individuals are stressed with the anxiety of wondering when the next AV flare will occur, since most are not predictable.22,23 A recent cross-sectional study analyzed AV severity in female medical students and found that an increase in stress severity was strongly correlated with increased AV severity.24 In another study, job stress was associated with increased severity of AV in women.25,26 These results truly resonate, especially as many adult women are noted to have AV that recurs or persists beyond adolescence or develop new-onset AV usually during or after their mid-twenties. Higher stress levels and having a psychologically stressful job also correlated with localized, mandibular AV in women.25 On a physiological level, it has been reported that the skin actively responds to stress through neurotransmitters, cellular immune responses, and hormonal fluctuations.21 The generalized stress response generated by the hypothalamic-pituitary-adrenal axis (HPA axis) releases corticotropin-releasing hormone (CRH), which is responsible for the release of androgenic and glucocorticoid hormones such as dehydroepiandrosterone sulfate (DHEA-S) and cortisol respectively, both known to play contributory roles in the development of AV lesions.27,28 Interestingly, AV lesions from female patients were found to have significantly higher levels of CRH in the sebaceous glands compared to healthy control skin.29
Specifically, within the PSU, systemic stress induces a localized, cellular inflammatory response directly within the skin. Keratinocytes express receptors for pro-inflammatory neurotransmitters (ie, nerve growth factor, histamine), making them an important link for neuro-endocrine interaction at the PSU level.30 Moreover, keratinocytes, immune cells, and mast cells are all capable of synthesizing CRH,31 which mediates lipid synthesis within sebocytes, thus modulating the PSU lipid composition.31 Substance P (SP), a key neuro-inflammatory mediator released during local stress and noxious stimuli, accumulates around sebaceous glands.32 In this location, SP may induce mast cell degranulation, which can augment the perilesional inflammatory processes by increasing the expression of the pro-inflammatory mediators interleukin (IL)-1, IL-6, and tumor necrosis factor-alpha (TNF-alpha).32 SP has also been shown to act directly on the PSU by promoting proliferation and differentiation of the sebaceous gland and upregulating lipid synthesis by sebocytes.32
On a broader scale, daily stress can prolong wound healing time, believed to be an integral contributor to the resolution of AV flares, likely due to cortisol release, which can inhibit early inflammatory responses.33 In a study of caregivers, a responsibility known to be psychologically stressful, wounds remained larger and took longer to heal compared to non-stressed controls.34 The proinflammatory cytokine IL-1beta response was impaired in the stressed caregiver group during exposure to lipopolysaccharides.34 The involvement of IL-1beta was later confirmed by studying the wound healing response in dental school students undergoing the acute stress of school exams compared to summer break.35 IL-1beta plays an important role in fibroblast chemotaxis and production of collagen, as well as immune response to foreign bodies, indicating that psycho-emotional stress can disrupt a healthy immune response, which is critical for normal wound healing.33
A systems-wide approach to understanding the multiple contributory factors that can drive AV development also allows us to consider the role of stress on other inflammatory cascades that impact AV. For example, chronic stress has been linked to oxidative stress in the skin, possibly through the renin-angiotensin system.36 Angiotensin II stimulates NADPH oxidase-dependent reactive oxygen species (ROS) production in neutrophils, which also triggers the release of inflammatory mediators at the PSU, compounding the impact that stress may have in the development of AV.36 The role of oxidative stress in the development of AV is discussed further in this review.
Diet and Metabolism
Dermatologists have long suspected a correlation between diet and AV development and/or flares, especially with excessive carbohydrate intake, high sugar-containing foods, and high dairy (milk) intake. There is now a more convincing body of evidence supporting the association between diet and AV.15,37,38 It has been shown that a modern Western diet high in processed sugars and simple carbohydrates and low in fiber has increased the incidence of diabetes and unbalanced insulin levels, which correlates with AV severity.38,39 A 2015 study showed that fasting insulin levels are higher in patients with severe AV than in a healthy control group.39 Another study showed that participants who consumed a diet of low glycemic load substituted with high protein had a marked decrease in the total AV lesion counts compared to a group consuming a traditional high glycemic load diet.38
The modern hypothesis explaining the correlation between sugar intake and AV focuses on the glycemic load, blood glucose, insulin, and the association between insulin-like growth factors (IGFs) and cutaneous endocrine responses.25-27 Receptors for insulin, the peptide hormone that regulates carbohydrate metabolism, and insulin-like growth factor-1 (IGF-1), an important trophic hormone that promotes bone and tissue growth, are both expressed in epidermal keratinocytes.40 In fact, IGF-1 in patients with AV is significantly elevated compared to controls.41 IGF-1 indirectly stimulates the nutrient sensitive kinase mammalian target of rapamycin (mTOR), which is a key regulator of cellular proliferation and lipid synthesis.15 When activated, there is an increase in sebocyte growth and sebaceous lipogenesis, as well as increases in androgen hormone secretion.15,42 High insulin levels also lead to altered proliferation of keratinocytes in the PSU.15 Indirectly, low glycemic index foods also reduce free
