Table of Contents  
REVIEW ARTICLE
Year : 2016  |  Volume : 9  |  Issue : 2  |  Page : 168-176  

Lingering immune dysregulation of inflammatory dermatoses, particularly psoriasis, probably drives metabolic syndrome culminating in cardiovascular damage and needs preventive public health guidelines as well as comprehensive management


Department of Dermatology, Dr. D. Y. Patil Medical College, Hospital and Research Centre, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, India

Date of Web Publication1-Mar-2016

Correspondence Address:
Naren Prakash
Flat No. 603, Anandibaug Phase-2, Kharalwadi, Pimpri, Pune - 411 018, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0975-2870.177653

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  Abstract 

Metabolic syndrome, a constellation of interrelated risk factors of metabolic origin namely, abdominal obesity, insulin resistance, dyslipidemia and hypertension, confers greater risk of cardiovascular disease on its patients than the sum of the individual components. It is increasingly being associated with inflammatory dermatoses, especially psoriasis. Determination of the diagnostic criteria of this syndrome is conditioned by the changing views regarding its pathogenesis. Approximately, a quarter of the world's population harbors this syndrome, whose reported prevalence in India (5-30%) has escalated with an increase in urbanization and socioeconomic status. Due to, up to 3 times, the risk of cardiovascular mortality and up to 24 times risk of diabetes mellitus, the epidemiological significance of metabolic syndrome ideally necessitates formulation of preventive guidelines by public health authorities. Chronic inflammation, involving several cytokines and adipokines, forms the bridge between this syndrome and psoriasis and underlies the formation of atherosclerotic plaque, the primary lesion of coronary artery disease, in whose pathogenesis oxidative stress and genetic factors also play a role. Up to 4-fold increase in the prevalence of metabolic syndrome and 3-fold increased risk of cardiovascular mortality is reported globally in psoriatics. Increasing index of suspicion of this syndrome by the dermatologists, prevention of cardiovascular damage by lifestyle modifications, smoking cessation and redressal of the inherent depression in these patients is as imperative in management as is the specific therapy of the skin lesions of this systemic, rather than "just a skin," disease as well as the lipid-lowering, antihypertensive and antidiabetic agents.

Keywords: Abdominal obesity, cardiovascular disease, dyslipidemia, insulin resistance, metabolic syndrome, psoriasis


How to cite this article:
Sharma YK, Prakash N, Gupta A, Bansal P. Lingering immune dysregulation of inflammatory dermatoses, particularly psoriasis, probably drives metabolic syndrome culminating in cardiovascular damage and needs preventive public health guidelines as well as comprehensive management. Med J DY Patil Univ 2016;9:168-76

How to cite this URL:
Sharma YK, Prakash N, Gupta A, Bansal P. Lingering immune dysregulation of inflammatory dermatoses, particularly psoriasis, probably drives metabolic syndrome culminating in cardiovascular damage and needs preventive public health guidelines as well as comprehensive management. Med J DY Patil Univ [serial online] 2016 [cited 2023 Jan 31];9:168-76. Available from: https://www.mjdrdypu.org/text.asp?2016/9/2/168/177653


  Introduction Top


Psoriasis, an immune-mediated inflammatory disease, characterized by epidermal hyperproliferation, abnormal keratinocyte differentiation, angiogenesis, blood vessel dilatation and excess Th1/Th17 inflammation, affects 2-3% of the population worldwide. [1] The inexorable inflammation underlying its chronic course also predisposes its patients to a number of disorders having an inflammatory component, most notably cardiovascular and metabolic, collectively christened "metabolic syndrome." Hence rather than a mere dermatosis, psoriasis is increasingly being considered a systemic illness.

