Recebido em 19.06.2001. / Received in June, 19th of 2001.Aprovado pelo Conselho Consultivo e aceito para publicao em 15.02.2002. / Approved by the Consultive Council and accepted for publication in February, 15th of 2002.* Trabalho realizado no Servio de Endocrinologia do Hospital Universitrio Professor Edgard Santos, Faculdade de Medicina da Universidade Federal da Bahia e Laboratrio deInvestigao (Lim 18) da Faculdade de Medicina da Universidade de So Paulo. / Endocrinology Service of the Professor Edgard Santos University Hospital, Universidade Federal daBahia Faculty of Medicine and the Laboratrio de Investigao (Lim 18) of the Universidade de So Paulo Faculty of Medicine.

1 Professora de Endocrinologia da Faculdade de Medicina da Universidade Federal da Bahia./Professor of Endocrinology at the Universidade Federal da Bahia Faculty of Medicine.2 Acadmicos da Faculdade de Medicina da Universidade Federal da Bahia./Academics of the Universidade Federal da Bahia Faculty of Medicine.3 Auxiliar Tcnica do Laboratrio de Endocrinologia do Hospital Universitrio Professor Edgard Santos, Salvador, Bahia./Technical Assistant of the Endocrinology Laboratory at the

Hospital Universitrio Professor Edgard Santos, Salvador, Bahia State.4 Bioqumica da Faculdade de Medicina da Universidade de So Paulo./Biochemist at the Medicina da Universidade de So Paulo Faculty of Medicine .5 Professora de Endocrinologia da Faculdade de Medicina da Universidade de So Paulo./Professor of Endocrinology at the Universidade de So Paulo Faculty of Medicine.

2002 by Anais Brasileiros de Dermatologia

Acanthosis nigricans em mulheres obesas de uma populao miscigenada: um marcador de distrbiosmetablicos*Acanthosis nigricans in obese women in a mixed-racepopulation: a marker of metabolic disturbances*Leila Maria Batista Arajo1 Adriano Moura Costa de Viveiros2 Renata Cruz Lopes2Marcus Vaz Porto2 Aldenice de Carvalho Viana3 Rosa T Fukui4Mileni J M Ursich5

Resumo: FUNDAMENTOS - Acanthosis nigricans (AN) tem sido associada a diversos distrbios metablicos e endcrinos. OBJETIVO: O objetivo deste estudo avaliar a freqncia das co-morbidades da sndrome metablica em mulheres obesas de uma populaomiscigenada com AN, comparada a um grupo sem AN. CASUSTICA E MTODOS - Foram estudadas 481 mulheres, consecutivamente admitidas em um ambulatrio de obesidade (388 com AN e 93 semAN) e submetidas ao teste de tolerncia glicose oral, excetuando-se 20, que j se sabiam diabticas. RESULTADOS - A distribuio segundo a raa indicou 34,5% de brancas, 38,9% de pardas e 26,6% de negras. A freqncia global de AN foi de80,7%, sendo fortemente maior nas negras versus brancas (90,6 % e 66,9%, p=0,000000) e negras versus pardas (86% e 90,6%, p= 0,000006).Foi tambm maior nas pardas versus brancas (86% e 66,9%, p

538 Arajo, Viveiros, Lopes, Porto, Viana, Fukui & Ursich

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INTRODUOA Acanthosis nigricans (AN) condio dermatol-

gica caracterizada por espessamento, hiperpigmentao eacentuao das linhas da pele, gerando aspecto grosseiro eaveludado no local afetado. Histologicamente, comum aobservao de hiperceratose, projeo acentuada das papi-las da derme e discreto espessamento das camadas da epi-derme.1 Embora possa ocorrer em qualquer local da super-fcie corprea, a rea mais atingida a regio posterior dopescoo, seguida pelas axilas, face lateral do pescoo,superfcies flexoras dos membros, regio periumbilical,inframamria, mucosa oral ou mesmo, em casos raros, plan-ta dos ps e palma das mos.1

Basicamente, AN pode ser dividida nas formas ma-ligna e benigna. A forma maligna representa um marcadorde neoplasias abdominais, particularmente o adenocarcino-ma gstrico. As formas benignas so divididas em idiopti-ca, hereditria, induzida por drogas e as causadas por doen-as endcrinas.1

