Gender differences in the epidemiology, pathophysiological mechanisms and clinical features in chronic liver diseases that may be associated with type 2 diabetes (T2D) have been increasingly reported in recent years. This sexual dimorphism is due to a complex interaction between sex- and gender-related factors, including biological, hormonal, psychological and socio-cultural variables. However, the impact of sex and gender on the management of T2D subjects with liver disease is still unclear. In this regard, sex-related differences deserve careful consideration in pharmacology, aimed at improving drug safety and optimising medical therapy, both in men and women with T2D; moreover, low adherence to and persistence of long-term drug treatment is more common among women. A better understanding of sex- and gender-related differences in this field would provide an opportunity for a tailored diagnostic and therapeutic approach to the management of T2D subjects with chronic liver disease. In this narrative review, we summarized available data on sex- and gender-related differences in chronic liver disease, including metabolic, autoimmune, alcoholic and virus-related forms and their potential evolution towards cirrhosis and/or hepatocarcinoma in T2D subjects, to support their appropriate and personalized clinical management.

Background: Non-alcoholic fatty liver disease (NAFLD) is a highly frequent condition in patients with type 2 diabetes (T2D), but the identification of subjects at higher risk of developing the more severe forms remains elusive in clinical practice. The aim of this study was to evaluate the occurrence and severity of liver fibrosis and its predictive factors in T2D outpatients without a known history of chronic liver disease by using recommended non-invasive methods. Methods: Consecutive T2D outpatients underwent a set of measurements of clinical and laboratory parameters, FIB-4 score (Fibrosis-4 index), and liver stiffness with controlled attenuation-parameter (CAP) performed by transient elastography (FibroScan) after excluding previous causes of liver disease. Results: Among the 205 T2D outpatients enrolled in the study (median age: 64 years, diabetes duration: 11 years, HbA1c: 7.4%, and BMI: 29.6 kg/m²), 54% had high ALT and/or AST levels, 15.6% had liver stiffness value > 10.1 kPa (severe fibrosis), 55.1% had CAP values > 290 dB/m (severe steatosis), and FIB-4 score was >2 in 11.2% of subjects (>2.67 in 15 subjects). Moreover, 49 (23.9%) T2D patients had clinically meaningful liver harm, with either a FIB-4 score > 2 and/or FibroScan > 10.1 kPa. At regression analysis, BMI, HbA1c, creatinine, and triglycerides values were independent predictors of liver fibrosis. Conclusions: Liver fibrosis is a frequent finding in T2D outpatients without a known history of liver disease, especially in those with obesity, hypertriglyceridemia, worse glycemic control, and high creatinine levels.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently the most prevalent cause of chronic liver disease worldwide. Its pathogenesis is complex and not yet fully elucidated but is commonly explained by the “multiple hit” hypothesis, which suggests that pathological behaviours interact with an unfavourable genetic background and the presence of cardiovascular comorbidities. Recent evidence has highlighted a potential role of the gut microbiota in the onset and progression of MASLD to metabolic dysfunction-associated steatohepatitis (MASH) and hepatocellular carcinoma (HCC), potentially driven by epigenetic modifications mediated by microRNAs (miRNAs). MiRNAs are small, non-coding RNAs that regulate gene expression both intra- and extracellularly. Notably, emerging data suggests a bidirectional communication between the gut microbiota and the host, mediated by miRNAs via exosomes and outer membrane vesicles. The primary aim of this review is to explore the epigenetic crosstalk between the host and the gut microbiota through miRNA expression, with the goal of identifying specific pathways involved in MASLD development and natural history. A secondary objective is to evaluate the potential applications of artificial intelligence in the analysis of these complex host–microbiota interactions, to standardize the evaluation of microbiota and to create a model of the epigenetic changes in metabolic liver disease.

The predictive factors of long-term clinical benefits in patients with hepatitis C virus (HCV)—related liver cirrhosis after Direct Antiviral Agents (DAA) treatment are still undefined. The aim of this study was to identify any predictors of liver failure, hepatocellular carcinoma (HCC) and/or death in patients with compensated liver cirrhosis who achieved the sustained virological response (SVR). To this purpose, 324 consecutive cirrhotic patients who started DAA treatment from 1 April 2015 to 31 December 2016 were retrospectively analyzed. All patients were followed up for a median time of 63 months (range 19–77) through clinical/biochemical/instrumental examinations performed at baseline and after stopping the DAA treatment. At the end of the evaluation, 230 (71%) individuals showed stable clinical liver disease over time, 43 (13.3%) developed HCC, and 24 (7.4%) developed hepatic decompensation without HCC. Overall, 49 (15,1%) patients died. Multivariate regression analysis showed that hepatic decompensation was significantly associated with at baseline older age, higher liver stiffness, higher spleen longitudinal size values and hypergammaglobulinemia (p = 0.003, p = 0.005, p = 0.001, p = 0.029, respectively). HCC development was significantly associated with hypergammaglobulinemia (p < 0.001). Death was associated with older age and hypergammaglobulinemia (p < 0.001 and p = 0.007, respectively). Finally, survival analysis confirmed that patients with gamma globulin levels ≥ 1.8 gr/dl had a significantly higher risk of death compared to those with gamma globulin levels < 1.8 gr/dl (p < 0.001). In conclusion, hypergammaglobulinemia before starting DAA therapy represents a strong predictor of hepatic decompensation, HCC and death in cirrhotic patients even after HCV clearance.

