Combining nutraceuticals and a mediterranean diet for managing metabolic dysfunction associated with steatotic liver disease

Abstract

This study was performed by Cano Contreras et al, who explored the effects of alpha-lipoic acid (ALA) and Silybum marianum (SM) supplementation combined with a mediterranean diet (MD) on metabolic dysfunction-associated steatotic liver disease (MASLD). The randomized controlled design and use of transient elastography provide methodological strengths, whereas the focus on a Mexican cohort addresses a critical gap in regional MASLD research. Although improvements in visceral fat and controlled attenuation parameters (CAP) were observed, key metabolic markers, including transaminases and lipid profiles, showed no significant changes, raising concerns about the intervention's comprehensive metabolic impact. The reliance on CAP and the absence of mechanistic biomarker analysis limit insights into the antioxidant and anti-inflammatory pathways of ALA and SM. Future research should explore synergistic effects with other nutraceuticals, such as vitamin E and polyphenols, and include extended follow-up and patient stratification to assess long-term benefits and personalized therapeutic outcomes. Addressing these limitations could solidify the role of nutraceuticals in MASLD management and enable the development of more effective and sustainable interventions.

Key Words: Alpha-lipoic acid; Dietary interventions; Metabolic dysfunction-associated steatotic liver disease; Silybum marianum; Synergistic effects; Vitamin E

Core Tip: This study demonstrated the therapeutic potential of combining α-lipoic acid and Silybum marianum supplementation with a Mediterranean diet for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD). While the intervention reduced visceral adiposity and improved hepatic steatosis markers, key metabolic parameters, including transaminase levels and lipid profiles, remained unchanged. Future investigations should prioritize (1) Mechanistic studies on antioxidant and anti-inflammatory pathways; (2) Exploration of synergistic combinations with complementary nutraceuticals; and (3) Extended follow-up periods to evaluate long-term efficacy and safety. Importantly, patient stratification accounting for disease severity and comorbidity profiles will be essential for developing personalized treatment strategies in MASLD management.

TO THE EDITOR

We read with great interest the study by Cano Contreras et al[1], "Effect of alpha-lipoic acid and Silybum marianum supplementation with an Mediterranean diet on metabolic dysfunction-associated steatosis," which highlights the potential of integrating nutraceuticals with dietary interventions for managing metabolic dysfunction-associated steatotic liver disease (MASLD). The findings present an exciting avenue in the field of hepatology, yet we believe that there are additional considerations that merit discussion.

Strengths of the study

This study’s randomized controlled design and its use of transient elastography (TE) as a noninvasive tool for assessing liver steatosis are significant methodological strengths. Additionally, the focus on a Mexican cohort fills a critical gap in region-specific research on MASLD, offering valuable insights into the relationship between lifestyle factors and metabolic health in this population.

Evaluation of study limitations and emerging research opportunities

While this study highlights the potential benefits of combining Silybum marianum (SM) and α-lipoic acid (ALA) with the mediterranean diet (MD), several limitations warrant discussion. Notably, the improvements observed in visceral fat and controlled attenuation parameters (CAPs) did not translate into significant changes in key metabolic markers, such as transaminases and lipid profiles, raising questions about the comprehensive metabolic benefits of this intervention.

The reliance on TE as a noninvasive tool for assessing liver steatosis is commendable, but its inherent limitations are important. TE, which combines CAP for steatosis quantification and liver stiffness measurement for fibrosis staging, faces challenges in distinguishing early-stage fibrosis from inflammation and may overestimate steatosis in obese patients owing to subcutaneous fat interference. Moreover, TE has lower diagnostic accuracy than magnetic resonance imaging-proton density fat fraction (MRI-PDFF) and liver biopsy do, particularly in patients with advanced fibrosis or heterogeneous hepatic fat distribution. For example, liver biopsy remains the gold standard for assessing necroinflammatory activity and ballooning degeneration, which TEs cannot reliably capture[2-4].

The reliance on CAP as the sole method for assessing hepatic steatosis, although noninvasive, may not capture the complexity of histological changes[5]. The incorporation of advanced imaging techniques (e.g., MRI-PDFF) or liver biopsies in future studies could provide a more detailed understanding of hepatic improvements[6].

Furthermore, while the antioxidant and anti-inflammatory properties of ALA and SM were emphasized, the study lacked detailed mechanistic data. Insights into changes in biomarkers such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and oxidative stress markers (e.g., malondialdehyde) could elucidate the pathways driving the observed benefits. Future studies should integrate TE with advanced imaging modalities (e.g., MRI-PDFF) or minimally invasive biomarkers (e.g., PRO-C3) to improve diagnostic precision and reduce reliance on operator-dependent techniques. Addressing these gaps would align the findings more closely with current research priorities in hepatology[7,8].

Future research directions

Building upon the promising findings of this study, it is crucial to delve deeper into areas that remain unexplored or under investigated. Mechanistic studies should aim to elucidate the anti-inflammatory and antioxidative pathways activated by SM and ALA, particularly through the measurement of biomarkers such as IL-6, TNF-α, and oxidative stress indicators[9]. This could provide a more comprehensive understanding of their hepatoprotective effects[10]. Additionally, integrating these nutraceuticals with other compounds, such as polyphenols or vitamin E, might reveal synergistic benefits that enhance therapeutic outcomes for MASLD[11]. Future trials should prioritize extended follow-up durations to assess the long-term sustainability of observed metabolic and hepatic improvements, especially concerning fibrosis regression. Finally, stratifying patients on the basis of MASLD severity or comorbid conditions could identify subpopulations that benefit most, paving the way for more personalized treatment approaches in clinical practice.

