Metabolic Syndrome and Skin Disease:Potential Connection and Risk

Ni Lian and Min Chen?

Department of Dermatology, Hospital for Skin Diseases (Institute of Dermatology), Chinese Academy of Medical Sciences & Peking Union Medical Collage, Nanjing, Jiangsu 210042, China.

Introduction

Metabolic syndrome(MetS),also known as syndrome X,is a composite of multiple clinical symptoms and numerous postulated pathophysiological mechanisms that is becoming a common cause of mortality.Although MetS is not a dermatological diagnosis, it is closely implicated in a number of dermatological pathological conditions, and several cutaneous manifestations can serve as a clinical indicator for impending MetS as well as facilitate an early diagnosis and appropriate therapy to prevent the longterm sequela of MetS.1-2

Until recently, very little was known about the link between MetS and skin diseases. Over the past several years, it has been reported that MetS is potentially associated with numerous dermatological conditions, of which psoriasis, acne vulgaris, and hidradenitis suppurativa(HS)are most common and well known.Some other skin diseases that are related to autoimmune or systemic inflammatory conditions, like atopic dermatitis (AD)and androgenic alopecia(AGA), also have potential links with MetS.3-9

Pathophysiology

MetS is not an independent disease but rather a continuously developing pathophysiological process.10The most widely recognized and accepted pathophysiology process is insulin resistance caused by free fatty acids.1,11Insulin can stimulate the differentiation of adipocytes, enhance their glucose uptake, and inhibit adipocyte lipolysis.12In muscle tissue and liver, excess free fatty acids can raise the level of blood glucose by inhibiting glycogenolysis and accelerate glycogen production, which is an insulin-dependent process.11,13Some studies have indicated that,under the condition of insulin resistance in adipose tissue, adipocyte development is retarded and lipids are unable to convert from carbohydrates for storage. Consequently, both glucose and lipids redistribute in the circulation and organs, resulting in hyperlipidemia.14

Continuous increase of free fatty acid can cause cytotoxicity to pancreatic b-cell, which may also lead to insulin resistance, and further affect vasodilation. This process is closely linked with chronic cellular inflammation and vascular endothelial destruction.15Adipose tissue is now considered as an endocrine and a paracrine organ.Hypoxic adipocytes may lead to cell necrosis and simultaneously produce inflammatory-related cytokines,such as interleukin-6(IL-6)and tumor necrosis factor-a.11The increasing level of inflammatory cytokines in the blood may also contribute to insulin resistance and endothelial dysfunction, which has been proposed as one possible mechanism.16One study demonstrated that upregulated levels of cytokines on the Th1/Th2 axis were observed in patients with MetS.The serum levels of IL-12,IL-4,IL-5,and interferon-g were all higher in patients with MetS than those in the non-MetS population (P<0.05).This finding indicates that Th cytokines may also play an important role in the pathophysiology of skin inflammation and insulin resistance.17

Insulin resistance is usually accompanied by other pathophysiological changes, such as proinflammatory cytokine release and hyperhomocysteinemia, which can eventually lead to common diseases, including cardiovascular disease and type 2 diabetes mellitus(T2DM),as well as uncommon diseases such as nonalcoholic fatty liver and polycystic ovary syndrome. In fact, any pathophysiological dysfunction may contribute to metabolic balance disorders in the body, leading to skin diseasesn.18-19

MetS-associated dermatological conditions

Psoriasis

Increasingly, studies are reporting that psoriasis is a multisystemic disorder rather than a skin-limited disease alone. Various population-based studies from all continents have shown that MetS is an independent comorbidity in patients with psoriasis. A clinical study on 6,868 psoriatic patients revealed that MetS has a direct association with psoriasis.The risk of developing MetS in the psoriatic group was significantly higher than that in the non-psoriatic group (P<0.001). Furthermore, there was an elevated incidence of ischemic heart disease in the psoriasis group.20Ferdinando et al.21also reported a strong link between psoriasis and MetS in a clinical study.

A comparison between the MetS prevalence in psoriatic patients and healthy controls showed a significant difference (P=0.04); furthermore, psoriatic patients had a higher fasting plasma glucose level(P=0.04),an elevated blood pressure (P=0.007), a higher waist circumference(P=0.003),and a higher body mass(P=0.02).Gui et al.22found that the serum uric acid level in the psoriatic group was significantly higher than that in the non-psoriatic group(P=0.019).The prevalence of hyperuricemia in the two groups was also remarkable (P=0.009). These findings suggest that,as one of the clinical manifestations,elevated serum uric acid levels may have a significant association with psoriasis.

