Estimation of Metabolic Syndrome in Acanthosis Nigricans - A Hospital Based Cross-Sectional Study.

Background and
Objectives: Acanthosis nigricans is characterized by hyperpigmentation and velvet-like thickening of the skin. It symmetrically involves the neck, axilla, groins, antecubital and popliteal fossae, umbilical, and perianal areas. Acanthosis nigricans is a marker for insulin resistance and is increasingly found to be associated with metabolic syndrome. We conducted this study to estimate the frequency of metabolic syndrome in acanthosis nigricans.
Methods: In this hospital-based, cross-sectional study, we evaluated 60 patients with acanthosis nigricans with neck involvement. They were examined for other areas of involvement by acanthosis nigricans. Axillary and neck severity was graded based on the scale described by Burke et al. Insulin resistance was interpreted using homeostatic model assessment (HOMA-IR). Metabolic syndrome was diagnosed according to the SAM-NCEP criteria. Collected data were analyzed using IBM SPSS Statistics, Version 22 (Armonk, NY: IBM Corp).
Results: Axilla was the most common site involved in 51 patients (85%) followed by knuckles (55%). Metabolic syndrome was found in 78.3% of our patients, and 56.66% had insulin resistance. A statistically significant association of severity grading of axillary acanthosis nigricans with both metabolic syndrome (P = 0.001) and insulin resistance (P = 0.03) was noted. However, no meaningful association was found between the severity grading of neck acanthosis nigricans with both metabolic syndrome (P = 0.4) and insulin resistance (P = 0.08). The association of neck texture grading of acanthosis nigricans with insulin resistance was statistically significant (P = 0.005). Conclusions: Metabolic syndrome was seen in 78.3% of acanthosis nigricans. Axillary severity grading was associated with metabolic syndrome. Copyright:

Introduction

Metabolic syndrome is a cluster of risk factors, including obesity, dyslipidemia, hypertension, and glucose intolerance. It is thought to be caused by insulin resistance and altered adipocyte function.[1] Insulin resistance is due to ineffective utilization of produced insulin in the human body, leading to increased production and raised level of plasma insulin. Finally, beta cells of pancreatic islets fail to keep up with the body's increased need for insulin.[2] Without enough active insulin, excess glucose builds up in the bloodstream, leading to prediabetes, diabetes, and many other health disorders. Excess weight and physical inactivity are thought to be significant contributors to the development of insulin resistance.[3]

Acanthosis nigricans is recognized as a reliable cutaneous marker for insulin resistance. Acanthosis nigricans present as velvet-like, brown to black thickening of the skin, which mainly occur in the neck, armpits, antecubital fossae, groin, popliteal fossae, and umbilical region.[4] In reduced frequency, it can also be seen over eyelids, soles of the feet, nipples, palms, and phalanges. Rarely, it can affect the oral mucosa, respiratory mucosa, and genital region.[5] In the year 2000, it was incorporated into the list of indicators for the risk of diabetes by the American Diabetes Association (ADA).[6] A third of South Asia's population is now categorized in the obese category because of lifestyle changes and eating habits. Obesity promotes a subsequent rise in the insulin resistance and metabolic syndrome.[7] Metabolic syndrome is a known risk factor for coronary artery disease; recognizing this early will help in institution of measures to prevent coronary artery disease-associated morbidity and mortality. Very few Indian studies in the literature have addressed the issue of acanthosis nigricans and prevalent metabolic syndrome. Thus, we undertook this study.

Methods

We conducted a cross-sectional study on acanthosis nigricans in a tertiary care hospital. Clinically diagnosed patients with AN with neck involvement attending the Outpatient Department of Dermatology were enrolled in this study during the period from January 2015 to January 2016. Included patients were above the age of 14 years. Exclusion criteria included pregnant women, underlying malignancy, immune-compromised patients, and history of intake of oral contraceptive pills.

The sample size is determined using the formula n = z2pq/d2, where

n = denotes the sample size

z = value of the normal distribution corresponding to a significance level of 0.05 which is 1.96

p = expected proportion in the population = 0.17

q = (1 − p) = 0.83

d = precision = 0.1

N = (1.96)2 × 0.17 × 0.83/(0.1)2 = 54.20

While determining p, we considered the study done in Sri Lanka by Dassanayake et al.[8] who reported a prevalence of 17.4% as the population characteristics of Sri Lanka and our population characteristics are similar we chose this study.

The sample size of 54 thus obtained was rounded off to 60.

The study was started after obtaining the institutional ethical clearance. Informed assent/consent was obtained from all the patients. History of any medical illness and family history of acanthosis nigricans were noted. Thorough physical examination was done in all patients. BP was noted in the sitting position. Waist and hip circumference was measured in a standard manner and the waist-hip ratio was calculated. Body mass index was interpreted according to The Standard Consensus Statement for the Indian population.[9]

Acanthosis nigricans of neck and axilla was graded based on the standard scale as described by Burke et al.,[10] which is as follows

NECK grading-

Grade 0:Not visible.

