls). The concordance statistics of these NHANES-derived thresholds for liver disease detection were 0.85 (95% confidence interval [CI]: 0.74-0.96) in boys and 0.91 (95% CI: 0.83-0.99) in girls for NAFLD, 0.80 (95% CI: 0.70-0.91) in boys and 0.79 (95% CI: 0.69-0.89) in girls for HBV, and 0.86 (95% CI: 0.77-0.95) in boys and 0.84 (95% CI: 0.75-0.93) in girls for HCV. Using current children's hospitals ALT thresholds, the median sensitivity for detection of NAFLD, HBV, and HCV ranged from 32% to 48%; median specificity was 92% (boys) and 96% (girls). Using NHANES-derived thresholds, the sensitivities were 72% (boys) and 82% (girls); specificities were 79% (boys) and 85% (girls).The upper limit of ALT used in children's hospitals varies widely and is set too high to reliably detect chronic liver disease. Biology-based thresholds provide higher sensitivity and only slightly less specificity. Clinical guidelines for use of screening ALT and exclusion criteria for clinical trials should be modified.
Project description:Elevated alanine aminotransferase (ALT) activity, an important marker of liver injury, has been associated inconsistently with higher mortality. We evaluated whether persons with nonelevated ALT levels are the most appropriate comparison group by examining the relationships of low ALT with mortality and body composition in the US National Health and Nutrition Examination Survey (NHANES). In NHANES 1988-1994, the mortality risk of persons in ALT deciles 1, 2, 3, and 10 was compared with that of persons in deciles 4-9 (mortality was relatively flat across these deciles) over an 18-year period (through 2006) among 14,950 viral-hepatitis-negative adults. In NHANES 1999-2006, low ALT was evaluated in association with dual-energy x-ray absorptiometry body composition measures among 15,028 adults. Multivariate-adjusted mortality was higher for decile 1 (hazard ratio (HR) = 1.42, 95% confidence interval (CI): 1.24, 1.63), decile 2 (HR = 1.27, 95% CI: 1.06, 1.53), and decile 3 (HR = 1.25, 95% CI: 1.04, 1.50) and nonsignificantly higher for decile 10 (HR = 1.21, 95% CI: 0.91, 1.61) than for deciles 4-9. Adjusted appendicular lean mass was decreased among the lowest ALT deciles. In the US population, low ALT was associated with higher mortality risk, possibly attributable to decreased appendicular lean mass. For mortality studies of elevated ALT levels, the most appropriate comparison group is persons in the middle range of ALT rather than all persons with nonelevated ALT.
Project description:To investigate the histological spectrum of nonalcoholic fatty liver disease (NAFLD) in children with normal, mildly elevated (26-50 U/L boys, 23-44 U/L girls), or elevated (>50 U/L in boys, >44 U/L in girls) serum alanine aminotransferase (ALT) levels.The Nonalcoholic Steatohepatitis Clinical Research Network enrolls children aged 5-18 years with NAFLD. We analyzed baseline clinical and histological data from 91 children with suspected NAFLD and normal or mildly elevated ALT and liver biopsy analysis within 180 days of ALT measurement, and compared them with data from 392 children with elevated ALT.Seventeen of the 91 children with suspected NAFLD (19%) had a normal ALT level, and 74 (81%) had a mildly elevated ALT level. Overall, 45% of the biopsy specimens analyzed had steatosis ?33%, 22% had grade ?2 lobular inflammation, 81% had portal inflammation, 29% had ballooned hepatocytes, 35% had "suspicious/borderline" steatohepatitis, 8% had definite nonalcoholic steatohepatitis, 34% had an NAFLD activity score ?4, and 46% had fibrosis (38% mild/moderate and 8% bridging/cirrhosis). Marked steatosis (50% vs 24%) and fibrosis (54% vs 12%) were significantly more common in the patients with mildly elevated ALT compared with those with normal ALT, with no difference in ballooning, inflammation, or NAFLD activity score ?4 between the 2 groups. Fibrosis stage 3/4 was seen in none of the children with normal ALT, in 9% of those with mildly elevated ALT, and in 15% of those with elevated ALT.Liver biopsy specimens from children with NAFLD with normal or mildly elevated ALT levels show significant histological abnormalities, including advanced fibrosis in children with mildly elevated ALT. Thus, measurement of ALT may underestimate liver injury in NAFLD. The use of appropriate ALT cutoff levels can help identify children at risk for more severe disease.
