Metabolic syndrome and the skin: a more than superficial association. Reviewing the association between skin diseases and metabolic syndrome and a clinical decision algorithm for high risk patients

Reviewing the history of MeTS, Professor GM Reaven was the first to describe it as (then) Syndrome X in 1988. It was defined as the condition where individuals with hyperinsulinemia/insulin resistance are disproportionately glucose intolerant, with concomitant dyslipidemia characterized by a high plasma triglyceride (TG) and low high-density lipoprotein (HDL) concentration, and an increase in blood pressure (BP). Notably, all these changes increase cardiovascular disease (CVD) risk [9].

Ten years later the world health organization (WHO) proposed a modified definition. Patients needed to be insulin resistant or to have either T2DM, impaired glucose tolerance (IGT, defined as a glucose level above a predetermined cutoff, commonly 140 mg/dl, for 120 min after ingestion of 75 g of glucose load during an oral glucose tolerance test) or impaired fasting glucose more than 100 mg/dl (IFG). Euglycemic hyperinsulinemic clamp studies or Homeostatic model assessment (HOMA-IR) could be used as evidence of insulin resistance. In addition, two of the following criteria should also be met: obesity (abdominal or overall), dyslipidemia (high TG or low HDL) concentration, elevated blood pressure, or microalbuminuria [10]. The above definition finds mandatory the insulin resistance criterion but allows T2DM to be diagnosed with metabolic syndrome if they meet two of the rest of the criteria. Because some of the measurements are not performed routinely, for example, euglycemic clamp studies (for insulin resistance measurement), this definition is not easily applied in every day clinical practice.

In 1999, the European Group for the Study of Insulin Resistance (EGIR) proposed a modification to the WHO definition [11]. This time a fasting plasma insulin value that is greater than the 75th percentile is the main criterion for the syndrome something that simplified the diagnosis excluding however patients with T2DM. Also two of the following criteria need to be met: obesity, hypertension and dyslipidemia. The obesity criteria were simplified to waist circumference, whereas the WHO definition used a choice of waist-to-hip ratio or body-mass index. Microalbuminuria was excluded as a diagnostic criterion.

In 2001, the National Cholesterol Education Program Adult Treatment Panel (NCEP-ATP) III published their criteria for diagnosing MeTS. It is a more simple and easy to use definition. Five criteria were specified: abdominal obesity, estimated by an increased waist circumference, high TG and low HDL concentrations, elevated BP, and glucose intolerance [12]. Presence of any three of the above criteria is considered compatible with a MeTS diagnosis according to the NCEP-ATP III.

The International Diabetes Federation (IDF) in 2005 proposed yet another definition that included a definite criterion of waist obesity plus two of the other components. It should be mentioned though that today non-obese patients are also diagnosed with MeTS (termed metabolically obese). The basis for this lies in the fact that this group has increased visceral fat accumulation [12].

Due to possible confusion from their contradictory definitions, the IDF and the NCEP-ATP III more recently reached a common harmonized definition comprising five equal criteria: elevated waist circumference (defined according to specific population characteristics), low HDL levels, high TG levels, elevated BP, elevated fasting glucose [11‐15]. Once more, presence of at least three was necessary and sufficient for MeTS diagnosis (Table 1).

The previous data serves as a basic introduction to the history of MeTS. Of note, several authors argue that all risk factors should be treated equally and that use of the term MeTS in routine clinical practice should be done cautiously. It has also been suggested that MeTS could be considered a pathophysiologic mechanism/continuum rather than a syndrome and be graded according to severity and potential for CVD occurrence [14].

The most widely accepted theory for the pathophysiology of the syndrome is insulin resistance [16]. The muscle, fat and liver cells do not respond properly to hormone insulin and cannot absorb easily glucose from the bloodstream. Beta cells of the pancreas initially try to produce more insulin to achieve euglycemia. Progressively, pancreas fails to keep up with the increased demand for insulin and excess glucose builds up in the bloodstream [16].

