Prevalence, Predictors and Morphological Patterns of Acanthosis Nigricans Between Obese Non-diabetic Patients on Second Generation Antipsychotics Versus Non-obese Insulin Dependent Diabetes mellitus: A Nested Case-Control Study

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LIST OF ABBREVIATIONS

AN — acanthosis nigricans

BMI — body mass index

Wisp1 — Wnt1-inducible signaling pathway protein-1

INTRODUCTION

Acanthosis nigricans (AN) is characterized by dark, coarse, and thickened skin with at times velvety texture, being mostly symmetrically distributed predominantly on the neck, axillae, ante-cubital and popliteal fossae as well as groin folds. It is histopathologically characterized by papillomatosis and hyperkeratosis of the skin. The term ‘acanthosis nigricans’ was although originally proposed by Dr. Paul Unna from Hamburg, Germany but the first case of AN was described and published by Pollitzer and Janvosky from Prague in 1981 and thus it was included in the International Atlas for rare skin diseases [1].

It mostly occurs in individuals younger than 40 years, may be genetically inherited and is typically associated with obesity, endocrinopathies, such as hypothyroidism or hyperthyroidism, acromegaly, polycystic ovarian syndrome, insulin–resistant diabetes, or Cushing’s disease [2–4]. The most common cause of AN is observed to be an insulin resistance, which leads to increased circulating insulin levels. Insulin and insulin-like growth factor-1 with their receptors on keratinocytes and fibroblast are obviously implicated in the complex regulation leading to the peculiar epidermal hyperplasia. In fact, excess insulin levels cause the normal skin to reproduce rapidly and in obese patients it’s not insulin but insulin-like growth factor-1 levels that may contribute to keratinocyte and fibroblast proliferation [5, 6]. Thus, patients with diabetes mellitus and obese individuals are at least two times more prone to have AN compared to others [7, 8]. However, literature does not have so far found specific and distinctive predictors or categorical differences on morphologies of AN lesions, but it would be interesting to look out from psychiatric aspect if AN can help differentiating psychotropic drug induced weight gain versus drug induced diabetic patients.

Metabolic syndrome is on rise in chronic psychotic patients particularly on second generation antipsychotics like olanzapine and clozapine [9, 10] which basically is a clustering of factors including central obesity, glucose intolerance, hyperinsulinemia, low high-density lipoprotein cholesterol, high low-density lipoprotein cholesterol, high triglycerides and arterial hypertension. Some studies attributes occurrence of metabolic syndrome in psychotic patients to their sedentary lifestyle, lack of exercise and physical work, poor nutrition, chronic stress and abnormal hypothalamic-pituitary-adrenal axis [11]. However, accumulating evidence suggests that varying degrees of insulin resistance may be the common etiological factor for the individual components of metabolic syndrome [12]. In a randomized, 10-week, parallel-group, double-blind trial, the effect of second generation clozapine and conventional haloperidol on weight gain were tested. Among 19 patients on clozapine group all gained a mean weight of 5.3 kg over their baseline compared to 0.68 kg in 20 patients of haloperidol [13]. The patients of metabolic syndrome also have about five-fold greater risk of developing type 2 diabetes (if not already present) based on meta-analysis of 42,419 participants from 16 cohorts [4, 14, 15]. Indeed, predictability of metabolic syndrome for incident diabetes was found to be superior to the predictability associated with either Framingham risk score or classical clinical risk factors [16–17]. Apart from AN, acne valgaris, hidradenitis suppurativa, lipoatrophy, atopic dermatitis, skin tags and psoriasis are common skin markers associated with this metabolic syndrome reflecting the causal existence of increased numbers of oxidative stress and inflammatory markers [18–20]. AN may further also be seen with certain medications that lead to elevated insulin levels (e. g., glucocorticoids, niacin, insulin, oral contraceptives and protease inhibitors). Very few drugs in the armamentarium of neuropsychiatry have AN presentation on prima facie without co-occurrence of metabolic syndrome where common pathophysiological pathway exists. Further it is not known if the qualitative morphological patterns of AN is any different when they occur in these subgroups of individuals who apparently have drug induced obesity and underlying plethora inflammatory, immunomodulatory and stress-diathesis overload due to ongoing schizophrenic process. Although obesity-associated AN used to be once labelled as pseudoacanthosis and lesions may completely regress with weight reduction, there is no study in literature for analyzing AN in psychotropic induced obesity or hypercholesterolemia.

