Metabolic syndrome and skin: psoriasis and beyond.

Metabolic syndrome (Met S) is a clustering of risk factors comprising of abdominal obesity, dyslipidemia, elevated blood pressure, and abnormal glucose tolerance. The prevalence of Met S has been increasing in the last few years throughout the world. Psoriasis has consistently been associated with Met S as well as its various components. However, the association is no longer limited to psoriasis alone. Various dermatological conditions such as lichen planus, androgenetic alopecia, systemic lupus erythematosus, skin tags, acanthosis nigricans, and even cutaneous malignancies have also been found to be associated with this syndrome. Though chronic inflammation is thought to be the bridging link, the role of oxidative stress and endocrine abnormalities has recently been proposed in bringing them together.

What was known?

1. Chronic inflammation is the bridging link between psoriasis and components of metabolic syndrome (Met S).

2. Treatment of psoriasis has a beneficial effect on the treatment outcome of concomitant vascular diseases.

3. Conditions such as acanthosis nigricans (AN) and skin tags have been classically associated with Met S.

Introduction

Metabolic syndrome (Met S) is a clustering of risk factors which are of metabolic origin and are accompanied by increased risk of cardiovascular disease and type-2 diabetes mellitus. These risk factors include central obesity, atherogenic dyslipidemia, elevated blood pressure, and raised plasma glucose.[1] Mortality risk of coronary artery disease after adjustment for conventional cardiovascular risk factors is around three times in patients of Met S.[2] Different groups such as National Cholesterol Education Program's Adult Treatment Panel III, World Health Organization, and the European Group on Insulin Resistance, agree on the essential components of Met S with minor differences in details and criteria. Out of all these, the most commonly worldwide used criterion is the one proposed by National Cholesterol Education Program's ATP III. It requires the presence of at least three of the following: Abdominal obesity: Waist circumference: ≥ 102 cm in men or ≥ 88 cm in women; elevated triglycerides: ≥ 150 mg/dl; reduced high-density lipoprotein (HDL) cholesterol: < 40 mg/dl for men, < 50 mg/dl for women; elevated blood pressure: ≥ 130 mmHg systolic or ≥ 85 mmHg diastolic; and elevated fasting blood glucose: ≥ 110 mg/dl.[3] It has been found that the cardiovascular risk conferred by Met S is higher than the individual components and hence it is important to study the association of diseases with Met S as a whole.[4]

Over the past few decades, there has been an alarming increase in the prevalence of Met S in industrialized as well as developing nations in the world. Approximately, one-third of the adult population in developed countries can be categorized as having Met S by different definitions.[5] In India, incidence of Met S was found to be 18.3% in a large-scale trial in Chennai in 2006.[6]

Recent evidence suggests that various dermatological diseases are associated with Met S and/or its components. The diseases include psoriasis, androgenetic alopecia (AGA), acanthosis nigricans (AN), skin tags, lichen planus (LP), acne inversa (AI), systemic lupus erythematosus (SLE), and even skin cancer. As the exact mechanism by which these disorders are related to Met S is yet to be explained, systematic studies are needed to further our understanding on this topic.

The Skin: Metabolic Syndrome Connection

Inflammation

Chronic inflammation with a persistent elevation in the level of proinflammatory cytokines is the hallmark of Met S.[7] Leptin, adiponectin, tumor necrosis factor-α(TNF), interleukin 6 (IL-6), monocyte chemotactic protein-1(MCP-1), and other adipocytokines produced by adipocytes or the fat cells, which are now themselves recognized as a part of the innate immune system, have an important role in the pathogenesis of insulin resistance. They are also associated with metabolic complications such as dyslipidemia, hypertension, and premature heart disease and are elevated in many dermatological diseases associated with Met S.[8] It is proposed that cytokine (chemokine)-activated leukocytes in cutaneous sites could either enter the skin tissue or circulate after rolling on inflamed endothelial cells. These cells and cytokines released into the systemic circulation may alter the function of hepatocytes, vascular cells, and leukocytes and can be instrumental in formation of atheroma.[7] Moreover, the role of inflammation in the association between dermatological conditions and Met S is further proved by the fact that many therapeutic protocols designed primarily for the management of chronic dermatoses have succeeded in lowering the level of cytokines responsible for the development of associated cardiovascular comorbidities. Therapeutic intervention based on drugs such as methotrexate and TNF-α antagonist has been found to promote a decrease in insulin resistance, blood level of C-reactive protein (CRP) and IL-6, and an increase in HDL.[910]

