Acanthosis nigricans (AN) is a dermatosis characterized by velvety, papillomatous, brownish-black, hyperkeratotic plaques, typically of the intertriginous surfaces and neck 1. Although AN is associated with malignancy, the identification of its more common connection to obesity and insulin resistance allows the diagnosis of related disorders including type 2 diabetes, metabolic syndrome, and polycystic ovary syndrome 2. Insulin binds to insulin-like growth factor 1 receptors (IGF-1Rs), which are similar in size and subunit structure to insulin receptors, but bind IGF-1 with 100-fold to 1000-fold greater affinity than insulin 3. Elevated insulin concentrations result in both direct and indirect activation of IGF-1Rs on keratinocytes and fibroblasts, leading to cellular proliferation, and facilitate the development of AN 4. Patients with AN are at risk for all of the components of the metabolic syndrome 2.
Metabolic syndrome refers to the combination of obesity, hypertension, dyslipidemia, and insulin resistance. The metabolic syndrome is present if an individual has three or more of the following five health problems: high blood sugar (>100 mg/dl), reduced high-density lipoprotein (HDL) [<40 mg/dl (men) and <50 mg/dl (women)], high triglycerides (>150 mg/dl), high blood pressure (>130/85), and abdominal obesity [waist circumference>102 cm (men), waist circumference>88 cm (women)] 5. In adults, AN increases the risk of development of diabetes by 3.5-fold within 5 years 6; thus, early recognition of these conditions is essential for the prevention of disease progression.
The aim of this work was to determine the relation between the severity of AN skin lesions and metabolic syndrome components in obese patients, assuming that detection of AN provides an excellent opportunity to initiate treatment for obesity and related metabolic complications.
Patients and methods
This study was a case control study that included 30 obese patients with AN (group 1) selected randomly from the Dermatology Outpatients Clinic, Al-Zahraa University Hospital (Cairo, Egypt), and 30 obese age-matched and sex-matched individuals without AN as controls (group 2) from the Outpatients Clinic of Internal Medicine, Al-Zahraa University Hospital. The study was carried out over a duration of 9 months from March 2011 till the end of November 2011. Written consent was obtained from all participants and the study was approved by the Dermatology Research Ethics Committee of Faculty of Medicine for Girls, Al-Azhar University.
For all participants, assessment of full medical history and family history was carried out. Complete general and dermatological examinations were performed. Weight, height, and waist circumference were measured; BMI was calculated as weight in kg divided by height in m2. Obesity was defined as a BMI of 25 kg/m2 or greater 7.
Inclusion criteria were obese patients with AN and obese individuals without AN. Exclusion criteria were patients with diabetes, hypertension, and other associated endocrine and systemic diseases known to result in AN, and patients fulfilling the criteria of metabolic syndrome (combination of obesity, hypertension, dyslipidemia, and insulin resistance).
For the patient group, the severity of AN was assessed according to a quantitative scale of AN 8. Five anatomical sites were chosen to assess the presence and extent of AN: the neck, axilla, knuckles, elbows, and knees. The neck and axilla were graded for severity on a scale from 0 to 4. For those with AN present on the neck, the texture of the affected area was also measured on a scale from 0 to 3.The knuckles, elbows, and knees were graded as AN present (1) or absent (0) (Table 1).
According to the neck severity score, the patients were subdivided into three subgroups: grade 2 was considered as mild, grade 3 as moderate, and grade 4 as severe (grade 1 was not included in our study as no patients complained of or observed this stage).
Two venous blood samples were taken from both groups, the first after an 8-h fasting period for complete blood count, liver function tests, renal function tests, and fasting glucose, and the second after a 12-h fasting period for fasting insulin and lipid profile [(total cholesterol, triglycerides, HDL, low-density lipoprotein (LDL)]. Routine chemical tests were carried out using an autoanalyzer (Hitachi 911; Hitachi, Tokyo, Japan), complete blood count by Sysmex (KX-21n; J & S Medical Associates, Tokyo, Japan), and fasting insulin by Architect (Abbott, Hannover, Germany) by chemiluminscence.
The data were coded and entered using the statistical package SPSS version 15 (SPSS Inc., Chicago, Illinois, USA). The data were summarized using descriptive statistics: mean, SD for quantitative variables, and number and percentage for qualitative values. Statistical differences between groups were tested using the χ2-test for qualitative variables, and an independent-sample t-test and analysis of variance with the post-hoc Bonferroni test for quantitative normally distributed variables. The nonparametric Mann–Whitney test and the Kruskal–Wallis test were used for quantitative variables that were not normally distributed. The Pearson correlation test was carried out to test for linear relations between variables. A P-value of less than or equal to 0.05 was considered statistically significant 9.
Clinical data of the patients are shown in Table 2. Patient subgroups according to the neck severity score are shown in Fig. 1a–c.
There was no statistical difference in sex and age between the cases and the controls (P>0.05), and no statistical difference in triglyceride levels (P>0.05). There was a statistical difference between the cases and the controls in waist circumference (P<0.001), BMI (P<0.001), fasting blood glucose (P<0.001), total cholesterol (P<0.001), HDL (P<0.001), LDL (P<0.05) (Table 3), and fasting insulin levels (23.2±5 vs. 11.3±1.4, P<0.001) (Fig. 2).
