The relationship between acne and diet – Carbohydrates, Dairy, Fatty acids, Antioxidants, Vitamin A, Zinc and Iodine

INTRODUCTION

After the publication of a few landmark studies in the 1960s concluding that there is no relationship between diet and acne, the dogmatic teaching among dermatologists was as such for the next several decades. Interestingly, during this time of skepticism, the perception of a relationship between diet and acne per-sisted among patients across the world (1 3) and even among young medical school graduates (4). In the last 5 to 10 years, several compelling studies have introduced some intriguing new evidence supporting the link between diet and acne. Here we present the most up-to-date and strongest evidence regarding a relationship between acne and the intake of carbohydrates, dairy, w-3 fatty acids, antioxidants, zinc, vitamin A, and iodine.

CARBOHYDRATES AND ACNE

The strongest evidence favoring a relationship between diet and acne lies in a correlation between acne severity and carbohydrate intake. It has been observed through a survey-based study that acne severity may be related to intake of foods high in sugar (5), but the research in this area has broadened to quantify carbohydrate intake in general. Most of the studies in the area of carbohydrate intake utilize the glycemic index (GI) as a tool for quantifying serum glucose and insulin levels for various foods and then relating these measurements to clinical outcome. For instance, some of the most interesting evidence on glycemic index and its correlation with acne severity comes from studies on acne among peoples of non-Western societies where they consume very little highly refined foods with high glycemic indices. A cross-sectional study conducted in 2002 by Cordain et al. among peoples in Papua New Guinea and Paraguay found no acne among a total of 1300 subjects (6), although environmental influence and genetic pool were not taken into account (7,8).

Developed in 1981, the glycemic index is a numerical unit assigned to a given food that reflects the rate at which its consumption increases serum glu-cose and insulin (9). Similarly, the glycemic load was developed in 1997 to quantify total increase in serum glucose and insulin after multiplying glycemic index by carbohydrate content and serving size (10,11). In short, foods of a low glycemic index tend to be raw vegetables and multigrains, whereas those with higher glycemic index are comprised of more refined carbohydrates such as white spaghetti, cereal, chips, cookies, or foods made with white flour (12). While there is a perpetual challenge of isolating diet as a single variable among many with potential influences on acne, there is a common conclusion among these aforementioned studies that those foods with the highest glycemic index are associated with greater acne severity.

To date, the mechanism for this correlation is still theoretical. One notion holds that acne pathogenesis is the downstream effect of hyperinsulinemia and its upregulation and stimulation of various endocrinological pathways that include androgens, insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 3(IGFBP-3), and retinoid signaling cascades (13). Growth hormone (GH) is released by the anterior pituitary gland and stimulates GH receptors in the liver to form and release IGF-1, which then mediates the effects of GH (14). IGF-1 also serves as a surrogate marker for GH, which is potentially involved in acne pathogenesis (15). IGFBP-3 binds to both IFG-1 and IFG-2 and stabilizes it for transport in the serum, but then frees IFG at its receptors so that it may be biologically active (16). Thus, levels of IGFBP-3 are negatively corre-lated with levels of biologically active IGF-1. All of these pathways may influence various factors in acne pathogenesis such as sebum production, overgrowth of follicular epithelium, and abnormal keratinization (13).

The best clinical illustration of hyperinsulinemia and its concomitant endrocrinologic pathways that affect acne is in adult women with polycystic ovarian syndrome (PCOS). This condition is marked by hyperinsulinemia, insulin resistance, hyperandrogenemia, and resulting hyperandrogenism char-acterized by hirsutism and acne (17). When the hyperinsulinemia is targeted for therapy, symptoms improve, illustrating that hyperandrogenism and hyper-insulinemia may be linked. For instance, it has been shown that these patients have improvements in symptoms when treated with medications to improve insulin sensitivity such as metformin, tobutamide, pioglitazone, and acarbose (18,19). Furthermore, when they consume a diet comprised of foods with a low glycemic index, their androgen levels normalize (20).

