The effect of high-protein vs. low-protein diets on CRP, IL-6, TNF-α, and liver enzymes in adult participants: a systematic review and meta-analysis

Abstract

Background: High-protein diets (HPDs) are widely recommended for weight management and preservation of lean mass, but their impact on systemic inflammation and liver health remains controversial. Elevated liver enzymes and inflammatory biomarkers such as C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) are strongly associated with non-alcoholic fatty liver disease and cardiometabolic risk. Evidence from randomized controlled trials (RCTs) has been inconsistent, highlighting the need for a quantitative synthesis. Methods: We conducted a meta-analysis of RCTs comparing HPDs with lower-protein diets in adults. Databases were searched from inception to September 2025. Outcomes included liver enzymes and systemic inflammatory markers. Pooled estimates were calculated using random effects models. Results: A total of 37 RCTs were eligible. Compared with lower-protein diets, HPDs significantly reduced alanine aminotransferase (ALT) (WMD: −5.27 U L⁻¹; 95% CI: −8.70 to −1.85) and γ-glutamyltransferase (GGT) (WMD: −7.42 U L⁻¹; 95% CI: −12.88 to −1.97). CRP was modestly reduced (WMD: −0.51 mg L⁻¹; 95% CI: −1.01 to −0.02), although with substantial heterogeneity (I² = 96.9%). In contrast, IL-6 and TNF-α remained unchanged, with very high heterogeneity observed for TNF-α (I² = 99.6%). Subgroup analyses suggested greater reductions in ALT and GGT in short-term interventions (≤12 weeks) and more consistent CRP lowering with protein intake ≥30% of energy. Meta-regression did not detect clear associations between protein proportion or intervention duration and biomarker changes. Conclusion: HPDs conferred modest but significant improvements in selected liver enzymes (ALT and GGT) and in CRP. These findings suggest potential hepatic and anti-inflammatory benefits of high-protein regimens. However, considerable heterogeneity across trials and limited long-term data warrant further well-designed RCTs to confirm clinical relevance and safety.