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Liver steatosis is a frequent finding in clinical practice and it is estimated to affect 30% of the general adult population worldwide. It became one of the leading causes of end-stage liver disease and hepatocellular carcinoma. From its first description, a diagnosis of nonalcoholic fatty liver disease (NAFLD) required the exclusion of excessive alcohol consumption and concomitant chronic liver diseases of different origins, making it a diagnosis of exclusion. In recent years, the need to stress the strict association between liver steatosis and metabolic dysfunction (i.e., insulin resistance, overweight/obesity, type 2 diabetes, and metabolic syndrome), as well as the desire to define a condition in a positive rather than negative way, led to new definitions and new diagnostic criteria. Metabolic dysfunction-associated fatty liver disease (MAFLD) was proposed by Eslam et al. in 2020. More recently, a Delphi consensus endorsed by several international hepatologic societies proposed a new terminology [metabolic dysfunction-associated steatotic liver disease (MASLD)] and a new set of diagnostic criteria. The MAFLD and MASLD definitions have a good degree of concordance. They mainly differ in the number of metabolic derangements needed to define “metabolic dysfunction” in normal-weight individuals and in alcohol consumption. Indeed, while MAFLD does not exclude patients with significant alcohol consumption, the recent Delphi consensus included the metabolic dysfunction and alcohol-related liver disease (MetALD) disease entity, a condition in which steatosis, metabolic dysfunction, and moderate alcohol intake coexist. In the present narrative review, we underline the strengths and possible limitations of each definition and summarize available evidence from epidemiologic studies evaluating the clinical usefulness of each set of diagnostic criteria.

Objective: The purpose of this study was to determine the effectiveness of a new AI-based tool called NAIF (NAFLD-AI-Fibrosis) in identifying individuals from the general population with advanced liver fibrosis (stage F3/F4). We compared NAIF's performance to two existing risk score calculators, aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis-4 (Fib4). Methods: To set up the algorithm for diagnosing severe liver fibrosis (defined as Fibroscan® values E ≥ 9.7 KPa), we used 19 blood biochemistry parameters and two demographic parameters in a group of 5,962 individuals from the NHANES population (2017–2020 pre-pandemic, public database). We then assessed the algorithm's performance by comparing its accuracy, precision, sensitivity, specificity, and F1 score values to those of APRI and Fib4 scoring systems. Results: In a kept-out sub dataset of the NHANES population, NAIF achieved a predictive precision of 72 %, a sensitivity of 61 %, and a specificity of 77 % in correctly identifying adults (aged 18–79 years) with severe liver fibrosis. Additionally, NAIF performed well when tested with two external datasets of Italian patients with a Fibroscan® score E ≥ 9.7 kPa, and with an external dataset of patients with diagnosis of severe liver fibrosis through biopsy. Conclusions: The results of our study suggest that NAIF, using routinely available parameters, outperforms in sensitivity existing scoring methods (Fib4 and APRI) in diagnosing severe liver fibrosis, even when tested with external validation datasets. NAIF uses routinely available parameters, making it a promising tool for identifying individuals with advanced liver fibrosis from the general population. Word count abstract: 236.

CONTEXT: Despite being one of the major drivers of diabetes incidence, the degree of insulin resistance in patients with type 2 diabetes (T2D) is not usually evaluated in clinical practice or in large epidemiologic studies. OBJECTIVE: To identify a model of insulin sensitivity using widely available clinical and laboratory parameters in patients with T2D and evaluate its association with all-cause and cardiovascular mortality. METHODS: One hundred forty patients with T2D underwent a euglycemic hyperinsulinemic clamp to measure total body glucose disposal rate (mg kg-1 minute-1). We used demographic, clinical, and common laboratory parameters to estimate insulin sensitivity (IS) via stepwise linear regression on 85 patients (training cohort) and validated it in the remaining 55 (validation cohort). The identified equation was then applied to 3553 patients with T2D from the 1999-2010 cycles of the National Health and Nutrition Examination Survey (NHANES) to evaluate its association with all-cause and cardiovascular mortality up to December 2015. RESULTS: The best model included triglycerides, gamma glutamyl transpeptidase, albumin excretion rate, and body mass index. The identified IS score correlated well with the clamp-derived glucose disposal rate in both the training (r = 0.77, P < .001) and the validation (r = 0.74, P < .001) cohorts. In the NHANES cohort, after a median follow-up of 8.3 years, 1054 patients died, 265 of cardiovascular causes. In a multivariable Cox proportional hazard model adjusted for age, sex, race-ethnicity, education, cigarette smoke, total cholesterol, chronic kidney disease, blood pressure, prevalent cardiovascular disease, and alcohol consumption, a higher estimated IS was associated with a lower risk of both all-cause and cardiovascular mortality. CONCLUSION: We propose a new model of IS in patients with T2D based on readily available clinical and laboratory data. Its potential applications are in both diagnosis as well as prognos

Background and Aims: Fatty liver disease is a major public health threat due to its very high prevalence and related morbidity and mortality. Focused and dedicated interventions are urgently needed to target disease prevention, treatment, and care. Approach and Results: We developed an aligned, prioritized action agenda for the global fatty liver disease community of practice. Following a Delphi methodology over 2 rounds, a large panel (R1 n = 344, R2 n = 288) reviewed the action priorities using Qualtrics XM, indicating agreement using a 4-point Likert-scale and providing written feedback. Priorities were revised between rounds, and in R2, panelists also ranked the priorities within 6 domains: epidemiology, treatment and care, models of care, education and awareness, patient and community perspectives, and leadership and public health policy. The consensus fatty liver disease action agenda encompasses 29 priorities. In R2, the mean percentage of “agree” responses was 82.4%, with all individual priorities having at least a super-majority of agreement (> 66.7% “agree”). The highest-ranked action priorities included collaboration between liver specialists and primary care doctors on early diagnosis, action to address the needs of people living with multiple morbidities, and the incorporation of fatty liver disease into relevant non-communicable disease strategies and guidance. Conclusions: This consensus-driven multidisciplinary fatty liver disease action agenda developed by care providers, clinical researchers, and public health and policy experts provides a path to reduce fatty liver disease prevalence and improve health outcomes. To implement this agenda, concerted efforts will be needed at the global, regional, and national levels.

