Food for Thought

Dermatologists commonly manage a variety of wounds in the outpatient setting. Wound healing requires a multifaceted approach that often includes topical and oral therapies, adjustment of mechanical factors, and behavioral and lifestyle modifications. Physiologically, wound healing requires an inflammatory phase, a proliferative phase, and a remodeling phase. Chronic wounds undergo a prolonged inflammatory response hindered by decreased growth factors and increased wound bioburden.¹ Malnutrition has been routinely associated with wound chronicity and serves as a modifiable risk factor that may improve wound healing outcomes.²

Although the causes of wounds encountered in dermatology vary extensively, the importance of nutrition underlies all wound healing. Caloric needs in wound healing have been estimated at 30 to 40 kcal/kg dependent on baseline body weight, age, medical comorbidities, activity level, stage of wound healing, wound size, and number of wounds.^1,3,4 Nutritional supplementation is patient dependent, but this article serves to review the existing literature on macronutrient and micronutrient supplementation to clarify the potentially complementary role for nutritional support in chronic wounds. All patients should be screened with a thorough history, review of systems, and physical examination for existing nutrient deficiencies. Patients with age-related or chronic diseases are at increased risk for nutritional deficiency, and focused laboratory testing may be warranted. Supplementation for specific deficiencies with help from a registered dietician is recommended.

Macronutrients for Wound Healing

Protein—Protein is the most widely known macronutrient required for wound healing. The primary function of dietary protein is to provide amino acids to perform physiologic functions.⁵ Not only does cutaneous injury increase the metabolic needs of the wounded area, but large amounts of protein can be continually lost through wound exudates. Protein is necessary for the immune response required to transition from inflammatory to proliferative phases of wound healing.⁶ Protein energy deficiency has been reported to reduce fibroblast activity, delay angiogenesis, and decrease collagen formation.⁷ Additionally, protein is required for the formation of inflammatory cells and maintenance of oncotic pressure, specifically in venous insufficiency wounds.¹

The current recommended dietary allowance for protein in healthy adults is 0.8 g/kg daily of body weight. In patients with pressure ulcerations, a goal recommended dietary allowance of 1.25 to 2.0 g/kg daily of body weight, dependent on ulceration size, has been recommended by the National Pressure Ulcer Advisory Panel and European Pressure Ulcer Advisory Panel.⁸ This recommendation was based on a series of studies that reported enhanced healing rates in patients with pressure ulcers receiving higher-protein diets.⁹ The largest study to date was double-blinded and included 89 residents of long-term care facilities with stage II to stage IV pressure ulcers.¹⁰ Participants were randomized to receive commercial protein supplementation vs placebo. At the end of 8 weeks, a statistically significant difference was seen in mean (SD) pressure ulcer scale for healing scores (3.55 [4.66] vs 3.22 [4.11]; P<.05).¹⁰ A 2014 Cochrane review failed to identify benefit associated with nutritional interventions for either the prevention and/or treatment of pressure ulcers.¹¹ Specific recommendations on protein intake for other types of chronic wounds have not been proposed. Protein supplementation generally is provided orally, if tolerated. Liquid supplements such as Boost (Nestlé), Carnation Breakfast Essentials (Nestlé), NuBasics (SupremeMed), Resource (Nestlé Health Science), and Ensure (Abbott Laboratories) are frequently used to supplement both protein and caloric intake. Protein oversupplementation has not been associated with improved outcomes and may cause or exacerbate other medical comorbidities.

Fatty Acids for Wound Healing

Wound healing is an anabolic process that requires adequate intake of substrates such as glucose and fat. Carbohydrates serve as the major energy source required for wound healing, while fats are thought to play roles in cell membrane development and modulation of cellular signaling.¹ Fats utilize a unique pathway for energy production through beta-oxidation and the production of adenosine triphosphate, allowing available protein to be harnessed for wound healing.¹ Omega-3 and omega-6 fatty acids serve as precursors to prostaglandins, leukotrienes, and thromboxane—all key mediators of the inflammatory phase of wound healing.³ Omega-3 fatty acids are thought to downregulate genes involved in proinflammatory pathways,¹² as well as to diminish lymphocyte proliferation and levels of IL-1β, tumor necrosis factor α, and IL-6 in vitro.¹³ In vivo studies assessing the impact of omega-3 fatty acid supplementation on wound healing are minimal, and the role of dietary supplementation for this indication remains unknown. Fish oil contains the omega-3 fatty acid–rich eicosapentaenoic acid and docosahexaenoic acid, which has been compared to mineral oil supplementation for wound healing in healthy adults. When fish oil was supplemented for 4 weeks, no significant differences were identified in time to complete wound healing between groups. Interestingly, significantly higher levels of the proinflammatory cytokine IL-1β were identified in blister fluid at 24 hours after blistering vs the placebo group (t=2.52, df=25, P<.05).¹⁴ Prior studies evaluating wound healing in animal models similarly identified longer times to re-epithelialization after omega-3 polyunsaturated fatty acid supplementation orally and topically.^15,16 The fatty acid quality and composition consumed also may impact wound healing, as high-fat diets that are not rich in omega-3 fatty acids have been shown to promote inflammation and impair wound healing in rats, but this has not been thoroughly explored in human trials.¹⁷ Although adequate intake of these macronutrients is important, excessive intake may be harmful. Larger prospective trials are needed to shed light on the dose and composition of fatty acid supplementation that may optimize wound healing.

Vitamins and Micronutrients Required for Wound Healing

Vitamin A—Many vitamins serve as cofactors for the enzymatic processes required in wound healing. Vitamin A is an essential fat-soluble vitamin that serves a variety of dermatologic functions and promotes wound healing through stimulation of fibroblasts and ground substance, and it facilitates epithelial cell differentiation when applied topically.^3,18 Vitamin A works through the activation of retinoid receptors on endothelial cells, fibroblasts, keratinocytes, melanocytes, and sebocytes, and has purported anti-inflammatory effects that aid the healing of open wounds.³ Additionally, vitamin A is thought to enhance cytokine release in the inflammatory phase of wound healing.¹⁹ Supplemental vitamin A has been associated with positive effects on acute wound healing, burns, and radiation injuries.³ The utility of vitamin A supplementation in chronic wounds remains unknown; however, it has been shown to be beneficial in patients with inflammatory disease, such as rheumatoid arthritis, on corticosteroid therapy. Vitamin A supplementation in this population has been shown to counteract the negative effects of corticosteroids on wound healing via downregulation of transforming growth factor β and insulinlike growth factor 1.²⁰ Vitamin A deficiency has been associated with impaired progression through inflammatory and remodeling phases of healing due to altered B-cell and T-cell function and antibody production.¹ Some experts recommend short courses of oral vitamin A supplementation to enhance wound healing at doses between 10,000 and 25,000 IU daily.^2,3 Large, population-based studies are needed, and the safety supporting this recommendation in all patients remains unknown.

Vitamin C—Vitamin C is widely known for its role in collagen formation, immunomodulation, and antioxidant capacity.¹ Although vitamin C deficiency is associated with decreased collagen synthesis and impaired wound healing,²¹ the utility of long-term supplementation in patients who are not deficient remains unexplored. A systematic review evaluating interventional studies utilizing vitamin C supplementation on pressure ulcerations and surgical wound healing concluded that convincing evidence exists only for supplementation with at least 500 mg of vitamin C. The authors noted, “There is little evidence for improved healing of surgical wounds by high-dose single vitamin C supplementation (1–3 g/day).”²² In a prospective, randomized, controlled trial, 20 patients with pressure ulcerations were supplemented with vitamin C vs placebo with a mean reduction in pressure-sore area of 84% after 1 month in the vitamin C–supplemented group compared to 42.7% in the placebo group (P<.005). A limitation of this study is the small population.²³ One current recommendation for vitamin C supplementation in chronic wounds is for 500 mg daily in uncomplicated wounds to 2 g daily in severe wounds.³ Additional studies have suggested that the benefits of vitamin C supplementation are maximized when given in combination with zinc and arginine.²² At this time, evaluation for vitamin C deficiency and appropriate supplementation in patients with chronic wounds is needed.

Zinc—Minerals similarly play important roles in enzymatic regulation. Hundreds of zinc-containing enzymes are involved in wound healing and are required in tissue repair, growth, antioxidant capacity, and immune function.^1,24 Zinc is specifically critical to collagen, DNA, RNA, and protein synthesis, as well as cellular proliferation.⁴ Zinc deficiency has been encountered in the setting of chronic wounds with extensive drainage, decreased dietary intake, or excessive gastrointestinal losses.²⁵ Although many studies exist evaluating the utility of zinc supplementation on wound healing, many are confounded by multinutrient supplementation. No studies to date support zinc supplementation when zinc deficiency is absent. Patient assessment for medications or conditions that may impact zinc metabolism should be completed. Importantly, zinc supplementation can interfere with the absorption of other cations, so excessive supplementation should be avoided.¹

Amino Acids for Wound Healing

Arginine—Arginine is an essential amino acid that serves as a substrate for cellular proliferation, collagen deposition, and lymphocyte function.^8,26,27 Arginine serves as the biologic precursor for nitric oxide (NO), a substrate that has important wound healing properties. Nitric oxide metabolites have been shown to positively regulate wound repair while NO metabolites are reduced in wound environments in diabetic ulcerations.^28,29 Arginine also is a proline precursor, an essential building block for collagen synthesis,^6,30 and a stimulator of growth hormone and T cells.^30,31 Animal studies have suggested L-arginine supplementation may reverse impaired NO synthesis in diabetic wounds.²⁸ A single randomized trial assessing differing doses of arginine supplementation on stage II or stage IV pressure ulcers noted an almost two-fold improvement in healing time.³² However, human studies have not shown increased rates of re-epithelialization of skin graft donor sites when provided oral or parenteral arginine supplementation.³³ Inadequate data currently exist to support regular arginine supplementation for all types of wounds, and no safe dose of daily arginine intake has been established.

Glutamine—Similarly, glutamine supplementation has been proposed to accelerate wound healing due to its role as a primary metabolic fuel source for rapidly proliferating cells such as epithelial cells and fibroblasts.⁸ Glutamine is thought to induce expression of heat-shock proteins and protect against inflammatory and infectious wound complications.³⁴ Additionally, glutamine is thought to increase tissue insulin sensitivity, which may prove beneficial in wounds, as topical insulin previously has been shown in animal and human models to promote healing.³⁵ Glutamine is thought to play a role in the inflammatory phase of wound healing via superoxide production, leukocyte apoptosis, and phagocytosis.^6,34,36 Unfortunately, numerous randomized trials on glutamine supplementation have resulted in conflicting evidence confounded by multisupplementation within the same trial.^37,38 A double-blind, randomized, controlled trial of 270 participants assessed the effect of oral supplementation with arginine, glutamine, or β-hydroxy-β-methylbutyrate vs control in the healing time of diabetic foot ulcerations. Significant differences in wound closure time at week 16 were only identified in participants with low albumin levels (≤40 g/L) who were supplemented (50.8%) vs the control group (34.9%; P=.0325) and in those with poor limb perfusion (ankle-brachial index of <1.0) who were supplemented (60.3%) vs the control group (39.3%; P=.0079).³⁹ Ongoing clinical trials evaluating the effects of glutamine supplementation on differing wound types will hopefully shed light on the efficacy of supplementation.

Final Thoughts

Wound healing is multifactorial and should consider the health status and medical comorbidities of each patient treated. We propose an individualized approach to wound healing that includes exploration of specific macronutrient and micronutrient deficiencies, as malnutrition has been associated with wound chronicity and serves as a modifiable risk factor to improve healing.² The evidence backing specific nutrient supplementation in patients with deficiencies is strong and should be considered in patients with chronic wounds. Adequate caloric intake and protein content should be recommended for most wound patients; however, excessive protein intake has not been beneficial in wound healing. The data behind specific amino acid and vitamin supplementation are limited at this time. As with other therapeutics, there is likely an appropriate dose for supplementation that has not yet been elucidated. Consideration of wound type, size, depth, exudate, and underlying cause are important to optimize healing and tailor nutritional supplementation to each patient. We hope future studies will illuminate the complementary role of dietary intake and nutrient supplementation for the treatment of chronic nonhealing wounds.

Dermatologists commonly manage a variety of wounds in the outpatient setting. Wound healing requires a multifaceted approach that often includes topical and oral therapies, adjustment of mechanical factors, and behavioral and lifestyle modifications. Physiologically, wound healing requires an inflammatory phase, a proliferative phase, and a remodeling phase. Chronic wounds undergo a prolonged inflammatory response hindered by decreased growth factors and increased wound bioburden.¹ Malnutrition has been routinely associated with wound chronicity and serves as a modifiable risk factor that may improve wound healing outcomes.²

Although the causes of wounds encountered in dermatology vary extensively, the importance of nutrition underlies all wound healing. Caloric needs in wound healing have been estimated at 30 to 40 kcal/kg dependent on baseline body weight, age, medical comorbidities, activity level, stage of wound healing, wound size, and number of wounds.^1,3,4 Nutritional supplementation is patient dependent, but this article serves to review the existing literature on macronutrient and micronutrient supplementation to clarify the potentially complementary role for nutritional support in chronic wounds. All patients should be screened with a thorough history, review of systems, and physical examination for existing nutrient deficiencies. Patients with age-related or chronic diseases are at increased risk for nutritional deficiency, and focused laboratory testing may be warranted. Supplementation for specific deficiencies with help from a registered dietician is recommended.

Macronutrients for Wound Healing

Protein—Protein is the most widely known macronutrient required for wound healing. The primary function of dietary protein is to provide amino acids to perform physiologic functions.⁵ Not only does cutaneous injury increase the metabolic needs of the wounded area, but large amounts of protein can be continually lost through wound exudates. Protein is necessary for the immune response required to transition from inflammatory to proliferative phases of wound healing.⁶ Protein energy deficiency has been reported to reduce fibroblast activity, delay angiogenesis, and decrease collagen formation.⁷ Additionally, protein is required for the formation of inflammatory cells and maintenance of oncotic pressure, specifically in venous insufficiency wounds.¹

The current recommended dietary allowance for protein in healthy adults is 0.8 g/kg daily of body weight. In patients with pressure ulcerations, a goal recommended dietary allowance of 1.25 to 2.0 g/kg daily of body weight, dependent on ulceration size, has been recommended by the National Pressure Ulcer Advisory Panel and European Pressure Ulcer Advisory Panel.⁸ This recommendation was based on a series of studies that reported enhanced healing rates in patients with pressure ulcers receiving higher-protein diets.⁹ The largest study to date was double-blinded and included 89 residents of long-term care facilities with stage II to stage IV pressure ulcers.¹⁰ Participants were randomized to receive commercial protein supplementation vs placebo. At the end of 8 weeks, a statistically significant difference was seen in mean (SD) pressure ulcer scale for healing scores (3.55 [4.66] vs 3.22 [4.11]; P<.05).¹⁰ A 2014 Cochrane review failed to identify benefit associated with nutritional interventions for either the prevention and/or treatment of pressure ulcers.¹¹ Specific recommendations on protein intake for other types of chronic wounds have not been proposed. Protein supplementation generally is provided orally, if tolerated. Liquid supplements such as Boost (Nestlé), Carnation Breakfast Essentials (Nestlé), NuBasics (SupremeMed), Resource (Nestlé Health Science), and Ensure (Abbott Laboratories) are frequently used to supplement both protein and caloric intake. Protein oversupplementation has not been associated with improved outcomes and may cause or exacerbate other medical comorbidities.

Fatty Acids for Wound Healing

Wound healing is an anabolic process that requires adequate intake of substrates such as glucose and fat. Carbohydrates serve as the major energy source required for wound healing, while fats are thought to play roles in cell membrane development and modulation of cellular signaling.¹ Fats utilize a unique pathway for energy production through beta-oxidation and the production of adenosine triphosphate, allowing available protein to be harnessed for wound healing.¹ Omega-3 and omega-6 fatty acids serve as precursors to prostaglandins, leukotrienes, and thromboxane—all key mediators of the inflammatory phase of wound healing.³ Omega-3 fatty acids are thought to downregulate genes involved in proinflammatory pathways,¹² as well as to diminish lymphocyte proliferation and levels of IL-1β, tumor necrosis factor α, and IL-6 in vitro.¹³ In vivo studies assessing the impact of omega-3 fatty acid supplementation on wound healing are minimal, and the role of dietary supplementation for this indication remains unknown. Fish oil contains the omega-3 fatty acid–rich eicosapentaenoic acid and docosahexaenoic acid, which has been compared to mineral oil supplementation for wound healing in healthy adults. When fish oil was supplemented for 4 weeks, no significant differences were identified in time to complete wound healing between groups. Interestingly, significantly higher levels of the proinflammatory cytokine IL-1β were identified in blister fluid at 24 hours after blistering vs the placebo group (t=2.52, df=25, P<.05).¹⁴ Prior studies evaluating wound healing in animal models similarly identified longer times to re-epithelialization after omega-3 polyunsaturated fatty acid supplementation orally and topically.^15,16 The fatty acid quality and composition consumed also may impact wound healing, as high-fat diets that are not rich in omega-3 fatty acids have been shown to promote inflammation and impair wound healing in rats, but this has not been thoroughly explored in human trials.¹⁷ Although adequate intake of these macronutrients is important, excessive intake may be harmful. Larger prospective trials are needed to shed light on the dose and composition of fatty acid supplementation that may optimize wound healing.

Vitamins and Micronutrients Required for Wound Healing

Vitamin A—Many vitamins serve as cofactors for the enzymatic processes required in wound healing. Vitamin A is an essential fat-soluble vitamin that serves a variety of dermatologic functions and promotes wound healing through stimulation of fibroblasts and ground substance, and it facilitates epithelial cell differentiation when applied topically.^3,18 Vitamin A works through the activation of retinoid receptors on endothelial cells, fibroblasts, keratinocytes, melanocytes, and sebocytes, and has purported anti-inflammatory effects that aid the healing of open wounds.³ Additionally, vitamin A is thought to enhance cytokine release in the inflammatory phase of wound healing.¹⁹ Supplemental vitamin A has been associated with positive effects on acute wound healing, burns, and radiation injuries.³ The utility of vitamin A supplementation in chronic wounds remains unknown; however, it has been shown to be beneficial in patients with inflammatory disease, such as rheumatoid arthritis, on corticosteroid therapy. Vitamin A supplementation in this population has been shown to counteract the negative effects of corticosteroids on wound healing via downregulation of transforming growth factor β and insulinlike growth factor 1.²⁰ Vitamin A deficiency has been associated with impaired progression through inflammatory and remodeling phases of healing due to altered B-cell and T-cell function and antibody production.¹ Some experts recommend short courses of oral vitamin A supplementation to enhance wound healing at doses between 10,000 and 25,000 IU daily.^2,3 Large, population-based studies are needed, and the safety supporting this recommendation in all patients remains unknown.

Vitamin C—Vitamin C is widely known for its role in collagen formation, immunomodulation, and antioxidant capacity.¹ Although vitamin C deficiency is associated with decreased collagen synthesis and impaired wound healing,²¹ the utility of long-term supplementation in patients who are not deficient remains unexplored. A systematic review evaluating interventional studies utilizing vitamin C supplementation on pressure ulcerations and surgical wound healing concluded that convincing evidence exists only for supplementation with at least 500 mg of vitamin C. The authors noted, “There is little evidence for improved healing of surgical wounds by high-dose single vitamin C supplementation (1–3 g/day).”²² In a prospective, randomized, controlled trial, 20 patients with pressure ulcerations were supplemented with vitamin C vs placebo with a mean reduction in pressure-sore area of 84% after 1 month in the vitamin C–supplemented group compared to 42.7% in the placebo group (P<.005). A limitation of this study is the small population.²³ One current recommendation for vitamin C supplementation in chronic wounds is for 500 mg daily in uncomplicated wounds to 2 g daily in severe wounds.³ Additional studies have suggested that the benefits of vitamin C supplementation are maximized when given in combination with zinc and arginine.²² At this time, evaluation for vitamin C deficiency and appropriate supplementation in patients with chronic wounds is needed.

Zinc—Minerals similarly play important roles in enzymatic regulation. Hundreds of zinc-containing enzymes are involved in wound healing and are required in tissue repair, growth, antioxidant capacity, and immune function.^1,24 Zinc is specifically critical to collagen, DNA, RNA, and protein synthesis, as well as cellular proliferation.⁴ Zinc deficiency has been encountered in the setting of chronic wounds with extensive drainage, decreased dietary intake, or excessive gastrointestinal losses.²⁵ Although many studies exist evaluating the utility of zinc supplementation on wound healing, many are confounded by multinutrient supplementation. No studies to date support zinc supplementation when zinc deficiency is absent. Patient assessment for medications or conditions that may impact zinc metabolism should be completed. Importantly, zinc supplementation can interfere with the absorption of other cations, so excessive supplementation should be avoided.¹

Amino Acids for Wound Healing

Arginine—Arginine is an essential amino acid that serves as a substrate for cellular proliferation, collagen deposition, and lymphocyte function.^8,26,27 Arginine serves as the biologic precursor for nitric oxide (NO), a substrate that has important wound healing properties. Nitric oxide metabolites have been shown to positively regulate wound repair while NO metabolites are reduced in wound environments in diabetic ulcerations.^28,29 Arginine also is a proline precursor, an essential building block for collagen synthesis,^6,30 and a stimulator of growth hormone and T cells.^30,31 Animal studies have suggested L-arginine supplementation may reverse impaired NO synthesis in diabetic wounds.²⁸ A single randomized trial assessing differing doses of arginine supplementation on stage II or stage IV pressure ulcers noted an almost two-fold improvement in healing time.³² However, human studies have not shown increased rates of re-epithelialization of skin graft donor sites when provided oral or parenteral arginine supplementation.³³ Inadequate data currently exist to support regular arginine supplementation for all types of wounds, and no safe dose of daily arginine intake has been established.

