Nondiabetic Nonalcoholic Fatty Liver Disease Patients Research Articles

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 <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.

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.

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.

Effect of non-alcoholic fatty liver disease on carotid artery intima-media thickness as a risk factor for atherosclerosis.

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

A Study of Prevalence of Diabetes and Prediabetes in Patients of Non-Alcoholic Fatty Liver Disease and the Impact of Diabetes on Liver Histology in Coastal Eastern India

Background and Objectives: Non-alcoholic fatty liver disease (NAFLD) is more common in diabetic patients. There are limited studies on clinical, biochemical and histological features of NAFLD patients who are diabetic. The aim of the study was to determine the prevalence of diabetes and prediabetes in a cohort of NAFLD patients and to compare anthropometry, biochemical and metabolic parameters and hepatic histology of diabetic NAFLD patients with non-diabetic NAFLD patients. Methods: 515 consecutive NAFLD patients diagnosed by abdominal ultrasound and 100 healthy controls were subjected to detailed anthropometric measurements and biochemical assays including blood sugars, LFT, lipid profile and HOMA. Diabetes and prediabetes were defined according to WHO criteria. Patients were categorized and compared according to the presence or absence of diabetes. Liver biopsy was performed in 240 NAFLD patients and the liver histology was also compared between the two groups. Statistical analysis was performed on SPSS 16. Results: 124 out of the 515 (24.08%) NAFLD patients were diabetics, 118 out of 515 (22.9%) were pre-diabetics, while only 3 out of 100 controls had impaired glucose tolerance. Diabetic patients were older. NAFLD patients with diabetes had significantly higher waist circumference [98.02 ± 12.01 vs 93.89 ± 8.8, p = 0.000] as compared to the NAFLD patients without diabetes. Fasting blood sugar [124 ± 46.3 vs 90.8 ± 10.2, p = 0.000], triglyceride level [218.4 ± 17.6 vs 192 ± 9, p = 0.03] and HOMA-IR [2.6 ± 0.36 vs 1.84 ± 0.2, p < 0.001] were significantly higher in NAFLD-diabetes group. Hypertension [35% vs 11.7%, p = 0.000] was commoner in diabetic NAFLD patients. Histopathology in the diabetic patients revealed steatosis alone in 34.2% cases, borderline NASH in 31.4% and definite NASH in 34.2%. Fatty change alone was noted in 16.5% cases, borderline NASH in 34.1%, while 49% had definite NASH on liver biopsy of NAFLD patients without diabetes. Fibrosis was noted in 31.4% in diabetic and 27% in non-diabetic patients. IR alone had a linear correlation with necroinflammatory activity. Conclusion: The prevalence of diabetes and prediabetes is six times more in NAFLD patients than in healthy controls. NAFLD patients with diabetes have higher metabolic risk factors such as large waistline, hypertension, high triglyceride levels and increased insulin resistance. Diabetes or pre diabetes patients per se do not have histologically severe disease, rather insulin resistance play an important role in increasing the severity of the disease.

Elevated alanine aminotransferase activity is not associated with dyslipidemias, but related to insulin resistance and higher disease grades in non-diabetic non-alcoholic fatty liver disease

ObjectiveTo explore demographic and metabolic factors associated with increased alanine aminotransferase (ALT) activity in non-diabetic non-alcoholic fatty liver disease (NAFLD) patients. MethodsOverall 372 patients who consecutively attended to Gastroenterology Clinic of Baqiyatallah University of Medical Sciences, Tehran, Iran awere diagnosed as NAFLD entered into analysis. Exclusion criteria were having diabetes mellitus and fasting blood glucose over 126 mg/dL, active hepatitis B virus infection, having hepatitis C virus positive serology, and to be under corticosteroid therapy. ALT levels were considered pathologically high when it was over 30 IU/L for men and over 19 IU/L for women. ResultsBivariate analyses using t test and chi-square test showed that patients with pathologically augmented ALT levels had significantly higher NAFLD grades in their ultrasonographic evaluations (P = 0.003). Moreover, these patients represented significantly higher homeostatic model assessment levels (P = 0.003), levels of serum insulin (P = 0.002), fasting blood glucose (P < 0.001), and uric acid (P = 0.02). The prevalence of insulin resistance was also higher in patients with increased serum ALT concentrations. Multifactorial logistic regression models showed that ultrasonographic grading of NAFLD (P =0.027) and insulin resistance (P = 0.013) were the only variables significantly associated with abnormal ALT levels. ConclusionsThis study shows that the associations of increased ALT serum levels in NAFLD patients are different from what are supposed before. By excluding diabetic patients from our population, we find that increased ALT levels are not associated with dyslipidemias but are independently associated with insulin resistance and NAFLD grading on ultrasonographic evaluations. Further studies are needed to confirm our results.

Serum retinol-binding protein 4 in patients with nonalcoholic fatty liver disease: does it have a significant impact on pathogenesis?

