Non-diabetic Non-alcoholic Fatty Liver Disease Research Articles

Diabetic and Non-Diabetic Non-Alcoholic Fatty Liver Disease Patients: Assessment Using Non-Invasive Diagnostic Tools

Diabetic and Non-Diabetic Non-Alcoholic Fatty Liver Disease Patients: Assessment Using Non-Invasive Diagnostic Tools

Ankle systolic pressure index in non-diabetic non-alcoholic fatty liver disease: A case-control study

Several studies have shown that mortality in Non-alcoholic Fatty Liver Disease (NAFLD) or metabolic steatopathy is more related to cardiovascular diseases than to hepatic complications. Our work aimed to verify the relationship between this liver disease and the ankle-brachial pressure index (ABPI), which is a good screening tool for peripheral arterial disease (PAD) and a reliable marker of cardiovascular risk. A prospective sex- and age-matched case-control study was conducted in non-diabetic patients aged 30 to 70 years. All patients underwent a clinical and biological evaluation. Hepatic steatosis was diagnosed by ultrasound. All participants had their ankle-brachial pressure index measured using a Dopplex® Pocket Doppler in addition to arterial ultrasound of the supra-aortic trunk and a carotid-femoral pulse wave velocity (CfPWV) measurement. An ABPI<0.9 was considered pathological (suggestive of PAD). Statistical analyses were performed using SPSS 21.0 software (IBM). In total, 213 NAFLD patients (100 men/113 women) with a mean age of 48.5±10.14 years were matched to 213 controls. Metabolic syndrome (MS) was more common in NAFLD than in controls, regardless of the International Diabetes Federation (IDF 2005) criteria used (P<0.001). Low ABPI (<0.90) was noted in 19 (8.9%) NAFLD patients vs. 5 (2.3%) in controls (P=0.003). The mean age of these patients was 48.8±8.6 years with a female predominance (20 patients). 62.5% reported dyslipidemia on questioning, 70.8% a metabolic syndrome according to the IDF and 12.5% (3/24) of them were active smokers. There were no records of mediacalcosis. PAD was significantly associated with NAFLD in univariate analysis (OR=4.0 CI 95% (1.4-11.1)). Factors independently associated with PAD in NAFLD patients were nocturnal systolic blood pressure, smoking, thigh circumference, and being a female. The findings of our study show a significant association between NAFLD and low ABPI, likely reflecting the high vascular risk of this patient population.

ASSESSMENT OF INSULIN RESISTANCE IN NONALCOHOLIC FATTY LIVER DISEASE IN NON-DIABETIC PATIENTS

Background: Non-alcoholic fatty liver disease (NAFLD) refers to a spectrum of liver damage ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). The ectopic accumulation of fat in the liver has been strongly associated with insulin resistance. To Aim of the study: explore the proportion of insulin resistance in non-diabetic NAFLD patients compared to normal healthy populations using HOMA-IR model. Materials and Methods: This was a hospital based case control study carried out on 100 patients diagnosed with NAFLD by ultrasound. Fasting Insulin estimation was done by Insulin IRMA (IMMUNORADIOMETRIC ASSAY) Kit. P Results: atients with NAFLD had a higher prevalence (33%) of metabolic syndrome than the controls (15%) with an Odds Ratio of 2.791. Insulin resistance in non-diabetic NAFLD patients was higher (36%) than the control populations (11%) (p value was &lt;0.001). This study has shown that insuli Conclusion: n resistance has a positive association with NAFLD

Response to pioglitazone in non-alcoholic fatty liver disease patients with vs. without type 2 diabetes: A meta-analysis of randomized controlled trials.

Pioglitazone is considered a potential therapy for non-alcoholic fatty liver disease (NAFLD). However, different effects of pioglitazone on NAFLD have been demonstrated in diabetic and non-diabetic patients. Herein, a meta-analysis of randomized, placebo-controlled trials was carried out to indirectly compare pioglitazone in NAFLD patients with vs. without type 2 diabetes. Randomized controlled trials (RCTs) of pioglitazone vs. placebo involving NAFLD patients with or without type 2 diabetes/prediabetes collected from databases were enrolled into this analysis. Methodological quality was employed to evaluate the domains recommended by the Cochrane Collaboration. The analysis covered the changes in histology (fibrosis, hepatocellular ballooning, inflammation, steatosis), liver enzymes, blood lipids, fasting blood glucose (FBS), homeostasis model assessment-IR (HOMA-IR), weight and body mass index (BMI) before and after treatment, and adverse events. The review covered seven articles, with 614 patients in total, of which three were non-diabetic RCTs. No difference was found in patients with vs. without type 2 diabetes in histology, liver enzymes, blood lipids, HOMA-IR, weight, BMI, and FBS. Moreover, no significant difference was revealed in adverse effects between NAFLD patients with diabetes and without DM, except the incidence of edema that was found to be higher in the pioglitazone group than in the placebo group in NAFLD patients with diabetes. Pioglitazone could exert a certain effect on alleviating NAFLD, which was consistent between non-diabetic NAFLD patients and diabetic NAFLD patients in improving histopathology, liver enzymes, and HOMA-IR and reducing blood lipids. Furthermore, there were no adverse effects, except the incidence of edema which is higher in the pioglitazone group in NAFLD patients with diabetes. However, large sample sizes and well-designed RCTs are required to further confirm these conclusions.

