Eskişehir Osmangazi University Faculty of Medicine, Department of Skin and Venereal Diseases, Eskişehir, Turkey**
Memorial Şişli Hospital, Department of Dermatology, İstanbul, Turkey***
Eskişehir Osmangazi University Faculty of Medicine, Department of Pharmacology, Eskişehir, Turkey
Objective: To evaluate the relationship between the serum resistin levels and metabolic syndrome (MetS) in chronic spontaneous urticaria (CSU) patients.
Methods: In the study 42 CSU patients and 42 healthy volunteers were included. Height, weight, waist circumference, and blood pressure measurements were assesed for both of the groups. Fasting blood sugar, serum lipid levels, resistin and tumor necrosis factor-alpha (TNF-α) levels were evaluated in the venous blood samples. The metabolic syndrome (MetS) diagnosis was determined using the National Cholesterol Education Program Adult Treatment Panel III diagnostic criteria.
Results: MetS was found in 14 (33.3%) CSU patients and 5 (11.9%) control subjects. There was a statistically significant difference between the two groups (p=0.037) in terms of MetS presence. It was found that the mean serum resistin levels was 1928.31±212.85 pg/mL in the CSU patients and 2107.60±156.71 pg/mL in the control group. There was no statistically significant difference between the groups in terms of serum resistin levels. No difference was seen between the patients with and without a diagnosis of MetS regarding the urticaria activity score, duration of the disease, autologous serum skin test positivity, serum immunoglobulin E levels, presence of autoimmunity, serum resistin and TNF-α levels.
Conclusion: An increased incidence of MetS in the CSU patient group is found in our study. However, there was no difference between the CSU patients with and without MetS regarding the disorder-associated parameters and the serum resistin and TNF-α levels.
Metabolic syndrome (MetS) is a combination of central obesity, dyslipidemia, glucose intolerance and elevated blood pressure (1). Increased inflammatory markers, mainly interleukin (IL) (IL-1, IL-6), tumor necrosis factor-alpha (TNF-α) and C-reactive protein (CRP) have been related with development of MetS in pro-inflammatory and pro-coagulation steps (2). Chronic urticaria (CU) is a skin disease characterized by recurrent urticaria lasting longer than 6 weeks. The term chronic spontaneous urticaria (CSU) is used to define CU which occurs without any known triggering factor (3). The studies demonstrated that circulating CRP, pro-inflammatory cytokines such as IL-6, TNF-α and metabolic markers are increased and procoagulation pathway is activated in CSU (4-6).
Resistin, identified firstly in 2001, is a 12.5 kDa adipokine containing 114 aminoacids (7). It is secreted from mainly adipose tissue and other tissues such as macrophages, mononuclear leukocytes, in bone marrow and spleen and induced the secretion of cytokines responsible for MetS development such as IL-6, IL-12, TNF-α (7,8). Many studies reported that resistin was associated with insulin resistance, hyperglycemia and obesity (9-11). In addition, resistin was shown to be related with inflammation and immunity in many disorders including atherosclerosis, renal disorders, respiratory system disorders and psoriasis (11,12).
Although chronic systemic inflammation is seen in patients with CSU, only one previous study investigated the relationship of MetS and CU in literature (13). In this study, we aimed to investigate serum resistin and TNF-α levels together with other metabolic parameters in patients with CSU, and we also aimed to compare urticaria-related parameters in CSU patients with or without MetS.
The study included 42 CSU patients and 42 healthy volunteers. The study protocol was approved by local ethics committee. All patients and healthy volunteers gave written informed consent after they were informed about the study. Patients with complaint of urticaria or urticaria plus angioedema for at least six weeks were classified as CU. According to EAACI/GA2LEN/EDF/WAO (3) guidelines, patients without inducible urticaria etiology were accepted as CSU. Exclusion criteria were pregnancy, lactation, liver or kidney dysfunction, medication due to liver or kidney dysfunction, history of systemic inflammatory disease, systemic immunosuppressive treatment within the last 1 month and accompanying dermatologic diseases other than CSU.
