Non-alcoholic fatty liver disease and diabetes: From physiopathological interplay to diagnosis and treatment

Non-alcoholic fatty liver disease (NAFLD) is highly prevalent in patients with diabetes mellitus and increasing evidence suggests that patients with type 2 diabetes are at a particularly high risk for developing the progressive forms of NAFLD, non-alcoholic steatohepatitis and associated advanced liver fibrosis. Moreover, diabetes is an independent risk factor for NAFLD progression, and for hepatocellular carcinoma development and liver-related mortality in prospective studies. Notwithstanding, patients with NAFLD have an elevated prevalence of prediabetes. Recent studies have shown that NAFLD presence predicts the development of type 2 diabetes. Diabetes and NAFLD have mutual pathogenetic mechanisms and it is possible that genetic and environmental factors interact with metabolic derangements to accelerate NAFLD progression in diabetic patients. The diagnosis of the more advanced stages of NAFLD in diabetic patients shares the same challenges as in non-diabetic patients and it includes imaging and serological methods, although histopathological evaluation is still considered the gold standard diagnostic method. An effective established treatment is not yet available for patients with steatohepatitis and fibrosis and randomized clinical trials including only diabetic patients are lacking. We sought to outline the published data including epidemiology, pathogenesis, diagnosis and treatment of NAFLD in diabetic patients, in order to better understand the interplay between these two prevalent diseases and identify the gaps that still need to be fulfilled in the management of NAFLD in patients with diabetes mellitus.     

Association between impaired glucose metabolism and quality of life: results from the Australian diabetes obesity and lifestyle study

AIMS: We examined the association of quality of life with glucose tolerance status in an Australian population to determine the stage in the development of diabetes that quality of life is impaired. METHODS: The Australian Diabetes, Obesity and Lifestyle study (AusDiab) was a population-based study of 11,247 people from randomly selected areas of Australia. As part of the study, participants underwent an oral glucose tolerance test and completed the SF-36 quality of life questionnaire. RESULTS: Previously diagnosed diabetes was associated with a significantly greater risk of being in the lowest quartile of each dimension of the SF-36 scale (except for mental health) and this association was only partially attenuated by adjustment for age, sex, body mass index (BMI), physical activity and treatment for hypertension and lipid abnormalities (adjusted odds ratios [95% CI]: bodily pain, 1.51 [1.18-1.94]; general health, 2.20 [1.64-2.95]; physical functioning, 1.50 [1.10-2.05]; role limitation (emotional), 1.43 [1.07-1.91]; role limitation (physical), 1.57 [1.13-2.18]; social functioning, 1.93 [1.46-2.54] and vitality, 2.24 [1.56-3.22]. Among those with newly diagnosed diabetes (NDM) and impaired glucose tolerance (IGT), there was also evidence of reduced quality of life on some dimensions of the SF-36 scale (NDM, general health, physical functioning and role limitation (physical); IGT, physical functioning and social functioning) after adjustment for confounders. CONCLUSION: These findings show that diabetes is associated with a reduced quality of life and that this is evident in the early stage of the disease, particularly in relation to the ability to perform physical activities.     

Non-alcoholic fatty liver disease in Malaysia: a demographic, anthropometric, metabolic and histological study