First described by Kylin in 1923 as the clustering of hypertension, hyperglycemia and gout, [2] metabolic syndrome is a constellation of interrelated risk factors of metabolic origin that appear to promote directly the development of atherosclerotic cardiovascular disease (CVD). [3] Gerald Reaven introduced the concept of "syndrome X" in 1988 proposing insulin resistance to be the underlying cause of all other components. [4] In the diagnostic criteria for the metabolic syndrome proposed by the World Health Organization task force on diabetes, presence of insulin resistance is mandatory. [5] With the growing evidence of its critical role, abdominal obesity has now become pivotal for the diagnosis of metabolic syndrome. Though the unequivocal final consensus on the criteria of this syndrome is yet to be arrived at, most commonly used diagnostic guidelines are summarized in [Table 1].
Table 1: Diagnostic criteria for the metabolic syndrome

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  Components of Metabolic Syndrome Top


The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) 2001, [6] the most widely used guidelines for epidemiological studies, recognized a constellation of the following cardiovascular risk factors of metabolic (lipid and nonlipid) origin as definitive criteria for diagnosing metabolic syndrome and considered it desirable, rather than mandatory, to also estimate proinflammatory (C-reactive protein [CRP]) and prothrombotic (plasma plasminogen activator inhibitor [PAI]-1/fibrinogen) markers, as additional components. [8] The rise in these acute phase reactants due to a high cytokine state observed in the setting of obesity, insulin resistance and other features of metabolic syndrome, has been shown in large prospective studies to correlate with increased cardiovascular risk in these patients. [9],[10]

Abdominal obesity

In contrast to other criteria, all consequences of insulin resistance, obesity is a lifestyle variable that along with physical inactivity has an adverse effect on insulin-mediated glucose disposal. More specifically obesity, rather than being a result of insulin resistance, leads to its increased causation in these individuals. [11] Different fat depots exhibit varying metabolic activity, intra-abdominal obesity being most strongly associated with insulin resistance. [12]

Insulin resistance/glucose intolerance

The term "insulin resistance syndrome" was proposed with the belief in the priority of deranged glucose disposal, its association with other metabolic risk factors and independent correlation with CVD. [9] The selection by the NCEP ATP III of impaired fasting glucose as a diagnostic aid of the metabolic syndrome is based on the use of plasma fasting glucose concentrations to diagnose diabetes, a disease unequivocally known to increase CVD risk. [11]

Atherogenic dyslipidemia

Atherogenic dyslipidemia in routine lipoprotein analysis is characterized by raised triglycerides (TGs) and low high density lipoprotein cholesterol (HDL-C). While the ability of the latter to predict CVD risk has been known for many years, some authors have raised concerns regarding the inclusion of raised TG as an "independent" CVD risk factor in view of the equivocal evidence. However, a decrease in particle diameter of low density lipoprotein (LDL) and increase in postprandial TG-rich remnant lipoproteins, though included in an atherogenic lipoprotein profile, are not cited as part of the criteria for diagnosing the metabolic syndrome. [11]

Raised blood pressure

The most widely debated component of metabolic syndrome and considered by many to be "less metabolic" than the others, is the role of essential hypertension. Though no more than 50% of patients with essential hypertension are insulin resistant, [13] these are the ones at greatest CVD risk. [7] Mechanisms proposed for hypertension in the setting of insulin resistance include the loss of vasodilatory affect of insulin with its affect on sodium reabsorption and the sympathetic system remaining intact. [14]


  Prevalence of Metabolic Syndrome Top


Worldwide prevalence of metabolic syndrome ranges from <10% to as much as 84%, depending on the region, urban or rural environment, composition (sex, age, race, and ethnicity) of the population studied, and the definition of the syndrome used. [15] It is estimated to be ∼25 % in the United States, 23% in Europe, and 20-25% in South Asians. [16] Surveys in large cities in different parts of India suggest about one-third of the urban population to have this syndrome, with the prevalence in the rural population, as low as 5%. [17] Even within the urban environment significantly increased prevalence is seen with improved socioeconomic status. [18] In the Indian migrant populations in other countries, the occurrence of metabolic syndrome and its components is reported to be even higher than in the indigenous populations. [17],[19],[20]


  Metabolic Syndrome and Atherosclerosis Top


Impressive evidence has accumulated over the past decade suggesting the regulation of the atherosclerotic process by inflammatory mechanisms. [21] Several components of metabolic syndrome, including visceral obesity and insulin resistance, are also associated with a low-grade inflammatory state. [22] The interaction between different components of the metabolic syndrome (insulin resistance, dyslipidemia, etc.), contributes to the development of a proinflammatory state characterized by increased oxidative stress and chronic subclinical vascular inflammation. The adipose tissue is a source of several adipokines-leptin, PAI-1, tumor necrosis factor alpha (TNF-α), angiotensinogen and interleukin-6 (IL-6)-that directly contribute to this process [23] resulting in endothelial dysfunction followed by formation of unstable atherosclerotic plaque, [24] the leading cause of death and morbidity worldwide [25] [Figure 1].
Figure 1: Possible mechanism leading to unstable atherosclerotic plaque in metabolic syndrome

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  Impact of Metabolic Syndrome Top


For the development of preventive and therapeutic guidelines of this rapidly spreading syndrome, it is crucial to learn its impact on cardiovascular and overall mortality of the general population.

