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Background: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a novel term that distinguishes patients at risk of adverse clinical outcomes with higher accuracy than those with non-alcoholic fatty liver disease (NAFLD). Cardiovascular mortality is the leading cause of death in MAFLD. The current literature lacks large-scale prospective studies that address preventive approaches for cardiovascular health in MAFLD. We investigated whether MAFLD patients benefit from a fixed-dose combination therapy (Aspirin, hydrochlorothiazide, atorvastatin, valsartan), known as a Polypill., Methods: Analysis was performed (stratified based on MAFLD status) of a clinical trial that included 1596 individuals randomly allocated to an intervention (polypill) or a control (usual care) group. Patients were followed up for five years for any adverse drug reaction, major cardiovascular events, and mortality. Univariable and multivariable survival analyses were performed, and the interaction level was assessed by R programming., Results: Patients who consumed the polypill had significantly lower hazard ratios of major cardiovascular events incidence (HR 0.56, 95% CI 0.41-0.78) and cardiovascular mortality (HR 0.41, 95% CI 0.2-0.86) compared to the control group. Polypill showed significantly better results in lowering cardiovascular events in MAFLD patients than in the general population. (p-value for interaction: 0.028). Moreover, comparing those patients who had high adherence to the Polypill, with the control group, further enhanced the results., Conclusions: Major cardiovascular events are prevented in MAFLD patients who consume the Polypill. MAFLD patients benefit from the Polypill more than the general population., (© 2023. Asian Pacific Association for the Study of the Liver.)

Aims: Individuals with non-alcoholic steatohepatitis or elevated liver enzymes have increased cardiovascular mortality but are often excluded from prevention trials. We investigated the effectiveness of fixed-dose combination therapy for the prevention of major cardiovascular events (MCVE) among individuals with and without presumed non-alcoholic steatohepatitis (pNASH)., Methods and Results: Two thousand four hundred participants over 50 were randomized into the intervention and control groups. Consent was obtained post-randomization. Consenting participants in the intervention group were given a pill containing aspirin, atorvastatin, hydrochlorothiazide, and valsartan (polypill). Participants were followed for 5 years. Presumed non-alcoholic steatohepatitis was diagnosed by ultrasonography and elevated liver enzymes. The primary outcome was MCVE. ClinicalTrials.gov: NCT01245608. Among the originally randomized population, 138 of 1249 in the intervention group (11.0%) and 137 of 1017 controls (13.5%) had MCVE during the 5-year follow-up [unadjusted risk ratio (RR) 0.83, 95% confidence interval (CI) 0.66-1.03]. Of the 1508 participants who consented to additional measurements and treatment, 63 of 787 (8.0%) intervention group participants and 86 of 721 (11.9%) controls had MCVE (adjusted RR 0.61, 95% CI 0.44-0.83). Although the adjusted relative risk of MCVE in participants with pNASH (0.35, 95% CI 0.17-0.74) was under half that for participants without pNASH (0.73, 95% CI 0.49-1.00), the difference did not reach statistical significance. There was no change in liver enzymes in participants taking polypill but among those with pNASH, there was a significant decrease after 60 months of follow-up (intragroup -12.0 IU/L, 95% CI -14.2 to -9.6)., Conclusion: Among patients consenting to receive fixed-dose combination therapy, polypill is safe and effective for the prevention of MCVE, even among participants with fatty liver and increased liver enzymes., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Nonalcoholic fatty liver disease (NAFLD), as the most common liver disease in the world, can range from simple steatosis to steatohepatitis. We evaluated the association between meat consumption and risk of NAFLD in the Golestan Cohort Study (GCS)., Methods: The GCS enrolled 50,045 participants, aged 40-75 years in Iran. Dietary information was collected using a 116-item semiquantitative food frequency questionnaire at baseline (2004-2008). A random sample of 1,612 cohort members participated in a liver-focused study in 2011. NAFLD was ascertained through ultrasound. Total red meat consumption and total white meat consumption were categorized into quartiles based on the GCS population, with the first quartile as the referent group. Multivariable logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs)., Results: The median intake of total red meat was 17 and total white meat was 53 g/d. During follow-up, 505 individuals (37.7%) were diagnosed with NAFLD, and 124 of them (9.2%) had elevated alanine transaminase. High total red meat consumption (ORQ4 vs Q1 = 1.59, 95% CI = 1.06-2.38, P trend = 0.03) and organ meat consumption (ORQ4 vs Q1 = 1.70, 95% CI = 1.19-2.44, P trend = 0.003) were associated with NAFLD. Total white meat, chicken, or fish consumption did not show significant associations with NAFLD., Discussion: In this population with low consumption of red meat, individuals in the highest group of red meat intake were at increased odds of NAFLD. Furthermore, this is the first study to show an association between organ meat consumption and NAFLD (see Visual Abstract, http://links.lww.com/AJG/B944)., (Copyright © 2021 by The American College of Gastroenterology.)