The relationship between non-alcoholic fatty liver disease and incidence of chronic kidney disease for diabetic and non-diabetic subjects: A meta-analysis.

The prevalence of chronic kidney disease (CKD) rises with age and co-morbid diseases such as liver diseases. The main aim of the current meta-analysis is to assess the relationship between Non-alcoholic fatty liver disease (NAFLD) and chronic kidney disease incidence in both diabetic and non-diabetic subjects compared with control. A systematic literature search of papers published from January 1, 2005, till April 30, 2022, found 19 studies including 1,111,046 subjects; 310,804 were diagnosed with NAFLD, and 800,242 were non-NAFLD. The measured outcome was the incidence of CKD among NAFLD subjects compared to non-NAFLD subjects in diabetic and non-diabetic subjects. Dichotomous analysis methods were used within the random effects model to calculate the odds ratio (OR) with 95% confidence intervals (95% CIs). The incidence of CKD is highly significant in NAFLD subjects compared with controls (OR: 1.95; 95% CI: 1.65-2.31). The diabetic non-NAFLD subjects showed a significantly increased incidence of CKD compared to the non-diabetic subjects with NAFLD (OR: 1.79; 95% CI: 1.35-2.38).. In addition, the incidence of CKD was significantly higher in the NAFLD group compared with the non-NAFLD non-diabetic subjects (OR: 2.52; 95% CI: 1.91-3.32). Diabetes acts as an independent risk factor for CKD, as proven by a significant increase in incidence of diabetic subjects compared to non-diabetic NAFLD subjects (OR: 1.82; 95% CI: 1.15-2.88). Non-alcoholic fatty liver disease is significantly related to an increased incidence of CKD, which is significantly higher in diabetic subjects.

Study of Serum Lipid Profile and Aminotransferases (ALT and AST) in Non-obese, Non-diabetic Nonalcoholic Fatty Liver Disease

Background: Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum of liver diseases characterized by simple steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. It is the most common cause of cryptogenic cirrhosis. NAFLD is associated with obesity, insulin resistance, hypertension, type 2 diabetes mellitus, and dyslipidemia.&#x0D; Objective: The study aimed to assess the changes in lipid profile and aminotransferases (ALT and AST) in Non-alcoholic fatty liver disease (NAFLD).&#x0D; Methods: This observational cross-sectional study was carried out in the department of Biochemistry, Mymensingh Medical College in cooperation with the Centre for Nuclear Medicine and Ultrasound, Mymensingh from January 2012 to June 2013 after the approval of the protocol. A total of 120 subjects were included through purposive sampling, among them, 60 subjects were with fatty liver disease (group-I) and another 60 were without fatty liver (group-II) with ultrasonography. The sampling method was purposive (non-random). Relevant laboratory investigations were performed by using established methods to achieve the objectives.&#x0D; Results: The majority of the subjects with NAFLD (33.33%) were in 51-60 years (in Group-I). Mean serum total cholesterol, triacylglycerol, LDL-cholesterol, and HDL-cholesterol were 203.33±21.83, 184.41±33.31, 126.28±18.75, and 40.17±6.32 mg/dl in group-I and 167.65±9.83, 128.77±11.65, 101.74±9.29 and 40.16±3.55 mg/dl in group-II respectively. Significant differences were found in the case of total cholesterol (p&lt;0.001), triacylglycerol (p&lt;0.001), and LDL-cholesterol (&lt;0.001), but no significant difference was found in the case of HDL-cholesterol (p&gt;0.05). Serum ALT and AST were 49.43±16.98, 45.20±13.56 U/L in group-I and 32.83±4.54, 28.68±4.31 U/L in the group- II respectively. Significant differences were found in case of ALT (p &lt;0.001) and AST (p &lt;0.001).&#x0D; Conclusion: Nonalcoholic fatty liver disease is associated with dyslipidemia and with the elevation of serum ALT and AST.&#x0D; J Rang Med Col. September 2022; Vol. 7, No. 2:35-39

Adipose tissue dysfunction and visceral fat are associated with hepatic insulin resistance and severity of NASH even in lean individuals.