Hence, the aim of this study to investigate morphological pattern differences and predictors of acanthosis nigricans in patients of hyperlipidemia with the psychotropic medications versus those of conventionally seen lesions of acanthosis nigricans in insulin dependent diabetes mellitus without hypercholesterolemia.

MATERIALS AND METHODS

The current study was conducted in collaboration with out-patient department of Psychiatry, Dermatology, Internal Medicine and Biochemistry of our tertiary care hospital after receiving institutional ethical approval and consent from the patients. We used a nested case-control study design since the estimates of diagnostic accuracy in such sampling method were observed to be very similar to those in full study population [21] and recruited patients from January 2019 to June 2021 for a period of 30 months.

A pool of 491 patients of chronic schizophrenia and other psychosis (≥ 2 years of disorders) who were either on Olanzapine, Clozapine, Risperidone or Quetiapine were screened to find out for the presence of obesity induced by psychotropics and further investigated for hypercholesterolemia / hypertriglyceridemia and/or weight gain (at least > 10% of body mass index (BMI)) over last 6 months or more after the use of medications and who also eventually developed AN skin lesions in their due course.

The other group was pooled from Department of Internal Medicine and Dermatology after screening out 177 patients of insulin dependent diabetes mellitus for identifying AN patients from insulin resistant diabetes mellitus subgroup receiving treatment from our tertiary care hospital. We used the data from this particular group of AN who were already diagnosed with diabetes mellitus and had insulin resistance but screened particularly those individuals who does not have obesity (BMI > 29.9 kg/m²) and/or hypercholesterolemia (cut off level of serum cholesterol > 200 mg/dl).

Thus, in the duration of last 30 months, we could get 26 out of 491 patients in group A (AN with hypercholesterolemia secondary to antipsychotics without comorbid diabetes mellitus) and 24 patients in group B (AN with diabetes mellitus without obesity or hypercholesterolemia). The insulin resistance was calculated using commonly used formula: (Blood Glucose Level × Blood Insulin Level) /22.5.

The confirmation of the clinical diagnosis of AN was essentially done by senior consultants from department of dermatology whichever patients were having skin lesions characterized by velvety papillomatous brownish or black, thickened, hyperpigmented plaques typically of inter-trigonous surfaces on neck and in case of diagnostic doubt, the biopsy of plaqueswas taken to identify histopathological patterns as and when required. We used Burke’s Indices [22] for grading the texture and severity of AN as well as clinical acumen for comparing the differences of morphological patterns between these two groups. Specific warning sign evaluations for any presence of malignancy in AN were ruled out by applying the following exclusive points, for example we excluded the patients who have rapid onset of extensive AN, specifically with atypical sites, florid cutaneous papillomatosis and unintentional weight loss. We also excluded the cases of comorbid presence of other simultaneous metabolic disorders like Addison’s disease, acromegaly, hypothyroidism, primary biliary cirrhosis and few auto-immune conditions like systemic lupus erythematosus, systemic sclerosis and dermatomyositis. To identify the presence of hypercholesterolemia we ensure that the patient had been on their psychotropics for more than 6 months with regular compliance and screened the serum cholesterol levels for at least two times over a period of 12 weeks with standard laboratory assessments, whereas for the patients of insulin resistant diabetes mellitus we evaluated the serum levels of glycosylated hemoglobin levels and fasting glucose and Insulin levels.