Background: Non-alcoholic fatty liver disease (NAFLD) is much more frequent and more severe, including cirrhosis, hepatocellular carcinoma in patients with type 2 diabetes. Coffee is a complex beverage with hundreds of compounds whereas caffeine and chlorogenic acid are the most abundant bioactive compounds. The published epidemiological data demonstrating beneficial associations between all categories of coffee exposure and ranges of liver outcomes are rapidly growing; however, the main contributors and cause-effect relationships have not yet been elucidated. To address existing knowledge gaps, we sought to determine the efficacy and safety of 6 months chlorogenic acid and/or caffeine supplementation in patients with type 2 diabetes affected by NAFLD., Methods: This trial was carried out at two Diabetes Centers to assess the effects of supplementation with daily doses of 200 mg chlorogenic acid, 200 mg caffeine, 200 mg chlorogenic acid plus 200 mg caffeine or placebo (starch) in patients with type 2 diabetes and NAFLD. The primary endpoint was reduction of hepatic fat and stiffness measured by FibroScan, and changes in serum hepatic enzymes and cytokeratin - 18 (CK-18) levels. Secondary endpoints were improvements in metabolic (including fasting glucose, homeostasis model assessment-estimated insulin resistance (HOMA-IR), hemoglobin A1c (HBA1C), C-peptide, insulin and lipid profiles) and inflammatory (including nuclear factor k-B (NF-KB), tumor necrosis factor (TNF-α), high sensitive- C reactive protein(hs-CRP)) parameters from baseline to the end of treatment., Results: Neither chlorogenic acid nor caffeine was superior to placebo in attenuation of the hepatic fat and stiffness and other hepatic outcomes in patients with diabetes and NAFLD. Except for the lower level of total cholesterol in caffeine group (p = 0.04), and higher level of insulin in chlorogenic acid plus caffeine group (p = 0.01) compared with placebo, there were no significant differences among the treatment groups., Conclusion: These findings do not recommend caffeine and/or chlorogenic acid to treat NAFLD in type 2 diabetes patients., Trial Registration: IRCT201707024010N21 . Registered 14 September 2017.

Background: With the increasing prevalence of obesity, non-alcoholic fatty liver disease (NAFLD), has become a frequent cause of chronic liver disease, often leading to cirrhosis. In recent decades, gut microbiota have been evaluated as an effective factor in NAFLD pathogenesis, causing steatohepatitis by involving the host immune system. The aim of this study is to evaluate gut microbiota dysbiosis in NAFLD/NASH patients in comparison to healthy controls., Methods: We conducted a systematic search of published studies that have examined the composition of gut microbiota in relation to NAFLD. PubMed, Scopus and ISI Web of Science were searched. After the exclusion of irrelevant studies, 15 eligible studies were included and summarized., Results: Overall, some studies reported the composition of microbiota at the phyla level, while others reported them at smaller subgroups; the results of studies were contradictory in some cases., Conclusion: Overall, study findings indicate a relationship between microbial composition and NAFLD. Study methods and sequencing techniques influenced these results., (© 2020 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.)

