Objective Non-alcoholic fatty liver disease (NAFLD) is prevalent in patients with type 2 diabetes. Here, we estimate the proportion of patients with type 2 diabetes that should be referred to hepatologists according to the European Association for the Study of the Liver (EASL)-European Association for the Study of Diabetes (EASD)-European Association for the Study of Obesity (EASO) Guidelines and evaluate the association between non-invasive biomarkers of steatosis and fibrosis and diabetic complications. Research design and methods This is a retrospective analysis of type 2 diabetes patients who attended on a regular basis our diabetes clinic between 2013 and 2018 (n=2770). Steatosis was assessed using Fatty Liver Index (FLI), Hepatic Steatosis Index and NAFLD Ridge Score and fibrosis using NAFLD Fibrosis Score (NFS), Fibrosis-4 (FIB-4), aspartate aminotransferase (AST) to platelet ratio index (APRI) and AST/alanine aminotransferase (ALT) ratio. Outcome measures were altered albumin excretion rate (AER), chronic kidney disease (CKD) and cardiovascular disease (CVD). Results The prevalence of advanced fibrosis varied from 1% (APRI) to 33% (NFS). The application of the guidelines using a sequential combination of FLI and FIB-4 would lead to referral of 28.3% of patients when using standard FIB-4 cut-offs, while this number dropped to 13.4% when age-adjusted FIB-4 thresholds were applied. A higher prevalence of altered AER was associated with liver steatosis (FLI: OR: 3.49; 95% CI 2.05 to 5.94, p<0.01), whereas liver fibrosis was associated with CKD (FIB-4: OR: 6.39; 95% CI 4.05 to 10.08, p<0.01) and CVD (FIB-4: OR: 2.62; 95% CI 1.69 to 4.04, p<0.01). Conclusions While specific fibrosis scores identify different proportion of patients with advanced fibrosis, the use of age-adjusted FIB-4 cut-offs leads to a drop in gray-zone results, making referrals to hepatologists more sustainable. Interestingly non-invasive biomarkers were consistently associated with a different pattern of diabetic complications.

In the present narrative review, we have summarized evidence on the pharmacological treatment of non-alcoholic fatty liver disease (NAFLD)/metabolic dysfunction-associated steatotic liver disease (MASLD). We start by reviewing the epidemiology of the condition and its close association with obesity and type 2 diabetes. We then discuss how randomized–controlled trials are performed following guidance from regulatory agencies, including differences and similarities between requirements of the US Food and Drug Administration and the European Medicine Agency. Difficulties and hurdles related to limitations of liver biopsy, a large number of screening failures in recruiting patients, as well as unpredictable response rates in the placebo group are evaluated. Finally, we recapitulate the strategies employed for potential drug treatments of this orphan condition. The first is to repurpose drugs that originally targeted T2DM and/or obesity, such as pioglitazone, glucagon-like peptide 1 receptor agonists (liraglutide and semaglutide), multi-agonists (tirzepatide and retatrutide), and sodium-glucose transporter 2 inhibitors. The second is to develop drugs specifically targeting NAFLD/MASLD. Among those, we focused on resmetirom, fibroblast growth factor 21 analogs, and lanifibranor, as they are currently in Phase 3 of their clinical trial development. While many failures have characterized the field of pharmacological treatment of NAFLD/MASLD in the past, it is likely that approval of the first treatments is near. As occurs in many chronic conditions, combination therapy might lead to better outcomes. In the case of non-alcoholic steatohepatitis, we speculate that drugs treating underlying metabolic co-morbidities might play a bigger role in the earlier stages of disease, while liver-targeting molecules will become vital in patients with more advanced disease in terms of inflammation and fibrosis.

Few population-based studies investigated the association between body fat distribution and the risk of nonalcoholic fatty liver disease (NAFLD) and significant liver fibrosis. To evaluate the relationship between total body fat and body fat distribution and NAFLD in the general US population. This is a cross-sectional, population-based study based on the 2017-2018 cycle of the National Health and Nutrition Examination Survey. Participants aged 18-59 without known liver conditions or significant alcohol consumption were studied by dual energy x-ray absorptiometry (DXA) and vibration controlled transient elastography (VCTE) to assess body composition and liver steatosis and fibrosis, respectively. Multivariable logistic regression analysis was performed to evaluate the contribution of body mass index (BMI) and android/gynoid ratio (A/G ratio) on the prevalence of liver steatosis and fibrosis in males and females. Weighted prevalence of steatosis were 41.5% and 29.9% among the 1115 and 1113 males and females included in the study, whereas 7.0% of males and 4.0% of females had elastographic evidence of significant liver fibrosis. After adjustment for age, race-Hispanic origin, diabetes, cigarette smoke and BMI, a higher A/G ratio was associated with increased odds of steatosis in both males (odds ratio (OR) 1.79, 95% CI 1.07,2.99, p=0.029) and females (OR 1.95, 95% CI 1.11,3.41, p=0.023). Conversely, a significant association between A/G ratio and liver fibrosis was identified in females (OR 2.09, 95% CI 1.11,3.97, p=0.026), but not in males (OR 0.56, 95% CI 0.29,1.08, p=0.078). Independently from BMI, an android fat deposition pattern is associated with increased prevalence of NAFLD in both sexes, while the effect on fibrosis was only evident in females.