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Psoriasis Independently Associated With Hyperleptinemia Contributing to Metabolic Syndrome
Yi-Ju Chen, MD;
Chun-Ying Wu, MD, PhD, MPH;
Jui-Lung Shen, MD;
Szu-Ying Chu, MD;
Chih-Kang Chen, MD;
Yun-Ting Chang, MD, PhD;
Chuan-Mu Chen, PhD
Arch Dermatol. 2008;144(12):1571-1575.
ABSTRACT
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Objective To evaluate the role of leptin, a 16-kDa adipocyte-derived hormone, in the development of metabolic dysregulation of psoriasis.
Design Case-control study.
Setting Referral centers.
Patients Seventy-seven patients with psoriasis and 81 age- and sex-matched control subjects were included in the study.
Intervention Enzyme-linked immunoassay of serum samples from study subjects.
Main Outcome Measures Serum leptin levels and proportions of comorbidities (including hypertension, diabetes mellitus, metabolic syndrome, hypertriglyceridemia, and reduced high-density lipoprotein cholesterol concentrations) in cases vs controls were compared using  2 and Mann-Whitney tests. The clinical significance of leptin in psoriasis was analyzed using logistic regression models.
Results Significantly more obesity (odds ratio [OR], 2.67) and hypertension (2.17) (P =.04 for both) were observed in subjects with psoriasis. High serum leptin levels ( 7397.43 pg/mL) were found in female subjects (OR, 6.05; P < .001) and in subjects with obesity (3.45; P =.01), hypertension (2.19; P =.04), metabolic syndrome (3.58; P =.008), and psoriasis (2.25; P =.02). On multivariate analysis, psoriasis (OR, 4.57; P =.009) was significantly associated with hyperleptinemia independent of female sex (26.36; P < .001), metabolic syndrome (4.37; P =.04), and obesity (2.83; P =.12). Finally, patients with psoriasis who had hyperleptinemia tended to be female (P < .001) and manifested obesity (P =.002) and metabolic syndrome (P =.003).
Conclusions Hyperleptinemia is associated with psoriasis independent of female sex and other conventional cardiovascular risk factors such as obesity and metabolic syndrome. Hyperleptinemia in psoriasis may contribute to metabolic syndrome.
INTRODUCTION
Associations among psoriasis, obesity, hypertension, cardiovascular diseases, diabetes mellitus (DM), and metabolic syndrome have been reported.1-9 Occlusive vascular events, including ischemic heart disease and cerebral infarction, are significantly more common in patients with psoriasis compared with the general population.1 Multiple cardiovascular risk factors, including DM, smoking, obesity, hypertension, and metabolic syndrome, are significantly associated with psoriasis.2-7 Psoriasis recently has been proposed as an independent risk factor for myocardial infarction, especially in young subjects with severe psoriasis.
Although the underlying mechanisms may be complex, the "obesity of psoriasis" is thought to be a key link to cardiovascular diseases, including DM, stroke, heart disease, hypertension, and myocardial infarction.8 Recent studies4-5,9-10 have demonstrated that the risk of psoriasis is directly related to body mass index (BMI [calculated as weight in kilograms divided by height in meters squared]) and that patients with obesity are likely to have severe psoriasis. Psoriasis and obesity share similar mediators of inflammation, mainly tumor necrosis factor (TNF) and interleukin (IL) 6, and the effectors of adipocytic and psoriatic inflammation, mainly adipocytes and macrophages, derive from a common mesothelial origin.11-13
Leptin, a 16-kDa adipocyte-derived hormone discovered in 1994 (followed by the discovery of many other adipokines), stimulates endocrine activity in adipose tissue and has an active role in regulating energy homeostasis, metabolism, and immune-inflammatory processes.14Leptin exerts biologic actions through activation of its cognate receptors, which are encoded by the db gene and belong to the type 1 cytokine receptor superfamily. In addition to being a hypothalamus modulator of food intake, body weight, and fat stores, leptin has a role in acute and chronic inflammation via regulation of cytokine expression that modulates the balance of helper T-cell types 1 and 2.15 Therefore, leptin has been implicated in the pathogenesis of autoimmune inflammatory conditions such as type 1 DM, rheumatoid arthritis, and chronic bowel disease.15 Elevated circulating leptin levels recently were reported to be associated with psoriasis.16
The objective of this study was to evaluate the role of leptin, a 16-kDa adipocyte-derived hormone, in the development of metabolic dysregulation of psoriasis. The clinical implications of serum leptin levels relative to psoriasis are also discussed.