Amongst the various skin conditions investigated, psoriasis holds a great interest in relation to MeTS. Psoriasis is a chronic inflammatory disease, affecting 1–4% of the general population, considered a multisystem disorder, rather than a skin disease alone. The prevalence of the MeTS has been estimated to be about 15–25% in the general population, appearing significantly higher (an increase by about threefold) in psoriatic patients, as documented by many case–controls studies [24, 25].

The association between psoriasis and MeTS is directly correlated with the severity of psoriasis. Various population based studies from all continents show that MeTS is an independent comorbidity in psoriatic patients. In 1978 McDonald et al. investigated connection of psoriasis with vascular disease and Gisondi et al. found a prevalence of 30.1% of MeTS in psoriasis patients vs 20.6% in control [26, 27]. The cross–sectional study of Cohen et al. also showed an association between psoriasis and MeTS [28]. The study of Praveenkumar et al. suggests that MeTS, as well as dyslipidemia (low HDL), are more common in psoriasis patients (MeTS prevalence in psoriasis 60% vs 40% in controls, p = 0.12). In particular, risk factors such as dyslipidemia, increased BP, obesity, insulin resistance were more prevalent in psoriatic patients, although differences did not reach statistical significance [29]. Another study from Thailand conducted by Kokpol et al. showed that all psoriatic patients had higher prevalence of MeTS than the general population (49.25% vs 30.65%) [30]. The metabolic components which were significantly higher in the cases than controls included hyperglycemia, high blood pressure (HBP) and abdominal obesity. Studies in a large population from Henseler et al. showed similar results, with systemic disorders, such as diabetes and obesity occurring significantly more often in patients with psoriasis than in control subjects [31]. Itani et al. investigated 150 patients with psoriasis, and noted a twofold increase in MeTS in relation to controls (35.3% vs 18.0%, p < 0.001) and even higher in cases of inverse psoriasis and nail pitting [32]. Meziane et al. also found a higher incidence of MeTS among 150 psoriatic patient [33]. An indirect relation also has to be considered, given that psoriatic male patients are more often smokers thus more susceptible to MeTS-related disorders. Owczarczyc-Suczonek et al. found, in a group of 69 psoriatic patients, that the prevalence of MeTS was 25.81% vs 21.02% in the control group (p = NS), the mean HOMA-IR (insulin resistance index) being 1.93 vs 1.94 (p = NS) [34]. It has also been reported that liver fibrosis due to fat accumulation is more frequent in comparison to the general population [35].

Neimann et al. investigated cardiovascular risk factors in patients with mild and severe psoriasis. CAD risk factors where more prevalent in patients with severe psoriasis [24]. A plausible mechanistic hypothesis postulates that psoriasis predisposes to MeTS and arterial stiffness due to the various inflammatory markers circulating in the blood, the so-called ‘psoriatic march’. The hypothesis states that psoriasis is a chronic systemic inflammatory disease resulting in insulin resistance by down-regulation of insulin receptors. Cytokines of the Th1 pathway [interferon-γ, interleukin (IL)-2, IL-12, and tumor necrosis factor (TNF)-α] predominate in both psoriatic and atherosclerotic plaques [21]. In addition, the decrease in the expression of insulin receptors in endothelial cells results in reduction of nitric oxide (NO), a vasodilatory agent. Thus, vasoconstriction ensues, leading to increased arterial stiffness. As a result, increased incidence of myocardial infraction (MI) and stroke has been reported. It has been shown that the use of an insulin stimulating agent (glucagon like peptide 1—GLP-1) can improve psoriasis emphasizing the effect of insulin resistance in inflammation [25, 35, 36]. There are successful attempts to prove that various inflammatory markers increase initially on the skin and then systemically on psoriasis as C reactive protein. This markers can deteriorate the metabolic syndrome. Also oxidative stress and DNA/RNA damage is increased in patients with psoriasis and metabolic syndrome. So, the evidence shows at least similarities on the pathophysiology of both conditions [37]. Chronic inflammation of psoriasis and the downregulation of insulin receptors predisposes to MeTS. The chronic inflammation of MeTS affects the homeostasis of the skin in combination with genetic and other factors. A late article for Korkmaz et al. states that a change in expression of apoptosis activators may contribute to the development of MeTs in patients with psoriasis [38].

