Evaluating Bioactive-Substance-Based Interventions for Adults with MASLD: Results from a Systematic Scoping Review

Abstract

Objective: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic condition affecting a broad population. This review aimed to identify and summarize the current evidence on bioactive-substance-based interventions for adults with MASLD, formerly known as nonalcoholic fatty liver disease (NAFLD), covering publications from 2000 to 2023. Methods: A search was conducted across six databases (MEDLINE, CINAHL, Cochrane CENTRAL, Cochrane Database of Systematic Reviews, Food Science Source, and SPORTDiscus) for randomized controlled trials and other study types (e.g., prospective cohort studies and systematic reviews), reflecting the scoping nature of this review. The search was limited to studies in adults (>18 years old), with an intervention of interest and at least one comparator group. Results: A total of 4572 articles were retrieved, with 201 full-text articles screened for eligibility. Of these, 131 primary studies and 49 systematic reviews were included in the scoping review. The most studied bioactive substances were Curcumin (Turmeric) (n = 25), Silymarin (Milk Thistle) (n = 17), Resveratrol (n = 10), Coffee (n = 7), Green Tea (n = 5), and Berberine (n = 5 each). Moreover, 46 studies reported on 36 other bioactive substances with 2 or fewer articles each. Among the included systematic reviews, 13 focused on Curcumin, 12 on Coffee or Tea, 10 on bioactive substance combinations, 6 on Resveratrol, and 2 each on Silymarin and Artichoke Leaf. The included studies showed substantial heterogeneity in reported outcomes, which primarily focused on hepatic health, body weight, adverse events, glycemic control, blood lipids, and body composition. Conclusions: This scoping review highlights a range of bioactive substances used in the treatment of MASLD. While evidence is abundant for bioactive substances like Curcumin and Silymarin, further research and synthesis of findings is necessary to establish the clinical efficacy of all bioactive substances.

Keywords: MASLD; bioactive substances; lifestyle management; non-alcoholic fatty liver disease; scoping review.

Figure 1

PRISMA flowchart [141] for the bioactive substances in adults with MASLD scoping review.

Figure 2

Number of articles meeting inclusion criteria according to publication year.

Figure 3

Number of articles meeting inclusion criteria according to type of bioactive substance (bioactive reported in ≥3 articles) (n = 85).

Figure 4

Number of included articles providing dietary (a) and physical activity (b) co-interventions in addition to bioactive supplementation.