Grade 1:Present: clearly present on close visual inspection, not visible to the casual observer, extent not measurable.

Grade 2:Mild: limited to the base of the skull, does not extend to the lateral margin of the neck (usually, 3 inches in breadth).

Grade 3:Extending to the lateral margins, not visible from the front.

Grade 4:Extending anteriorly.

AXILLA grading

Grade 0: Absent.

Grade 1: Present on close visual examination.

Grade 2: Localized to the central portion of axilla

Grade 3: Involving the entire axilla.

Grade 4: Extends beyond axilla.

Neck texture:

Grade 0: Smooth to touch: no differentiation from normal skin to palpation.

Grade 1: Rough to touch: clearly differentiated from normal skin.

Grade 2: Coarseness can be observed visually, portions of the skin clearly raised above other areas.

Grade 3:Extremely coarse: “hills and valleys” observable on visual examination.

Other skin conditions were also noted.

All patients underwent the following laboratory tests after overnight fasting: fasting lipid profile, fasting glucose level, and fasting serum insulin levels. Insulin resistance was estimated and interpreted using the homeostatic model assessment for insulin resistance (HOMA-IR) method for insulin resistance. The formula used was

fasting insulin (μUI/mL) x fasting plasma glucose (mmol/L)/22.5

A HOMA-IR value of ≥2.6 was considered as insulin resistance.

Metabolic syndrome was diagnosed if three or more of the SAM-NCEP criteria were fulfilled. The criteria included abdominal obesity (considered as waist circumference ≥90 cm for males and ≥80 cm for females), blood pressure >130/85 mm Hg, fasting blood glucose ≥100 mg/dl, hypertriglyceridemia >150 mg/dl, or low HDL cholesterol (<40 mg/dl for males and <50 mg/dl for females).

The data collected were entered into a Microsoft Excel spreadsheet and analyzed using IBM SPSS Statistics, Version 22 (Armonk, NY: IBM Corp). Descriptive data for categorical variables were presented as frequency and percentages. Fisher's Exact test was used to test the association between insulin resistance and metabolic syndrome with the study variables. Correlation analysis was done to see any correlation between HOMA-IR and BMI. Regression analysis done see the risk factors for metabolic syndrome in AN patients.

Results

The study included 60 clinically diagnosed cases of acanthosis nigricans with neck involvement. Male:female ratio was found to be 1:1.6. Mean age of the study group was 34 years. Forty-nine patients (81.67%) were clustered between 21 and 50 years of age. Eighteen patients (30%) had family history of acanthosis nigricans. Majority (95%) of patients were found to be in the obese category. Metabolic syndrome was found to be present in 47 patients (78.3%). Insulin resistance as calculated by HOMA-IR was seen in 34 patients (56.66%). A poor correlation was observed between HOMA-IR and BMI (rs = 0.265). Fifty-one patients (85%) had AN over axilla. Thirty-three patients (55%) had AN over the knuckles. Elbow and knee involvement were seen in 16 patients (26.7%) and 9 patients (15%), respectively. The association between the site of involvement with presence of metabolic syndrome and insulin resistance is given in Table 1. Association of knuckle involvement with insulin resistance and metabolic syndrome was statistically meaningful. Axillary involvement and knee involvement were significantly associated with metabolic syndrome and insulin resistance, respectively. The association between the severity grading of neck and axilla with metabolic syndrome and insulin resistance is shown in Tables 2 and 3, respectively. There was a statistically meaningful association seen between severity of neck texture and insulin resistance (P = 0.005). Statistically significant association was also seen between the severity grading of the axilla with metabolic syndrome (P = 0.009) and insulin resistance (P = 0.01). When patients with metabolic syndrome are compared with those without, we found the difference in all the components of metabolic syndrome are statistically significant except for HDL and diastolic blood pressure as depicted in Table 4. Logistic regression analysis in AN patients revealed that FBS was a risk factor for metabolic syndrome [Table 5].

