Most sebaceous glands develop embryologically from hair germs, but a few free glands arise from the epidermis. Those associated with hairs lie in the obtuse angle between the follicle and the epidermis (see Figure 13.1). The glands themselves are multilobed and contain cells full of lipid, which are shed whole (holocrine secretion) during secretion so that sebum contains their remnants in a complex mixture of triglycerides, free fatty acids, wax esters, squalene and cholesterol. Sebum is discharged into the upper part of the hair follicle. It lubricates and waterproofs the skin, and protects it from drying; it is also mildly bacteriocidal and fungistatic. Sebaceous follicles are most commonly found on the face, behind the ears, and on the upper chest and back. Free sebaceous glands not associated with hair follicles may be found in the eyelid (meibomian glands), mucous membranes (Fordyce spots), nipple, peri-anal region and genitalia.
Androgenic hormones, especially dihydrotestosterone, stimulate sebaceous gland activity. Human sebaceous glands contain 5α-reductase, 3α- and 17α-hydroxysteroid dehydrogenase, which convert weaker androgens to dihydrotestosterone, which in turn binds to specific receptors in sebaceous glands, increasing sebum secretion. The sebaceous glands react to maternal androgens for a short time after birth, and then lie dormant until puberty when a surge of androgens produces a sudden increase in sebum excretion and sets the stage for acne.
Nearly all teenagers have some acne (acne vulgaris). It affects the sexes equally, starting usually between the ages of 12 and 14 years, tending to be earlier in females. The peak age for severity in females is 16–17 and in males 17–19 years. Variants of acne are much less common.
Many factors combine to cause acne (Figure 12.1), characterized by chronic inflammation around pilosebaceous follicles.
Sebum over-production. Sebum excretion is increased. However, this alone need not cause acne; patients with acromegaly, or with Parkinson’s disease, have high sebum excretion rates but no acne. Furthermore, sebum excretion often remains high long after the acne has gone away.
Hormonal. Androgens (from the testes, ovaries, adrenals and sebaceous glands themselves) are the main stimulants of sebum excretion, although other hormones (e.g. thyroid hormones and growth hormone) have minor effects too. Those castrated before puberty, or with androgen insensitivity, never develop acne. In acne, the sebaceous glands respond excessively to what are usually normal levels of these hormones (increased target organ sensitivity). This may be caused by 5α-reductase activity being higher in the target sebaceous glands than in other parts of the body. Fifty per cent of females with acne have slightly raised free testosterone levels – usually because of a low level of sex hormone binding globulin rather than a high total testosterone – but this is still only a fraction of the concentration in males, and its relevance is debatable.
Poral occlusion. Both genetic and environmental factors (e.g. some cosmetics) cause the epithelium to overgrow the follicular surface. Follicles then retain sebum that has an increased concentration of bacteria and free fatty acids. Rupture of these follicles is associated with intense inflammation and tissue damage, mediated by oxygen free radicals and enzymes such as elastase, released by white cells.
Increased bacterial colonization. Propionibacterium acnes, a normal skin commensal, plays a pathogenic part. It colonizes the pilosebaceous ducts, breaks down triglycerides releasing free fatty acids, and induces the ductal epithelium to secrete pro-inflammatory cytokines via activation of Toll-like receptor 2 (TLR2) pathway. Activated neutrophils release lysosomal enzymes which lead to follicular rupture. The release of follicular content results in a foreign body reaction which furthers the inflammatory reaction.
Genetic. The condition is familial in about half of those with acne. There is a high concordance of the sebum excretion rate and acne in monozygotic, but not dizygotic, twins. Further studies are required to determine the precise mode of inheritance.
Diet. Recent systematic reviews of diet on acne suggest that dairy products (particularly milk) and high glycaemic load may be associated with increased risk and severity of acne. Prospective studies are needed to determine if a low glycaemic diet and reduced dairy intake may help acne.
Lesions are confined to the face, shoulders, upper chest and back. Seborrhoea (a greasy skin; Figure 12.2) is often present. Open comedones (blackheads), because of the plugging by keratin and sebum of the pilosebaceous orifice, or closed comedones (whiteheads), caused by overgrowth of the follicle openings by surrounding epithelium, are always seen. Inflammatory papules, nodules and cysts occur (Figures 12.3 and 12.4), with one or two types of lesion predominating. Depressed or hypertrophic scarring and post-inflammatory hyperpigmentation can follow.
Figure 12.2 The seborrhoea, comedones and scattered inflammatory papules of teenage acne.
Figure 12.3 Prominent and inflamed cysts are the main features here.
Figure 12.4 Conglobate acne with inflammatory nodules, pustulocystic lesions and depressed scars.
