Surrogate Marker Of Nonalcoholic Fatty Liver Disease Research Articles

Non-Alcoholic Fatty Liver Disease and Its Association with Kidney and Cardiovascular Outcomes in Moderate to Advanced Chronic Kidney Disease

Introduction: Non-alcoholic fatty liver disease (NAFLD) has emerged as a potential indicator for cardio-metabolic risk. However, clinical implications of NAFLD in patients with chronic kidney disease (CKD) are still elusive. We investigated to explore the association between NAFLD and adverse clinical outcomes among patients with CKD. Methods: In this national population-based retrospective cohort study, we analyzed 816,857 individuals who underwent National Health Insurance Service health examinations and had an estimated glomerular filtration rate of 15–59 mL/min/1.73 m2. The main predictor was the fatty liver index (FLI), a surrogate marker for NAFLD. The primary outcome was a composite cardiovascular or kidney events, which were examined combined or separately. Results: During a median follow-up of 7.7 (IQR, 6.4–9.6) years, the composite outcome events occurred in 74,266 (9.1%) individuals. Among these, there were 55,525 (6.8%) cardiovascular events and 22,961 (2.8%) kidney events, respectively. Compared to FLI of <30, the hazard ratio (HRs; 95% confidence intervals [CIs]) for the composite outcome were 1.16 (1.14–1.18) and 1.30 (1.26–1.33) for the FLIs of 30–59 and ≥60, respectively. The corresponding HRs for cardiovascular events were 1.21 (95% CI, 1.18–1.23) and 1.36 (95% CI, 1.31–1.40), respectively. Furthermore, FLIs of 30–59 and ≥60 were associated with an 11% (HR, 1.11; 95% CI, 1.07–1.15) and 24% (HR, 1.24; 95% CI, 1.17–1.30) increased risk of kidney events, respectively. Conclusions: NAFLD was associated with higher risk of adverse clinical outcomes in individuals with CKD. These findings suggest that NAFLD, as assessed by the FLI, can serve as a predictor of cardiovascular and kidney events in CKD population.

Predictive value of the Framingham steatosis index for cardiovascular risk: a nationwide population-based cohort study.

Non-alcoholic fatty liver disease (NAFLD) is common and is associated with cardiovascular (CV) disease and mortality. The Framingham steatosis index (FSI) was recently proposed as a diagnostic marker of NAFLD and was calculated from age, body mass index, triglyceride, aspartate aminotransferase, alanine aminotransferase, diabetes history, and hypertension status. We aimed to evaluate the predictive ability of FSI for CV risk using a large-scale population dataset from the Korean National Health Insurance Service-National Health Screening Cohort (NHIS-HEALS). Among 514,866 individuals in the NHIS-HEALS, we excluded those who died, had a history of admission due to a CV event, and were heavy drinkers. The final study cohort comprised 283,427 participants. We employed both unadjusted and covariate-adjusted models in Cox proportional hazards regression analyses to determine the association between FSI and major adverse cardiovascular events (MACEs), CV events, and CV mortality. During a median follow-up of 5.9 years, we documented 9,674, 8,798, and 1,602 cases of MACEs, CV events, and CV mortality, respectively. The incidence of MACEs was 1.28%, 2.99%, 3.94%, and 4.82% in the first to fourth quartiles of FSI, respectively. The adjusted hazard ratios (95% confidence interval) for MACEs gradually and significantly increased with the FSI quartiles [1.302 (1.215-1.395) in Q2, 1.487 (1.390-1.590) in Q3, and 1.792 (1.680-1.911) in Q4], following an adjustment for conventional CV risk factors, including age, sex, smoking, drinking, physical activities, low-density lipoprotein cholesterol, estimated glomerular filtration rate, and waist circumference. Participants in the higher quartiles of FSI exhibited a noteworthy increase in the occurrence of CV event. However, upon adjusting for relevant risk factors, the association between FSI and CV mortality did not reach statistical significance. Our study suggests that the FSI, which is a surrogate marker of NAFLD, has a prognostic value for detecting individuals at higher risk of CV events.

Intermittent fasting for the management of NAFLD: Is there enough evidence?