Glutamine—Similarly, glutamine supplementation has been proposed to accelerate wound healing due to its role as a primary metabolic fuel source for rapidly proliferating cells such as epithelial cells and fibroblasts.⁸ Glutamine is thought to induce expression of heat-shock proteins and protect against inflammatory and infectious wound complications.³⁴ Additionally, glutamine is thought to increase tissue insulin sensitivity, which may prove beneficial in wounds, as topical insulin previously has been shown in animal and human models to promote healing.³⁵ Glutamine is thought to play a role in the inflammatory phase of wound healing via superoxide production, leukocyte apoptosis, and phagocytosis.^6,34,36 Unfortunately, numerous randomized trials on glutamine supplementation have resulted in conflicting evidence confounded by multisupplementation within the same trial.^37,38 A double-blind, randomized, controlled trial of 270 participants assessed the effect of oral supplementation with arginine, glutamine, or β-hydroxy-β-methylbutyrate vs control in the healing time of diabetic foot ulcerations. Significant differences in wound closure time at week 16 were only identified in participants with low albumin levels (≤40 g/L) who were supplemented (50.8%) vs the control group (34.9%; P=.0325) and in those with poor limb perfusion (ankle-brachial index of <1.0) who were supplemented (60.3%) vs the control group (39.3%; P=.0079).³⁹ Ongoing clinical trials evaluating the effects of glutamine supplementation on differing wound types will hopefully shed light on the efficacy of supplementation.

Final Thoughts

Wound healing is multifactorial and should consider the health status and medical comorbidities of each patient treated. We propose an individualized approach to wound healing that includes exploration of specific macronutrient and micronutrient deficiencies, as malnutrition has been associated with wound chronicity and serves as a modifiable risk factor to improve healing.² The evidence backing specific nutrient supplementation in patients with deficiencies is strong and should be considered in patients with chronic wounds. Adequate caloric intake and protein content should be recommended for most wound patients; however, excessive protein intake has not been beneficial in wound healing. The data behind specific amino acid and vitamin supplementation are limited at this time. As with other therapeutics, there is likely an appropriate dose for supplementation that has not yet been elucidated. Consideration of wound type, size, depth, exudate, and underlying cause are important to optimize healing and tailor nutritional supplementation to each patient. We hope future studies will illuminate the complementary role of dietary intake and nutrient supplementation for the treatment of chronic nonhealing wounds.

Dermatologists commonly manage a variety of wounds in the outpatient setting. Wound healing requires a multifaceted approach that often includes topical and oral therapies, adjustment of mechanical factors, and behavioral and lifestyle modifications. Physiologically, wound healing requires an inflammatory phase, a proliferative phase, and a remodeling phase. Chronic wounds undergo a prolonged inflammatory response hindered by decreased growth factors and increased wound bioburden.¹ Malnutrition has been routinely associated with wound chronicity and serves as a modifiable risk factor that may improve wound healing outcomes.²

Although the causes of wounds encountered in dermatology vary extensively, the importance of nutrition underlies all wound healing. Caloric needs in wound healing have been estimated at 30 to 40 kcal/kg dependent on baseline body weight, age, medical comorbidities, activity level, stage of wound healing, wound size, and number of wounds.^1,3,4 Nutritional supplementation is patient dependent, but this article serves to review the existing literature on macronutrient and micronutrient supplementation to clarify the potentially complementary role for nutritional support in chronic wounds. All patients should be screened with a thorough history, review of systems, and physical examination for existing nutrient deficiencies. Patients with age-related or chronic diseases are at increased risk for nutritional deficiency, and focused laboratory testing may be warranted. Supplementation for specific deficiencies with help from a registered dietician is recommended.

Macronutrients for Wound Healing

Protein—Protein is the most widely known macronutrient required for wound healing. The primary function of dietary protein is to provide amino acids to perform physiologic functions.⁵ Not only does cutaneous injury increase the metabolic needs of the wounded area, but large amounts of protein can be continually lost through wound exudates. Protein is necessary for the immune response required to transition from inflammatory to proliferative phases of wound healing.⁶ Protein energy deficiency has been reported to reduce fibroblast activity, delay angiogenesis, and decrease collagen formation.⁷ Additionally, protein is required for the formation of inflammatory cells and maintenance of oncotic pressure, specifically in venous insufficiency wounds.¹

The current recommended dietary allowance for protein in healthy adults is 0.8 g/kg daily of body weight. In patients with pressure ulcerations, a goal recommended dietary allowance of 1.25 to 2.0 g/kg daily of body weight, dependent on ulceration size, has been recommended by the National Pressure Ulcer Advisory Panel and European Pressure Ulcer Advisory Panel.⁸ This recommendation was based on a series of studies that reported enhanced healing rates in patients with pressure ulcers receiving higher-protein diets.⁹ The largest study to date was double-blinded and included 89 residents of long-term care facilities with stage II to stage IV pressure ulcers.¹⁰ Participants were randomized to receive commercial protein supplementation vs placebo. At the end of 8 weeks, a statistically significant difference was seen in mean (SD) pressure ulcer scale for healing scores (3.55 [4.66] vs 3.22 [4.11]; P<.05).¹⁰ A 2014 Cochrane review failed to identify benefit associated with nutritional interventions for either the prevention and/or treatment of pressure ulcers.¹¹ Specific recommendations on protein intake for other types of chronic wounds have not been proposed. Protein supplementation generally is provided orally, if tolerated. Liquid supplements such as Boost (Nestlé), Carnation Breakfast Essentials (Nestlé), NuBasics (SupremeMed), Resource (Nestlé Health Science), and Ensure (Abbott Laboratories) are frequently used to supplement both protein and caloric intake. Protein oversupplementation has not been associated with improved outcomes and may cause or exacerbate other medical comorbidities.

Fatty Acids for Wound Healing

Wound healing is an anabolic process that requires adequate intake of substrates such as glucose and fat. Carbohydrates serve as the major energy source required for wound healing, while fats are thought to play roles in cell membrane development and modulation of cellular signaling.¹ Fats utilize a unique pathway for energy production through beta-oxidation and the production of adenosine triphosphate, allowing available protein to be harnessed for wound healing.¹ Omega-3 and omega-6 fatty acids serve as precursors to prostaglandins, leukotrienes, and thromboxane—all key mediators of the inflammatory phase of wound healing.³ Omega-3 fatty acids are thought to downregulate genes involved in proinflammatory pathways,¹² as well as to diminish lymphocyte proliferation and levels of IL-1β, tumor necrosis factor α, and IL-6 in vitro.¹³ In vivo studies assessing the impact of omega-3 fatty acid supplementation on wound healing are minimal, and the role of dietary supplementation for this indication remains unknown. Fish oil contains the omega-3 fatty acid–rich eicosapentaenoic acid and docosahexaenoic acid, which has been compared to mineral oil supplementation for wound healing in healthy adults. When fish oil was supplemented for 4 weeks, no significant differences were identified in time to complete wound healing between groups. Interestingly, significantly higher levels of the proinflammatory cytokine IL-1β were identified in blister fluid at 24 hours after blistering vs the placebo group (t=2.52, df=25, P<.05).¹⁴ Prior studies evaluating wound healing in animal models similarly identified longer times to re-epithelialization after omega-3 polyunsaturated fatty acid supplementation orally and topically.^15,16 The fatty acid quality and composition consumed also may impact wound healing, as high-fat diets that are not rich in omega-3 fatty acids have been shown to promote inflammation and impair wound healing in rats, but this has not been thoroughly explored in human trials.¹⁷ Although adequate intake of these macronutrients is important, excessive intake may be harmful. Larger prospective trials are needed to shed light on the dose and composition of fatty acid supplementation that may optimize wound healing.

Vitamins and Micronutrients Required for Wound Healing

Vitamin A—Many vitamins serve as cofactors for the enzymatic processes required in wound healing. Vitamin A is an essential fat-soluble vitamin that serves a variety of dermatologic functions and promotes wound healing through stimulation of fibroblasts and ground substance, and it facilitates epithelial cell differentiation when applied topically.^3,18 Vitamin A works through the activation of retinoid receptors on endothelial cells, fibroblasts, keratinocytes, melanocytes, and sebocytes, and has purported anti-inflammatory effects that aid the healing of open wounds.³ Additionally, vitamin A is thought to enhance cytokine release in the inflammatory phase of wound healing.¹⁹ Supplemental vitamin A has been associated with positive effects on acute wound healing, burns, and radiation injuries.³ The utility of vitamin A supplementation in chronic wounds remains unknown; however, it has been shown to be beneficial in patients with inflammatory disease, such as rheumatoid arthritis, on corticosteroid therapy. Vitamin A supplementation in this population has been shown to counteract the negative effects of corticosteroids on wound healing via downregulation of transforming growth factor β and insulinlike growth factor 1.²⁰ Vitamin A deficiency has been associated with impaired progression through inflammatory and remodeling phases of healing due to altered B-cell and T-cell function and antibody production.¹ Some experts recommend short courses of oral vitamin A supplementation to enhance wound healing at doses between 10,000 and 25,000 IU daily.^2,3 Large, population-based studies are needed, and the safety supporting this recommendation in all patients remains unknown.

Vitamin C—Vitamin C is widely known for its role in collagen formation, immunomodulation, and antioxidant capacity.¹ Although vitamin C deficiency is associated with decreased collagen synthesis and impaired wound healing,²¹ the utility of long-term supplementation in patients who are not deficient remains unexplored. A systematic review evaluating interventional studies utilizing vitamin C supplementation on pressure ulcerations and surgical wound healing concluded that convincing evidence exists only for supplementation with at least 500 mg of vitamin C. The authors noted, “There is little evidence for improved healing of surgical wounds by high-dose single vitamin C supplementation (1–3 g/day).”²² In a prospective, randomized, controlled trial, 20 patients with pressure ulcerations were supplemented with vitamin C vs placebo with a mean reduction in pressure-sore area of 84% after 1 month in the vitamin C–supplemented group compared to 42.7% in the placebo group (P<.005). A limitation of this study is the small population.²³ One current recommendation for vitamin C supplementation in chronic wounds is for 500 mg daily in uncomplicated wounds to 2 g daily in severe wounds.³ Additional studies have suggested that the benefits of vitamin C supplementation are maximized when given in combination with zinc and arginine.²² At this time, evaluation for vitamin C deficiency and appropriate supplementation in patients with chronic wounds is needed.

Zinc—Minerals similarly play important roles in enzymatic regulation. Hundreds of zinc-containing enzymes are involved in wound healing and are required in tissue repair, growth, antioxidant capacity, and immune function.^1,24 Zinc is specifically critical to collagen, DNA, RNA, and protein synthesis, as well as cellular proliferation.⁴ Zinc deficiency has been encountered in the setting of chronic wounds with extensive drainage, decreased dietary intake, or excessive gastrointestinal losses.²⁵ Although many studies exist evaluating the utility of zinc supplementation on wound healing, many are confounded by multinutrient supplementation. No studies to date support zinc supplementation when zinc deficiency is absent. Patient assessment for medications or conditions that may impact zinc metabolism should be completed. Importantly, zinc supplementation can interfere with the absorption of other cations, so excessive supplementation should be avoided.¹

Amino Acids for Wound Healing

Arginine—Arginine is an essential amino acid that serves as a substrate for cellular proliferation, collagen deposition, and lymphocyte function.^8,26,27 Arginine serves as the biologic precursor for nitric oxide (NO), a substrate that has important wound healing properties. Nitric oxide metabolites have been shown to positively regulate wound repair while NO metabolites are reduced in wound environments in diabetic ulcerations.^28,29 Arginine also is a proline precursor, an essential building block for collagen synthesis,^6,30 and a stimulator of growth hormone and T cells.^30,31 Animal studies have suggested L-arginine supplementation may reverse impaired NO synthesis in diabetic wounds.²⁸ A single randomized trial assessing differing doses of arginine supplementation on stage II or stage IV pressure ulcers noted an almost two-fold improvement in healing time.³² However, human studies have not shown increased rates of re-epithelialization of skin graft donor sites when provided oral or parenteral arginine supplementation.³³ Inadequate data currently exist to support regular arginine supplementation for all types of wounds, and no safe dose of daily arginine intake has been established.

Glutamine—Similarly, glutamine supplementation has been proposed to accelerate wound healing due to its role as a primary metabolic fuel source for rapidly proliferating cells such as epithelial cells and fibroblasts.⁸ Glutamine is thought to induce expression of heat-shock proteins and protect against inflammatory and infectious wound complications.³⁴ Additionally, glutamine is thought to increase tissue insulin sensitivity, which may prove beneficial in wounds, as topical insulin previously has been shown in animal and human models to promote healing.³⁵ Glutamine is thought to play a role in the inflammatory phase of wound healing via superoxide production, leukocyte apoptosis, and phagocytosis.^6,34,36 Unfortunately, numerous randomized trials on glutamine supplementation have resulted in conflicting evidence confounded by multisupplementation within the same trial.^37,38 A double-blind, randomized, controlled trial of 270 participants assessed the effect of oral supplementation with arginine, glutamine, or β-hydroxy-β-methylbutyrate vs control in the healing time of diabetic foot ulcerations. Significant differences in wound closure time at week 16 were only identified in participants with low albumin levels (≤40 g/L) who were supplemented (50.8%) vs the control group (34.9%; P=.0325) and in those with poor limb perfusion (ankle-brachial index of <1.0) who were supplemented (60.3%) vs the control group (39.3%; P=.0079).³⁹ Ongoing clinical trials evaluating the effects of glutamine supplementation on differing wound types will hopefully shed light on the efficacy of supplementation.

Final Thoughts

Wound healing is multifactorial and should consider the health status and medical comorbidities of each patient treated. We propose an individualized approach to wound healing that includes exploration of specific macronutrient and micronutrient deficiencies, as malnutrition has been associated with wound chronicity and serves as a modifiable risk factor to improve healing.² The evidence backing specific nutrient supplementation in patients with deficiencies is strong and should be considered in patients with chronic wounds. Adequate caloric intake and protein content should be recommended for most wound patients; however, excessive protein intake has not been beneficial in wound healing. The data behind specific amino acid and vitamin supplementation are limited at this time. As with other therapeutics, there is likely an appropriate dose for supplementation that has not yet been elucidated. Consideration of wound type, size, depth, exudate, and underlying cause are important to optimize healing and tailor nutritional supplementation to each patient. We hope future studies will illuminate the complementary role of dietary intake and nutrient supplementation for the treatment of chronic nonhealing wounds.

Complementary alternative medicine (CAM) has been described by the National Center for Complementary and Integrative Medicine as “health care approaches that are not typically part of conventional medical care or that may have origins outside of usual Western practice.”¹ Although this definition is broad, CAM encompasses therapies such as traditional Chinese medicine, herbal therapies, dietary supplements, and mind/body interventions. The use of CAM has grown, and according to a 2012 National Center for Complementary and Integrative Health survey, more than 30% of US adults and 12% of US children use health care approaches that are considered outside of conventional medical practice. In a survey study of US adults, at least 17.7% of respondents said they had taken a dietary supplement other than a vitamin or mineral in the last year.¹ Data from the 2007 National Health Interview Survey showed that the prevalence of adults with skin conditions using CAM was 84.5% compared to 38.3% in the general population.² In addition, 8.15 million US patients with dermatologic conditions reported using CAM over a 5-year period.³ Complementary alternative medicine has emerged as an alternative or adjunct to standard treatments, making it important for dermatologists to understand the existing literature on these therapies. Herein, we review the current evidence-based literature that exists on CAM for the treatment of atopic dermatitis (AD), psoriasis, and alopecia areata (AA).

Atopic Dermatitis

Atopic dermatitis is a chronic, pruritic, inflammatory skin condition with considerable morbidity.^4,5 The pathophysiology of AD is multifactorial and includes aspects of barrier dysfunction, IgE hypersensitivity, abnormal cell-mediated immune response, and environmental factors.⁶ Atopic dermatitis also is one of the most common inflammatory skin conditions in adults, affecting more than 7% of the US population and up to 20% of the total population in developed countries. Of those affected, 40% have moderate or severe symptoms that result in a substantial impact on quality of life.⁷ Despite advances in understanding disease pathology and treatment, a subset of patients opt to defer conventional treatments such as topical and systemic corticosteroids, antibiotics, nonsteroidal immunomodulators, and biologics. Patients may seek alternative therapies when typical treatments fail or when the perceived side effects outweigh the benefits.^5,8 The use of CAM has been well described in patients with AD; however, the existing evidence supporting its use along with its safety profile have not been thoroughly explored. Herein, we will discuss some of the most well-studied supplements for treatment of AD, including evening primrose oil (EPO), fish oil, and probiotics.⁵

Oral supplementation with polyunsaturated fatty acids commonly is reported in patients with AD.^5,8 The idea that a fatty acid deficiency could lead to atopic skin conditions has been around since 1937, when it was suggested that patients with AD had lower levels of blood unsaturated fatty acids.⁹ Conflicting evidence regarding oral fatty acid ingestion and AD disease severity has emerged.^10,11 One unsaturated fatty acid, γ-linolenic acid (GLA), has demonstrated anti-inflammatory properties and involvement in barrier repair.¹² It is converted to dihomo-GLA in the body, which acts on cyclooxygenase enzymes to produce the inflammatory mediator prostaglandin E₁. The production of GLA is mediated by the enzyme delta-6 desaturase in the metabolization of linoleic acid.¹² However, it has been reported that in a subset of patients with AD, a malfunction of delta-6 desaturase may play a role in disease progression and result in lower baseline levels of GLA.^10,12 Evening primrose oil and borage oil contain high amounts of GLA (8%–10% and 23%, respectively); thus, supplementation with these oils has been studied in AD.¹³

EPO for AD
Studies investigating EPO (Oenothera biennis) and its association with AD severity have shown mixed results. A Cochrane review reported that oral borage oil and EPO were not effective treatments for AD,¹⁴ while another larger randomized controlled trial (RCT) found no statistically significant improvement in AD symptoms.¹⁵ However, multiple smaller studies have found that clinical symptoms of AD, such as erythema, xerosis, pruritus, and total body surface area involved, did improve with oral EPO supplementation when compared to placebo, and the results were statistically significant (P=.04).^16,17 One study looked at different dosages of EPO and found that groups ingesting both 160 mg and 320 mg daily experienced reductions in eczema area and severity index score, with greater improvement noted with the higher dosage.¹⁷ Side effects associated with oral EPO include an anticoagulant effect and transient gastrointestinal tract upset.^8,14 There currently is not enough evidence or safety data to recommend this supplement to AD patients.

Although topical use of fatty acids with high concentrations of GLA, such as EPO and borage oil, have demonstrated improvement in subjective symptom severity, most studies have not reached statistical significance.^10,11 One study used a 10% EPO cream for 2 weeks compared to placebo and found statistically significant improvement in patient-reported AD symptoms (P=.045). However, this study only included 10 participants, and therefore larger studies are necessary to confirm this result.¹⁸ Some RCTs have shown that topical coconut oil, sunflower seed oil, and sandalwood album oil improve AD symptom severity, but again, large controlled trials are needed.⁵ Unfortunately, many essential oils, including EPO, can cause a secondary allergic contact dermatitis and potentially worsen AD.¹⁹

Fish Oil for AD
Fish oil is a commonly used supplement for AD due to its high content of the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Omega-3 fatty acids exert anti-inflammatory effects by displacing arachidonic acid, a proinflammatory omega-6 fatty acid thought to increase IgE, as well as helper T cell (T_H2) cytokines and prostaglandin E₂.^8,20 A 2012 Cochrane review found that, while some studies revealed mild improvement in AD symptoms with oral fish oil supplementation, these RCTs were of poor methodological quality.²¹ Multiple smaller studies have shown a decrease in pruritus, severity, and physician-rated clinical scores with fish oil use.^5,8,20,22 One study with 145 participants reported that 6 g of fish oil once daily compared to isoenergetic corn oil for 16 weeks identified no statistically significant differences between the treatment groups.²⁰ No adverse events were identified in any of the reported trials. Further studies should be conducted to assess the utility and dosing of fish oil supplements in AD patients.

