Acanthosis nigricans in obese patients: Presentations and implications for prevention of atherosclerotic vascular disease
Published Web Locationhttps://doi.org/10.5070/D36fj340w2
Acanthosis nigricans in obese patients: Presentations and implications for prevention of atherosclerotic vascular disease
Departments of Dermatology1 Public Health Science2, and Pathology3 Wake Forest University School of Medicine, Winston-Salem, North Carolina
Aaron S. Katz, M.D.1, David C.Goff, M.D., Ph.D.2,Steven R. Feldman, M.D., Ph.D.1,3
Dermatology Online Journal 6(1): 1
Acanthosis nigricans is traditionally characterized by hyperpigmented, velvety plaques of body folds. Involvement of other areas occurs as well. The condition is caused by hyperinsulinemia, a consequence of insulin resistance that occurs associated with obesity. As the frequency and degree of obesity increase in the population, a concomitant increase in acanthosis nigricans can be expected. The dermatologist has an important role in identifying the subset of obese patients with acanthosis nigricans. These patients have hyperinsulinemia and may be at greater risk of consequent atherosclerotic cardiovascular disease. It is essential for dermatologists to recognize the many presentations of acanthosis nigricans to identify patients at risk for associated medical conditions. This article illustrates a variety of presentations of acanthosis nigricans associated with insulin resistance.
Acanthosis nigricans is traditionally characterized by hyperpigmented, velvety plaques in body folds, though involvement of other areas occurs as well. Hyperinsulinemia, a consequence of insulin resistance that occurs associated with obesity, stimulates the formation of these characteristic plaques.[2,3,4] As the frequency and degree of obesity increase in the population, a concomitant increase in acanthosis nigricans can be expected.[5,6] Since the subset of obese patients with acanthosis nigricans have hyperinsulinemia and may be at greater risk for atherosclerotic cardiovascular disease, dermatologists must play a key role in identifying these patients.[7,8]
References in the dermatology literature have discussed the many syndromes and malignancies associated with acanthosis nigricans.[1,9,10] Less emphasis is put on the most common cause of acanthosis nigricans, hyperinsulinemia associated with obesity. This article illustrates the variety of presentations associated with insulin resistance that dermatologists must be prepared to recognize. We also discuss the medical implications of insulin resistance that indicate the need for therapeutic and dietary intervention.
Presentations of acanthosis nigricans
|Figure 2B||Figure 2C|
|Figure 2B. Typical acanthosis nigricans of the neck.|
|Figure 2C. Plaques on the extremities had a psoriasiform appearance. Both of these images are from the hyperinsulinemic patient shown in Figure 2A.|
The "classic" presentation of obesity-related acanthosis nigricans is a velvety, hyperpigmented thickening of the skin in the axillae and back of neck (figure 1). While this presentation is well-known to physicians, more subtle or otherwise atypical presentations are common in the authors' experience and may be overlooked or misdiagnosed. Involvement of the scalp occurs (figure 2) and may have a tinea amiantacea appearance. Involvement over joints appears quite common, including the elbow, knees and knuckles (figures 3,4). Well-defined hyperkeratotic plaques may occur, even on the face (figure 5,6) and palms (figure 7).
The hyperkeratotic plaques of the elbows, knees, and scalp in acanthosis nigricans may be easily confused with psoriasis. Acanthosis nigricans should be considered when obese patients are seen with hyperkeratotic plaques. Clinically, acanthosis nigricans can be differentiated from psoriasis in several ways. The plaques of acanthosis nigricans are not inflamed, while psoriasis plaques are typically red. Classic involvement of acanthosis nigricans in the axillae may be confirmatory; similarly, psoriatic plaques of the gluteal cleft or other characteristic changes of psoriasis (such as nail dystrophy) confirm the clinical impression of psoriasis.
Histologically, psoriasis and acanthosis nigricans are easily differentiated. The changes of acanthosis nigricans are manifest by a mammillated, acanthotic epidermis with orthohyperkeratosis, and there is no significant inflammatory infiltrate (figure 8). Psoriasis is also characterized by epidermal thickening, but in contrast to acanthosis nigricans, this thickening occurs by elongation of the rete ridges and is associated with parakeratosis and a superficial perivascular infiltrate.
Acanthosis nigricans can occur with psoriasis, though the frequency of this combination is unknown. Perhaps this relationship is tied to the observed association between obesity and psoriasis. Lesions of psoriasis in patients with acanthosis nigricans may exhibit verrucous hyperkeratosis (figure 9). Both conditions may occur separately or together in the same patient (figure 10).