Non-alcoholic fatty liver disease (NAFLD) is a heterogeneous disorder, but the factors that determine this heterogeneity remain poorly understood. Adipose tissue dysfunction is causally linked to NAFLD since it causes intrahepatic triglyceride (IHTG) accumulation through increased hepatic lipid flow, due to insulin resistance and pro-inflammatory adipokines release. While many studies in NAFLD have looked at total adiposity (i.e. mainly subcutaneous fat, SC-AT), it is still unclear the possible impact of visceral fat (VF). Thus, we investigated how VF versus SC-AT was related to NAFLD severity in lean, overweight and obese individuals versus lean controls. Thirty-two non-diabetic NAFLD with liver biopsy (BMI 21.4-34.7kg/m2 ) and eight lean individuals (BMI 19.6-22.8kg/m2 ) were characterized for fat distribution (VF, SC-AT and IHTG by magnetic resonance imaging), lipolysis and insulin resistance by tracer infusion, free fatty acids (FFAs) and triglyceride (TAG) concentration and composition (by mass spectrometry). Intrahepatic triglyceride was positively associated with lipolysis, adipose tissue insulin resistance (Adipo-IR), TAG concentrations, and increased saturated/unsaturated FFA ratio. Compared to controls VF was higher in NAFLD (including lean individuals), increased with fibrosis stage and associated with insulin resistance in liver, muscle and adipose tissue, increased lipolysis and decreased adiponectin levels. Collectively, our results suggest that VF accumulation, given its location close to the liver, is one of the major risk factors for NAFLD. These findings propose VF as an early indicator of NAFLD progression independently of BMI, which may allow for evidence-based prevention and intervention strategies.

The effect of diabetes and prediabetes on the prevalence, complications and mortality in nonalcoholic fatty liver disease.

Background/AimsNonalcoholic fatty liver disease (NAFLD) is closely associated with diabetes. The cumulative impact of both diseases synergistically increases risk of adverse events. However, present population analysis is predominantly conducted with reference to non-NAFLD individuals and has not yet examined the impact of prediabetes. Hence, we sought to conduct a retrospective analysis on the impact of diabetic status in NAFLD patients, referencing non-diabetic NAFLD individuals.MethodsData from the National Health and Nutrition Examination Survey 1999–2018 was used. Hepatic steatosis was defined with United States Fatty Liver Index (US-FLI) and FLI at a cut-off of 30 and 60 respectively, in absence of substantial alcohol use. A multivariate generalized linear model was used for risk ratios of binary outcomes while survival analysis was conducted with Cox regression and Fine Gray model for competing risk.ResultsOf 32,234 patients, 28.92% were identified to have NAFLD. 36.04%, 38.32% and 25.63% were non-diabetic, prediabetic and diabetic respectively. Diabetic NAFLD significantly increased risk of cardiovascular disease (CVD), stroke, chronic kidney disease, all-cause and CVD mortality compared to non-diabetic NAFLD. However, prediabetic NAFLD only significantly increased the risk of CVD and did not result in a higher risk of mortality.ConclusionsGiven the increased risk of adverse outcomes, this study highlights the importance of regular diabetes screening in NAFLD and adoption of prompt lifestyle modifications to reduce disease progression. Facing high cardiovascular burden, prediabetic and diabetic NAFLD individuals can benefit from early cardiovascular referrals to reduce risk of CVD events and mortality.

Impaired fibrinolysis without hypercoagulability characterises patients with non-alcoholic fatty liver disease