Evaluation of the Presence of Metabolic Syndrome
Age, gender, height, weight, body mass index (BMI), waist circumference, and blood pressure levels of CSU patients and controls were recorded. MetS diagnosis was based on National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) (1) criteria and MetS was diagnosed in patients with 3 or more criteria [NCEP-ATP III diagnostic criteria: waist circumference in males >90 cm and in females >80 cm, triglyceride (TG) ≥150 mg/dL, high density lipoprotein (HDL) in males <40 mg/dL, in females <50 mg/dL, blood pressure >130/85 mmHg, glucose level ≥110 mg/dL].
Assessment of Urticaria Activity Score
In order to assess the disease activity in CSU patients, we used urticaria activity score (UAS). Number of wheals (0, none: 1, <10 wheals: 2, 10-50 wheals: 3, >50 wheals), and intensity of itch (0, none: 1, mild: 2, moderate: 3, severe) were assessed. Sum of daily UAS scores gave weekly UAS7 score between 0-42 points (3).
Evaluation of Autologous Serum Skin Test
Autologous serum skin test (ASST) evaluation was based on EACCI/GA2LEN/EDF/WAO guideline (3). If the wheal and flare response with autologous serum (i.e. the diameter of erythematous papule) is 1.5 mm or greater than saline, the response was positive.
Assessment of Laboratory Findings
Venous blood samples were collected from CSU patients and controls after an 8-hour fasting. Serum fasting blood glucose (FBG), TG, HDL, low-density lipoprotein (LDL) levels, high sensitivity CRP (hsCRP) were measured. In addition to these parameters, complement 3 (C3), complement 4 (C4), antinuclear antibody (ANA), thyroid stimulating hormone (TSH), anti-thyroglobulin (anti-TG), anti-microsomal antibody (anti-TPO), total IgE levels, resistin, and TNF-α levels were also evaluated in CSU patients.
Serum FBG, HDL, LDL and TG levels were all measured by using the enzymatic colorimetric method. Serum hsCRP levels was determined with the immunoturbidimetric method by using Roche/Hitachi Modular (Mannheim, Germany), C3, C4, ANA, TSH, anti-TG, anti-TPO, total IgE levels were measured by using Roche Hitachi Cobas 602 autoanalyser (Mannheim, Germany).
To assay serum resistin and TNF-α levels, venous blood samples were centrifuged and serum samples were stored at -40 °C (SANYO Freezer, Japonya) until assay. Commercial sandwich ELISA kits were used to measure serum resistin and TNF-α levels in accordance to instructions of manufacturer (resistin kit: BMS2040, eBioscience, Vienne, Austria, and TNF-α kit: BMS223/4, eBioscience, Vienne, Austria). Measurements were performed by spectrophotometry using 450 nm filter and ELISA reader (ELX-800, Biotek Instruments, United States of America). Resistin and TNF-α levels were expressed in pg/mL.
Analysis of the data was performed by using IBM SPSS Statistics 21.0 package software. Continuous variates were expressed as mean ± standard deviation. Categoric variates were expressed as percent (%) values. Normal distribution of variables were tested by Shapiro Wilk test. Comparisons of normally distributed parameters between two groups were made by independent samples t-test. Parameters without normal distribution were compared by Mann-Whitney U test between two groups. Crosstabs were analysed by Pearson’s chi-square and Pearson’s exact chi-square tests. Correlation between parameters was tested by Spearman correlation test. Statistical significance level was adjusted to p<0.05.