Oxidative stress

Oxidative stress, a condition of relative imbalance between reactive oxygen species (ROS) and antioxidants, is believed to play a central role in the pathogenesis of Met S.[1112] Xenobiotics such as exogenous chemicals, drugs, environmental pollutants, cosmetics, and dietary components form a major source of ROS and many of them are eliminated through the skin.[13] The skin expresses all known xenobiotic metabolizing enzymes, such as cytochrome P450 enzymes, flavin-dependent monooxygenase, monoamine oxidase, alcohol dehydrogenase, aldehyde dehydrogenase, nicotinamide adenine dinucleotide phosphate: Quinone oxidoreductase, glutathione S-transferase, and catechol-O methyltransferase.[14] It has been proposed that a derangement in the elimination of ROS through sebum results in an increased blood level of circulating lipids and cholesterol, thereby increasing the risk of dyslipidemia and Met S.[141516] The various components of Met S show seasonal variations in their symptoms and signs: Both blood pressure and blood cholesterol levels are increased in winter.[1718] Being more sensitive to environmental temperature than other organs, it's possible that the skin has a role in the association between blood pressure fluctuations and ambient temperature cannot be ruled out. The seasonal variation of Met S may involve seasonal fluctuations in skin-mediated metabolism and elimination of ROS. Dietary xenobiotics have significantly increased in the life of modern man, while the skin functions, especially sweat-mediated excretion, have decreased due to sedentary lifestyles.[1920]

Endocrine abnormalities

Intra-abdominal fat is an endocrine organ capable of secreting proteins such as adiponectins and leptin, thereby promoting inflammation, altered glucose metabolism, and vascular endothelial biology. Met S has been consistently associated with decreased plasma adiponectin level.[21] Hypoadipoleptinemia is found in chronic inflammatory diseases like psoriasis compared with healthy controls, therefore contributing toward the development of Met S.[2223] Similarly, leptin in addition to being a hypothalamus modulator of food intake, body weight, and fat stores, exerts an important role in acute and chronic inflammatory processes through regulation of cytokine expression that modulates the balance of helper T-cell types 1 and 2.[24] Hyperinsulinemia induced local androgen production is thought to be responsible in the causation of AGA in patients of Met S.[25]

Diseases of the Skin Associated with Met S

Psoriasis

Among all cutaneous disorders, psoriasis has been found to be having the strongest association with Met S as well as its individual components. In view of increasing literature about it being a systemic disease, it is now classified as an immune-mediated inflammatory disease (IMID) of the skin.[7] It is possible that the first event that occurs is the onset of psoriasis, followed by lifestyle changes and depression associated with smoking or overeating. These habits can lead to the Met S.[26] The National Psoriasis Foundation found a moderate to large negative impact of the disease on the quality of their life, with an alteration of everyday activities.[27] Impaired health-related quality of life may lead to unhealthy lifestyle behaviors such as smoking, alcohol consumption, decreased physical activity, and obesity, which are independent risk factors for cardiovascular diseases.[2829] In contrast, it is possible that obesity favors psoriasis in predisposed individuals because of the proinflammatory state and release of inflammatory mediators such as adipocytokines.

Chronic inflammation is thought to be the bridging link between psoriasis and Met S. Inflammatory markers such as Th1 cytokines (intracellular adhesion molecule-1, TNF-α) play a role in the pathogenesis of psoriasis, Met S, obesity, atherosclerosis, and myocardial infarction.[30] Cytokines of the Th1 pathway (interferon-γ, IL-2, IL-12, and TNF-α) predominate in psoriatic and atherosclerotic plaques.[3132] Adhesion molecules including Intercellular adhesion molecule-1 ICAM-1 and vascular cell adhesion molecule VCAM-1 are upregulated in psoriasis promoting adhesion of inflammatory cells to vascular endothelium, which in turn promote the formation of atherosclerotic plaques and obesity-related insulin resistance by oxidation of low-density lipoprotein in vessel wall.[33] Proinflammatory glycoproteins like osteopontin, peptide hormones like leptin and adiponectin and other markers like homocysteine and CRP have also been implicated in bringing the two conditions together.[34] Dysregulation of T-cell interactions and overexpression of proinflammatory cytokines lead to the hyperproliferaton of keratinocytes and activation of neutrophils in the epidermis.[35] This results in chronic T-cell activation, resulting in a persistent cycle of inflammation and formation of psoriatic plaques.[36] Vascular endothelial growth factor-induced angiogenesis, found both in psoriasis and atherosclerosis, has also been proposed as a common link between the two conditions.[37] Several drugs used to treat psoriasis and/or psoriatic arthritis also have effects on the endothelium and may result in vascular complications.[38]