Abstract The pathogenesis of the non-alcoholic fatty liver disease (NAFLD) has been described as multifactorial, with genetic and environmental factors acting synergistically and causing excessive hepatic lipid accumulation, insulin resistance, and downstream pathogenetic insults. High-calorie diets, particularly those rich in foods with high (saturated) fat and sugar content, and sugar-sweetened beverages, are among the behavioral risk factors with a crucial role in the disease pathogenesis. In addition, meal frequency and meal timing appear to be relevant factors associated with NAFLD. Current guidelines recommend a hypocaloric, preferably Mediterranean diet as the main dietary intervention approach, but various other dietary models have been evaluated in patients with NAFLD. Among these, several intermittent fasting regimens have shown promising results. Diets based on Time-Restricted Feeding and Intermittent Energy Restriction have demonstrated some improvements in body adiposity, liver enzymes, and hepatic steatosis, but most studies included a small number of subjects, were of relatively short-duration, and used surrogate markers of NAFLD. The best intermittent fasting regimen for NAFLD is not yet known, and further well-designed research that evaluates the feasibility (mainly on long-term), safety and efficacy outcomes of these dietary interventions is still needed. Our review has evaluated the up-to-date information regarding the intermittent fasting dietary intervention in NAFLD and generated some key-point messages that are relevant to physicians and dietitians involved in the care of patients with NAFLD.

Androgen dysfunction in non-alcoholic fatty liver disease: Role of sex hormone binding globulin.

Non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease in the world. It is linked mainly to insulin resistance and metabolic syndrome including obesity and dyslipidemia. In addition, various endocrine dysfunctions including polycystic ovary syndrome (PCOS) and hypogonadism are involved in the development and progression of NAFLD. We need to know the disease pathophysiology more accurately due to the heterogeneity of clinical presentation of fatty liver disease. The liver is the major metabolic organ with sexual dimorphism. Sexual dimorphism is associated not only with behavioral differences between men and women, but also with physiological differences reflected in liver metabolism. In men, normal androgen levels prevent hepatic fat accumulation, whereas androgen deficiency induce hepatic steatosis. In women, higher androgens can increase the risk of NAFLD in PCOS. Sex hormone binding globulin (SHBG) is involved in androgen regulation. Recently, SHBG may be reported as a surrogate marker for NAFLD. Therefore, this review will focus on the mechanism of androgen dysfunction in the regulation of hepatic metabolism, the risk of developing NAFLD, and the potential role of SHBG in the course of NAFLD.; Keywords: Non-alcoholic fatty liver disease, insulin resistance, sexual dimorphism, androgen, sex hormone binding globulin.

Combined Effects of Chronic Kidney Disease and Nonalcoholic Fatty Liver Disease on the Risk of Cardiovascular Disease in Patients with Diabetes.

Background: We investigated the combined effect of chronic kidney disease (CKD) and nonalcoholic fatty liver disease (NAFLD) on the risk of cardiovascular disease (CVD) in patients with type 2 diabetes. Methods: Data were obtained from the Korean National Health Insurance Service. Patients with diabetes who participated in health screenings from 2009 to 2011 were included. The fatty liver index (FLI) was used as a surrogate marker for NAFLD. Results: During a mean follow-up of 6.9 years, 40,863 incidents of myocardial infarction (MI), 58,427 strokes, and 116,977 deaths were reported in 1,607,232 patients with type 2 diabetes. After adjusting for conventional risk factors, patients with CKD and NAFLD showed the highest risk of MI and stroke (hazard ratio (HR) = 1.49; 95% confidence interval (CI): 1.42–1.57 and stroke, HR = 1.48; 95% CI: 1.41–1.54, respectively) compared with those without either CKD or NAFLD. Both overall and cardiovascular mortality were highest in the CKD/NAFLD group compared with other groups (HR = 2.00; 95% CI: 1.94–2.06, and HR = 2.20; 95% CI: 2.07–2.35, respectively). Advanced liver fibrosis was significantly associated with an increased risk of CVD in patients with NAFLD. Proteinuria was significantly associated with incidence of CVD events in patients with CKD. Conclusions: The combination of CKD and NAFLD was associated with an increased risk of CVD and mortality in patients with type 2 diabetes. Close monitoring and appropriate management of CKD and NAFLD may be warranted to prevent CVD in these patients.