Background: NAFLD patients have higher risk of atherosclerosis cardiovascular disease (ASCVD). apo B/apoA-I ratio and atherogenic index of plasma (AIP) have been suggested as biomarker for ASCVD., Methods: apo A-I, apoB, aryl esterase (ARE) and paraoxonase (PON) activities and carotid intima media thickness (cIMT) were determined in 49 NAFLD patients and 33 controls., Results: Plasma levels of apo A-I, adiponectin, ARE and PON activities decreased in NAFLD patients, while apo B, AIP and apoB/apo A-I ratio level were higher in NAFLD patients compared to controls. Furthermore, cIMT showed a positive association with AIP, apo B/apo A-I ratio and AIP + (apo B/apo A-I) in NAFLD patients. Strikingly, AIP + (apo B/apo A-I) showed a good ability to discriminating increased cIMT in NAFLD patients., Conclusions: The result showed that AIP and apo B/apo A-I associated with cIMT in NAFLD patients; however, more study are needed to prove this concept.

Non-alcoholic fatty liver disease (NAFLD) is associated with a substantial increased risk of atherosclerotic cardiovascular disease (ASCVD), which is partly related to dyslipidemia and low HDL-C level. The cardioprotective activity of HDL in the body is closely connected to its role in promoting cholesterol efflux, which is determined by cholesterol efflux capacity (CEC). Hitherto, the role of HDL, as defined by CEC has not been assessed in NAFLD patients. In this research study, we present the results of a study of cAMP-treated J774 CEC and THP-1 macrophage CEC in ApoB-depleted plasma of 55 newly diagnosed NAFLD patients and 30 controls. Circulating levels of ApoA-I, ApoB, preβ-HDL, plasma activity of CETP, PLTP, LCAT and carotid intima-media thickness (cIMT) were estimated. cAMP-treated J774 and THP-1 macrophage CEC were found to be significantly lower in NAFLD patients compared to controls (P < 0.001 and P = 0.003, respectively). In addition, it was discovered that both ApoA-I and preβ1-HDL were significantly lower in NAFLD patients (P < 0.001). Furthermore, cAMP-treated J774 CEC showed independent negative correlation with cIMT, as well as the presence of atherosclerotic plaque in NAFLD patients. In conclusion, our findings showed that HDL CEC was suppressed in NAFLD patients, and impaired cAMP-treated J774 CEC was an independent risk factor for subclinical atherosclerosis in NAFLD patients, suggesting that impaired HDL functions as an independent risk factor for atherosclerosis in NAFLD.

Although non-alcoholic fatty liver disease (NAFLD) is the leading aetiology of liver disorders in the world, there is no proven treatment for NAFLD patients with normal or low BMI. The aim of this study was to evaluate the efficacy of synbiotics supplementation in NAFLD patients with normal or low BMI. In this randomised, double-blind, placebo-controlled, clinical trial, fifty patients with NAFLD were assigned to take either a synbiotic supplement or a placebo capsule for 28 weeks. Both groups were advised to follow a healthy lifestyle. At the end of the study, hepatic steatosis and fibrosis reduced in both groups; however, the mean reduction was significantly greater in the synbiotic group rather than in the placebo group (P<0·001). Furthermore, serum levels of fasting blood sugar, TAG and most of the inflammatory mediators reduced in the synbiotic group significantly compared with the placebo group (P<0·05). Our results provide evidence that synbiotic supplementation improves the main features of NAFLD in patients with normal and low BMI, at least partially through reduction in inflammatory indices. Further studies are needed to address the exact mechanism of action of these effects.