Among the patient subgroups, there was no significant difference between mild, moderate, and severe subgroups in age, fasting glucose, total cholesterol, triglycerides, HDL, and LDL (P>0.05), whereas there was a significant difference in waist circumference and BMI (P<0.001). In terms of blood pressure, there was a significant difference in systolic blood pressure (SBP) and diastolic blood pressure (DBP) in the severe group compared with the mild and moderate group (P>0.01), but no significant difference was found between mild and moderate AN (P>0.05) (Table 4). There was a significant difference between mild, moderate, and severe subgroups in fasting insulin levels (Fig. 3).
Among the patient group, we found a positive correlation between the neck score, axilla score, and the neck texture with each of waist circumference, BMI, SBP, DBP, fasting insulin levels, total cholesterol, and triglycerides, whereas there was a negative correlation with HDL. There was no significant correlation with age, duration, fasting glucose, and LDL (Table 5).
We found a positive correlation between the fasting insulin levels and waist circumference, BMI, SBP, DBP, and triglycerides, and a negative correlation with HDL. No significant correlation was found between the fasting insulin levels and age, duration, total cholesterol, and LDL (Table 6).
As the frequency and degree of obesity increase in the population, a concomitant increase in AN can be expected. Eight types of AN have been described; obesity-associated AN is the most common type 10.
We carried out this study to determine the relation between the severity of AN and metabolic syndrome components in obese patients. This may be helpful for early recognition of obesity-related metabolic complications and prevention of disease progression.
Most of our patients were women (90%) as the improvement in the skin lesions is often of primary concern to them, whereas Grandhe et al. 11 found no significant difference in the prevalence of AN among men (48.7%) and women (51.4%).
The patients ranged in age between 22 and 47 years, which is in agreement with Stuart et al. 12, who reported a lower prevalence of AN in individuals older than 50 years of age. The skin type of our patients was graded between types III and V. AN is very common in individuals with darker skin 13.
The neck affection was present in all patients (100%), whereas axilla was affected in 23 patients (76.7%). The predilection of AN for areas such as the neck and axillae suggests that perspiration and/or friction may also be necessary cofactors 14. Affection of knees, elbows, and knuckles were 26.7, 43.35, and 30%, respectively, which is in agreement with Puri 13, who detected neck affection in 93.3% of patients, followed by the axilla in 66.6% of patients and flexural involvement (flexures of groins, knees, and elbows) in 40% of patients. The neck severity score was used in subgrouping of patients as it was present in all patients, and has the advantage that it allows easy and quick assessment of AN. The largest number of patients of the current study were in moderate and severe degree as these are the most patients seeking medical advice.
There was a family history of AN, diabetes, hypertension, and obesity in 43.3, 46.6, 10, and 56.7% of patients, respectively. These data are in agreement with those of Kong et al. 15, who reported that AN was most prevalent among individuals with higher number of risk factors for diabetes such as a family history of diabetes.
Similar to Burke et al.8, we found a significant difference between patients with AN and individuals without AN in terms of waist circumference, BMI, fasting glucose, and HDL. Moreover, in the present study, the AN group had significantly increased total cholesterol and LDL levels compared with the non-AN group. This in contrast to Guran et al.16, who did not find significant differences in glucose, triglyceride, LDL, HDL, and total cholesterol levels in obese children with AN and obese children without AN.
There was a significant difference between the patient and the control group in fasting insulin levels as hyperinsulinemia, which is a result of insulin resistance and associated with obesity, stimulates the formation of characteristic plaques of AN 17. The high insulin level is often able to maintain glucose homeostasis in the presence of insulin resistance; thus, the blood glucose in these patients is generally in the normal range, and this indicates a prediabetic condition 18.
In terms of patients’ subgroups, there were significant differences in waist circumference and BMI, which is in agreement with Grandhe et al. 11, who reported a statistically significant correlation of increasing severity of AN with increasing BMI, waist circumference, hip circumference, waist–hip ratio, skin fold thickness, and body fat percentage in diabetic patients. Moreover, we found a significant difference in fasting insulin levels between the patient subgroups.
Neck severity scores were positively correlated to neck texture and the axillary severity score. There was a positive correlation between the neck severity score and fasting insulin levels; this was also in agreement with Grandhe et al. 11, who reported that the severity of AN of the neck correlates with fasting insulin concentration and correction of hyperinsulinemia often reduces the burden of hyperkeratotic lesions.
To our knowledge, this is the first report to find a positive correlation between the neck severity score and SBP, DBP, total cholesterol, and triglycerides.
Hyperinsulinemia is known to enhance hepatic very LDL synthesis and may thus contribute directly to the increased plasma triglyceride and LDL 19.
Weight reduction in obesity-associated AN may result in resolution of the dermatosis 11. Studies in obese adults have shown a sustained improvement in the risk of cardio vascular system disorders in association with a 10 to 15% weight loss maintained over time 20. Another report, however, has suggested that 16% weight loss resulted in a differential risk factor response, including a marked reduction in the incidence of type 2 diabetes 21.
AN is not simply a skin disease that can be missed. The severity of AN skin lesion correlates with hyperinsulinemia and components of metabolic syndrome that requires intervention and motivate patients and physicians care to prevent complications.
Conflicts of interest
There are no conflicts of interest.
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