The association between metabolic syndrome and vitiligo: a systematic review

Introduction

Vitiligo is a chronic autoimmune disorder characterized by the loss of melanocytes, leading to non-scaly, chalky-white macules on the skin. The global prevalence of vitiligo is estimated to be between 0.5% and 2.0% [1, 2] impacting approximately 28 million people worldwide [3]. The etiopathogenesis of vitiligo is complex, multifactorial, and remains largely elusive. Recent research highlights oxidative stress hypersensitivity as a key contributor to melanocyte degeneration. Dysregulation of the immune response in vitiligo may be exacerbated by oxidative stress and abnormalities in metabolic pathways. The resulting redox imbalance can trigger melanocyte death through the activation of cytotoxic CD8+ T cells and various cell death mechanisms, including necroptosis, apoptosis, necrosis, ferroptosis and oxeiptosis [4, 5]. Vitiligo is now understood to be more than a skin disorder; it is frequently linked with a variety of other autoimmune, systemic, and dermatological conditions. Notably, these include thyroid disease, alopecia areata, type 1 diabetes, systemic lupus erythematosus, rheumatoid arthritis, and Addison’s disease [6]. Researchers highlight that vitiligo may contribute to broader systemic abnormalities, including glucose intolerance and lipid dysregulation, underscoring the disease’s potential systemic impact [7, 8].

Earlier, other dermatological disorders, including psoriasis, lichen planus, acne vulgaris, hidradenitis suppurativa, and atopic dermatitis, have been linked with metabolic syndrome (MetS) [9]. MetS has increasingly become relevant due to the exponential increase in obesity worldwide [10]. MetS, first described as syndrome X in 1988, has undergone numerous revisions in its diagnostic criteria over the years. Notable frameworks include the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) guidelines from 2001, later modified in 2004, as well as standards from the International Diabetes Federation (IDF) of 2005, the IDF Consortium of 2009 [11], and more recently, the Polish Scientific Society Consortium of 2022 [12]. Polish researchers suggest that MetS should be diagnosed based on the presence of obesity (assessed by waist circumference or BMI), along with at least two of the following three conditions: hypertension, impaired glucose metabolism or elevated blood glucose, and atherogenic dyslipidaemia [12]. Regardless of the diagnostic criteria applied, key features, such as a set of comorbidities that include obesity, hypertension, and carbohydrate and lipid metabolism disorders remain central to the development of MetS [10].

Despite extensive global efforts, the complex pathophysiology of MetS still needs to be better understood. Its geographic distribution and rising prevalence, particularly in developing countries, suggest a strong link to environmental and lifestyle factors, such as high-calorie diets combined with reduced or insufficient physical activity [10]. Both MetS and vitiligo are thought to stem from an imbalance in oxidative and inflammatory processes. In MetS, elevated levels of proinflammatory mediators, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1, IL-6, plasminogen activator inhibitor-1 (PAI-1), and C-reactive protein (CRP), have been documented, underscoring the role of systemic inflammation [8]. Melanocytes within adipose tissue are thought to play an important anti-inflammatory role, mitigating reactive oxygen species (ROS) and thus contributing to oxidative balance. In vitiligo, however, excessive ROS accumulation is believed to damage melanocytes by compromising the structural and functional integrity of their deoxyribonucleic acid (DNA), lipids, and proteins. This oxidative damage leads to decreased melanogenesis and a reduction in melanocyte populations, potentially impairing their anti-inflammatory capacity [4, 13]. Consequently, the rise in ROS levels may exacerbate oxidative stress, a factor implicated in the development of MetS. Thus, a decreased number of melanocytes and reduced melanogenesis in adipose tissue may represent a shared underlying mechanism contributing to oxidative stress in both vitiligo and MetS.

Aim

Therefore, this review provides an overview of the connection between vitiligo and MetS, describing inflammatory cytokines, factors, and mediators involved in vitiligo and linked to metabolic complications.

Methods

A comprehensive literature search was conducted in the electronic databases PubMed and Google Scholar conducted according to PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines to search all published literature from inception to 16 April 2024 for relevant studies. The search terms included “vitiligo”, “metabolic syndrome”, “BMI” and “hypertriglyceridaemia”. A manual search was also performed by going through the reference list of a few articles. Two reviewers (A.B. and B.K.) independently carried out each stage of the study.

Results

A total of 619 studies were identified in the initial search. Among these, 23 studies met all four inclusion criteria and provided data on the prevalence of MetS in patients with vitiligo. These studies were included in the final analysis, with their key characteristics summarized in Table 1.