Background: Expression of miR-122 is highly specific to hepatocytes of the liver.  This miRNA is involved in lipid hemostasis of the tissue; however, there is no comprehensive understanding of its function in lipid hemostasis., Materials and Methods: Since hepatocytes are responsible for part of Triacylglycerol (TAG) synthesis in the body, we hypothesized that miR-122, as the most abundant miRNA in the tissue, might regulate TAG metabolism by targeting key enzymes that are involved in its production pathway. A systematic computational analysis of putative targets of miR-122 identified CTDNEP1 and LPIN1 genes in the TAG pathway. We used dual-luciferase reporter assay, quantitative RT-PCR as well as western blot to confirm the repressive effect of miR-122 on CTDNEP1 and LPIN1 in TAG pathway., Results: Real time PCR on liver needle biopsies with hepatosteatosis showed that miR-122 is up-regulated in hepatosteatosis. Surprisingly, the protein and RNA level of identified targets of miR-122 are also up-regulated in clinical samples, probably as a disproportionate feedback response to the high level of miR-122., Conclusion: Our findings suggest that up-regulation of miR-122 can trigger the compensatory response of LPIN1 and CTDNEP1 in hepatosteatosis.

Background: To investigate the association between non-alcoholic fatty liver disease (NAFLD) and quantitative measures of central adiposity in the general population using a semi-automated method on magnetic resonance imaging (MRI) data., Methods: Subjects were recruited from Golestan Cohort Study. Two groups of 120 individuals with and without fatty liver were randomly selected based on findings of ultrasound. Non-invasive diagnosis of NAFLD was made by combination of ultrasound and MRI. Various anthropometric indices including body mass index (BMI), waist-to-hip ratio (WHR) and waist-to-height ratio (WHtR) were measured. Segmentation and calculation of visceral (VFA) and subcutaneous fat area (SFA) were performed on three levels of MRI slices using semi-automated software., Results: A total of 109 individuals fulfilled the NAFLD criteria, while 92 subjects were selected as the control group. All obesity measures, except for SFA, were significantly higher in subjects with NAFLD compared to controls. Significant associations were found between NAFLD and adiposity indices, except for SFA, with the highest odds ratio observed in WHR (OR: 3.37, CI: 1.40-3.70, P < 0.001). VFA also had the greatest correlation with ultrasound (r = 0.523, P < 0.001) and MRI (r = 0.546, P < 0.001) indicators of NAFLD., Conclusions: Quantitative measures of visceral adiposity are associated with NAFLD, while subcutaneous fat measures are poor indicators for identifying NAFLD. Compared to conventional anthropometric indices, VFA best correlates with ultrasound and MRI criteria of fatty liver.

Introduction: Currently, Nonalcoholic Fatty Liver Disease (NAFLD) is the most common liver disease in the world. The only approved treatment for it is lifestyle modification and weight loss; however, there is no treatment option for patients with normal or low body mass index (BMI). The aim of this study is to evaluate the efficacy of synbiotics supplementation in NAFLD patients with normal or low BMI., Methods and Analysis: In our randomized, double-blind, placebo-controlled clinical trial protocol, forty-two patients will be assigned to take either a synbiotic or a placebo capsule for 28 weeks. Both groups will undergo the standard treatment., Ethics and Dissemination: The study protocol has been approved by ethics committee of Shahid Beheshti University of Medical Sciences. At the beginning of the study, a written informed consent form will be signed and dated by subjects and investigators. The results will be published in due time.

Background/aim: Existing evidence points to an altered status of iron metabolism in obesity. We aimed to investigate whether central obesity is independently associated with estimated liver iron content (liver T2* value) in general population that used the noninvasive assessment method by MRI., Methods: The study was carried out on 200 subjects randomly selected from the Golestan Cohort Study who underwent abdominal MRI. Quantitative T2* maps of entire cross-sectional area of liver were calculated using a semi-automated software for estimating the levels of iron content. Segmentation and calculation of visceral (VFA) and subcutaneous fat area (SFA) were also performed., Results: There was no significant difference in mean liver T2* values between obese (body mass index, BMI >30 kg/m2) and non-obese (BMI ≤30 kg/m2) subjects. After controlling for other covariates, no statistically significant association was detected between liver T2* values and VFA, SFA and VFA/SFA ratio. The drop in the relative signal intensity as an indicator of steatosis and serum ferritin predicted liver T2* values that almost had the same strength (standardized β of -0.41 and -0.41, respectively)., Conclusions: Central obesity indices are not correlated with estimated liver iron content by MRI. Hepatic steatosis and serum ferritin seem to be the best predictors of hepatic T2* value. Since central obesity indices were not direct predictors of hepatic T2* value after the adjustment for confounding factors, it is possible that lipid accumulation in the liver locally, but not systematically, influences hepatic iron metabolism., (© 2016 S. Karger AG, Basel.)

