Clinics in Dermatology (2018) 36, 48–53
Acanthosis nigricans and the metabolic syndrome Ayse Serap Karadağ, MD a,1 , Yi You, MD, PhD b,1 , Retno Danarti, MD c , Safaa Al-Khuzaei, MD d , WenChieh Chen, MD e,f,⁎ a
Department of Dermatology, Goztepe Research and Training Hospital, School of Medicine, Istanbul Medeniyet University, Istanbul, Turkey b Department of Dermatology, Southwest Hospital, The Third Military Medical University, Chongqing, P.R. China c Department of Dermatology and Venereology, Faculty of Medicine, Universitas Gadjah Mada/Dr. Sardjito Hospital, Jalan Farmako Sekip Utara, Yogyakarta, Indonesia d Department of Dermatology, Hamad Medical Corporation, Rumailah Hospital, Doha, Qatar e IZZ Immunologie-Zentrum Zürich, Walchestr. 11, CH 8006 Zurich, Switzerland f Department of Dermatology and Allergy, Technische Universität München, Munich, Germany
Abstract Acanthosis nigricans (AN) describes clinically a darkly pigmented thickening skin, which produces epidermal and dermal hyperplasia with orthokeratotic hyperkeratosis and papillomatosis of the stratum spinosum with basal layer hyperpigmentation, in the absence of actual acanthosis and melanocytosis on histologic examination. It is a reactive cutaneous change closely associated with obesity, insulin resistance, and hyperinsulinemia; endocrinopathy; or malignancy, in particular gastrointestinal adenocarcinoma. The prevalence varies, and ethnicity seems an independent factor. Evidence indicates that AN is a useful clinical marker to identify patients susceptible to insulin resistance, the MetS, and type 2 diabetes. Whether AN can be regarded as one of the risk factors for the diagnosis of MetS, like large waist circumference and elevated blood pressure, is unclear. Correlation between AN and degree of hyperglycemia, insulin resistance, impaired glucose tolerance, and dyslipidemia remains to be confirmed. Classification of AN is inconsistent, and assessment of its severity is less studied. Several monogenic diseases are known to present extensive AN of early onset and can act as models for a better understanding of its pathogenesis. Therapeutic options are limited, and results are unsatisfactory. Retinoids seem to be the most effective topical treatment, and insulin sensitizers, represented by metformin to target insulin resistance, are promising, but controlled studies are lacking. Change of lifestyle to diminish the manifestations of MetS is beneficial, but the influence remains unclarified. Spontaneous remission seems more complete in paraneoplastic AN than in the form associated with obesity and insulin resistance. © 2018 Elsevier Inc. All rights reserved.
Introduction ⁎ Corresponding author. Tel.: + 41 (0) 44 434 10 00. E-mail address:
[email protected] (W. Chen). 1 A.S. Karadağ and Y. You share the first authorship.
https://doi.org/10.1016/j.clindermatol.2017.09.008 0738-081X/© 2018 Elsevier Inc. All rights reserved.
The term acanthosis nigricans (AN) was first described in Paul Gerson Unna's (1850-1929) eminent International Atlas of Rare Skin Diseases, published in 1890.1 It commonly
Acanthosis nigricans and the metabolic syndrome manifests as symmetrical, hyperpigmented, dark, rough patches and plaques typically in the intertriginous areas, flexures, and the neck.2 Elbows and knees, dorsal joints of hands and fingers (knuckles), external genitalia, and occasionally face and eyelids can be involved.3 Lesions may develop over the areolae, umbilicus, anus, lips, and rarely the conjunctiva and oral mucosa, with delicate smooth furrows and verrucous changes.3 The skin lesions begin with brown pigmentation in fair-skinned or gray pigmentation in dark-skinned people, accompanied by dryness and roughness, then become palpably thickened and covered with small papillomatous elevations and a velvety texture.4 The distribution and severity are not always symmetrical, whereas the sequence of involvement varies individually. Superimposed skin tags (acrochordon) are common in advanced lesions.