Conglobate (gathered into balls; from the Latin globus meaning ‘ball’) is the name given to a severe form of acne with all of the above features as well as abscesses or cysts with intercommunicating sinuses that contain thick serosanguinous fluid or pus. On resolution, it leaves deeply pitted or hypertrophic scars, sometimes joined by keloidal bridges. Although hyperpigmentation is usually transient, it can persist, particularly in those with an already dark skin. Psychological depression is common in persistent acne, which need not necessarily be severe.
Variants of acne
Neonatal acne. This occurs in more than 20% of healthy newborn babies between 2 weeks to 3 months of age. It may follow transplacental stimulation of a child’s sebaceous glands by maternal androgens.
Infantile acne. This rare type of acne is present at 3–6 months of age and typically resolves in 12 months. It is more common in males and may last up to 3 years. Its morphology is like that of common acne and it may be the forerunner of severe acne in adolescence. Maternal hormones have a minor role at this age. Rather, the immature infantile adrenal gland produces elevated dehydroepiandrosterone (DHEA) and delayed maturation of the gonadal feedback system results in increased levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH) and testosterone.
Late onset. This occurs mainly in women and is often limited to the chin and jawline (Figure 12.5). Nodular and cystic lesions predominate. It is stubborn and persistent.
Acne fulminans. Acne fulminans is a rare variant in which conglobate acne is accompanied by fever, joint pains and a high erythrocyte sedimentation rate (ESR).
Mechanical. Excessive scrubbing, picking or the rubbing of chin straps or a fiddle (Figure 12.6) can rupture occluded follicles.
Tropical. Heat and humidity are responsible for this variant, which affects Caucasoids with a tendency to acne. This occurs mainly on the trunk and may be conglobate. Sweat causes follicular occlusion by causing the peri-follicular epidermis to swell.
Excoriated. This is most common in young girls. Obsessional picking or rubbing leaves discrete denuded areas.
Exogenous. Tars, chlorinated hydrocarbons, oils and oily cosmetics may induce comedone formation or precipitate inflammation around vellous hair follicles. Suspicion should be raised if the distribution is odd or if comedones predominate (Figure 12.7).
Drug-induced (Figure 12.8). Corticosteroids, androgenic and anabolic steroids, gonadotrophins, oral contraceptives, lithium, iodides, bromides, antituberculosis and anticonvulsant therapy can all cause an acneiform rash. Follicular acneiform eruption has commonly been reported in patients receiving inhibitors of the epidermal growth factor receptor (EGF-R). Suspicion should be raised when acne, dominated by monomorphous papulo-pustules rather than comedones, appears suddenly in a non-teenager and coincides with the prescription of a drug known to cause acneiform lesions.
Follicular occlusion tetrad. Severe nodulocystic acne can be associated with dissecting cellulitis of the scalp, suppurative hidradenitis and pilonidal cysts.
Polycystic ovarian syndrome. Consider this in obese females with oligomenorrhoea or secondary amenorrhoea or infertility. Glucose intolerance, dyslipidaemia, hirsutism and hypertension may be other features. Acne accompanying the polycystic ovarian syndrome is caused by modestly raised circulating androgen levels.
Congenital adrenal hyperplasia. Hyperpigmentation, ambiguous genitalia, history of salt-wasting in childhood and a Jewish background are all clues to this rare diagnosis caused by 21-hydroxylase deficiency.
Androgen-secreting tumours. These cause the rapid onset of virilization (clitoromegaly, deepening of voice, breast atrophy, male pattern balding and hirsutism) as well as acne.
Figure 12.5 Late-onset acne in a woman. Often localized to the chin.
Figure 12.6 Papulopustular lesions in an odd distribution. The patient played the violin (‘fiddler’s neck’).
Figure 12.7 A group of open comedones (blackheads) following the use of a greasy cosmetic.
Figure 12.8 Steroid-induced acne in a seriously ill patient.
Acne vulgaris clears by the age of 23–25 years in 90% of patients, but some 5% of women and 1% of men still need treatment in their thirties or even forties.
None are usually necessary. Cultures are occasionally needed to exclude a pyogenic infection, an anaerobic infection or Gram-negative folliculitis. Only a few laboratories routinely culture P. acnes and test its sensitivity to antibiotics.
Any acne, including infantile acne, which is associated with virilization, needs investigation to exclude an androgen-secreting tumour of the adrenals, ovaries or testes, and to rule out congenital adrenal hyperplasia caused by 21-hydroxylase deficiency. Tests should then include the measurement of plasma levels of total and free testosterone, sex hormone binding globulin, LH, FSH, DHEA sulfate, androstenedione, 17-hydroxyprogesterone, urinary free cortisol and, depending on the results, ultrasound examination or computed tomography scan of the ovaries and adrenals. Female patients should not be taking the oral contraceptive pill when these hormone levels are measured. Congenital adrenal hyperplasia is associated with high levels of 17-hydroxyprogesterone, and androgen secreting tumours with high androgen levels.