The study included 42 CSU patients (66.7% female, 33.3% male) and 42 healthy volunteers (66.7% female, 33.3% male). The mean age in CSU group and control group were 40.78±7.62 years and 40.00±12.26 years, respectively. There was no statistical differences patient and control group in terms of age and gender (p=0.334, p=1.00) (Table 1). BMI, waist circumference, serum TG, and hsCRP values of CSU patients were significantly higher than control group (p=0.001, p=0.01, p=0.048, p=0.031, respectively, Table 1). Serum FBG, HDL and resistin levels were not statisticaly different between the groups (p=0.380, p=0.802, p=0.057, respectively, Table 1). When serum mean TNF-α levels were compared between CSU patients and controls, serum TNF-α was significantly higher in control group than in patient group (p=0.036, Table 1). The mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) were significantly higher in CSU patients compared to controls (p=0.013, p=0.018, Table 1). In terms of MetS presence, MetS was present in 14 (33.33%) patients of CSU group and 5 (11.90%) individuals in control group. MetS was significantly more common among CSU patients than controls (p=0.037, Table 1). Demographic and laboratory characteristics of CSU patients and controls are given in Table 1.
CSU patients were divided into two subgroups as MetS-positive and MetS-negative patients. Comparison of demographic and laboratory findings between MetS-positive and negative groups are given in Table 2. Serum resistin and TNF-α levels were similar in MetS-positive and MetS-negative CSU patients (p=0.296, p=0.788, Table 2). ASST positivity, ANA positivity, disease duration, presence of thyroid auto antibody, serum IgE, C3 and C4 levels, angioedema and atopy were not statisticaly different between MetS-positive and MetS-negative CSU groups (Table 2).
Comparison of UAS7 score between the MetS-positive and MetS-negative CSU patients revealed that UAS7 score was significantly lower in MetS-positive group than in MetS-negative group (19.28±8.73 vs. 26.67±9.00, respectively; p=0.020, Table 2).
Correlation analysis showed that there was no correlation between serum resistin levels UAS7 score, serum FBG, TG, HDL, LDL, TNF-α, IgE level, and disease duration in CSU patients (Table 3).
The role of adipokines and inflammatory cytokines including TNF-α, IL-6, IL-1β, CRP in relationship of obesity and inflammation is well known (2). It has been demonstrated that chronic systemic inflammation in dermatologic disorders such as atopic dermatitis, psoriasis, and lichen planus have an increased the risk of MetS (14-17). Although systemic inflammation has been described in CSU patients, only one study investigated the relationship of MetS and CU (13). Ye et al. (13). reported that 39 (29.8%) of 131 patients with CU had MetS. In our study, we also observed MetS in 33.3% of CSU patients. Ye et al. (13). found that diagnostic criteria of MetS, i.e. FBG, TG, and waist circumference, were significantly higher in CU group than in control group, but SBP and DBP values were comparable between the two groups. Similarly in our study, we found that waist circumference and serum TG levels were significantly higher in CSU patient group compared to controls. Unlike that study, serum FBG and HDL levels were similar in both study group of our study. In addition, the mean SBP and DBP levels were significantly higher in CSU patients than controls in this study. Besides, Chung et al. (18). reported that hyperlipidemia was significantly higher in CU patients than controls Consequently, literature data and our findings reveal that MetS components may be more common among patients with CU.
Many mediators including TNF-α are released from mast cells of urticarial lesions (19). Studies, based on this theory, found higher TNF-α levels in CU patients, and treatments targeting TNF-α have been studied (20,21). However, some of the studies reported similar serum TNF-α levels in both CU patients and normal controls (22). Ye et al. (13) found serum TNF-α levels higher in MetS-positive CU patients. On the contrary, serum TNF-α levels were lower in our patients with CSU compared to controls. We think that local increases in TNF-α levels in wheals may not contribute to systemic inflammatory response in urticaria. In addition, similar serum TNF-α levels in both MetS-positive and negative CSU patients may suggest that various markers may be involved in development of MetS in CSU patients.
Resistin is a pro-inflammatory adipokine which induces inflammation, angiogenesis, and smooth muscle proliferation (7). Serum resistin levels were reported to be associated with obesity, insulin resistance, diabetes and inflammation (7,9,11,23-25). In our study, serum resistin levels were similar in CSU patients and controls. Furthermore, resistin levels were similar in MetS-positive and negative CSU patients. This may imply that resistin may not be involved in increased inflammation of patients with urticaria.