Screening of psoriatic patients for CVD risk factors may uncover those both at high risk and suboptimally managed [39]. Recent algorithm for patients with psoriasis and metabolic syndrome has been published by Radtke et al. [40]. According to the algorithm patients with psoriasis and metabolic syndrome should be referred for further management when they develop three of the following criteria: visceral obesity (waist circumference > 94 cm in men or > 80 cm in women), triglycerides > 150 mg/dl or on specific therapy, HDL < 40 mg/dl in men or < 50 mg/dl in women or on specific treatment, systolic pressure > 130 mmHg or diastolic > 85 mmHg or on treatment, fasting plasma glucose > 100 mg/dl. Follow up should be arranged every 6 months for severe psoriasis (or for those on systemic medication), or annually for mild cases. Furthermore, lifestyle changes, such as smoking and alcohol cessation, dietary habits and exercise should be pursued.

Overall psoriasis may be independently associated with the development of MI and ischemic heart disease [22]. Conflicting studies do not prove always such a relation. There are however populations differences on the severity of obesity on Western society in comparison to other populations possibly explaining this results [41]. Consequently, physicians should be aware of an increase in CVD risk in psoriatic patients and adjust their management accordingly [24, 35, 36, 42‐49].

In 2012 Nagel et al. investigated the relationship of MeTS parameters with skin cancer. A positive relation was found in women with malignant melanoma (MM) and increased blood pressure. Also, men with MM tend to have higher body mass indices (BMI). Women with squamous cell carcinoma/non melanoma skin cancer had a tendency towards increased glucose and TG. Moreover, development of xanthelasmata and tendon xanthomas (although obviously not proliferative, tumor-like disorders) is quite typical of congenital hyperlipoproteinemias [73‐75].

Nagase et al. investigated the skin aging process in animal models with MeTS. They found evidence of both oxidative stress and upregulated inflammatory markers as well as increased expression of mineralocorticoid receptors in the skin [76]. They propose a similar mechanism of aging to the one adopted for internal organs in MeTS. More specifically, oxidative stress and inflammation are related to MeTS, consequently, free oxygen species damaging DNA, mitochondrial function and producing hormonal dysregulation (including insulin resistance) have been associated with the aging process [77]. It appears that skin collagen glycation is related to both MeTS parameters and aging.

Glycation products cross-link with collagen bundles interfering with its function. This phenomenon becomes more intense in diabetics, accelerating skin aging. Intrinsic factors like the Maillard reaction but also oxidative stress affect fibroblast gene expression reducing levels of metalloprotease inhibitors and increasing production of metalloproteases that degrade collagen. Moreover, collagen itself becomes stiffer with an altered function. Based on this theory, many studies propose antioxidants and inhibitors of collagen glycation as preventive treatments. This condition, along with oxidative stress, inflammation and endothelial dysfunction, has been studied in relation to diabetes. Antidiabetic medication for patients with T2DM would theoretically reduce the reactions’ extend by controlling blood glucose levels [78]. In general, collagen glycation is considered a platform for research on the pathogenesis of skin aging [79, 80]. Skin autofluorescence showed to be effective on detection of individuals with advanced glycation end products and predisposition to MeTS. This could be a promising method for research and future population studies [19].

Conditions such as holoderma (knuckle pads), striae, skin tags, impaired wound healing, vitiligo have been directly or indirectly connected to MeTS [81‐86].

Investigators have shown interest in the microscopic changes to the skin structure in individuals with MeTS. Janovska and colleagues microscopically observed dyspigmentations and telangiectasias on the skin of patients. Moreover, histological sections showed dermal elastosis, thickening of stratum spinosum and basal membrane, acanthosis, as well as mild Τ lymphocytic infiltration around capillaries. Bcl-2 anti-apoptotic protein was accumulated in the epidermis more significantly in participants with MeTS [87].

Furthermore, Puchau et al. found an inverse correlation between several trace element levels (including zinc, selenium and copper) from nail samples of individuals and blood inflammatory cytokine levels, stressing the importance of these antioxidant elements against chronic inflammatory states and skin aging [88].

Table 3 summarizes studies exploring associations between MeTS and various skin diseases.