All the data of the patients was analyzed using statistical software IBM SPSS Statistics 21 (IBM Corp., USA). Since most of our data is quantitative and ordinal in nature wherein these clinical and laboratory variables exist in naturally occurring ordered categories, we used a Mann–Whitney U test for identifying the degree of differences between these two independent groups for identifying the significance. Because Mann–Whitney U test is a non-parametric test, it clearly does not assume any assumptions related to the distribution of scores which makes it more pertinent. We further used Pearson’s correlation coefficient for comparing the predictors and quantitative nature of associations with increased insulin, cholesterol and triglyceride levels to severity of AN using Burke’s Index. A p-value of < 0.05 was considered significant and < 0.005 was considered very significant.

RESULTS

In group A we screened 491 patients of chronic schizophrenia from our center who were either on Olanzapine, Clozapine, Quetiapine or Risperidone and developed significant weight gain over last 12 months. We identified 26 out of 491 patients who developed hypercholesterolemia, thus the prevalence of AN in obesity secondary to psychotropic drugs was 5.29%. We observed that males were slightly more preponderant (1.5:1) compared to females and their mean age was 34.25 ± 11.36 years. Their mean cholesterol levels were about 246 mg/dl and serum insulin levels were 54.6 µIU/ml which is nearly four times the normal range. None of them were found to have diabetes mellitus (mean blood glucose levels 112.74 ± 6.8 mg/dl, Table 1). The mean BMI was 26.2 kg/m² while mean weight gain observed in these patients who are on second generation antipsychotics was 7.2 ± 2.1 kg. 80.7% (21 out of 26) of them were on Olanzapine, 15.3% (4 out of 26) were on Risperidone, 3.8% (1 out of 26) were on Clozapine. The mean duration of darkening of AN was 9.2 months. AN lesions were predominantly noted on neck (90%), axilla (84%), periorbital (38%) and groin (22%) but uncommonly also seen in palms, soles, perioral, nipple, and antecubital fossa. Many patients have AN lesions at multiple body regions.

 

Table 1. Baseline socio-demographic and clinical characteristics of acanthosis nigricans with or without obesity

Variable	Group A: AN with obesity and hypercholesterolemia	Group B: AN without obesity with insulin resistant diabetes mellitus
n	26	24
No of patients screened	491	177
Prevalence Percentage, %	5.29	13.55
Mean age, years	34.25 ± 11.36	26.8 ± 10.69
Male : Female	1.5 : 1	1 : 2
Mean blood sugar levels, mg/dl	112.74 ± 6.8	145 ± 13.5
Mean insulin levels, µIU/ml	54.6 ± 3.6	104.7 ± 17.2 µIU/ml
Mean cholesterol levels, mg/dl	246.6 ± 29.5	163.45 ± 4.01
Mean triglycerides levels, mg/dl	149.5 ± 11.4	131.1 ± 8.3
Mean BMI, kg/m2	26.2 ± 0.7	23.2 ± 2.8
Mean weight gain in last 12 months, kg	7.21 ± 1.22	1.5 ± 0.9
History of childhood low birth weight, n	18	6
Mean duration of darkening of AN, months	9.2	14.3
Distribution of AN lesions in groups
Periorbital, n (%)	10 (38)	9 (40)
Temples, n (%)	3 (12)	5 (22)
Perinasal, n (%)	3 (12)	5 (22)
Perioral, n (%)	2 (7)	3 (12)
Infralabial, n (%)	3 (12)	5 (20)
Skin over hyoid bone, n (%)	0	2 (10)
Neck, n (%)	23 (90)	23 (96)
Axilla, n (%)	22 (84)	21 (88)
Antecubital fossa, n (%)	4 (18)	3 (13)
Knuckles, n (%)	8 (32)	2 (10)
Sides of waist, n (%)	0	1 (6)
Inframammary, n (%)	0	2 (8)
Periumbilical, n (%)	2 (6)	0
Groin, n (%)	6 (22)	3 (13)
Popliteal fossa, n (%)	3 (12)	1 (4)
Knees, n (%)	0	5 (24)
Palms, n (%)	1 (6)	0
Nipples, n (%)	1 (2)	0
Soles, n (%)	2 (4)	0