Fatty liver index and development of cardiovascular disease in Koreans without pre-existing myocardial infarction and ischemic stroke: a large population-based study

BackgroundDespite the known association between non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD), whether NAFLD predicts future CVD events, especially CVD mortality, remains uncertain. We evaluated the relationship between fatty liver index (FLI), a validated marker of NAFLD, and risk of major adverse cardiac events (MACEs) in a large population-based study.MethodsWe identified 3011,588 subjects in the Korean National Health Insurance System cohort without a history of CVD who underwent health examinations from 2009 to 2011. The primary endpoint was a composite of cardiovascular deaths, non-fatal myocardial infarction (MI), and ischemic stroke. A Cox proportional hazards regression analysis was performed to assess association between the FLI and the primary endpoint.ResultsDuring the median follow-up period of 6 years, there were 46,010 cases of MACEs (7148 cases of cardiovascular death, 16,574 of non-fatal MI, and 22,288 of ischemic stroke). There was a linear association between higher FLI values and higher incidence of the primary endpoint. In the multivariable models adjusted for factors, such as body weight and cholesterol levels, the hazard ratio for the primary endpoint comparing the highest vs. lowest quartiles of the FLI was 1.99 (95% confidence interval [CIs], 1.91–2.07). The corresponding hazard ratios (95% CIs) for cardiovascular death, non-fetal MI, and ischemic stroke were 1.98 (1.9–2.06), 2.16 (2.01–2.31), and 2.01 (1.90–2.13), respectively (p < 0.001). The results were similar when we performed stratified analyses by age, sex, use of dyslipidemia medication, obesity, diabetes, and hypertension.ConclusionsOur findings indicate that the FLI, which is a surrogate marker of NAFLD, has prognostic value for detecting individuals at higher risk for cardiovascular events.

Higher fatty liver index is associated with increased risk of new onset heart failure in healthy adults: a nationwide population-based study in Korea

BackgroundHeart failure (HF) is relatively common cardiovascular disease with high mortality and morbidity. Although it is associated with many cardiovascular risk factors, the association between nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disease, and HF has not been evaluated in a large-scale cohort study. Thus, we evaluated the ability of the fatty liver Index (FLI), a surrogate marker of NAFLD, to predict the development of HF in healthy individuals.MethodsWe analyzed the association between the FLI and new-onset HF with multivariate Cox proportional-hazards models in 308,578 healthy persons without comorbidities who underwent the National Health check-ups in the republic of Korea from 2009 to 2014.ResultsA total of 2532 subjects (0.8%) were newly diagnosed with HF during the study period (a median of 5.4 years). We categorized our subjects into quartile groups according to FLI (Q1, 0–4.9; Q2, 5.0–12.5; Q3, 12.6–31.0; and Q4, > 31.0). The cumulative incidence of HF was significantly higher in the highest FLI group than in the lowest FLI group (Q1, 307 [0.4%] and Q4, 890 [1.2%]; P < 0.001). Adjusted hazard ratio (HRs) indicated that the highest FLI group was independently associated with an increased risk for HF (HR between Q4 and Q1, 2.709; 95% confidence interval = 2.380–3.085; P < 0.001). FLI was significantly associated with an increased risk of new-onset HF regardless of their baseline characteristics.ConclusionsHigher FLI was independently associated with increased risk of HF in a healthy Korean population.

A Close Relationship between Non-Alcoholic Fatty Liver Disease Marker and New-Onset Hypertension in Healthy Korean Adults.

Background and ObjectivesNonalcoholic fatty liver disease (NAFLD) is an excessive accumulation of fat into the liver as a result of increased inflammation and insulin resistance. Although there can be common pathogenic mechanisms for NAFLD and hypertension associated with the development of cardiovascular diseases, little data are showing the association between NAFLD and hypertension in a large-scale cohort study. Thus, we evaluated the ability of the fatty liver index (FLI), a surrogate marker of NAFLD, to predict the development of hypertension in healthy individuals.MethodsWe included 334,280 healthy individuals without known comorbidities who underwent the National Health check-ups in South Korea from 2009 to 2014. The association between the FLI and hypertension was analyzed using multivariate Cox proportional-hazards models.ResultsDuring a median of 5.2 years' follow-up, 24,678 subjects (7.4%) had new-onset hypertension. We categorized total subjects into quartile groups according to FLI (range: Q1, 0–4.9; Q2, 5.0–12.5; Q3, 12.6–31.0; and Q4, >31.0). The incidence of hypertension was higher in subjects with the highest FLI than in those with the lowest FLI (Q4, 9,968 [11.9%] vs. Q1, 2,277 [2.7%]; p<0.001). There was a significant correlation between the highest FLI and an increased risk of new-onset hypertension (adjusted hazard ratio between Q4 and Q1, 2.330; 95% confidence interval, 2.218–2.448; p<0.001). FLI was significantly associated with an increased risk of new-onset hypertension regardless of baseline characteristics.ConclusionsHigher FLI was independently associated with increased risk of hypertension in a healthy Korean population.