Elevated IGF-1 levels and testosterones such as dehydroepiandrosterone sulfate (DHEAS) and dihydrotestosterone (DHT) have been reported to be cor-related with acne lesion count, and IGF-1 may influence testosterone production and vice versa (21). In one study, adult women with acne were found to have elevated IGF-1 levels, and IGF-1, in addition to DHEAS and DHT, correlated with comedonal and inflammatory lesion count. However, men with acne did not have significantly higher levels of IGF-1 when compared with their controls, nor did the levels correlate with acne count (21). A study in which postmenopausal women were administered DHEA found that IGF-1 levels rose in addition to testosterone (22), and IGF-1 has been shown to promote expression of steroidogenic enzymes that create precursors to both DHEAS and androgens (23).

Nonetheless, GH may influence acne severity independently of androgen levels. A study from 1995 on postadolescent eumenorrheic women with acne found that in comparison with their age- and sex-matched controls, they pos-sessed higher IGF-1 levels. However, higher IGF-1 levels did not necessarily correlate with higher androgens (free and total testosterone, DHEA-S) or acne severity (15). A subsequent study also among postadolescent eumenorrheic women with acne attempted to correlate androgen levels with both basal insulin levels and insulin measured after an oral glucose tolerance test (OGTT). The OGTT involves administering 75 grams of oral glucose and then measuring serum insulin levels two hours thereafter. When compared with their age- and sex-matched controls, the women with acne had higher levels of DHEA-S, DHT, and serum free testosterone, but comparable levels of basal insulin. However, the subjects with acne showed evidence of insulin resistance after administration of the OGTT in that they demonstrated significantly higher levels of summed insulin. Also at the two-hour mark, androgen levels were drawn in both the acne patients and their controls, and neither total nor free testosterone was shown to have changed significantly with administration of the OGTT (24). Thus, while adult women with acne and higher levels of androgens show evidence of post-prandial hyperinsulinemia, it does not appear to have a direct or at least immediate effect on androgen levels.

A series of two cohort studies by Smith et al. on males with acne showed evidence that foods with a low glycemic load may decrease androgen bio-availability and improve insulin resistance, but the role of weight loss as it relates to these outcomes is unclear. When 23 young males with acne adhered to a diet with a low glycemic load, they experienced reductions in weight and BMI, decreased free androgen index, increased IGFBP-1, and improved insulin sens-itivity. Nonetheless, whether weight reduction or low glycemic load improved these parameters is unclear, as adjustment for BMI resulted in a loss of signif-icance in the association of low glycemic load and both lesion count and insulin resistance (25,26). A subsequent prospective cohort study randomized males with acne to diets of low and high glycemic indices, and designed their food intake to avoid weight changes. The results indicated that in comparison with the subjects who consumed a diet with a low glycemic load, those consuming a high glycemic load showed evidence of higher androgen ability, and the subjects who consumed a low glycemic load had evidence of increases in IGF-1-binding proteins and, therefore, decreased IGF-1 bioavailability (27). While neither of these studies are generalizable to women and are limited by small sample size, their results question whether glycemic load or its frequent result in weight reduction is responsible for the changes in serum free androgens, insulin sens-itivity, or IGF-1 bioavailability.

Several of the aforementioned studies conducted on acne severity as it relates to glycemic load and glycemic index are limited by small sample size, failure to control for weight changes that may affect serum insulin levels, and inability to generalize results to women or nonadolescent males. Nonetheless, the results across all studies are consistent in suggesting that low glycemic loads may improve acne severity, and more carefully designed studies should certainly be conducted to validate these preliminary findings.

DAIRY

Many of the studies conducted to investigate the connection between dairy and acne relied on self-reported questionnaires regarding dairy intake, and yet the conclusions remained consistent. For instance, two retrospective studies separated by over 50 years assessed the acne severity in their subjects as it related to self-reported dairy intake (28,29). Both studies concluded that not only dairy intake was related to acne severity but also the type of milk most frequently implicated was skim milk (28,29). Two prospective studies in 2006 and 2008 upheld these previous findings (30,31). In two cohorts of adult women (29,31) and boys (30), a positive correlation remained between skim milk and acne severity.