IntroductionCardiovascular disease is the major cause of mortality in non-alcoholic fatty liver disease (NAFLD), a disease affecting one quarter of the world's population. Coagulation imbalance may be a contributing factor but is yet to be convincingly disclosed. AimTo perform an extensive mapping of the hemostatic system; primary and secondary hemostasis and the fibrinolytic system in non-diabetic NAFLD patients. Materials and methodsTwenty-five non-diabetic, biopsy-proven NAFLD patients [12 simple steatosis; 13 non-alcoholic steatohepatitis (NASH)] investigated by a comprehensive panel of coagulation and fibrinolysis tests in a cross-sectional study. Fifty age- and sex-matched healthy persons served as controls for each of the dynamic analyses: platelet aggregation, thrombin generation, fibrin formation and lysis. Body composition, insulin resistance makers, and liver fat assessed by proton density magnetic resonance imaging were measured in the patients. ResultsFibrinolytic function was impaired in simple steatosis [median 50% clot lysis time 1123 (min–max, 618–1967) s] and NASH [1448 (521–2618) s] compared to healthy controls [403 (184–1179) s] (p < 0.0001). Plasminogen activator inhibitor-1 (PAI-1) increased stepwise above reference interval from simple steatosis [54 (29–80) ng/ml] to NASH patients [109 (65–153) ng/ml; p = 0.03]. Impaired fibrinolysis correlated with hepatic fat fraction and insulin resistance; PAI-1 correlated with obesity and insulin resistance (ρ ≥ 0.42; p ≤ 0.04). Platelet aggregation, coagulation factors, natural anticoagulants, and thrombin generation were comparable to healthy controls and established reference intervals. ConclusionsNAFLD patients had impaired fibrinolysis without significant prothrombotic changes in coagulation. The impact of this abnormality on the increased cardiovascular risk remains to be investigated.

Evaluating Carotid intima media thickness (CIMT) of patients with Non - Alcoholic fatty liver disease (NAFLD) as a risk factor for atherosclerosis and correlation with metabolic syndrome

This study aimed to evaluate the effect of NAFLD on CIMT as a risk factor for atherosclerosis. The incidence of non-alcoholic fatty liver disease (NAFLD) is escalating worldwide due to mount of obesity and diabetes mellitus (DM) prevalence. Non-invasive appraisal of carotid intima-media thickness (CIMT) by high-resolution carotid B-mode ultrasonography is broadly used for determining atherosclerosis. In this case-control setting, 151 subjects were categorized in three groups: group I counting 49 patients with NAFLD and DM; group II counting 50 non-diabetic NAFLD patients; and the control with 52 normal subjects as group III. The right and left CIMTs and its maximum reading (CIMT max) were deliberated by a skilled sonographist blind to the groups. The sonographic grading of the NAFLD was dogged in groups I and II. Median CIMT max was extensively higher in group I comparing with group II and control group (p&lt;0.001). This disparity between group I and group II were not significant after adjusting for age and history of hypertension and hyperlipidemia (p=0.089). After scheming the confounders, there was a statistically significant between-group I and group II with the control group (p&lt;0.05). There was no significant disparity in median maximal thickness of intima-media in the carotid of group I compare to group II in patients with and without prominent liver enzymes (in both groups, 0.6 mm, p= 0.402). Based on our findings, there is a significant relationship between the presence of NAFLD and atherosclerosis. This association was independent to the Diabetes mellitus presence. The grade of NAFLD and elevated liver function tests had no effect on the severity of atherosclerosis.

Interplay between Oxidative Stress and Metabolic Derangements in Non-Alcoholic Fatty Liver Disease: The Role of Selenoprotein P.

Background: Pathogenetic mechanisms involved in the progression of non-alcoholic fatty liver disease (NAFLD) are complex and multifactorial. We investigated oxidative stress through the measurement of selenoprotein P (SeP) in serum and we explored its relation to metabolic derangements and liver damage in a group of non-diabetic NAFLD subjects. Methods: 57 NAFLD patients underwent a double-tracer oral glucose tolerance test (OGTT). Insulin resistance (IR) components were calculated at baseline as follows: hepatic-IR = (endogenous glucose production*insulin); peripheral-IR = (glucose rate of disappearance(Rd)); adipose-tissue(AT)-IR as Lipo-IR = (glycerol rate of appearance (Ra)*insulin) or AT-IR = (free fatty acids (FFAs)*insulin). The lipid and amino acid (AA) profiles were assessed by gas chromatography–mass spectrometry. SeP levels were measured by enzyme immunosorbent assay. Results: Circulating SeP correlated with insulin (rS = 0.28), FFAs (rS = 0.42), glucose Rd (rS = −0.33) and glycerol Ra (rS = −0.34); consistently, SeP levels correlated with Lipo-IR and AT-IR (rS > 0.4). Among the AA and lipid profiles, SeP inversely correlated with serine (rS = −0.31), glycine (rS = −0.44) and branched chain AA (rS = −0.32), and directly correlated with saturated (rS = 0.41) and monounsaturated FFAs (rS = 0.40). Hepatic steatosis and fibrosis increased in subjects with higher levels of SeP. In multivariable regression analysis, SeP was associated with the degree of hepatic fibrosis (t = 2.4, p = 0.022). Conclusions: SeP levels were associated with an altered metabolic profile and to the degree of hepatic fibrosis, suggesting a role in the pathogenesis of NAFLD.