Dietary polyunsaturated fatty acids mediate the inverse association of stearoyl-CoA desaturase activity with the risk of fatty liver in dyslipidaemic individuals.

The activity of stearoyl-CoA desaturase-1 (SCD1) is increased in non-alcoholic fatty liver disease (NAFLD). Polyunsaturated fatty acids (PUFA) inhibit SCD1, but clinical studies on whether all dietary PUFA species are equal in SCD1 inhibition are scarce. Serum phospholipids are an objective proxy of dietary intake of plant-derived PUFA (C18:2n-6, C18:3n-3) and marine-derived PUFA (C20:5n-3, C22:6n-3). In 355 participants with primary dyslipidemia, we cross-sectionally investigated whether the presumed association between surrogate markers of NAFLD and SCD1 activity is mediated by intake of PUFA, and, if it is, what PUFA species are relevant in this regard. We determined the fatty acid profile of serum phospholipids by gas chromatography, and used the ratio C16:1n-7/C16:0 as a marker of SCD1 activity. NAFLD was diagnosed by values ≥ 60 in the fatty liver index (FLI), a surrogate recently validated against ultrasonography. FLI ≥ 60 was detected in 37.5% (n = 133) of study participants. In a multivariate model, SCD1 activity showed an expected significant association with the risk of NAFLD, with odds ratio (OR) (95% confidence interval) of 1.44 (1.04-2.01) for each 0.01 increase. In a model further allowing the stepwise inclusion of plant-derived PUFA, marine-derived PUFA, and total PUFA (vegetable + marine), total PUFA replaced SCD1 activity as a significant (inverse) association of NAFLD, with OR 0.89 (0.81-0.99). Total PUFA, regardless of their origin, mediates the relationship between SCD1 activity and NAFLD. This provides a new insight in the protective effects of PUFA against NAFLD, heretofore mostly focussed on PUFA species from marine origin.

Metabolic and genetic markers' associations with elevated levels of alanine aminotransferase in adolescents.

Non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease in adolescents, is a feature of metabolic syndrome (MetS). Obesity and insulin resistance (IR) are risk factors for NAFLD, as well as inflammation-related genetic markers. The relationship between metabolic or inflammation-related genetic markers and alanine aminotransferase (ALT) is not fully understood. We examined the relationship of MetS, metabolic and inflammation-related genetic markers with elevated ALT in adolescents. A total of 674 adolescents participated in a cross-sectional study in Guadalajara, Mexico. Elevated ALT (>40 IU/L), a surrogate marker of NAFLD, and MetS (International Diabetes Federation definition) were evaluated. Obesity, IR, lipids, C-reactive protein (CRP) and genetic markers (TNFA-308G>A, CRP+1444C>T, IL1RN and IL6-597/-572/-174 haplotype) were evaluated. Multivariate logistic regression was performed. Elevated ALT was observed in 3% and 14.1% (total and obese, respectively) of the adolescents. Obesity (odds ratio [OR], 5.86; 95% confidence interval [95% CI], 1.16-25.89), insulin (OR, 8.51; 95% CI, 2.61-27.71), IR (OR, 9.10; 95% CI, 2.82-29.38), total cholesterol (TC) (OR, 3.67; 95% CI, 1.25-10.72), low-density lipoprotein-cholesterol (LDL-C) (OR, 3.06; 95% CI, 1.06-8.33), non-high-density lipoprotein-cholesterol (HDL-C) (OR, 3.88; 95% CI, 1.27-11.90) and IL1RN (OR, 4.64; 95% CI, 1.10-19.53) were associated with elevated ALT. Among males, ≥2 MetS criteria were associated with elevated ALT (OR, 4.22; 95% CI, 1.14-15.71). Obesity, insulin, IR, high TC, high LDL-C, high non-HDL-C and IL1RN polymorphism were associated with elevated ALT. Among males, ≥2 MetS criteria were associated with elevated ALT. There is an urgent need to reduce obesity and IR in adolescents to prevent NAFLD.

The fatty liver index as a predictor of incident chronic kidney disease in a 10-year prospective cohort study.

