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The article focuses on the challenges of pharmacotherapy in patients with nonalcoholic steatohepatitis (NASH) and the difficulty in achieving meaningful results due to the complex nature of NASH, variable disease progression, and challenges in assessing histologic endpoints. It discusses the potential of Pegozafermin, a therapeutic targeting fibroblast growth factor 21 (FGF21), to address some of these challenges and improve metabolic and inflammatory aspects of NASH.

Summary: Background: Non‐alcoholic fatty liver disease (NAFLD) is a highly prevalent condition that requires a comprehensive and coordinated response across sectors and disciplines. Aims: In the absence of a multisectoral framework to tackle this condition, we developed one using the sustainable development goals (SDGs) as the basis for converging thinking about the design and delivery of public health responses. Methods: A multidisciplinary group identified the SDG targets and indicators for inclusion in the new framework through a two‐stage process. Firstly, a core team of three researchers independently reviewed the 169 targets and 231 indicators of the SDGs to select a shortlist. Over two Delphi rounds, a multidisciplinary group of 12 experts selected which of the shortlisted targets and indicators to include. Respondents also provided written feedback on their selection. Targets and indicators with 75% or greater agreement were included in the final framework. Results: The final framework comprises 16 targets—representing 9% of all targets and 62% (16/26) of the shortlisted targets—and seven indicators, accounting for 50% (7/14) of the shortlisted indicators and 3% of all indicators. The selected targets and indicators cover a broad range of factors, from health, food and nutrition to education, the economy, and the built environment. Conclusions: Addressing the challenge of NAFLD will require a re‐envisioning of the liver health landscape, with greater focus on joined‐up systems thinking and action. This new framework can help guide this process, including by outlining the stakeholders with whom the liver health community needs to engage. [ABSTRACT FROM AUTHOR]

Background & Aims: Insulin 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. Methods: Three 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. Results: Three 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. Conclusion: Trajectories 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. [ABSTRACT FROM AUTHOR]

Summary: Background: Given the lack of long‐term prospective studies, it is challenging for clinicians to make informed decisions about screening and treatment decisions regarding the risk of hepatocellular carcinoma (HCC) in patients with non‐alcoholic steatohepatitis (NASH) who do not have cirrhosis. Aim: To characterise the pooled risk of HCC in the non‐cirrhosis population. Methods: Published studies were identified through April 2016 in MEDLINE, Scopus, Science Citation Index, AMED and the Cochrane Library. Two independent reviewers screened citations and extracted data. Random effect odds ratios (OR) were calculated to obtain aggregate estimates of effect size between NASH and non‐NASH groups. Between‐study variability and heterogeneity were assessed. Results: Nineteen studies with 168 571 participants were included. Eighty‐six per cent of included subjects had cirrhosis. The prevalence of HCC in non‐cirrhotic NASH was 38.0%; among other aetiologies in non‐cirrhotics, it was 14.2% (P < 0.001). Non‐cirrhotic NASH subjects were at greater odds of developing HCC than non‐cirrhotic subjects of other aetiologies (OR 2.61, 95% CI 1.27‐5.35, P = 0.009). When examining all NASH subjects either with or without cirrhosis, those with NASH as the underlying liver disease did not have a significantly increased risk of HCC (OR 1.43, 95% CI 0.77‐2.65, P = 0.250). Conclusions: In non‐cirrhotic subjects, those with NASH have a higher risk of HCC compared to other aetiologies of liver disease. Further study investigating the risk factors of HCC among non‐cirrhotic NASH patients is needed. [ABSTRACT FROM AUTHOR]

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]