Note: AN — acanthosis nigricans, BMI — body mass index

 

In group B we selected 24 patients of AN who were diagnosed case of insulin resistant diabetes mellitus without obesity after screening out 177 patients of insulin dependent diabetes mellitus. Thus, the prevalence of AN in these group of samples was found to be 13.55%. Most 62.5% (15 out of 24) of them were from 21 to 30 years, while 21.1% (7 out of 24) of them belonged to 31 to 40 years age and the rest 8.3% (2 out of 24) were from 41 to 50 years age. We found that females were two times more likely to have AN in insulin dependent diabetes mellitus without having obesity compared to males as none of them were found to have hypercholesterolemia (mean cholesterol level was 163.45 ± 4.01 mg/dl). However, most of them showed increased fasting serum Insulin levels (104.7 ± 7.2 µIU/ml) and the mean fasting blood sugar level was 145.0 ± 13.5 mg/dl. Their mean BMI was found to be 24.2 ± 2.8 kg/m². Mean duration of AN lesions were 14.3 months which were clearly more compared to group A patients. Although neck and axilla remained the most common body regions of AN in these patients, knee, temples, perinasal area were also involved although in few cases. Thus, uncommon occurrences of AN is one of the key distinctive features in these two groups of patients. Finally, we also noted that history of low birth weight was three times more prevalent in group A patients compared to group B reflecting obesity develops more in those who were earlier had low birth weight.

The distribution of the severity of Burke’s index with reference level of serum cholesterol is shown in Table 2. Mann–Whitney U test works by converting scores into ranks while ignoring the grouping variables in our nested cases (cholesterol levels < 200 mg/dl and > 200 mg/dl) and then compared the mean rank of each group. We observed a very significant difference (p < 0.005) between the mean ranks for Burke’s neck severity, neck texture and axilla between normal versus high serum cholesterol levels.

 

Table 2. Comparison of Acanthosis Nigricans with or without hypercholesterolemia

Variables	Cholesterol groups, mg/dl	Mean rank	Sum of ranks	Mann–Whitney, U	p
Burke's neck severity	< 200 (n=24)	17.50	420	120	< 0.001
	> / 200 (n=26)	32.88	855
Burke's neck texture	< 200 (n=24)	18.58	446	146	0.001
	> / 200 (n=26)	31.88	829
Bruke's axilla	< 200 (n=24)	20.02	480.5	180.5	0.007
	> / 200 (n=26)	30.56	794.5

 

Further, on Pearson’s Correlation, we observed that serum cholesterol levels were positively (ρ = 0.505) and significantly (p = 0.008) associated with occurrence of AN and its neck severity, while even more significant positive association (p < 0.005) of serum triglycerides were noted with AN neck severity and texture but not significantly (p = 0.165) with axilla or other region lesions of AN (Table 3).

 

Table 3. Pearson Correlations among Burke’s Indices and Biochemical Parameters

Variables	Serum insulin	Triglyceride levels	Burke's Neck Severity	Burke's Neck Texture	Bruke's Axilla
Cholesterol level	r = 0.187 (p = 0.361)	r = 0.697 (p < 0.001)	r = 0.505 (p = 0.008)	r = 0.352 (p = 0.077)	r = 0.330 (p = 0.100)
Serum insulin	–	r = 0.114 (p < 0.578)	r = 0.279 (p = 0.167)	r = 0.011 (p = 0.957)	r = 0.088 (p = 0.669)
Triglyceride levels	–	–	r = 0.800 (p < 0.001)	r = 0.531 (p = 0.005)	r = 0.281 (p = 0.165)
Burke's Neck Severity	–	–	–	r = 0.674 (p < 0.001)	r = 0.278 (p = 0.170)
Burke's Neck Texture	–	–	–	–	r = 0.467 (p = 0.016)

 

