Chapter 24 Acne vulgaris
AETIOLOGY
Acne vulgaris is a condition typified by inflammation of the pilosebaceous follicles in the skin.1 It is characterised by a variety of lesions including nodules, papules, pustules and open and closed comedones. However, the sequence of the pathophysiological development of these lesions is still unclear. The dominant hypothesis at this stage focuses on increased circulating androgens stimulating sebaceous gland activity, and the resulting sebum production triggering hyperkeratosis. This process blocks the follicle and results in dilation and the ultimate formation of a comedone.1 The transition from a comedone to a lesion such as a pustule, papule or nodule is believed to be due to a bacterium, called Propionibacterium acnes, colonising the follicle and triggering an inflammatory response within the follicle wall.2 This cascade involves T helper cells (CD4+), most likely subtype T helper 1, and macrophages, which infiltrate the local area, possibly as a result of antigenic stimulation. The antigen identified as the most likely initiator of inflammation is Propionibacterium acnes (see the box below). This trigger is believed to develop due to weakness in the follicular basement membranes, associated with reduced linoleic acid levels in the follicular wall. This has been explained through increased sebum production depleting local fatty acid stores. Once an inflammatory cascade has begun, hyperproliferation of follicles can occur. As keratinised cells and sebum compact within the follicular lumen, a ‘horny plug’ forms. This process ultimately results in the development of a comedone and is referred to as ‘comedonegenesis’.2
RISK FACTORS
Predisposing and exacerbating factors relating to the development of acne vulgaris include hereditary predisposition, premenstrual hormonal fluctuations, increased androgen levels, heavy or irritating clothing, backpacks or helmets, the application of oily creams, the use of certain drugs and exposure to increased heat and humidity.5 Some dietary factors, such as dairy intake6 or glycaemic load,7 may also increase the risk of acne; however, specific attributable risk in this area remains unclear until further research is done.
PROPIONIBACTERIUM ACNES
Propionibacterium acnes was initially considered the cause of acne vulgaris following its identification in acne lesions in 1896. This has been supported by evidence of a failure of antibiotic treatment of acne due to erythromycin-resistant strains of P. acnes. However, more recent research has determined that P. acnes may trigger or exacerbate acne vulgaris, but it is not the only factor. In fact, some acne lesions do not have any sign of bacterial infection. It is now considered that P. acnes is not the primary cause of acne, although it is still considered a significant contributor to the inflammation.3,4 P. acnes is more commonly connected with the appearance of pustules, rather than the least severe comedones. This occurs due to the bacteria breaking down sebum into specific fatty acids, which trigger an inflammatory response. The inflammation weakens the dermal layer and opportunistic staphylococcal organisms invade, forming a pustule.5
CONVENTIONAL TREATMENT
Treatment of acne vulgaris focuses on the bacterial and hormonal aetiology of the condition. The hormonal mainstays of medical intervention include oral contraceptives and antiandrogen medication (spironolactone, cyproterone acetate or flutamide).8 Approaching acne management through hormonal regulation is justified through the presence of androgen receptors in the basal layer of sebaceous glands and in the outer root sheath keratinocytes in the hair follicle. Oral contraceptives interfere with the stimulation of these receptors by reducing ovarian production of androgens, while the other antiandrogen medications act as receptor blockers.8 Topical management through the use of peeling agents (benzoyl peroxide, tretinoin or isotretinoin) and antibacterial agents (tetracycline) are also commonly used to control lesions.5
The most common drug used in severe, chronic acne vulgaris is isotretinoin. Isotretinoin affects epidermis health through a number of mechanisms, including promotion of epidermal cell differentiation, stimulation of keratinocyte proliferation and reduction of sebaceous gland size (by suppressing the proliferation of basal sebocytes and sebum production). Immunomodulatory and anti-inflammatory properties have also been identified. Isotretinoin is usually prescribed on average for 20 weeks, with a starting dose of between 0.5 and 1 mg/kg/day and concomitant prescription of oral antibiotics for the first 4 weeks of treatment.9