Discussion

Of the scientific articles analysed in this review, 16 out of 23 indicate a significant association between vitiligo and MetS.

Oxidative dysregulation and the consequent lipid peroxidation are implicated as key contributors to the pathogenesis of metabolic syndrome and vitiligo. Karadag et al. found that high-density lipoprotein (HDL) cholesterol levels were decreased and the low-density lipoprotein (LDL)/HDL ratio was increased in the patients with vitiligo [14] similarly to Taneja et al. [15]. Researchers showed that even in patients with vitiligo without diabetes, greater insulin resistance (IR) and higher levels of insulin and C-peptide were observed compared to the control group [14, 16–18].

Ataş et al. and Varma et al. found that active, extensive, segmental vitiligo was associated with an increased risk of developing MetS [19, 20]. In contrast, Gourh et al. and Tanacan et al. observed disease activity and non-segmental vitiligo as an important predictor of MetS [13, 21]. Furthermore, prolonged vitiligo duration demonstrated a correlation with MetS [18, 21, 22]. However, other studies suggested that neither the severity nor the activity of vitiligo correlated with the risk of MetS [16, 22]. Bathina et al. stated that MetS was more frequently linked to younger age, female gender, the vitiligo vulgaris type, and higher Vitiligo Disease Activity Score (VIDA) and Vitiligo Area Scoring Index (VASI) scores among vitiligo patients [23]. These findings highlight variability in the reported associations, preventing a definitive conclusion about the roles of vitiligo type, duration, or extent in the development of MetS.

Additionally, intima-media thickness of the common carotid artery (MIMT-CCA) has emerged as a significant marker of subclinical atherosclerosis in vitiligo patients. Studies show that MIMT-CCA is elevated in individuals with vitiligo, correlating positively with disease severity, duration, and associated MetS [24].

In patients with vitiligo, autoantibodies against melanin-concentrating hormone receptor 1 (MCHR1) have been identified, which exhibit a stimulatory effect on pancreatic islet cells, potentially contributing to hyperinsulinemia. This finding aligns with a few studies suggesting an association between IR and vitiligo [14, 16–18]. Also the presence of markers of inflammation, such as circulating interleukins, is involved in the mechanism of IR and atherosclerosis. Papaccio et al. identified elevated levels of inflammatory cytokines, including IL-6 and chemokine 10 (CXCL10), as well as the accumulation of insulin-like growth factor binding protein 5 (IGFBP5) and advanced glycation end products (AGEs) [7]. Elevated levels of proinflammatory cytokines disrupt the insulin signalling pathway by activating p38MAPK, which in turn phosphorylates serine residues on insulin receptor substrate-1 leading to the development of IR [25].

Melanin in the adipose tissue has both anti-inflammatory and antioxidant effects. The number of melanocytes and degree of melanogenesis is reduced in adipose tissue of vitiligo patients. Leptin and resistin increase the production of pro-inflammatory cytokines and chemokines [26]. Studies have shown that serum leptin levels are significantly elevated in vitiligo patients compared to healthy controls [26–28] while adiponectin levels are notably decreased [26]. These findings suggest that adipose tissue may play a pivotal role in the pathogenesis of vitiligo by regulating cytokine production. Additionally, markers like fatty acid binding protein 4 (FABP4), associated with metabolic and cardiovascular risks, were significantly elevated in vitiligo patients [29, 30].

In contrast, some studies have not shown that patients with vitiligo have a worse metabolic profile [18, 31–33] or even Rodríguez-Martín et al. found that vitiligo patients present a more favourable lipid profile, with higher HDL levels and lower triglycerides (TG) than the control group [34].

The findings’ discrepancies may stem from variations in the study design and population, definition and assessment of MetS, clinical heterogeneity in vitiligo: subtypes like segmental versus non-segmental vitiligo, and disease duration impact the metabolic profile.

Potential therapeutic areas

Managing vitiligo continues to pose a significant challenge in modern dermatology. Certain therapeutic interventions for vitiligo have demonstrated cardiovascular benefits. In a study by Bae et al. [35], vitiligo patients treated with narrowband ultraviolet B (NB-UVB) phototherapy exhibited a significantly lower incidence of cardiovascular and cerebrovascular events compared to untreated controls.

