Acne: The Role of Medical Nutrition Therapy

INTRODUCTION

- Acne affects approximately 80-90% of American adolescents.

- Although acne incidence peaks during adolescence, the condition frequently continues into adulthood with the mean age of treatment approximately 24 years of age

- Acne has substantial effects on quality of life, including social withdrawal, anxiety, and depression, making treatment important

- The role of medical nutrition therapy (MNT) to help manage acne is not new.

- Early research reported an association between diet and acne, particularly chocolate, sugar, and fat.

- However, during the latter half of the 20th century, diet was not believed to play a role in acne development

- This change occurred because of the results of two important research studies that are repeatedly cited in the literature and popular culture as evidence to refute the association between diet and acne. (Fulton et al. JAMA. 1969;210(11):2071-2074; Anderson. Am Fam Physician. 1971; 3(3):102-103)

- More recently, dermatologists and registered dietitians have revisited the diet–acne relationship and become increasingly interested in the role of MNT in acne treatment. This reversal is based on several thought-provoking studies examining the role of diet and acne, and on relatively new evidence elucidating the influence of diet on the endocrine and immune responses involved in acne pathogenesis.

- Thus, the history of diet and acne can be categorized in three distinct phases: early history, the rise of the diet–acne myth, and recent research.

Objective

- To review the 3 phases of history of diet and acne and to evaluate the evidence for diet and acne.

Methodology

- Conducted literature search between Jan 2012 to July 2012.

- Using PubMed MeSH terms Acne Vulgaris and Diet or Nutrition Therapy or Glycemic Index or Dairy Products or Milk or Fatty Acids, Omega-3 or Dietary Fats.

- Limited to original human research published in the English language.

- Articles were excluded if the primary intervention included a vitamin, mineral, or herbal supplement.

- Research design was not a reason for exclusion, due to the high number of studies with methodologic limitations, small sample sizes, unclear or no statistical analysis, lack of a control group, or observational or anecdotal data

DIET AND ACNE: EARLY HISTORY

1800-1900

- Dermatology textbooks during the late 1800s and early 1900s frequently recommended dietary restriction as an adjunct treatment to existing dermatology therapy.

- At this time, however, dermatologists did not fully understand the mechanisms underlying acne pathogenesis.

- Therefore, the diet–acne hypothesis and subsequent dietary recommendations were predominantly based on observation, anecdotal evidence, and speculation.

1920-1959

- In 1921, researchers observed chocolate increased blood lipid concentrations, and they surmised that chocolate similarly increased oil production by the sebaceous glands, augmenting acne severity

- In 1931, researchers reported patients with acne to have impaired glucose tolerance

- As a result, the researchers recommended patients avoid excessive carbohydrate consumption, including chocolate and sugar.

- This suggestion was further supported by later research demonstrating an improvement in acne severity among patients following a restricted carbohydrate diet. They speculated a disorder of carbohydrate metabolism increased acne.(Belisario. Aust J Dermatol. 1951;1(2):85-111)

- In 1949, observational study reported an association between frequent milk consumption and acne severity and recommended patients with acne restrict high-fat dairy products

- In 1959, a small case study demonstrated a decrease in acne severity among patients following a low-saturated–fat and low-total–fat diet.

- Taken together, these early studies generally reported an association between diet and acne.

Early Studies that Effectively Disassociated Diet and Acne (1960-1970)

- Researchers began to conduct actual intervention studies.

- In 1961, researchers reported normal glucose tolerance among acne patients and a restricted carbohydrate diet did not improve acne severity.

- In 1965, researchers reported no changes in acne among participants consuming chocolate, in addition to usual dietary intake, after 1 week.

- Conversely, in 1965, a different group of researchers demonstrated improvements in acne among participants consuming a low-sodium diet. The researchers suggested sodium promotes inflammation, increasing acne severity.

- In 1967, other researchers found no differences in sugar consumption between patients with acne and healthy controls.