As endocrinopatias so as principais causas de AN,sendo a obesidade o distrbio mais comum, freqentemen-te associado ao hiperinsulinismo, ao diabetes mellitus e resistncia insulina.2-15 Outros distrbios endcrinos asso-ciados AN so descritos: doena de Cushing, ovrios poli-csticos, tireoideopatias, hirsutismo, doena de Addison,acromegalia, entre outros, alguns dos quais cursam comresistncia insulina.5,6,8,11,13

A prevalncia de AN em populaes no selecionadasvaria de sete a 74%, de acordo com idade, raa, freqncia dotipo e do grau de obesidade e da concomitncia com endocri-nopatia.9-11 Em 34 indivduos obesos de ambos os sexos,numa populao predominantemente de negros (59%), Hud ecol.10 descreveram prevalncia de AN em 74% dos pacientes.

Considerando a alta prevalncia de AN em obesos, oobjetivo deste artigo foi avaliar a freqncia de complicaesmetablicas nesta doena e sua relao com a raa em mulhe-res obesas, com e sem AN uma populao miscigenada.

CASUSTICA E METDOSForam avaliadas 481 mulheres obesas, com idade

variando de 15 a 68 anos, e ndice de massa corprea (IMC= peso/altura), de 33 a 47kg/m2. As pacientes procuraramespontaneamente o ambulatrio de obesidade do HospitalUniversitrio Professor Edgard Santos, em Salvador, Bahia,para tratamento. A populao que freqenta esse ambulat-rio constituda predominantemente por mulheres, sendoesse o motivo pelo qual os homens foram excludos. Foramexcludas tambm as pacientes asmticas, psicticas e por-tadoras de doena crnica, exceto aquelas da sndromemetablica. Todas foram submetidas a um protocolo queinclua avaliao clnica e bioqumica antes do incio do tra-tamento para obesidade.

O critrio para definio de AN foi a inspeo clni-ca, sempre orientada por um dos autores (Figura A e B).

Para classificao da raa foram consideradas as

INTRODUCTIONAcanthosis nigricans (AN) is a dermatological con-

dition characterized by thickening of the skin, hyperpig-mentation and accentuated skin lines, generating a roughand velvety aspect at the affected site. Histologically, hyper-keratosis, accentuated projecting of dermal papillae anddiscrete thickening of the epidermal layers are commonlyobserved.1 Although it may occur at any site on the bodysurface, the most affected area is the posterior neck region,followed by the axillae, the side of the neck, flexible surfa-ces of the limbs, periumbilical and inframammary regions,mucous membrane of the oral cavity or even, in rare cases,the soles of the feet and palms of the hands. 1

AN may be divided into two broad forms, malignantand benign. The malignant form is a marker of abdominalneoplasias, particularly gastric adenocarcinoma. Benignforms can be idiopathic, hereditary or drug induced, as wellas caused by endocrine diseases.1

Endocrinopathies are the main causes of AN, withobesity as the most common disturbance, frequently asso-ciated with hyperinsulinism, diabetes mellitus and insulinresistance.2-15 Other endocrine disturbances associated withAN are described as Cushing's disease, policystic ovaries,thyroidopathies, hirsutism, Addison's disease, acromegaly,among others, some of which occur along with insulin resis-tance. 5,6,8,11,13

The prevalence of AN in non select populationsvaries from 7 to 74%, according to age, race, frequency oftype and degree of obesity and concomitance with endocri-nopathy.9-11 In 34 obese individuals of both sexes, in a pre-dominantly black population (59%), Hud et al.10 describedAN prevalence in 74% of patients.

Given the high prevalence of AN in obese patients,the objective of this article was to evaluate the frequency ofmetabolic complications and its relation with the skin colorof obese women with and without AN in a mixed-race popu-lation.

SAMPLING AND METHODSA total of 481 obese women were evaluated, ranging

in age from 15 to 68 years and in body mass index (BMI =weight/height) from 33 to 47 kg/m. The patients sponta-neously sought care at the obesity outpatient clinic of theHospital Universitrio Professor Edgard Santos, inSalvador, Bahia State. The population frequenting this cli-nic consists predominantly of women, which is the reasonwhy men were excluded from the study. Also excluded wereasthmatic and psychotic patients, and carriers of chronicdiseases, except for those with a metabolic syndrome. Allwere submitted to a protocol that included clinical and bio-chemical evaluation prior to initiating treatment for obesity.

The criterion for defining AN was clinical inspection,continually monitored by one of the authors (Figure A and B).