BACKGROUND AND OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is increasing rapidly in the Asia–Pacific region. There has been a paucity of studies from the region. The aims of this study were to define the demographic, anthropometric, metabolic and histological characteristics of patients with NAFLD in our local population and to determine independent predictors of severe liver fibrosis. METHODS: Patients with persistently raised liver enzymes and/or fatty liver detected on ultrasonography with exclusion of other liver disorders were prospectively recruited. Their insulin resistance was assessed using the homeostasis model assessment of insulin resistance score. A liver biopsy was performed in all cases for grading (for steatohepatitis) and staging (for fibrosis) of NAFLD. Independent risk factors for fibrosis were determined using multiple logistic regression analysis. RESULTS: Seventy‐five patients were recruited: 39 men (52%) and 36 women (48%). The mean age of the patients was 47.0 ± 12.2 years. Of these, 58 patients (77.3%) were centrally obese, 29 patients (38.7%) were diabetic and 15 patients (20.0%) had impaired glucose tolerance. Insulin resistance was diagnosed in 62 out of 64 (96.9%) patients. Benign steatosis, nonalcoholic steatohepatitis and cirrhosis were diagnosed in three (4.3%), 59 (84.3%) and eight (11.4%) of 70 patients, respectively. Significant independent predictors of liver fibrosis were; male sex (P = 0.019, OR = 5.55, CI = 1.33–23.18) and Indian race (P = 0.013, OR = 8.21, CI = 1.56–43.16). CONCLUSIONS: The full histological spectrum of NAFLD was seen in our patients. The majority of patients were insulin resistant, centrally obese and either diabetic or had impaired glucose tolerance. The predictors of severe liver fibrosis were male sex and Indian race.     

Non-alcoholic fatty liver disease: a multicentre clinical study by the Italian Association for the Study of the Liver

AIM: To define the characteristics of the Italian patient presenting non-alcoholic fatty liver disease. PATIENTS AND METHODS: A total of 305 patients with abnormally high plasma aminotransferase and/or gamma-glutamyl-transpeptidase levels for at least 12 months, with no known cause of chronic liver damage, were consecutively enrolled in the study. Clinical, routine biochemical and liver histology investigations were carried out in all patients. Also evaluated were: (a) oral glucose load; (b) insulinaemia and insulin-resistance using the HOMA test model; and (c) plasma endotoxaemia, total antioxidant plasma capability, tumour necrosis factor-alpha, plasma interleukin-6 and -10 levels. Malondialdehyde and 4-hydroxynonenal content were determined on liver samples from 120 patients. RESULTS: The majority of patients were young overweight or obese males, with dyslipidaemia (20-60%), diabetes (10.5%), hyperinsulinaemia (40%), hyperferritinaemia (35%). Endotoxaemia was negative in all patients and cytokines were only sporadically altered. Total antioxidant plasma capability was decreased in 38.4% of the patients. Eighty percent of the cases had histological steatosis with a mild degree of inflammation and fibrosis. Seven patients had cirrhosis. Lipid peroxidation markers were increased in 90% of the cases, inversely correlated with fibrosis. Even if at univariate analysis, age, ferritin and tissue 4-hydroxynonenal were independent factors of steatosis (P < 0.01), and insulin, HOMA and ferritin of inflammation and fibrosis (P < 0.01), at multivariate analysis no single factor was found to be an independent predictor of hepatic lesions. CONCLUSIONS: The typical Italian patient with non-alcoholic fatty liver disease is a young male, obese, not diabetic, with a variable incidence of dyslipidaemia and hyperinsulinaemia. Only liver biopsy may define the type of liver damage.     

Risk of cardiovascular disease in patients with fatty liver disease as defined from the metabolic dysfunction associated fatty liver disease or nonalcoholic fatty liver disease point of view: a retrospective nationwide claims database study in Japan

Background

Nonalcoholic fatty liver disease (NAFLD) and metabolic dysfunction associated fatty liver disease (MAFLD) have important associations with cardiovascular disease (CVD). The main objective of this study was to compare the frequency of incidence rate of CVD in the NAFLD or MAFLD patients utilizing a large claims database.

Methods

Using the JMDC database from April 2013 to March 2019, we retrospectively analyzed data for 1,542,688 and 2,452,949 people to estimate the relationship between CVD and NAFLD, MAFLD, respectively.