Mechanistic pathway analysis: Future research should incorporate a comprehensive panel of biomarkers, including IL-6, TNF-α, malondialdehyde, and nuclear factor-κB (NF-κB) activation, to elucidate the specific anti-inflammatory and antioxidative mechanisms of SM and ALA[11,12]. For example, IL-6 and TNF-α are key mediators of hepatic inflammation in MASLD and are directly linked to insulin resistance and hepatocyte apoptosis. ALA, through its thiol-disulfide redox activity, may suppress NF-κB signaling, thereby reducing TNF-α production and downstream inflammatory cascades. Similarly, silibinin (the active constituent of SM) has been shown to inhibit IL-6 synthesis via modulation of the JAK/STAT pathway, ameliorating hepatic steatosis and fibrosis in preclinical models[13-15]. This approach aligns with the growing emphasis on precision medicine and could reveal nuanced interactions between these nutraceuticals and molecular pathways linked to MASLD pathophysiology[16,17].

Combination therapies: The synergistic potential of combining ALA, SM, and MD lies in their complementary mechanisms, which target multiple facets of MASLD pathophysiology[11,18]. ALA, a mitochondrial coenzyme, enhances glutathione synthesis and scavenges reactive oxygen species, whereas SM (via silibinin) modulates hepatic lipid metabolism by activating AMP-activated protein kinase and suppressing the SREBP-1c pathway. The MD, which is rich in polyphenols (e.g., hydroxytyrosol from olive oil), omega-3 fatty acids, and fiber, potentiates these effects by reducing systemic inflammation and improving insulin sensitivity[1,11,18]. For example, omega-3 fatty acids in the MD inhibit NLRP3 inflammasome activation, synergizing with ALA’s antioxidant properties to attenuate hepatic oxidative stress. Similarly, polyphenols from MD components (e.g., nuts and red wine) enhance the antifibrotic effects of SM through the modulation of the TGF-β1 pathway[19-21].

Vitamin E, a potent antioxidant, not only mitigates lipid peroxidation but also downregulates IL-6 and TNF-α expression in Kupffer cells, as demonstrated in NASH clinical trials[11,22]. This dual mechanism reduces hepatic inflammation and improves histological features in MASLD, particularly in nonalcoholic steatohepatitis (NASH)[11,22]. Similarly, polyphenols such as curcumin and resveratrol have shown promising effects in mitigating oxidative stress and modulating inflammatory pathways (e.g., NF-κB and the NLRP3 inflammasome) in preclinical and clinical studies. Integrating these nutraceuticals with the MD creates a multimodal intervention that addresses insulin resistance, lipotoxicity, and gut-liver axis dysregulation, which are central to MASLD progression[23-25]. Clinical trials should prioritize the evaluation of such combinations to optimize dosages and identify patient subgroups (e.g., those with PNPLA3 polymorphisms) that may derive maximal benefit[24,26].

Long-term outcomes: Extending the follow-up period beyond 24 weeks is crucial to assess the durability of the metabolic and hepatic improvements observed in this study. Emerging research emphasizes the progressive nature of MASLD and the variability in individual responses to interventions. Evaluating fibrosis regression over extended durations could provide insights into the long-term efficacy of SM and ALA, particularly in reversing or halting disease progression[27]. Additionally, incorporating advanced metrics such as serial elastography assessments and molecular biomarkers of fibrosis may offer a more comprehensive understanding of sustained therapeutic benefits and potential relapse patterns[27,28].

Patient subgroup analysis: Stratifying patients on the basis of MASLD severity; comorbid conditions such as diabetes and hypertension; or genetic predispositions could provide nuanced insights into therapeutic responses. Recent studies suggest that MASLD progression and treatment efficacy are influenced by patient-specific factors, including metabolic syndrome components and genetic variants such as PNPLA3 and TM6SF2[29,30]. Understanding these differences could optimize patient stratification, enabling the development of tailored interventions that maximize therapeutic outcomes and improve clinical applicability[31].

CONCLUSION

Cano Contreras et al[1] demonstrated promising clinical potential for integrating nutraceuticals, specifically the synergistic combination of SM and ALA with MD principles, into MASLD management. While their findings establish a valuable foundation, two critical limitations merit attention: The exclusive use of noninvasive diagnostic modalities and insufficient exploration of the underlying biological mechanisms. These methodological constraints highlight the necessity for subsequent studies incorporating histological validation and multiomics approaches to elucidate molecular interactions. To advance clinical translation, future research should prioritize systematic investigations of nutraceutical-pharmacodynamic interactions, conduct large-scale longitudinal trials with extended follow-up periods (> 5 years), and perform comparative effectiveness studies against standard therapeutic regimens. Addressing these knowledge gaps would significantly enhance the evidence base for developing precision nutrition protocols in MASLD care. The authors' work importantly bridges nutritional science and hepatology, paving the way for innovative, cost-effective strategies to combat this escalating global health challenge.