Many studies have suggested that the severity of psoriasis is directly correlated to MetS and that this association could, at least partly, be attributed to adiposity.5,20,23Notably, the risk of developing MetS in psoriatic patients is at least twofold higher than that in non-psoriatic individuals. In addition, MetS development is more frequent in patients with moderate-to-severe psoriasis than in patients with mild psoriasis, which suggests that the psoriasis area severity index(PASI)score is significantly correlated with MetS prevalence.24A recent meta-analysis provided a graded association between the prevalence of MetS and the severity of psoriasis.5In pediatric psoriasis,similar to findings in adult patients,the disease severity is also closely related with the MetS incidence.25MetS is not only closely associated with the incidence of psoriasis,it also has a huge negative impact on the prognosis of this disease.Korkmaz et al.26found that psoriasis may lead to retinal damage and that MetS may cause additional retinal and macular changes in psoriatic patients, such as a significantly thinner retinal nerve fiber layer and a thicker central macula.

C-reactive protein (CRP) plays a role in promoting atherosclerosis and thrombosis. Elevated concentrations of CRP mRNA and/or protein were observed in atherosclerotic plaques and adipose tissue. A study involving 90 patients found that the prevalence of MetS was 43.4% in psoriatic patients, without a gender difference (P=0.14). However, female patients usually had higher risks for obesity and hypertension(P=0.04 and 0.006, respectively). Among all the psoriatic patients,approximately 77.8% had higher CRP levels. The CRP level was nearly sixfold higher in patients with MetS than those without MetS (P=0.05). Moreover, every unit increase of CRP elevated the risk for MetS by an average of 17% (P=0.05), and every unit increase of PASI score elevated the risk for MetS by an average of 6% (P=0.03).27

Regarding the treatment of MetS in patients with psoriasis, some research has indicated that systemic therapies may be beneficial for disease control. A few studies have shown that patients with psoriasis had a reduced cardiovascular disease risk after statin therapy.5However, there is a lack of high-quality, randomized,placebo-controlled researches on patients with psoriasis.A clinical study conducted on 24 patients with plaque psoriasis, who received subcutaneous methotrexate injections (15mg per week) for 12 weeks, demonstrated that levels of the anti-inflammatory cytokine IL-10 increased,whereas those of TGF-b had no significant changes following the treatment. No significant improvements in the lipid profile,fasting plasma glucose level,or serum uric acid level were observed. Thus, systemic methotrexate therapies improved the psoriatic lesions as well as the conditions of MetS,and they may also help to decrease the risk of cardiovascular accident in patients with moderateto-severe psoriasis.28Another clinical study demonstrated that, after 10 sections of narrowband ultraviolet B treatment, significant PASI improvement was observed in the patients without MetS (P<0.001), and the treatment-induced decreases in IL-17 and IL-6 levels were also significant in patients who had not developed MetS(P<0.05). A multivariate logistic regression analysis showed that MetS was an independent risk factor that may produce a negative effect on the narrowband ultraviolet B treatment (P<0.05).29

Acne vulgaris

Acne vulgaris is a sebaceous gland disease related to inflammation and metabolism. The sebum secretion of sebaceous glands is mainly influenced by hormones,especially dihydrotestosterone.Although the composition of sebum is roughly the same in people with or without acne, acne populations are always accompanied by varying degrees of excessive secretion and seborrhea.30Experimental evidence has indicated that mechanistic target of rapamycin(mTOR)expression levels in the skin lesions of acne patients is positively correlated with the magnitude of insulin resistance.The activity of mechanistic target of rapamycin complex 1 (mTORC1) was found to be elevated in the glands and injured skin of patients with acne compared with those who had no acne. Enhanced mTORC1 signaling is a known characteristic of insulin resistance, obesity, and T2DM.9Metformin, a commonly used drug for diabetes treatment that was identified as an mTORC1 inhibitor, is currently being considered as a candidate for treating insulin-resistant skin diseases,including acne vulgaris.A reduction of acne was observed in young males who adopted a hypoglycemic diet in conjunction with metformin therapy.31A cross-sectional study indicated that the incidence of insulin resistance in the acne patients was significantly higher than that in controls without acne (P=0.03). However, there was no significant difference in the incidence of insulin resistance or MetS among the patients characterized by varying degrees of acne.32Overall,young patients with acne have a higher tendency to develop insulin resistance, which may be a stage of prediabetes,and these patients may eventually go on to develop T2DM. Thus, close observation of insulin-resistant acne patients is clinically significant for controlling disease progression.

Hidradenitis suppurativa

Hidradenitis suppurativa (HS) is a chronic inflammatory disease that has recently been recognized as being linked to anincreased prevalenceofmetabolicdisease,such asobesity and hypertension.33-34It was proposed that the proinflammatory state of MetS may be closely related to HS.35A large-sample study that the prevalence of MetS in the HS groupwassignificantlyhigher than thatofthecontrolgroup(P<0.001).Additionally,a higher incidence of obesity was also clearly significant in the HS group (P<0.001), and patients with central obesity accounted for a larger proportion of this group (P=0.004). Furthermore, other metabolic conditions,such as high triglyceride(P=0.009),low high-density lipoprotein(P<0.001),and T2DM (P=0.007)were also observed in the HS group.33Recent studies demonstrated that HS severity is positively correlated with body mass index,and the incidence of HS is notably higher in the obese population.After decreasing body weight,35%fewer patients displayed symptoms of HS,and the area of lesions was reduced(P<0.005).36T2DM was diagnosed in 20%of the HS patients but only in 1.5%of the controls.3Studies have demonstrated that HS is closely correlated to elevated body weight and abdominal circumstance, and these associations were confirmed by a retrospective review.37Overall, there is strong support for a significant correlation between HS and the prevalence of MetS.38