Probiotics for AD
Probiotics consist of live microorganisms that enhance the microflora of the gastrointestinal tract.^8,20 They have been shown to influence food digestion and also have demonstrated potential influence on the skin-gut axis.²³ The theory that intestinal dysbiosis plays a role in AD pathogenesis has been investigated in multiple studies.^23-25 The central premise is that low-fiber and high-fat Western diets lead to fundamental changes in the gut microbiome, resulting in fewer anti-inflammatory metabolites, such as short-chain fatty acids (SCFAs).^23-25 These SCFAs are produced by microbes during the fermentation of dietary fiber and are known for their effect on epithelial barrier integrity and anti-inflammatory properties mediated through G protein–coupled receptor 43.²⁵ Multiple studies have shown that the gut microbiome in patients with AD have higher proportions of Clostridium difficile, Escherichia coli, and Staphylococcus aureus and lower levels of Bifidobacterium, Bacteroidetes, and Bacteroides species compared to healthy controls.^26,27 Metagenomic analysis of fecal samples from patients with AD have shown a reduction of Faecalibacterium prausnitzii species when compared to controls, along with a decreased SCFA production, leading to the hypothesis that the gut microbiome may play a role in epithelial barrier disruption.^28,29 Systematic reviews and smaller studies have found that oral probiotic use does lead to AD symptom improvement.^8,30,31 A systematic review of 25 RCTs with 1599 participants found that supplementation with oral probiotics significantly decreased the SCORAD (SCORing Atopic Dermatitis) index in adults and children older than 1 year with AD but had no effect on infants younger than 1 year (P<.001). They also found that supplementation with diverse microbes or Lactobacillus species showed greater benefit than Bifidobacterium species alone.³⁰ Another study analyzed the effect of oral Lactobacillus fermentum (1×10⁹ CFU twice daily) in 53 children with AD vs placebo for 16 weeks. This study found a statically significant decrease in SCORAD index between oral probiotics and placebo, with 92% (n=24) of participants supplementing with probiotics having a lower SCORAD index than baseline compared to 63% (n=17) in the placebo group (P=.01).³¹ However, the use of probiotics for AD treatment has remained controversial. Two recent systematic reviews, including 39 RCTs of 2599 randomized patients, found that the use of currently available oral probiotics made little or no difference in patient-rated AD symptoms, investigator-rated AD symptoms, or quality of life.^32,33 No adverse effects were observed in the included studies. Unfortunately, the individual RCTs included were heterogeneous, and future studies with standardized probiotic supplementation should be undertaken before probiotics can be routinely recommended.

The use of topical probiotics in AD also has recently emerged. Multiple studies have shown that patients with AD have higher levels of colonization with S aureus, which is associated with T-cell dysfunction, more severe allergic skin reactions, and disruptions in barrier function.^34,35 Therefore, altering the skin microbiota through topical probiotics could theoretically reduce AD symptoms and flares. Multiple RCTs and smaller studies have shown that topical probiotics can alter the skin microbiota, improve erythema, and decrease scaling and pruritus in AD patients.^35-38 One study used a heat-treated Lactobacillus johnsonii 0.3% lotion twice daily for 3 weeks vs placebo in patients with AD with positive S aureus skin cultures. The S aureus load decreased in patients using the topical probiotic lotion, which correlated with lower SCORAD index that was statistically significant compared to placebo (P=.012).³⁶ More robust studies are needed to determine if topical probiotics should routinely be recommended in AD.

Psoriasis

Psoriasis vulgaris is a chronic inflammatory skin condition characterized by pruritic, hyperkeratotic, scaly plaques.^39,40 Keratinocyte hyperproliferation is central to psoriasis pathogenesis and is thought to be a T-cell–driven reaction to antigens or trauma in genetically predisposed individuals. Standard treatments for psoriasis currently include topical corticosteroids and anti-inflammatories, oral immunomodulatory therapy, biologic agents, and phototherapy.⁴⁰ The use of CAM is highly prevalent among patients with psoriasis, with one study reporting that 51% (n=162) of psoriatic patients interviewed had used CAM.⁴¹ The most common reasons for CAM use included dissatisfaction with current treatment, adverse side effects of standard therapy, and patient-reported attempts at “trying everything to heal disease.”⁴² Herein, we will discuss some of the most frequently used supplements for treatment of psoriatic disease.³⁹

Fish Oil for Psoriasis
One of the most common supplements used by patients with psoriasis is fish oil due to its purported anti-inflammatory qualities.^20,39 The consensus on fish oil supplementation for psoriasis is mixed.^43-45 Multiple RCTs have reported reductions in psoriasis area and severity index (PASI) scores or symptomatic improvement with variable doses of fish oil.^44,46 One RCT found that using EPA 1.8 g once daily and DHA 1.2 g once daily for 12 weeks resulted in significant improvement in pruritus, scaling, and erythema (P<.05).⁴⁴ Another study reported a significant decrease in erythema (P=.02) and total body surface area affected (P=.0001) with EPA 3.6 g once daily and DHA 2.4 g once daily supplementation compared to olive oil supplementation for 15 weeks.⁴⁶ Alternatively, multiple studies have failed to show statistically significant improvement in psoriatic symptoms with fish oil supplementation at variable doses and time frames (14–216 mg daily EPA, 9–80 mg daily DHA, from 2 weeks to 9 months).^40,47,48 Fish oil may impart anticoagulant properties and should not be started without the guidance of a physician. Currently, there are no data to make specific recommendations on the use of fish oil as an adjunct psoriatic treatment.

Curcumin for Psoriasis
Another supplement routinely utilized in patients with psoriasis is curcumin,^40,49,50 a yellow phytochemical that is a major component of the spice turmeric. Curcumin has been shown to inhibit certain proinflammatory cytokines including IL-17, IL-6, IFN-γ, and tumor necrosis factor α and has been regarded as having immune-modulating, anti-inflammatory, and antibacterial properties.^40,50 Curcumin also has been reported to suppress phosphorylase kinase, an enzyme that has increased activity in psoriatic plaques that correlates with markers of psoriatic hyperproliferation.^50,51 When applied topically, turmeric microgel 0.5% has been reported to decrease scaling, erythema, and psoriatic plaque thickness over the course of 9 weeks.⁵⁰ In a nonrandomized trial with 10 participants, researchers found that phosphorylase kinase activity levels in psoriatic skin biopsies of patients applying topical curcumin 1% were lower than placebo and topical calcipotriol applied in combination. The lower phosphorylase kinase levels correlated with level of disease severity, and topical curcumin 1% showed a superior outcome when compared to topical calcipotriol.^40,49 Although these preliminary results are interesting, there still are not enough data at this time to recommend topical curcumin as a treatment of psoriasis. No known adverse events have been reported with the use of topical curcumin to date.

Oral curcumin has poor oral bioavailability, and 40% to 90% of oral doses are excreted, making supplementation a challenge.⁴⁰ In one RCT, oral curcumin 2 g daily (using a lecithin-based delivery system to increase bioavailability) was administered in combination with topical methylprednisolone aceponate 0.1%, resulting in significant improvement in psoriatic symptoms and lower IL-22 compared to placebo and topical methylprednisolone aceponate (P<.05).⁵² Other studies also have reported decreased PASI scores with oral curcumin supplementation.^53,54 Adverse effects reported with oral curcumin included gastrointestinal tract upset and hot flashes.⁵³ Although there is early evidence that may support the use of oral curcumin supplementation for psoriasis, more data are needed before recommending this therapy.

Indigo Naturalis for Psoriasis
Topical indigo naturalis (IN) also has been reported to improve psoriasis symptoms.^39,53,55 The antipsoriatic effects are thought to occur through the active ingredient in IN (indirubin), which is responsible for inhibition of keratinocyte proliferation.⁴⁰ One study reported that topical IN 1.4% containing indirubin 0.16% with a petroleum ointment vehicle applied to psoriatic plaques over 12 weeks resulted in a significant decrease in PASI scores from 18.9 at baseline to 6.3 after IN treatment (P<.001).⁵⁶ Another study found that over 8 weeks, topical application of IN 2.83% containing indirubin 0.24% to psoriatic plaques vs petroleum jelly resulted in 56.3% (n=9) of the treatment group achieving PASI 75 compared to 0% in the placebo group (n=24).⁵⁵ One deterrent in topical IN treatment is the dark blue pigment it contains; however, no other adverse outcomes were found with topical IN treatment.⁵⁶ Larger clinical trials are necessary to further explore IN as a potential adjunct treatment in patients with mild psoriatic disease. When taken orally, IN has caused gastrointestinal tract disturbance and elevated liver enzyme levels.⁵⁷

Herbal Toxicities
It is important to consider that oral supplements including curcumin and IN are widely available over-the-counter and online without oversight by the US Food and Drug Administration.⁴⁰ Herbal supplements typically are compounded with other ingredients and have been associated with hepatotoxicity as well as drug-supplement interactions, including abnormal bleeding and clotting.⁵⁸ There exists a lack of general surveillance data, making the true burden of herbal toxicities more difficult to accurately discern. Although some supplements have been associated with anti-inflammatory qualities and disease improvement, other herbal supplements have been shown to possess immunostimulatory characteristics. Herbal supplements such as spirulina, chlorella, Aphanizomenon flos-aquae, and echinacea have been shown to upregulate inflammatory pathways in a variety of autoimmune skin conditions.⁵⁹

Probiotics for Psoriasis
Data on probiotic use in patients with psoriasis are limited.²³ A distinct pattern of dysbiosis has been identified in psoriatic patients, as there is thought to be depletion of beneficial bacteria such as Bifidobacterium, lactobacilli, and F prausnitzii and increased colonization with pathogenic organisms such as Salmonella, E coli, Heliobacter, Campylobacter, and Alcaligenes in psoriasis patients.^23,59,60 Early mouse studies have supported this hypothesis, as mice fed with Lactobacillus pentosus have developed milder forms of imiquimod-induced psoriasis compared to placebo,⁵⁵ and mice receiving probiotic supplementation have lower levels of psoriasis-related proinflammatory markers such as T_H17-associated cytokines.⁶¹ Another study in humans found that daily oral Bifidobacterium infantis supplementation for 8 weeks in psoriatic patients resulted in lower C-reactive protein and tumor necrosis factor α levels compared to placebo.⁶² Studies on the use of topical probiotics in psoriasis have been limited, and more research is needed to explore this relationship.³⁸ At this time, no specific recommendations can be made on the use of probiotics in psoriatic patients.

Alopecia Areata

Alopecia areata is nonscarring hair loss that can affect the scalp, face, or body.^63,64 The pathophysiology of AA involves the attack of the hair follicle matrix epithelium by inflammatory cells without hair follicle stem cell destruction. The precise events that precipitate these episodes are unknown, but triggers such as emotional or physical stress, vaccines, or viral infections have been reported.⁶⁵ There is no cure for AA, and current treatments such as topical minoxidil and corticosteroids (topical, intralesional, or oral) vary widely in efficacy.⁶⁴ Although Janus kinase inhibitors recently have shown promising results in the treatment of AA, the need for prolonged therapy may be frustrating to patients.⁶⁶ Severity of AA also can vary, with 30% of patients experiencing extensive hair loss.⁶⁷ The use of CAM has been widely reported in AA due to high levels of dissatisfaction with existing therapies.⁶⁸ Herein, we discuss the most studied alternative treatments used in AA

Garlic and Onion for Alopecia
One alternative treatment that has shown promising initial results is application of topical garlic and onion extracts to affected areas.^64,69,70 Both garlic and onion belong to the Allium genus and are high in sulfur and phenolic compounds.⁷⁰ They have been reported to possess bactericidal and vasodilatory activity,⁷¹ and it has been hypothesized that onion and garlic extracts may induce therapeutic effects through induction of a mild contact dermatitis.⁷⁰ One single-blinded, controlled trial using topical crude onion juice reported that 86.9% (n=20) of patients had full regrowth of hair compared to 13.3% (n=2) of patients treated with a tap water placebo at 8 weeks (P<.0001). This study also noted that patients using onion juice had a higher rate of erythema at application site; unfortunately, the study was small with only 38 patients.⁷⁰ Another double-blind RCT using garlic gel 5% with betamethasone valerate cream 0.1% compared to betamethasone valerate cream alone found that after 3 months, patients in the garlic gel group had increased terminal hairs and smaller patch sizes compared to the betamethasone valerate cream group.⁶⁹ More studies are needed to confirm these results.

Aromatherapy With Essential Oils for Alopecia
Another alternative treatment in AA that has demonstrated positive results is aromatherapy skin massage with essential oils to patches of alopecia.⁷² Although certain essential oils, such as tea tree oil, have been reported to have specific antibacterial or anti-inflammatory properties, essential oils have been reported to cause allergic contact dermatitis and should be used with caution.^73,74 For example, tea tree oil is a well-known cause of allergic contact dermatitis, and positive patch testing has ranged from 0.1% to 3.5% in studies assessing topical tea tree oil 5% application.⁷⁵ Overall, there have been nearly 80 essential oils implicated in contact dermatitis, with high-concentration products being one of the highest risk factors for an allergic contact reaction.⁷⁶ One RCT compared daily scalp massage with essential oils (rosemary, lavender, thyme, and cedarwood in a carrier oil) to daily scalp massage with a placebo carrier oil in AA patients. The results showed that at 7 months of treatment, 44% (n=19) of the aromatherapy group showed improvement compared to 15% (n=6) in the control group.⁷⁷ Another study used a similar group of essential oils (thyme, rosemary, atlas cedar, lavender, and EPO in a carrier oil) with daily scalp massage and reported similar improvement of AA symptoms compared to control; the investigators also reported irritation at application site in 1 patient.⁷⁸ There currently are not enough data to recommend aromatherapy skin massage for the treatment of AA, and this practice may cause harm to the patient by induction of allergic contact dermatitis.

There have been a few studies to suggest that the use of total glucosides of peony with compound glycyrrhizin and oral Korean red ginseng may have beneficial effects on AA treatment, but efficacy and safety data are lacking, and these therapies should not be recommended without more information.^64,79,80

Final Thoughts

Dermatologic patients frequently are opting for CAM,² and although some therapies may show promising initial results, alternative medicines also can drive adverse events.^19,30 The lack of oversight from the US Food and Drug Administration on the products leads to many unknowns for true health risks with over-the-counter CAM supplements.⁴⁰ As the use of CAM becomes increasingly common among dermatologic patients, it is important for dermatologists to understand the benefits and risks, especially for commonly treated conditions. More data is needed before CAM can be routinely recommended.

Complementary alternative medicine (CAM) has been described by the National Center for Complementary and Integrative Medicine as “health care approaches that are not typically part of conventional medical care or that may have origins outside of usual Western practice.”¹ Although this definition is broad, CAM encompasses therapies such as traditional Chinese medicine, herbal therapies, dietary supplements, and mind/body interventions. The use of CAM has grown, and according to a 2012 National Center for Complementary and Integrative Health survey, more than 30% of US adults and 12% of US children use health care approaches that are considered outside of conventional medical practice. In a survey study of US adults, at least 17.7% of respondents said they had taken a dietary supplement other than a vitamin or mineral in the last year.¹ Data from the 2007 National Health Interview Survey showed that the prevalence of adults with skin conditions using CAM was 84.5% compared to 38.3% in the general population.² In addition, 8.15 million US patients with dermatologic conditions reported using CAM over a 5-year period.³ Complementary alternative medicine has emerged as an alternative or adjunct to standard treatments, making it important for dermatologists to understand the existing literature on these therapies. Herein, we review the current evidence-based literature that exists on CAM for the treatment of atopic dermatitis (AD), psoriasis, and alopecia areata (AA).

Atopic Dermatitis

Atopic dermatitis is a chronic, pruritic, inflammatory skin condition with considerable morbidity.^4,5 The pathophysiology of AD is multifactorial and includes aspects of barrier dysfunction, IgE hypersensitivity, abnormal cell-mediated immune response, and environmental factors.⁶ Atopic dermatitis also is one of the most common inflammatory skin conditions in adults, affecting more than 7% of the US population and up to 20% of the total population in developed countries. Of those affected, 40% have moderate or severe symptoms that result in a substantial impact on quality of life.⁷ Despite advances in understanding disease pathology and treatment, a subset of patients opt to defer conventional treatments such as topical and systemic corticosteroids, antibiotics, nonsteroidal immunomodulators, and biologics. Patients may seek alternative therapies when typical treatments fail or when the perceived side effects outweigh the benefits.^5,8 The use of CAM has been well described in patients with AD; however, the existing evidence supporting its use along with its safety profile have not been thoroughly explored. Herein, we will discuss some of the most well-studied supplements for treatment of AD, including evening primrose oil (EPO), fish oil, and probiotics.⁵

Oral supplementation with polyunsaturated fatty acids commonly is reported in patients with AD.^5,8 The idea that a fatty acid deficiency could lead to atopic skin conditions has been around since 1937, when it was suggested that patients with AD had lower levels of blood unsaturated fatty acids.⁹ Conflicting evidence regarding oral fatty acid ingestion and AD disease severity has emerged.^10,11 One unsaturated fatty acid, γ-linolenic acid (GLA), has demonstrated anti-inflammatory properties and involvement in barrier repair.¹² It is converted to dihomo-GLA in the body, which acts on cyclooxygenase enzymes to produce the inflammatory mediator prostaglandin E₁. The production of GLA is mediated by the enzyme delta-6 desaturase in the metabolization of linoleic acid.¹² However, it has been reported that in a subset of patients with AD, a malfunction of delta-6 desaturase may play a role in disease progression and result in lower baseline levels of GLA.^10,12 Evening primrose oil and borage oil contain high amounts of GLA (8%–10% and 23%, respectively); thus, supplementation with these oils has been studied in AD.¹³

EPO for AD
Studies investigating EPO (Oenothera biennis) and its association with AD severity have shown mixed results. A Cochrane review reported that oral borage oil and EPO were not effective treatments for AD,¹⁴ while another larger randomized controlled trial (RCT) found no statistically significant improvement in AD symptoms.¹⁵ However, multiple smaller studies have found that clinical symptoms of AD, such as erythema, xerosis, pruritus, and total body surface area involved, did improve with oral EPO supplementation when compared to placebo, and the results were statistically significant (P=.04).^16,17 One study looked at different dosages of EPO and found that groups ingesting both 160 mg and 320 mg daily experienced reductions in eczema area and severity index score, with greater improvement noted with the higher dosage.¹⁷ Side effects associated with oral EPO include an anticoagulant effect and transient gastrointestinal tract upset.^8,14 There currently is not enough evidence or safety data to recommend this supplement to AD patients.

Although topical use of fatty acids with high concentrations of GLA, such as EPO and borage oil, have demonstrated improvement in subjective symptom severity, most studies have not reached statistical significance.^10,11 One study used a 10% EPO cream for 2 weeks compared to placebo and found statistically significant improvement in patient-reported AD symptoms (P=.045). However, this study only included 10 participants, and therefore larger studies are necessary to confirm this result.¹⁸ Some RCTs have shown that topical coconut oil, sunflower seed oil, and sandalwood album oil improve AD symptom severity, but again, large controlled trials are needed.⁵ Unfortunately, many essential oils, including EPO, can cause a secondary allergic contact dermatitis and potentially worsen AD.¹⁹

Fish Oil for AD
Fish oil is a commonly used supplement for AD due to its high content of the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Omega-3 fatty acids exert anti-inflammatory effects by displacing arachidonic acid, a proinflammatory omega-6 fatty acid thought to increase IgE, as well as helper T cell (T_H2) cytokines and prostaglandin E₂.^8,20 A 2012 Cochrane review found that, while some studies revealed mild improvement in AD symptoms with oral fish oil supplementation, these RCTs were of poor methodological quality.²¹ Multiple smaller studies have shown a decrease in pruritus, severity, and physician-rated clinical scores with fish oil use.^5,8,20,22 One study with 145 participants reported that 6 g of fish oil once daily compared to isoenergetic corn oil for 16 weeks identified no statistically significant differences between the treatment groups.²⁰ No adverse events were identified in any of the reported trials. Further studies should be conducted to assess the utility and dosing of fish oil supplements in AD patients.