- In 1969, Fulton and colleagues determined chocolate did not affect acne development in a double-blind crossover study. Although they utilized a control group and conducted quantitative statistical analyses, this study was flawed for several reasons. (Eg: intervention and placebo treatment were nearly identical in total energy, fat, and sugar; methods used to score changes in acne severity lacked precision)

- In 1971, Anderson and colleagues divided university students (n=27) to small groups and instructed them to consume a large portion  of chocolate, milk, roasted peanuts or carbonated beverage, daily, in addition to usual dietary patterns. After only 1 week, the participants did not exhibit any new flares of acne, leading to the conclusion that diet does not influence acne development. This study had several methodologic errors (Eg: small sample size; participants were subdivided into smaller groups of unknown sizes (unlikely to have adequate statistical power); no control group; methods for grading acne was not described; quantitative statistical analysis and randomization was not done and baseline dietary habits was not analysed)

- The studies conducted in 1960s-1970s erroneously led to the general consensus that diet was not associated with acne

- These studies were designed before the establishment of the Glycemic Index (GI) and glycemic load (GL) and before dermatologists fully understood the role of endocrine mechanisms in acne pathogenesis or the duration of time necessary for a treatment to influence acne development.

- Despite flaws, diet and acne were not further investigated for nearly 40 years

- The rediscovery of the diet–acne association was due to a variety of factors, including advances in our understanding of acne pathogenesis, new epidemiologic evidence supporting diet and acne, and a thorough critical analysis of early studies.

ACNE PATHOGENESIS

- Acne pathogenesis is related to several key factors:

i) Excess sebum production by the sebaceous glands,

ii) Follicular occlusion,

iii) Hyperproliferation of Propionobacterium acnes (P. acnes) bacteria, and

iv) Inflammation

- Excess sebum production and hyperproliferation of follicular cells à follicular occlusion and comodone formation.

- Follicular occlusion creates a sebum rich, oxygen-poor environment, ideal for the proliferation of P. acnes.

- Immune recognition of P. acnes, as well as other factors, initiates an immune response causing inflammation.

- Androgen hormones and insulin-like growth factor-1 (IGF-1) influence sebum production and are implicated in the development of acne.

- Additional compounds, including insulin, sex hormone binding protein (SHBP), sterol regulatory element binding protein-1 (SREBP-1), and inflammatory mediators are also associated with the development of acne.

- These factors are also associated with diet and may provide the link between diet and acne.

- This hypothesis is further supported by evidence that deficiencies in hormones, such as IGF-1, are associated with decreased acne severity.

- The understanding of these physiologic mechanisms has contributed to a renewed interest in the diet–acne hypothesis.

MODERN STUDIES INVESTIGATING DIET AND ACNE

Diet and Dairy

- To date, 3 large studies, all conducted by Abedamowo and colleagues, have examined the relationship between frequent dairy consumption and acne.

1) Retrospective cohort

- Adult female nurses (n=47,355) were asked to recall their usual dietary intakes during high school using a food frequency questionnaire (FFQ) and if a physician had ever diagnosed them with acne

- After adjusting for confounders, acne prevalence was associated with total milk consumption (prevalence ratio [PR] 1.22; P for trend=0.002).

- The association was stronger with skim milk (PR 1.44; P for trend=0.03) compared with low-fat milk (PR 1.16; P for trend=0.25) and whole milk (PR 1.12; P for trend=0.56).

- Limitations: retrospective self-reported subjective data compilation; collected data eating habits >10 years before the study; may not be generalizable to adults

2) Prospective studies

- In 2006 and 2008, Abedamowo and colleagues re-examined this relationship in 2 prospective studies among adolescents aged 9 to 15 years (n=6,094 girls and 4,273 boys) using a validated FFQ

- After adjusting for confounding variables among female participants, self-reported acne was positively associated with consumption of total milk (PR 1.2; P for trend=0.001), skim milk (PR 1.08; P for trend=0.001), low-fat milk (PR 1.17; P for trend=0.002), and whole milk (PR 1.19; P for trend=0.001).