DISCUSSION

The present qualitative, nested case-control study not only evaluated the relative prevalence of AN in obese (perhaps futuristically vulnerable metabolic syndrome) chronic psychotic patients who were on second generation antipsychotics like Olanzapine or Clozapine for more than 12 months but it also compared the morphological rarities of differences in occurrence of AN lesions within the subgroup of non-obese, insulin dependent diabetes mellitus. Since the age of onset of AN in most cases irrespective of its underlying diathesis or medical comorbidities is mostly below 40 years of age, the intra-class homogeneity of both nested patient groups viz. chronic psychotics who were obese forming our predominant part of group A and also those of non-obese, insulin dependent diabetes patients from group B are in well conformity for objective phase of thematic differences evaluation in the present study. We observed about 5.29% prevalence of AN in group A having obesity secondary to psychotropic drugs which was significantly less than what even non-obese, insulin dependent diabetic patients who almost had 13.55% prevalence, close to three times. This suggests that diabetes is strongly linked with occurrence of AN lesion and might reflect the continuity in the paradigm of metabolic syndrome as its definitive predictor of severity while obesity is the initiation of phase shift in the process. Interestingly past few studies had reported the different prevalence of the AN in obesity at different regions of the world, for example couple of studies from Texas, the United States widest range difference (Т. Guran, et al. had reported 7% [23] while study by F. Sayarifard, et al. had reported 74% in obese people in Dallas [24]). The prevalence of AN in New Mexico was 49.2% in obese adolescents compared with 7.7% in those who were not obese reflecting as much as seven times more likelihood of its vicariousness [25].

To our knowledge, this is the first published study of comparative prevalence of AN in obese and diabetic population from India and there is no other study in literature that systematically explored the prevalence of AN in patients of either psychotropic induced metabolic syndrome or even hypercholesterolemia, thus head-to-head comparisons of our findings cannot be directly possible. In both the groups of our sample population, most of lesions were noted on neck (> 90%) and axilla (> 80%) but very rarely on knuckles specially in obese group who were on psychotropics. The mean level of serum insulin in insulin dependent diabetes mellitus group (B) was 104.7 ± 7.2 µIU/ml while it was 54.6 ± 3.6 µIU/ml in group A obese patients which were clearly above the mean normal serum levels. However, as we know insulin resistance is present in both disorders, G. Gonzalez–Saldivar, et al. [25] considered AN in knuckles to be a sensitive and straightforward clinical biomarker to predict insulin resistance. While this is in conformity that there lies a prolonged time lag for developing insulin resistance in drug induced obesity which may be slower and partially reversible with weight reduction strategies. Except for presence of additional acrochordons and atypical site of lesions in the body, there were hardly any morphological or biopsy differences observed in AN patients of both groups. Thus, alterations in morphological patterns and textures often do not seem to differ between hypercholesterolemic/obese and non-obese, insulin-resistant diabetic patients and subtle changes in them are dynamic and therefore they may overlap or change with time henceforth we rather need more deeper understandings and molecular evaluation either at AN evolving commencing point or end point (which is difficult to identify practically) for having enough precision in its pathophysiological pathways. For example, the Wnt1-inducible signaling pathway protein-1 (Wisp1) was recently described as a new adipokine and its expression and secretion are increased in the course of differentiation of human adipocytes. Relative changes in body weight regulate both expression of Wisp-1 in adipose tissue and plasma levels of secreted Wisp-1 [26]. Interestingly, Wisp-1 serum levels are elevated in obese patients affected with polycystic ovary syndrome and in patients with gestational diabetes mellitus and Olanzapine is known to be associated with both later conditions [27–28] and it would be more enticing to get such prototypical additional group for its variability of AN occurrence. Finally, in the backdrop of extensive work by C. E. Koro, et al. [29] who showed the strong association between olanzapine exposure and hyperlipidemia in schizophrenic patients and found nearly five-fold increase in odds of developing hyperlipidemia compared with no antipsychotic exposure [odds ratio 4.65; 95% confidence interval 2.44–8.885; p < 0.001] and more than a three-fold increase compared with those receiving first generation conventional agents [odds ratio 3.36; 95% confidence interval 1.77–6.39; p < 0.001], choosing large group of Olanzapine induced obese but non-diabetic patients from the pool of chronic schizophrenia makes this study more relevant as well as intrigued for understanding additional clinical biomarker like AN in psychiatric population. However, none of the previous studies in the literature systematically tried to evaluate if AN develops in obese patients who receives long term antipsychotics like Olanzapine and Clozapine and there is clearly much scope in future to understand trends, patterns and variabilities to be explored.