The aforementioned studies published from 2005 onward demonstrate an association between milk and acne in three separate populations. Nonetheless, they were limited by their reliance on subjects’ self-reports rather than objective measures as well as their observational design that falls short of the gold standard randomized controlled clinical trial (29 31). Lastly, the associations that were detected were all weak by epidemiological standards in that the odds ratios of associations were consistently close to one.

The comedogenicity of milk draws on its tendency to increase IGF-1 levels, and its containing testosterone prescursors such as androstenedione and DHEA-S (32). These precursors are reduced by 5oc-reductase to form DHT, which directly stimulates sebum production at hair follicles. At the same time, DHT may be formed directly from 5oc-reduced testosterones such as 5oc-androstanedione and 5oc-pregnanedione, both of which are found in milk (32,33). Thus, endogenous testosterone precursors, in addition to 5oc-reduced testosterones, ingested with milk are channeled toward the same hormonal pathway to form DHT, which stimulates sebum production and hyperkeratinization of the pilosebaceous unit.

FATTY ACIDS

The effects of glycemic load may extend beyond hormonal pathways to include an effect on sebum composition, which was recently shown to be related to acne severity (34). That is, adolescent males who consumed a low glycemic load diet produced sebum with a higher ratio of skin surface fatty acids (SFAs) to mon-ounsaturated fatty acids (MUFAs), and they also had fewer acne lesions. Also, increased sebum production or the stimulation of sebum production was asso-ciated with a higher proportion of MUFAs, suggesting that desaturase enzyme in sebaceous lipogenesis may play a key role in sebum production, modification, and then acne development.

Moreover, the role of polyunsaturated fatty acids and specifically the relative ratio of w-6 to w-3 fatty acids may have direct effects on the inflam-matory pathway involved in acne development (35,36). Whereas fat intake in a typical Western diet is mainly comprised of w-6 fatty acids, the fat intake of non-Western or hunter-gather societies is mainly comprised of w-3 fatty acids with a higher intake of fish, wild game, and vegetables (37). In fact, the current ratio of w-6 to w-3 fatty acids intake in North America is 20:1, which is stark contrast to the 2:1 ratio recommendation by lipid panel experts (38). Although a previous study by Cordain et al. attributed lower acne prevalence among non-Western societies to their intake of foods with lower glycemic load (6), it has been postulated that the intake of a higher ratio of w-3 to w-6 fatty acids among these non-Western societies could be another factor in decreasing acne prevalence through both hormonal and anti-inflammatory effects (37). First, w-3 polyun-saturated fatty acids (PUFAs) have been associated with lower IGF-1 levels (39). Second, w-3 PUFAs may suppress cytokine production (36) in that they inhibit the formation of leukotriene B4 (LTB4), which is linked with inflammatory acne (40). Proinflammatory eicosanoids such as prostaglandin E2 (PGE2) and LTB4 are derived from w-6 fatty acids such as arachidonic acid (AA) (41). Omega-6 fatty acids found in fish such as eicosapentaenoic acid (EPA) and docosahex-aenoic acid (DHA) may act as competitive inhibitors of AA conversion into PGE2 or LTB4.

However, one study has suggested that the relative concentration of w-3 fatty acids in the body may also be affected by estrogen, thereby suggesting a new mechanism of birth control pills and their effects on acne. Women have been found to have higher levels of DHA, and consumption of birth control pills increases DHA, while administration of testosterone decreases it; at the same time, administration of estradiols to male to female transsexual subjects resulted in an increase in DHA. Thus, it is possible that estradiols in birth control pills exert their positive effect on improving acne by increasing the ratio of w-3 fatty acids in the body (42).

Nonetheless, very few studies among humans have been conducted to establish the role of fatty acid consumption and acne. An epidemiologic study conducted in 1961 associated the consumption of large amounts of fish, a potent source of w-3 fatty acids, with fewer acne lesions (43), while a limited case series from 2008 attributed consumption of an w-3 dietary supplement with fewer inflammatory acne lesions and improved well-being (44). Further clinical studies must be conducted to verify the findings in the basic science literature.