BackgroundAlthough non-alcoholic fatty liver disease (NAFLD) is considered to be associated with chronic kidney disease (CKD), long-term follow up data is lacking. We investigated whether NAFLD, as determined by the fatty liver index (FLI), could predict incident CKD in 10-year prospective cohort study. We also assessed the clinical utility of FLI to predict the development of CKD.Methods6,238 adults aged 40 to 69 years without baseline CKD from the Ansan—Ansung cohort were examined. Patients were classified according to FLI as follows: FLI<30, no NAFLD; FLI≥60, NAFLD; and 30≤ FLI<60, intermediate. Incident CKD was defined as estimated glomerular filtration rate (eGFR) <60 ml/min per 1.73 m2. The clinical utility of FLI in predicting incident CKD was estimated via area under the receiver-operating characteristic curve (AUC), net reclassification improvement (NRI), and integrated discrimination improvement (IDI) analyses.ResultsDuring an average of 10 years of follow-up, 724 subjects (15.21%) developed CKD. The adjusted hazard ratio [95% confidence interval (CI)] for incident CKD increased in a graded manner with FLI increased (<30 vs. 30–59 vs. ≥60 = 1 vs. 1.17 [0.997–1.375] vs. 1.459 [1.189–1.791], respectively, P for trend = 0.0012). Incorporation of FLI into traditional risk factors of CKD significantly increased prediction of incident CKD based on NRI (17%; 95% CI, 8.9–25%; P-value <0.001) and IDI (0.002; 95% CI, 0.0046–0.0143; P-value = 0.046).ConclusionsFLI, a surrogate marker of NAFLD, was an independent risk factor for incident CKD. FLI provides meaningful incremental risk reclassification beyond that of conventional risk factors of CKD.

A cohort study on Helicobacter pylori infection associated with nonalcoholic fatty liver disease.

Previous studies have suggested a link between Helicobacter pylori (H. pylori) infection and nonalcoholic fatty liver disease (NAFLD), yet large-scale longitudinal studies are lacking to elucidate this association. A cohort study of 17,028 adults without NAFLD at baseline, who participated in a repeated health screening examination including an H. pylori-specific immunoglobulin G antibody test, was conducted to evaluate the association between H. pylori and NAFLD development. Fatty liver was diagnosed by ultrasonography. During the 83,130 person-years follow-up, participants with H. pylori infection had a higher rate of incident NAFLD than those who were uninfected. In a multivariable model adjusted for age, sex, body mass index, smoking status, alcohol intake, regular exercise, year of screening exam, and education level, the hazard ratio (HR) for NAFLD development in participants with H. pylori infection compared to those without infection was 1.21 [95% confidence interval (CI), 1.10-1.34]. The association persisted after further adjustment for metabolic variables, inflammatory marker, and liver enzymes. The association between H. pylori and NAFLD was still evident in an analysis using fatty liver index as a surrogate marker of NAFLD. In addition, the association between H. pylori infection and incident NAFLD did not differ across clinically relevant subgroups evaluated. H. pylori infection was significantly associated with the development of NAFLD, independent of metabolic and inflammatory risk factors. H. pylori infection may play a pathophysiologic role in NAFLD development, indicating that H. pylori eradication might play a role in reducing the risk of NAFLD.

Bioavailable testosterone is independently associated with Fatty Liver Index in postmenopausal women.

IntroductionPrevious studies have examined the correlation between hyperandrogenemia and non-alcoholic fatty liver disease (NAFLD) in women and showed contradictory results. Therefore, we aimed to evaluate the relationship between testosterone level and Fatty Liver Index (FLI), as a surrogate marker for NAFLD, in a cohort of postmenopausal women.Material and methodsA total of 150 postmenopausal women were included in this cross-sectional study. Anthropometric and biochemical parameters, as well as blood pressure, were obtained. Non-alcoholic fatty liver disease is assessed by FLI, an algorithm based on body mass index, waist circumference, triglycerides and γ-glutamyl transferase, as a simple and accurate predictor of hepatic steatosis. Women were divided into three groups (FLI < 30, n = 80; 30 ≤ FLI < 60, n = 44; FLI ≥ 60, n = 26). Homeostasis model assessment of insulin resistance (HOMA-IR) as a surrogate marker of insulin resistance was calculated.ResultsMultiple linear regression analysis revealed that the best model consisted of 4 parameters (e.g., bioavailable testosterone (β = 0.288, p = 0.001), log HOMA-IR (β = 0.227, p = 0.005), log high-sensitivity C-reactive protein (β = 0.322, p < 0.001), and retinol-binding protein 4 (β = 0.226, p < 0.001)). Adjusted R2 for the best model was 0.550, which means that as much as 55.0% of variation in FLI could be explained with this model.ConclusionsBioavailable testosterone is independently associated with FLI in postmenopausal women.