Serum Vitamin E Levels of Adults with Nonalcoholic Fatty Liver Disease: An Inverse Relationship with All-Cause Mortality in Non-Diabetic but Not in Pre-Diabetic or Diabetic Subjects.

Nonalcoholic fatty liver disease (NAFLD) is a growing health threat worldwide. Vitamin E supplementation is recommended for nonalcoholic steatohepatitis (NASH) patients, but only for non-diabetic subjects. We aimed to investigate whether serum vitamin E levels differently impact long-term prognosis in diabetic versus non-diabetic NAFLD individuals. A total of 2404 ultrasonographically defined NAFLD individuals from National Health and Nutrition Examination Survey (NHANES) III were stratified by their glycemic statuses into diabetic (N = 662), pre-diabetic (N = 836) and non-diabetic (N = 906), and the relationship between serum vitamin E levels and all-cause mortality was analyzed. The serum vitamin E concentrations were 31.1 ± 14.1, 26.7 ± 9.6, and 24.7 ± 9.8 µmol/L and vitamin E: total cholesterol ratios were 5.16 ± 1.70, 4.81 ± 1.46, and 4.80 ± 1.34 µmol/mmol in in diabetic, pre-diabetic, and non-diabetic groups, respectively. Of 2404 NAFLD subjects, 2403 have mortality information and 152 non-diabetic, 244 pre-diabetic, and 342 diabetic participants died over a median follow-up period of 18.8 years. Both serum vitamin E levels and vitamin E: total cholesterol ratios were negatively associated with all-cause mortality after adjusting for possible confounders in non-diabetic subjects (HR = 0.483, and 0.451, respectively, p < 0.005), but not in either diabetic or pre-diabetic subjects. In NAFLD individuals, both serum vitamin E and lipid-corrected vitamin E were (1) higher in the diabetic group; and (2) negatively associated with all-cause mortality only in the non-diabetic group. Further investigations are warranted to elucidate the underlying mechanism of this inverse association of serum vitamin E concentration with all-cause mortality in non-diabetic but not pre-diabetic or diabetic subjects.

Angiotensin II Type 1 Receptor rs5186 Gene Variant Predicts Incident NAFLD and Associated Hypertension: Role of Dietary Fat-Induced Pro-Inflammatory Cell Activation.

Hypertension has been linked to the presence and severity of nonalcoholic fatty liver disease (NAFLD) through unclear mechanisms. The gain-of-function rs5186 A1166C variant in angtiotensin receptor type 1 (AGTR1) gene has been linked to hypertension, cardiovascular disease and metabolic syndrome. We assessed the impact of AGTR1 A1166C variant on NAFLD incidence and severity and on glucose and lipid metabolism and explored the underlying mechanisms. We followed up 314 healthy nonobese, nondiabetic, nonhypertensive, insulin-sensitive participants in a population-based study, characterized for AGTR1 rs5186 A1166C variant, adipokine profile, inflammatory and endothelial dysfunction markers. An independent cohort of 78 biopsy-proven nondiabetic NAFLD patients and controls underwent an oral glucose tolerance test with Minimal Model analysis of glucose homeostasis, and an oral fat tolerance test with measurement of plasma lipoproteins, adipokines, MCP-1, calprotectin, and nuclear factor-κB activation in circulating mononuclear cells. AGTR1 A1166C polymorphism predicted 9.8-year incident NAFLD (odds ratio: 1.67, 95% CI: 1.26-2.21) and hypertension (odds ratio: 1.49, 95% CI: 1.12-2.63) and 9-year increase in cardiovascular disease risk and endothelial dysfunction markers. In the cross-sectional cohort, AGTR1 C allele carriers had higher insulin resistance. Despite comparable fasting lipid profiles, AGTR1 C allele carriers showed postprandial triglyceride-rich and cholesterol-rich VLDL lipoprotein accumulation, higher resistin, MCP-1 and calprotectin responses and nuclear factor-κB activation in mononuclear cells, and a blunted postprandial adiponectin response to fat, which predicted liver histology, hepatocyte apoptosis activation, insulin resistance, and endothelial dysfunction. AGTR1 A1166C variant affects liver disease, insulin resistance, and endothelial dysfunction in NAFLD, at least in part by modulating adipokine, chemokine, and pro-inflammatory cell activation in response to fat ingestion.