- Among male participants, self-reported acne was positively associated with consumption of total milk (PR 1.16; P for trend=0.77) and skim milk (1.19; P for trend=0.02).

- Limitations: self-reported acne and dietary habits; unable to distinguish a trend between low-fat and whole milk consumption and acne prevalence

- The same research group conducted all three of these large prospective studies and the PRs were close to 1, making it difficult to determine the clinical relevance of the results.

3) Case-control study

- Adolescents and young adults (aged 10 to 24 years) with moderate to severe acne (n=205) were case-matched to participants with no or mild acne (n=358)

- Dietary habits were analysed using a non-validated FFQ

- After adjusting for confounding variables, acne was positively associated with frequent consumption of total milk (odds ratio [OR] 1.78) and skim milk (OR 2.2), but not whole milk or cheese

- Limitations: non-validated FFQ, self-reported dietary intake, inclusion of participants with mild acne into the control cases, and a retrospective study design

4) Randomized controlled trial

- To date, no (convincing) randomized controlled studies investigating the association between dairy and acne exist

A small randomized study with lactoferrin-enriched fermented milk was conducted

- Participants (n=36, aged 18 to 30 years) were randomly assigned to consume fermented milk with 200 mg lactoferrin or placebo

- After 12 weeks of consumption of lactoferrin-enriched fermented milk, participants with acne demonstrated an improvement in acne severity, total lesion count, and sebum composition

- The researchers concluded lactoferrin-enriched fermented milk decreases acne severity due to the anti-inflammatory effects of lactoferrin and its ability to suppress microbial growth

Summary:

- Although most evidence suggests total milk consumption as the most critical dairy component promoting acne, currently, there is insufficient evidence to recommend milk restriction as a treatment for patients with acne.

- However, these preliminary results may provide a potential milk alternative or adjunct therapy for a subgroup of patients with acne in which restricted milk diet is appropriate

GI/GL and Acne

- Traditionally, Canadian Inuits, pre-World War II Okinawans, and Zulu populations do not have acne; however, acne prevalence increased among the Canadian Inuits after acculturation with neighboring countries and the adoption of processed foods, beef, and dairy

- Similarly, acne prevalence increased among pre-World War II Okinawans after increasing consumption of animal products

- Among the Zulu population, increases in acne prevalence are attributed to the migration into cities from rural villages

- To explain these phenomenon, Cordain and colleagues examined the relationship between carbohydrate consumption and acne.

- They examined acne prevalence among the Kitavan Islanders of Papua New Guinea (n=1,200) and the Ache hunter-gatherers of Paraguay (n=115) and did not find any cases of acne after a skin examination

- The Kitavan Islanders and Ache consume a substantially lower GL diet compared with Westernized nations.

-  A high-GI or -GL food increases hyperinsulinemia Therefore, researchers speculated a high-GL diet might increase acne by triggering a hormonal cascade

- Limitations: no control group, making it difficult to determine whether the absence of acne was due to a low-GL diet, genetics, or other environmental factors.

- This hypothesis was challenged by a cross-sectional study in 2007.

- Among university students aged 19 to 34 years with (n=49) and without acne (n=42), there were no significant differences in glucose, insulin, IGF-1, or GL in participants with or without acne. Furthermore, none of the participants demonstrated insulin resistance.

- Therefore, the researchers concluded hyperinsulinemia is not involved in acne pathogenesis

- Limitations: retrospective, non-validated FFQ, did not calculate the GL for meat, poultry, fish, vegetables, cheese, or dairy (In small quantities, these foods minimally affect the overall GL; however, large amounts may significantly influence postprandial blood glucose response. In particular, dairy causes hyperinsulinemia and has a high GL, representing an important confounder of the study design)

- In 2007-2008, Smith and colleagues conducted 3 studies examining the association between GL and acne.