Association between exposures to brominated trihalomethanes, hepatic injury and type II diabetes mellitus

Non-alcoholic fatty liver disease (NAFLD) is considered the most common liver disorder in the Western world, commonly diagnosed in the majority of obese patients with type 2 diabetes mellitus (T2DM). Metabolic disrupting chemicals with short half-lives, such as those of halogenated structure (trihalomethanes, THM) have been linked with hepatic insulin resistance phenomena in animal studies. However, human studies evaluating the role of THM exposure on liver pathogenesis and T2DM disease process are scarce. The objectives of this study were to: i) determine the association of urinary brominated THM (BrTHM) levels and T2DM disease status, and ii) investigate the association between urinary BrTHM levels and serum alanine aminotransferase (ALT) concentrations, often used as surrogate markers of NAFLD. A pilot case–control study was conducted in Nicosia, Cyprus (n=95). Cases were physician-diagnosed T2DM patients and controls were healthy individuals. Liver enzymes, leptin and TNF-α were measured in sera, while urinary THM levels were measured using tandem mass spectrometry. Diabetics had higher levels of serum leptin, body mass index and ALT than the controls. Among all study participants those with serum ALT levels above the median (17IU/L) had higher mean tribromomethane (TBM) concentrations compared to those with serum ALT below 17IU/L. A significant increase in the odds of having above the median serum ALT levels [OR 6.38, 95% CI: 1.11, 42.84 (p=0.044)] was observed for each unit increase in creatinine-unadjusted urinary TBM levels, along with BMI and past smoking, after adjusting for possible confounders, such as urinary creatinine, age, sex, and leptin; no other THM compound showed a significant association with serum ALT. Logistic regression models for T2DM using the urinary BrTHM as exposure variables did not reach the predetermined level of significance. The interplay between exposures to BrTHM and the initiation of key pathophysiological events relating to hepatic injury (ALT) and inflammation (leptin) was recognized via the use of selected biomarkers of effect. Our evidence that THM could act as hepatic toxins with a further initiation of diabetogenic effects call for additional studies to help us better understand the disease process of the two co-morbidities (NAFLD and T2DM).

Abstract 16988: Fatty Liver Index is Reduced With Ezetimibe in an Analysis of 15,095 Patients Randomized to Ezetimibe vs Placebo in the Improve-it Trial

Background: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the US, and is associated with early atherogenesis and increased risk of cardiovascular (CV) death. Although no pharmacologic therapy has proven benefit in NAFLD, recent clinical studies suggest that ezetimibe may reduce histologic evidence of liver inflammation and improve serum markers of NAFLD. In this post hoc analysis of the IMPROVE-IT trial, we assessed the impact of ezetimibe in patients with presumed NAFLD, using the Fatty Liver Index (FLI), a validated prediction score for hepatic steatosis. Methods: Of the 18,144 IMPROVE-IT patients randomized to ezetimibe/simvastatin (E/S) or placebo/simvastatin (P/S), 15,095 had both baseline ALT 2x ULN and sufficient data with which to calculate FLI, a calculated score composed of triglycerides (TG), gamma-glutamyltransferase (GGT), body mass index (BMI), and waist circumference. FLI ≥ 60 has been strongly correlated with NAFLD, while values &lt;30 indicate low probability of NAFLD. Differences in FLI between treatment arms over time were tested with non-parametric Wilcoxon rank-sum tests. Results: Baseline FLI was ≥ 60 in 6798 (45%) patients and &lt;30 in 3438 (23%). E/S reduced median absolute FLI from 55.0 to 51.2 over 72 months, a reduction of 6.9%, which was significantly greater than that observed in P/S group (all p&lt;0.001 at each time-point, Fig). Of those with initial FLI ≥ 60 treated with E/S, 26.3% had 48-month FLI score &lt; 60 (compared to 21.6% in P/S group, p&lt;0.001). E/S significantly reduced both TG and GGT compared to P/S (both p&lt;0.001 at 72 months). E/S significantly reduced FLI regardless of baseline ALT (normal vs. 1-2x ULN) ( p =0.002; interaction p =0.53). Conclusion: Ezetimibe significantly reduced surrogate markers of NAFLD, suggesting that it may offer protection against progression of non-alcoholic fatty liver disease, metabolic syndrome, and atherogenic risk.

