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The Pathophysiology of Acne Vulgaris in Children and Adolescents, Part 1

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The Pathophysiology of Acne Vulgaris in Children and Adolescents, Part 1 CONTINUING MEDICAL EDUCATION The Pathophysiology of Acne Vulgaris in Children and Adolescents, Part 1 Wilma F. Bergfeld, MD GOAL To understand the pathophysiology of acne vulgaris in children and adolescents OBJECTIVES Upon completion of this activity, dermatologists and general practitioners should be able to: 1. Describe the pathophysiology of acne. 2. Explain how adrenarche influences acne. 3. Discuss the role of androgens in the development of acne. CME Test on page 112. This article has been peer reviewed and is accredited by the ACCME to provide continuing approved by Michael Fisher, MD, Professor of medical education for physicians. Medicine, Albert Einstein College of Medicine. Albert Einstein College of Medicine designates Review date: July 2004. this educational activity for a maximum of 1 This activity has been planned and implemented category 1 credit toward the AMA Physician’s in accordance with the Essential Areas and Policies Recognition Award. Each physician should claim of the Accreditation Council for Continuing Medical only that hour of credit that he/she actually spent Education through the joint sponsorship of Albert in the activity. Einstein College of Medicine and Quadrant This activity has been planned and produced in HealthCom, Inc. Albert Einstein College of Medicine accordance with ACCME Essentials. Dr. Bergfeld reports no conflict of interest. The author reports no discussion of off-label use. Dr. Fisher reports no conflict of interest. Microcomedones, the earliest lesions of acne, are produced and colonization of follicles by appear at adrenarche, which typically occurs at Propionibacterium acnes increases. Inflamma- about 8 years of age when androgens of adrenal tory lesions, such as pustules, papules, and origin begin to stimulate follicular hyperkeratosis nodules, are the result of the host’s immune and sebaceous hyperplasia in pilosebaceous responses to P acnes; the proinflammatory units on the face. Comedones appear about cytokines are released by immunocompetent 2 years later, when androgens of gonadal origin leukocytes that are recruited in response to this bacterium and its metabolic by-products. Andro- gens also affect the barrier function of the skin, Accepted for publication June 14, 2004. and disturbances of barrier function may stimu- Dr. Bergfeld is Head, Dermatological Research, Department late epidermal DNA synthesis. This leads to epi- of Dermatology, Cleveland Clinic, Ohio, and Clinical Associate dermal hyperplasia, which may also contribute to Professor, Department of Dermatology, Case Western follicular hyperkeratosis in acne. Optimal treat- University, Cleveland. ment for this disorder will address these various Reprints: Wilma F. Bergfeld, MD, Cleveland Clinic Foundation, 9500 Euclid Ave, A61, Cleveland, OH 44195 pathophysiologic factors. (e-mail: [email protected]). Cutis. 2004;74:92-97. 92 CUTIS® Pathophysiology of Acne Vulgaris cne is predominantly a disorder of late acnes; and perifollicular inflammation.5-13 Follicular childhood and adolescence, despite the fact hyperkeratinization, sebocytic hyperplasia, and A that it may persist into, recur, or begin dur- seborrhea are all dependent on androgens.14-16 ing adulthood. Although acne has been reported in otherwise healthy children as young as 8 years,1 Role of Adrenarche and even earlier in those with abnormal viriliza- The pathogenetic process appears to commence tion or precocious puberty,2 most cases occur with androgenic hormonal stimulation of piloseba- between the ages of 14 and 19 years.1 The preva- ceous units, the density of which is greatest on the lence of acne was assessed among 6768 boys and face and scalp (400–800 glands/cm2) and least on girls aged 12 to 17 years in the National Health the extremities (50 glands/cm2).5 Before levels of Examination Survey of 1966 to 1970.3 Based on circulating androgens increase, pilosebaceous physical examinations, only an estimated 27.7% of units consist of soft, fine, unpigmented vellus hairs children were found to have essentially normal and small sebaceous glands.17 Circulating andro- skin, whereas 68.1% had lesions diagnosed as gens bind to androgen receptors that are localized facial acne (minimal requirement for diagnosis was to the basal layer of the outer-root–sheath kerat- sparse comedones with no inflammatory reaction). inocytes of the hair follicle and to sebaceous Prevalence increased with age more rapidly among glands.15 In sexual hair areas, such as the axilla, younger than older youths, from 39% at age pilosebaceous units begin to differentiate into 12 years to 86.4% at age 17 years, and the increase large terminal hair follicles. In sebaceous