Probiotics for AD
Probiotics consist of live microorganisms that enhance the microflora of the gastrointestinal tract.^8,20 They have been shown to influence food digestion and also have demonstrated potential influence on the skin-gut axis.²³ The theory that intestinal dysbiosis plays a role in AD pathogenesis has been investigated in multiple studies.^23-25 The central premise is that low-fiber and high-fat Western diets lead to fundamental changes in the gut microbiome, resulting in fewer anti-inflammatory metabolites, such as short-chain fatty acids (SCFAs).^23-25 These SCFAs are produced by microbes during the fermentation of dietary fiber and are known for their effect on epithelial barrier integrity and anti-inflammatory properties mediated through G protein–coupled receptor 43.²⁵ Multiple studies have shown that the gut microbiome in patients with AD have higher proportions of Clostridium difficile, Escherichia coli, and Staphylococcus aureus and lower levels of Bifidobacterium, Bacteroidetes, and Bacteroides species compared to healthy controls.^26,27 Metagenomic analysis of fecal samples from patients with AD have shown a reduction of Faecalibacterium prausnitzii species when compared to controls, along with a decreased SCFA production, leading to the hypothesis that the gut microbiome may play a role in epithelial barrier disruption.^28,29 Systematic reviews and smaller studies have found that oral probiotic use does lead to AD symptom improvement.^8,30,31 A systematic review of 25 RCTs with 1599 participants found that supplementation with oral probiotics significantly decreased the SCORAD (SCORing Atopic Dermatitis) index in adults and children older than 1 year with AD but had no effect on infants younger than 1 year (P<.001). They also found that supplementation with diverse microbes or Lactobacillus species showed greater benefit than Bifidobacterium species alone.³⁰ Another study analyzed the effect of oral Lactobacillus fermentum (1×10⁹ CFU twice daily) in 53 children with AD vs placebo for 16 weeks. This study found a statically significant decrease in SCORAD index between oral probiotics and placebo, with 92% (n=24) of participants supplementing with probiotics having a lower SCORAD index than baseline compared to 63% (n=17) in the placebo group (P=.01).³¹ However, the use of probiotics for AD treatment has remained controversial. Two recent systematic reviews, including 39 RCTs of 2599 randomized patients, found that the use of currently available oral probiotics made little or no difference in patient-rated AD symptoms, investigator-rated AD symptoms, or quality of life.^32,33 No adverse effects were observed in the included studies. Unfortunately, the individual RCTs included were heterogeneous, and future studies with standardized probiotic supplementation should be undertaken before probiotics can be routinely recommended.

The use of topical probiotics in AD also has recently emerged. Multiple studies have shown that patients with AD have higher levels of colonization with S aureus, which is associated with T-cell dysfunction, more severe allergic skin reactions, and disruptions in barrier function.^34,35 Therefore, altering the skin microbiota through topical probiotics could theoretically reduce AD symptoms and flares. Multiple RCTs and smaller studies have shown that topical probiotics can alter the skin microbiota, improve erythema, and decrease scaling and pruritus in AD patients.^35-38 One study used a heat-treated Lactobacillus johnsonii 0.3% lotion twice daily for 3 weeks vs placebo in patients with AD with positive S aureus skin cultures. The S aureus load decreased in patients using the topical probiotic lotion, which correlated with lower SCORAD index that was statistically significant compared to placebo (P=.012).³⁶ More robust studies are needed to determine if topical probiotics should routinely be recommended in AD.

Psoriasis

Psoriasis vulgaris is a chronic inflammatory skin condition characterized by pruritic, hyperkeratotic, scaly plaques.^39,40 Keratinocyte hyperproliferation is central to psoriasis pathogenesis and is thought to be a T-cell–driven reaction to antigens or trauma in genetically predisposed individuals. Standard treatments for psoriasis currently include topical corticosteroids and anti-inflammatories, oral immunomodulatory therapy, biologic agents, and phototherapy.⁴⁰ The use of CAM is highly prevalent among patients with psoriasis, with one study reporting that 51% (n=162) of psoriatic patients interviewed had used CAM.⁴¹ The most common reasons for CAM use included dissatisfaction with current treatment, adverse side effects of standard therapy, and patient-reported attempts at “trying everything to heal disease.”⁴² Herein, we will discuss some of the most frequently used supplements for treatment of psoriatic disease.³⁹

Fish Oil for Psoriasis
One of the most common supplements used by patients with psoriasis is fish oil due to its purported anti-inflammatory qualities.^20,39 The consensus on fish oil supplementation for psoriasis is mixed.^43-45 Multiple RCTs have reported reductions in psoriasis area and severity index (PASI) scores or symptomatic improvement with variable doses of fish oil.^44,46 One RCT found that using EPA 1.8 g once daily and DHA 1.2 g once daily for 12 weeks resulted in significant improvement in pruritus, scaling, and erythema (P<.05).⁴⁴ Another study reported a significant decrease in erythema (P=.02) and total body surface area affected (P=.0001) with EPA 3.6 g once daily and DHA 2.4 g once daily supplementation compared to olive oil supplementation for 15 weeks.⁴⁶ Alternatively, multiple studies have failed to show statistically significant improvement in psoriatic symptoms with fish oil supplementation at variable doses and time frames (14–216 mg daily EPA, 9–80 mg daily DHA, from 2 weeks to 9 months).^40,47,48 Fish oil may impart anticoagulant properties and should not be started without the guidance of a physician. Currently, there are no data to make specific recommendations on the use of fish oil as an adjunct psoriatic treatment.

Curcumin for Psoriasis
Another supplement routinely utilized in patients with psoriasis is curcumin,^40,49,50 a yellow phytochemical that is a major component of the spice turmeric. Curcumin has been shown to inhibit certain proinflammatory cytokines including IL-17, IL-6, IFN-γ, and tumor necrosis factor α and has been regarded as having immune-modulating, anti-inflammatory, and antibacterial properties.^40,50 Curcumin also has been reported to suppress phosphorylase kinase, an enzyme that has increased activity in psoriatic plaques that correlates with markers of psoriatic hyperproliferation.^50,51 When applied topically, turmeric microgel 0.5% has been reported to decrease scaling, erythema, and psoriatic plaque thickness over the course of 9 weeks.⁵⁰ In a nonrandomized trial with 10 participants, researchers found that phosphorylase kinase activity levels in psoriatic skin biopsies of patients applying topical curcumin 1% were lower than placebo and topical calcipotriol applied in combination. The lower phosphorylase kinase levels correlated with level of disease severity, and topical curcumin 1% showed a superior outcome when compared to topical calcipotriol.^40,49 Although these preliminary results are interesting, there still are not enough data at this time to recommend topical curcumin as a treatment of psoriasis. No known adverse events have been reported with the use of topical curcumin to date.

Oral curcumin has poor oral bioavailability, and 40% to 90% of oral doses are excreted, making supplementation a challenge.⁴⁰ In one RCT, oral curcumin 2 g daily (using a lecithin-based delivery system to increase bioavailability) was administered in combination with topical methylprednisolone aceponate 0.1%, resulting in significant improvement in psoriatic symptoms and lower IL-22 compared to placebo and topical methylprednisolone aceponate (P<.05).⁵² Other studies also have reported decreased PASI scores with oral curcumin supplementation.^53,54 Adverse effects reported with oral curcumin included gastrointestinal tract upset and hot flashes.⁵³ Although there is early evidence that may support the use of oral curcumin supplementation for psoriasis, more data are needed before recommending this therapy.

Indigo Naturalis for Psoriasis
Topical indigo naturalis (IN) also has been reported to improve psoriasis symptoms.^39,53,55 The antipsoriatic effects are thought to occur through the active ingredient in IN (indirubin), which is responsible for inhibition of keratinocyte proliferation.⁴⁰ One study reported that topical IN 1.4% containing indirubin 0.16% with a petroleum ointment vehicle applied to psoriatic plaques over 12 weeks resulted in a significant decrease in PASI scores from 18.9 at baseline to 6.3 after IN treatment (P<.001).⁵⁶ Another study found that over 8 weeks, topical application of IN 2.83% containing indirubin 0.24% to psoriatic plaques vs petroleum jelly resulted in 56.3% (n=9) of the treatment group achieving PASI 75 compared to 0% in the placebo group (n=24).⁵⁵ One deterrent in topical IN treatment is the dark blue pigment it contains; however, no other adverse outcomes were found with topical IN treatment.⁵⁶ Larger clinical trials are necessary to further explore IN as a potential adjunct treatment in patients with mild psoriatic disease. When taken orally, IN has caused gastrointestinal tract disturbance and elevated liver enzyme levels.⁵⁷

Herbal Toxicities
It is important to consider that oral supplements including curcumin and IN are widely available over-the-counter and online without oversight by the US Food and Drug Administration.⁴⁰ Herbal supplements typically are compounded with other ingredients and have been associated with hepatotoxicity as well as drug-supplement interactions, including abnormal bleeding and clotting.⁵⁸ There exists a lack of general surveillance data, making the true burden of herbal toxicities more difficult to accurately discern. Although some supplements have been associated with anti-inflammatory qualities and disease improvement, other herbal supplements have been shown to possess immunostimulatory characteristics. Herbal supplements such as spirulina, chlorella, Aphanizomenon flos-aquae, and echinacea have been shown to upregulate inflammatory pathways in a variety of autoimmune skin conditions.⁵⁹

Probiotics for Psoriasis
Data on probiotic use in patients with psoriasis are limited.²³ A distinct pattern of dysbiosis has been identified in psoriatic patients, as there is thought to be depletion of beneficial bacteria such as Bifidobacterium, lactobacilli, and F prausnitzii and increased colonization with pathogenic organisms such as Salmonella, E coli, Heliobacter, Campylobacter, and Alcaligenes in psoriasis patients.^23,59,60 Early mouse studies have supported this hypothesis, as mice fed with Lactobacillus pentosus have developed milder forms of imiquimod-induced psoriasis compared to placebo,⁵⁵ and mice receiving probiotic supplementation have lower levels of psoriasis-related proinflammatory markers such as T_H17-associated cytokines.⁶¹ Another study in humans found that daily oral Bifidobacterium infantis supplementation for 8 weeks in psoriatic patients resulted in lower C-reactive protein and tumor necrosis factor α levels compared to placebo.⁶² Studies on the use of topical probiotics in psoriasis have been limited, and more research is needed to explore this relationship.³⁸ At this time, no specific recommendations can be made on the use of probiotics in psoriatic patients.

Alopecia Areata

Alopecia areata is nonscarring hair loss that can affect the scalp, face, or body.^63,64 The pathophysiology of AA involves the attack of the hair follicle matrix epithelium by inflammatory cells without hair follicle stem cell destruction. The precise events that precipitate these episodes are unknown, but triggers such as emotional or physical stress, vaccines, or viral infections have been reported.⁶⁵ There is no cure for AA, and current treatments such as topical minoxidil and corticosteroids (topical, intralesional, or oral) vary widely in efficacy.⁶⁴ Although Janus kinase inhibitors recently have shown promising results in the treatment of AA, the need for prolonged therapy may be frustrating to patients.⁶⁶ Severity of AA also can vary, with 30% of patients experiencing extensive hair loss.⁶⁷ The use of CAM has been widely reported in AA due to high levels of dissatisfaction with existing therapies.⁶⁸ Herein, we discuss the most studied alternative treatments used in AA

Garlic and Onion for Alopecia
One alternative treatment that has shown promising initial results is application of topical garlic and onion extracts to affected areas.^64,69,70 Both garlic and onion belong to the Allium genus and are high in sulfur and phenolic compounds.⁷⁰ They have been reported to possess bactericidal and vasodilatory activity,⁷¹ and it has been hypothesized that onion and garlic extracts may induce therapeutic effects through induction of a mild contact dermatitis.⁷⁰ One single-blinded, controlled trial using topical crude onion juice reported that 86.9% (n=20) of patients had full regrowth of hair compared to 13.3% (n=2) of patients treated with a tap water placebo at 8 weeks (P<.0001). This study also noted that patients using onion juice had a higher rate of erythema at application site; unfortunately, the study was small with only 38 patients.⁷⁰ Another double-blind RCT using garlic gel 5% with betamethasone valerate cream 0.1% compared to betamethasone valerate cream alone found that after 3 months, patients in the garlic gel group had increased terminal hairs and smaller patch sizes compared to the betamethasone valerate cream group.⁶⁹ More studies are needed to confirm these results.

Aromatherapy With Essential Oils for Alopecia
Another alternative treatment in AA that has demonstrated positive results is aromatherapy skin massage with essential oils to patches of alopecia.⁷² Although certain essential oils, such as tea tree oil, have been reported to have specific antibacterial or anti-inflammatory properties, essential oils have been reported to cause allergic contact dermatitis and should be used with caution.^73,74 For example, tea tree oil is a well-known cause of allergic contact dermatitis, and positive patch testing has ranged from 0.1% to 3.5% in studies assessing topical tea tree oil 5% application.⁷⁵ Overall, there have been nearly 80 essential oils implicated in contact dermatitis, with high-concentration products being one of the highest risk factors for an allergic contact reaction.⁷⁶ One RCT compared daily scalp massage with essential oils (rosemary, lavender, thyme, and cedarwood in a carrier oil) to daily scalp massage with a placebo carrier oil in AA patients. The results showed that at 7 months of treatment, 44% (n=19) of the aromatherapy group showed improvement compared to 15% (n=6) in the control group.⁷⁷ Another study used a similar group of essential oils (thyme, rosemary, atlas cedar, lavender, and EPO in a carrier oil) with daily scalp massage and reported similar improvement of AA symptoms compared to control; the investigators also reported irritation at application site in 1 patient.⁷⁸ There currently are not enough data to recommend aromatherapy skin massage for the treatment of AA, and this practice may cause harm to the patient by induction of allergic contact dermatitis.

There have been a few studies to suggest that the use of total glucosides of peony with compound glycyrrhizin and oral Korean red ginseng may have beneficial effects on AA treatment, but efficacy and safety data are lacking, and these therapies should not be recommended without more information.^64,79,80

Final Thoughts

Dermatologic patients frequently are opting for CAM,² and although some therapies may show promising initial results, alternative medicines also can drive adverse events.^19,30 The lack of oversight from the US Food and Drug Administration on the products leads to many unknowns for true health risks with over-the-counter CAM supplements.⁴⁰ As the use of CAM becomes increasingly common among dermatologic patients, it is important for dermatologists to understand the benefits and risks, especially for commonly treated conditions. More data is needed before CAM can be routinely recommended.

Complementary alternative medicine (CAM) has been described by the National Center for Complementary and Integrative Medicine as “health care approaches that are not typically part of conventional medical care or that may have origins outside of usual Western practice.”¹ Although this definition is broad, CAM encompasses therapies such as traditional Chinese medicine, herbal therapies, dietary supplements, and mind/body interventions. The use of CAM has grown, and according to a 2012 National Center for Complementary and Integrative Health survey, more than 30% of US adults and 12% of US children use health care approaches that are considered outside of conventional medical practice. In a survey study of US adults, at least 17.7% of respondents said they had taken a dietary supplement other than a vitamin or mineral in the last year.¹ Data from the 2007 National Health Interview Survey showed that the prevalence of adults with skin conditions using CAM was 84.5% compared to 38.3% in the general population.² In addition, 8.15 million US patients with dermatologic conditions reported using CAM over a 5-year period.³ Complementary alternative medicine has emerged as an alternative or adjunct to standard treatments, making it important for dermatologists to understand the existing literature on these therapies. Herein, we review the current evidence-based literature that exists on CAM for the treatment of atopic dermatitis (AD), psoriasis, and alopecia areata (AA).

Atopic Dermatitis

Atopic dermatitis is a chronic, pruritic, inflammatory skin condition with considerable morbidity.^4,5 The pathophysiology of AD is multifactorial and includes aspects of barrier dysfunction, IgE hypersensitivity, abnormal cell-mediated immune response, and environmental factors.⁶ Atopic dermatitis also is one of the most common inflammatory skin conditions in adults, affecting more than 7% of the US population and up to 20% of the total population in developed countries. Of those affected, 40% have moderate or severe symptoms that result in a substantial impact on quality of life.⁷ Despite advances in understanding disease pathology and treatment, a subset of patients opt to defer conventional treatments such as topical and systemic corticosteroids, antibiotics, nonsteroidal immunomodulators, and biologics. Patients may seek alternative therapies when typical treatments fail or when the perceived side effects outweigh the benefits.^5,8 The use of CAM has been well described in patients with AD; however, the existing evidence supporting its use along with its safety profile have not been thoroughly explored. Herein, we will discuss some of the most well-studied supplements for treatment of AD, including evening primrose oil (EPO), fish oil, and probiotics.⁵

Oral supplementation with polyunsaturated fatty acids commonly is reported in patients with AD.^5,8 The idea that a fatty acid deficiency could lead to atopic skin conditions has been around since 1937, when it was suggested that patients with AD had lower levels of blood unsaturated fatty acids.⁹ Conflicting evidence regarding oral fatty acid ingestion and AD disease severity has emerged.^10,11 One unsaturated fatty acid, γ-linolenic acid (GLA), has demonstrated anti-inflammatory properties and involvement in barrier repair.¹² It is converted to dihomo-GLA in the body, which acts on cyclooxygenase enzymes to produce the inflammatory mediator prostaglandin E₁. The production of GLA is mediated by the enzyme delta-6 desaturase in the metabolization of linoleic acid.¹² However, it has been reported that in a subset of patients with AD, a malfunction of delta-6 desaturase may play a role in disease progression and result in lower baseline levels of GLA.^10,12 Evening primrose oil and borage oil contain high amounts of GLA (8%–10% and 23%, respectively); thus, supplementation with these oils has been studied in AD.¹³

EPO for AD
Studies investigating EPO (Oenothera biennis) and its association with AD severity have shown mixed results. A Cochrane review reported that oral borage oil and EPO were not effective treatments for AD,¹⁴ while another larger randomized controlled trial (RCT) found no statistically significant improvement in AD symptoms.¹⁵ However, multiple smaller studies have found that clinical symptoms of AD, such as erythema, xerosis, pruritus, and total body surface area involved, did improve with oral EPO supplementation when compared to placebo, and the results were statistically significant (P=.04).^16,17 One study looked at different dosages of EPO and found that groups ingesting both 160 mg and 320 mg daily experienced reductions in eczema area and severity index score, with greater improvement noted with the higher dosage.¹⁷ Side effects associated with oral EPO include an anticoagulant effect and transient gastrointestinal tract upset.^8,14 There currently is not enough evidence or safety data to recommend this supplement to AD patients.

Although topical use of fatty acids with high concentrations of GLA, such as EPO and borage oil, have demonstrated improvement in subjective symptom severity, most studies have not reached statistical significance.^10,11 One study used a 10% EPO cream for 2 weeks compared to placebo and found statistically significant improvement in patient-reported AD symptoms (P=.045). However, this study only included 10 participants, and therefore larger studies are necessary to confirm this result.¹⁸ Some RCTs have shown that topical coconut oil, sunflower seed oil, and sandalwood album oil improve AD symptom severity, but again, large controlled trials are needed.⁵ Unfortunately, many essential oils, including EPO, can cause a secondary allergic contact dermatitis and potentially worsen AD.¹⁹

Fish Oil for AD
Fish oil is a commonly used supplement for AD due to its high content of the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Omega-3 fatty acids exert anti-inflammatory effects by displacing arachidonic acid, a proinflammatory omega-6 fatty acid thought to increase IgE, as well as helper T cell (T_H2) cytokines and prostaglandin E₂.^8,20 A 2012 Cochrane review found that, while some studies revealed mild improvement in AD symptoms with oral fish oil supplementation, these RCTs were of poor methodological quality.²¹ Multiple smaller studies have shown a decrease in pruritus, severity, and physician-rated clinical scores with fish oil use.^5,8,20,22 One study with 145 participants reported that 6 g of fish oil once daily compared to isoenergetic corn oil for 16 weeks identified no statistically significant differences between the treatment groups.²⁰ No adverse events were identified in any of the reported trials. Further studies should be conducted to assess the utility and dosing of fish oil supplements in AD patients.

Probiotics for AD
Probiotics consist of live microorganisms that enhance the microflora of the gastrointestinal tract.^8,20 They have been shown to influence food digestion and also have demonstrated potential influence on the skin-gut axis.²³ The theory that intestinal dysbiosis plays a role in AD pathogenesis has been investigated in multiple studies.^23-25 The central premise is that low-fiber and high-fat Western diets lead to fundamental changes in the gut microbiome, resulting in fewer anti-inflammatory metabolites, such as short-chain fatty acids (SCFAs).^23-25 These SCFAs are produced by microbes during the fermentation of dietary fiber and are known for their effect on epithelial barrier integrity and anti-inflammatory properties mediated through G protein–coupled receptor 43.²⁵ Multiple studies have shown that the gut microbiome in patients with AD have higher proportions of Clostridium difficile, Escherichia coli, and Staphylococcus aureus and lower levels of Bifidobacterium, Bacteroidetes, and Bacteroides species compared to healthy controls.^26,27 Metagenomic analysis of fecal samples from patients with AD have shown a reduction of Faecalibacterium prausnitzii species when compared to controls, along with a decreased SCFA production, leading to the hypothesis that the gut microbiome may play a role in epithelial barrier disruption.^28,29 Systematic reviews and smaller studies have found that oral probiotic use does lead to AD symptom improvement.^8,30,31 A systematic review of 25 RCTs with 1599 participants found that supplementation with oral probiotics significantly decreased the SCORAD (SCORing Atopic Dermatitis) index in adults and children older than 1 year with AD but had no effect on infants younger than 1 year (P<.001). They also found that supplementation with diverse microbes or Lactobacillus species showed greater benefit than Bifidobacterium species alone.³⁰ Another study analyzed the effect of oral Lactobacillus fermentum (1×10⁹ CFU twice daily) in 53 children with AD vs placebo for 16 weeks. This study found a statically significant decrease in SCORAD index between oral probiotics and placebo, with 92% (n=24) of participants supplementing with probiotics having a lower SCORAD index than baseline compared to 63% (n=17) in the placebo group (P=.01).³¹ However, the use of probiotics for AD treatment has remained controversial. Two recent systematic reviews, including 39 RCTs of 2599 randomized patients, found that the use of currently available oral probiotics made little or no difference in patient-rated AD symptoms, investigator-rated AD symptoms, or quality of life.^32,33 No adverse effects were observed in the included studies. Unfortunately, the individual RCTs included were heterogeneous, and future studies with standardized probiotic supplementation should be undertaken before probiotics can be routinely recommended.

