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Diabetes and obesity are associated with nonalcoholic fatty liver disease (NAFLD) and an increased incidence of hepatocellular carcinoma (HCC). NAFLD is the commonest cause of chronic liver disease. HCC can develop in NAFLD patients even without cirrhosis, suggesting an association between the metabolic process and HCC and raising a concern that many cancers could be missed given high NAFLD prevalence and screening limitations. The increasing prevalence of these conditions and lack of effective treatments necessitate a better understanding of their connection. This article defines the known interrelationships and common pathways between NAFLD, diabetes, obesity and HCC and possible chemoprevention strategies., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background & Aims: ABCB11 is a canalicular transport protein that controls the rate-limiting step in hepatic bile acid secretion. Its expression levels vary in humans, and it is not clear how these variations affect lipid metabolism. We investigated whether overexpression of Abcb11 in mice increases lipid absorption in the intestine and affects the development of obesity or hypercholesterolemia., Methods: Transgenic mice that overexpress Abcb11 in liver (TTR-Abcb11) and FVB/NJ mice (controls) were fed a high-cholesterol or high-fat diet for 12 weeks. Intestinal lipid absorption was measured by the dual fecal isotope method. Energy expenditure was measured by indirect calorimetry. The bile acid pool was analyzed by high-performance liquid chromatography., Results: TTR-Abcb11 mice had a nearly 2-fold increase in intestinal cholesterol absorption compared with controls. TTR-Abcb11 mice fed a high-cholesterol diet had greater increases in plasma and hepatic levels of cholesterol and became more obese than controls; they also had increased intestinal absorption of fatty acids and decreased energy expenditure. In the TTR-Abcb11 mice, the sizes of plasma and total bile acid pools were reduced; the bile acid pool contained more species of hydrophobic bile acids compared with controls., Conclusions: Hepatic overexpression of Abcb11 in mice promotes diet-induced obesity and hypercholesterolemia; increased intestinal cholesterol absorption by hydrophobic bile acids might cause these features. Increased absorption of fatty acids in the intestine and reduced expenditure of energy could increase weight gain in TTR-Abcb11 mice. In humans, variations in expression of ABCB11 might confer genetic susceptibility to diet-induced hyperlipidemia and obesity., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & aimsInsulin resistance is a risk marker for non-alcoholic fatty liver disease, and a risk factor for liver disease progression. We assessed temporal trajectories of insulin resistance and β-cell response to serum glucose concentration throughout adulthood and their association with diabetes risk in non-alcoholic fatty liver disease.MethodsThree thousand and sixty participants from Coronary Artery Risk Development in Young Adults, a prospective bi-racial cohort of adults age 18-30 years at baseline (1985-1986; Y0) who completed up to 5 exams over 25 years and had fasting insulin and glucose measurement were included. At Y25 (2010-2011), non-alcoholic fatty liver disease was assessed by noncontrast computed tomography after exclusion of other liver fat causes. Latent mixture modelling identified 25-year trajectories in homeostatic model assessment insulin resistance and β-cell response homeostatic model assessment-β.ResultsThree distinct trajectories were identified, separately, for homeostatic model assessment insulin resistance (low-stable [47%]; moderate-increasing [42%]; and high-increasing [12%]) and homeostatic model assessment-β (low-decreasing [16%]; moderate-decreasing [63%]; and high-decreasing [21%]). Y25 non-alcoholic fatty liver disease prevalence was 24.5%. Among non-alcoholic fatty liver disease, high-increasing homeostatic model assessment insulin resistance (referent: low-stable) was associated with greater prevalent (OR 95% CI = 8.0, 2.0-31.9) and incident (OR = 10.5, 2.6-32.8) diabetes after multivariable adjustment including Y0 or Y25 homeostatic model assessment insulin resistance. In contrast, non-alcoholic fatty liver disease participants with low-decreasing homeostatic model assessment-β (referent: high-decreasing) had the highest odds of prevalent (OR = 14.1, 3.9-50.9) and incident (OR = 10.3, 2.7-39.3) diabetes.ConclusionTrajectories of insulin resistance and β-cell response during young and middle adulthood are robustly associated with diabetes risk in non-alcoholic fatty liver disease. Thus, how persons with non-alcoholic fatty liver disease develop resistance to insulin provides important information about risk of diabetes in midlife above and beyond degree of insulin resistance at the time of non-alcoholic fatty liver disease assessment.