METHODS
PATIENTS
From January 1, 2006, to May 31, 2007, serum samples from 77 patients with psoriasis were obtained from the dermatology outpatient departments of Taichung Veterans General Hospital and Taipei Veterans General Hospital, Taiwan. Clinical characteristics of the patients (including age, sex, height, body weight, phenotypes of psoriasis, psoriasis severity score at enrollment, and the presence of psoriatic arthritis) were collected, as well as comorbidities such as DM, hypertension, dyslipidemia (including hypercholesterolemia, hypertriglyceridemia, and reduced high-density lipoprotein [HDL] cholesterol concentration), and other cardiovascular diseases such as heart failure, ischemic heart disease, and cerebral ischemia incidents. Control serum samples were obtained from 81 age- and sex-matched subjects without psoriasis who visited the health examination clinics for routine physical checkups. All participant-derived specimens were collected and archived under protocols approved by the institutional review boards of Taichung Veterans General Hospital and Taipei Veterans General Hospital. A full verbal explanation of the study was given to all participants. They consented to participate on a voluntary basis. Missing clinical information from patients with psoriasis and control subjects was recorded as censored data.
CRITERIA OF METABOLIC SYNDROME
We adopted the definition of the National Cholesterol Education Program's Adult Treatment Panel III for Asian subjects17 in which metabolic syndrome is diagnosed as the presence of 3 or more of the following 5 risk factors: (1) fasting serum glucose level of at least 100 mg/dL (to convert glucose level to millimoles per liter, multiply by 0.0555) or previous diagnosis of type 2 DM; (2) blood pressure of at least 130/85 mm Hg or treatment for hypertension; (3) serum triglyceride level of at least 150 mg/dL (to convert triglyceride level to millimoles per liter, multiply by 0.0113); (4) serum HDL cholesterol concentration of less than 40 mg/dL in men and less than 50 mg/dL in women (to convert cholesterol level to millimoles per liter, multiply by 0.0259); and (5) obesity, defined as waist circumference exceeding 90 cm in men and exceeding 80 cm in women. Instead of measuring waist circumference, we classified BMI of at least 28 as obesity in this study, based on the American College of Endocrinology position statement on the insulin resistance syndrome.18
MEASUREMENT OF SERUM LEPTIN LEVELS
Leptin enzyme-linked immunosorbent assay kits were commercially obtained (Quantikine, product code DLP00; R&D Systems Europe, Oxon, England). The assay kit precoats a monoclonal antibody specific for human leptin onto a microplate to bind soluble leptin in the samples. The sensitivity limit of the assay was 7.8 pg/mL. Serum leptin levels were measured in samples prepared in tubes coated with lithium heparin. All serum samples were preserved at –80°C. Serum samples were diluted, and the immunoassays were performed according to the manufacturer's instructions. All assays were duplicated. The intra-assay and interassay variabilities were less than 5%.
STATISTICAL ANALYSIS
The demographic characteristics of cases and controls were compared using 2 test. The differences in serum leptin levels were compared using nonparametric Mann-Whitney test. The correlations of serum leptin levels with BMI and age were compared using simple linear regression models. Analyses of nonparametric receiver operating characteristic (ROC) curves were performed to calculate the cutoff values according to the most accurate values obtained. To score the disease severity of psoriasis, we adopted the Physician's Global Assessment system, which comprises a scale from 1 to 7, with 1 representing no skin lesions and 7 representing severe psoriasis. Univariate and multivariate logistic regression analyses were performed to evaluate the associations between serum leptin levels and clinical features of patients with psoriasis. Data were analyzed using commercially available statistical software (SPSS for Windows, version 11.0; SPSS Inc, Chicago, Illinois). Analyses of nonparametric ROC curves were also performed using a software program (STATA for Windows, version 8.0; StataCorp LP, College Station, Texas).
RESULTS
DEMOGRAPHIC DIFFERENCES BETWEEN CASES AND CONTROLS
The mean ages at enrollment of cases and controls were 57.39 and 55.63 years, respectively (Table 1). No statistically significant difference was noted in sex or age between the 2 groups. The median BMI values were 25.39 in cases and 23.54 in controls (P =.03). Obesity (BMI, 28) was observed more often in cases compared with controls (odds ratio [OR], 2.67; P =.04). Hypertension (OR, 2.17; P =.04) and hyperglycemia or DM (1.45; P =.32) were more prevalent in cases. The incidence of metabolic syndrome among cases was no higher than that among controls (14.1% vs 16.3%; OR, 0.84). Hypertriglyceridemia and reduced HDL cholesterol concentrations were seen in 28.8% (22 subjects) and 17.5% (13 subjects) of 77 controls, respectively. These results are consistent with the findings of a recent Taiwanese population–based study,19 in which the prevalences of increased triglyceride levels and reduced HDL cholesterol concentrations were 27.5% and 23.4%, respectively. In the present study, a lower incidence of reduced HDL cholesterol concentrations (10.3%) was seen in patients with psoriasis, but this did not reach statistical significance (P = .24). However, a significantly lower incidence of hypertriglyceridemia (10.3%) was observed in patients with psoriasis in our study (P = .01) (Table 1).