Polycystic ovarian syndrome is characterized by modestly elevated testosterone, androstenedione and DHEA sulfate levels, a reduced sex hormone binding level and an LH : FSH ratio of greater than 2.5 : 1. Pelvic ultrasound may reveal multiple small ovarian cysts, although some patients with acne have ovarian cysts without biochemical evidence of the polycystic ovarian syndrome.
Rosacea (see Rosacea) affects older individuals. Comedones are absent, the papules and pustules occur only on the face and the rash has a centrofacial erythematous background. Pyogenic folliculitis can be excluded by culture. Hidradenitis suppurativa (see Hidradenitis suppurativa) is associated with acne conglobata, but attacks the axillae and groin. Pseudofolliculitis barbae and acne keloidalis nuchae, caused by ingrowing hairs, occur on the necks and scalps of men with curly facial hair and clears up if shaving is stopped. Always suspect cosmetic acne, especially in post-adolescent women with acne limited to the face.
Acne frequently has marked psychological effects. Even mild acne can have significant impact on self-esteem and quality of life. An optimistic approach is essential, and regular encouragement worthwhile.
Occasionally, an underlying cause (see Variants of acne) is found; this should be removed or treated.
At some time most teenagers try antiacne preparations bought from their pharmacist. Local treatment is the standard of care for most patients with comedo-papular acne, although both local and systemic treatments are needed for pustulocystic scarring acne (Figure 12.9).
Figure 12.9 A successful systemic treatment of acne – the picture tells its own story.
Local treatment (Formulary 1, p. 405)
Regular gentle cleansing with soap and water should be encouraged, to remove surface sebum.
Salicylic acid is widely available as an over-the-counter acne treatment; it is a mild comedolytic agent.
The antibacterial agent benzoyl peroxide is applied only at night initially, but can be used twice daily if this does not cause too much dryness and irritation. It is most effective for inflammatory lesions and is not affected by propionibacterial antibiotic resistance. It is wise to start with a 2.5 or 5% preparation, moving up to 10% if necessary. Benzoyl peroxide bleaches coloured materials, particularly towels and flannels.
The vitamin A (retinol) analogues (tretinoin, isotretinoin, adapalene, tazarotene) normalize follicular keratinization, down-regulate TLR 2 expression and reduce sebum production. Retinoids are especially effective against comedones. Patients should be warned about skin irritation (start with small amounts) and photosensitivity. Concomitant eczema is usually a contraindication to their use. Tretinoin can be prescribed as a lotion, cream or gel. Patients with oily skin may prefer gels which are drying, while those with sensitive skin tend to prefer the more emollient creams. Newer preparations (in the United States) use microspheres (Retin-A micro) or specially formulated bases (Avita, Avage) that minimize irritation. The weakest preparation should be used first, and applied every 2–3 nights, increasing frequency after several weeks as tolerated. Sometimes, after a week or two, it will have to be stopped temporarily because of irritation. The combination of benzoyl peroxide in the morning and tretinoin at night has many advocates.
Isotretinoin 0.05% is made up in a gel base (not available in United States) and applied once or twice daily. It irritates less than the same concentration of tretinoin.
Adapalene (0.1% gel) is a retinoid-like drug indicated for mild to moderate acne. Compared with tretinoin, it is a milder comedolytic but also better tolerated.
Tazarotene (0.1% gel), applied once daily, was found in one study to be more effective than tretinoin (0.1% microsponge).
Topical retinoids should not be prescribed for pregnant woman with acne.
Azelaic acid is bacteriocidal for P. acnes: it is also anti-inflammatory and inhibits the formation of comedones by reducing the proliferation of keratinocytes. It should be applied twice daily. It is often used in darker skin patients as it may help to lighten post-inflammatory hyperpigmentation.
Topical antibiotics include topical clindamycin, erythromycin and sulfacetamide (Formulary 1, p. 405) but antibacterial resistance of P. acnes is a growing problem, with most erythromycin-resistant strains being cross-resistant to clindamycin. Combining antibiotics with benzoyl peroxide reduces P. acnes numbers and the likelihood of resistant strains emerging (Formulary 1, p. 405). The addition of zinc acetate complex to erythromycin enhances the anti-inflammatory effect of the antibiotic.
Topical dapsone 5% gel is a newer option for treating acne. It is safe in patients with a deficiency in glucose-6-phosphate dehydrogenase.
Cosmetic camouflage help some patients, especially females, whose scarring is unsightly. Cover-ups also obscure post-inflammatory pigmentation. A range of makeup is available in the United Kingdom and the United States (Formulary 1, p. 399).
Systemic treatment (Formulary 2, p. 411)
Antibiotics
The prevalence of antibiotic-resistant P. acnes, particularly to erythromycin, is rising even in patients never previously exposed to it. As well as reducing P. acnes numbers, antibiotics also have a direct anti-inflammatory effect so will continue to be beneficial, but wherever possible they should be used in combination with topical benzoyl peroxide or retinoids to limit colonization by antibiotic-resistant bacteria.
Tetracyclines
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