The frequency of metabolic syndrome in patients with acrochordons

Objective: To investigate the frequency of metabolic syndrome (MetS) in patients with acrochordons. Materials and Methods: 102 patients with acrochordons and 76 controls were enrolled into the study. The presence of MetS was evaluated under the criteria NCEP-ATP III. Results and Discussion: Waist circumference (p<0.001), body mass index (p<0.001), systolic (p=0.014) and diastolic blood pressure (p<0.001), insulin (p<0.001) and triglyceride (TG) levels (p<0.001) were higher in the group with acrochordons. The presence of MetS was found as 71.6% in patients with acrochordon and 40.8% in controls (p<0.001). Conclusions: Patients with acrochordons should be evaluated in terms of the presence of MetS and its components.


Introduction:
Also known as skin tags, acrochordons are the most common fibro-epithelial benign skin lesions and observed in the major flexor and natural folds surface of the body, such as neck, axillary and inguinal regions, and breast 1 .They may also be seen on the face and eyelids.The prevalence of acrochordons has been reported up to 46% in the general population.Acrochordons are more commonly seen in the obese and women, as well as rarely being witnessed in patients with polycystic ovary syndrome, acromegaly and Birt-Hogg-Bube syndrome 2 .Acrochordons are in the form of flesh colored to brown, soft, dermal papillomas-pedinculated lesions with smooth or irregular appearance 1 .Microscopically, a fibro-vascular core, sometimes with fat cells, covered by an unremarkable epidermis can be seen.Metabolic syndrome (MetS), the most common endocrinopathy, is defined as the co-occurrence of metabolic risk factors in the development of both type 2 diabetes mellitus (DM) and coronary artery disease.Abdominal obesity, insulin resistance (IR), impaired glucose tolerance (IGT) or DM, dyslipidemia and hypertension are commonly seen in patients with MetS. 3 Several definitions have been described for MetS, and those defined by National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) 4 and International Diabetes Federation (IDF) 5 are commonly used.Insulin resistance is a major component of MetS.The presence of hyperinsulinemia and IR, insulin and insulin-like growth factors are known to induce the proliferation of keratinocytes and fibroblasts 6 .In diabetic patients with sign of IR, the frequencies of acrochordons and acanthosis nigricans were reported as 26.2% and 5%, respectively 7 .In many studies, conflicting results have been reported, as to the relationship among acrochordons, seborrheic keratosis, pseudoacanthosis nigricans, DM, IR and MetS, [8][9][10][11][12] and MetS components rather than the presence of MetS have been evaluated.As well as the limited number of literature including only two studies that investigated the presence of MetS in patients with acrochordons, 10,13 we also aimed at evaluating the presence of MetS in patients with acrochordons under the criteria of NCEP-ATP III.

Materials and methods:
One hundred and two patients admitted to the department of dermatology in Konya Health Application and Research Center, University of Health Sciences between June 2013 and June 2014 with at least one complaint of acrochordons (skin tag) were enrolled into this prospective and controlled study.However, 76 age-and sex-matched individuals without acrochordons, lack of following exclusion criteria and admitted to the same clinic within the same time period constituted our control group in the study.While constituting the control group, BMI similarity between both groups was not evaluated because obesity and related diseases, such as hyperglycemia, dyslipidemia and hypertension are the main components of MetS.Upon the approval by the Local Ethics Committee of Selcuk University, written informed consents were taken from all participants.Patients with pregnancy, malignancy of autoimmune diseases and under the age of 18 were excluded from the study.Age, gender, weight, height, waist circumference (WC), blood pressure, previous history of DM and hypertension, estimated detection time of acrochordons, and number and localization of acrochordons were measured and recorded in both groups.Height (m) and weight (kg) were measured with underwear.Waist circumference was measured as the minimum size between iliac crest and lateral costal margin.Body mass index (BMI) was calculated as weight (kg) divided by height square (m 2 ).Blood pressure was measured by a mercury sphyngomanometer after resting for 10 min in both arms.After overnight fasting, blood samples were drawn at 08:00-09:00 am and centrifuged for 5 min at 3000 rpm.The sera were separated and stored at -80 °C until analysis.Glucose was measured using hexokinase method; high density lipoprotein (HDL)-cholesterol and triglycerides (TGs) were assessed with a routine enzymatic method using an auto analyzer by Abbott Architech C16000 (Abbott Laboratories, Abbott Park IL, US).Insulin levels were measured by Adviva Cetaur XP (Siemens Healthcare Diagnostics, Siemens AG, Germany) with chemiluminescence method.Insulin resistance was calculated by homeostasis model assessmentinsulin resistance (HOMA-IR) [fasting plasma glucose (mmol/l) x fasting serum insulin (µIU/ ml)/22.5].Intra-and inter-assay coefficients of variations for insulin were 4.6 and 5.9, respectively.HOMA-IR levels were calculated in 78 patients with acrochordons and 67 controls whose insulin levels were measured and that were on no anti-diabetic medication.
As the determinants of MetS presence, the diagnosis of MetS was performed under the criteria of NCEP-ATP III 4 in accordance with the presence of three of the following five criteria: 1) fasting blood glucose levels ≥100 mg/dL or drug use for diabetes, 2) HDL-cholesterol <40 mg/dL in men, <50 mg/dL in women, or receiving lipid lowering treatment, 3) TG levels ≥150 mg/dL or receiving lipid lowering treatment, 4) WC ≥102 cm for men, ≥88 cm for women, and 5) blood pressure ≥130/85 mmHg or on antihypertensive drug treatment.