Project description:BACKGROUND:The prevalence of nonalcoholic fatty liver disease (NAFLD) in the non-obese population has increased and NAFLD is not always recognized in individuals with metabolic syndrome (MS). The risk of cirrhosis is higher in patients having NAFLD with elevated alanine aminotransferase (ALT) levels than in those having NAFLD with normal ALT levels. OBJECTIVE:To measure the differences in clinical factors associated with NAFLD having elevation of ALT among subjects with Non-MS, Pre-MS, and MS, and to measure differences in metabolites between MS subjects with and without NAFLD having elevation of ALT. METHODS:Among 7,054 persons undergoing health check-ups, we included 3,025 subjects who met the selection criteria. We measured differences in clinical factors for NAFLD having elevation of ALT among subjects with Non-MS, Pre-MS, and MS, and compared metabolites between subjects with and without NAFLD having elevation of ALT in 32 subjects with MS. RESULTS:The prevalence of NAFLD and NAFLD having elevation of ALT was significantly progressively greater in subjects with Non-MS, Pre-MS, and MS (p <0.001, respectively). In the Non-MS group, there were significant differences between subjects with and without NAFLD having elevation of ALT with respect to body mass index (BMI), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, hemoglobin A1c, uric acid, aspartate aminotransferase (AST); In the Pre-MS group, there were significant differences in BMI, hypertension, AST, and gamma-glutamyl transpeptidase (GGT); In the MS group, there were significant differences in HDL-C, impaired glucose tolerance, AST, and GGT. There were significant differences in levels of metabolites of nicotinamide, inosine, and acetyl-L-carnitine between MS subjects with and without NAFLD having elevation of ALT (all p <0.05). CONCLUSIONS:Although NAFLD having elevation of ALT is important for development of NAFLD, differences in factors associated with NAFLD having elevation of ALT at various stages of MS should be considered. Additionally, several metabolites may play roles in the identification of risk for NAFLD in individuals with MS.
Project description:The aim of the current study was to examine the independent association of physical activity with nonalcoholic fatty liver disease (NAFLD) and aminotransferases while adjusting for obesity and diet. Cross-sectional data from 32,391 participants aged ? 20 years in the Korea National Health and Nutrition Examination Surveys (KNHANES) was analyzed by logistic regression models and general linear models. Physical activity was assessed from the questionnaire by health-enhancing physical activity (HEPA). The physical activity was negatively associated with NAFLD and lean NAFLD after adjustment for multiple factors with an odds ratio of 0.7 (95% CI, 0.6-0.8) and 0.5 (95% CI, 0.4-0.7) comparing the most active (HEPA active) and the least active (inactive) participants. Among the participants with NAFLD, physical activity also showed an independent negative association with alanine aminotransferase (ALT) levels but not with aspartate aminotransferase levels. These independent associations were not observed when comparing the minimally active and inactive participants except for the risk of lean NAFLD. Physical activity is independently associated with the degree of hepatocellular injury in patients with NAFLD as well as the risk of NAFLD and lean NAFLD in the general population. Sufficiently active physical activity greater than a minimally active level may be needed to lower the risk of NAFLD and ALT levels.