Table 1

Site of involvement of acanthosis nigricans and frequency of insulin resistance and metabolic syndrome

site	Involvement	Insulin resistance		Total	P	Metabolic Syndrome		Total	P
		Absent	present			Absent	present
Neck	present	26	34	60	-	13	47	60	-
		43.34%	56.66%	100.00%		21.7%	78.3%	100.00%
Axilla	absent	5	4	9	0.48(NS)#	6	3	9	0.002*#
		19.20%	11.80%	15.00%		46.20%	6.40%	15.00%
	present	21	30	51		7	44	51
		80.80%	88.20%	85.00%		53.80%	93.60%	85.00%
Knuckles	absent	17	10	27	0.006*	9	18	27	0.04*
		65.40%	29.40%	45.00%		69.20%	38.30%	45.00%
	present	9	24	33		4	29	33
		34.60%	70.60%	55.00%		30.80%	61.70%	55.00%
Elbows	absent	21	23	44	0.26 (NS)	9	35	44	0.73 (NS)#
		80.80%	67.60%	73.30%		69.20%	74.50%	73.30%
	present	5	11	16		4	12	16
		19.20%	32.40%	26.70%		30.80%	25.50%	26.70%
Knees	absent	26	25	51	0.004*#	11	40	51	1.00 (NS)#
		100.00%	73.50%	85.00%		84.60%	85.10%	85.00%
	present	0	9	9		2	7	9
		0.00%	26.50%	15.00%		15.40%	14.90%	15.00%

#Fisher’s Exact test. *P<0.05 Statistically Significant, P>0.05 Not Significant, NS

Table 2

Acanthosis nigricans severity grading and its relation to insulin resistance

	Insulin resistance		Total	Fisher’s Exact test P
	absent	present
Neck Grade
1	2	2	4	0.07 (NS)#
	7.70%	5.90%	6.70%
2	8	4	12
	30.80%	11.80%	20.00%
3	15	20	35
	57.70%	58.80%	58.30%
4	1	8	9
	3.80%	23.50%	15.00%
Axilla Grade
0	5	4	9	0.01*
	19.20%	11.80%	15.00%
1	1	2	3
	3.80%	5.90%	5.00%
2	18	13	31
	69.20%	38.20%	51.70%
3	2	14	16
	7.70%	41.20%	26.70%
4	0	1	1
	0.00%	2.90%	1.70%
Neck Texture
0	0	1	1	0.005*
	0.00%	2.90%	1.70%
1	16	8	24
	61.50%	23.50%	40.00%
2	10	20	30
	38.50%	58.80%	50.00%
3	0	5	5
	0.00%	14.70%	8.30%

Table 3

Acanthosis nigricans severity grading and its relation to metabolic syndrome

	Metabolic Syndrome		Total	Fisher’s Exact test P
	absent	present
Neck Grade
1	1	3	4	0.38 (NS)#
	7.70%	6.40%	6.70%
2	3	9	12
	23.10%	19.10%	20.00%
3	9	26	35
	69.20%	55.30%	58.30%
4	0	9	9
	0.00%	19.10%	15.00%
Axilla Grade
0	6	3	9	0.009*
	46.20%	6.40%	15.00%
1	1	2	3
	7.70%	4.30%	5.00%
2	4	27	31
	30.80%	57.40%	51.70%
3	2	14	16
	15.40%	29.80%	26.70%
4	0	1	1
	0.00%	2.10%	1.70%
Neck Texture
0	0	1	1	0.78 (NS)
	0.00%	2.10%	1.70%
1	6	18	24
	46.20%	38.30%	40.00%
2	7	23	30
	53.80%	48.90%	50.00%
3	0	5	5
	0.00%	10.60%	8.30%

Table 4

Characteristics of acanthosis nigricans patients with metabolic syndrome and without metabolic syndrome

Characteristics	Without MS		With MS		P
	Mean	Standard deviation	Mean	Standard deviation
Age	27.8	8.2	35.8	10.9	0.01
BMI	26.5	3.8	29.5	3.5	0.01
Waist circumference	87.6	14.1	104.5	11.7	0.0003
Hip circumference	96	13.7	112.4	10.6	0.00001
Systolic BP	120	5.7	135.7	12.2	0
Diastolic BP	84.1	8.2	88.7	5.7	0.01
cholesterol	192.2	32.3	210.2	37.8	0.1
Fasting blood sugar	89.9	6.8	102.4	22.01	0.005
Fasting serum insulin	9.08	4.3	14.09	8.1	0.051
HDL	41.6	10.5	40.5	10.6	0.7
HOMA IR	2	0.8	3.5	2.2	0.01

Table 5

Logistic regression for factors influencing metabolic syndrome in the study population

Variables	Unadjusted Odds Ratio (95% confidence interval)	P	Adjusted Odds Ratio (95% Confidence Interval)	P
FBS	1.128 (1.023, 1.243)	0.015	1.195 (1.017, 1.403)	0.030
FSI	1.153 (1.005, 1.322)	0.042
CHO	1.015 (0.996, 1.034)	0.126
TGL	1.021 (1.003, 1.039)	0.022
HDL	0.989 (0.933, 1.049)	0.723
HOMAIR	1.976 (1.073, 3.641)	0.029
SBP	1.176 (1.066, 1.298)	0.001
DBP	1.115 (1.015, 1.225)	0.023
BMI	1.367 (1.059, 1.765)	0.016	1.101 (0.788, 1.538)	0.573
WC	1.137 (1.049, 1.233)	0.002	0.955 (0.766, 1.191)	0.681
HC	1.149 (1.054, 1.252)	0.002	1.197 (0.944, 1.516)	0.137

