What causes acanthosis nigricans?

Abstract

As recently as a quarter of a century ago, the senior author of this editorial (PDC) was taught in medical school of the pre-eminent link between acanthosis nigricans and internal malignancy, particularly gastric adenocarcinoma.1 Thus, each patient with acanthosis nigricans represented an obligation to search for internal malignancy. The imperative for this approach was relaxed following the publication in 1976 of the landmark paper by Kahn et al.,2 that rightfully focused attention to the more common and pathophysiologically more rational association of acanthosis nigricans with insulin-resistant states. Kahn et al.’s paper highlighted the very rare cases of the type A and type B syndromes of insulin resistance and acanthosis nigricans.2 More importantly, it provided a biological framework for considering most (if not all) cases of acanthosis nigricans in the context of: tissue resistance to insulin, consequent hyperinsulinaemia and downstream binding of excess insulin to insulin-like growth factor (IGF) receptors that can stimulate growth and proliferation of cells, including keratinocytes and fibroblasts.2 Indeed, even tumour-associated acanthosis nigricans has been hypothesized to result from the effects of tumour-derived factor(s) that can trigger IGF-like activity.3 The association of acanthosis nigricans with insulin resistance also explained the widely known high prevalence of the skin disorder in obese individuals (up to 80%).4, 5 Thus, the ‘pseudo’ acanthosis nigricans of obesity prior to 1976 became ‘real’ acanthosis nigricans due to insulin resistance in obese individuals, in whom either the number of insulin receptors is reduced or the function of postreceptor pathways is defective. In this issue Munoz-Perez and Camacho report on a retrospective analysis of over 1000 patients and two new associations of acanthosis nigricans. We believe that the first association, that of acanthosis nigricans with Down syndrome, is real, linked by the finding of obesity in all of the patients studied. This association is consistent with the findings of a study of obese children in Galveston, Texas, in which 28% of cases weighing greater than 120% of ideal body weight were shown to have acanthosis nigricans.4 In adults, a study of patients from the Obesity Clinic of Parkland Hospital in Dallas, Texas also showed a positive correlation between the severity of obesity and the prevalence of acanthosis nigricans.3 The failure to document hyperinsulinaemia in three (of the 51) Down syndrome cases tested by Munoz-Perez and Comacho in this issue does not necessarily negate the relevance of insulin resistance as this diagnosis requires comparison of plasma insulin with plasma glucose, which was not done. Insulin resistance is defined as inappropriately elevated circulating levels of insulin for glucose. In addition, we speculate that small amounts of tissue insulin (despite normoinsulinaemia) may transduce proliferative effects in skin cells, leading to acanthosis nigricans. Munoz-Perez and Camacho’s second claim in this issue (pp. 000–000), that of an association between atopic dermatitis and acanthosis nigricans, rests on very tenuous grounds. Of the 987 atopic patients studied, only 4.9% were diagnosed with acanthosis nigricans. Tests of statistical significance were not performed. Furthermore, despite the authors’ acknowledgement of the pitfall of mistaking lichenification for acanthosis nigricans, confirmatory histology was performed only in a few clinically controversial cases. We are thus sceptical that atopic dermatitis is truly associated with acanthosis nigricans. In conclusion, the newly recognized association among Down syndrome, obesity and acanthosis nigricans is consistent with the established concept of insulin resistance playing a key part in the causation of this distinctive skin disorder.