1) Randomly assigned participants (43 men ages 15 to 25 years) to a low-GL diet or high-GL diet for 12 weeks. After adjusted for differences in baseline values, participants following a low-GL diet decreased total and inflammatory acne lesions (P=0.01 and 0.02, respectively), lost more weight (P=0.001), decreased BMI (P=0.002), decreased androgen concentrations (P=0.04), and showed a greater improvement in insulin sensitivity (P=0.02) compared with participants following a high-GL diet. On this basis, the researchers concluded that the amount and type of carbohydrate plays a role in acne pathogenesis

2) A non-randomized, parallel, prospective controlled feeding study was conducted. 12 men (aged 15 to 20 years) with acne consumed either a low-GL diet or a high-GL diet. After 1-week, the low-GI group had lower androgen concentrations (P=0.04) and showed greater improvements in insulin sensitivity (P=0.03) and increased IGFBP-3 concentrations from baseline (P=0.03). They concluded a low-GL diet increases IGFBPs and reduces IGF activity, decreasing circulating androgen concentrations, and subsequently, acne development

3) Participants (31 men aged 15 to 20 years) were randomly assigned to a low-GL diet or a control diet (high-carbohydrate diet without reference to GL). After 12 weeks, the researchers measured facial follicular sebum outflow and the composition of skin surface triglycerides. Among participants on the low-GL diet, the ratio of saturated to monounsaturated fatty acids increased, which negatively correlated with total acne lesion counts (r= -0.39; P=0.03) and follicular sebum outflow (r= -0.49; P=0.006). These findings suggest a low-GL diet may alter factors associated with acne development, such as sebum composition and output

- Taken together, these results are particularly compelling because the researchers used strong study designs, including provision of staple foods, dietary counseling, regular telephone sessions, urine samples, controlled feeding environments, and food records.
- Limitations: only 1 study utilized randomized grouping; these results cannot be generalized to women or anyone outside the age range of 15-25 years; participants in low GL group lost significantly more weight and consumed a diet lower in

fat and higher in dietary fiber (therefore the decrease in acne cannot be solely attributed to a change in dietary GL); small sample size

- In 2010, Reynolds and colleagues alternately assigned participants (58 men with a mean age 16.5±1 years) to a high- or low-GL diet.

- After 8 weeks, facial acne improved more among participants following the low-GL diet, without reaching statistical significance.

- There were no differences in insulin sensitivity.

- Limitations: short duration, high dropout rate, limited generalizability, failure to account for baseline diet, small sample size, and a nonrandomized design

- In 2012, Kwon and colleagues published results from a blinded, randomized controlled trial - Participants (N=32) aged 20 to 27 years were randomized to follow either a low-GL diet or control group diet (emphasizing carbohydrate-rich foods).

- After 5 weeks, participants following the low-GL diet decreased inflammatory lesions (P=0.03).

- After 10 weeks, participants following the low-GL diet decreased non-inflammatory lesions (P=0.02), size of sebaceous glands (P=0.03), and expression of sterol regulatory element-binding protein (SREBP)-1 (P=0.03).

- No significant changes in BMI between groups

- Limitations: short duration of study; self-reported dietary intake; small sample size; failure to adjust for possible acne promoting confounding factors, including dairy, saturated fat, trans fat, and fiber consumption; did not measure key hormone factors, including IGF-1, SHBG, and IGFBP-3.

Note: The GI is a system of measuring the effect of carbohydrate on blood glucose whereas GL combines the quantity and effect of the carbohydrate on blood glucose

Dietary fat and Acne Severity

- As mentioned, low acne prevalence was observed among the Kitavan and Ache populations.

- Although these populations traditionally consume a low-GL diet, they also consume a diet low in processed foods, dairy, and total fat and high in fruits, vegetables, and fish.

- The estimated n-3:n-6 ratio of traditional hunter–gather diets, such as the Kitavan and Ache populations, is 1:1,61 whereas the ratio among Westernized nations is approximately 1:20.62 - Thus, the low prevalence of acne among these populations could be due to several other dietary components, including the high consumption of n-3 fatty acids or total fat.