High serum hsCRP levels are seen in MetS and studies demonstrated that increased serum hsCRP level is an important inflammatory marker in the risk of cardiovascular disease (26-29). In the CU pathogenesis, increased serum CRP level was reported and it showed positive correlation with disease activity (5,17,30). In our study, serum hsCRP level was significantly higher in CSU patients than in controls. On the other hand, although the mean serum hsCRP level was higher in MetS-positive CSU patients when compared to MetS-negative patients, the difference was not statistically significant.
Ye et al. (13) reported higher UAS score in MetS-positive patients, but UAS7 scores were higher in MetS-negative patients of our study. Any increase in UAS7 may lead to systemic inflammation, thus an increase in the risk of MetS may be expected. However, the contrary result of our study may indicate that different factors may play role in the pathogenesis of MetS and urticaria. We think that while the drugs such as systemic steroids, antihistamine, siklosporine used in the treatment of urticaria cause a decrease in urticaria activity, these treatments may also lead to deterioration in the metabolic condition. However, we could not evaluate the patient’s past medications.
Similar to the study of Ye et al. (13) we found no difference in atopy presence, ANA, thyroid auto antibody positivity of MetS-positive and negative CSU patients. On the other hand, unlike their study there was no difference in ASST, serum C3-C4 levels in this study.
MetS was seen more common in CSU patients. However, we did not show any relationship between inflammatory markers inducing MetS development and CSU. This result suggests that there is a need for larger molecular studies to show the cause-and-effect relationship of CSU and MetS.
Ethics Committee Approval: The ethics commitee of Eskişehir Osmangazi University Faculty of Medicine (Number: 2015/20), Informed Consent: Informed consent was signed by the volunteers.
Peer-review: Internally peer-reviewed.
Concept: Işıl Bulur, Design: Işıl Bulur, Zeynep Nurhan Saraçoğlu, Data Collection or Processing: Hanife Merve Akça, Işıl Bulur, Hilal Kaya Erdoğan, Analysis or Interpretation: Semra Çelebi, Literature Search: Hanife Merve Akça, Işıl Bulur, Writing: Hanife Merve Akça, Işıl Bulur.
Conflict of Interest: No conflict of interest was declared by the authors.
Financial Disclosure: The authors declared that this study received no financial support.
1. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002;106:3143-21.
2. Devaraj S, Rosenson RS, Jialal I. Metabolic syndrome: an appraisal of the pro-inflammatory and procoagulant status. Endocrinol Metab Clin North Am 2004;33:431-53.
3. Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA(2)LEN/EDF/WAO Guideline for the definition, classification, diagnosis, and management of urticaria: the 2013 revision and update. Allergy 2014;69:868-87.
4. Kaplan AP, Greaves M. Pathogenesis of chronic urticaria. Clin Exp Allergy 2009;39:777-87.
5. Kasperska-Zajac A, Sztylc J, Machura E, et al. Plasma IL-6 concentration correlates with clinical disease activity and serum C-reactive protein concentration in chronic urticaria patients. Clin Exp Allergy 2011;41;1386-91.
6. Dos Santos JC, Azor MH, Nojima VY, et al. Increased circulating proinflammatory cytokines and imbalanced regulatory T-cell cytokines production in chronic idiopathic urticaria. Int Immunopharmacol 2008;8:1433-40.
7. Steppan CM, Bailey ST, Bhat S, et al. The hormone resistin links obesity to diabetes. Nature 2001;409:307-12.
8. Rodriguez-Pacheco F, Novelle MG, Vazquez MJ, et al. Resistin regulates pituitary lipid metabolism and inflammation in vivo and in vitro. Mediators Inflamm 2013;2013:479739.
9. Silha JV, Krsek M, Skrha JV, et al. Plasma resistin, adiponectin and leptin levels in lean and obese subjects: correlations with insulin resistance. Eur J Endocrinol 2003;149:331-5.
10. Fujinami A, Obayashi H, Ohta K, et al. Enzyme-linked immunosorbent assay for circulating human resistin: resistin concentrations in normal subjects and patients with type 2 diabetes. Clin Chim Acta 2004;339:57-63.
