Opportunities of combination therapy for chronic liver diseases: results of the multicenter PROMETHEUS study

The global prevalence of chronic liver diseases (CLD) is steadily increasing, with the most common etiologies being metabolic disorders and alcohol misuse. Despite the effectiveness of non-pharmacological interventions, their impact is often insufficient. Objective. To conduct a clinical and epidemiological analysis of common forms of CLD —nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), and drug-induced liver injury (DILI) — in outpatient practice, and to assess the use of hepatotropic agents, including combination therapy with glycyrrhizic acid and phospholipids (GA+PL). Material and methods. The multicenter PROMETHEUS study comprised two stages: a retrospective analysis of 9,149 medical records and a prospective non-interventional observation of 574 patients treated with GA+PL (Phosphogliv). Changes in biochemical liver function parameters, treatment tolerability, and adverse event rates were evaluated. Results. NAFLD accounted for 72.8% of cases, ALD for 20.1%, and DILI for 7.1%. Comorbidities were present in 90% of patients, and non-pharmacological interventions were prescribed in 95.1%. Monotherapy with hepatotropic agents was associated with reductions in ALT and AST levels (ΔALT 17.28±17.46 U/L; ΔAST 15.04±15.45 U/L). Combination therapy with GA+PL achieved normalization of ALT, AST, and ALP in patients with initially elevated enzyme levels within comparable time frames (p<0.05). At the end of GA+PL therapy, AST normalized in 69% of patients and ALT in 45%. A stepwise regimen (parenteral followed by oral administration) resulted in ALT normalization in 53.5% of patients after a 3-week course. Subjective improvement was reported by over 99% of patients, while the incidence of adverse events was 0.03%. Conclusions. In outpatient practice, NAFLD predominates among CLD cases. Monotherapy with hepatotropic agents reduces liver enzyme activity, while combination therapy with GA+PL yields greater improvements in clinical and biochemical parameters. A stepwise regimen shortens treatment duration without compromising efficacy. © 2025 Elsevier B.V., All rights reserved.