- Unfortunately, very limited data support this theory

- In 2008, a case study (5 participants aged 18 to 23 years) investigated the effects of an n-3 fatty acid supplement containing eicosapentaenoic acid and antioxidants on acne development

- After 8 weeks, the researchers observed a decrease in acne development

- Limitations: small sample size, short duration, lack of a control group, observational study

- In 2012, Di Landro and colleagues conducted a case-control study (as previously discussed, primarily investigated the association between dairy and acne) and examined the relationship between fish consumption and acne.

- After adjusting for confounding factors, fish consumption was negatively associated with acne severity (OR 0.68), indicating frequent consumption of n-3 fatty acids have a protective effect on acne

- However, the type and quantity of fish consumed was not reported.

- In 2007 (3,163 participants aged 10 to 18 years) and 2010 (5,696 participants aged 17 to 25 years), two cross-sectional studies which were not specifically designed to measure the association between acne and dietary fat showed conflicting findings.  

- The first study did not find an association between a high-fat diet nor frequent seafood consumption, suggesting total fat and n-3 fatty acids are not associated with acne development.

- The second study found an association between acne and a high-fat diet (OR 1.439; P<0.05) and frequent intake of fried food (OR 1.174; P<0.05)

- Limitations: non-validated questionnaire, limited generalizability, and failure to account for potential confounding factors.

DISCUSSION

- Based on the current literature, a high-GI/GL diet and frequent dairy consumption are the leading factors in establishing the link between diet and acne, as shown in Figure 2.

High GL-diet and acne: Biological plausible mechanism

- A high-GL diet increases hyperinsulinemia, which elicits an endocrine response that simultaneously stimulates IGF-1 while suppressing IGFBP-3.

- IGF-1 is a powerful mediator of cellular growth, including unregulated tissue and follicular growth, and amplifies androgen bioavailability.

- Androgen hormones have multiple effects, including the promotion of sebum production and secretion, which is a well-established factor in acne pathogenesis

- IGF-1 additionally stimulates sebum production by increasing the expression of SREBP-1, which may stimulate additional lipogenesis in sebocytes via the activation of the phosphoinositide 3-kinase/Akt pathway

- Normally, IGFBP-3 and SHBP function as inhibitory molecules by binding IGF-1 and androgen hormones, respectively.

- Insulin induced suppression of IGFBP-3 and SHBP results in an increase in available IGF-1 and androgen hormones, augmenting acne development.

- This hypothesis is further supported by evidence that deficiencies in hormones, such as

IGF-1, are associated with decreased acne severity and some IGF-1 polymorphisms are associated with increased circulating IGF-1 concentrations and acne severity. Furthermore, hormone management, including medications to reduce insulin secretion, has shown to be effective in treating acne

- Hyperinsulinemia-mediated reduction of IGFBP-3 further induces acne development by increasing follicular growth through the nuclear retinoid-signaling pathway.

- Retinoids are a class of chemical compounds related to vitamin A that inhibit cellular proliferation and encourage apoptosis via binding of retinoic receptors.

- Specifically, IGFBP-3 is a ligand for the retinoid X receptor-alpha and binding leads to decreased cellular growth.

- Consequently, decreased IGFBP-3 bioavailability decreases the activity of the retinoid X receptor-alpha, increasing cellular growth and enhancing acne development

Dairy and acne: Biological plausible mechanism

- Dairy is linked to increased acne severity through similar pathways.

- Dairy products contain carbohydrates and are hypothesized to increase acne severity through diet-induced hyperinsulinemia, which stimulates increased IGF-1 concentrations.

- Both skim and whole milk, but not cheese products, have a three- to six-fold higher GL and insulinotrophic response than predicted, based on the carbohydrate content of the milk.

- This response suggests total milk consumption or total milk protein may have a greater influence on acne, compared with other carbohydrate foods.

- Milk contains a magnitude of growth-stimulating hormones, including IGF-1, and concentrations remain high even after pasteurization, homogenization, and digestion.

- Bovine IGF-1 is identical to human IGF-1 and both are able to bind to the human IGF receptor.