Atopic dermatitis

Atopic dermatitis (AD) is a chronic inflammation-related pruritic skin disease that has been shown to be closely associated with MetS. A cross-sectional study in Korea showed a clear association between AD and MetS (P=0.02) in female patients. The incidence of AD was also positively correlated with an elevated triglyceride level(P=0.05).39A retrospective research demonstrated that obesity was strongly associated with an increased incidence of AD (P=0.006).40Additionally, a metaanalysis including 30 studies showed that central obese or overweight patients have a higher rate of AD compared with patients of normal weight.41

Despite the above findings,the associations of AD with hypertension,diabetes,and gallstones are not yet clear.A cohort study of 6,742 Danish adult AD patients showed a significant reduction in the frequencies of diabetes,hypertension, and cholesterol-lowering medications in adults with AD compared with the general population.42Furthermore, an analysis of 14 studies on the association between AD and MetS concluded that the association seems unlikely to be causal.43However,women with AD tend to be more susceptible to developing MetS compared with those without AD.A positive correlation between AD and central obesity was reported, and this correlation was stronger for women than for men.43As such,further studies are required to confirm the association between AD and MetS.

Androgenic alopecia

Androgenic alopecia (AGA) is a common benign disease that was thought to be associated closely with imbalanced levels of hormones, especially sexual hormones. Several possibilities regarding the exact relationship of AGA and MetS have been proposed, including hypertension and insulin resistance.8Recently,the association between AGA and MetS was proven to be strong.In India,a case-control study showed that more patients were found to have MetS in the AGA group(P=0.001).Additionally,higher serum triglyceride levels and blood pressure were detected in the patients with AGA (P<0.05).44A cross-sectional survey showed a significant association between AGA and gender, T2DM, central obesity, and elevated blood pressure. The female subjects with AGA had a higher risk of central obesity, cerebrovascular disease, and dyslipidemia.45Lee et al.46systematically evaluated 87 observational studies of prevalent or incidental disease in patients with AGA that were published before February 28, 2018. They found that MetS was more prevalent in patients with AGA. Additionally, hyperinsulinemia and MetS were more prevalent in AGA patients compared with non-AGA controls. Furthermore, the severity of AGA is also associated with MetS.Patients with severe AGA have a higher risk of developing hyperglycemia and elevated fasting insulin levels compared with those with mild AGA.Moreover,patients with severe AGA are more likely to die of diabetes or negative cardiovascular events than those with mild AGA.4Further controlled and prospective studies with longitudinal observations are still needed to confirm the interaction between AGA and MetS.

Acanthosis nigricans

Acanthosis nigricans(AN),also named keratosis nigricans or dystrophie papillaire et pigmentaire,is characterized by skin pigmentation and papillary thickening or velvety thickening. The etiology of this disease is not currently clear and is generally thought to be associated with the tyrosine kinase growth factor receptor signaling pathway in the epidermis.47It was reported to be the most common skin manifestation of obesity,with an incidence of 74%.48Normal levels of insulin in the serum can promote glucose metabolism,whereas high levels of insulin can promote skin fibroblast and keratinocyte proliferation.7Patients with AN had a higher risk of developing MetS, and there was a significant correlation between AN and obesity,high waist circumference,hyperinsulinemia,dyslipidemia,and elevated blood pressure.49Researchers found that the AN group had the highest insulin level, which indicates that AN patients may have a higher risk of hyperinsulinemia compared with obese patients without AN.50-51Children with obesity, hyperinsulinemia, or diabetes are more likely to develop AN,and they may go on to have a higher cardiovascularrisk asadults.37,48,52Untilnow,theclassificationof AN has been inconsistent, and assessments of its severity have been insufficient;further studies are still needed.

Conclusion

MetS is a collection of clinical manifestations that include dyslipidemia, hypertension, hyperglycemia, and central obesity. Hyperinsulinemia and insulin resistance are currently proved to be the pathophysiological basis for MetS. Numerous studies have found that there is a close relationship between MetS and various inflammatory skin diseases, such as psoriasis. For healthcare providers, the clinical applications of these associations will help them to better monitor and care for patients with MetS and an inflammatory skin condition. In addition, recent research supports the role of the skin as a target organ of insulinregulating functions in the pathogenesis of inflammatory diseases. These findings further support the coordinated interaction between every system of the human body,and confirm that skin manifestations could be treated as an early indicator of systemic metabolic disorders.