Naturopathic management of patients taking this medication needs to be approached carefully due to potential side effects of oral retinoid therapy (see the box below). Individuals who have been prescribed isotretinoin should avoid pregnancy, due to potential congenital malformations associated with the drug. There is also a risk of psychiatric conditions such as depression, psychoses and suicidal thoughts. It is also worth noting that, however rare, liver conditions such as acute hepatitis can be triggered through isotretinoin therapy and, because of this, hepatoprotective interventions may be worth considering. At the very least ethanol extracts of herbs may need to be modified to reduce potentially compounding the impact upon liver health. Most commonly, however, isotretinoin affects mucous membranes and can cause cheilitis, dry eyes, dry mouth, dry skin and desquamation of lips.10 Furthermore, recent research has also identified elevated serum homocysteine levels in patients with cystic acne undergoing isotretinoin therapy,11 as well as decreased plasma folate concentrations.12 The health implications of these results are discussed in more detail
POTENTIAL SIDE EFFECTS OF ISOTRETINOIN THERAPY
The side effects of isotretinoin therapy are essentially the same as vitamin A toxicity (hypervitaminosis A syndrome) and include the following:9
in Section 3 on the cardiovascular system. Some possible complementary prescriptions that may support individuals taking isotretinoin include zinc, methionine, arginine, vitamin E, soy protein, fish oil and L-carnitine. However, any inclusion of these interventions in the treatment plan would require careful and close monitoring as research in this area is still preliminary.10
KEY TREATMENT PROTOCOLS
Hormone modulation
The sebaceous glands, and the skin in general, are sites for androgen synthesis within the human body. In fact, prior to puberty, the sebaceous glands, particularly in the face and scalp, are the primary sites of androgen conversion from adrenal precursor hormones such as DHEA-S. All key enzymes required to convert cholesterol to androgens, particularly testosterone, are locally present within the sebaceous gland. Androgens, specifically dihydrotestosterone, are understood to be involved in both the regulation of cell proliferation and lipogenesis. In contrast, oestrogens are understood to inhibit excessive sebaceous gland activity, possibly by increasing androgen binding to its binding globulin.3,13
Management of acne focusing specifically on the elevated androgen levels includes the application of herbs such as Serenoa repensSerenoa repens acts to reduce the conversion of testosterone to dihydrotestosterone through inhibition of the enzyme responsible, 5-α-reductase. Although no research is apparently specifically related to acne vulgaris, successful outcomes have been found when using this herb in a range of other androgen-dominant conditions.14–16 A different approach to the herbal management of hormone modulation often considered in acne vulgaris is Vitex agnus-castus.17 V. agnus-castus has been traditionally used for the regulation of hormonal conditions particularly focusing on sexual and reproductive functions,18 and this has been supported through more recent research identifying dopaminergic and oestrogenic compounds extracted from the herb.19 Another herbal intervention to be considered is a kampo (traditional Japanese medicine) combination formula of Paeonia spp. and Glycyrrhiza spp., which has been found to reduce testosterone and improve oestrogen/testosterone ratio in women with polycystic ovarian syndrome.20 Although the exact mechanism is unclear, it has been argued that this occurs due to an increased aromatase activity, thereby converting testosterone to 17β-oestradiol, and/or central nervous system activity resulting in an increase in pituitary secretion of follicle-stimulating hormone and luteinising hormone.20
Similarly, other natural substances may be used in the management of acne vulgaris, although not yet specifically investigated for the condition, based upon their known activity within the body. For example, enterolactone, a phytoestrogenic compound derived from flaxseed, has been found to reduce the Free Androgen Index.21 However, this substance is activated from precursors found in flaxseed by the microflora found in the human colonic intestinal tract; this microflora may be affected by the use of oral antibiotics.22
FREE ANDROGEN INDEX (FAI)
The Free Androgen Index (sometimes called the Testosterone Free Index, or TFI) is determined by calculating the ratio of the total testosterone concentration to the concentration of sex hormone binding globulin. It often increases in severe acne, hirsutism, polycystic ovarian syndrome and male androgenic alopecia (male-pattern baldness).34
Androgens and the stress response
