A Mediterranean and low-fat dietary intervention in non-alcoholic fatty liver disease patients: Exploring participant experience and perceptions about dietary change.

BACKGROUND: A Mediterranean diet (MD) appears to be beneficial in non-alcoholic fatty liver disease (NAFLD) patients in Mediterranean countries; however, the acceptability of a MD in non-Mediterranean populations has not been thoroughly explored. The present study aimed to explore the acceptability through understanding the barriers and enablers of the MD and low-fat diet (LFD) interventions as perceived by participating Australian adults from multicultural backgrounds with NAFLD. METHODS: Semi-structured telephone interviews were performed with 23 NAFLD trial participants at the end of a 12-week dietary intervention in a multicentre, parallel, randomised clinical trial. Data were analysed using thematic analysis. RESULTS: Participants reported that they enjoyed taking part in the MD and LFD interventions and perceived that they had positive health benefits from their participation. Compared with the LFD, the MD group placed greater emphasis on enjoyment and intention to maintain dietary changes. Novelty, convenience and the ability to swap food/meals were key enablers for the successful implementation for both of the dietary interventions. Flavour and enjoyment of food, expressed more prominently by MD intervention participants, were fundamental components of the diets with regard to reported adherence and intention to maintain dietary change. CONCLUSIONS: Participants randomised to the MD reported greater acceptability of the diet than those randomised to the LFD, predominantly related to perceived novelty and palatability of the diet.

Impact of a Mediterranean diet on hepatic and metabolic outcomes in non-alcoholic fatty liver disease: The MEDINA randomised controlled trial.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is predominantly managed by lifestyle intervention, in the absence of effective pharmacotherapies. Mediterranean diet (MedDiet) is the recommended diet, albeit with limited evidence. AIMS: To compare an ad libitum MedDiet to low-fat diet (LFD) in patients with NAFLD for reducing intrahepatic lipids (IHL) by proton magnetic resonance spectroscopy (1 H-MRS). Secondary outcomes include insulin resistance by homeostatic model of assessment (HOMA-IR), visceral fat by bioelectrical impedance analysis (BIA), liver stiffness measurement (LSM) and other metabolic outcomes. METHODS: In this parallel multicentre RCT, subjects were randomised (1:1) to MedDiet or LFD for 12 weeks. RESULTS: Forty-two participants (25 females [60%], mean age 52.3 ± 12.6 years) were included, 23 randomised to LFD and 19 to MedDiet.; 39 completed the study. Following 12 weeks, there were no between-group differences. IHL improved significantly within the LFD group (-17% [log scale]; p = .02) but not within the MedDiet group (-8%, p = .069). HOMA-IR reduced in the LFD group (6.5 ± 5.6 to 5.5 ± 5.5, p < .01) but not in the MedDiet group (4.4 ± 3.2 to 3.9 ± 2.3, p = .07). No differences were found for LSM (MedDiet 7.8 ± 4.0 to 7.6 ± 5.2, p = .429; LFD 11.8 ± 14.3 to 10.8 ± 10.2 p = .99). Visceral fat reduced significantly in both groups; LFD (-76% [log scale], p = <.0005), MedDiet (-61%, p = <.0005). CONCLUSIONS: There were no between-group differences for hepatic and metabolic outcomes when comparing MedDiet to LFD. LFD improved IHL and insulin resistance. Significant improvements in visceral fat were seen within both groups. This study highlights provision of dietary interventions in free-living adults with NAFLD is challenging.

A randomised controlled trial of a Mediterranean Dietary Intervention for Adults with Non Alcoholic Fatty Liver Disease (MEDINA): study protocol.

BACKGROUND: Non-alcoholic fatty liver disease, the most prevalent liver disease in developed countries, remains difficult to manage with no proven safe and effective pharmacotherapy available. While weight reduction is the most commonly practiced treatment strategy, this is difficult to both achieve and/or maintain in the majority. Furthermore evidence-based dietary recommendations to guide the nutritional management of these patients are lacking. Using a randomised controlled trial design, this study compares the effectiveness of the Mediterranean diet to a standard low fat diet in terms of differences in insulin sensitivity, hepatic steatosis and metabolic outcomes in participants with non-alcoholic fatty liver disease. METHODS: Ninety four eligible patients who have non-alcoholic fatty liver disease and who are insulin resistant, will be randomised into either a Mediterranean or low fat diet group for a 3 month intervention period. Insulin sensitivity will be measured on peripheral blood using Homeostatic Model Assessment and liver fat content quantified using Magnetic Resonance Spectroscopy. Both arms will consist of three face to face and three telephone call follow up consultations delivered by an Accredited Practicing Dietitian. The intervention arm focuses on recommendations from the traditional Mediterranean diet which have been tailored for use in the Australian population The standard arm uses the Australian Guide to Healthy Eating and the Australian National Heart Foundation dietary guidelines. Study recruitment will take place at four major metropolitan hospitals in Melbourne, Australia. Data collection will occur at all face to face reviews including baseline, 6, and 12 weeks. A follow up assessment to measure sustainability will take place at 6 and 12 months. The primary end point is improved insulin sensitivity scores at the 12 week time point. DISCUSSION: This trial aims to demonstrate in a large cohort of participants with NALFD that a Mediterranean diet independent of weight loss can result in significant benefits in liver fat and insulin sensitivity and that these changes are sustained at 12 months. These metabolic changes would potentially lead to reductions in the risk of chronic liver disease, heart disease, type 2 diabetes and liver cancer. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register ACTRN: ACTRN12615001010583 .