Conflicting data have been reported in the literature about the role of retinol-binding protein 4 (RBP4) in insulin sensitivity, type 2 diabetes, and obesity in humans. It is of interest whether serum RBP4 is associated with various features of nonalcoholic fatty liver disease (NAFLD). Serum RBP4, adiponectin, leptin, and resistin were measured by enzyme-linked immunosorbent assay in 76 nondiabetic NAFLD patients, 55 of whom had elevated alanine aminotransferase (ALT). Thirty-four of 55 underwent a liver biopsy. Fasting insulin, liver and lipid panels were analyzed and ultrasound score, body mass index, and homeostasis model assessment for insulin resistance were recorded for each patient. Twenty-four healthy individuals served as controls. Serum RBP4 levels were not different between the steatosis group and controls as well as between the groups with high and normal ALT. Serum adiponectin was significantly lower and resistin was higher (P<0.001) in steatosis group compared with controls. RBP4 and resistin were negatively correlated, whereas leptin and resistin were correlated positively in patients with high ALT. At multivariate analysis, homeostasis model assessment for insulin resistance [odds ratio (OR): 10.71; 95% confidence interval (95% CI): 1.40-81.74], leptin (OR: 22.14; 95% CI: 2.40-204.12), resistin (OR: 6.29; 95% CI: 0.94-41.91), ALT (OR: 1.205; 95% CI: 1.05-1.39), and aspartate aminotransferase (OR: 0.846; 95% CI: 0.72-0.99) were independent variables associated with steatosis. Serum leptin, adiponectin, resistin, gamma-glutamyl transferase, and cholesterol were associated with histological activity by multivariate linear regression. Serum RBP4 is not a predictive factor in NAFLD irrespective of ALT. Low adiponectin, elevated resistin, and leptin were significantly associated with necroinflammation.

Relationship between cerebral arterial pulsatility and carotid intima media thickness in diabetic and non-diabetic patients with non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is considered a risk factor for atherosclerosis. The aim of the present study was to investigate the association of the pulsatility index (PI) of basilar artery (BA) and carotid intima media thickness (IMT) in diabetic and non-diabetic NAFLD patients. We compared a group of 80 stroke-free, diabetic and non-diabetic NAFLD patients and a control group of 26 healthy subjects without NAFLD. We then evaluated the PI of the BA by transcranial Doppler ultrasonography, and carotid IMT. The PI was significantly higher in diabetic NAFLD patients than in controls (p<0.003). Carotid IMT and asymmetrical dimethylarginine (ADMA) levels were higher in NAFLD patients than controls respectively (p<0.003, p<0.04). The PI of the BA was significantly correlated with age (R=0.369, p<0.001), male gender (R=0.207, p=0.035), diabetes (R=0.332, p=0.001), carotid IMT (R=0.296, p=0.002) and ADMA (R=0.349, p=0.015). A multiple regression analysis was performed with PI as the dependent variable with known clinical risk factors. Age (beta=3.54, p<0.001), diabetes (beta=2.32, p=0.022), gender (beta=2.20, p<0.03), ADMA (beta=2.25, p<0.031), and carotid IMT (beta=2.41, p<0.017), were independent predictive factors of BA PI. Adjustment for age and gender did not alter these relative risks, exhibiting a significant independent contribution to PI. The increased PI observed in this study represents enhanced cerebrovascular resistance, and we observed that the age, male gender, diabetes, ADMA levels, and carotid IMT were independent predictive factors of BA PI.

A Randomized Controlled Trial of Metformin versus Vitamin E or Prescriptive Diet in Nonalcoholic Fatty Liver Disease

Metformin proved useful in the treatment of nonalcoholic fatty liver disease (NAFLD), but its superiority over nutritional treatment and antioxidants has never been demonstrated. We aimed to compare the usefulness of metformin versus prescriptive diet or vitamin E. In an open label, randomized trial, nondiabetic NAFLD patients were given metformin (2 g/day; n = 55) for 12 months. The control cases were given either vitamin E (800 IU/day; n = 28) or were treated by a prescriptive, weight-reducing diet (n = 27). Outcome measures were liver enzymes, insulin resistance (homeostasis model assessment), parameters of the metabolic syndrome, and histology. Aminotransferase levels improved in all groups, in association with weight loss. The effects in the metformin arm were larger (p < 0.0001), and alanine aminotransferase normalized in 56% of cases (odds ratio (OR) versus. controls, 3.11; 95% confidence interval (CI), 1.56-6.20; p= 0.0013). In multivariate analysis, metformin treatment was associated with higher rates of aminotransferase normalization, after correction for age, gender, basal aminotransferases, and change in body mass index (OR, 5.98; 95% CI, 2.05-17.45). Differences were maintained when the two control groups were separately analyzed. The distribution of positive criteria for the metabolic syndrome was reduced only in the metformin arm (p= 0.001, signed rank test). A control biopsy in 17 metformin-treated cases (14 nonresponders) showed a significant decrease in liver fat (p= 0.0004), necroinflammation, and fibrosis (p= 0.012 for both). No side effects were observed during metformin treatment. Metformin treatment is better than a prescriptive diet or vitamin E in the therapy of NAFLD patients receiving nutritional counseling. Limited histological data support an association between improved aminotransferases and biopsy findings, which require confirmation in a double-blind trial with appropriate statistical power based on liver histology.