Comorbidities seen were asthma (13.3%), thyroid disorder (11.7%), hypertension (10%), PCOD (8.3%), and diabetes mellitus (6.7%). In this study, acrochordons were seen in 21 patients (35%). We found significant association of acrochordons with metabolic syndrome (P = 0.0007) and insulin resistance (P = 0.005) in our patients. Hirsutism (16.7%), pityriasis versicolor (13.3%), acne (10%), seborrheic dermatitis (6.7%), xerosis (8.3%), and allergic contact dermatitis (5%) were the other cutaneous lesions seen.

Discussion

Insulin resistance is the reduced sensitivity or responsiveness of the human body to the metabolic actions of insulin. When people have insulin resistance, glucose increases in the blood instead of being absorbed by the cells, leading to a prediabetes state or type 2 diabetes mellitus.[4] Thirty-four (56.7%) of our patients were shown to have insulin resistance. We found that knuckle and knee involvement were significantly associated with insulin resistance. We also noted that neck texture severity grading [Figure 1a-c] and axillary severity grading [Figure 2a-c] were significantly associated with insulin resistance. Atwa et al.[11] found that 65.4% of AN patients had insulin resistance and 15.4% of patients had diabetes mellitus. They opined that AN may be clinical marker to identify individuals with high risk for type 2 diabetes mellitus. A study on overweight Hispanic children by Kobaissi et al.[12] found that AN was an independent risk factor for insulin resistance. This study opined that body fat is primarily responsible for insulin resistance and AN grading is of little help in clinical assessment of the severity of insulin resistance. They used combined neck grading and texture scoring described by Burke et al. and excluded the axillary grading.[12] However, we have to take into account the fact that our study subjects were mostly adults while their study was on children. In an Indian study by Patidar et al.[13] on diabetic patients, a significant association of neck grading [Figure 3a-c] with insulin resistance was found. However, there was no association with axillary grading and insulin resistance, which had a significant association in our study.

Figure 1

(a) Neck texture severity grade 1 (b) Neck texture severity grade 2 (c) Neck texture severity grade 3

Figure 2

(a) Axilla severity grade 2 (b) Axilla severity grade 3 (c) Axilla severity grade 4

Figure 3

(a) Neck severity grade 2 (b) Neck severity grade 3 (c) Neck severity grade 4

The overall prevalence of MS identified with SAM-NCEP criteria among Asian Indians is 30%–40%, which is almost double that of the 15%–20% prevalence in Europeans.[5] Metabolic syndrome has been found to be associated with various dermatological conditions such as psoriasis, androgenetic alopecia, lichen planus, acne vulgaris, and hidradenitis suppurativa.[1415161718] We found MS in 78.3% of our patients with AN. We also found that AN patients are at risk for almost all components of metabolic syndrome. Dassanayake et al.[8] found that the prevalence of AN in 17.4% and metabolic syndrome in 34.8% of participants in the Sri Lankan urban population. They noted that AN patients were at risk for all the components of MS which was diagnosed on the basis of the ATP III criteria. They concluded that AN could not be a screening test for MS because of its low sensitivity; however, it could predict the presence of MS because of its high specificity. Obese women with AN appear to be at higher risk for metabolic syndrome. In our study, out of 37 women, 34 were found to be in obese category (BMI > 25 kg/m2); among them, metabolic syndrome was present in 57.4%. In a study by Ayaz et al.[19] done on 250 obese women, 100 patients had acanthosis nigricans, and metabolic syndrome was seen in 60 (60%) of the patients, which was comparable to our study. We observed that the association of metabolic syndrome with knuckle [Figure 4] and axillary involvement was statistically meaningful. Axillary severity grading was also significantly associated with metabolic syndrome (P = 0.001). We suggest examining the axilla, knuckle, and knee [Figure 5] for acanthosis nigricans when confronted with patient with acanthosis nigricans affecting the neck. The severity of axillary acanthosis nigricans should also be assessed. We believe this will help in recognizing the underlying insulin resistance and metabolic syndrome.

Figure 4

Acanthosis nigricans of knuckles

Figure 5

Acanthosis nigricans of knees

Limitations

No control arm in our study due to financial constraints to do the investigations in matched healthy subjects.

As this is a hospital-based study rather than a community-based study, the results cannot be extrapolated to the general population.

We did not evaluate axillary acanthosis nigricans alone. All of our axillary acanthosis nigricans patients had neck involvement also. This might have affected the outcome.

Conclusion

Metabolic syndrome was seen in 78.3% of acanthosis nigricans.

Axillary severity grading was associated with metabolic syndrome.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.