Diet Overall and Hypocaloric Diets Are Associated With Improvements in Depression but Not Anxiety in People With Metabolic Conditions: A Systematic Review and Meta-Analysis.

The risk of depression and anxiety is higher in people with metabolic conditions, but whether dietary approaches, which are central to the management of metabolic conditions, can also improve depression and anxiety is uncertain. The primary aim of this systematic review and meta-analysis was to evaluate the effects of dietary interventions on depression and anxiety in adults with metabolic conditions. The secondary aim was to evaluate the effects of hypocaloric and isocaloric dietary interventions on these outcomes. Four databases (MEDLINE, PsychINFO, EMBASE, and CINAHL) were searched from inception to March 2023. Randomized controlled trials (RCTs) including dietary interventions in adults with metabolic conditions (type 2 diabetes mellitus, hyperlipidemia, hypertension, and/or overweight/obesity) that assessed depression and/or anxiety as outcomes were included. Overall, 13 RCTs were included in the systematic review, ≤13 of which were included in the meta-analysis. Estimates were pooled using random-effect meta-analysis for dietary interventions compared with controls. Improvements in depression scores were found in meta-analytic models including all dietary interventions [pooled estimate for the standardized mean difference (SMD) = -0.20 (95% CI: -0.35, -0.05); P = 0.007] and hypocaloric only diets [SMD = -0.27 (95% CI: -0.44, -0.10); P = 0.002]. There were no improvements in depression scores with isocaloric dietary interventions only [SMD = -0.14 (95% CI: -0.38, 0.10); P = 0.27]. In addition, there were no significant effects of any dietary interventions on anxiety scores. In adults with metabolic conditions, all dietary interventions and hypocaloric diets improved depression, but not anxiety. These findings suggest that dietary interventions including hypocaloric diets can play an important role in the management of depression in people with metabolic conditions. This systematic review and meta-analysis has been registered with PROSPERO (CRD42021252307).

The Mediterranean diet improves hepatic steatosis and insulin sensitivity in individuals with non-alcoholic fatty liver disease.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) affects up to 30% of the population and signifies increased risk of liver fibrosis and cirrhosis, type 2 diabetes, and cardiovascular disease. Therapies are limited. Weight loss is of benefit but is difficult to maintain. We aimed at examining the effect of the Mediterranean diet (MD), a diet high in monounsaturated fatty acids, on steatosis and insulin sensitivity, using gold standard techniques. METHODS: Twelve non-diabetic subjects (6 Females/6 Males) with biopsy-proven NAFLD were recruited for a randomised, cross-over 6-week dietary intervention study. All subjects undertook both the MD and a control diet, a low fat-high carbohydrate diet (LF/HCD), in random order with a 6-week wash-out period in- between. Insulin sensitivity was determined with a 3-h hyperinsulinemic-euglycemic clamp study and hepatic steatosis was assessed with localized magnetic resonance (1)H spectroscopy ((1)H-MRS). RESULTS: At baseline, subjects were abdominally obese with elevated fasting concentrations of glucose, insulin, triglycerides, ALT, and GGT. Insulin sensitivity at baseline was low (M=2.7 ± 1.0 mg/kg/min(-1)). Mean weight loss was not different between the two diets (p=0.22). There was a significant relative reduction in hepatic steatosis after the MD compared with the LF/HCD: 39 ± 4% versus 7 ± 3%, as measured by (1)H-MRS (p=0.012). Insulin sensitivity improved with the MD, whereas after the LF/HCD there was no change (p=0.03 between diets). CONCLUSIONS: Even without weight loss, MD reduces liver steatosis and improves insulin sensitivity in an insulin-resistant population with NAFLD, compared to current dietary advice. This diet should be further investigated in subjects with NAFLD.

A problem of proportions: estimates of metabolic associated fatty liver disease and liver fibrosis in Australian adults in the nationwide 2012 AusDiab Study.