Statistical Analysis:
IBM SPSS statistical software was used for data analysis.Data normality was determined with the Shapiro-Wilk test.The descriptive statistics for variables with normal distribution, continuous data (mean±standard deviation), not normally distributed variables [median (minimum-maximum)], frequencies for categorical variables and percentage [n (%)] were indicated.The student's t and the Mann-Whitney U tests were used in the comparison of two independent samples for normally and abnormally distributed continuous data, respectively.In the analysis of categorical data, the Pearson's chi-square test was used.As the significance, the threshold level was determined as α=0.05.Power analyses were made, and statistically significant values were indicated bold in the tables.

Results:
Socio-demographic and study characteristics of study population are given in Table 1.Considering the remaining two criteria of NCEP-ATP III, including blood sugar and HDL-cholesterol, the number and percentage were found as similar.

Discussion
In the study, patients with acrochordons were determined to have higher levels of WC, body weight, BMI, systolic and diastolic blood pressure, TG, insulin and HOMA-IR.Moreover, the number of those with MS and its three components, WC, blood pressure and TG, was higher among patients.Known as the primary and widespread causes of atheroscerosis and type 2 DM, MetS whose most common characteristics are abdominal obesity, elevated blood pressure, lipid disorders, hyperinsulinemia, IR and IGT is an increasing health challenge worldwide [3][4][5]14 . Acrohordons are benign connective tissue tumors of the dermis and commonly seen in obese and insulin resistant patients.High insulin concentration has been shown to play a role in the development of acrochordons 15 .In keratinocytes and fibroblasts, insulin has a direct and/or indirect effect on growth factor receptors such as insulin-like growth factors 1 (IGF-1) and epidermal growth factor (EGF) receptors and induces their proliferation 16 .
The association between acrochordons and DM was first described in 1951 17 .Since then, limited data targeting to investigate the relationship between acrochordons and the components of MetS have been published with conflicting results [8][9][10][11][12][13]18 . In astudy performed by Sudy et al., 11 it was reported that eight or more acrochordons are related to basal and postprandial hyperinsulinemia and postprandial hyperglycemia, and that multiple acrochordons are more sensitive, but less specific than acanthosis nigricans in the evaluation of glucose/insulin metabolism.In the study published by Tamega et al., 12 it was also reported that acrochordons had been associated with HOMA-IR, TG, BMI, waist/ hip ratio (WHR) and the presence of DM.In another study, Agarwal et al. 19 found that the frequencies of overt DM and IGT were, respectively, 30.5% and 10.1% in patients with acrochordons, and that there was no correlation between glucose intolerance and the localization, size, color, and number of acrochordons. Asone of the limitations in our study, the size and color of acrochordons were not evaluated, as well as determining no correlation between the components of MetS and the number and localization of acrochordons (No data were presented).In another study performed by Akpinar et al., 8 it was emphasized that DM is more frequently observed in patients with acrochordons, compared to controls.Although finding similar fasting plasma glucose levels in both patients and controls, Akpinar et al. determined higher postpradial glucose levels in patients, compared with controls.In addition, when they re-classified their patients as blood glucose ≥100 mg/dL and <100 mg/dL, patients with blood glucose levels ≥100 mg/dL were found to have more acrochordons, compared to those with blood glucose levels <100 mg/dL (9.87±2.93vs 6.85±1.79,p=0.043, respectively).In the subgroup analysis, patients with DM were detected to have 22 more acrochordons mostly located under breast area.
In a study performed to investigate the frequency of acrochordons by Margolis et al. 20 the frequency of acrochordons was determined as 47 in 500 outpatients.Of these 47 cases, 34 were diagnosed with DM, and it was determined that an increasing risk of developing DM is present at a higher rate in male patients with bilateral, hyperpigmented, large and multiple lesions.In a study with a smaller sample size and published by Erdogan et al., 13 it was reported that patients with acrochordons have higher BMI and HOMA-IR levels while displaying similar fasting blood glucose levels and DM frequencies.Demir et al. 21reported that the frequencies of overt DM and IGT were 73.3% and 5% in patients with acrochordons, respectively.In the study, Sari et al. 10 reported higher levels of glucose, insulin, HOMA-IR and HbA1c in patients with acrochordons.Bhargava et al. 18 also found the frequency of DM or IGT as 28% in patients with acrochordons and reported that multiple number of acrochordons (3 or more) and their sites are a significant risk factor for the development of DM.Although previous history of DM was more commonly seen in our patients with acrochordons, serum glucose levels and NCEP-ATP III blood sugar criterion were found to be similar in both groups.On the other hand, insulin levels, and as a consequence of higher insulin levels, HOMA-IR levels were found higher in patients with acrochordons.Although serum fasting glucose and the blood sugar criterion of NCEP-ATP III were similar, glucose metabolism in patients with acrochordons should be meticulously evaluated in terms of IR and previous history of DM.
