**Background:** Non-alcoholic fatty liver disease (NAFLD) affects approximately 20% to 30% of the general adult population worldwide, with prevalence rising to approximately 50% in overweight individuals and approximately 80% to 90% in obese individuals. Despite its high prevalence and association with metabolic syndrome, type 2 diabetes, and insulin resistance, pharmacological treatment options remain limited. Silymarin, a flavonoid extracted from Silybum marianum, has been proposed as a hepatoprotective, anti-inflammatory, and antioxidant agent. Previous studies have suggested beneficial effects on liver enzymes in NAFLD patients, but a systematic review with meta-analysis including six clinical trials found high heterogeneity and low methodological quality across studies. The Siliver trial was designed to address these methodological limitations and provide robust evidence on silymarin's efficacy as adjuvant therapy for NAFLD.
**Methods:** This is a randomized double-blind placebo-controlled superiority trial conducted at the Nutrition and Hepatology Outpatient Clinic of the Professor Edgard Santos University Hospital Complex in Salvador, Brazil. Eligible participants are consenting adults aged 20–60 years of both sexes with a medically confirmed NAFLD diagnosis. Exclusion criteria include pregnancy, lactation, chronic diseases (congestive heart failure, severe lung disease, neoplasms, kidney disease, HIV, advanced chronic liver disease Child-Pugh B or C), alcohol intake >20 g/day, use of specified medications in the past 6 months, and recent infections or hospitalizations. Participants are randomized via computer-generated block randomization to intervention (I) or control (C) groups. Group I receives 700 mg silymarin + 8 mg vitamin E + 50 mg phosphatidylcholine daily; group C receives 700 mg maltodextrin + 8 mg vitamin E + 50 mg phosphatidylcholine daily, taken as two capsules after a meal for 12 weeks. The primary outcome is change in NAFLD stage assessed by CT liver-to-spleen attenuation difference. Secondary outcomes include changes in ALT, AST, γGT, AP, ferritin, fasting glucose, insulin, HbA1C, HOMA-IR, BMI, and waist circumference. The sample size was calculated as approximately 132 participants based on a significance level of 0.05 and 80% power. Recruitment ran from February 2019 to May 2022, with delays attributed to the SARS-CoV-2 pandemic. Participants undergo CT scans and blood tests at baseline and week 16, with monthly face-to-face consultations and weekly telephone follow-up. Statistical analysis will use descriptive statistics, chi-square or Fisher's exact test for categorical variables, and appropriate parametric or non-parametric tests for continuous variables, with a 5% significance level. Analysis will be by intention-to-treat.
**Key Results:** This is a study protocol paper; therefore, no results are reported. The trial is described as completed in terms of recruitment, with data analysis pending or ongoing. The paper details the methodological rationale, including the use of phosphatidylcholine and vitamin E to increase silymarin bioavailability, and the choice of CT without contrast as the reference standard for liver steatosis assessment. The authors note that silymarin at the adopted dosage is considered safe, with rare adverse events including nausea, vomiting, and abdominal discomfort reported in previous studies.
**Clinical Implications:** The Siliver trial is designed to provide high-quality evidence on whether silymarin supplementation can reduce liver fat content in NAFLD patients, addressing the current gap in pharmacological treatment options. If efficacy is demonstrated, silymarin could offer a safe, well-tolerated adjuvant therapy for NAFLD management. The rigorous methodological design—including double-blinding, placebo control, CT-based outcome assessment, and adequate sample size—addresses limitations of prior studies. The results may inform clinical practice guidelines and support further research into silymarin's role in NAFLD treatment. However, as a single-center trial in Brazil, generalizability may be limited, and the 12-week intervention period may not capture long-term outcomes or disease progression.