Metabolic Associated Fatty Liver Disease (MAFLD) is the most common cause of liver disease in Australia, but prevalence data are limited. We aimed to describe the frequency of alanine aminotransferase (ALT) elevation, and MAFLD within a large prospective Australian cohort. Cross-sectional analysis of the 2012 survey of the Australian Diabetes, Obesity and Lifestyle (AusDiab) study which included 4747 Australian adults (aged 34-97 yrs) was performed. Frequency of ALT elevation (men ≥ 40 IU/L, women ≥ 30 IU/L) and MAFLD (Fatty Liver Index (FLI) > 60 alongside metabolic risk factors) was determined and risk of advanced fibrosis stratified using the BARD score. Elevated ALT was found in 13% of the cohort, including 22% of people with diabetes, 18% with obesity, and 17% with the metabolic syndrome. 37% of the cohort had MAFLD, and those with MAFLD were more likely to be older (OR 1.01 per 1 year (95% CI 1.00-1.02)), male (OR 1.37 (95% CI 1.17-1.59)), have ALT elevation (OR 3.21 (95% CI 2.59-3.99)), diabetes (OR 3.39 (95% CI 2.61-4.39)), lower HDL-C (OR 0.15 per 1 mmol/L (95% CI 0.12-0.19)), higher diastolic blood pressure (OR 1.05 per 10 mmHg (95% CI 1.05-1.06)), a sedentary lifestyle (OR 1.99 (95% CI 1.59-2.50)) and less likely to have tertiary education (OR 0.81 (95% CI 0.7-0.94) compared to those without MAFLD. Of those with MAFLD, 61% had a BARD score suggesting risk of advanced fibrosis and 22% had an elevated ALT. Over 10% of this Australian cohort had elevated ALT, and 37% had MAFLD, with many at risk for advanced fibrosis.

The novel role of C-reactive protein in cardiovascular disease: risk marker or pathogen.

C-reactive protein (CRP) is a non-specific biomarker of inflammation. Recent research has shown that inflammation is an important step in the genesis of atherosclerosis, and is involved in the development of unstable plaques. Measurement of serum levels of CRP using a high sensitivity assay (hsCRP) can demonstrate subclinical inflammatory states, which may reflect vascular inflammation. Clinical studies have shown that elevated hsCRP levels in healthy populations predict vascular events such as myocardial infarction (MI) and stroke as well as the development of diabetes. In patients with acute coronary syndromes, higher hsCRP levels are associated with adverse outcomes and subsequent vascular events. There is data to suggest that aspirin, angiotensin converting enzyme (ACE) inhibitors and HMG Co-A reductase inhibitors (statins), which all reduce vascular event rates, also reduce serum levels of hsCRP and therefore hsCRP levels may potentially guide therapy. As well as having a critical role in risk prediction, recent evidence has emerged implicating CRP directly in atherogenesis. CRP has been found in human atherosclerotic plaque and CRP has been shown to cause endothelial cell dysfunction, oxidant stress and intimal hypertrophy in experimental models. We review the postulated roles of CRP in atherogenesis and prediction of vascular events, as well as discussing current recommendations for CRP testing in patients.

High incidence of insulin resistance and dysglycemia amongst nondiabetic cardiac surgical patients.

BACKGROUND: Undiagnosed glycometabolic dysfunction is prominent amongst nondiabetic cardiac surgical patients, whereas perioperative dysglycemia is associated with adverse outcomes. This study assessed whether the preoperative level of insulin resistance predicts the degree of perioperative dysglycemia in nondiabetic, normoglycemic cardiac surgical patients. METHODS: Twenty-two nondiabetic patients awaiting cardiac operations were assessed for metabolic parameters and whole-body insulin resistance (mean glucose infusion [GINF] rate) using the hyperinsulinemic-euglycemic clamp. Intraoperative and postoperative glucose levels and treatment requirements were analyzed. Linear regression analysis was used to find predictors of baseline, peak intraoperative, and mean postoperative fasting blood glucose (FBG). RESULTS: The mean GINF recorded in nondiabetic, normoglycemic patients was 3.5 ± 1.4 mg/kg/min. The mean peak intraoperative and mean postoperative FBG concentrations were 154.9 ± 34.2 mg/dL (range, 108.1 to 227.0 mg/dL) and 120.7 ± 16.2 mg/dL (range, 100.9 to 154.9 mg/dL), respectively. The GINF correlated inversely with mean peak intraoperative (r = -0.7, p = 0.02) and mean postoperative FBG (r = -0.8, p = 0.01). The GINF did not correlate with preoperative FBG levels (r = 0.3, p = 0.4). Preoperative FBG did not correlate with peak intraoperative (r = 0.4, p = 0.5) or mean postoperative FBG (r = 0.5, p = 0.3). CONCLUSIONS: Nondiabetic, normoglycemic cardiac surgical patients are highly insulin resistant using the hyperinsulinemic-euglycemic clamp. Preoperative insulin resistance, not FBG, is significantly associated with the development of perioperative dysglycemia. Insulin resistance screening may be useful to identify insulin resistance preoperatively and predict the degree of perioperative dysglycemia in cardiac surgical patients but should be performed with a more appropriate and reproducible test.