Statins, which inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA), are widely used for managing hypercholesterolemia. The cardiovascular benefits of statins extend beyond lipid lowering as their pleiotropic properties, particularly antioxidative effects, are instrumental in restoring redox balance and mitigating oxidative stress. They shift the immune response from a Th1-dominated (pro-inflammatory) to a Th2-oriented (anti-inflammatory) profile, reducing inflammation. By lowering levels of interferon-γ (IFN-γ) and diminishing autoreactive T-cells while increasing regulatory T-cells, statins promote immune balance and mild immunosuppression [36, 37]. Isoprenoids, produced during cholesterol biosynthesis, are known to trigger inflammation through intracellular signalling pathways. Simvastatin mitigates this process by inhibiting HMG-CoA reductase, thereby reducing isoprenoid formation [38]. Given the pathophysiological mechanisms of vitiligo, the pleiotropic effects of statins may offer therapeutic benefits for its treatment. The characteristics of the included studies examining the efficacy of statins in the treatment of vitiligo are presented in Table 2.

In vitro and animal studies

Chang et al. [39] investigated the antioxidant effects of simvastatin on melanocytes in vitro. The protective effect was attributed to the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) as its knockdown abolished this response. An animal study using mouse models demonstrated that simvastatin plays a dual role in preventing and reversing depigmentation. Treatment significantly reduced the infiltration of autoreactive CD8+ T cells in the skin. Flow cytometry further revealed a marked reduction in PMEL-specific TCR transgenic CD8+ T cells (PMELs) in the skin of simvastatin-treated mice compared to vehicle-treated controls [40].

Clinical studies

A case report documented an unintentional improvement in vitiligo following the administration of simvastatin for dyslipidaemia. The patient, treated with simvastatin at a dose of 80 mg/day for hyperlipidaemia, exhibited partial repigmentation of vitiligo lesions. This case provided early evidence of the systemic pleiotropic effects of simvastatin, particularly its anti-inflammatory properties [41]. Hu et al. reported promising results when topical simvastatin was combined with NB-UVB phototherapy, suggesting synergistic effects in promoting melanocyte regeneration [42]. However, evidence from Randomized Clinical Trials (RCT) remains inconclusive, with conflicting results across trials. Some studies observed significant prevention of disease progression compared to placebo or reductions in VIDA [37, 43]. Conversely, other RCTs yielded adverse outcomes. Zhang et al. [44] found oral simvastatin safe but clinically ineffective for vitiligo. Another study reported no statistically significant benefits from combining oral simvastatin with betamethasone valerate cream, despite reductions in VASI in both groups [45]. Also, adding atorvastatin 1% ointment to topical calcineurin inhibitor treatment proved to be ineffective [46]. Vanderweil et al. [47] noted a worsening of disease in patients treated with oral simvastatin, with no meaningful difference from placebo, suggesting a lack of therapeutic efficacy for simvastatin in vitiligo management. The combination of atorvastatin with NB-UVB also proved to be ineffective [48].

While in vitro and animal studies highlight simvastatin’s potential to modulate key pathogenic pathways in vitiligo, these effects do not consistently translate to clinical efficacy. With rising concerns over the safety profile of systemic simvastatin, its oral administration not only demonstrates limited therapeutic efficacy but may also pose potential toxicity risks. Conversely, topical simvastatin emerges as a promising alternative, enabling the localized delivery of therapeutic concentrations without the associated systemic toxicity. Recent advancements, such as the development of simvastatin-loaded nanostructured lipid carriers (simNLCs), have demonstrated both the effectiveness and safety of topical formulations. Studies have shown that simNLCs provide high drug entrapment efficiency, nanoscale particle stability, and controlled drug release, while clinical evaluations confirmed their safety for skin application without affecting biophysical parameters. This innovative approach holds potential for enhancing the therapeutic application of simvastatin in vitiligo treatment [49].

Thiazolidinediones

Thiazolidinediones, also known as glitazones act as agonists of peroxisome proliferator-activated receptor (PPAR)-γ, regulating genes involved in lipid and glucose metabolism, cellular proliferation, differentiation, and apoptosis [50]. Pioglitazone promotes keratinocyte differentiation by increasing the expression of differentiation markers, such as involucrin and filaggrin, and upregulating enzymes involved in forming the ceramide lipid matrix. Additionally, pioglitazone reduces inflammation by downregulating CXCL10, a key inflammatory chemokine associated with disease activity. Morphological improvements in keratinocytes also were observed, indicating enhanced skin barrier function [51]. Papaccio et al. found that pioglitazone improves mitochondrial function in melanocytes and fibroblasts derived from vitiligo-affected skin by enhancing mitochondrial membrane potential, boosting mtDNA copy numbers, and increasing adenosine triphosphate (ATP) production while simultaneously reducing levels of ROS [52].