Results

The incidence rates of CVD were 0.97 (95% CI 0.94–1.01) and 2.82 (95% CI 2.64–3.01) per 1000 person-years in the non-NAFLD and NAFLD groups, respectively, and 1.01 (95% CI 0.98–1.03) and 2.69 (95% CI 2.55–2.83) per 1000 person-years in the non-MAFLD and MAFLD groups, respectively. The overall prevalence of hypertriglyceridemia and diabetes mellitus (DM) was 13.1, and 4.2%, respectively, in the non-NAFLD group and 63.6, and 20.2%, respectively, in the NAFLD group. The overall prevalenceof hypertriglyceridemia and DM was 13.6 and 4.3%, respectively, in the non-MAFLD group and 64.1, and 20.6%, respectively, in the MAFLD group. HRs for CVD increased with hypertriglyceridemia and DM.

Conclusions

Results indicated that incident rate of CVD increased with NAFLD/MAFLD; the complication rate of DM and hypertriglyceridemia among NAFLD/MAFLD patients is high and may affect the development of CVD.

     

Limited impact of lifestyle education in patients with Type 2 diabetes mellitus and microalbuminuria: results from a randomized intervention study.

AIMS: To assess the effect of intensified education on lifestyle (diet, exercise and smoking) as part of an intensified multifactorial intervention over a 4-year period in patients with Type 2 diabetes mellitus with microalbuminuria. METHODS: Patients, aged 45-65 years, were randomly assigned either to an intensive group focusing on change of behaviour as well as polypharmacological treatment (n = 80) or to a control group receiving conventional treatment (n = 80). Diet intervention focused on dietary fat and carbohydrate. Food intake was estimated by dietary history interviews and nutrients were calculated from food tables. Exercise and smoking habits were evaluated by interviews. RESULTS: Mean follow-up was 3.8 (SD 0.3) years. The decrease in total fat intake (% of energy intake) was larger in the intensive group as compared to the control group (41.2 (6.2) to 34.2 (6.0) vs. 41.9 (6.5) to 38.3 (6.4)%, P = 0,0001). The decrease in saturated fatty acids (% of total fat intake) was from 47 (4) to 44 (6)% with intensive therapy vs. 45 (5) to 46 (5)%, P = 0.001 and the increase in polyunsaturated fatty acids was from 14 (4) to 18 (6) vs. 16 (5) to 14 (4)%, P < 0.0001. Also the increase in carbohydrate was larger with intensive therapy. However, changes in exercise and smoking habits did not differ between groups. CONCLUSION: Despite the many resources invested in behaviour modification in this study, only modest changes were obtained in nutrient intake. Further studies are required to determine the best method of inducing long-lasting changes in behaviour in Type 2 diabetic patients.     

Alanine aminotransferase as a marker of non-alcoholic fatty liver disease in relation to type 2 diabetes mellitus and cardiovascular disease

For a long time, hepatic steatosis was believed to be a benign condition. Only recently, liver steatosis, also termed non-alcoholic fatty liver disease (NAFLD), has gained much interest. In most cases of NAFLD, a condition regarded as the hepatic component of the metabolic syndrome, the enzyme alanine aminotransferase (ALT) is elevated and consequently has been used as a marker for NAFLD. More recently, several cross-sectional and prospective studies have demonstrated associations of this liver enzyme with features of the metabolic syndrome and type 2 diabetes mellitus. This review discusses the biochemical and metabolic properties of ALT, its applicability as a marker of NAFLD and describes its possible role in the pathogenesis of the metabolic syndrome and type 2 diabetes mellitus and subsequent cardiovascular disease. In addition, treatment strategies to ameliorate NAFLD and the associated risks are discussed.     