Nonalcoholic fatty liver disease (NAFLD) and its progressive form non-alcoholic steatohepatitis (NASH), are rapidly becoming among the top causes of cirrhosis, hepatocellular carcinoma, and indications for liver transplantation. Other than lifestyle modification through diet and exercise, there are currently no other approved treatments for NASH/NAFLD. Although weight loss can be effective, it is difficult to achieve and sustain. In contrast, bariatric surgery can improve metabolic conditions associated with NAFLD, and has been shown to improve liver histology. To have approved regimens for the treatment of NASH/NAFLD, several issues must be addressed. First, all stakeholders must agree on the most appropriate clinical trial endpoints for NASH. Currently, resolution of NASH (without worsening fibrosis) or reduction of fibrosis stage (without worsening NASH) are the accepted endpoints by the regulatory authorities. It is important to recognize the prognostic implication of histologic features of NASH. In this context, although histologic NASH has been associated with advanced fibrosis, it is not an independent predictor of long-term mortality. In contrast, there are significant data to suggest that fibrosis stage is the only robust and independent predictor of liver-related mortality. In addition to the primary endpoints, several important secondary endpoints, including noninvasive biomarkers, long-term outcomes, and patient-reported outcomes must be considered. In 2018, a few phase 3 clinical trials for the treatment of NASH have been initiated. Additionally, a number of phase 2a and 2b clinical trials targeting different pathogenic pathways in NASH are in the pipeline of emerging therapies.ConclusionOver the next 5 years, some of these regimens are expected to provide potential new treatment options for patients with NASH/NAFLD. (Hepatology 2018;68:361-371).

Background & aimsNon-alcoholic fatty liver disease is an epidemic. Identifying modifiable risk factors for non-alcoholic fatty liver disease development is essential to design effective prevention programmes. We tested whether 25-year patterns of body mass index change are associated with midlife non-alcoholic fatty liver disease.MethodsIn all, 4423 participants from Coronary Artery Risk Development in Young Adults, a prospective population-based biracial cohort (age 18-30), underwent body mass index measurement at baseline (1985-1986) and 3 or more times over 25 years. At Year 25, 3115 had liver fat assessed by non-contrast computed tomography. Non-alcoholic fatty liver disease was defined as liver attenuation ≤40 Hounsfield Units after exclusions. Latent mixture modelling identified 25-year trajectories in body mass index per cent change (%Δ) from baseline.ResultsWe identified four distinct trajectories of BMI%Δ: stable (26.2% of cohort, 25-year BMI %Δ = 3.1%), moderate increase (46.0%, BMI%Δ = 21.7%), high increase (20.9%, BMI%Δ = 41.9%) and extreme increase (6.9%, BMI%Δ = 65.9%). Y25 non-alcoholic fatty liver disease prevalence was higher in groups with greater BMI %Δ: 4.1%, 9.3%, 13.0%, and 17.6%, respectively (P-trend

Nonalcoholic fatty liver disease (NAFLD) is a disorder characterized by excess accumulation of fat in hepatocytes (nonalcoholic fatty liver (NAFL)); in up to 40% of individuals, there are additional findings of portal and lobular inflammation and hepatocyte injury (which characterize nonalcoholic steatohepatitis (NASH)). A subset of patients will develop progressive fibrosis, which can progress to cirrhosis. Hepatocellular carcinoma and cardiovascular complications are life-threatening co-morbidities of both NAFL and NASH. NAFLD is closely associated with insulin resistance; obesity and metabolic syndrome are common underlying factors. As a consequence, the prevalence of NAFLD is estimated to be 10-40% in adults worldwide, and it is the most common liver disease in children and adolescents in developed countries. Mechanistic insights into fat accumulation, subsequent hepatocyte injury, the role of the immune system and fibrosis as well as the role of the gut microbiota are unfolding. Furthermore, genetic and epigenetic factors might explain the considerable interindividual variation in disease phenotype, severity and progression. To date, no effective medical interventions exist that completely reverse the disease other than lifestyle changes, dietary alterations and, possibly, bariatric surgery. However, several strategies that target pathophysiological processes such as an oversupply of fatty acids to the liver, cell injury and inflammation are currently under investigation. Diagnosis of NAFLD can be established by imaging, but detection of the lesions of NASH still depend on the gold-standard but invasive liver biopsy. Several non-invasive strategies are being evaluated to replace or complement biopsies, especially for follow-up monitoring.