Adherence to Mediterranean Diet and Non-Alcoholic Fatty Liver Disease: Effect on Insulin Resistance.

The prevalence of cardiometabolic disorders, including non-alcoholic fatty liver disease (NAFLD), is increasing in western countries, because of changes in lifestyle and dietary habits. Mediterranean Diet (Med-Diet) is effective for cardiovascular prevention, but its relationship with NAFLD has been scarcely investigated. We included 584 consecutive outpatients presenting with one or more cardiovascular risk factor such as type 2 diabetes mellitus (T2DM), arterial hypertension, overweight/obesity, and dyslipidemia. Liver steatosis was assessed using ultrasonography. Med-Diet adherence was investigated by a validated semiquantitative nine-item dietary questionnaire; patients were divided into low, intermediate, and high adherence. Insulin resistance was defined by the 75th percentile of homeostasis model of insulin resistance (HOMA-IR; ≥3.8). The mean age was 56.2±12.4 years and 38.2% were women. Liver steatosis was present in 82.7%, and its prevalence decreased from low to high adherence group (96.5% vs. 71.4%, P<0.001). In a multiple logistic regression analysis, hypertriglyceridemia (odds ratio (OR): 2.913; P=0.002), log (ALT) (OR: 6.186; P<0.001), Med-Diet adherence (intermediate vs. low OR: 0.115; P=0.041, high vs. low OR: 0.093; P=0.030), T2DM (OR: 3.940; P=0.003), and high waist circumference (OR: 3.012; P<0.001) were associated with NAFLD. Among single foods, low meat intake (OR: 0.178; P<0.001) was inversely significantly associated with NAFLD. In 334 non-diabetic NAFLD patients, age (OR: 1.035, P=0.025), high waist circumference (OR: 7.855, P<0.001), hypertriglyceridemia (OR: 2.152, P=0.011), and Log (ALT) (OR: 2.549, P=0.002) were directly associated with HOMA-IR, whereas Med-Diet score was inversely associated (OR: 0.801, P=0.018). We found an inverse relationship between Med-Diet and NAFLD prevalence. Among NAFLD patients, good adherence to Med-Diet was associated with lower insulin resistance. Our findings suggest that Med-Diet may be a beneficial nutritional approach in NAFLD patients.

MERTK rs4374383 variant predicts incident nonalcoholic fatty liver disease and diabetes: role of mononuclear cell activation and adipokine response to dietary fat.

The loss-of-function rs4374383 G > A variant in Myeloid-epithelial-reproductive Tyrosine Kinase (MERTK) gene has been linked to hepatic fibrosis in chronic liver diseases. MERTK is expressed by immune and non-immune cells involved in inflammation, metabolism and vascular homeostasis. We assessed the impact of MERTK rs4374383 G > A variant on nonalcoholic fatty liver disease (NAFLD) incidence and severity and on glucose and lipid metabolism. We followed-up 305 healthy nonobese nondiabetic, metabolic syndrome-free insulin sensitive participants in a population-based study, characterized for MERTK G > A polymorphism, adipokine profile and inflammatory markers.An independent cohort of 69 biopsy-proven nondiabetic NAFLD patients and 69 healthy controls underwent indirect calorimetry, an OGTT with Minimal Model analysis of glucose homeostasis, and an oral fat tolerance test with measurement of plasma lipoproteins, adipokines, MCP-1, and of Nuclear Factor (NF)-κB activation in circulating mononuclear cells (MNCs). In the longitudinal cohort, MERTK G > A polymorphism protected against 9-year incident NAFLD (OR:0.48,95%CI:0.26-0.79) and diabetes (OR: 0.47, 95% CI: 0.19-0.87).In the cross-sectional cohort, MERTK A-allele carriers had higher fat oxidation rates and tissue insulin sensitivity. Despite comparable fastign and postprandial lipid profiles, MERTK A-allele carriers showed lower resistin and MCP-1 responses, milder MNC NF-κB activation, and a higher postprandial adiponectin response to fat, which predicted tissue insulin resistance hepatocyte apoptosis and liver histology. MERTK G > A variant affects liver disease, nutrient oxidation and glucose metabolism in NAFLD. The modulation of adipokine, chemokine and pro-inflammatory MNC activation in response to fat ingestion may contribute to the observed effects on liver and metabolic disease.