Modelling the long-term epidemiological and cost impact of a multicomponent lifestyle intervention and a sugar-sweetened beverage tax in the European Union: results from the EConDA project

BackgroundInformation on the efficacy and costs associated with targeting obesity can inform implementation of cost-effective policies. Within the Economics of Chronic Diseases (EConDA) project, we aimed to quantify the health and economic impact of two approaches to reduce chronic disease in eight European countries through to 2050: a multicomponent lifestyle intervention (MCLI) and a sugar-sweetened beverage tax.MethodsBody-mass index (BMI), disease epidemiology, and cost data for the diseases modelled (type 2 diabetes, coronary heart disease, stroke, and hypertension) were obtained from the literature for Bulgaria, Finland, Greece, Lithuania, the Netherlands, Poland, Portugal, and the UK. When country-specific data were not available, other countries were used as a proxy after adjustment for between-country differences. Mean change in BMI after annual MCLI to reduce energy intake and improve physical activity through behaviour change was obtained from the literature and was estimated after a 20% excise tax on sugar-sweetened beverages. A microsimulation model created country-representative synthetic populations. We determined simulated health outcomes in a baseline scenario using projections of BMI trends for each country up to 2050 and in two scenarios applying the interventions' respective BMI reduction to the BMI trends in the population. Simulated individuals developed diseases on the basis of their BMI and outputs provided the incidence and costs associated with the different scenarios.FindingsThe prevalence of obesity and incidence of BMI-related disease was forecast to increase in all countries to 2050. MCLI had the largest effect on type 2 diabetes, ranging from 147 cases per 100 000 avoided (SD 17) in Bulgaria to 1003 (21) in Portugal by 2050. The highest costs avoided were for stroke (up to €1·15 million, SD €0·008 million) in Portugal. Although tax on sugar-sweetened beverages also had the largest effect on diabetes (from 5 per 100 000 cases avoided [SD 8] in the Netherlands to 87 [13] in the UK), the costs avoided were lower than for MCLI.InterpretationThese results highlight the variation in impact depending on the type of intervention aimed at the prevention of chronic diseases. An integrated approach to reducing obesity is required, so that a battery of approaches, varying in uptake and targeted population group, could be useful to obtain a greater effect on BMI reduction.FundingEuropean Commission Health Programme and the Executive Agency for Health and Consumers (project number 2012 12 13).     

Nonalcoholic fatty liver disease as a sentinel marker for the development of diabetes mellitus in non-obese subjects

BackgroundNon alcoholic fatty liver disease (NAFLD) is associated with substantial cardiometabolic morbidity.AimsWe evaluated the long-term extrahepatic complications of NAFLD and sought to evaluate NAFLD in non-obese subjects.MethodsA total of 2920 participants were retrospectively selected from a health check-up center in 2000, and followed through to December 2010. NAFLD was diagnosed using ultrasonography. Subjects were stratified according to body mass index, NAFLD, and metabolic syndrome.ResultsThe prevalence of non-obese NAFLD subjects and metabolically unhealthy non-obese subjects was 14.4% and 8.7%, respectively. In the multivariate analysis, non-obese NAFLD subjects had a significantly higher risk for diabetes mellitus (DM; HR 2.69, 95% CI 1.72–4.20, P < 0.001); no increase was observed for hypertension or cardiovascular disease. Metabolically unhealthy non-obese subjects had a significantly higher risk for hypertension (HR 2.75, 95% CI 2.02–3.74, P < 0.001), DM (HR 5.72, 95% CI 3.68–8.89, P < 0.001), and cardiovascular disease (HR 2.93, 95% CI 1.53–5.63, P = 0.001). Subgroup analysis of non-obese subjects showed that NAFLD, without metabolic syndrome, conferred a higher risk for DM (HR 3.60, 95% CI 2.03–6.39, P < 0.001).ConclusionNon-obese subjects with NAFLD are at a higher risk for DM independent of metabolic syndrome.     

Sustaining short-term improvements over the long-term: results from a 2-year diabetes self-management support (DSMS) intervention

Aim

This study examined the long-term impact of a 24-month, empowerment-based diabetes self-management support (DSMS) intervention on sustaining health-gains achieved from previous diabetes self-management education (DSME).