For the classification of race the following phenoty-pic characteristics were considered (type of hair, shape of

Arajo, Viveiros, Lopes, Porto, Viana, Fukui & Ursich 539

An bras Dermatol, Rio de Janeiro, 77(5):537-543, set./out. 2002.

ears, nose and lips and skin color), given that there is abroad mixture of races, predominantly mulattos and blacksof African origin in Salvador. Moreover, the difference bet-ween white and light-mulatto, and dark-mulatto and blackis often difficult to define. 1

The waist circumference was determined along themean line between the lower rib margin and iliac crest,using an appropriate plastic measuring tape. Android obe-sity was determined by the waist circumference in relationto the hips > 0.85.

The present of diastolic arterial hypertension wasascertained when the diastolic arterial pressure was foundto be equal or greater than 85 mmHg in two determinations,either by using the Tycos Large Cuff Blood Pressure Meteror history of hypotensive drug.

With the exception of 20 patients, who were alreadydiagnosed with diabetes mellitus, all the others were sub-mitted to the oral glucose tolerance test (OGTT, 75 g) withthe collection of blood for insulin and glucose doses attimes: 0.60 and 120 minutes, while maintaining a diet ofmore than 150 g of carbohydrates three days prior to thetest. The glucose was measured in the plasma by the gluco-se-oxidase method, and World Health Organization (WHO)criteria were applied for the diagnosis of diabetes mellitusor glucose intolerance. 16

The insulin was measured in the serum by radioim-munoassay, using the pig anti-insulin antibody, purchasedfrom Sigma (n=130), or specific human anti-insulin, pur-chased from Linco (n=164).

The insulin resistance was evaluated by the methodof glucose homeostasis (HOMA IR), which considers theglycemic and insulinemic levels of fasting (HOMAIR={insulin (uU/ml) x glucose (mmol/l]/22.5}.18

The lipid profile was evaluated in all of the patients.The total-cholesterol, HDL-cholesterol, LDL-cholesteroland triglyceride determinations were carried out by theenzymatic method. The criterion for dyslipidemia wasadopted from the 2nd Brazilian Congress of Dyslipidemia.18

caractersticas fenotpicas (tipo de cabelo, conformao dasorelhas, do nariz e dos lbios e a cor da pele), uma vez queem Salvador existe grande miscigenao de raas, predomi-nando pardos e negros de ancestrais africanos, e muitasvezes as diferenas entre branco e pardo-claro ou entrepardo-escuro e negro so de difcil definio.17

A circunferncia da cintura foi determinada na linhamdia entre o ltimo arco costal e a crista ilaca, com fitaplstica apropriada. Obesidade andride foi determinadapela relao da circunferncia da cintura em relao aosquadris > 0,85.

Considerou-se a presena de hipertenso arterialdiastlica quando se encontrou presso arterial diastlicaigual ou maior do que 85mmHg em duas determinaes,com manguito de tensimetro largo da Tycos ou quando sefazia uso de hipotensores.

Excetuando 20 pacientes, que j tinham o diagnsti-co de diabetes mellitus, todas as demais foram submetidasao teste de tolerncia glicose oral (TTGO, 75g) com cole-ta de sangue para dosagens de insulina e glicose nos tempos0, 60 e 120 minutos, tendo sido mantida dieta com 150g decarboidratos trs dias antes do teste. A glicose foi dosada noplasma pelo mtodo da glicose-oxidase, e foram aplicadosos critrios da Organizao Mundial de Sade (OMS) paradiagnstico de diabetes mellitus ou intolerncia glicose.16

A insulina foi dosada no soro por radioimunoensaio,utilizando o anticorpo antiinsulina de porco, da Sigma(n=130), ou antiinsulina humana especfica, da Linco(n=164).

A resistncia insulina foi avaliada pelo mtodo dahomeostase glicmica (HOMA IR), que leva em considera-o os nveis glicmicos e insulinmicos de jejum {HOMAIR = [insulina (uU/ml) x glicose (mmol/l)]/22,5}.18

O perfil lipdico foi avaliado em todas as pacientes.As determinaes de colesterol total, HDL-colesterol, LDL-colesterol e triglicrides foram realizadas pelo mtodo enzi-mtico. O critrio adotado para dislipidemia foi o do IICongresso Brasileiro de Dislipidemia.18

A BFigura A e B: Aspectos da acanthosis nigricans, afetando pescoo e axila

Figure A and B: Features of acanthosis nigricans, affecting throat and axillae.