Cardiovascular disease

Though each component of the metabolic syndrome is an established cardiovascular risk factor, the presence of multiple components confers greater risk than the sum total of the risks associated with the individual components. Using data from the Kuopio Ischaemic Heart Disease Risk Factor Study of middle-aged Finnish men, the relative risk of almost four for coronary artery disease (CAD) mortality and 3.5 for CVD mortality was demonstrated in patients with metabolic syndrome. A sub-study of the Botnia trial demonstrated a 2-fold increase in CAD in the presence of this syndrome while this was shown to be 1.5 times by analysis of data from the Scandinavian Simvastatin Survival Study (4S) and Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). [26],[27],[28]

Diabetes

Individuals with metabolic syndrome were found to have a 5-fold higher relative risk for diabetes in the Framingham Heart data. [26] A 24-fold increased risk of diabetes was demonstrated in the West of Scotland Coronary Prevention Study in those with metabolic syndrome at 5 years follow-up. [29] In a 4-year longitudinal study of 890 nondiabetic Pima Indians, those with this syndrome were almost 3 times more likely to develop diabetes. [30]

Nonalcoholic steatohepatitis

The metabolic syndrome has been shown to be present in 88% of patients with nonalcoholic steatohepatitis (NASH), with up to 98% having insulin resistance, occurring independent of obesity. Hepatic fat content, a hallmark of NASH, was found to correlate most strongly with increased fasting insulin and plasma TG levels. [31]

Polycystic ovary syndrome

Insulin resistance is critical in the pathogenesis of both polycystic ovary syndrome (PCOS) and metabolic syndrome. Thus, it is not surprising that the two frequently coexist. A study showed that fasting blood glucose and insulin levels were significantly higher (P < 0.02 and P < 0.000001) in both lean and obese PCOS patients compared with a control group. [32]

Sleep apnea

The view that sleep apnea and excessive sleepiness in obese patients may be manifestations of the metabolic syndrome is supported by findings of: first, obesity, PCOS and type 2 diabetes are independently associated with excessive daytime sleepiness without sleep apnea; second, hypercytokinemia and insulin resistance indices in obese patients with sleep apnea are unaffected by continuous positive airway pressure; and finally, the prevalence of symptomatic sleep apnea, in general, random samples parallels that of the metabolic syndrome. [33]

Cancers

An increased risk of breast cancer of ∼40% in postmenopausal women with body mass index (BMI) in the highest quartile has been shown by several case-control studies. [34] In addition to a higher endogenous estrogen production, insulin and/or insulin-like growth factors may also contribute to this increased risk. A study of 860 patients with prostate cancer demonstrated that young obese (more likely insulin resistant) patients had a higher grade of cancer. [35] Increasing evidence also implicates insulin-like growth factors in the evolution of prostate and colorectal cancer. Liver cancer, perhaps as a result NASH and subsequent cirrhosis, also appears to be more common in metabolic syndrome patients. [31]


  Chronic Inflammation - The Bridge between Psoriasis, Metabolic Syndrome and Atherosclerosis? Top


Chronic inflammation is thought to be the etiopathogenetic mechanism underlying metabolic syndrome, atherosclerosis, and psoriasis, the last being an independent risk factor for subclinical atherosclerosis and subsequent adverse cardiovascular events. [36],[37] In psoriasis as well as the metabolic syndrome, similar inflammatory markers such as Th1 cytokines (intracellular adhesion molecule-1, TNF-α), osteopontin, leptin, adiponectin, homocysteine, and CRP, play a pathogenetic role. [38] Not only are the Th1/Th2 imbalances common to psoriasis and atherosclerosis, but also similar proinflammatory cytokines - interferon-γ, TNF-α, IL-1, IL-6, etc.,-may operate in their evolution. Osteopontin, an inflammatory glycoprotein, that exerts a Th1 cytokine effect and is thought to play a role in the development of atherosclerosis, is also elevated in psoriasis. [39]