Background & aim: Liver fibrosis is the strongest predictor of liver-related mortality in many chronic liver diseases. NT-ProBNP is independently associated with cardiovascular mortality in general population settings. Here, we evaluate the relative contribution of non-invasively identified liver fibrosis and NT-ProBNP on all-cause and cardiovascular mortality in patients with metabolic (dysfunction)-associated steatotic liver disease (MASLD). Methods and results: Serum NT-ProBNP levels were measured in 4229 patients with MASLD from the general population without a known history of heart failure that participated in the 1999–2004 cycles of the National Health and Nutrition Examination Survey. Presence of liver fibrosis was estimated using the Fibrosis-4 index (FIB-4). We applied Cox proportional hazard models adjusted for cardiovascular risk factors to evaluate the association between NT-ProBNP and FIB-4 levels and all-cause and cardiovascular mortality through December 2019. Mortality was lower for participants with normal levels of both biomarkers, intermediate if a single biomarker was elevated and highest when both were above the chosen threshold. In the multivariable-adjusted models, both elevated FIB-4 (≥2.67) and elevated NT-ProBNP levels (≥125 pg/ml) were independently associated with higher risks of all-cause mortality (HR 2.2, 95 % CI 1.5–3.2 and HR 1.6, 95 % CI 1.4–2.0, respectively) and cardiovascular mortality (HR 2.1, 95 % CI 1.2–3.7 and HR 2.1, 95 % CI 1.5–2.9, respectively). The associations remained consistent in subgroup analyses based on sex, obesity and age. Conclusions: Both FIB-4 and NT-ProBNP are independently associated with higher mortality in patients with MASLD. Their combined use might prove useful to risk-stratify patients in clinical practice.

Context: Patients with diabetes are at increased risk of dying from liver-related events, but little is known on whether this increased risk changed in recent years. Objective: The aim of the present study is to describe time trends in cause-specific liver-related mortality in people with and without diabetes from the general Italian population. Methods: Data were retrieved from the healthcare utilization databases of Lombardy, a region of Italy that accounts for about 16% (almost ten million) of its population. Annual cause-specific mortality rates and proportionate mortality were computed among individuals with and without diabetes from 2010 to 2019. Liver-related deaths were categorized as viral, alcohol related and non-viral non-alcohol related (NVNA). Results: Liver diseases were responsible for 2% and 1% of deaths in people with and without diabetes (2019). Among patients with diabetes, the crude mortality rate for liver diseases decreased from 1.13 to 0.64 deaths per 1,000 person-years from 2010 to 2019. The largest proportion of liver-related deaths was attributable to NVNA diseases and it increased from 63% in 2010 to 68% in 2019, with a corresponding relative reduction of viral causes (from 27% to 23%). The Standardized Mortality Ratio for patients with diabetes was 3.35 (95% CI 2.96-3.76) for NVNA, 1.66 (95% CI 1.33-2.01) for viral hepatitis and 1.61 (95% CI 1.13-2.17) for alcoholic liver disease and it remained relatively stable over time. Excess mortality risk in patients with diabetes for liver-related mortality was higher than for cardiovascular mortality and cancer. Conclusion: While liver-related mortality rates decreased significantly among patients with diabetes, NVNA causes comprised the majority of cases. Excess mortality for liver-related causes in patients with diabetes compared with controls remained constant in the studied period.

Aims: To evaluate the impact of adherence to glucagon like peptide-1 receptor agonists (GLP1-RA) and sodium-glucose transporter two inhibitors (SGLT2-I) on clinical outcomes and costs in patients with type 2 diabetes mellitus (T2DM). Materials and Methods: The 121,115 residents of the Lombardy Region (Italy) aged ≥40 years newly treated with metformin during 2007–2015 were followed to identify those who started therapy with GLP1-RA or SGLT2-I. Adherence to drug therapy over the first year was defined as the proportion of days covered >80%. Within each drug class, for each adherent patient, one non-adherent patient was matched for age, sex, duration, adherence to metformin treatment and propensity score. The primary clinical outcome was a composite of insulin initiation, hospitalisation for micro- and macrovascular complications and all-cause mortality after the first year of drug treatment. Costs were evaluated based on reimbursements from the national healthcare system. Results: After matching, 1182 pairs of adherent and non-adherent GLP1-RA users and 1126 pairs of adherent and non-adherent SGLT2-I users were included. In both groups, adherent patients experienced a significantly lower incidence of the primary outcome (HR: 0.85, 95% CI 0.72–0.98 for GLP1-RA and HR: 0.69, 95% CI 0.55–0.87 for SGLT2-I). A significant reduction in hospitalizations was found for adherent patients in the GLP1-RA group but not for the SGLT2-I group. Results were consistent when analyses were stratified by age and sex. While higher drug-related costs in the adherent group were counterbalanced by decreased hospitalisation costs in SGLT2-I treated patients, this was not the case for GLP1-RA. Conclusions: Higher adherence to drug treatment with GLP1-RA and SGLT2-I during the first year of the drug intake is associated with a lower incidence of adverse clinical outcomes in a real-world setting.