Epidemiology and prevalence The prevalence of AN varies significantly, depending on age, ethnicity, skin type, degree of obesity, and concomitant diseases, especially endocrinopathy, which can reach up to 25% in general surveys and more than 60% in studies of overweight and obese children (Figure 1). Individuals with dark skin display this sign more often,5 with native Americans and African Americans being most commonly affected, followed by Hispanics, Asians, and much less often Caucasians.3,6 In overweight and obese children, the ethnic influence on the prevalence rates appears less obvious.7 Occurrence of AN increases with age and has no gender difference, whereas some studies reveal a higher prevalence in girls of school age and in women with obesity or diabetes.8,9
49 In most epidemiologic surveys of AN, only the nape was examined, which very likely underestimated the prevalence and severity of the disease. This may be why some studies report the presence of AN to be less sensitive than body index percentile for identification of youth with insulin resistance.10
Classification Different classifications of AN have been proposed, mainly based on the etiologic factors.11–13 One researcher11 classified AN as malignant, benign or true, pseudo (related to endocrinopathies), and drug induced. Another12 proposed a simple AN unrelated to malignancy and paraneoplastic AN. A third group13 combined etiology and localization, dividing AN into obesity associated, benign, syndromic, malignant, unilateral, acral, drug induced, and mixed type. Many of the proposed nomenclatures are overlapping, unclear, and confusing (eg, benign, pseudo or true, malignant, mixed), reflecting the complexity of the disease pathogenesis. We would suggest discarding the use of benign, pseudo or true, and malignant to describe AN, because AN itself is a reactive skin change in its nature, and a malignant transformation has so far never been reported. Overlapping also occurs in acral AN, which can be idiopathic,14 drug, or malignancy associated.15 Repeated insulin injection is reported to induce local AN.16 The term familial AN refers to diverse presentations caused by mutations in insulin receptor gene or fibroblast growth factor receptor (FGFR)3,17,18 idiopathic or indeterminate cases with unclarified genetics.19,20 Aromatase deficiency syndrome is caused by genetic mutations of CYP19A1, but the ensuing
Fig. 1 A 10-year-old Indonesian boy with body weight 70 kg and body height 150 cm (body mass index 31.1), fasting blood glucose 120 mg/ dL, insulin 25 mIU/L (Homeostasis Model Assessment of Insulin Resistance index 7.4). Acanthosis nigricans was observed in the anterior neck, nape, and bilateral axillae.
50 Table 1
A.S. Karadağ et al. Proposed classification of acanthosis nigricans by Chen et al.
Subtypes Localized
Generalized
Examples Unilateral Acral Focal Obestiy associated a Endocrinologic b Monogenic c
Multigenic d Paraneoplastic Drug induced Indeterminate
Unilateral nevoid AN Acral AN2 Insulin injection–induced AN Diabetes mellitus, Cushing syndrome, Addison disease, gigantism/acromegaly Rabson-Mendenhall syndrome Donohue syndrome Berardinelli-Seip syndrome Alström syndrome Bardet-Biedl syndrome HAIR-AN syndrome, PCOS Gastrointestinal adenocarcinoma Insulin, testosterone, estrogen, nicotinic acid So-called benign AN, familial AN of unknown genetics or mixed form
AN, acanthus nigricans; HAIR-AN, hyperandrogenism, insulin resistance, acanthosis nigricans; PCOS, polycystic ovary syndrome. a Obesity but does not fulfill the diagnosis of diabetes mellitus. b Endocrinopathy with well-established diagnosis. c Genetic mutations identified and published in Online Mendelian Inheritance in Man (OMIM). d Syndromes based on clinical diagnosis with heterogenous etiologies.
endocrinologic disturbance leads to AN.21 A modification of the existing classification is proposed in Table 1. Limited classifications address the disease severity. One group22 has suggested a quantitative scale of AN severity from 0 to 4, based on the affected areas with no consideration of the degree of skin alterations in each region. Another group23 has evaluated AN skin texture, hyperpigmentation, and the body parts involved (neck, axillae, trunk, extremities, or mucous membranes).23 A third group24 has included five anatomic sites (neck, axilla, knuckles, elbows, and knees) and the skin texture in each affected area and found the scales correlated with fasting insulin and body mass index.