Abstract: Background & Aims: Non‐alcoholic fatty liver disease is an epidemic. Identifying modifiable risk factors for non‐alcoholic fatty liver disease development is essential to design effective prevention programmes. We tested whether 25‐year patterns of body mass index change are associated with midlife non‐alcoholic fatty liver disease. Methods: In all, 4423 participants from Coronary Artery Risk Development in Young Adults, a prospective population‐based biracial cohort (age 18‐30), underwent body mass index measurement at baseline (1985‐1986) and 3 or more times over 25 years. At Year 25, 3115 had liver fat assessed by non‐contrast computed tomography. Non‐alcoholic fatty liver disease was defined as liver attenuation ≤40 Hounsfield Units after exclusions. Latent mixture modelling identified 25‐year trajectories in body mass index per cent change (%Δ) from baseline. Results: We identified four distinct trajectories of BMI%Δ: stable (26.2% of cohort, 25‐year BMI %Δ = 3.1%), moderate increase (46.0%, BMI%Δ = 21.7%), high increase (20.9%, BMI%Δ = 41.9%) and extreme increase (6.9%, BMI%Δ = 65.9%). Y25 non‐alcoholic fatty liver disease prevalence was higher in groups with greater BMI %Δ: 4.1%, 9.3%, 13.0%, and 17.6%, respectively (P‐trend <.0001). In multivariable analyses, participants with increasing BMI%Δ had increasingly greater odds of non‐alcoholic fatty liver disease compared to the stable group: OR: 3.35 (95% CI: 2.07‐5.42), 7.80 (4.60‐13.23) and 12.68 (6.68‐24.09) for moderate, high and extreme body mass index increase, respectively. Associations were only moderately attenuated when adjusted for baseline or Y25 body mass index. Conclusions: Trajectories of weight gain during young adulthood are associated with greater non‐alcoholic fatty liver disease prevalence in midlife independent of metabolic covariates and baseline or concurrent body mass index highlighting the importance of weight maintenance throughout adulthood as a target for primary non‐alcoholic fatty liver disease prevention. [ABSTRACT FROM AUTHOR]

Abstract: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the developed world. NAFLD is tightly linked to insulin resistance and considered to be the hepatic manifestation of the metabolic syndrome. The cornerstone of any treatment regimen for patients with NAFLD is lifestyle modification focused on weight loss, exercise, and improving insulin sensitivity. Here we review the literature and discuss the role of diet and nutrient composition in the management of NAFLD. Because there are currently no specific dietary guidelines for NAFLD, this review proposes a dietary framework for patients with NAFLD based on the available evidence and extrapolates from dietary guidelines aimed at reducing insulin resistance and cardiovascular risk. [Copyright &y& Elsevier]

Background: Nonalcoholic fatty liver disease (NAFLD) is associated with high cardiovascular mortality, including heart failure (HF). Left ventricular hypertrophy (LVH) increases the risk of future HF. The relationship between NAFLD and LV geometry is unknown. In a large prospective population-based sample of black and white adults free from liver or heart disease, we examined the relationship between NAFLD and markers of LV remodeling. Methods: Participants from the CARDIA study (Y25 exam; age 43-55 years) with concurrent CT quantification of liver fat and tissue Doppler echocardiography were included (n=2,576). Echocardiography was repeated at Y30 follow up (age 47-62 years). LV geometry was classified into normal and abnormal geometry by integrating relative wall thickness and LV mass index. NAFLD was defined as CT liver attenuation ≤ 40 Hounsfield units after excluding other causes of liver fat. Logistic and polytomous regression models were used to test associations. Results: NAFLD prevalence was 9.6%. NAFLD participants were more likely to be male (57.7% vs. 40.0%), white (57.3% vs. 50.2%), and had higher BMI (36.0 vs. 29.9 kg/m²) than non-NAFLD. At Y30 NAFLD participants had higher LV mass, left atrial diameter, and LV relative wall thickness compared to non-NAFLD (p<0.01). Those with NAFLD had higher prevalence of LVH (31.9% vs. 18.2%), concentric remodeling (15.3% vs. 13.1%), concentric hypertrophy (12.9% vs. 7.9%) and eccentric hypertrophy (18.9% vs. 10.1%, p<0.0001). In multivariable analyses NAFLD was independently associated with prevalent LV remodeling (Table). Associations were attenuated after adjustment for HF risk factors. In contrast, NAFLD was associated with incident LVH independent of HF risk factors. Adjustment for BMI attenuated this association. There was no interaction by race or sex. Conclusion: NAFLD is associated with subclinical changes in LV geometry and remodeling, a precursor to HF. The role of NAFLD in LV remodeling as a potential therapeutic target warrants further investigation. [ABSTRACT FROM AUTHOR]