The use of topical probiotics in AD also has recently emerged. Multiple studies have shown that patients with AD have higher levels of colonization with S aureus, which is associated with T-cell dysfunction, more severe allergic skin reactions, and disruptions in barrier function.^34,35 Therefore, altering the skin microbiota through topical probiotics could theoretically reduce AD symptoms and flares. Multiple RCTs and smaller studies have shown that topical probiotics can alter the skin microbiota, improve erythema, and decrease scaling and pruritus in AD patients.^35-38 One study used a heat-treated Lactobacillus johnsonii 0.3% lotion twice daily for 3 weeks vs placebo in patients with AD with positive S aureus skin cultures. The S aureus load decreased in patients using the topical probiotic lotion, which correlated with lower SCORAD index that was statistically significant compared to placebo (P=.012).³⁶ More robust studies are needed to determine if topical probiotics should routinely be recommended in AD.

Psoriasis

Psoriasis vulgaris is a chronic inflammatory skin condition characterized by pruritic, hyperkeratotic, scaly plaques.^39,40 Keratinocyte hyperproliferation is central to psoriasis pathogenesis and is thought to be a T-cell–driven reaction to antigens or trauma in genetically predisposed individuals. Standard treatments for psoriasis currently include topical corticosteroids and anti-inflammatories, oral immunomodulatory therapy, biologic agents, and phototherapy.⁴⁰ The use of CAM is highly prevalent among patients with psoriasis, with one study reporting that 51% (n=162) of psoriatic patients interviewed had used CAM.⁴¹ The most common reasons for CAM use included dissatisfaction with current treatment, adverse side effects of standard therapy, and patient-reported attempts at “trying everything to heal disease.”⁴² Herein, we will discuss some of the most frequently used supplements for treatment of psoriatic disease.³⁹

Fish Oil for Psoriasis
One of the most common supplements used by patients with psoriasis is fish oil due to its purported anti-inflammatory qualities.^20,39 The consensus on fish oil supplementation for psoriasis is mixed.^43-45 Multiple RCTs have reported reductions in psoriasis area and severity index (PASI) scores or symptomatic improvement with variable doses of fish oil.^44,46 One RCT found that using EPA 1.8 g once daily and DHA 1.2 g once daily for 12 weeks resulted in significant improvement in pruritus, scaling, and erythema (P<.05).⁴⁴ Another study reported a significant decrease in erythema (P=.02) and total body surface area affected (P=.0001) with EPA 3.6 g once daily and DHA 2.4 g once daily supplementation compared to olive oil supplementation for 15 weeks.⁴⁶ Alternatively, multiple studies have failed to show statistically significant improvement in psoriatic symptoms with fish oil supplementation at variable doses and time frames (14–216 mg daily EPA, 9–80 mg daily DHA, from 2 weeks to 9 months).^40,47,48 Fish oil may impart anticoagulant properties and should not be started without the guidance of a physician. Currently, there are no data to make specific recommendations on the use of fish oil as an adjunct psoriatic treatment.

Curcumin for Psoriasis
Another supplement routinely utilized in patients with psoriasis is curcumin,^40,49,50 a yellow phytochemical that is a major component of the spice turmeric. Curcumin has been shown to inhibit certain proinflammatory cytokines including IL-17, IL-6, IFN-γ, and tumor necrosis factor α and has been regarded as having immune-modulating, anti-inflammatory, and antibacterial properties.^40,50 Curcumin also has been reported to suppress phosphorylase kinase, an enzyme that has increased activity in psoriatic plaques that correlates with markers of psoriatic hyperproliferation.^50,51 When applied topically, turmeric microgel 0.5% has been reported to decrease scaling, erythema, and psoriatic plaque thickness over the course of 9 weeks.⁵⁰ In a nonrandomized trial with 10 participants, researchers found that phosphorylase kinase activity levels in psoriatic skin biopsies of patients applying topical curcumin 1% were lower than placebo and topical calcipotriol applied in combination. The lower phosphorylase kinase levels correlated with level of disease severity, and topical curcumin 1% showed a superior outcome when compared to topical calcipotriol.^40,49 Although these preliminary results are interesting, there still are not enough data at this time to recommend topical curcumin as a treatment of psoriasis. No known adverse events have been reported with the use of topical curcumin to date.

Oral curcumin has poor oral bioavailability, and 40% to 90% of oral doses are excreted, making supplementation a challenge.⁴⁰ In one RCT, oral curcumin 2 g daily (using a lecithin-based delivery system to increase bioavailability) was administered in combination with topical methylprednisolone aceponate 0.1%, resulting in significant improvement in psoriatic symptoms and lower IL-22 compared to placebo and topical methylprednisolone aceponate (P<.05).⁵² Other studies also have reported decreased PASI scores with oral curcumin supplementation.^53,54 Adverse effects reported with oral curcumin included gastrointestinal tract upset and hot flashes.⁵³ Although there is early evidence that may support the use of oral curcumin supplementation for psoriasis, more data are needed before recommending this therapy.

Indigo Naturalis for Psoriasis
Topical indigo naturalis (IN) also has been reported to improve psoriasis symptoms.^39,53,55 The antipsoriatic effects are thought to occur through the active ingredient in IN (indirubin), which is responsible for inhibition of keratinocyte proliferation.⁴⁰ One study reported that topical IN 1.4% containing indirubin 0.16% with a petroleum ointment vehicle applied to psoriatic plaques over 12 weeks resulted in a significant decrease in PASI scores from 18.9 at baseline to 6.3 after IN treatment (P<.001).⁵⁶ Another study found that over 8 weeks, topical application of IN 2.83% containing indirubin 0.24% to psoriatic plaques vs petroleum jelly resulted in 56.3% (n=9) of the treatment group achieving PASI 75 compared to 0% in the placebo group (n=24).⁵⁵ One deterrent in topical IN treatment is the dark blue pigment it contains; however, no other adverse outcomes were found with topical IN treatment.⁵⁶ Larger clinical trials are necessary to further explore IN as a potential adjunct treatment in patients with mild psoriatic disease. When taken orally, IN has caused gastrointestinal tract disturbance and elevated liver enzyme levels.⁵⁷

Herbal Toxicities
It is important to consider that oral supplements including curcumin and IN are widely available over-the-counter and online without oversight by the US Food and Drug Administration.⁴⁰ Herbal supplements typically are compounded with other ingredients and have been associated with hepatotoxicity as well as drug-supplement interactions, including abnormal bleeding and clotting.⁵⁸ There exists a lack of general surveillance data, making the true burden of herbal toxicities more difficult to accurately discern. Although some supplements have been associated with anti-inflammatory qualities and disease improvement, other herbal supplements have been shown to possess immunostimulatory characteristics. Herbal supplements such as spirulina, chlorella, Aphanizomenon flos-aquae, and echinacea have been shown to upregulate inflammatory pathways in a variety of autoimmune skin conditions.⁵⁹

Probiotics for Psoriasis
Data on probiotic use in patients with psoriasis are limited.²³ A distinct pattern of dysbiosis has been identified in psoriatic patients, as there is thought to be depletion of beneficial bacteria such as Bifidobacterium, lactobacilli, and F prausnitzii and increased colonization with pathogenic organisms such as Salmonella, E coli, Heliobacter, Campylobacter, and Alcaligenes in psoriasis patients.^23,59,60 Early mouse studies have supported this hypothesis, as mice fed with Lactobacillus pentosus have developed milder forms of imiquimod-induced psoriasis compared to placebo,⁵⁵ and mice receiving probiotic supplementation have lower levels of psoriasis-related proinflammatory markers such as T_H17-associated cytokines.⁶¹ Another study in humans found that daily oral Bifidobacterium infantis supplementation for 8 weeks in psoriatic patients resulted in lower C-reactive protein and tumor necrosis factor α levels compared to placebo.⁶² Studies on the use of topical probiotics in psoriasis have been limited, and more research is needed to explore this relationship.³⁸ At this time, no specific recommendations can be made on the use of probiotics in psoriatic patients.

Alopecia Areata

Alopecia areata is nonscarring hair loss that can affect the scalp, face, or body.^63,64 The pathophysiology of AA involves the attack of the hair follicle matrix epithelium by inflammatory cells without hair follicle stem cell destruction. The precise events that precipitate these episodes are unknown, but triggers such as emotional or physical stress, vaccines, or viral infections have been reported.⁶⁵ There is no cure for AA, and current treatments such as topical minoxidil and corticosteroids (topical, intralesional, or oral) vary widely in efficacy.⁶⁴ Although Janus kinase inhibitors recently have shown promising results in the treatment of AA, the need for prolonged therapy may be frustrating to patients.⁶⁶ Severity of AA also can vary, with 30% of patients experiencing extensive hair loss.⁶⁷ The use of CAM has been widely reported in AA due to high levels of dissatisfaction with existing therapies.⁶⁸ Herein, we discuss the most studied alternative treatments used in AA

Garlic and Onion for Alopecia
One alternative treatment that has shown promising initial results is application of topical garlic and onion extracts to affected areas.^64,69,70 Both garlic and onion belong to the Allium genus and are high in sulfur and phenolic compounds.⁷⁰ They have been reported to possess bactericidal and vasodilatory activity,⁷¹ and it has been hypothesized that onion and garlic extracts may induce therapeutic effects through induction of a mild contact dermatitis.⁷⁰ One single-blinded, controlled trial using topical crude onion juice reported that 86.9% (n=20) of patients had full regrowth of hair compared to 13.3% (n=2) of patients treated with a tap water placebo at 8 weeks (P<.0001). This study also noted that patients using onion juice had a higher rate of erythema at application site; unfortunately, the study was small with only 38 patients.⁷⁰ Another double-blind RCT using garlic gel 5% with betamethasone valerate cream 0.1% compared to betamethasone valerate cream alone found that after 3 months, patients in the garlic gel group had increased terminal hairs and smaller patch sizes compared to the betamethasone valerate cream group.⁶⁹ More studies are needed to confirm these results.

Aromatherapy With Essential Oils for Alopecia
Another alternative treatment in AA that has demonstrated positive results is aromatherapy skin massage with essential oils to patches of alopecia.⁷² Although certain essential oils, such as tea tree oil, have been reported to have specific antibacterial or anti-inflammatory properties, essential oils have been reported to cause allergic contact dermatitis and should be used with caution.^73,74 For example, tea tree oil is a well-known cause of allergic contact dermatitis, and positive patch testing has ranged from 0.1% to 3.5% in studies assessing topical tea tree oil 5% application.⁷⁵ Overall, there have been nearly 80 essential oils implicated in contact dermatitis, with high-concentration products being one of the highest risk factors for an allergic contact reaction.⁷⁶ One RCT compared daily scalp massage with essential oils (rosemary, lavender, thyme, and cedarwood in a carrier oil) to daily scalp massage with a placebo carrier oil in AA patients. The results showed that at 7 months of treatment, 44% (n=19) of the aromatherapy group showed improvement compared to 15% (n=6) in the control group.⁷⁷ Another study used a similar group of essential oils (thyme, rosemary, atlas cedar, lavender, and EPO in a carrier oil) with daily scalp massage and reported similar improvement of AA symptoms compared to control; the investigators also reported irritation at application site in 1 patient.⁷⁸ There currently are not enough data to recommend aromatherapy skin massage for the treatment of AA, and this practice may cause harm to the patient by induction of allergic contact dermatitis.

There have been a few studies to suggest that the use of total glucosides of peony with compound glycyrrhizin and oral Korean red ginseng may have beneficial effects on AA treatment, but efficacy and safety data are lacking, and these therapies should not be recommended without more information.^64,79,80

Final Thoughts

Dermatologic patients frequently are opting for CAM,² and although some therapies may show promising initial results, alternative medicines also can drive adverse events.^19,30 The lack of oversight from the US Food and Drug Administration on the products leads to many unknowns for true health risks with over-the-counter CAM supplements.⁴⁰ As the use of CAM becomes increasingly common among dermatologic patients, it is important for dermatologists to understand the benefits and risks, especially for commonly treated conditions. More data is needed before CAM can be routinely recommended.

Within the last decade, almost 3000 articles have been published on the role of diet in the prevention and management of dermatologic conditions. Patients are increasingly interested in—and employing—dietary modifications that may influence skin appearance and aid in the treatment of cutaneous disease.¹ It is essential that dermatologists are familiar with existing evidence on the role of diet in dermatology to counsel patients appropriately. Herein, we discuss the compositions of several popular diets and their proposed utility for dermatologic purposes. We highlight the limited literature that exists surrounding this topic and emphasize the need for future, well-designed clinical trials that study the impact of diet on skin disease.

Ketogenic Diet

The ketogenic diet has a macronutrient profile composed of high fat, low to moderate protein, and very low carbohydrates. Nutritional ketosis occurs as the body begins to use free fatty acids (via beta oxidation) as the primary metabolite driving cellular metabolism. It has been suggested that the ketogenic diet may impart beneficial effects on skin disease; however, limited literature exists on the role of nutritional ketosis in the treatment of dermatologic conditions.

Mechanistically, the ketogenic diet decreases the secretion of insulin and insulinlike growth factor 1, resulting in a reduction of circulating androgens and increased activity of the retinoid X receptor.² In acne vulgaris, it has been suggested that the ketogenic diet may be beneficial in decreasing androgen-induced sebum production and the overproliferation of keratinocytes.^2-7 The ketogenic diet is one of the most rapidly effective dietary strategies for normalizing both insulin and androgens, thus it may theoretically be useful for other metabolic and hormone-dependent skin diseases, such as hidradenitis suppurativa.^8,9

The cutaneous manifestations associated with chronic hyperinsulinemia and hyperglycemia are numerous and include acanthosis nigricans, acrochordons, diabetic dermopathy, scleredema diabeticorum, bullosis diabeticorum, keratosis pilaris, and generalized granuloma annulare. There also is an increased risk for bacterial and fungal skin infections associated with hyperglycemic states.¹⁰ The ketogenic diet is an effective nonpharmacologic tool for normalizing serum insulin and glucose levels in most patients and may have utility in the aforementioned conditions.^11,12 In addition to improving insulin sensitivity, it has been used as a dietary strategy for weight loss.^11-15 Because obesity and metabolic syndrome are highly correlated with common skin conditions such as psoriasis, hidradenitis suppurativa, and androgenetic alopecia, there may be a role for employing the ketogenic diet in these patient populations.^16,17

Although robust clinical studies on ketogenic diets in skin disease are lacking, a recent single-arm, open-label clinical trial observed benefit in all 37 drug-naïve, overweight patients with chronic plaque psoriasis who underwent a ketogenic weight loss protocol. Significant reductions in psoriasis area and severity index (PASI) score and dermatology life quality index score were reported (P<.001).¹⁸ Another study of 30 patients with psoriasis found that a 4-week, low-calorie, ketogenic diet resulted in 50% improvement of PASI scores, 10% weight loss, and a reduction in the proinflammatory cytokines IL-1β and IL-2.¹⁹ Despite these results, it is a challenge to tease out if the specific dietary intervention or its associated weight loss was the main driver in these reported improvements in skin disease.

There is mixed evidence on the anti-inflammatory nature of the ketogenic diet, likely due to wide variation in the composition of foods included in individual diets. In many instances, the ketogenic diet is thought to possess considerable antioxidant and anti-inflammatory capabilities. Ketones are known activators of the nuclear factor erythroid 2–related factor 2 pathway, which upregulates the production of glutathione, a major endogenous intracellular antioxidant.²⁰ Additionally, dietary compounds from foods that are encouraged while on the ketogenic diet, such as sulforaphane from broccoli, also are independent activators of nuclear factor erythroid 2–related factor 2.²¹ Ketones are efficiently utilized by mitochondria, which also may result in the decreased production of reactive oxygen species and lower oxidative stress.²² Moreover, the ketone body β-hydroxybutyrate has demonstrated the ability to reduce proinflammatory IL-1β levels via suppression of nucleotide-binding domain-like receptor protein 3 inflammasome activity.^23,24 The activity of IL-1β is known to be elevated in many dermatologic conditions, including juvenile idiopathic arthritis, relapsing polychondritis, Schnitzler syndrome, hidradenitis suppurativa, Behçet disease, and other autoinflammatory syndromes.²⁵ Ketones also have been shown to inhibit the nuclear factor–κB proinflammatory signaling pathway.^22,26,27 Overexpression of IL-1β and aberrant activation of nuclear factor–κB are implicated in a variety of inflammatory, autoimmune, and oncologic cutaneous pathologies. The ketogenic diet may prove to be an effective adjunctive treatment for dermatologists to consider in select patient populations.^23,24,28-30

For patients with keratinocyte carcinomas, the ketogenic diet may offer the aforementioned anti-inflammatory and antioxidant effects, as well as suppression of the mechanistic target of rapamycin, a major regulator of cell metabolism and proliferation.^31,32 Inhibition of mechanistic target of rapamycin activity has been shown to slow tumor growth and reduce the development of squamous cell carcinoma.^25,33,34 The ketogenic diet also may exploit the preferential utilization of glucose exhibited by many types of cancer cells, thereby “starving” the tumor of its primary fuel source.^35,36 In vitro and animal studies in a variety of cancer types have demonstrated that a ketogenic metabolic state—achieved through the ketogenic diet or fasting—can sensitize tumor cells to chemotherapy and radiation while conferring a protective effect to normal cells.^37-40 This recently described phenomenon is known as differential stress resistance, but it has not been studied in keratinocyte malignancies or melanoma to date. Importantly, some basal cell carcinomas and BRAF V600E–mutated melanomas have worsened while on the ketogenic diet, suggesting more data is needed before it can be recommended for all cancer patients.^41,42 Furthermore, other skin conditions such as prurigo pigmentosa have been associated with initiation of the ketogenic diet.⁴³

Low FODMAP Diet

Fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) are short-chain carbohydrates that are poorly absorbed, osmotically active, and rapidly fermented by intestinal bacteria.⁴⁴ The low FODMAP diet has been shown to be efficacious for treatment of irritable bowel syndrome, small intestinal bacterial overgrowth (SIBO), and some cases of inflammatory bowel disease (IBD).^44-49 A low FODMAP diet may have potential implications for several dermatologic conditions.

Rosacea has been associated with various gastrointestinal tract disorders including irritable bowel syndrome, SIBO, and IBD.^50-54 A single study found that patients with rosacea had a 13-fold increased risk for SIBO.^55,56 Treatment of 40 patients with SIBO using rifaximin resulted in complete resolution of rosacea in all patients, with no relapse after a 3-year follow-up period.⁵⁵ Psoriasis also has been associated with SIBO and IBD.^57,58 One small study found that eradication of SIBO in psoriatic patients resulted in improved PASI scores and colorimetric values.⁵⁹

Although the long-term health consequences of the low FODMAP diet are unknown, further research on such dietary interventions for inflammatory skin conditions is warranted given the mounting evidence of a gut-skin connection and the role of the intestinal microbiome in skin health.^50,51

Gluten-Free Diet

Gluten is a protein found in a variety of grains. Although the role of gluten in the pathogenesis of celiac disease and dermatitis herpetiformis is indisputable, the deleterious effects of gluten outside of the context of these diseases remain controversial. There may be a compelling case for eliminating gluten in psoriasis patients with seropositivity for celiac disease. A recent systematic review found a 2.2-fold increased risk for celiac disease in psoriasis patients.⁶⁰ Antigliadin antibody titers also were found to be positively correlated with psoriatic disease severity.⁶¹ In addition, one open-label study found a reduction in PASI scores in 73% of patients with antigliadin antibodies after 3 months on a gluten-free diet compared to those without antibodies; however, the study only included 22 patients.⁶² Several other small studies have yielded similar results^63,64; however, antigliadin antibodies are neither the most sensitive nor specific markers of celiac disease, and additional testing should be completed in any patient who may carry this diagnosis. A survey study by the National Psoriasis Foundation found that the dietary change associated with the greatest skin improvement was removal of gluten and nightshade vegetables in approximately 50% of the 1200 psoriasis patients that responded.⁶⁵ Case reports of various dermatologic conditions including sarcoidosis, vitiligo, alopecia areata, lichen planus, dermatomyositis, pyoderma gangrenosum, erythema nodosum, leukocytoclastic vasculitis, linear IgA bullous dermatosis, and aphthous ulcerations have reportedly improved with a gluten-free diet; however, this should not be used as primary therapy in patients without celiac disease.^66-71 Because gluten-free diets can be expensive and challenging to follow, a formal assessment for celiac disease should be considered before recommendation of this dietary intervention.