Background and aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common cause of chronic liver disease worldwide. Type 2 diabetes (T2D) and obesity are major risk factors for its development and progression. Body mass index (BMI), although widely used in clinical practice, fails to adequately reflect individual differences in body composition and fat distribution. This study evaluated the association of adiposity and reduced muscle mass – measured by dual-energy X-ray absorptiometry (DXA) – with hepatic steatosis severity in patients with MASLD and T2D. Methods: Consecutive patients with MASLD and T2D were recruited at a tertiary hepatology centre. Body composition was assessed by DXA. Adiposity was defined using fat mass percentage, with values >25% in men and >35% in women indicating obesity. Muscle mass was assessed using the appendicular lean mass/height ² (ALM/height²) index, with pathological values defined as <7.0 kg/m ² in men and <5.5 kg/m ² in women. Hepatic steatosis and fibrosis were evaluated by controlled attenuation parameter (CAP) and liver stiffness measurement (LSM), respectively. Statistical analyses included Spearman’s rank correlation, Chi Square test, logistic regression, and receiver operating characteristic (ROC) curve analyses. Results: Ninety-seven patients (median age 61 years) were enrolled. DXA identified a pathological fat mass percentage in 97.9% of patients, whereas 46.4% met the BMI-based criteria for obesity. At multivariate analysis, fat mass percentage and pathological ALM/height ² were independently related with severe hepatic steatosis (CAP ≥280 dB/m; OR 1.100, p = 0.011; OR 0.292, p = 0.013, respectively). ROC curve analysis identified specific cut-offs for fat mass percentage (38.65%, area under the curve [AUC] of 0.636) and ALM/height ² index (6.7 kg/m ² , AUC of 0.611) for detecting severe liver steatosis. A model combining both cut-offs yielded an AUC of 0.715 (95% C.I. 0.610 – 0.820, p = 0.001). Conclusions: In patients with MASLD and T2D, DXA-derived body composition measures may complement conventional anthropometric assessment and help identify individuals with severe hepatic steatosis.

Background and Aims: The long‐term impact of HCV cure on hepatic and metabolic outcomes in patients with type 2 diabetes (T2D) remains insufficiently defined. This study evaluated T2D‐related vascular complications, liver disease progression and overall survival over 9 years of follow‐up, also exploring genetic variability contribution. Methods: Consecutive T2D patients with HCV‐related chronic liver disease or cirrhosis treated with direct‐acting antivirals (DAAs) between 2015 and 2018 at the University Hospital of Messina were prospectively followed until September 2024. Demographic, biochemical, and clinical data were collected at baseline and throughout follow‐up. Regression models were applied to identify predictors of metabolic and hepatic outcomes. Genetic variants— PNPLA3 rs738409, TM6SF2 rs58542926 and rs641738 at the MBOAT7/TMC4 locus—were also assessed. Results: A total of 183 patients (52% males, median age 67 years; 56% cirrhotic) were followed for a median of 48 months (range 24–84). Despite significant improvements in HbA1c ( p = 0.006), liver‐stiffness ( p < 0.001), gamma‐globulins ( p < 0.001), and aminotransferases ( p < 0.001), only 27.3% maintained clinical stability. Liver disease progression occurred in 20.8% of patients and was related to cirrhosis ( p = 0.021), prior decompensation ( p = 0.07), and the MBOAT7 variant ( p = 0.025). Macrovascular and microvascular complications developed in 50.8% and 33.9% of patients, respectively, mostly within 2 years after SVR. In multivariate models, higher TyG index ( p = 0.038) predicted the composite progression endpoint, while elevated LDL cholesterol ( p = 0.048), mortality. Conclusions: Although DAAs lead to metabolic and hepatic improvements, long‐term prognosis in T2D patients remains largely determined by baseline liver disease severity, insulin resistance, and genetic background. These findings emphasize the importance of early antiviral treatment and optimized metabolic management in this high‐risk population.