After the initial work done by McDonald and Calabresi[39] in 1978, several hundred studies have been conducted worldwide to examine the association between psoriasis and cardiovascular diseases. Individual components of Met S such as obesity, hypertension, dyslipidemia, and insulin resistance have been proved beyond doubt to be the comorbidities of psoriasis.[404142] Psoriatics have 2-3 fold higher risk of developing Met S as compared to age-matched controls.[434445] The incidence of Met S is significantly higher in psoriatics after the age of 40.[43444546] One Indian study, however, found the highest prevalence of Met S in the age group 18-30.[47] This association has been found regardless of the gender of the patient,[43454748] except in a single study showing definite female preponderance.[46] Much work has been done to correlate the severity of psoriasis and risk of developing Met S and its complications. Psoriatic patients with a higher Psoriasis area severity index score are more likely to develop Met S[43] although the claim has been refuted by others.[49] It has also been observed that psoriasis patients with Met S had a longer disease duration compared with psoriatics without Met S.[4345]

The worldwide prevalence of psoriasis among children is approximately 1%.[50] Even in children, it has been found to be associated with obesity, hyperlipidemia, diabetes, and a statistically significant increased rate of the Met S when compared with age-and gender-matched controls.[51]

Moreover, there is evidence that treatment of psoriasis has a beneficial effect on the treatment outcome of concomitant vascular diseases. Methotrexate reduces the risk of major cardiovascular events in patients with psoriasis, psoriatic arthritis, and rheumatoid arthritis compared to untreated controls.[52] Therapy with TNF-α antagonists has been found to reduce levels of CRP, particularly in obese patients,[53] and to improve insulin sensitivity in patients with co-existing diabetes.[54]

In spite of so many reported studies signifying the association between psoriasis and Met S, many study groups worldwide have failed to find any causal association between the two conditions.[555657]

Androgenetic alopecia

AGA, the most common type of baldness, is a hereditary thinning of hair induced by androgens in genetically susceptible individuals.[58] Gradual transformation of large terminal follicles to miniature ones is triggered by binding of dihydrotestosterone (DHT) to androgenic receptors in hair follicles of the scalp.[59]

An association between AGA and Met S has been reported, but the mechanism explaining this association remains unclear. Genetic factors and family history have been proposed to explain the association between AGA and cardiovascular disease.[6061] Hyperinsulinemia, hyperaldosteronism, and chronic inflammation are also some of the commonly blamed culprits for this association. Elevated insulin level favors vasoconstriction and nutritional deficiency in the follicles of the scalp, and it enhances the effect of DHT on follicular miniaturization.[62] Hyperaldosteronism contributes to increase in blood pressure and also stimulates hair receptors, thus favoring progression of alopecia.[63] Microinflammation in hair follicles in AGA with an increase in proinflammatory cytokines may be a local manifestation of the systemic inflammation which is associated with higher risk of Met S in these individuals.[64]

The overall prevalence of Met S in AGA varies from 16.6% to 28%.[6566] This association has been most commonly found among people beyond the fifth decade of their life.[6567] The relative risk of getting Met S in AGA has consistently shown a definite male preponderance[68] except in a single study where females outnumbered the males.[66] Family history plays a significant role in particularly those subgroup of AGA who develop cardiovascular disease early in their life.[6869] It has also been seen that severe AGA itself confers a higher risk of Met S[65] as well as coronary artery disease[70] compared with moderate AGA after adjusting for age, family history, and smoking status.

Acanthosis Nigricans

Rapid urbanization, sedentary lifestyle, and a higher rate of childhood obesity have led to the recent increase in the prevalence of AN,[71] which may well reflect increasing trends in obesity and type-2 diabetes worldwide.[72] A number of studies have shown an association between AN and insulin resistance.[7374] Hyperinsulinemia interacts with epidermal keratinocytes, resulting in the formation of AN in frictional areas of the body.[75] In a study conducted among urban population in Sri Lanka, AN was found to be more common among both males and females with Met S.[76]

In a recent study in the USA, 49% of fifth-grade children with AN fulfilled criteria for Met S,[77] following which the authorities have started encouraging their doctors to look for AN in children in order to detect those at high risk of developing diabetes mellitus.[78]

Skin Tags

The association between skin tags, leptin and insulin resistance is a well-researched topic. Increased level of tissue leptin has been reported in skin tags compared to normal skin linking multiple skin tags with obesity and hyperlipidemia.[79] Raised circulating insulin levels can lead to increased epidermal proliferation due to activation of insulin-like growth factor 1 receptor activation in areas of skin folds.[80] Multiple skin tags have also been associated with abnormalities in the glucose metabolism, specifically type-2 diabetes, hyperinsulinemia, and insulin resistance.[818283] However, unlike its individual components, Met S as a whole is yet to be conclusively associated with skin tags.