- Interestingly, the association is stronger in skim milk, compared with high-fat milk, implying acne is unlikely to be influenced by the fat content in milk.

- The increased comedogenicity demonstrated in skim milk may be due to other factors within milk, including milk proteins.

- Whey and casein are the main milk proteins and exhibit different growth-promoting effects. - Whey protein is a potent inducer of postprandial hyperinsulinemia, whereas casein increases IGF-1 concentrations.

- One theory suggests leucine-rich whey protein increases acne by inducing cellular growth, androgen hormone secretion, and sebaceous lipogenesis possibly mediated by the mammalian target of rapamycin complex 1 and related pathways.

- In addition, whey protein concentrates, commonly found in popular sports supplements, may influence acne severity.

N-3 fatty acids and acne: Biological plausible mechanism

- Although evidence is limited, n-3 fatty acids are hypothesized to reduce acne severity by suppressing inflammatory cytokine and leukotriene production.

- Leukotrienes are primarily synthesized from the 5-lipooxygenase pathways and are associated with increased markers of inflammation and acne severity.

- Suppression of leukotriene B4 concentrations after administration of a 5-lipoxygenase inhibitor decreases inflammatory acne, suggesting a therapeutic role for n-3 fatty acids among acne patients.

- In addition, n-3 fatty acids may decrease acne by decreasing insulin and IGF-1 concentrations, and increasing IGFBP-3 concentrations, demonstrating similar effects on acne development as GI/GL and dairy consumption.

CONCLUSIONS

- Taken together, epidemiologic, observational, and experimental evidence suggests an association between diet and acne.

- This evidence, to date, does not demonstrate that diet causes acne, but may aggravate or influence it to some degree

- The association between dairy and acne are based on observational studies, therefore causation or the quantity of milk necessary to exacerbate acne cannot be determined.

- Currently, researchers are not certain if the association between dairy and acne is independently or synergistically due to the hormones in milk, milk protein, or the effect of milk on insulin and IGF-1 concentrations.

- Limitations and methodologic issues make it difficult to compare studies, conduct meta-analyses, or establish firm conclusions for the association between dietary GL and acne. Besides, intervention studies had limited generalizability, and did not control for potentially important confounding variables. In addition, research has not yet defined the cut points for a high or low GL score necessary to influence acne development. Furthermore, no research has yet examined the influence of a low-GL and low-dairy diet on acne development.

- The role of dietary fat and/or n-3 fatty acids also remains unknown. To date, studies are sparse and the evidence is weak

RECOMMENDATIONS FOR MNT

- MNT may be a reasonable option for a subset of patients with acne to consider, as an adjunct to dermatology therapy.

- A low-GL diet is a healthy dietary intervention, typically low in saturated fat and high in whole grains, fruit, and vegetables. The health benefits of a low-GL diet may have multiple benefits beyond acne, including weight loss and decreasing risk of obesity, cancer, and diabetes.

- Similarly, n-3 fatty acids are associated with health benefits including prevention of cancer and cardiovascular disease and treatment of a variety of mental illnesses.

- In addition, a diet lower in dairy, if sufficient in calcium and vitamin D, may be considered adequate.

Future studies

- These gaps in the literature should not intimidate but challenge dermatologists and registered dietitians to work collaboratively to design and conduct quality research

- Randomized controlled trials are necessary, with proper consideration on the potential confounding variables, including various acne medications, race, sex, previous acne treatment, age, age at menarche, baseline dietary analysis, and past medical history.

- Acne quality of life should be measured before and after MNT treatment.

- Although these studies are necessary before comprehensive evidence-based MNT recommendations can be established, preliminary evidence regarding diet and acne is certainly worth mentioning.

Final words!

- The medical community should not dismiss the possibility of diet therapy as an adjunct treatment for acne.

- At this time, the best approach is to address each acne patient individually, carefully considering the possibility of dietary counselling.

Burris et al. J AcadNutr Diet 2013;113:416-430.