Methods

Prior to the intervention, all participants received 6 months of mailed DSME consisting of weekly educational newsletters coupled with clinical feedback. The intervention consisted of 88 weekly group-based sessions that participants were encouraged to attend as frequently as they needed. Sessions were guided by participants’ self-management questions and also emphasized experiential learning, coping, goal-setting, and problem-solving. Baseline, 6-month, and 30-month assessments measured A1C, weight, body mass index (BMI), blood pressure, lipids, self-care behaviors, and QOL.

Results

This report is based on 60 African-American adults with type 2 diabetes (n = 89 recruited at baseline) who completed the study. Post 6-month DSME, participants demonstrated significant improvements for diastolic BP (p < 0.05), serum cholesterol (p < 0.001), healthy diet (p < 0.01), blood glucose monitoring (p < 0.05) and foot exams (p < 0.01). Post 24-month intervention, participants sustained the improvements achieved from the 6-month DSME and reported additional improvements for healthy diet (p < 0.05), carbohydrate spacing (p < 0.01), insulin use (p < 0.05), and quality of life (p < 0.05).

Conclusions

Findings suggest that an empowerment-based DSMS model can sustain or improve diabetes-related health gains achieved from previous short-term DSME.     

Readiness for diabetes prevention and barriers to lifestyle change in women with a history of gestational diabetes mellitus: Rationale and study design

Aims

Women with gestational diabetes mellitus (GDM) have a high risk of future diabetes, which can be prevented with lifestyle modification. Prior diabetes prevention programmes in this population have been limited by lack of adherence. The aim of this study is to evaluate readiness for behaviour change at different time points after GDM diagnosis and identify barriers and facilitators, to inform a lifestyle modification programme specifically designed for this group. The objective of this paper is to present the rationale and methodological design of this study.

Methods

The ongoing prospective cohort study has recruited a multi-ethnic cohort of 1353 women with GDM from 7 Ontario, Canada hospitals during their pregnancy. A questionnaire was developed to evaluate stage of readiness for behaviour change, and sociodemographic, psychosocial, and clinical predictors of healthy diet and physical activity. Thus far, 960 women (71%) have completed a baseline survey prior to delivery. Prospective postpartum follow-up is ongoing. We are surveying women at 2 time-points after delivery: 3–12 months postpartum, and 13–24 months postpartum. Survey data will be linked to health care administrative databases for long-term follow-up for diabetes. Qualitative interviews were conducted in a subset of women to gain a deeper understanding of barriers and facilitators to lifestyle change.

Conclusions

Our study is a fundamental first step in effectively addressing diabetes prevention in women with GDM. Our findings will aid in the design of a diabetes prevention intervention specifically targeted to women with recent GDM, which can then be evaluated in a clinical trial.     

Ethnic differences in response to lifestyle intervention for the prevention of type 2 diabetes in adults: A systematic review and meta-analysis

The risk of type 2 diabetes mellitus (T2DM) varies by ethnicity, but ethnic differences in response to diabetes prevention interventions remain unclear. This systematic review and meta-analysis assessed ethnic differences in the effects of lifestyle interventions on T2DM incidence, glycemic outcomes (fasting glucose, 2-h glucose, HbA_1c), anthropometric measures (weight, BMI, waist circumference), and lifestyle behaviors (physical activity, energy intake, energy from fat, fiber intake). MEDLINE, EMBASE, and other databases were searched (to June 15, 2020) for randomized and non-randomized controlled trials on lifestyle interventions (diet and/or physical activity) in adults at risk of T2DM. Ethnicity was categorized into European, South Asian, East and Southeast Asian, Middle Eastern, Latin American, and African groups. Forty-four studies were included in meta-analyses. Overall, lifestyle interventions resulted in significant improvement in T2DM incidence, glycemic outcomes, anthropometric measures, physical activity, and energy intake (all P < 0.01). Significant subgroup differences by ethnicity were found for 2-h glucose, weight, BMI, and waist circumference (all P < 0.05) but not for T2DM incidence, fasting glucose, HbA_1c, and physical activity (all P > 0.05). Few studies in non-European groups reported dietary intake. Lifestyle interventions in different ethnic groups may have similar effects in reducing incidence of T2DM although this needs to be confirmed in further studies.     