Figure 5

Heat map describing outcomes reported for each bioactive substance with at least n = 3 articles for adults with MASLD. Intervention descriptions: ¹ Curcumin: Curcumin (n = 9), Nano-curcumin (n = 1), Curcuminoids + Piperine (n = 5), phospholipid Curcumin (n = 1), Phytosomal Curcumin (n = 3), Curcumin Complex + other bioactive substances (nutraceutical) (n = 1), Turmeric (n = 3), Turmeric, Chicory (n = 2); ² Silymarin: Silymarin (n = 9), Silymarin + other substances (n = 8); ³ Resveratrol: (n = 10); ⁴ Coffee: Coffee components (n = 2), Green Coffee extract (n = 5); ⁵ Green Tea: Green Tea (n = 1), Green Tea extract (n = 4); ⁶ Berberine: Berberine (n = 2), Berberine + bicyclol (n = 1), Berberis integerrima (n = 1), Berberis aristate + other substances (n = 1); ⁷ Nigella sativa: N. Sativa oil (n = 2), N. Sativa (n = 2); ⁸ Camelina sativa: (n = 3); ⁹ Garlic: Garlic powder (n = 3); ¹⁰ Cornus mas L: Cornus mas L. fruit extract (n = 3); ¹¹ Citrus bergamot: Bergamot citrus + wild cardoon (n = 1) and Citrus bergamias + Cynara cardunculus (n = 2); Outcome descriptions: ¹² Hepatic health: includes liver function tests [e.g., alanine aminotransferase (ALT); aspartate aminotransferase (AST); gamma-glutamyl transferase (GGT); alkaline phosphatase (ALP)], various measures of hepatic steatosis and fibrosis [e.g., Controlled Attenuation Parameter (CAP) score, NAFLD grade, etc.], ballooning injury score, liver stiffness, liver volume, and bilirubin. ¹³ Body weight: includes body weight and body mass index. ¹⁴ Adverse events: includes any self-reported adverse effect of intervention (e.g., nausea, constipation, bloating, etc.) or other adverse event identified by research staff (e.g., biliary disorder, abnormal lab values, etc.). ¹⁵ Glycemic control: includes blood glucose, total available glucose, hemoglobin A1c, Homeostatic Model Assessment of Insulin Resistance, insulin levels, quantitative insulin sensitivity check index (QUICKI), and C-peptide. ¹⁶ Blood lipids: includes total cholesterol, high-density lipoproteins, low-density lipoproteins, non-HDL-C, triglycerides, TC:HDL ratio, lipoprotein remnants. ¹⁷ Body composition: includes body fat, lean body mass, waist, hip and abdominal circumference, waist-to-hip ratio, fat mass, fat-free mass, and visceral fat. ¹⁸ I/OS markers: inflammatory and oxidative stress markers includes immunological, inflammatory, and oxidative stress markers such as C-reactive protein, interleukin-6, Tumor Necrosis Factor, adipokines and cytokines (leptin, adiponectin, etc.), malondialdehyde (MDA), total antioxidant capacity (TAC), fibroblast growth factor (FGF-21), glutathione peroxidase (GSH), superoxide dismutase (SOD), total glutathione, and many others. ¹⁹ Dietary intake: includes intake of energy, macro- and micronutrients, antioxidants, fiber, flavonoids, and caffeine. ²⁰ Physical activity: includes any physical activity (aerobic, muscle-strengthening, stretching, balance, etc.). ²¹ Blood pressure: includes systolic and diastolic blood pressure. ²² Renal: includes renal function lab values (creatinine, blood urea nitrogen, etc.). ²³ Uric acid: includes uric acid blood test. ²⁴ CBC: includes albumin, hematocrit, hemoglobin, neutrophils, white blood cells, platelets, etc. ²⁵ Serum fatty acids: includes lipid accumulation product (LAP), serum fatty acid profile (includes phospholipids, saturated and polyunsaturated fatty acids, etc.), and free fatty acids. ²⁶ Other CVD: cardiovascular outcomes (other than lipids), including atherogenic index of plasma (AIP), homocysteine, coronary artery calcium (CAC), Castelli risk index I (CRI-I), CRI-II, and atherogenic coefficient (AC). ²⁷ Serum vit/min: includes serum vitamin and minerals: 25-hydroxy vitamin D [25(OH)D3], potassium, iron, ferritin, transferrin, and magnesium. ²⁸ Heart rate: includes heart rate and pulse. ²⁹ Gastrointestinal: includes intestinal permeability and gut microbiota. ³⁰ Other: other outcomes: ^A frequency of comorbidities, nesfatin, 8-Hydroxy-2′-Deoxyguanosine, methylation in MutL homolog 1, MutS homolog 2 (MSH2), carboxymethyl lisine (CML), 8-hydroxy-2′-deoxyguanosine, urea, liver-to-spleen CT attenuation ratio. ^B Thiobarbituric acid reactive substances (n = 2), tissue inhibitor of metalloproteinase-I/II, amino terminal propeptide of type III procollagen, endocan, high mobility group box-1, and thiobarbituric acid reactive substances. ^C Thyroid-stimulating hormone. ^D Liver-to-spleen computed attenuation ratio, nonprotein RQ, substrate oxidation. ^E Liver-to-spleen computed attenuation ratio, urea. ^F Mental health: general health questionnaire, depression, anxiety and stress scale. ^G Endothelial dysfunction parameters.