Abdominal obesity plays a role in the development of MetS and is reported to precede other MetS components 22 .In our study, patients with acrochordons exhibited higher WC, body weight and BMI values than controls.Under NCEP ATP III criteria, the frequency of abdominal obesity in our acrochordon group was higher.Of patients with acrochordons, moreover, 98.1% and 77.5% were detected as overweight and obese, respectively.Only 1.9% of patients had normal BMI.Various studies suggest that abdominal obesity is more closely associated with IR, [3][4][5] and higher insulin levels could play a role in the development of acrochordons by stimulating IGF-1 and EGF receptors, as discussed earlier 16 .Acrochordons are more commonly observed in obese patients, and a positive correlation is present between acrochordons and the severity of obesity 1 .As consistent with the findings of previous studies, elevated insulin and HOMA-IR levels were determined in patients with acrochordons.In the study Akpinar et al. 8 reported that BMI values were higher in patients with acrochordons.However, they reported no WC values although the presence of MetS was evaluated.Likewise, Tanega et al. 12 reported acrochordons are associated with BMI and WHR.In their study, Sarı et al. 10 found higher levels of BMI and WC in patients with acrochordons, in line with the findings of the present study.Demir et al. 21lso found that 70.8% of patients with acrochordons were obese.Hence, it can be concluded that obesity, especially abdominal obesity, can contribute to the development of acrochordons.
Of our patients with acrochordons, 64.7% met the blood pressure criterion of NCEP ATP III and also were determined to have higher systolic and diastolic blood pressure.Likewise, Sari et al. 10 reported higher systolic and diastolic blood pressure in patients with acrochordons, along with a hypertension frequency of 30.1%.Similar results were reported by Akpinar et al. 8 In their study, Demir et al. 21also reported that 65% of patients with acrochordons had hypertension.
Therefore, while patients with acrochordons were being evaluated, the presence of hypertension should be considered by health professionals in line with the findings of the present and previous studies.
In our study, serum TG levels were found to be higher in patients with acrochordons, compared to controls.Furthermore, the number of patients with TG ≥150 g/dL or treated with TG-lowering medicine, one of MetS criteria under NCEP ATP III, were higher among patients with acrochordons, compared with controls.On the other hand, levels of HDL-cholesterol and the number of patients meeting the HDL-cholesterol criterion of NCEP-ATP III were detected similar in both groups.In literature, various reports investigating the relationship between acrochordons and dyslipidemia are present.In different studies performed by, Tamega et al., 12 Sari et al. 10 and Akpinar et al., 8 it was reported that TG levels were elevated in patients with acrohordons.Other studies performed by Crook et al., 23 Akpinar et al. 8 and Sari et al. 10 reported decreased HDLcholesterol levels.In their studies, Gorpelioglu et al. 9 reported higher levels of total cholesterol and LDL-cholesterol while Erdogan et al. 13 reported higher total cholesterol levels in patients, compared with controls.The frequency of dyslipdemia was reported as 45.8% 21 and 59.3% 10 in patients with acrochordons.In the present study, no total and LDL-cholesterol levels were measured because of the fact that they are not included among NCEP-ATP III criteria.Therefore, only HDL-cholesterol and TG levels were measured in our study.No matter how similar HDL-cholesterol levels were found among our findings, we recommend that all patients with acrochordons be evaluated in terms of the presence of dyslipidemia, especially considering the existence of increased levels of TG .
In the present study, the frequency of MetS syndrome was higher in patients with acrochordon, compared to controls [73 patients (71.6%) vs 31 patients (40.8%), p<0.001, respectively].To the best of our knowledge, only two studies evaluating the frequency of MetS in patients with acrochordons, in which Sari et al. 10 reported the frequency of MetS as 39.3% while Akpinar et al. 8 were reporting as 56.2%, are present in literature.
In conclusion, such features as WC, body weight, BMI, systolic and diastolic blood pressure, TG, insulin and HOMA-IR levels, frequency of MetS and its components, including NCEP-ATP III criteria related to WC, blood pressure and TG were determined to be increased in patients with acrochordons.Therefore, in the presence of acrochordons, we consider that patients should be evaluated as to the presence of MetS and accompanying components in order to prevent and treat MetS earlier.

Table 1 : Socio-demographic and study characteristics of cases with acrochordons and controls.
Note: Values are expressed as mean ± standard deviation, median (minimum-maximum), or n (%).DM: Diabetes Mellitus, BMI: Body-mass index, HDL-Cholesterol: High density lipoprotein-Cholesterol. HOMA-IR: Homeostasis model assessment-insulin resistance