No increase in the expression of key unfolded protein response genes in HCV genotype 3 patients with severe steatosis.

Although hepatic steatosis is common in patients infected with HCV, the mechanisms leading to cellular triglyceride retention are obscure. A role for the Unfolded Protein Response (UPR) has been postulated, either through its activation or dysfunction. In this study we set out to investigate the expression of key UPR genes in HCV genotype 3 patients with moderate to severe steatosis. RNA was extracted from liver obtained by percutaneous biopsy and key genes from the UPR were semi quantified using real-time PCR. We compared values in patients with minimal steatosis to those with high steatosis. Patients with high steatosis were younger (44.6 ± 2.4 vs. 37.4 ± 2.1, p<0.05) and had higher hepatic viral RNA loads (1.00 ± 0.21 vs. 3.98 ± 0.22, p<0.05). We found no significant difference in the expression of UPR genes, except for a small increase in EDEM1 in the high steatosis group (1.00 ± 0.13 vs. 1.38 ± 0.09, p<0.05). In conclusion, despite a four-fold greater concentration of HCV RNA in tissue with a high level of steatosis, we found no change in the expression of key UPR related genes, except for a only a modest up-regulation of EDEM1. Our data does not support a sustained change in expression of UPR genes in the steatogenesis of HCVGT3 infected human liver.

The severity of nonalcoholic fatty liver disease is associated with increased cardiovascular risk in a large cohort of non-obese Asian subjects.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) has been linked to cardiovascular disease (CVD) but it is largely unknown if such a relationship between NAFLD and CVD risk relates to severity of liver disease or if it is independent. We aimed to study the severity of NAFLD in a well characterized non-obese population and to compare this to prevalence of CVD risk factors and Framingham risk score. METHODS: This study included 30,172 subjects. Based on the presence or absence of steatosis on ultrasound and serum alanine aminotransferase (ALT), subjects were divided into controls, an increased serum ALT group without steatosis and a group with presumed nonalcoholic fatty liver disease (NAFLD), which included a steatosis alone group and a group with presumed nonalcoholic steatohepatitis (NASH) with steatosis and an elevated ALT. RESULTS: The odds ratio for 10-year risk by total Framingham risk scores > or =10% was 5.3 times higher in NASH groups. The prevalence of diabetes, hypertension, elevated CRP and metabolic syndrome were all increased up to 15-fold over controls, independent of age, BMI, smoking and exercise habits. Overall CVD risk was significantly greater in NASH than in either steatosis or raised ALT alone. CONCLUSION: Young, non-obese subjects with NAFLD are at significantly increased CVD risk, especially those with NASH. As well as specific therapy for liver disease, a diagnosis of NAFLD should lead to targeted risk assessment and risk factor modification.

Relationships between estimates of adiposity, insulin resistance, and nonalcoholic fatty liver disease in a large group of nondiabetic Korean adults.

OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD) is emerging as a major health problem in parallel with an increasing prevalence of obesity. Insulin resistance and abdominal and overall adiposity are closely associated with NAFLD; however, the interplay between them in the relationship with NAFLD is unclear, especially in nondiabetic individuals. RESEARCH DESIGN AND METHODS: Abdominal ultrasound, hepatitis serology, and measurements of fasting plasma insulin (FPI), lipid concentrations, overall obesity (BMI), and abdominal obesity (waist circumference) were performed in 56,249 Korean subjects. RESULTS: After rigorous exclusion criteria, 36,654 nondiabetic subjects (54% male) were enrolled. Subjects were divided into control (no fatty liver on ultrasound, serum alanine aminotransferase [ALT] <30 units/l [men] or <19 units/l [women]), fatty liver with normal ALT (FL-NALT), and fatty liver with a high ALT (FL-HALT) groups. After adjusting for age, BMI, and waist circumference, FPI and ratio of triglycerides to HDL cholesterol (TG/HDL-C ratio) were significantly higher in the FL-NALT than in the control group and even higher in the FL-HALT group. Odds ratios for the presence of FL-HALT with increasing quartiles of FPI and TG/HDL-C ratio were increased five- to sevenfold over those of the control group, independent of age, BMI, and waist circumference. CONCLUSIONS: In this large population of individuals of Korean ancestry, results indicate that while overall (BMI) and abdominal (waist circumference) overweight/obesity are associated with features of NAFLD, surrogate estimates of insulin resistance, FPI concentration, and TG/HDL-C ratio predict NAFLD independently of age, BMI, and waist circumference.