Low Histamine Diet

Histamine is a biogenic amine produced by the decarboxylation of the amino acid histidine.⁷² It is found in several foods in varying amounts. Because bacteria can convert histidine into histamine, many fermented and aged foods such as kimchi, sauerkraut, cheese, and red wine contain high levels of histamine. Individuals who have decreased activity of diamine oxidase (DAO), an enzyme that degrades histamine, may be more susceptible to histamine intolerance.⁷² The symptoms of histamine intolerance are numerous and include gastrointestinal tract distress, rhinorrhea and nasal congestion, headache, urticaria, flushing, and pruritus. Histamine intolerance can mimic an IgE-mediated food allergy; however, allergy testing is negative in these patients. Unfortunately, there is no laboratory test for histamine intolerance; a double-blind, placebo-controlled food challenge is considered the gold-standard test.⁷²

As it pertains to dermatology, a low histamine diet may play a role in the treatment of certain patients with atopic dermatitis and chronic spontaneous urticaria. One study reported that 17 of 54 (31.5%) atopic patients had higher basal levels of serum histamine compared to controls.⁷³ Another study found that a histamine-free diet led to improvement in both histamine intolerance symptoms and atopic dermatitis disease severity (SCORing atopic dermatitis) in patients with low DAO activity.⁷⁴ In chronic spontaneous urticaria, a recent systematic review found that in 223 patients placed on a low histamine diet for 3 to 4 weeks, 12% and 44% achieved complete and partial remission, respectively.⁷⁵ Although treatment response based on a patient’s DAO activity level has not been correlated, a diet low in histamine may prove useful for patients with persistent atopic dermatitis and chronic spontaneous urticaria who have negative food allergy tests and report exacerbation of symptoms after ingestion of histamine-rich foods.^76,77

Mediterranean Diet

The Mediterranean diet has been touted as one of the healthiest diets to date, and large randomized clinical trials have demonstrated its effectiveness in weight loss, improving insulin sensitivity, and reducing inflammatory cytokine profiles.^78,79 A major criticism of the Mediterranean diet is that it has considerable ambiguity and lacks a precise definition due to the variability of what is consumed in different Mediterranean regions. Generally, the diet emphasizes high consumption of colorful fruits and vegetables, aromatic herbs and spices, olive oil, nuts, and seafood, as well as modest amounts of dairy, eggs, and red meat.⁸⁰ The anti-inflammatory effects of this diet largely have been attributed to its abundance of polyphenols, carotenoids, monounsaturated fatty acids, and omega-3 polyunsaturated fatty acids (PUFAs).^80,81 Examples of polyphenols include resveratrol in red grapes, quercetin in apples and red onions, and curcumin in turmeric, while examples of carotenoids include lycopene in tomatoes and zeaxanthin in dark leafy greens. Oleic acid is a monounsaturated fatty acid present in high concentrations in olive oil, while eicosapentaenoic acid and docosahexaenoic acid are omega-3 PUFAs predominantly found in fish.⁸²

Unfortunately, rigorous clinical trials regarding the Mediterranean diet as it pertains to dermatology have not been undertaken. Numerous observational studies in patients with psoriasis have suggested that close adherence to the Mediterranean diet was associated with improvement in PASI scores.^83-86 The National Psoriasis Foundation now recommends a trial of the Mediterranean diet in some patients with psoriasis, emphasizing increased dietary intake of olive oil, fish, and vegetables.⁸⁷ Adherence to a Mediterranean diet also has been inversely correlated to the severity of acne vulgaris and hidradenitis suppurativa^88,89; however, these studies failed to account for the multifactorial risk factors associated with these conditions. Mediterranean diets also may impart a chemopreventive effect, supported by a number of in vivo and in vitro studies demonstrating the inhibition and/or reversal of cutaneous DNA damage induced by UV radiation through supplementation with various phytonutrients and omega-3 PUFAs.^81,90-92 Although small case-control studies have found a decreased risk of basal cell carcinoma in those who closely adhered to a Mediterranean diet, more rigorous clinical research is needed.⁹³

Whole-Food, Plant-Based Diet

A whole-food, plant-based (WFPB) diet is another popular dietary approach that consists of eating fruits, vegetables, legumes, nuts, seeds, and grains in their whole natural form.⁹⁴ This diet discourages all animal products, including red meat, seafood, dairy, and eggs. It is similar to a vegan diet except that it eliminates all highly refined carbohydrates, vegetable oils, and other processed foods.⁹⁴ Randomized clinical studies have demonstrated the WFPB diet to be effective in the treatment of obesity and metabolic syndrome.^95,96

A WFPB diet has been shown to increase the antioxidant capacity of cells, lengthen telomeres, and reduce formation of advanced glycation end products.^94,97,98 These benefits may help combat accelerated skin aging, including increased skin permeability, reduced elasticity and hydration, decreased angiogenesis, impaired immune function, and decreased vitamin D synthesis. Accelerated skin aging can result in delayed wound healing and susceptibility to skin tears and ecchymoses and also may promote the development of cutaneous malignancies.⁹⁹ There remains a lack of clinical data studying a properly formulated WFPB diet in the dermatologic setting.

Paleolithic Diet

The paleolithic (Paleo) diet is an increasingly popular way of eating that attempts to mirror what our ancestors may have consumed between 10,000 and 2.5 million years ago.¹⁰⁰ It is similar to the Mediterranean diet but excludes grains, dairy, legumes, and nightshade vegetables. It also calls for elimination of highly processed sugars and oils as well as chemical food additives and preservatives. There is a strict variation of the diet for individuals with autoimmune disease that also excludes eggs, nuts, and seeds, as these can be inflammatory or immunogenic in some patients.^100-106 Other variations of the diet exist, including the ketogenic Paleo diet, pegan (Paleo vegan) diet, and lacto-Paleo diet.¹⁰⁰ An often cited criticism of the Paleo diet is the low intake of calcium and risk for osteoporosis; however, consumption of calcium-rich foods or a calcium supplement can address this concern.¹⁰⁷

Although small clinical studies have found the Paleo diet to be beneficial for various autoimmune diseases, clinical data evaluating the utility of the diet for cutaneous disease is lacking.^108,109 Numerous randomized trials have demonstrated the Paleo diet to be effective for weight loss and improving insulin sensitivity and lipid levels.^110-116 Thus, the Paleo diet may theoretically serve as a viable adjunct dietary approach to the treatment of cutaneous diseases associated with obesity and metabolic derangement.¹¹⁷

Carnivore Diet

Arguably the most controversial and radical diet is the carnivore diet. As the name implies, the carnivore diet is based on consuming solely animal products. A properly structured carnivore diet emphasizes a “nose-to-tail” eating approach where all parts of the animal including the muscle meats, organs, and fat are consumed. Proponents of the diet cite anthropologic evidence from fossil-stable carbon-13/carbon-12 isotope analyses, craniodental features, and numerous other adaptations that indicate increased consumption of meat during human evolution.^118-122 Notably, many early humans ate a carnivore diet, but life span was very short at this time, suggesting the diet may not be as beneficial as has been suggested.

Despite the abundance of anecdotal evidence supporting its use for a variety of chronic conditions, including cutaneous autoimmune disease, there is a virtual absence of high-quality research on the carnivore diet.^123-125

The purported benefits of the carnivore diet may be attributed to the consumption of organ meats that contain highly bioavailable essential vitamins and minerals, such as iron, zinc, copper, selenium, thiamine, niacin, folate, vitamin B₆, vitamin B₁₂, vitamin A, vitamin D, vitamin K, and choline.^126-128 Other dietary compounds that have demonstrated benefit for skin health and are predominantly found in animal foods include carnosine, carnitine, creatine, taurine, coenzyme Q10, and collagen.^129-134 Nevertheless, there is no data to recommend the elimination of antioxidant- and micronutrient-dense plant-based foods. Rigorous clinical research evaluating the efficacy and safety of the carnivore diet in dermatologic patients is needed. A carnivore diet should not be undertaken without the assistance of a dietician who can ensure adequate micronutrient and macronutrient support.

Final Thoughts

The adjunctive role of diet in the treatment of skin disease is expanding and becoming more widely accepted among dermatologists. Unfortunately, there remains a lack of randomized controlled trials confirming the efficacy of various dietary interventions in the dermatologic setting. Although evidence-based dietary recommendations currently are limited, it is important for dermatologists to be aware of the varied and nuanced dietary interventions employed by patients.

Ultimately, dietary recommendations must be personalized, considering a patient’s comorbidities, personal beliefs and preferences, and nutrigenetics. The emerging field of dermatonutrigenomics—the study of how dietary compounds interact with one’s genes to influence skin health—may allow for precise dietary recommendations to be made in dermatologic practice. Direct-to-consumer genetic tests targeted toward dermatology patients are already on the market, but their clinical utility awaits validation.¹ Because nutritional science is a constantly evolving field, becoming familiar with these popular diets will serve both dermatologists and their patients well.

Within the last decade, almost 3000 articles have been published on the role of diet in the prevention and management of dermatologic conditions. Patients are increasingly interested in—and employing—dietary modifications that may influence skin appearance and aid in the treatment of cutaneous disease.¹ It is essential that dermatologists are familiar with existing evidence on the role of diet in dermatology to counsel patients appropriately. Herein, we discuss the compositions of several popular diets and their proposed utility for dermatologic purposes. We highlight the limited literature that exists surrounding this topic and emphasize the need for future, well-designed clinical trials that study the impact of diet on skin disease.

Ketogenic Diet

The ketogenic diet has a macronutrient profile composed of high fat, low to moderate protein, and very low carbohydrates. Nutritional ketosis occurs as the body begins to use free fatty acids (via beta oxidation) as the primary metabolite driving cellular metabolism. It has been suggested that the ketogenic diet may impart beneficial effects on skin disease; however, limited literature exists on the role of nutritional ketosis in the treatment of dermatologic conditions.

Mechanistically, the ketogenic diet decreases the secretion of insulin and insulinlike growth factor 1, resulting in a reduction of circulating androgens and increased activity of the retinoid X receptor.² In acne vulgaris, it has been suggested that the ketogenic diet may be beneficial in decreasing androgen-induced sebum production and the overproliferation of keratinocytes.^2-7 The ketogenic diet is one of the most rapidly effective dietary strategies for normalizing both insulin and androgens, thus it may theoretically be useful for other metabolic and hormone-dependent skin diseases, such as hidradenitis suppurativa.^8,9

The cutaneous manifestations associated with chronic hyperinsulinemia and hyperglycemia are numerous and include acanthosis nigricans, acrochordons, diabetic dermopathy, scleredema diabeticorum, bullosis diabeticorum, keratosis pilaris, and generalized granuloma annulare. There also is an increased risk for bacterial and fungal skin infections associated with hyperglycemic states.¹⁰ The ketogenic diet is an effective nonpharmacologic tool for normalizing serum insulin and glucose levels in most patients and may have utility in the aforementioned conditions.^11,12 In addition to improving insulin sensitivity, it has been used as a dietary strategy for weight loss.^11-15 Because obesity and metabolic syndrome are highly correlated with common skin conditions such as psoriasis, hidradenitis suppurativa, and androgenetic alopecia, there may be a role for employing the ketogenic diet in these patient populations.^16,17

Although robust clinical studies on ketogenic diets in skin disease are lacking, a recent single-arm, open-label clinical trial observed benefit in all 37 drug-naïve, overweight patients with chronic plaque psoriasis who underwent a ketogenic weight loss protocol. Significant reductions in psoriasis area and severity index (PASI) score and dermatology life quality index score were reported (P<.001).¹⁸ Another study of 30 patients with psoriasis found that a 4-week, low-calorie, ketogenic diet resulted in 50% improvement of PASI scores, 10% weight loss, and a reduction in the proinflammatory cytokines IL-1β and IL-2.¹⁹ Despite these results, it is a challenge to tease out if the specific dietary intervention or its associated weight loss was the main driver in these reported improvements in skin disease.

There is mixed evidence on the anti-inflammatory nature of the ketogenic diet, likely due to wide variation in the composition of foods included in individual diets. In many instances, the ketogenic diet is thought to possess considerable antioxidant and anti-inflammatory capabilities. Ketones are known activators of the nuclear factor erythroid 2–related factor 2 pathway, which upregulates the production of glutathione, a major endogenous intracellular antioxidant.²⁰ Additionally, dietary compounds from foods that are encouraged while on the ketogenic diet, such as sulforaphane from broccoli, also are independent activators of nuclear factor erythroid 2–related factor 2.²¹ Ketones are efficiently utilized by mitochondria, which also may result in the decreased production of reactive oxygen species and lower oxidative stress.²² Moreover, the ketone body β-hydroxybutyrate has demonstrated the ability to reduce proinflammatory IL-1β levels via suppression of nucleotide-binding domain-like receptor protein 3 inflammasome activity.^23,24 The activity of IL-1β is known to be elevated in many dermatologic conditions, including juvenile idiopathic arthritis, relapsing polychondritis, Schnitzler syndrome, hidradenitis suppurativa, Behçet disease, and other autoinflammatory syndromes.²⁵ Ketones also have been shown to inhibit the nuclear factor–κB proinflammatory signaling pathway.^22,26,27 Overexpression of IL-1β and aberrant activation of nuclear factor–κB are implicated in a variety of inflammatory, autoimmune, and oncologic cutaneous pathologies. The ketogenic diet may prove to be an effective adjunctive treatment for dermatologists to consider in select patient populations.^23,24,28-30

For patients with keratinocyte carcinomas, the ketogenic diet may offer the aforementioned anti-inflammatory and antioxidant effects, as well as suppression of the mechanistic target of rapamycin, a major regulator of cell metabolism and proliferation.^31,32 Inhibition of mechanistic target of rapamycin activity has been shown to slow tumor growth and reduce the development of squamous cell carcinoma.^25,33,34 The ketogenic diet also may exploit the preferential utilization of glucose exhibited by many types of cancer cells, thereby “starving” the tumor of its primary fuel source.^35,36 In vitro and animal studies in a variety of cancer types have demonstrated that a ketogenic metabolic state—achieved through the ketogenic diet or fasting—can sensitize tumor cells to chemotherapy and radiation while conferring a protective effect to normal cells.^37-40 This recently described phenomenon is known as differential stress resistance, but it has not been studied in keratinocyte malignancies or melanoma to date. Importantly, some basal cell carcinomas and BRAF V600E–mutated melanomas have worsened while on the ketogenic diet, suggesting more data is needed before it can be recommended for all cancer patients.^41,42 Furthermore, other skin conditions such as prurigo pigmentosa have been associated with initiation of the ketogenic diet.⁴³

Low FODMAP Diet

Fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) are short-chain carbohydrates that are poorly absorbed, osmotically active, and rapidly fermented by intestinal bacteria.⁴⁴ The low FODMAP diet has been shown to be efficacious for treatment of irritable bowel syndrome, small intestinal bacterial overgrowth (SIBO), and some cases of inflammatory bowel disease (IBD).^44-49 A low FODMAP diet may have potential implications for several dermatologic conditions.

Rosacea has been associated with various gastrointestinal tract disorders including irritable bowel syndrome, SIBO, and IBD.^50-54 A single study found that patients with rosacea had a 13-fold increased risk for SIBO.^55,56 Treatment of 40 patients with SIBO using rifaximin resulted in complete resolution of rosacea in all patients, with no relapse after a 3-year follow-up period.⁵⁵ Psoriasis also has been associated with SIBO and IBD.^57,58 One small study found that eradication of SIBO in psoriatic patients resulted in improved PASI scores and colorimetric values.⁵⁹

Although the long-term health consequences of the low FODMAP diet are unknown, further research on such dietary interventions for inflammatory skin conditions is warranted given the mounting evidence of a gut-skin connection and the role of the intestinal microbiome in skin health.^50,51

Gluten-Free Diet

Gluten is a protein found in a variety of grains. Although the role of gluten in the pathogenesis of celiac disease and dermatitis herpetiformis is indisputable, the deleterious effects of gluten outside of the context of these diseases remain controversial. There may be a compelling case for eliminating gluten in psoriasis patients with seropositivity for celiac disease. A recent systematic review found a 2.2-fold increased risk for celiac disease in psoriasis patients.⁶⁰ Antigliadin antibody titers also were found to be positively correlated with psoriatic disease severity.⁶¹ In addition, one open-label study found a reduction in PASI scores in 73% of patients with antigliadin antibodies after 3 months on a gluten-free diet compared to those without antibodies; however, the study only included 22 patients.⁶² Several other small studies have yielded similar results^63,64; however, antigliadin antibodies are neither the most sensitive nor specific markers of celiac disease, and additional testing should be completed in any patient who may carry this diagnosis. A survey study by the National Psoriasis Foundation found that the dietary change associated with the greatest skin improvement was removal of gluten and nightshade vegetables in approximately 50% of the 1200 psoriasis patients that responded.⁶⁵ Case reports of various dermatologic conditions including sarcoidosis, vitiligo, alopecia areata, lichen planus, dermatomyositis, pyoderma gangrenosum, erythema nodosum, leukocytoclastic vasculitis, linear IgA bullous dermatosis, and aphthous ulcerations have reportedly improved with a gluten-free diet; however, this should not be used as primary therapy in patients without celiac disease.^66-71 Because gluten-free diets can be expensive and challenging to follow, a formal assessment for celiac disease should be considered before recommendation of this dietary intervention.

Low Histamine Diet

Histamine is a biogenic amine produced by the decarboxylation of the amino acid histidine.⁷² It is found in several foods in varying amounts. Because bacteria can convert histidine into histamine, many fermented and aged foods such as kimchi, sauerkraut, cheese, and red wine contain high levels of histamine. Individuals who have decreased activity of diamine oxidase (DAO), an enzyme that degrades histamine, may be more susceptible to histamine intolerance.⁷² The symptoms of histamine intolerance are numerous and include gastrointestinal tract distress, rhinorrhea and nasal congestion, headache, urticaria, flushing, and pruritus. Histamine intolerance can mimic an IgE-mediated food allergy; however, allergy testing is negative in these patients. Unfortunately, there is no laboratory test for histamine intolerance; a double-blind, placebo-controlled food challenge is considered the gold-standard test.⁷²

As it pertains to dermatology, a low histamine diet may play a role in the treatment of certain patients with atopic dermatitis and chronic spontaneous urticaria. One study reported that 17 of 54 (31.5%) atopic patients had higher basal levels of serum histamine compared to controls.⁷³ Another study found that a histamine-free diet led to improvement in both histamine intolerance symptoms and atopic dermatitis disease severity (SCORing atopic dermatitis) in patients with low DAO activity.⁷⁴ In chronic spontaneous urticaria, a recent systematic review found that in 223 patients placed on a low histamine diet for 3 to 4 weeks, 12% and 44% achieved complete and partial remission, respectively.⁷⁵ Although treatment response based on a patient’s DAO activity level has not been correlated, a diet low in histamine may prove useful for patients with persistent atopic dermatitis and chronic spontaneous urticaria who have negative food allergy tests and report exacerbation of symptoms after ingestion of histamine-rich foods.^76,77

Mediterranean Diet

The Mediterranean diet has been touted as one of the healthiest diets to date, and large randomized clinical trials have demonstrated its effectiveness in weight loss, improving insulin sensitivity, and reducing inflammatory cytokine profiles.^78,79 A major criticism of the Mediterranean diet is that it has considerable ambiguity and lacks a precise definition due to the variability of what is consumed in different Mediterranean regions. Generally, the diet emphasizes high consumption of colorful fruits and vegetables, aromatic herbs and spices, olive oil, nuts, and seafood, as well as modest amounts of dairy, eggs, and red meat.⁸⁰ The anti-inflammatory effects of this diet largely have been attributed to its abundance of polyphenols, carotenoids, monounsaturated fatty acids, and omega-3 polyunsaturated fatty acids (PUFAs).^80,81 Examples of polyphenols include resveratrol in red grapes, quercetin in apples and red onions, and curcumin in turmeric, while examples of carotenoids include lycopene in tomatoes and zeaxanthin in dark leafy greens. Oleic acid is a monounsaturated fatty acid present in high concentrations in olive oil, while eicosapentaenoic acid and docosahexaenoic acid are omega-3 PUFAs predominantly found in fish.⁸²

Unfortunately, rigorous clinical trials regarding the Mediterranean diet as it pertains to dermatology have not been undertaken. Numerous observational studies in patients with psoriasis have suggested that close adherence to the Mediterranean diet was associated with improvement in PASI scores.^83-86 The National Psoriasis Foundation now recommends a trial of the Mediterranean diet in some patients with psoriasis, emphasizing increased dietary intake of olive oil, fish, and vegetables.⁸⁷ Adherence to a Mediterranean diet also has been inversely correlated to the severity of acne vulgaris and hidradenitis suppurativa^88,89; however, these studies failed to account for the multifactorial risk factors associated with these conditions. Mediterranean diets also may impart a chemopreventive effect, supported by a number of in vivo and in vitro studies demonstrating the inhibition and/or reversal of cutaneous DNA damage induced by UV radiation through supplementation with various phytonutrients and omega-3 PUFAs.^81,90-92 Although small case-control studies have found a decreased risk of basal cell carcinoma in those who closely adhered to a Mediterranean diet, more rigorous clinical research is needed.⁹³

Whole-Food, Plant-Based Diet

A whole-food, plant-based (WFPB) diet is another popular dietary approach that consists of eating fruits, vegetables, legumes, nuts, seeds, and grains in their whole natural form.⁹⁴ This diet discourages all animal products, including red meat, seafood, dairy, and eggs. It is similar to a vegan diet except that it eliminates all highly refined carbohydrates, vegetable oils, and other processed foods.⁹⁴ Randomized clinical studies have demonstrated the WFPB diet to be effective in the treatment of obesity and metabolic syndrome.^95,96

A WFPB diet has been shown to increase the antioxidant capacity of cells, lengthen telomeres, and reduce formation of advanced glycation end products.^94,97,98 These benefits may help combat accelerated skin aging, including increased skin permeability, reduced elasticity and hydration, decreased angiogenesis, impaired immune function, and decreased vitamin D synthesis. Accelerated skin aging can result in delayed wound healing and susceptibility to skin tears and ecchymoses and also may promote the development of cutaneous malignancies.⁹⁹ There remains a lack of clinical data studying a properly formulated WFPB diet in the dermatologic setting.