Nonalcoholic fatty liver and metabolic syndrome in Italy: results from a multicentric study of the Italian Arteriosclerosis society

Nonalcoholic fatty liver disease (NAFLD) is associated with all the components of metabolic syndrome (MS) and might to be considered an additional component of MS itself. The Italian Society for the Study of Atherosclerosis (SISA) in 2005 started a research project aimed to study the NAFLD, using ultrasound (US), in nondiabetic MS subjects matching at least one of the ATP III criteria for HDL-C or triglycerides [TG]. Prevalence of US-NAFLD and its associated risk factors and prevalence of hypertransaminasemia and its possible determinants were evaluated. NAFLD prevalence was 0.78. Men with steatosis compared to men without steatosis were younger (P < 0.05) with higher TG (P < 0.03), homeostasis model assessment insulin resistance (HOMA-R) (P < 0.003), and visceral fat thickness (VFT) (P < 0.0001). Women with steatosis showed higher TG (P < 0.05), HOMA-R (P < 0.04), VFT (P < 0.0001), and lower age (P < 0.05). At multivariate analyses, VFT (P < 0.0001), HOMA-R (P < 0.02), and TG/HDL (P < 0.05) were associated with severity of NAFLD. Age (P < 0.05), LogTG (P < 0.005), and VFT (P < 0.01) were associated with higher ALT. The US prevalence of steatosis in this study (0.78) is the highest reported in patients with MS. Considering the exclusion of severe obese and diabetic patients and the recruitment criteria, this finding highlights the prominent role played by the alterations of lipid metabolism in the pathogenesis of NAFLD.     

Alendronate and estrogen-progestin in the long-term prevention of bone loss: four-year results from the early postmenopausal intervention cohort study. A randomized, controlled trial

BACKGROUND: Up to 3 years of treatment with alendronate, 5 mg/d, prevents postmenopausal bone loss. OBJECTIVE: To determine whether the effect of alendronate is sustained at 4 years of treatment and persists after treatment is discontinued. DESIGN: Randomized, controlled trial. SETTING: United States and Europe. PARTICIPANTS: 1609 postmenopausal women 45 to 59 years of age. INTERVENTION: Participants were randomly assigned to receive oral alendronate, 5 mg/d or 2.5 mg/d; placebo; or open-label estrogen-progestin. Women in the alendronate groups received alendronate for the first 2 years of the study. Treatment was then continued without change or replaced with placebo for the last 2 years of the study. MEASUREMENTS: Annual measurement of bone mineral density. RESULTS: By year 4, the bone mineral density of participants in the placebo group had decreased by 1% to 6% (P < 0.001). Four years of treatment with 5 mg of alendronate per day increased bone mineral density at the spine (mean change [+/-SE], 3.8%+/-0.3%), hip (mean, 2.9%+/-0.2%), and total body (mean, 0.9%+/-0.2%) (P < 0.001 overall). By year 4, bone mineral density at most skeletal sites was greater in participants who switched from alendronate to placebo than in those who continuously received placebo. In years 3 and 4, bone loss in participants who switched from alendronate to placebo was similar to that seen during years 1 and 2 in those who continuously received placebo. Compared with 5 mg of alendronate per day, estrogen-medroxyprogesterone acetate produced similar increases in bone mineral density and estradiol-norethisterone acetate produced increases that were substantially greater. CONCLUSIONS: Four years of treatment with alendronate or estrogen-progestin prevented postmenopausal bone loss. A residual effect was seen 2 years after alendronate therapy was stopped; however, continuous alendronate treatment was more effective in preventing postmenopausal bone loss than 2 years of alendronate followed by 2 years of placebo.