areas, in prevalence with age was more rapid and consis- such as the face, pilosebaceous units become seba- tent among boys than girls. Although facial acne ceous follicles while the hair remains vellus.17 was about as prevalent among girls as boys in the Without a source of circulating androgens, the 12- to 17-year age range (69.8% and 66.4%, respec- sebaceous glands remain small.6 tively), the onset occurred somewhat earlier in The adrenals and the gonads produce the major- girls, and the severity tended to be greater in boys. ity of circulating androgens.15 During the prepuber- More severe facial acne (defined in the survey as tal period, adrenal androgens appear to be the major at least comedones, small pustules, and a tendency determinant of sebaceous gland activity.18 In both toward inflamed lesions deeper than the follicular boys and girls, plasma concentrations of the adrenal orifice) was present in a much smaller proportion androgens dehydroepiandrosterone (DHEA) and of youths. dehydroepiandrosterone sulfate (DHEAS) normally More recently, estimates from the National begin to increase at adrenarche, or adrenal puberty, Health Interview Survey of 1996, which included which typically occurs at about age 8 years, and 24,371 households containing 63,402 persons, continue to rise through puberty.19 Conditions such identified “chronic” acne (acne with a duration as adrenal hyperplasia or polycystic ovary disease Ͼ3 months) in 2.44% of those 17 years and are associated with hyperandrogenism; sudden younger,4 which corresponds approximately with onset of acne or treatment-resistant acne may be the prevalence of “more severe facial acne” in the associated with these conditions.15 earlier survey. These results suggest a relationship Androgen stimulation drives the changes in both between the onset of puberty and the pathophysi- follicular keratinocytes and sebocytes that lead to ology of acne. This article reviews recent advances the formation of microcomedones,10 which are not in our understanding of acne in children and ado- visible but are already present in 40% of children lescents, with an emphasis on the triggering role of aged 8 to 10 years.17 Microcomedones develop when adrenarche. Part 2 of this article will review treat- desquamated cornified cells of the upper canal of the ment options. sebaceous follicle become highly adherent and obstruct the lumen in the presence of increased Pathophysiology of Acne sebum production (retention hyperkeratosis). A number of pathophysiologic factors contribute to The onset of adrenal production of DHEA and the development of acne, beginning with increased DHEAS is followed by a rise in plasma levels of prepubertal androgen production, followed in a adrenal androstenedione 1 to 2 years later, which generally sequential manner by abnormal pilose- approximately coincides with an increase in baceous follicular keratinization and desquama- gonadal testosterone production—the so-called tion; increased proliferation of sebocytes, enlarged gonadarche or pubarche. It is at this time that sebaceous glands, and augmented secretion of microcomedones begin to enlarge and become vis- sebum; obstruction of sebaceous follicles; coloniza- ible, forming open and closed comedones, which tion of pilosebaceous units by Propionibacterium are noninflammatory lesions.10 This comedogenesis VOLUME 74, AUGUST 2004 93 Pathophysiology of Acne Vulgaris may be driven in part by increased levels of factor.17 For example, Imperato-McGinley and col- interleukin 1␣, which is derived from ductal kerat- leagues28 showed that patients with an inherited inocytes.20 Colonization of the follicular canal 5 ␣-reductase deficiency and decreased DHT pro- with P acnes, an anaerobic, aerotolerant, duced no sebum, just as preadrenarchal children lipophilic diphtheroid that thrives in triglyceride- produce no sebum. In a 5-year longitudinal study of rich sebum, follows comedogenesis.21 Inflamma- adolescent girls, Lucky and colleagues29 observed a tory acne appears to be the result of the host correlation between early onset of acne, androgen response to P acnes and the proinflammatory levels, and more severe comedonal acne later. Girls cytokines released by immunocompetent cells that who experienced early onset of acne had higher are recruited by this bacterium and its metabolic levels of DHEAS, testosterone, and free testos- by-products.11,13,21,22 Depending on the intensity of terone. The researchers speculated that DHEAS the inflammatory process and its localization appears to be involved in the initiation of acne.29 within the follicle, erythema, superficial pustules, Concentrations of testosterone and DHT can papules, and/or nodules (cysts) may develop.7 be decreased by local conversion to estrogens; to Most patients have a variety of noninflammatory weaker androgens such as 3 ␣-androstenediol; or and inflammatory
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