ANTIOXIDANTS

Oxidative stress and the production of reactive oxygen species (ROS) by neu-trophils may contribute to acne severity (45). There is evidence that acne patients have lower levels of certain antioxidants and therefore may be less capable of removing ROS, suggesting a potential role for antioxidant supplementation (46,47). Cross-sectional studies have found that levels of endogenous anti-oxidants such as glucose-6-phosphate dehydrogenase and catalase (46) as well as vitamins A and E (48) are lower in acne patients. Furthermore, compared with their controls, acne patients have demonstrated higher than normal levels of malondialdehyde (MDA), which is a marker of lipid peroxidation and oxidative damage (46,47). Both selenium and selenium-dependant glutathione peroxidase activities are lower in acne patients compared with their controls (49), and yet the data from one study supporting a benefit of selenium supplementation lacked a control (50).

Basic science experiments continue to elaborate on the role of ROS and antioxidants in acne, paving the way for further human-based experimentation. For instance, epigallocatechin-3-gallate (EGCG), an antioxidant found in green tea, has been linked to lower sebum production when applied to male hamster foreskin (51). A flavonoid with antioxidant properties known as nobiletin, found in the juice of Citrus depressa, was applied to hamster auricles and shown to decrease lipogenesis and cell proliferation in sebaceous glands, while facilitating the excretion of sebum from mature sebocytes (52). The flower Impatiens balsamina, which is used in Eastern medicine, possesses the fla-vonoids kaempferol and quercetin, both of which have demonstrated bacteri-cidal activity against Propionibacterium acnes. The well-known phytoalexin resveratrol that is found in red grape skin, red wine, peanuts, mulberries, spruce, and eucalyptus has been shown in vitro to also be bactericidal against P. acnes (53).

The conclusions regarding the role of antioxidants in acne improvement are primarily presumptive and based on evidence of higher ROS in these patients. Nonetheless, the evidence from the basic science literature suggests that administration of exogenous antioxidants may improve acne severity, such that clinical trials are needed to confirm this theory.

VITAMIN A

As mentioned previously, levels of vitamin A, an antioxidant, have been shown to be lower in acne patients (48). Humans consume vitamin A in one of two forms: preformed vitamin A, which is from animal sources and absorbed by the gut in the form of retinol, and provitamin A carotenoid, which is from colorful fruits and vegetables. Retinol is one of the most active forms of vitamin A and is easily absorbed in the gut. Once absorbed, it is made into retinal and retinoic acids, which are two other active forms of vitamin A. Preformed vitamin A is most prevalent in liver, whole milk, and fortified food products. In contrast, provitamin A carotenoid is from fruits and vegetables, and must be converted into retinol once absorbed during ingestion. Of the 563 identified carotenoids, fewer than 10% can be converted into vitamin A by the body, with R-carotene being the most easily absorbed (54). In general, vitamin A deficiency is rare in the United States and is really only seen in the developing world along with extreme malnourishment. Nonetheless, it may be seen in conjunction with strict dietary restrictions, alcoholism, zinc deficiency (zinc is needed to make retinol-binding protein), and conditions predisposing patients to low fat absorption such as celiac disease and Crohn’s disease (54).

The Institute of Medicine recommends about 900 µg/day and 700 µg/day of vitamin A daily for men and women, respectively, over 19 years of age (55). However, dermatologists have traditionally been reluctant to give oral supple-mentation for fear of inducing hypervitaminosis A, which may cause birth defects, hepatotoxicity, reduced bone mineral density, and central nervous system abnormalities such as pseudotumor cerebri (55,56). The upper limit of tolerable daily intake of vitamin A for otherwise healthy individuals is 3000 µg/day, which should not induce toxicity (55).

The role of high doses of vitamin A in treating refractory and severe acne is well known since isotretinoin was first approved by the FDA in 1982 (57). Isotretinoin is a synthetic retinoid, which is a compound that is chemically similar to vitamin A (54). In 1981, Kligman et al. first reported that with doses as high as 300,000 IU in women and 400,000 to 500,000 IU in men, severe acne and other disorders of the pilosebaceous unit could be treated effectively. This study had followed subjects for up to four months and concluded that the fears of hypervitaminosis were, for the most part, exaggerated. They reported that the most common side effects of these high doses of medications were xerosis and cheilitis (58).