Background: Cardiovascular disease (CVD) is among the most common causes of mortality in all populations. Nonalcoholic steatohepatitis is a common finding in patients with CVD. Prevention of CVD in individual patients typically requires periodic clinical evaluation, as well as diagnosis and management of risk factors such as hypertension and hyperlipidemia. However, this is resource consuming and hard to implement, especially in developing countries. We designed a study to investigate the effects of a simpler strategy: a fixed-dose combination pill consisting of aspirin, valsartan, atorvastatin and hydrochlorthiazide (PolyPill) in an unselected group of persons aged over 50 years., Design: The PolyIran-Liver study was performed in Gonbad city as an open label pragmatic randomized controlled trial nested within the Golestan Cohort Study. We randomly selected 2,400 cohort study participants aged above 50 years, randomly assigned them to intervention or usual care and invited them to participate in an additional measurement study (if they met the eligibility criteria) to measure liver related outcomes. Those agreeing and randomized to the intervention arm were offered a daily single dose of PolyPill. We will follow participants for 5 years. The primary outcome is major cardiovascular events, secondary outcomes include all-cause mortality and liver related outcomes: liver stiffness and liver enzyme levels. Cardiovascular outcomes and mortality will be determined from the cohort study and liver-related outcomes in those consenting to follow up. Analysis will be by allocated group., Trial Status: Between October and December 2011, 1,320 intervention and 1,080 control participants were invited to participate in the additional measurement study. For all these participants, the major cardiovascular events will be determined using blind assessment of outcomes through the cohort study. In the intervention and control arms, 875 (66%) and 721 (67%) respectively, met the eligibility criteria and agreed to participate in the additional measurement study. Liver related outcomes will be measured in these participants. Of the 1,320 participants randomized to the intervention, 787 (60%) accepted the PolyPill., Conclusion: The PolyIran-liver urban study will provide us with important information on the effectiveness of PolyPill on major cardiovascular events, all-cause mortality and liver related outcomes. (ClinicalTrials.gov ID: NCT01245608).

Rationale and Objectives: Existing evidence suggests potential contribution of iron in pathogenesis of nonalcoholic fatty liver disease (NAFLD). We aimed to investigate whether hepatic iron content correlates with liver enzyme levels in NAFLD using a noninvasive magnetic resonance imaging (MRI) technique., Materials and Methods: Subjects from Golestan Cohort Study were randomly selected. Diagnosis of NAFLD was made by combination of ultrasound and MRI. Subjects with NAFLD were divided into two groups with high (H-NAFLD) and low (L-NAFLD) enzyme level according to 95th percentile of alanine aminotransferase (ALT) value in normal population. Quantitative T2* maps of entire cross-sectional area of liver were calculated on pixel-by-pixel basis using a semiautomated software., Results: A total of 207 subjects were enrolled. Mean T2* values were significantly lower in NAFLD group than controls (P < .001) indicating higher iron content. Male subjects with H-NAFLD had statistically lower T2* values than those with L-NAFLD in multivariate analysis (odds ratio, 0.74; 95% confidence interval [CI], 0.58-0.95), whereas this was not observed in women. Unlike women, there was significant negative correlation between ALT levels and T2* values in men with H-NAFLD (r = -0.66, P = .01). Every 1-millisecond decrement in T2* value was associated with 6.37 IU/L increase in ALT level (95% CI, 1.8-10.9, P = .01) in men with H-NAFLD., Conclusions: Higher hepatic iron in men with H-NAFLD, estimated by T2* mapping, may support the role of iron in possible progression of simple steatosis to nonalcoholic steatohepatitis. Lack of such correlation in women could be attributed to relatively lower iron storage or other mechanisms rather than iron., (Copyright © 2015 AUR. Published by Elsevier Inc. All rights reserved.)