Paleolithic Diet

The paleolithic (Paleo) diet is an increasingly popular way of eating that attempts to mirror what our ancestors may have consumed between 10,000 and 2.5 million years ago.¹⁰⁰ It is similar to the Mediterranean diet but excludes grains, dairy, legumes, and nightshade vegetables. It also calls for elimination of highly processed sugars and oils as well as chemical food additives and preservatives. There is a strict variation of the diet for individuals with autoimmune disease that also excludes eggs, nuts, and seeds, as these can be inflammatory or immunogenic in some patients.^100-106 Other variations of the diet exist, including the ketogenic Paleo diet, pegan (Paleo vegan) diet, and lacto-Paleo diet.¹⁰⁰ An often cited criticism of the Paleo diet is the low intake of calcium and risk for osteoporosis; however, consumption of calcium-rich foods or a calcium supplement can address this concern.¹⁰⁷

Although small clinical studies have found the Paleo diet to be beneficial for various autoimmune diseases, clinical data evaluating the utility of the diet for cutaneous disease is lacking.^108,109 Numerous randomized trials have demonstrated the Paleo diet to be effective for weight loss and improving insulin sensitivity and lipid levels.^110-116 Thus, the Paleo diet may theoretically serve as a viable adjunct dietary approach to the treatment of cutaneous diseases associated with obesity and metabolic derangement.¹¹⁷

Carnivore Diet

Arguably the most controversial and radical diet is the carnivore diet. As the name implies, the carnivore diet is based on consuming solely animal products. A properly structured carnivore diet emphasizes a “nose-to-tail” eating approach where all parts of the animal including the muscle meats, organs, and fat are consumed. Proponents of the diet cite anthropologic evidence from fossil-stable carbon-13/carbon-12 isotope analyses, craniodental features, and numerous other adaptations that indicate increased consumption of meat during human evolution.^118-122 Notably, many early humans ate a carnivore diet, but life span was very short at this time, suggesting the diet may not be as beneficial as has been suggested.

Despite the abundance of anecdotal evidence supporting its use for a variety of chronic conditions, including cutaneous autoimmune disease, there is a virtual absence of high-quality research on the carnivore diet.^123-125

The purported benefits of the carnivore diet may be attributed to the consumption of organ meats that contain highly bioavailable essential vitamins and minerals, such as iron, zinc, copper, selenium, thiamine, niacin, folate, vitamin B₆, vitamin B₁₂, vitamin A, vitamin D, vitamin K, and choline.^126-128 Other dietary compounds that have demonstrated benefit for skin health and are predominantly found in animal foods include carnosine, carnitine, creatine, taurine, coenzyme Q10, and collagen.^129-134 Nevertheless, there is no data to recommend the elimination of antioxidant- and micronutrient-dense plant-based foods. Rigorous clinical research evaluating the efficacy and safety of the carnivore diet in dermatologic patients is needed. A carnivore diet should not be undertaken without the assistance of a dietician who can ensure adequate micronutrient and macronutrient support.

Final Thoughts

The adjunctive role of diet in the treatment of skin disease is expanding and becoming more widely accepted among dermatologists. Unfortunately, there remains a lack of randomized controlled trials confirming the efficacy of various dietary interventions in the dermatologic setting. Although evidence-based dietary recommendations currently are limited, it is important for dermatologists to be aware of the varied and nuanced dietary interventions employed by patients.

Ultimately, dietary recommendations must be personalized, considering a patient’s comorbidities, personal beliefs and preferences, and nutrigenetics. The emerging field of dermatonutrigenomics—the study of how dietary compounds interact with one’s genes to influence skin health—may allow for precise dietary recommendations to be made in dermatologic practice. Direct-to-consumer genetic tests targeted toward dermatology patients are already on the market, but their clinical utility awaits validation.¹ Because nutritional science is a constantly evolving field, becoming familiar with these popular diets will serve both dermatologists and their patients well.

Within the last decade, almost 3000 articles have been published on the role of diet in the prevention and management of dermatologic conditions. Patients are increasingly interested in—and employing—dietary modifications that may influence skin appearance and aid in the treatment of cutaneous disease.¹ It is essential that dermatologists are familiar with existing evidence on the role of diet in dermatology to counsel patients appropriately. Herein, we discuss the compositions of several popular diets and their proposed utility for dermatologic purposes. We highlight the limited literature that exists surrounding this topic and emphasize the need for future, well-designed clinical trials that study the impact of diet on skin disease.

Ketogenic Diet

The ketogenic diet has a macronutrient profile composed of high fat, low to moderate protein, and very low carbohydrates. Nutritional ketosis occurs as the body begins to use free fatty acids (via beta oxidation) as the primary metabolite driving cellular metabolism. It has been suggested that the ketogenic diet may impart beneficial effects on skin disease; however, limited literature exists on the role of nutritional ketosis in the treatment of dermatologic conditions.

Mechanistically, the ketogenic diet decreases the secretion of insulin and insulinlike growth factor 1, resulting in a reduction of circulating androgens and increased activity of the retinoid X receptor.² In acne vulgaris, it has been suggested that the ketogenic diet may be beneficial in decreasing androgen-induced sebum production and the overproliferation of keratinocytes.^2-7 The ketogenic diet is one of the most rapidly effective dietary strategies for normalizing both insulin and androgens, thus it may theoretically be useful for other metabolic and hormone-dependent skin diseases, such as hidradenitis suppurativa.^8,9

The cutaneous manifestations associated with chronic hyperinsulinemia and hyperglycemia are numerous and include acanthosis nigricans, acrochordons, diabetic dermopathy, scleredema diabeticorum, bullosis diabeticorum, keratosis pilaris, and generalized granuloma annulare. There also is an increased risk for bacterial and fungal skin infections associated with hyperglycemic states.¹⁰ The ketogenic diet is an effective nonpharmacologic tool for normalizing serum insulin and glucose levels in most patients and may have utility in the aforementioned conditions.^11,12 In addition to improving insulin sensitivity, it has been used as a dietary strategy for weight loss.^11-15 Because obesity and metabolic syndrome are highly correlated with common skin conditions such as psoriasis, hidradenitis suppurativa, and androgenetic alopecia, there may be a role for employing the ketogenic diet in these patient populations.^16,17

Although robust clinical studies on ketogenic diets in skin disease are lacking, a recent single-arm, open-label clinical trial observed benefit in all 37 drug-naïve, overweight patients with chronic plaque psoriasis who underwent a ketogenic weight loss protocol. Significant reductions in psoriasis area and severity index (PASI) score and dermatology life quality index score were reported (P<.001).¹⁸ Another study of 30 patients with psoriasis found that a 4-week, low-calorie, ketogenic diet resulted in 50% improvement of PASI scores, 10% weight loss, and a reduction in the proinflammatory cytokines IL-1β and IL-2.¹⁹ Despite these results, it is a challenge to tease out if the specific dietary intervention or its associated weight loss was the main driver in these reported improvements in skin disease.

There is mixed evidence on the anti-inflammatory nature of the ketogenic diet, likely due to wide variation in the composition of foods included in individual diets. In many instances, the ketogenic diet is thought to possess considerable antioxidant and anti-inflammatory capabilities. Ketones are known activators of the nuclear factor erythroid 2–related factor 2 pathway, which upregulates the production of glutathione, a major endogenous intracellular antioxidant.²⁰ Additionally, dietary compounds from foods that are encouraged while on the ketogenic diet, such as sulforaphane from broccoli, also are independent activators of nuclear factor erythroid 2–related factor 2.²¹ Ketones are efficiently utilized by mitochondria, which also may result in the decreased production of reactive oxygen species and lower oxidative stress.²² Moreover, the ketone body β-hydroxybutyrate has demonstrated the ability to reduce proinflammatory IL-1β levels via suppression of nucleotide-binding domain-like receptor protein 3 inflammasome activity.^23,24 The activity of IL-1β is known to be elevated in many dermatologic conditions, including juvenile idiopathic arthritis, relapsing polychondritis, Schnitzler syndrome, hidradenitis suppurativa, Behçet disease, and other autoinflammatory syndromes.²⁵ Ketones also have been shown to inhibit the nuclear factor–κB proinflammatory signaling pathway.^22,26,27 Overexpression of IL-1β and aberrant activation of nuclear factor–κB are implicated in a variety of inflammatory, autoimmune, and oncologic cutaneous pathologies. The ketogenic diet may prove to be an effective adjunctive treatment for dermatologists to consider in select patient populations.^23,24,28-30

For patients with keratinocyte carcinomas, the ketogenic diet may offer the aforementioned anti-inflammatory and antioxidant effects, as well as suppression of the mechanistic target of rapamycin, a major regulator of cell metabolism and proliferation.^31,32 Inhibition of mechanistic target of rapamycin activity has been shown to slow tumor growth and reduce the development of squamous cell carcinoma.^25,33,34 The ketogenic diet also may exploit the preferential utilization of glucose exhibited by many types of cancer cells, thereby “starving” the tumor of its primary fuel source.^35,36 In vitro and animal studies in a variety of cancer types have demonstrated that a ketogenic metabolic state—achieved through the ketogenic diet or fasting—can sensitize tumor cells to chemotherapy and radiation while conferring a protective effect to normal cells.^37-40 This recently described phenomenon is known as differential stress resistance, but it has not been studied in keratinocyte malignancies or melanoma to date. Importantly, some basal cell carcinomas and BRAF V600E–mutated melanomas have worsened while on the ketogenic diet, suggesting more data is needed before it can be recommended for all cancer patients.^41,42 Furthermore, other skin conditions such as prurigo pigmentosa have been associated with initiation of the ketogenic diet.⁴³

Low FODMAP Diet

Fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) are short-chain carbohydrates that are poorly absorbed, osmotically active, and rapidly fermented by intestinal bacteria.⁴⁴ The low FODMAP diet has been shown to be efficacious for treatment of irritable bowel syndrome, small intestinal bacterial overgrowth (SIBO), and some cases of inflammatory bowel disease (IBD).^44-49 A low FODMAP diet may have potential implications for several dermatologic conditions.

Rosacea has been associated with various gastrointestinal tract disorders including irritable bowel syndrome, SIBO, and IBD.^50-54 A single study found that patients with rosacea had a 13-fold increased risk for SIBO.^55,56 Treatment of 40 patients with SIBO using rifaximin resulted in complete resolution of rosacea in all patients, with no relapse after a 3-year follow-up period.⁵⁵ Psoriasis also has been associated with SIBO and IBD.^57,58 One small study found that eradication of SIBO in psoriatic patients resulted in improved PASI scores and colorimetric values.⁵⁹

Although the long-term health consequences of the low FODMAP diet are unknown, further research on such dietary interventions for inflammatory skin conditions is warranted given the mounting evidence of a gut-skin connection and the role of the intestinal microbiome in skin health.^50,51

Gluten-Free Diet

Gluten is a protein found in a variety of grains. Although the role of gluten in the pathogenesis of celiac disease and dermatitis herpetiformis is indisputable, the deleterious effects of gluten outside of the context of these diseases remain controversial. There may be a compelling case for eliminating gluten in psoriasis patients with seropositivity for celiac disease. A recent systematic review found a 2.2-fold increased risk for celiac disease in psoriasis patients.⁶⁰ Antigliadin antibody titers also were found to be positively correlated with psoriatic disease severity.⁶¹ In addition, one open-label study found a reduction in PASI scores in 73% of patients with antigliadin antibodies after 3 months on a gluten-free diet compared to those without antibodies; however, the study only included 22 patients.⁶² Several other small studies have yielded similar results^63,64; however, antigliadin antibodies are neither the most sensitive nor specific markers of celiac disease, and additional testing should be completed in any patient who may carry this diagnosis. A survey study by the National Psoriasis Foundation found that the dietary change associated with the greatest skin improvement was removal of gluten and nightshade vegetables in approximately 50% of the 1200 psoriasis patients that responded.⁶⁵ Case reports of various dermatologic conditions including sarcoidosis, vitiligo, alopecia areata, lichen planus, dermatomyositis, pyoderma gangrenosum, erythema nodosum, leukocytoclastic vasculitis, linear IgA bullous dermatosis, and aphthous ulcerations have reportedly improved with a gluten-free diet; however, this should not be used as primary therapy in patients without celiac disease.^66-71 Because gluten-free diets can be expensive and challenging to follow, a formal assessment for celiac disease should be considered before recommendation of this dietary intervention.

Low Histamine Diet

Histamine is a biogenic amine produced by the decarboxylation of the amino acid histidine.⁷² It is found in several foods in varying amounts. Because bacteria can convert histidine into histamine, many fermented and aged foods such as kimchi, sauerkraut, cheese, and red wine contain high levels of histamine. Individuals who have decreased activity of diamine oxidase (DAO), an enzyme that degrades histamine, may be more susceptible to histamine intolerance.⁷² The symptoms of histamine intolerance are numerous and include gastrointestinal tract distress, rhinorrhea and nasal congestion, headache, urticaria, flushing, and pruritus. Histamine intolerance can mimic an IgE-mediated food allergy; however, allergy testing is negative in these patients. Unfortunately, there is no laboratory test for histamine intolerance; a double-blind, placebo-controlled food challenge is considered the gold-standard test.⁷²

As it pertains to dermatology, a low histamine diet may play a role in the treatment of certain patients with atopic dermatitis and chronic spontaneous urticaria. One study reported that 17 of 54 (31.5%) atopic patients had higher basal levels of serum histamine compared to controls.⁷³ Another study found that a histamine-free diet led to improvement in both histamine intolerance symptoms and atopic dermatitis disease severity (SCORing atopic dermatitis) in patients with low DAO activity.⁷⁴ In chronic spontaneous urticaria, a recent systematic review found that in 223 patients placed on a low histamine diet for 3 to 4 weeks, 12% and 44% achieved complete and partial remission, respectively.⁷⁵ Although treatment response based on a patient’s DAO activity level has not been correlated, a diet low in histamine may prove useful for patients with persistent atopic dermatitis and chronic spontaneous urticaria who have negative food allergy tests and report exacerbation of symptoms after ingestion of histamine-rich foods.^76,77

Mediterranean Diet

The Mediterranean diet has been touted as one of the healthiest diets to date, and large randomized clinical trials have demonstrated its effectiveness in weight loss, improving insulin sensitivity, and reducing inflammatory cytokine profiles.^78,79 A major criticism of the Mediterranean diet is that it has considerable ambiguity and lacks a precise definition due to the variability of what is consumed in different Mediterranean regions. Generally, the diet emphasizes high consumption of colorful fruits and vegetables, aromatic herbs and spices, olive oil, nuts, and seafood, as well as modest amounts of dairy, eggs, and red meat.⁸⁰ The anti-inflammatory effects of this diet largely have been attributed to its abundance of polyphenols, carotenoids, monounsaturated fatty acids, and omega-3 polyunsaturated fatty acids (PUFAs).^80,81 Examples of polyphenols include resveratrol in red grapes, quercetin in apples and red onions, and curcumin in turmeric, while examples of carotenoids include lycopene in tomatoes and zeaxanthin in dark leafy greens. Oleic acid is a monounsaturated fatty acid present in high concentrations in olive oil, while eicosapentaenoic acid and docosahexaenoic acid are omega-3 PUFAs predominantly found in fish.⁸²

Unfortunately, rigorous clinical trials regarding the Mediterranean diet as it pertains to dermatology have not been undertaken. Numerous observational studies in patients with psoriasis have suggested that close adherence to the Mediterranean diet was associated with improvement in PASI scores.^83-86 The National Psoriasis Foundation now recommends a trial of the Mediterranean diet in some patients with psoriasis, emphasizing increased dietary intake of olive oil, fish, and vegetables.⁸⁷ Adherence to a Mediterranean diet also has been inversely correlated to the severity of acne vulgaris and hidradenitis suppurativa^88,89; however, these studies failed to account for the multifactorial risk factors associated with these conditions. Mediterranean diets also may impart a chemopreventive effect, supported by a number of in vivo and in vitro studies demonstrating the inhibition and/or reversal of cutaneous DNA damage induced by UV radiation through supplementation with various phytonutrients and omega-3 PUFAs.^81,90-92 Although small case-control studies have found a decreased risk of basal cell carcinoma in those who closely adhered to a Mediterranean diet, more rigorous clinical research is needed.⁹³

Whole-Food, Plant-Based Diet

A whole-food, plant-based (WFPB) diet is another popular dietary approach that consists of eating fruits, vegetables, legumes, nuts, seeds, and grains in their whole natural form.⁹⁴ This diet discourages all animal products, including red meat, seafood, dairy, and eggs. It is similar to a vegan diet except that it eliminates all highly refined carbohydrates, vegetable oils, and other processed foods.⁹⁴ Randomized clinical studies have demonstrated the WFPB diet to be effective in the treatment of obesity and metabolic syndrome.^95,96

A WFPB diet has been shown to increase the antioxidant capacity of cells, lengthen telomeres, and reduce formation of advanced glycation end products.^94,97,98 These benefits may help combat accelerated skin aging, including increased skin permeability, reduced elasticity and hydration, decreased angiogenesis, impaired immune function, and decreased vitamin D synthesis. Accelerated skin aging can result in delayed wound healing and susceptibility to skin tears and ecchymoses and also may promote the development of cutaneous malignancies.⁹⁹ There remains a lack of clinical data studying a properly formulated WFPB diet in the dermatologic setting.

Paleolithic Diet

The paleolithic (Paleo) diet is an increasingly popular way of eating that attempts to mirror what our ancestors may have consumed between 10,000 and 2.5 million years ago.¹⁰⁰ It is similar to the Mediterranean diet but excludes grains, dairy, legumes, and nightshade vegetables. It also calls for elimination of highly processed sugars and oils as well as chemical food additives and preservatives. There is a strict variation of the diet for individuals with autoimmune disease that also excludes eggs, nuts, and seeds, as these can be inflammatory or immunogenic in some patients.^100-106 Other variations of the diet exist, including the ketogenic Paleo diet, pegan (Paleo vegan) diet, and lacto-Paleo diet.¹⁰⁰ An often cited criticism of the Paleo diet is the low intake of calcium and risk for osteoporosis; however, consumption of calcium-rich foods or a calcium supplement can address this concern.¹⁰⁷

Although small clinical studies have found the Paleo diet to be beneficial for various autoimmune diseases, clinical data evaluating the utility of the diet for cutaneous disease is lacking.^108,109 Numerous randomized trials have demonstrated the Paleo diet to be effective for weight loss and improving insulin sensitivity and lipid levels.^110-116 Thus, the Paleo diet may theoretically serve as a viable adjunct dietary approach to the treatment of cutaneous diseases associated with obesity and metabolic derangement.¹¹⁷

Carnivore Diet

Arguably the most controversial and radical diet is the carnivore diet. As the name implies, the carnivore diet is based on consuming solely animal products. A properly structured carnivore diet emphasizes a “nose-to-tail” eating approach where all parts of the animal including the muscle meats, organs, and fat are consumed. Proponents of the diet cite anthropologic evidence from fossil-stable carbon-13/carbon-12 isotope analyses, craniodental features, and numerous other adaptations that indicate increased consumption of meat during human evolution.^118-122 Notably, many early humans ate a carnivore diet, but life span was very short at this time, suggesting the diet may not be as beneficial as has been suggested.