540 Arajo, Viveiros, Lopes, Porto, Viana, Fukui & Ursich

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O perfil lipdico foi avaliado em jejum e os critriosdo II Consenso Brasileiro de Dislipidemia foram adotados. 19

Para anlise estatstica, utilizou-se o programa Epi-info, verso 6.0, sendo realizada a comparao dos distr-bios metablicos entre os grupos de mulheres com e semAN pela anlise de varincia e teste de propores.Diferenas com o valor de p > 0,05 foram consideradas sig-nificantes. Anlise de regresso logstica mltipla comauxlio do programa Statistical Package for Social Studies(SPSS, verso 9.0) foi aplicada para clculo dos odds ratioem relao presena de AN , tendo como variveis a idade,o IMC, a circunferncia da cintura, diabetes e hipertensodiastlica, e raa.

RESULTADOSOs dados clnicos e laboratoriais das pacientes esto

expostos na Tabela 1.A distribuio da raa das 481 mulheres obesas estu-

dadas revelou 34,5% de brancas, 38,9% de pardas e 26,6% depretas. A presena de AN nessas pacientes foi de 80,7%. Afreqncia de AN nas raas branca, parda e negra foi de66,9%, 86,1% e 90,6%, respectivamente (Grfico). O teste depropores mostrou que a freqncia de AN foi significativa-mente maior nas mulheres negras em comparao s brancase nas pretas versus mulatas (p=0,000000 e 0,000006). Foitambm maior nas mulheres pardas versus brancas (p 130 mg % / % LDL cholesterol > 130 mg %% Triglicrides > 200 mg % / % Triglycerides > 200 mg %

35 1041 6

106 1240.060.311.1 14.9

19.7 12.74.32 3.30

38.113.9 37.1

9

38 1039 6

102 1129.053.84.39.7

18.6 10.73.88 2.30

36.614.035.511.8

0.01< 0.01

Frequency (%) of AN in relation to racial group

Freqncia (%) de AN em relao ao grupo racial

Arajo, Viveiros, Lopes, Porto, Viana, Fukui & Ursich 541

An bras Dermatol, Rio de Janeiro, 77(5):537-543, set./out. 2002.

In the group of womenwith AN, average age was sig-nificantly lower, and the BMIsignificantly higher than in thegroup without AN (p < 0.01 forboth). The waist circumferen-ce and frequency of androidobesity were significantlygreater in the group with AN(p < 0.001 and p=0.05, res-pectively).

The prevalence of type-2 diabetes with AN was11.1% in contrast to 4.3% in patients without this condition,revealing a statistically significant difference (p < 0.05).This increase was three times higher, controlling age, BMIand race, with OR=3.1; CI 95% (1.1 - 9.8). A tendencytoward higher frequency of impaired glucose tolerance wasobserved in the group with AN in relation to the groupwithout AN (14.9% and 9.7%, respectively p=0.18).

Levels of fasting insulin and insulin resistance(HOMA IR) were greater for the group with AN than for thegroup without AN (p=0.05 for both), Table 1.

Frequencies of diastolic hypertension, total-choles-terol equal or above 200 mg%, LDL-cholesterol equal ofgreater than 130 mg%, HDL-cholesterol < 35 mg% andtriglycerides equal or greater than 200 mg% were similarin both groups (Table 1).

DISCUSSIONVarious papers have considered AN as a marker for

many endocrine disturbances, among which are diabetesmellitus and glucose intolerance, frequently associated withobesity. 5,6,11,14,20,21

In the present study, obese women were observed tohave a higher frequency of diabetes mellitus and androidobesity, higher levels of fasting insulin and insulin resistan-ce as well as a tendency to greater presence of glucose into-lerance in the women with AN in relation to those without.

Stuart et al.11,14 suggested that AN is a marker foreasily detecting diabetes mellitus. In a study of 89 African-Americans with AN type 2 diabetes was observed at a fre-quency of 21.3%.14 In a study of 406 Mexican-Americans ofboth sexes conducted by Burke et al.,15 type 2 diabetes wasobserved in 27% of patients with AN and 19.7% in patientswithout AN, the difference of which was not significant. Inthe study, a lower frequency was observed (11.1% inpatients with AN and 4.3% in those without AN). The fre-quency differences pointed to by the authors could be rela-ted to genetic or environmental factors, because onlyMexican-Americans were included.

In the present study, the levels of fasting insulin as

No grupo de mulherescom AN, a idade mdia foi sig-nificativamente menor, e oIMC significativamente maiordo que a do grupo sem AN (p