Cardiometabolic Risk Factors in Asymptomatic School Children: Significance of Redefining Alt Limits

Background: Childhood obesity and non-alcoholic fatty liver disease (NAFLD) are increasing globally. Nurturing of cardiometabolic risk factors (CMRF) in childhood can lead to atherogenic and metabolic complications later. ALT is a surrogate marker for NAFLD, which is part of a metabolic syndrome. This prospective observational study was planned to define prevalence of CMRF and NAFLD and whether ALT can predict CMRF. Methods: Asymptomatic school children (ASC) of 5–14 years from western India were included. Anthropometry (weight, height, waist circumference [WC]), blood pressure, sonography and blood tests (blood sugar, ALT, AST, HBsAg, antiHCV, cholesterol) were performed. CMRF were analyzed by applying old upper limit of normal (ULN) of ALT (40 u/l) and new ULN of ALT (19 u/l female, 30 u/l for male as in adults). Statistics was performed using chi square test. Results: A total of 2837 ASC (5–9 years = 1368, male = 835; 10–14 years = 1469, males = 964) were screened. Prevalence of CMRF was: overweight = 142 (5%), obese = 77 (2.7%), hypertension = 850 (29.9%), hypercholesterolemia = 49 (1.7%), central obese = 401 (14.1%) [abnormal WC = 75 (2.6%), abnormal waist/height ratio (WHR) = 401 (14.1%)], and fasting hyperglycemia = 2 (0.01%). Both age groups (5–9 vs. 10–14) and genders were comparable for CMRF. All CMRF were significantly higher in new criteria when compared to old criteria: overweight = [49.2% (70/142) vs. 23.2% (33/142)]; obese = [63.6% (49/77) vs. 38.9% (30/77)]; WC = [66.6% (50/75) vs.45.3% (34/75)]; WHR = [44.8% (180/401)vs.18.2% (73/401)]; hypertension = [29.8% (254/850) vs. 5.2% (45/850)]; hypercholesterolemia = [28.5% (14/49) vs. 6.1% (3/49)]. While applying new criteria, probable NAFLD increased from 4.1% to 28.9% in study population. Conclusions: In Indian ASC, central obesity defined by WHR was the more common CMRF than obesity defined by BMI. By lowering ULN of ALT, significantly more CMRF and more NAFLD could be diagnosed. So, there is need for lowering ULN of ALT to predict CMRF in pediatric population.

Abstract P216: Fatty Liver Index and Stroke Risk: the Reasons for Geographic and Racial Differences in Stroke Study

Background: Nonalcoholic fatty liver disease (NAFLD) is a common condition driven by the obesity epidemic. It is associated with cardiometabolic risk factors including diabetes, obesity, and hyperlipidemia, but also cardiovascular disease events, independent of these factors. No prospective studies have investigated the association of NAFLD with stroke risk. Hypothesis: NAFLD is associated with the risk of stroke in the REasons for Geographic and Racial Differences in Stroke (REGARDS) case-cohort study. Methods: The REGARDS study recruited 30,239 participants from the contiguous U.S., in order to study the reasons for regional and racial differences in stroke mortality. The REGARDS case-cohort study consists of 569 cases of incident stroke with 5.4 years follow up and a cohort random sample of 1,104. The Fatty Liver Index (FLI) was used a surrogate marker for NAFLD. It is calculated as e X /(1 + e X ) x 100, where x = 0.953*log(triglycerides) + 0.139*BMI + 0.718*log(γ-glutamyltransferase) + 0.053*waist circumference - 15.745. An FLI &gt;60 is considered a positive score, 20-60 an intermediate score, and &lt;20 a negative score. After excluding 68 participants who reported heavy alcohol consumption and 87 with baseline stroke, Cox proportional hazards models were used to calculate the hazard ratio (HR) and 95% confidence interval (CI) of stroke for FLI category, adjusting for age, race, sex, and the Framingham stroke risk factors and stratified by body mass index (BMI). Results: In the cohort sample, 44% of participants had NAFLD based on the FLI and 19% had a negative score. Compared to those without NAFLD, individuals with a positive score were more likely to be male (51% vs. 28%), have hypertension (69% vs. 40%), dyslipidemia (68% vs. 37%) diabetes (35% vs. 8%), and higher BMI (mean 33.7 vs. 23.0 kg/m 2 ; all p&lt;0.001). No participant with BMI &lt; 20 kg/m 2 had NAFLD by FLI. NAFLD was not associated with risk of stroke in a model adjusted for age, race and sex; HR 1.00 (95% CI 0.69-1.46), or a model further adjusted for Framingham stroke risk factors; HR 0.71 (95% CI 0.45-1.11). Stratifying by BMI group (20-30 kg/m 2 ), there was no association between NAFLD and stroke risk in those with BMI 20-&lt;25 or 25-30 kg/m 2 . We were unable to analyze NAFLD in the BMI &gt;30 group, due to low number of negative scores. When analyzed as a continuous variable among those with BMI 30 kg/m 2 , the HRs for a 10 unit higher FLI score were 0.92 (95% CI 0.84-1.01) and 1.17 (95% CI 0.97-1.42), respectively, adjusted for age, sex, race, and stroke risk factors. Discussion: NAFLD, as determined by a positive FLI score, was not associated with risk of stroke although FLI score was borderline associated with stroke risk in those with a BMI &gt;30. Results raise the possibility that NAFLD represents end organ damage from an adverse metabolic profile, and is not a mediator of stroke risk.