Assessment of Left Ventricular Diastolic Function in Nonalcoholic Fatty Liver Disease

Background: nonalcoholic fatty liver disease (NAFLD) is a spectrum of fat-associated liver conditions that can result in end stage liver disease. NAFLD patients when compared to control subjects have a higher prevalence of atherosclerosis which is independent of obesity and other established risk factors. Recent studies have identified NAFLD as a risk factor for early subclinical abnormalities in myocardial metabolism as well as in cardiac structure and function. In particular, it has been shown that NAFLD is associated with left ventricular hypertrophy and impaired diastolic function. The Objective: the aim of this study is to assess left ventricular diastolic function in NAFLD patients. Patients and Methods: the study included thirty Egyptian NAFLD patients their age between 20 and 45 years old, and twenty healthy control subjects who were age and sex matched. Full medical history, complete physical examination and laboratory tests were done in form of ALT, AST, total cholesterol, LDL, HDL, triglyceride, hemoglobin A1C, creatinine, urea and CBC. Abdominal ultrasonography and transthoracic echocardiography also were done. Results: NAFLD patients had higher diastolic blood pressures, increased body mass indices, ALT, AST and glycated hemoglobin A1C more than controls. Also in our study the mean of E, E/A ratio, DT, lateral E/e? and septal E/e? is significant higher in NAFLD patients than control group. The mean of lateral e? and septal e? is lower in NAFLD patients than control group. Conclusion: patients with NAFLD had significant impairment on diastolic function in the non-diabetic and normotensive NAFLD patients compared to the controls as measured by two-dimensional echocardiography Doppler imaging in addition to tissue Doppler imaging.

MERTK rs4374383 variant predicts incident nonalcoholic fatty liver disease and diabetes: role of mononuclear cell activation and adipokine response to dietary fat.

The loss-of-function rs4374383 G > A variant in Myeloid-epithelial-reproductive Tyrosine Kinase (MERTK) gene has been linked to hepatic fibrosis in chronic liver diseases. MERTK is expressed by immune and non-immune cells involved in inflammation, metabolism and vascular homeostasis. We assessed the impact of MERTK rs4374383 G > A variant on nonalcoholic fatty liver disease (NAFLD) incidence and severity and on glucose and lipid metabolism. We followed-up 305 healthy nonobese nondiabetic, metabolic syndrome-free insulin sensitive participants in a population-based study, characterized for MERTK G > A polymorphism, adipokine profile and inflammatory markers.An independent cohort of 69 biopsy-proven nondiabetic NAFLD patients and 69 healthy controls underwent indirect calorimetry, an OGTT with Minimal Model analysis of glucose homeostasis, and an oral fat tolerance test with measurement of plasma lipoproteins, adipokines, MCP-1, and of Nuclear Factor (NF)-κB activation in circulating mononuclear cells (MNCs). In the longitudinal cohort, MERTK G > A polymorphism protected against 9-year incident NAFLD (OR:0.48,95%CI:0.26-0.79) and diabetes (OR: 0.47, 95% CI: 0.19-0.87).In the cross-sectional cohort, MERTK A-allele carriers had higher fat oxidation rates and tissue insulin sensitivity. Despite comparable fastign and postprandial lipid profiles, MERTK A-allele carriers showed lower resistin and MCP-1 responses, milder MNC NF-κB activation, and a higher postprandial adiponectin response to fat, which predicted tissue insulin resistance hepatocyte apoptosis and liver histology. MERTK G > A variant affects liver disease, nutrient oxidation and glucose metabolism in NAFLD. The modulation of adipokine, chemokine and pro-inflammatory MNC activation in response to fat ingestion may contribute to the observed effects on liver and metabolic disease.

An open-label randomized control study to compare the efficacy of vitamin e versus ursodeoxycholic acid in nondiabetic and noncirrhotic Indian NAFLD patients