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Table 1. Demographic Characteristics of Cases and Controls
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ASSOCIATION BETWEEN SERUM LEPTIN LEVELS AND OCCURRENCE OF PSORIASIS
Serum leptin levels were positively correlated with BMI (β = .47, P < .001) but not with age (P = .8). The median serum leptin level in cases was significantly higher than that in controls (7311.76 pg/mL vs 4804.11 pg/mL, P =.005) (Figure and Table 2). The median serum leptin levels were significantly higher in female vs male subjects (10 368.75 pg/mL vs 4130.84 pg/mL, P < .001) and in subjects with vs without obesity (11 408.21 pg/mL vs 4882.58 pg/mL, P =.001). Elevated serum leptin levels were observed in subjects with hypertension and ischemic heart disease, but these did not reach statistical significance (P = .12 and P = .54, respectively). Significantly higher serum leptin levels were observed in subjects with metabolic syndrome than in those without metabolic syndrome (median, 7814.12 pg/mL vs 4826.58 pg/mL, P = .02).
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Figure. Serum leptin levels in the study groups. Values noted are the medians.
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Table 2. Associations Between Serum Leptin Levels and Clinical Characteristics of Study Subjects
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INDEPENDENT ASSOCIATION OF PSORIASIS WITH HYPERLEPTINEMIA
To further examine the predictive values of serum leptin levels relative to comorbidities of psoriasis, cutoff values were calculated using ROC curve analyses. Metabolic syndrome could be predicted with an accuracy of 66.89% (65.22% sensitivity and 67.19% specificity) using a serum leptin level cutoff value of 7397.43 pg/mL. Female sex (OR, 6.05; P < .001), obesity (3.45; P =.01), metabolic syndrome (3.58; P =.008), psoriasis (2.25; P =.02), and hypertension (2.19; P =.04) were significantly associated with hyperleptinemia (Table 3). On multivariate logistic regression analysis, psoriasis was an independent risk factor for hyperleptinemia (OR, 4.57; 95% confidence interval [CI], 1.47-14.23; P =.009). Other independent risk factors for hyperleptinemia were female sex (OR, 26.36; 95% CI, 7.41-93.75; P < .001) and metabolic syndrome (4.37; 1.06-17.96; P =.04).
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Table 3. Univariate and Multivariate Analyses of Risk Factors for High Serum Leptin Levels
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ASSOCIATION OF HYPERLEPTINEMIA WITH MULTIPLE RISK FACTORS FOR METABOLIC SYNDROME IN PATIENTS WITH PSORIASIS
We next analyzed the clinical significance of serum leptin levels among patients with psoriasis. Female sex (13 816.31 pg/mL in women vs 4882.58 pg/mL in men, P < .001) and obesity (14 500.40 pg/mL in obese subjects vs 5143.98 pg/mL in nonobese subjects, P =.002) were associated with significantly higher serum leptin levels (Table 4). Age, severity of psoriasis, presence of psoriatic arthritis, and clinical phenotypes of psoriasis (psoriasis vulgaris vs erythrodermic, pustular, and guttate psoriasis) seemed to have no effect on serum leptin levels in patients with psoriasis. With regard to comorbidities, significantly higher serum leptin levels were seen in patients having psoriasis with metabolic syndrome compared with those without metabolic syndrome (median, 16 059.46 pg/mL vs 5175.92 pg/mL, P =.003). Elevated serum leptin levels were also observed in patients with psoriasis who had DM, hypertension, and dyslipidemia, but these did not reach statistical significance (P = .23, P = .10, and P = .12, respectively).
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Table 4. Associations Between Serum Leptin Levels and Clinical Characteristics of Cases
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COMMENT
In this study, psoriasis was associated with several adverse cardiovascular factors, including obesity, hypertension, and hyperglycemia, although these did not always reach statistical significance. Our results are consistent with those of previous studies.1-9 Metabolic syndrome prevalences of 20% to 40% have been reported among epidemiologic studies19-20 in Taiwan. Our lower prevalences of metabolic syndrome (16.3% [13 subjects] in controls vs 14.1% [11 patients] in cases) may have occurred because of missing data on lipid profiles and BMI values in our study.