Acne Inversa

AI (also referred to as hidradenitis suppurativa) is a chronic, destructive, and scarring inflammatory skin disease with prevalence of 1-4%.[8485] The prevalence of central obesity, hypertriglyceridemia, hypo-HDL-cholesterolemia, hyperglycemia and Met S as a whole have been reported to be significantly higher in AI patients than in controls.[86] Chronic inflammation present in AI patients which promotes and enhances metabolic alterations has been proposed as the culprit. However, no correlation between the severity or duration of the disease and Met S has been found till date.[86]

Skin Cancer

The role of metabolic alterations in the etiology of skin cancer is an emerging concept. Body mass index[87] and high blood glucose level[88] have consistently been found to be high risk factors for malignant melanoma (MM) among men. Recently, high blood pressure has also been associated with an increased risk of MM cases in both men and women.[89] In non-melanoma skin cancer, diabetes mellitus type-1 and high blood pressure have been implicated as high risk factors in the process of carcinogenesis.[9091] Too few studies and none of them with direct causal relation makes the association between skin cancer and Met S, a topic still to be researched thoroughly.

Lichen Planus

LP is a chronic disease affecting skin, mucous membranes, and appendages. As chronic inflammation plays a role in its pathogenesis, it has always caught the attention of dermatologists trying to find cutaneous associations of Met S. Among the different components of Met S, dyslipidaemia has been found to be significantly associated with LP.[9293] Increased prevalence of diabetes and carbohydrate intolerance has been observed in patients with LP.[9495] Chronic inflammation in the form of increased erythrocyte sedimentation rate, CRP, and fibrinogen levels in patients of LP has been proposed as the main culprit in its association with dyslipidemia. Lipid levels screening in men or women with LP may be useful to detect individuals at risk and start preventive treatment against the development of cardiovascular disease.

Systemic Lupus Erythematosus

SLE is also an IMID like psoriasis which mainly affects young women. Prevalence of Met S in SLE patients varies between 17% and 40%.[969798] The risk factors identified for development of Met S in patients with SLE include advancing age, low socioeconomic status, lack of exercise, use of high doses of prednisone, and increased level of proinflammatory cytokines.[96] In the last decade, premature atherosclerosis has been identified as an important cause of mortality in SLE patients leading to 5-8 fold higher risk of development of ischemic heart disease as compared to controls.[969798] Thus, it warrants early identification and more aggressive control of risk factors in these patients.

Conclusion

The cardiovascular comorbidity of psoriasis is a well-known fact. Leaving aside a few, majority of the studies conducted worldwide have clearly pointed toward a positive association between psoriasis and Met S. Recently, this association has been extended to various other dermatological conditions such as AGA, skin tags, AN, LP, SLE, and even skin cancers. Though there is a paucity of clinical trials relating dermatoses other than psoriasis with Met S, the trend is clearly visible. As far as persistent proinflammatory state, oxidative stress, and endocrine abnormalities are concerned, many of the chronic dermatological conditions share at least one of them as their pathogenetic mechanisms. Therefore, it is imperative to look for the features of Met S in them also. Dermatologists should be sensitized to look into metabolic derangements in all such patients so that the dreaded complications can be prevented well in time. A multidisciplinary approach in diagnosis and treatment with a focus on the disease as well as its existing and potential comorbidities will definitely be more rewarding for the patient as well as his physician.

What is new?

1. Psoriasis is now classified as an immune-mediated inflammatory disease (IMID) of the skin with a number of cardiovascular comorbidities.

2. Skin plays a major role in the metabolism and elimination of reactive oxygen species (ROS). A derangement in this process results in an increased risk of dyslipidemia and metabolic syndrome (Met S).

3. Psoriasis in children has also been found to be associated with Met S.

4. Many cutaneous diseases other than psoriasis, where chronic inflammation plays a role, have been found to be associated with Met S.

5. Looking for signs of Met S such as skin tags and acanthosis nigricans (AN) early in life could be beneficial in preventing cardiovascular morbidities later.