Pathogenesis AN is most commonly associated with obesity, hyperinsulinemia, and insulin resistance in adults and children alike.5 Mutations in the insulin receptor gene, leading to insulin resistance, are known to cause extensive AN with early onset in childhood.25 Also, genetic mutations involving FGFR2 and FGFR3 gene,26,27 phosphatase and tensin homolog gene,28 and V-Ha-RAS Harvey rat sarcoma viral oncogene homolog gene show severe AN phenotypically.29 Paraneoplastic AN, more appropriately termed than malignant AN, is often associated with gastrointestinal adenocarcinoma,30 followed by lung cancers, then such gynecologic malignancies as breast or ovarian. Drug-induced AN is rare, where hormone dependent, especially insulin but also sexual hormones, and glucocorticoids are described. There are also many case reports of AN as a side effect of nicotinic acid in the treatment of dyslipidemia.31 Pathogenesis of AN is incompletely understood. The histopathology is characterized mainly by hyperkeratosis and epidermal papillomatosis with minimal or no acanthosis and
basal hyperpigmentation with mild melanosis or discreet melanocytosis. In correlation with the etiologies, it suggests that proliferation of epidermal keratinocytes or probably more the dermal fibroblasts induced by certain growth factors is of central pathogenic role. Insulin and insulin-like growth factor (IGF) are best characterized, whereby insulin at low concentrations binds to classic insulin receptors. With insulin resistance and compensatory hyperinsulinemia, insulin binds to IGF-1 receptors,31 which have been found in keratinocytes and fibroblasts.32 There is no direct evidence to indicate the activation of IGF-1 receptors in epidermal keratinocytes or dermal fibroblasts in the lesions of AN. The interaction among insulin, IGF-1, androgens, and growth factors may further explain the association between AN and obesity, endocrinopathies, or hormonal treatment.33 As in paraneoplastic AN, transforming growth factor α is supposed to act on the increased epidermal growth factor receptor expressed in the epidermis.34 FGFR, phosphatase and tensin homolog, and V-Ha-RAS Harvey rat sarcoma viral oncogene homolog genes control and regulate the cell proliferation, differentiation, and apoptosis.
Acanthosis nigricans and metabolic syndrome There is substantial evidence that patients with AN bear a higher risk for developing the metabolic syndrome (MetS) and type 2 diabetes in different age groups, with a significant correlation among AN and body mass index, waist circumference, elevated blood pressure, dyslipidemia, hyperinsulinemia, hyperglycemia, impaired glucose intolerance, and Homeostasis Model Assessment index of insulin resistance. Clustering of these components can be significant.6,35–37 Pregnant women with and without AN were found to have a ratio of gestational diabetes at 35.8% and 9.2%, respectively.38 Presence of acanthosis nigricans during pregnancy could
Acanthosis nigricans and the metabolic syndrome increase the risk of conversion of gestational diabetes to type 2 diabetes mellitus or prediabetes within 5 years postpartum (odds ratio 3.10; 95% confidence interval [CI] 1.64-5.87).39 Very few studies have examined the accuracy of applying AN in the prediction of insulin resistance or type 2 diabetes and the correlation between the extent and severity of AN and degree of obesity or insulin resistance. In a prospective cohort study of 76 obese Caucasian children, the sensitivity, specificity, positive and negative predictive values, and accuracy level for AN to detect insulin resistance were 73.5%, 50%, 54.3%, 70%, and 49%, respectively, with a low correlation between insulin and fasting glucose levels in AN-negative or AN-positive patients.40 In obese children, reactive insulinemia was found to be more pronounced, triglycerides higher, high density lipoprotein cholesterol lower, and atherogenic dyslipidemia more common in those with AN than without AN.41 Further large-scale studies in consideration of age and ethnicity are required.