CONCLUSION

We evaluated the prevalence and predictors of acanthosis nigricans with antipsychotics induced obese patients, its various morphological differences among obese non-diabetic and diabetic non-obese patients. One of the challenges in preventing diabetes or obesity is to identify its early risk-prediction marker like insulin resistance which usually is missed or ignored clinically. Such studies were not conducted in past and these insights can perhaps potentially signify acanthosis nigricans as a clinical biomarker or component which can predict the prognosis for metabolic syndrome too in near future. More research is needed to determine the time course and magnitude of developing acanthosis nigricans to uncover the mechanisms underlying the apparent differences.

ADDITIONALLY

Funding. This study was not supported by any external sources of funding.

Conflict of interests. The authors declare no conflicts of interests.

Contribution of the authors: P. Vidyasagar — study concept and design, data collection, statistical analysis, and interpretation, text writing; A. Kamble — study concept and design, statistical analysis and interpretation, text writing; P. Khairkar — study concept and design, statistical analysis and interpretation, text writing; B. Shravya — study concept and design, statistical analysis, data analysis and interpretation, text writing, final approval for publication of the manuscript; Y. Sumera — study design, data collection, and interpretation, text writing; A. R. Mateti, V. Reddy — study design, data analysis, interpretation, text writing; R. Biswas — study concept, text writing; R. Ransing — checking the critical intellectual content of the work, final approval for publication of the manuscript. The authors confirm the correspondence of their authorship to the ICMJE International Criteria. All authors made a substantial contribution to the conception of the work, acquisition, analysis, interpretation of data for the work, drafting and revising the work, final approval of the version to be published and agree to be accountable for all aspects of the work.

About the authors

Pappula Vidyasagar

Kamineni Institute of Medical Sciences

Email: Sgarpappula@gmail.com
ORCID iD: 0000-0001-6359-2603

MBBS, MD

India, Narketpally

Ashwini Kamble

Kamineni Institute of Medical Sciences

Email: dr.ashwinipravin@gmail.com
ORCID iD: 0000-0003-3396-8010

MD, Dr. Sci. (Chem.), Professor

India, Narketpally

Praveen Khairkar

Kamineni Institute of Medical Sciences

Email: praveen.khairkar280@gmail.com
ORCID iD: 0000-0003-3166-3547

MD, Dr. Sci. (Med.), Professor

India, Narketpally

Bogum Shravya

Kamineni Institute of Medical Sciences

Email: shravyab04@gmail.com
ORCID iD: 0000-0001-6490-1754

MBBS, MD

India, Narketpally

Yasmin Sumera

Kamineni Institute of Medical Sciences

Email: dr.sumeray@gmail.com
ORCID iD: 0000-0002-6142-7222

MBBS, MD

India, Narketpally

Ashok Rao Matety

Kamineni Institute of Medical Sciences

Email: armatety@yahoo.co.in
ORCID iD: 0000-0002-2585-6783

MBBS, MD

India, Narketpally

Vishwak Reddy

Kamineni Institute of Medical Sciences

Email: vishwakreddy.v@gmail.com
ORCID iD: 0000-0003-1133-3612

MBBS, MD

India, Narketpally

Rakesh Biswas

Kamineni Institute of Medical Sciences

Email: rakesh7biswas@gmail.com
ORCID iD: 0000-0001-7694-3660

MBBS, MD

India, Narketpally

Ramdas Ransing

BKL Walawalkar Rural Medical College

Author for correspondence.
Email: ramdas_ransing123@yahoo.co.in
ORCID iD: 0000-0002-5040-5570

MBBS, MD

India, Maharashtra

References

Supplementary files