Clinical, Metabolic, and Virological Insights into Hepatitis C Virus-Infected Patients through the Combinatorial Metabolic Dysfunction-associated Steatotic Liver Disease Framework: Evidence from an Italian Cohort

Background & Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) frequently overlaps with hepatitis C virus (HCV) infection, yet the recently proposed combinatorial MASLD (cMASLD) classification remains poorly characterized in this setting. This study aimed to evaluate the prevalence, metabolic profile, and virological determinants of cMASLD in an Italian cohort of HCV-infected patients. Methods: We conducted a cross-sectional study on 169 HCV-infected patients evaluated at two referral Centers in Southern Italy (between 2020 and 2024). All subjects underwent transient elastography, and cMASLD was diagnosed according to international guidelines. Group comparisons were performed using ANOVA or Kruskal-Wallis tests with appropriate post-hoc analyses, categorical variables by Chi-square or Fisher’s exact test, and multivariate logistic regression to identify factors independently associated with cMASLD (p<0.05). Results: Among 169 patients, n=52 (31%) fulfilled cMASLD criteria, n=14 (8%) had HCV with liver steatosis, and n=103 (61%) had HCV infection alone. Compared with other groups, cMASLD patients showed higher body mass index (28±8 kg/m²; p<0.001), larger waist circumference (p<0.001), increased controlled attenuation parameter (298±41 dB/m; p<0.001), and higher fasting insulin (p=0.029). HCV RNA levels were significantly elevated in the cMASLD group (p=0.014). Multivariate logistic regression identified HCV RNA as independently associated with cMASLD (OR=1.48; 95%CI: 1.01-2.17; p=0.045). Conclusions: Applying the cMASLD nomenclature emphasizes the need for a multidisciplinary management approach integrating antiviral and metabolic care. This classification provides a more comprehensive understanding of liver injury mechanisms in patients with overlapping metabolic and viral etiologies.