Research has found that the symptoms of acne vulgaris are worse in times of psychological stress. Physiological adaptation to stress may also be a contributing factor to acne vulgaris due to the hormonal cascade this produces. In particular, increased physiological stress results in hypothalamic secretion of noradrenalin and thereby corticotrophic-releasing hormone (CRH). CRH then stimulates release of adrenocorticotrophic hormone (ACTH) from the anterior pituitary. The primary target of ACTH is the adrenal cortex through which it affects adrenal androgen secretion.23 Furthermore, CRH also inhibits secretion of gonadotrophic releasing hormone, resulting in lower gonadic hormones, thereby further exacerbating the androgen:oestrogen imbalance often seen in acne vulgaris.23 For this reason, herbs that have adaptogenic activity may be considered (see Chapter 8 on respiratory disorders) including Rhodiola rosea,24 Panax ginseng and Withania somnifera.25
Androgen metabolism and clearance
Naturopathically, the skin has been referred to as ‘the third kidney’. The rationale behind this statement is the role the skin plays in detoxification of the system. Both phase I and phase II detoxification enzymes are found in human skin. The phase I enzymes are mostly represented by alcohol dehydrogenase; however, CYP450 enzymes are also present although at much lower levels.26 The subtypes of CYP450 found in
ALTERATIVES AND DEPURATIVES
Historically, naturopaths have emphasised the importance of detoxification to manage a number of conditions including renal, urinary, hepatic, endocrine and skin disease.32 It is explained by Benedict Lust in his seminal text that ‘the origin of all is again to be readily explained by accumulations of foreign matter; and here we have especially to do with the accumulations affecting the normal function of those organs so important for the secretion of waste matter from the body: the kidneys and the skin’.32 This is the foundation upon which the herbal medicine management of skin disorders was originally based: the use of alteratives and depuratives. An alterative or depurative has been defined as a herb that ‘improves detoxification and aids elimination to reduce the accumulation of metabolic waste products within the body’.28 Herbs that are traditionally considered to have this action include (but are by no means limited to) Iris versicolor, Arctium lappa, Galium aparine, Echinacea spp., Chionanthus virginicus, Berberis aquifolium, Smilax ornata and Rumex crispus. However, it is interesting to note that no current research validating the empirical use of these herbs has been found. This is an important area within naturopathic management of skin diseases, and such research would provide great benefit to evidence-based naturopathic practice.
the skin are generally involved in hydroxylation of a number of compounds, including retinoids, prostanoids, inflammatory mediators, arachidonic acid and cholesterol. In contrast, the phase II enzymes are expressed in high concentrations. These include glutathione-S-transferase, catechol-O-methyltransferase and steroid sulfotransferase.26 Likewise, aromatase has been found in high concentrations in sebaceous glands and may act to clear excess androgens.27 This implies that the skin does have an important role in detoxification, particularly through phase II enzymes. It also suggests that compromised or stressed liver detoxification may place further burden on the skin, thereby aggravating dermal conditions such as acne vulgaris. With this in mind, it may be more accurate to refer to the skin as the ‘second liver’ rather than the third kidney.
Clearance of excess hormones and other aggravating substances has historically been managed naturopathically using depurative herbs. These herbs are associated with improved detoxification and elimination of metabolic wastes.28 There are a number of herbs which have been traditionally used for chronic skin disorders, including Iris versicolor, Arctium lappa, Galium aparine, Berberis aquifolium and Smilax ornata (see the box on alteratives and depuratives for more information). However, very little modern research has been undertaken investigating the benefits of these herbs in acne vulgaris.17 More recently, naturopaths have been using an extract from cruciferous vegetables, known as indole-3-carbinol, to stimulate hepatic metabolism of excess steroidal hormones, including androgens.29 Like the depurative herbs, however, there is no specific research linking this compound with acne vulgaris, but understanding its mechanism of action does suggest some potential clinical benefit.
In contrast to these beneficial interventions, cigarette smoking and tobacco-related products have been found to inhibit aromatase activity,30 and as such may exacerbate acne vulgaris, but this has not yet been supported through epidemiological research.31
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