Chronic psoriasis also impacts oxidative metabolic pathways through the generation of free radicals, reactive oxygen species, and superoxide anion. The resultant oxidative stress, believed to play a central role in the pathogenesis of metabolic syndrome, has systemic implications with respect to atherosclerosis and myocardial infarction. [38],[40] Genetics also play a critical role with several psoriasis susceptibility loci, namely, PSORS2, PSORS3, and PSORS4 also known to associate with the metabolic syndrome, type 2 diabetes, familial hyperlipidemia, and CVD. [40]


  Psoriasis and Components of Metabolic Syndrome Top


Obesity and psoriasis

Psoriasis and obesity not only share similar mediators of inflammation such as TNF-α and IL-6, but also have the common mesothelial origin of the macrophage and adipocyte-the engines of psoriatic and adipocytic inflammation, respectively. Importantly, psoriasis, like obesity, is associated with high systemic and local levels of TNF-α. [41],[42] This suggests that obesity may potentiate the TNF-α and IL-6-driven inflammation seen in psoriasis, additionally vitiating glucose regulation, dyslipidemia, endothelial dysfunction and hypertension and cumulatively heightening the inherent cardiovascular risk of cutaneous psoriatic inflammation. Patients with severe psoriasis also have a higher BMI that is directly related to the risk of cardiovascular mortality. [43] A randomized, controlled, investigator-blinded clinical trial suggested an increased therapeutic response to a low dose of cyclosporine in psoriasis patients with moderate reduction in body weight (5-10%), by demonstrating a PASI 75 response in 66.7% patients treated with cyclosporine plus a low-calorie diet as compared to 29.0% in patients treated with cyclosporine alone (P < 0.001). [44] Many inflammatory products synthesized in skin lesions of psoriasis have the potential to interact with adipose tissue, which is expanded in obese psoriatics, at the dermal/adipose interface. [45]

Diabetes and psoriasis

Diabetes is related to psoriasis independent of obesity, hypertension, and hyperlipidemia and is more prevalent in patients with severe psoriasis than in those with the mild disease. Inflammation could be a biologically plausible mechanism underlying this association. Insulin resistance has previously been attributed to inflammation, [46] and elevated CRP levels are predictive of diabetes. [47] Data from large cross-sectional studies have revealed substantial risk of diabetes in psoriasis patients, with a 62% increase in risk with severe disease. [45]

Hypertension and psoriasis

Though the precise pathophysiologic mechanisms that underlie psoriasis and hypertension are unknown, the link may be attributed to the increased levels of the angiotensin-converting enzyme, endothelin-1 and rennin in patients with psoriasis. [48] Elevated CRP (as seen in psoriasis) has been shown to foretell the development of hypertension on follow-up in multiple cohorts. [49] The association may also be attributed to the increased oxidative stress in psoriasis patients. [50] Sommer et al. reported that inpatients with psoriasis had more than a 3-fold higher prevalence of hypertension compared with inpatients without psoriasis (odds ratio: 3.3; 95% confidence interval: 2.4-4.4). [51] One prospective study demonstrated an increased risk of diabetes and hypertension in women with psoriasis, even after adjustment for age, BMI, alcohol intake, and smoking status. [52]

Dyslipidemia and psoriasis

There is conflicting information about how lipid profiles might be affected by psoriasis. An atherogenic lipid profile comprising, high cholesterol, LDL and TG and low HDL levels was noted in psoriasis patients in some studies, [53],[54] with no significant difference between patients and controls noted in others. [54],[55],[56] Lipoprotein (a), whose role has been implied in cardiovascular pathology, has also been reported to be elevated. [57] Oxidized LDL (ox-LDL), a molecule thought to contribute to initiation as well as the progression of atherosclerosis, [58] is produced by oxidative damage of lipids and proteins in response to increased production of oxygen metabolites as seen in psoriatics. Anti-ox-LDL antibodies demonstrated by Vanizor Kura [59] and Φrem [60] in psoriatics, have been suggested to reflect the in vivo oxidation of LDL.