Lifestyle interventions for the treatment of non-alcoholic fatty liver disease.

The burden of non-alcoholic fatty liver disease (NAFLD) worldwide is a significant clinical and public health issue, affecting approximately one third of the Western population. This review assesses the effect and impact lifestyle interventions have on the treatment of this common condition. We review studies comparing the effect of calorie restriction and exercise programs, as well as comparison of lifestyle intervention with pharmaceutical intervention. Both calorie restriction and exercise programs are shown to be beneficial in improving features of metabolic syndrome and surrogate markers of NAFLD. The paucity of studies using histological improvement hinders the ability to conclude a benefit on improvement of histological NAFLD, although this is shown in a small number of studies. There is a need to extend the intervention period to show a sustained improvement with intervention as most studies have a follow up period of 12 months of less.

Association of 11β-hydroxysteroid dehydrogenase type 1 gene polymorphisms with serum alanine aminotransferase activity

Aims11β-Hydroxysteroid dehydrogenase type 1 (HSD11B1), which converts inactive glucocorticoid to active glucocorticoid, plays a critical role in pathogenesis of non-alcoholic fatty liver disease (NAFLD). Serum alanine aminotransferase (ALT), an indicator of hepatocellular injury, has been suggested as a surrogate marker for NAFLD. To date, no study has specifically examined the relationship between HSD11B1 gene polymorphisms and ALT. MethodsA study was conducted to examine the association of common single nucleotide polymorphisms (SNPs) in HSD11B1 (rs12086634, rs1000283) with serum ALT level in 756 Korean subjects (348 males and 408 females). ALT values were divided into two groups: elevated (>33U/l in males, >25U/l in females) and normal. ResultsSNPs showed a significant association with elevated ALT. According to results of logistic regression analysis adjusted for confounding variables, the GT+GG genotype for rs12086634 and the GA+AA genotype for rs1000283 showed significantly higher frequencies of elevated ALT, compared with the TT and GG genotypes, respectively (GT/GG vs. TT; OR 1.685, 95% CI 1.175–2.416, P=0.005, GA/AA vs. GG; OR 2.057, 95% CI 1.401–3.020, P<0.001, respectively). ConclusionsHSD11B1 polymorphisms (rs12086634 and rs1000283) are associated with elevated levels of ALT. Findings from this study suggest a possible association between HSD11B1 polymorphisms and hepatocellular injury, such as that seen in patients with NAFLD.

Why Does NAFLD Predict Type 2 Diabetes?

Based on the "lipotoxic" hypothesis, the free fatty acid flux from the excessive amount of adipose tissue toward the peripheral tissues would induce the development of insulin resistance especially when the triglyceride storage or the concentration of intermediate fat metabolites (diacylglycerides, ceramides) within the cytoplasm of these cells become excessive. Nonalcoholic fatty liver disease (NAFLD) includes a wide spectrum of liver damage, ranging from simple steatosis to steatohepatitis and advanced fibrosis. NAFLD is associated with general and intra-abdominal obesity and with a reduced ability of insulin to stimulate metabolic pathways in the liver itself and in other tissues. There are animal models and models in human diseases sustaining the hypothesis that a primary hepatic disease may determine the development of type 2 diabetes (T2DM). Epidemiologic data generated on surrogate markers of NAFLD (transaminases and γ-glutamyltransferase), semiquantitative assessment of fatty liver (ultrasound), and surrogate algorithms of NAFLD also support a causative effect of NAFLD on the risk to develop T2DM. In spite of the presence of these indirect associations, a clear-cut link between NAFLD and abnormal β-cell function is yet to be reported. Therefore, more data are warranted to prove what is considered a likely causative relationship between NAFLD and T2DM.