Project description:<h4>Background and objectives</h4>Serum alanine aminotransferase (ALT) activity is the most common tool for the assessment of liver diseases. However, it is not clear whether the current normal ALT range really discriminate patients with or without liver diseases. The present study was to establish a new normal range of ALT and examine its ability to identify patients with hepatitis B or nonalcoholic fatty liver disease (NAFLD) in Chinese Han population.<h4>Methods</h4>53037 adults were included in this study from January 1st 2008 to August 31st 2010. The 95th percentile of ALT in population with relative low risk factors for liver diseases was set as the new upper limits of normal ALT in gender-specific manner.<h4>Results</h4>The 95(th) percentile levels at low risk factors for liver diseases were achieved at 35 U/L for men and 23 U/L for women. The concordance statistics for detection were 0.873 (95%CI: 0.865-0.881) for HBV and 0.932 (95%CI: 0.927-0.937) for NAFLD in men while 0.857 (95%CI: 0.850-0.864) for HBV and 0.909 (95%CI: 0.903-0.915) for NAFLD in women. The median sensitivity of the current used ALT upper limit (40 U/L) was 6.6% for HBV and 29.7% for NAFLD and median specificity was 98.7% for men and 99.4% for women. Using our new-derived thresholds, the sensitivities ranged from 35.3% to 61.1% and the specificities were 94.8% for men and 94.6% for women.<h4>Conclusions</h4>Our results suggest that upper limits of ALT 35 U/L for men and 23 U/L for women in Chinese Han population. Re-consideration of normal limits of ALT should be recommended.<h4>Trial registration</h4>ChiCTR.org ChiCTR-OCS-11001173.
Project description:Nonalcoholic fatty liver disease (NAFLD), characterized by hepatocyte dysfunction, fat accumulation, and fibrosis, is the most common cause of chronic liver disease in children. Elevated levels of serum alanine aminotransferase (ALT) are used clinically to identify potential liver dysfunction. Our goal was to assess for changes in the national prevalence of elevated ALT over time and potential relationship to trends in the metabolic syndrome (MetS) severity and elevated body mass index (BMI).We studied 5411 non-Hispanic white, non-Hispanic black, and Hispanic adolescents aged 12-19 with complete MetS Z-score and ALT data from the National Health and Nutrition Examination Survey 1999-2014. Elevated ALT levels were defined by two different cutoffs: one for both sexes (30?U/L) and another that was sex specific (22?U/L girls; 25?U/L boys). MetS severity was assessed using a sex- and race-/ethnicity-specific MetS Z-score.We did not find a statistically significant linear increase in either mean ALT or the prevalence of elevated ALT differed over time. As expected, ALT levels were significantly correlated with BMI Z-score and MetS Z-score (P?<?0.0001). Over time, BMI Z-scores increased and MetS severity Z-score decreased.Prevalence of elevated ALT did not exhibit a linear change between 1999 and 2014 in U.S. adolescents, potentially due to divergent trends regarding BMI and MetS severity. Continued vigilance in monitoring BMI and ALT levels is advised for the U.S. adolescent population. MetS Z-score could act as an additional tool to monitor risk of elevated ALT and subsequent development of NAFLD.
Project description:<h4>Objective</h4>To estimate and compare associations of alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT) with incident diabetes.<h4>Research design and methods</h4>ALT and GGT were studied as determinants of diabetes in the British Women's Heart and Health Study, a cohort of 4,286 women 60-79 years old (median follow-up 7.3 years). A systematic review and a meta-analysis of 21 prospective, population-based studies of ultrasonography, which diagnosed nonalcoholic fatty liver disease (NAFLD), ALT, and GGT as determinants of diabetes, were conducted, and associations of ALT and GGT with diabetes were compared.<h4>Results</h4>Ultrasonography-diagnosed NAFLD was associated with more than a doubling in the risk of incident diabetes (three studies). ALT and GGT both predicted diabetes. The fully adjusted hazard ratio (HR) for diabetes per increase in one unit of logged ALT was 1.83 (95% CI 1.57-2.14, I(2) = 8%) and for GGT was 1.92 (1.66-2.21, I(2) = 55%). To directly compare ALT and GGT as determinants of diabetes, the fully adjusted risk of diabetes in the top versus bottom fourth of the ALT and GGT distributions was estimated using data from studies that included results for both markers. For ALT, the HR was 2.02 (1.59-2.58, I(2) = 27%), and for GGT the HR was 2.94 (1.98-3.88, I(2) = 20%), suggesting that GGT may be a better predictor (P = 0.05).<h4>Conclusions</h4>Findings are consistent with the role of liver fat in diabetes pathogenesis. GGT may be a better diabetes predictor than ALT, but additional studies with directly determined liver fat content, ALT, and GGT are needed to confirm this finding.