ZINC AND IODINE

Zinc is an essential element for proper skin development and function (59), has a bacteriostatic effect against P. acnes, and may decrease production of TNF-oc, a proinflammatory cytokine (60). Up until the 1980s, zinc sulfate was the only form of the element available for supplementation, after which it become available as zinc gluconate, a more tolerable form for ingestion. Acne patients have been found to have lower levels of zinc (61,62), and randomized double-blind clinical trials comparing zinc with placebo (63 68) have shown that patients with severe acne improve with zinc supplementation. However, patients with mild or moderate inflammatory acne may not benefit when compared with placebo (69), and zinc may be most beneficial for inflammatory and not com-edonal lesions (70). Most of these previous studies on zinc were comprised of small sample sizes, lacked controlling for dietary intake, and administered high doses of both zinc gluconate (200 mg) and zinc sulfate (400 or 600 mg), which were associated with gastrointestinal side effects such as nausea, vomiting, and diarrhea (64,65,68,70). Nonetheless, a few randomized and controlled clinical trials have shown that zinc supplementation is as effective as or less so than oral tetracyclines (71,72). The studies on acne and zinc supplementation have utilized doses of zinc with high side effect profiles while failing to show any benefit over oral antibiotics. Nonetheless, since the aforementioned experiments comparing zinc with placebo seem to show a benefit with zinc supplementation, further studies are warranted, especially in light of increasing resistance of P. acnes to many traditionally used oral antibiotics.

Iodine consumption in the form of iodine-rich foods such as kelp or systemic medications containing iodine may create a monomorphic eruption of pustules (73,74). Studies that have claimed an association with certain foods containing iodine and acne severity have been confounded by the other con-tents of these foods. For instance, a study from 1961 concluded that adolescents consuming high amounts of seafood, which is very high in iodine, also have decreased severity of acne (43), and yet it is impossible to attribute these results to iodine alone when seafood also contains high amounts of w-3 fatty acids. Similarly, that milk consumption may be associated with acne severity as found in previous experiments (28 31) could be determined by the iodine content of milk (75), which may vary depending on the location of the milk farm, the season, the use of fortified animal feed, and the use of iodophor sanitizing solutions (76).

THE RELATIONSHIP BETWEEN ACNE AND DIET CONCLUSION

It has long been posited that diet has no impact on acne, but recent clinical trials have suggested that a relationship does indeed exist. While the clinical evidence is compelling, much of what we can attribute to diet as a factor in acne severity draws from inferences based on our expanding knowledge of hormonal and endocrinologic pathways.

The association between glycemic load and acne is especially convincing. Further studies should include a thorough analysis of women with PCOS, as it is these patients who would likely most benefit from dietary intervention, given their metabolic abnormalities. Indeed, further clinical trials among a wider patient base could better define recommendations for modifying carbohydrate intake, but until then, it is appropriate for dermatologists to recommend a lower glycemic load diet among patients with acne.

Although the link between dairy and acne is less convincing than that between a high glycemic load diet and acne, both deserve consideration during any dietary counseling efforts. The exact mechanism by which dairy may impact acne, whether it is via a hormonal pathway or upregulated IGF-1, remains to be further clarified. If physicians choose to counsel their patients that dairy con-sumption may indeed exacerbate their acne, it is reasonable to simultaneously advise patients to supplement their diets with vitamin D and calcium, the levels of which may suffer with a decrease in dairy intake.

The role of w-3 fatty acids, antioxidants, zinc, vitamin A, and iodine in acne vulgaris remains to be elucidated. Given the level of evidence available, the authors currently advise their patients to supplement their diets on the basis of personal preferences and experiences, remaining vigilant for signs of intolerance or toxicity.

In light of the last decade of research investigating the relationship between diet and acne, it is no longer dermatological dogma to state that any association between diet and acne is mere myth. If a particular patient notes an association between a certain dietary factor and acne severity, it is best to support that patient’s dietary supplementation or restriction and to encourage the patient to keep a food diary to test his or her hypothesis.

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Jean-Paul Marat

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