11. Reilly MP, Lehrke M, Wolfe ML, et al. Resistin is an inflammatory marker of atherosclerosis in humans. Circulation 2005;111:932-9.
12. Huang H, Shen E, Tang S, et al. Increased serum resistin levels correlate with psoriasis: a meta-analysis. Lipids Health Dis 2015;14:44.
13. Ye YM, Jin HJ, Hwang EK, et al. Co-existence of chronic urticaria and metabolic syndrome: clinical implications. Acta Derm Venereol 2013;93:156-60.
14. Love TJ, Qureshi AA, Karlson EW, et al. Prevalence of the metabolic syndrome in psoriasis: results from the National Health and Nutrition Examination Survey 2003-2006. Arch Dermatol 2011;147:419-24.
15. Silverberg JI, Silverberg NB, Lee-Wong M. Association between atopic dermatitis and obesity in adulthood. Br J Dermatol 2012:166;498-504.
16. Hersoug LG, Linneberg A. The link between the epidemics of obesity and allergic diseases: does obesity induce decreased immune tolerance? Allergy 2007;62:1205-13.
17. Kasperska-Zajac A, Grzanka A, Machura E, et al. Analysis of procalcitonin and CRP concentrations in serum of patients with chronic spontaneous urticaria. Inflamm Res 2013;62:309-12.
18. Chung SD, Wang KH, Tsai MC, et al. Hyperlipidemia Is Associated with Chronic Urticaria: A Population-Based Study. PLoS One 2016 10;11:e0150304.
19. Walsh LJ, Trinchieri G, Waldorf HA, et al. Human dermal mast cells contain and release tumor necrosis factor alpha, which induces endothelial leukocyte adhesion molecule 1. Proc Natl Acad Sci USA 1991;88:4220-4.
20. Piconi S, Trabattoni D, Iemoli E, et al. Immune profiles of patients with chronic idiopathic urticaria. Int Arc Allergy Immunol 2002;128:59-66.
21. Sand FL,Thomsen SF. TNF-Alpha Inhibitors for Chronic Urticaria: Experience in 20 Patients. J Allergy (Cairo) 2013;2013:130905.
22. Tedeschi A, Kolkhir P, Asero R, et al. Chronic urticaria and coagulation: pathophysiological and clinical aspects. Allergy 2014;69:683-91.
23. Azuma K, Katsukawa F, Oguchi S, et al. Correlation between serum resistin level and adiposity in obese individuals. Obes Res 2003;11:997-1001.
24. Patel L, Buckels AC, Kinghorn IJ, et al. Resistin is expressed in human macrophages and directly regulated by PPAR gamma activators. Biochem Biophys Res Commun 2003;300:472-6.
25. Shetty GK, Economides PA, Horton ES, et al. Circulating adiponectin and resistin levels in relation to metabolic factors, inflammatory markers, and vascular reactivity in diabetic patients and subjects at risk for diabetes. Diab Care 2004;10:2450-7.
26. Emerging Risk Factors Collaboration; Kaptoge S, Di Angelantonio E, et al. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet 2010:375;132-40.
27. Saisho Y, Hirose H, Seino Y, et al. Usefulness of C-reactive protein to high-molecular-weight adiponectin ratio to predict insulin resistance and metabolic syndrome in Japanese men. J Atheroscler Thromb 2010;17:944-52.
28. Tomiyama H, Koji Y, Yambe M, et al. Elevated C-reactive protein augments increased arterial stiffness in subjects with the metabolic syndrome. Hypertension 2005;45:997-1003.
29. Ridker PM, Wilson PW, Grundy SM. Should C-reactive protein be added to metabolic syndrome and to assessment of global cardiovascular risk? Circulation 2004;109:2818-25.
30. Tedeschi A, Asero R, Lorini M, et al. Plasma levels of matrix metalloproteinase-9 in chronic urticaria patients correlate with disease severity and C-reactive protein but not with circulating histamine-releasing factors. Clin Exp Allergy 2010;40:875-81.