Syndromic acanthosis nigricans associated with the metabolic syndrome Among the syndromes associated with AN, the hyperhormonotrophic form is induced by overproduction of hormones, mainly glucocorticoid, androgen, insulin, and growth hormone, either through functional disturbances due to enzyme abnormalities or tumorigenic origin such as neoplastic or paraneoplastic. Examples are Cushing syndrome, Addison disease, polycystic ovary syndrome, gigantism/acromegaly, PraderWilli syndrome, and primary hypogonadism. The common occurrence of Cushing syndrome, precocious puberty, pituitary tumor, and acromegaly in McCune-Albright syndrome but with rare manifestation of AN indicates that a certain promoting or suppressing factor is involved in its formation.42 Another group of syndromes are characterized by autosomal recessive inheritance, insulin resistance with early onset of hyperinsulinemia, and AN in a usually extensive way. Examples are Rabson-Mendenhall syndrome, Alström syndrome, Bardet-Biedl syndrome, Donohue syndromes, and Berardinelli-Seip congenital lipodystrophy syndrome types I and II.42 Hirsutism is a common manifestation. Mutations in the insulin receptor gene are found in the RabsonMendenhall syndrome and Donohue syndrome, which can cause retarded posttranslational processing of the receptor, impaired transport of the receptor to the cell membrane, reducing numbers of receptors on the cell surface, and reduced affinity of the receptor for insulin. Alström syndrome and Bardet-Biedl syndrome are associated with defective ciliogenesis, stunted cilium, and ciliopathies, which induce dysfunction in intracellular and intercellular sensing and signaling. Alström syndrome is caused solely by mutations in the ALMS1 gene, whereas more than 19 genes on different chromosomes have been identified in Bardet-Biedl syndrome. In spite of obesity to a similar frequency and extent, patients with Alström syndrome are more
51 likely than those with Bardet-Biedl syndrome to develop childhood type 2 diabetes mellitus and AN.43 Berardinelli-Seip syndrome type 1 is caused by mutations in the 1-acylglycerol-3-phosphate O-acyltransferase 2 gene (AGPAT2), also known as lysophosphatidic acid acyltransferase-beta, which catalyzes the biosynthesis of glycerophospholipids and triacylglycerol.44 Overexpression leads to increased enzyme activity in correlation with enhanced transcription and synthesis of interleukin 6 and tumor necrosis factor α, indicating that AGPAT2 overexpression may amplify the cellular response to cytokine stimulation. BerardinelliSeip syndrome type 2 is caused by mutations in the BSCL gene/seipin gene, which is involved in endoplasmic reticulum function and the remodeling of actin cytoskeleton for adipocyte differentiation. Aromatase deficiency syndrome is caused by mutations in the CYP19A1 gene leading to the failure in the conversion of androgens to estrogens.21 Virilization occurs in pregnant mothers during the antenatal period and also in female fetuses at birth with pseudohermaphroditism. Affected individuals of either gender later manifest with features of estrogen deficiency and androgen excess. Concurrence of MetS with obesity, diabetes due to insulin resistance, and hyperinsulinemia, as well as AN, is commonly observed in affected patients. A laminopathy due to a heterozygous missense mutation in ZMPSTE24 has been described in a patient with severe MetS, including hypertriglyceridemia, early-onset type 2 diabetes, central obesity but without subcutaneous lipoatrophy, and AN, liver steatosis, and dilated cardiomyopathy. Mutations in ZMPSTE24 involve the only metalloprotease, transforming prelamin into mature lamin A.45 HAIR-AN (hyperandrogenism, insulin resistance, and acanthosis nigricans) syndrome is a well-known but illdefined entity, especially regarding the diagnosis of hyperandrogenism.46 It may be a subtype of polycystic ovary syndrome, but obesity and/or other endocrinopathies play a primary pathogenic role. The association between AN and cutaneous