Project description:The changes in the gut microbiota of healthy hepatitis B virus (HBV) carriers, including asymptomatic and non-cirrhotic subjects, have been rarely scrutinized. From 1463 faecal samples in health examinees, in total 112 subjects, including 36 hepatitis B surface antigen (HBsAg)-positive and 76 control subjects, were included. Twenty-eight of 36 HBsAg-positive individuals (78%) showed normal alanine aminotransferase (ALT) levels (normal ALT group), whereas eight subjects exhibited elevated ALT levels (22%, high ALT group). By using 16S rRNA gene sequencing, the distance between normal and high ALT groups among HBsAg-positive subjects showed a significant separation after the pairwise comparison of weighted UniFrac distance (permutational analysis of variance q-value = 0.039), when compared with the distances to the control group. In comparison with the control group, the normal ALT group had Anaerostipes as a significant taxon that showed a positive association (Coefficient (Coef.) = 0.028, q = 0.039). Desulfovibrio (Coef. = 0.54, q = 0.014) and Megasphaera (Coef. = 1.41, q = 0.030) showed positive correlations, and Acidaminococcus (Coef. = -1.31, q = 4.15 × 10-75) exhibited a negative correlation with high ALT level. Gut microbial composition was different according to HBV-induced serum ALT levels, indicative of a potential link between gut and liver metabolism.
Project description:<h4>Unlabelled</h4><h4>Background</h4>The association between serum alanine aminotransferase (ALT) levels and hepatic insulin resistance (IR) has been evaluated with the hyperinsulinemic-euglycemic clamp. However, there is no information about the association of ALT with the Hepatic Insulin Resistance Index (HIRI). The aim of this study was to evaluate the association between serum ALT levels and HIRI in subjects with differing degrees of impaired glucose metabolism.<h4>Methods</h4>This cross-sectional study included subjects that had an indication for testing for type 2 diabetes mellitus (T2DM) with an oral glucose tolerance test (OGTT). Clinical and biochemical evaluations were carried out including serum ALT level quantification. HIRI was calculated for each participant. Correlation analyses and lineal regression models were used to evaluate the association between ALT levels and HIRI.<h4>Results</h4>A total of 324 subjects (37.6% male) were included. The mean age was 40.4?±?14.3?years and the mean body mass index (BMI) was 32.0?±?7.3?kg/m2. Individuals were divided into 1 of 5 groups: without metabolic abnormalities (n?=?113, 34.8%); with the metabolic syndrome (MetS, n?=?179, 55.2%), impaired fasting glucose (IFG, n?=?85, 26.2%); impaired glucose tolerance (IGT, n?=?91, 28.0%), and T2DM (n?=?23, 7.0%). The ALT (p?<?0.001) and HOMA2-IR (p?<?0.001) values progressively increased with HIRI quartiles, while ISI-Matsuda (p?<?0.001) progressively decreased. After adjustment for sex, age, and BMI, we identified a significant correlation between HIRI and ALT in persons with the MetS (r?=?0.22, p?=?0.003), IFG (r?=?0.33, p?<?0.001), IGT (r?=?0.37, p?<?0.001), and T2DM (r?=?0.72, p?<?0.001). Lineal regression analysis adjusting for age, HDL-C, TG and waist circumference (WC) showed an independent association between ALT and HIRI in subjects with the MetS (beta?=?0.07, p?=?0.01), IFG (beta?=?0.10, p?=?0.02), IGT (beta?=?0.09, p?=?0.007), and T2DM (beta?=?0.31, p?=?0.003). This association was not identified in subjects without metabolic abnormalities.<h4>Conclusions</h4>ALT levels are independently associated with HIRI in subjects with the MetS, IFG, IGT, and T2DM. The ALT value in these subjects may be an indirect parameter to evaluate hepatic IR.