Pathophysiology: Insulin resistance
Generally, acanthosis nigricans is caused by hyperinsulinemia. Hyperinsulinemia results in binding of insulin to insulin-like growth factor receptors on keratinocytes and fibroblasts, with resultant hyperplasia of the skin. Insulin resistance due to obesity underlies the hyperinsulinemia in obesity-associated acanthosis nigricans.[2,3] An elevated fasting blood insulin level confirms the presence of hyperinsulinemia underlying the diagnosis of atypical acanthosis nigricans; it also demonstrates to the patient, in a tangible way, the systemic biochemical abnormality causing the cutaneous changes. The high level of insulin that causes symptoms of hyperinsulinemia often is able to maintain glucose homeostasis in the face of insulin resistance. Thus, the blood glucose in these patients is generally in the normal range, though frank non-insulin dependent diabetes mellitus may be present, particularly in patients over 40.[7,14] The blood insulin level may be used as a marker for improvement in the condition achieved through dietary and exercise interventions.
Implications of insulin resistance
Though it may be important for dermatologists to recognize acanthosis nigricans for appropriate treatment of the cutaneous manifestations, acanthosis nigricans has greater significance as a sign of systemic disease. Dermatologists should search for acanthosis nigricans in obese patients in order to identify those patients requiring intervention for the prevention of the systemic adverse effects of hyperinsulinemia.[7,9,15] There is a growing body of evidence of the deleterious effects of hyperinsulinemia. Hyperinsulinemia is an established cofactor in polycystic ovary syndrome.[2,3] Hyperinsulinemia with a normal glucose may indicate a pre-diabetic condition; these patients may have impaired glucose tolerance. Non-insulin-dependent diabetes mellitus represents a later stage of insulin resistance in which there is no longer an ability to produce sufficient insulin to maintain normal glucose.
Insulin resistance, that is, resistance to insulin mediated glucose disposal, has long been noted in non-insulin dependent diabetes mellitus (NIDDM) . Over the last several years, insulin resistance has received attention as a possible etiologic factor for cardiovascular diseases. [14,16,17] In 1988, Reaven suggested that insulin resistance may underlie a number of disorders including hypertension, dyslipidemia (especially high triglyceride and low high density lipoprotein levels), impaired glucose tolerance (IGT), and coronary heart disease (CHD) . It has long been observed that diabetes mellitus is associated with severe atherosclerotic cardiovascular disease. Tight control of blood glucose improves the microvascular components of diabetic vasculopathy but is relatively ineffective at controlling the atherosclerosis of large vessels, including coronary and carotid disease. It is speculated that hyperinsulinemia may be an important contributor to the large vessel atherosclerosis associated with diabetes mellitus. [7,15]
The potential mechanisms mediating the association of insulin resistance with atherosclerosis include effects on traditional risk factors. Elevated blood pressure, abnormal lipoproteins and thrombotic/fibrinolytic factors, as well as pathological smooth muscle cell and fibroblast proliferation and matrix deposition may all be mediated through direct effects of insulin resistance. [16,17,18,19] In the IRAS study, a positive relationship was shown between insulin resistance (as assessed by the Frequently Sampled Intravenous Glucose Tolerance test) and atherosclerosis (by B-mode ultrasound of the carotid) in a large multiethnic population.  Although no putative mechanism for a direct atherogenic effect of insulin resistance has been proposed, the persistence of the association between insulin resistance and atherosclerosis after adjustment for other traditional risk factors supports the contention that other mechanisms are yet to be elucidated.
Intervention in acanthosis nigricans
Optimal treatment of cutaneous manifestations has not been defined. Symptomatic treatments, though anecdotal, include topical antibiotics, topical (or systemic) retinoids, and keratolytics.  Although acanthosis nigricans is not an inflammatory disorder, superpotent topical corticosteroids can be tried for their atrophogenic effect. The most effective treatment is weight loss and exercise to correct the underlying endocrinologic abnormality. The cutaneous changes of acanthosis nigricans do respond to reductions in blood insulin levels. 
Obesity causes the insulin resistance, and weight loss can correct the problem. Dietary measures are obviously relevant. Increased exercise is also helpful and important. Insulin resistance improves quickly in response to improved diet and increased exercise, and may normalize before patients achieve a normal body weight. Thus, once patients begin to lose weight, there is the expectation of rapid improvement in the acanthosis nigricans. Patients may reduce also reduce their risk of long-term vascular complications.
Acanthosis nigricans is not simply a benign skin disorder that can be casually dismissed. The presence of obesity should initiate a search for evidence of acanthosis nigricans. The presence of acanthosis nigricans indicates to both the physician and the patient that there is a serious biochemical disorder that requires intervention. These findings demonstrate concretely to patients that their obesity is causing systemic disease and may motivate patients and their families to make necessary changes in diet and exercise.
When findings of acanthosis nigricans are present, body weight, blood glucose and fasting blood insulin levels should be obtained. Elevated blood insulin levels are helpful for demonstrating to patients the cause of their condition and the need for exercise and dietary interventions. Follow up care should be coordinated with the patient's primary care physician and should include periodic measurements of body weight and blood insulin levels.
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