Bioinformatics analysis of vitiligo datasets identified pathways and genes potentially involved in melanogenesis and disease progression, including the PPAR-γ signalling pathway. Rosiglitazone increased melanin synthesis in melanocytes by activating PPAR-γ and upregulating melanin-related genes, including tyrosinase (TYR), tyrosinase-related protein (TYRP)-1, and TYRP-2 [53].

These findings provide insights into the pathogenesis of non-segmental vitiligo and highlight glitazones as a potential therapeutic agent for the condition.

Others

Proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors are innovative medications that effectively reduce LDL cholesterol levels and lower the incidence of cardiovascular events [54]. Kang et al. explored the therapeutic potential of PCSK9 inhibitors in treating vitiligo. Through Mendelian randomization (MR) analyses using genetic data, they uncovered a protective effect of PCSK9 inhibitors in reducing vitiligo risk. Their findings indicated that conventional lipid profiles do not mediate the connection between PCSK9 and vitiligo. Instead, they identified five possible protein mediators – CCN5, CXCL12, FCRL1, legumain, and FGF2 – suggesting that PCSK9 inhibitors and these proteins could be promising targets for developing effective vitiligo treatments [55].

Glucagon-like peptide-1 (GLP-1) receptor agonists represent a class of therapeutics primarily used to treat type 2 diabetes and obesity. Recent evidence suggests these agents may also contribute to managing dermatological disorders, potentially through their anti-inflammatory mechanisms. Specifically, GLP-1 agonists modulate cytokines that play a pivotal role in the pathogenesis of vitiligo, including TNF-α and IL-17 [56, 57]. Wen-Jun et al. investigated the effects of geniposide (GP), an active compound from the fruit of Gardenia jasminoides Ellis, in treating vitiligo. They suggest that GP may offer a new and efficient way to treat vitiligo by promoting melanogenesis through GLP-1R activation and enhancing c-kit signalling in melanocytes [58]. Lu et al. also highlight the potential therapeutic use of geniposide, particularly in oxidative stress, providing evidence that human melanocytes are protected by geniposide from oxidative damage by activating the PI3K–Akt signalling pathway [59].

Diet and nutrition

As the patient’s metabolic profile is also significantly influenced by the diet, the eating habits of vitiligo patients are becoming an increasingly frequent topic of interest among researchers, particularly through mechanisms like reducing ROS and modulating immune responses. For example, polyunsaturated fatty acids (PUFAs) possess immunosuppressive properties, suggesting they may help reduce excessive immune activation that targets melanocytes [60]. Research by Derakhshandeh-Rishehri et al. found that a high-fat diet, particularly one rich in saturated fatty acids (SFA), was linked to an increased risk of vitiligo, whereas intake of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) was lower in vitiligo patients [61]. Another study revealed dysregulated PUFA metabolism in vitiligo patients, with elevated levels of ALA and reduced arachidonic acid (ARA), with ALA correlating to disease severity. Supplementing with ARA or nordihydroguaiaretic acid (NDGA) was found to suppress CD8+ T cell activity [62]. Conversely, a study in China evaluating the efficacy of oral α-lipoic acid (ALA) in combination with NB-UVB phototherapy found no significant difference in repigmentation rates between the ALA and placebo groups [63]. Furthermore, a study among adult Japanese patients with nonsegmental vitiligo identified a correlation between higher BMI and lower intake of manganese, vitamin D, and pulses with vitiligo. Dietary habits also influenced VASI, with variations based on gender, age, and specific food intake [64]. There is growing evidence that antioxidant-rich diets may reduce oxidative stress [65]. The combination of dietary interventions with standard therapies appears promising, particularly in terms of reducing dosages and minimizing the side effects of systemic treatments. However, further research involving larger patient populations is needed to establish therapeutic standards and dietary support for treatment, with a particular focus on obese patients and those with metabolic syndrome [66].

Conclusions

Vitiligo is a complex autoimmune disorder linked with systemic inflammation, oxidative stress, and metabolic dysregulation, including an association with MetS. Many studies demonstrate a higher prevalence of MetS in vitiligo patients, suggesting shared mechanisms such as oxidative stress and pro-inflammatory pathways. However, inconsistencies remain regarding the role of vitiligo severity, type, and duration in MetS development.

Treatments that target oxidative and inflammatory pathways, such as statins, thiazolidinediones, offer promising avenues for managing both vitiligo and associated systemic risks. However, the inconsistent outcomes of systemic therapies and safety concerns indicate the need for localized and combination treatments tailored to individual patient profiles.

As treatments evolve, addressing the interconnected nature of oxidative stress and immune dysregulation holds the promise for more effective and holistic care strategies.