Background/Aim:The study was carried out to compare the efficacy of Vitamin E versus Ursodeoxycholic acid (UDCA) in nondiabetic nonalcoholic fatty liver disease (NAFLD) patients.Patients and Methods:We randomized 250 non cirrhotic and non diabetic NAFLD patients diagnosed on ultrasound, with raised alanine aminotransferase (ALT) level. (>40 IU/L), to receive Vitamin E 400 mg twice a day (Group A) or UDCA 300 mg twice a day (Group B) for 52 weeks. Lifestyle modification to achieve at least 5% weight reduction and subsequent weight control and regular exercise was advised to both groups. The primary study endpoint was normalization of ALT. Secondary endpoints were the proportion of patients with reduction in ALT, relative reduction in the NAFLD Fibrosis score (NFS), symptomatic improvement and tolerability.Results:One hundred and fifty patients received UDCA as compared to 100 patients receiving Vitamin E. The treatment groups were comparable at entry with regard to age (44.1 vs 42.4 years), gender (67% vs 63% female), risk factors for nonalcoholic steatohepatitis, hypochondriac pain, serum liver biochemistries, and NAFLD Fibrosis score. The primary endpoint was achieved in 21 (14%) and 19 (19%) of patients in Group A and Group B, respectively (P = 0.2). The proportion of patients with reduction in ALT (56% vs 63%, P = 0.2), symptomatic improvement (78% vs 67%, P= 0.058), reduction in the NFS (44% vs 47%, P= 0.69), and tolerability (98% vs 95%, P= 0.2) were similar between Group A and Group B, respectively.Conclusion:UDCA is an effective and safe alternative to Vitamin E in nondiabetic–noncirrhotic Indian NAFLD patients.

Peripheral insulin resistance predicts liver damage in nondiabetic subjects with nonalcoholic fatty liver disease.

Surrogate indexes of insulin resistance and insulin sensitivity are widely used in nonalcoholic fatty liver disease (NAFLD), although they have never been validated in this population. We aimed to validate the available indexes in NAFLD subjects and to test their ability to predict liver damage also in comparison with the NAFLD fibrosis score. Surrogate indexes were validated by the tracer technique (6,6-D2 -glucose and U-(13) C-glucose) in the basal state and during an oral glucose tolerance test. The best-performing indexes were used in an independent cohort of 145 nondiabetic NAFLD subjects to identify liver damage (fibrosis and nonalcoholic steatohepatitis). In the validation NAFLD cohort, homeostasis model assessment of insulin resistance, insulin to glucose ratio, and insulin sensitivity index Stumvoll had the best association with hepatic insulin resistance, while peripheral insulin sensitivity was most significantly related to oral glucose insulin sensitivity index (OGIS), insulin sensitivity index Stumvoll, and metabolic clearance rate estimation without demographic parameters. In the independent cohort, only oral glucose tolerance test-derived indexes were associated with liver damage and OGIS was the best predictor of significant (≥F2) fibrosis (odds ratio = 0.76, 95% confidence interval 0.61-0.96, P = 0.0233) and of nonalcoholic steatohepatitis (odds ratio = 0.75, 95% confidence interval 0.63-0.90, P = 0.0021). Both OGIS and NAFLD fibrosis score identified advanced (F3/F4) fibrosis, but OGIS predicted it better than NAFLD fibrosis score (odds ratio = 0.57, 95% confidence interval 0.45-0.72, P < 0.001) and was also able to discriminate F2 from F3/F4 (P < 0.003). OGIS is associated with peripheral insulin sensitivity in NAFLD and inversely associated with an increased risk of significant/advanced liver damage in nondiabetic subjects with NAFLD.

The relationship between insulin resistance, metabolic syndrome and nonalcoholic fatty liver disease in non-obese non-diabetic Turkish individuals: A pilot study.

Nonalcoholic fatty liver disease is related to obesity, metabolic syndrome, and insulin resistance. Nonalcoholic fatty liver disease and metabolic syndrome may also be encountered in non-obese, non-diabetic individuals, and there are no published data about the prevalence of these conditions in non-obese, non-diabetic Turkish subjects. We aimed to determine the difference between non-obese, non-diabetic nonalcoholic fatty liver disease patients and healthy controls in terms of insulin resistance and metabolic syndrome in Turkish subjects. Non-obese, non-diabetic individuals (n=219) were enrolled. The cohort was divided into two groups according to presence of steatosis in ultrasonography: nonalcoholic fatty liver disease group (n=143) and healthy control group (n=76). Insulin resistance and metabolic syndrome were analyzed and compared between the two groups. The prevalences of metabolic syndrome (32.2% vs. 5.3%, respectively; p<0.001) and insulin resistance (46.2% vs. 9.2%, respectively; p<0.001) were significantly higher in the nonalcoholic fatty liver disease group. According to multiple logistic regression analysis, age (odds ratio 1.534; p=0.0032), insulin resistance (odds ratio 1.074; p<0.001), and serum ALT levels (odds ratio 1.102; p<0.001) were independently associated with nonalcoholic fatty liver disease. Insulin resistance and metabolic syndrome are not rare in non-obese, non-diabetic Turkish subjects with nonalcoholic fatty liver disease. Ultrasonographically detected fatty liver was independently associated with insulin resistance, irrespective of the presence of metabolic syndrome.