  Psoriasis, Metabolic Syndrome, and Cardiovascular Disease Top


Given the evidence for the association between psoriasis and the core components of the metabolic syndrome, it is no surprise that psoriasis has been proved to be associated with increased risk of the complete syndrome by several studies in India and abroad. [61] Recently, a study in Italy found the risk of being diagnosed with metabolic syndrome to be double in the psoriasis group when compared to the control group with the risk increasing with disease severity. [62] A higher prevalence was also observed in an Indian study by Ali et al. (P = 0.005), although they did not find any association with disease severity or duration. The same authors also found psoriatic arthritis to be significantly more common in psoriatic patients with metabolic syndrome (40.5%) than in those without it (19%). [61],[63]

Overall epidemiological data unanimously support the link between psoriasis and cardiovascular risk. [64] The several possible biological factors that may explain such a link include a higher prevalence of conventional cardiovascular risk factors (e.g., smoking, obesity, low physical activity) in psoriatics, systemic medications used to treat psoriasis and the underlying inflammatory activity in psoriasis. [65] A study by Gelfand et al. [66] in 2006, which included 130,976 psoriasis patients, demonstrated an increased risk of myocardial infarction, more so in the younger patients with severe disease (e.g., a 30-year-old with severe psoriasis had a relative risk of 3.10). However, these observations need to be confirmed by larger studies.

Understanding the specific relationships between its components and their link to subsequent macrovascular disease is an important prerequisite for developing public health policy to reduce clinical risk. Particular vigilance is advised as is early clinical intervention to prevent the complications of this syndrome. First line therapy for this syndrome recommended by the American Heart Association comprises of lifestyle modifications including weight loss (BMI <25 kg/m 2 ), 30 min of moderate-intensity activity most days of the week and healthy eating habits. [67] Finnish Diabetes Prevention Study involving overweight individuals with impaired glucose intolerance demonstrated a 58% reduced risk of diabetes at 4-years follow-up with modest weight loss by dietary changes and exercise. [68] Concurrent hypertension, diabetes, and hypercholesterolemia should be adequately managed. The Veterans Affairs HDL Intervention Trial demonstrated a 35% reduction in risk of cardiovascular death in patients with metabolic syndrome who received gemfibrozil. [31] In the AFCAPS/TexCAPS study, those with the metabolic syndrome had a 37% reduced risk of an acute coronary event with lovastatin therapy. [69] In psoriasis patients, several studies have shown remission of the disease with weight loss. [70],[71] Furthermore, smoking cessation (a well-established CVD risk factor and shown to be associated with psoriasis in many studies) and redressal from depression consequent to the disease, have the potential to at least partially offset the increased inherent risk of cardiovascular catastrophes and complications of diabetes present in these patients. [67]

Some skin conditions other than psoriasis, less commonly associated with metabolic syndrome are summarized in [Table 2], along with the mechanism of their association and findings of the relevant studies.
Table 2: Dermatoses other-than-psoriasis causing metabolic syndrome

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  Conclusion Top


Metabolic syndrome, though not considered to represent a distinct disease entity, due to its chronic underlying inflammation has the importance of conferring greatly increased risk for a number of comorbidities, e.g., CAD, myocardial infarction, stroke, and type 2 diabetes. [86] Though further large-scale studies are needed to definitively quantify the cardiovascular risk in psoriasis patients, it is imperative for a dermatologist, who also doubles as a primary care physician in many cases of psoriasis, to suspect, manage and adequately counsel these patients regarding the potential comorbidities due to concomitant metabolic syndrome rather than letting them get away with the belief that their diseases are "just a skin disease." Practicing clinicians also should be aware of this syndrome as timely control of its components can add some years to the patient's life by early detection and management of the associated cardiovascular comorbidities. Large-scale population-based studies could provide help in promulgation of country specific preventive health as well as management guidelines by the concerned authorities.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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Abstract
Introduction
Components of Me...
Prevalence of Me...
Metabolic Syndro...
Impact of Metabo...
Chronic Inflamma...
Psoriasis and Co...
Psoriasis, Metab...
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