hyperandrogenism, such as acne, hirsutism, and androgenic alopecia in the presence or absence of obesity, should be clarified. A recent study found that AN, especially axillary AN, together with hirsutism, are the most reliable cutaneous markers of polycystic ovary syndrome.47 Whether it is secondary to the often coexisting MetS remains to be clarified. Similarly, the common presentation of AN in adults with Down syndrome was attributed to the higher prevalence of obesity,48 but studies on the lipid profile, prevalence of insulin resistance, and MetS between adults with Down syndrome and controls are inconclusive.49 There are several syndromes associated with endocrinopathy or hyperglycemia, but the presentation of AN is unclear. In inherited adrenocorticotropic resistance syndromes, such as triple A syndrome (achalasia-Addisonianism-alacrimia) and familial glucocorticoid deficiency syndrome, diffuse skin hyperpigmentation is common.50 H syndrome is characterized by hyperpigmentation, hypertrichosis, hyperglycemia (insulin-dependent diabetes mellitus) and hypergonadotropic
52 hypogonadism, in addition to histiocytosis and lymphadenopathy in the head and neck region, bilateral inguinal lymphadenopathy, phalangeal contractures, sensorineural hearing loss, and hyperglobulinemia. The responsible gene mutations were identified in solute carrier family 29, member 3 (SLC29A3), encoding equilibrated nucleoside transporter 3 (hENT3).51
Treatment Treatment of AN is usually unsatisfactory or frustrating. Well-controlled comparative studies with long-term followup are scarce. Topical retinoids, including tretinoin, adapalene, and tazarotene, are partially effective. Oral retinoids, such as acitretin and isotretinoin, have been reported to be effective for extensive involvement. Single case reports on the efficacy of topical agents, like vitamin D analogs, ammonium lactate, trichloroacetic acid, triple-combination depigmentation cream, urea, podophyllin, and salicylic acid, remain to be confirmed.52 Dermabrasion or abrasive laser therapy can also be attempted, but the long-term benefits are unknown. Correction of the contributing factors, such as obesity, hyperinsulinemia, and insulin resistance related to the MetS, lead to clinical improvement of AN,13 but usually in the early phase, and the improvement varies. Paraneoplastic AN mostly vanishes when the associated cancers are eliminated. Use of insulin sensitizers such as metformin, thiazolidinediones (eg, pioglitazone), and inositols (eg, myo-inositol and d-chiroinositol) to treat insulin resistance in the MetS may have promising effects on AN, especially metformin.53 Octreotide, a synthetic analog of the hypothalamic hormone somatostatin, was also found to work on AN presumably via inhibition of glucagon, growth hormone, and insulin release.54 We recommend a phase-oriented cocktail treatment for obesity-associated AN. In the early phase with pigmentary change, it should start with lifestyle modification and improvement of insulin resistance and the use of keratolytic agents like α-hydroxy acids and salicylic acids, in combination with depigmenting agents like hydroquinone or azelaic acid. We add topical tretinoin when velvety skin change appears. It usually takes 3 to 6 months to see a significant improvement, and complete resolution is rare. Skin irritation is a major concern, especially for children and in the axillary regions.
Conclusions AN has been reported to be a useful screening marker for obesity and insulin resistance. Early onset and extensive involvement is observed in genetic mutations affecting insulin receptor gene, ciliopathies, or lipogenesis. AN can be secondary to the associated MetS or the involved genes can directly induce AN. Research on the activation and interaction of insulin/IGF-1, epidermal growth factor receptor, and FGF/ FGFR signaling pathways will improve the understanding of the pathogenesis and help develop novel targeted therapies.
A.S. Karadağ et al.
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