The direct mechanisms of the association between metabolic disturbances and unfavorable cardiovascular events in psoriasis have yet to be elucidated. In a cross-sectional study,21 subjects with metabolic syndrome had lower serum adiponectin levels and higher serum leptin levels than subjects without metabolic syndrome, and both adipokine levels were found to be related to insulin sensitivity independent of age and BMI. Both adipokines are strongly associated with sex steroids, and this might explain the female-specific adipokine expression.21 High leptin levels have also been reported to be significantly associated with stroke and myocardial infarction independent of traditional cardiovascular risk factors and obesity.22
After adjustment for sex, BMI, and conventional cardiovascular risk factors (including hypertension and metabolic syndrome), psoriasis was independently associated in our study with hyperleptinemia. In addition, hyperleptinemia in psoriasis is associated with higher risk of developing metabolic syndrome. This novel finding links the chronic inflammation status of psoriasis with metabolic disturbances. It seems that high circulating leptin levels in psoriasis derive not only from adipose tissue but also from an inflammation process. Body weight loss has been reported to significantly decrease leptin levels and improve insulin sensitivity23-24 and may reduce the likelihood of developing metabolic syndrome and adverse cardiovascular diseases. Body weight loss could potentially become part of the general treatment of psoriasis, especially in patients with obesity.
However, association may not equal causation. Do the proinflammatory mediators in psoriasis stimulate leptin expression, which eventually leads to metabolic dysregulation? Evidence has shown that different inflammatory stimuli, including IL-1, IL-6, and lipopolysaccharides, regulate leptin messenger RNA expression and circulating leptin levels.25 Furthermore, leptin has been reported to be produced by inflammatory regulatory cells, suggesting that leptin expression could trigger or participate in the inflammatory process through direct paracrine or autocrine action.26 Finally, the effect of leptin on immune cells and keratinocytes within psoriatic lesions—or on circulating immune cells of patients with psoriasis—needs to be examined.
AUTHOR INFORMATION
Correspondence: Chuan-Mu, Chen, PhD, Department of Life Sciences, National Chung-Hsing University, No. 250, Kuo-Kang Rd, Taichung 402, Taiwan (chchenl{at}dragon.nchu.edu.tw) or Yun-Ting Chang, MD, PhD, Department of Dermatology, Taipei Veterans General Hospital, No. 201, Section 2, Shih-Pai Rd, Taipei, Taiwan 112 (ytchang{at}vghtpe.gov.tw).
Accepted for Publication: April 23, 2008.
Author Contributions: Dr Y.-J. Chen had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Y.-J. Chen and Wu contributed equally to the article. Study concept and design: Y.-J. Chen, Wu, and Chang. Acquisition of data: Y.-J. Chen, Wu, Shen, Chu, C.-K. Chen, and Chang. Analysis and interpretation of data: Y.-J. Chen, Wu, and Chang. Drafting of the manuscript: Y.-J. Chen. Critical revision of the manuscript for important intellectual content: Y.-J. Chen, Chang, and C.-M. Chen. Statistical analysis: Y.-J. Chen and Wu. Obtained funding: Y.-J. Chen, Wu, and Shen. Administrative, technical, or material support: Y.-J. Chen, Wu, Shen, Chu, C.-K. Chen, Chang, and C.-M. Chen. Study supervision: Chang.
Financial Disclosure: None reported.
Funding/Support: This study was supported in part by research grants TCVGH-956801A and TCVGH-956802B (2006) and TCVGH-966801A (2007) from Taichung Veterans General Hospital.
Additional Contribution: Nai-Hui Chi provided technical assistance.
Author Affiliations: Departments of Dermatology (Drs Y.-J. Chen and Shen) and Gastroenterology (Dr Wu), Taichung Veterans General Hospital, Department of Life Sciences, National Chung Hsing University (Drs Y.-J. Chen and C.-M. Chen), and College of Public Health, China Medical University (Dr Wu), Taichung; Departments of Dermatology (Drs Y.-J. Chen and Chang) and Internal Medicine (Dr C.-K. Chen), National Yang Ming University, Department of Dermatology, Taipei Veterans General Hospital (Drs Chu and Chang), and Departments of Dermatology, Cardinal Tien Hospital (Dr C.-K. Chen), Taipei, and National Yang Ming University Hospital, I-Lan (Dr Chang), Taiwan.
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