Despite the abundance of anecdotal evidence supporting its use for a variety of chronic conditions, including cutaneous autoimmune disease, there is a virtual absence of high-quality research on the carnivore diet.^123-125

The purported benefits of the carnivore diet may be attributed to the consumption of organ meats that contain highly bioavailable essential vitamins and minerals, such as iron, zinc, copper, selenium, thiamine, niacin, folate, vitamin B₆, vitamin B₁₂, vitamin A, vitamin D, vitamin K, and choline.^126-128 Other dietary compounds that have demonstrated benefit for skin health and are predominantly found in animal foods include carnosine, carnitine, creatine, taurine, coenzyme Q10, and collagen.^129-134 Nevertheless, there is no data to recommend the elimination of antioxidant- and micronutrient-dense plant-based foods. Rigorous clinical research evaluating the efficacy and safety of the carnivore diet in dermatologic patients is needed. A carnivore diet should not be undertaken without the assistance of a dietician who can ensure adequate micronutrient and macronutrient support.

Final Thoughts

The adjunctive role of diet in the treatment of skin disease is expanding and becoming more widely accepted among dermatologists. Unfortunately, there remains a lack of randomized controlled trials confirming the efficacy of various dietary interventions in the dermatologic setting. Although evidence-based dietary recommendations currently are limited, it is important for dermatologists to be aware of the varied and nuanced dietary interventions employed by patients.

Ultimately, dietary recommendations must be personalized, considering a patient’s comorbidities, personal beliefs and preferences, and nutrigenetics. The emerging field of dermatonutrigenomics—the study of how dietary compounds interact with one’s genes to influence skin health—may allow for precise dietary recommendations to be made in dermatologic practice. Direct-to-consumer genetic tests targeted toward dermatology patients are already on the market, but their clinical utility awaits validation.¹ Because nutritional science is a constantly evolving field, becoming familiar with these popular diets will serve both dermatologists and their patients well.

Nutritional dermatoses are classically associated with dietary nutrient deficiencies; however, cutaneous disease as a consequence of nutrient excess often is overlooked. Chronic hyperglycemia and hyperinsulinemia resulting from excess carbohydrate intake may be implicated in a number of cutaneous pathologies, of which every dermatologist should be aware.^1-3

Although diabetic patients exhibit many cutaneous manifestations of excess carbohydrate consumption, the absence of a diagnosis of type 2 diabetes mellitus (T2DM) does not necessarily preclude them.^4-6 Emerging evidence now highlights the development of insulin resistance well before a patient ever meets the diagnostic criteria for T2DM.^7,8 Cutaneous disease can provide early insight into a patient’s glucose tolerance and may be the first sign of metabolic derangement. Prompt recognition of these cutaneous alterations and management of the patient’s underlying systemic disease can improve their quality of life and help prevent severe systemic complications associated with insulin resistance and impaired glucose tolerance.

The aim of this review is to highlight both common and rare cutaneous manifestations associated with the persistent consumption of high glycemic load diets, resultant hyperglycemic and hyperinsulinemic states, and the pathophysiologic mechanisms that underlie them.

Acanthosis Nigricans

Acanthosis nigricans (AN) is a highly prevalent cutaneous finding in individuals with insulin resistance that clinically presents as thickened, hyperpigmented, velvety plaques on the intertriginous and flexural surfaces. The most frequently involved sites include the neck, axillae (Figure), and inframammary and inguinal folds. Black and Hispanic patients most commonly are affected. Although classically associated with T2DM, AN also can be observed in normoglycemic individuals.^7-9 One recent study reported the rate of AN to be 36% in a cohort of middle-aged patients (N=320) with normal fasting blood glucose levels, while the rate of AN in matched patients with hyperglycemia (prediabetes and T2DM) was approximately 50%.⁷ Quantification of insulin resistance was performed using the homeostatic model assessment of insulin resistance index. Interestingly, the specificity for insulin resistance in normoglycemic and hyperglycemic subjects with AN was 85% and 90%, respectively.⁷ These findings suggest that AN may serve as a convenient surrogate marker for subclinical insulin resistance, a conclusion that has been reported in a series of previous studies.^8-10

Although the pathogenesis of AN has not been fully elucidated, it is known that persistently elevated blood glucose triggers continual secretion of insulin and insulinlike growth factor 1 (IGF-1), which results in the overstimulation of insulin and IGF-1 receptors on keratinocytes and dermal fibroblasts through direct and indirect pathways.^11,12 The resultant cellular proliferation can be observed histologically in the forms of orthokeratotic hyperkeratosis and papillomatosis, as occurs in AN.^11,13 Further supporting the association between elevated insulin and AN are reports of AN developing at sites of repeated insulin injection as well as genetic mutations in the insulin receptor resulting in severe AN in children.^14-16

The treatment of AN ultimately focuses on improving glycemic control and reducing insulin resistance through lifestyle modification and pharmacotherapy with agents such as metformin.^11,13 Dermatologic treatment with oral and topical keratolytic agents such as isotretinoin and other retinoids, salicylic acid, urea, or ammonium lactate may be used, but their efficacy generally has been limited.^11,13,17,18

Diabetic Dermopathy

Diabetic dermopathy (DD), commonly known as shin spots, refers to the red-brown, atrophic, circinate macules and patches that often appear on the lower extremities in patients with T2DM. Although the pretibial area is the most frequently involved site, other areas of bony prominence such as the forearms can be affected. The prevalence of DD in the diabetic population can be exceedingly high, with some studies reporting incidence rates greater than 50%, particularly in those with poorly controlled T2DM.^19-21 Interestingly, DD also has been documented in patients without T2DM and has been postulated to be an early sign of insulin resistance.^20,22

The pathogenesis of DD remains uncertain, but one proposed mechanism is through microvascular damage caused by hyperglycemia-induced, nonenzymatic glycation, possibly in conjunction with mild trauma, that leads to the deposition of hemosiderin and melanin in the skin.^20,23 A recent study identified increased vascularization of dermopathy lesions when compared with surrounding tissue.²⁴ Subcutaneous nerve ischemia and degeneration secondary to diabetic neuropathy also have been postulated as causative.^20,23 Given the lack of effective therapies and the asymptomatic nature of DD, treatment typically is not pursued. However, DD is associated with other diabetic microvascular complications, including diabetic nephropathy, retinopathy, and neuropathy. For this reason, identification of DD warrants further characterization and management of a patient’s underlying diabetes.^19,20

Scleredema Diabeticorum

Scleredema diabeticorum (SD) refers to the slowly progressive, painless thickening and woody induration of the neck, shoulders, and upper back in individuals with long-standing, poorly controlled diabetes. The condition is almost exclusively seen in the diabetic population, with prevalence rates reported to be as high as 14%.^25-27 Although SD generally is asymptomatic, some individuals may experience restricted mobility and decreased sensation in affected areas.^25,27,28 The diagnosis of SD frequently is missed or ignored clinically. Biopsy can provide diagnostic confirmation of this entity, as histopathology reveals a thickened reticular dermis with an accumulation of collagen and adjacent mucinous infiltrate with no edema or sclerosis.^28,29

Although the pathogenesis of SD is not well established, it is theorized that the binding of advanced glycation end products (AGEs) to collagen fibers impairs proper cross-linking and degradation by collagenase.^29-31 It is well known that hyperglycemic conditions can promote endogenous formation of AGEs, which occur when reducing sugar molecules become glycated through a nonenzymatic reaction.^30-32 The Western diet also is high in preformed AGEs, which are created primarily through certain high-heat cooking methods such as frying and grilling.^31,32 Hyperglycemia-induced stimulation of fibroblasts also has been proposed as a driver of increased collagen deposition observed histologically in SD.^28,29,33 Treatment of SD can be difficult, as there are no consistently reported therapies, and even improvement in glycemic control does not appear to reverse this condition.²⁹ Case reports have demonstrated some efficacy with various phototherapeutic modalities, including psoralen plus UVA and narrowband UVB phototherapy.^34-36

Ichthyosiform Skin Changes

Ichthyosiform skin changes refer to areas of xerosis and scaling that classically present on the anterior distal lower extremities. Although ichthyosiform alterations have been associated with numerous systemic diseases, they often represent an early finding in diabetic patients.^27,37 The development of ichthyosiform skin changes has been linked to the formation and accumulation of AGEs, which can cause defective cell adhesion in the stratum corneum.^37,38 Treatment with topical emollients and keratolytics may prove beneficial for the skin but do not improve the underlying systemic condition.³⁹

Acrochordons

Acrochordons (skin tags) are common benign fibroepithelial polyps that classically present on the face, neck, and trunk. The underlying mechanism responsible for the development of acrochordons is uncertain, but the association with insulin resistance and impaired carbohydrate metabolism is well validated.^40-46 Several large cross-sectional and case-control studies have reported rates of T2DM ranging from 23% to 72% in patients with acrochordons.^41,42,47 The pathophysiology may involve an increase in tissue and epidermal growth factors driven by elevated serum insulin levels, stimulation of IGF-1 receptors, and a localized proliferation of cutaneous tissue in elastin-poor areas.^45,48,49 Interestingly, the quantity of acrochordons has been positively correlated with fasting blood glucose levels. Additionally, the presence of 30 or more acrochordons was found to increase the risk of developing T2DM.⁴¹ Therefore, the presence and number of acrochordons may serve as a convenient indicator of systemic glycemic control and insulin resistance. Screening for T2DM is warranted in individuals without a prior diagnosis who present with multiple acrochordons.

Keratosis Pilaris

Keratosis pilaris (KP) is a benign skin condition characterized by pink-red, erythematous, monomorphic, follicular papules often seen on the extensor arms, thighs, buttocks, and cheeks. Keratosis pilaris is exceedingly common in the general population but occurs more frequently and with more extensive involvement in those with atopic dermatitis and T2DM.^27,50,51 The mechanism underlying the hyperkeratosis and inflammatory change observed in KP is not well understood and is likely multifactorial.^52,53 Hyperandrogenism, as a consequence of hyperinsulinemia, may play an important role in KP, as elevated circulating androgens are known drivers of keratinocyte proliferation of the pilosebaceous unit of hair follicles.^52,54 Support for this theory includes the clinical exaggeration of KP frequently encountered around puberty when androgen levels peak.^55,56 Moreover, one study found a higher incidence of KP among adolescent patients with type 1 diabetes mellitus than among healthy age-matched controls.²⁷ The most effective treatment of KP appears to be laser therapy, particularly the Q-switched Nd:YAG laser. Numerous topical modalities have been employed to treat KP but exhibit limited efficacy, including mineral oil, tacrolimus, azelaic acid, and salicylic acid, among others.⁵⁷

Necrobiosis Lipoidica

Necrobiosis lipoidica (NL) is a chronic granulomatous skin condition of unknown origin that presents with well-demarcated, yellow-brown, atrophic patches and plaques often found exclusively on the shins. There is a strong association with type 1 diabetes mellitus, with reported rates ranging from 11% to 65% in patients with NL.^58-60 In a recent retrospective study of 236 patients with NL, 58.5% of patients had diabetes.⁶¹ Nevertheless, NL is a rare entity that affects less than 1% of the diabetic population.⁶⁰ Given its correlation with diabetes, it has been postulated that the pathogenesis of NL is due to microvascular ischemic changes resulting from prolonged hyperglycemia.⁶⁰ However, studies revealing an increase in blood flow to NL lesions suggest that the condition may instead be attributed to an inflammatory process.⁶² Despite the disfiguring appearance, the lesions of NL often are asymptomatic. Pain or pruritus may develop secondary to ulceration, which occurs in approximately one-third of patients. Although many treatment options have been attempted—including topical and intralesional corticosteroids, immunomodulators, platelet inhibitors, and phototherapy—efficacy is limited.⁶⁰

Bullosis Diabeticorum

Bullosis diabeticorum (BD) is the abrupt onset of noninflammatory vesicles and bullae developing in the setting of diabetes. The prevalence of BD in the diabetic population ranges from 0.16% to 0.5%.^63-66 Bullosis diabeticorum occasionally has been reported to occur prior to the onset of diabetes, warranting screening hemoglobin A_1c in patients without an established diagnosis of diabetes.⁶⁷ Bullae most commonly present over the acral surfaces, but the lower extremities also are routinely affected. Bullae typically are large and painless, contain clear fluid, and may progress from tense to flaccid over the course of several days. Although histologic analysis reveals nonspecific findings, biopsy may be useful in excluding other bullous disorders. Because BD is a benign condition that spontaneously resolves over several weeks, treatment rarely is pursued.^63,64

Generalized Granuloma Annulare

Generalized granuloma annulare (GA) is an idiopathic inflammatory cutaneous disorder characterized by pink-red, arciform and annular, nonscaly, beaded papules and plaques. Granuloma annulare can be localized or generalized with perforating, patch, and palmoplantar variants. Although the pathogenesis is poorly understood, some studies have demonstrated a correlation between GA and type 1 diabetes mellitus.^68-71 Generalized GA appears to be most strongly associated with diabetes, and approximately 10% to 15% of cases occur in this population.^70,72 Because GA has been reported to precede the diagnosis of diabetes, patients with generalized or recurrent localized GA should be screened for persistent hyperglycemia with a hemoglobin A_1c test.^71,73 Although some GA is self-resolving, treatment options for persevering GA include topical and intralesional steroids, isotretinoin, dapsone, tacrolimus, antimalarials, biologic medications, and psoralen plus UVA therapy.⁷⁴

Final Thoughts

Mechanistic links between common cutaneous conditions and persistent hyperglycemic and hyperinsulinemic states are slowly emerging. Hyperglycemia promotes nonenzymatic glycation of the vascular endothelium as well as formation of AGEs that impair cross-linking of collagen in the skin. The consequent microangiopathic damage may lead to cutaneous conditions such as DD, NL, and BD. In addition to microvascular compromise, impaired collagen cross-linking may result in ichthyosiform skin changes and SD. Hyperinsulinemia causes increased circulating levels of IGF-1, which leads to the overactivation of IGF-1 receptors present on fibroblasts and keratinocytes. This aberrant IGF-1 signaling drives cellular hyperproliferation and differentiation, which may be responsible for cutaneous findings such as AN, KP, and/or acrochordons. An insulin-dependent increase in IGF-1 and androgenic signaling may have implications for hormonally driven inflammatory skin disorders such as acne vulgaris and hidradenitis suppurativa, warranting further investigation.

Physicians should be aware of these dermatologic manifestations and their proposed underlying pathophysiologic mechanisms related to impaired glucose tolerance and insulin resistance. A diagnosis of T2DM is not a prerequisite for metabolic disturbance, and the skin may serve as the first clue to underlying systemic disease. Early identification of these cutaneous conditions may lead to timely patient counseling, lifestyle modification, and/or medical management, preventing the long-term sequelae associated with metabolic disorders.

Nutritional dermatoses are classically associated with dietary nutrient deficiencies; however, cutaneous disease as a consequence of nutrient excess often is overlooked. Chronic hyperglycemia and hyperinsulinemia resulting from excess carbohydrate intake may be implicated in a number of cutaneous pathologies, of which every dermatologist should be aware.^1-3

Although diabetic patients exhibit many cutaneous manifestations of excess carbohydrate consumption, the absence of a diagnosis of type 2 diabetes mellitus (T2DM) does not necessarily preclude them.^4-6 Emerging evidence now highlights the development of insulin resistance well before a patient ever meets the diagnostic criteria for T2DM.^7,8 Cutaneous disease can provide early insight into a patient’s glucose tolerance and may be the first sign of metabolic derangement. Prompt recognition of these cutaneous alterations and management of the patient’s underlying systemic disease can improve their quality of life and help prevent severe systemic complications associated with insulin resistance and impaired glucose tolerance.

The aim of this review is to highlight both common and rare cutaneous manifestations associated with the persistent consumption of high glycemic load diets, resultant hyperglycemic and hyperinsulinemic states, and the pathophysiologic mechanisms that underlie them.

Acanthosis Nigricans

Acanthosis nigricans (AN) is a highly prevalent cutaneous finding in individuals with insulin resistance that clinically presents as thickened, hyperpigmented, velvety plaques on the intertriginous and flexural surfaces. The most frequently involved sites include the neck, axillae (Figure), and inframammary and inguinal folds. Black and Hispanic patients most commonly are affected. Although classically associated with T2DM, AN also can be observed in normoglycemic individuals.^7-9 One recent study reported the rate of AN to be 36% in a cohort of middle-aged patients (N=320) with normal fasting blood glucose levels, while the rate of AN in matched patients with hyperglycemia (prediabetes and T2DM) was approximately 50%.⁷ Quantification of insulin resistance was performed using the homeostatic model assessment of insulin resistance index. Interestingly, the specificity for insulin resistance in normoglycemic and hyperglycemic subjects with AN was 85% and 90%, respectively.⁷ These findings suggest that AN may serve as a convenient surrogate marker for subclinical insulin resistance, a conclusion that has been reported in a series of previous studies.^8-10

Although the pathogenesis of AN has not been fully elucidated, it is known that persistently elevated blood glucose triggers continual secretion of insulin and insulinlike growth factor 1 (IGF-1), which results in the overstimulation of insulin and IGF-1 receptors on keratinocytes and dermal fibroblasts through direct and indirect pathways.^11,12 The resultant cellular proliferation can be observed histologically in the forms of orthokeratotic hyperkeratosis and papillomatosis, as occurs in AN.^11,13 Further supporting the association between elevated insulin and AN are reports of AN developing at sites of repeated insulin injection as well as genetic mutations in the insulin receptor resulting in severe AN in children.^14-16

The treatment of AN ultimately focuses on improving glycemic control and reducing insulin resistance through lifestyle modification and pharmacotherapy with agents such as metformin.^11,13 Dermatologic treatment with oral and topical keratolytic agents such as isotretinoin and other retinoids, salicylic acid, urea, or ammonium lactate may be used, but their efficacy generally has been limited.^11,13,17,18

Diabetic Dermopathy

Diabetic dermopathy (DD), commonly known as shin spots, refers to the red-brown, atrophic, circinate macules and patches that often appear on the lower extremities in patients with T2DM. Although the pretibial area is the most frequently involved site, other areas of bony prominence such as the forearms can be affected. The prevalence of DD in the diabetic population can be exceedingly high, with some studies reporting incidence rates greater than 50%, particularly in those with poorly controlled T2DM.^19-21 Interestingly, DD also has been documented in patients without T2DM and has been postulated to be an early sign of insulin resistance.^20,22

The pathogenesis of DD remains uncertain, but one proposed mechanism is through microvascular damage caused by hyperglycemia-induced, nonenzymatic glycation, possibly in conjunction with mild trauma, that leads to the deposition of hemosiderin and melanin in the skin.^20,23 A recent study identified increased vascularization of dermopathy lesions when compared with surrounding tissue.²⁴ Subcutaneous nerve ischemia and degeneration secondary to diabetic neuropathy also have been postulated as causative.^20,23 Given the lack of effective therapies and the asymptomatic nature of DD, treatment typically is not pursued. However, DD is associated with other diabetic microvascular complications, including diabetic nephropathy, retinopathy, and neuropathy. For this reason, identification of DD warrants further characterization and management of a patient’s underlying diabetes.^19,20

Scleredema Diabeticorum

Scleredema diabeticorum (SD) refers to the slowly progressive, painless thickening and woody induration of the neck, shoulders, and upper back in individuals with long-standing, poorly controlled diabetes. The condition is almost exclusively seen in the diabetic population, with prevalence rates reported to be as high as 14%.^25-27 Although SD generally is asymptomatic, some individuals may experience restricted mobility and decreased sensation in affected areas.^25,27,28 The diagnosis of SD frequently is missed or ignored clinically. Biopsy can provide diagnostic confirmation of this entity, as histopathology reveals a thickened reticular dermis with an accumulation of collagen and adjacent mucinous infiltrate with no edema or sclerosis.^28,29

Although the pathogenesis of SD is not well established, it is theorized that the binding of advanced glycation end products (AGEs) to collagen fibers impairs proper cross-linking and degradation by collagenase.^29-31 It is well known that hyperglycemic conditions can promote endogenous formation of AGEs, which occur when reducing sugar molecules become glycated through a nonenzymatic reaction.^30-32 The Western diet also is high in preformed AGEs, which are created primarily through certain high-heat cooking methods such as frying and grilling.^31,32 Hyperglycemia-induced stimulation of fibroblasts also has been proposed as a driver of increased collagen deposition observed histologically in SD.^28,29,33 Treatment of SD can be difficult, as there are no consistently reported therapies, and even improvement in glycemic control does not appear to reverse this condition.²⁹ Case reports have demonstrated some efficacy with various phototherapeutic modalities, including psoralen plus UVA and narrowband UVB phototherapy.^34-36

Ichthyosiform Skin Changes

Ichthyosiform skin changes refer to areas of xerosis and scaling that classically present on the anterior distal lower extremities. Although ichthyosiform alterations have been associated with numerous systemic diseases, they often represent an early finding in diabetic patients.^27,37 The development of ichthyosiform skin changes has been linked to the formation and accumulation of AGEs, which can cause defective cell adhesion in the stratum corneum.^37,38 Treatment with topical emollients and keratolytics may prove beneficial for the skin but do not improve the underlying systemic condition.³⁹

Acrochordons

Acrochordons (skin tags) are common benign fibroepithelial polyps that classically present on the face, neck, and trunk. The underlying mechanism responsible for the development of acrochordons is uncertain, but the association with insulin resistance and impaired carbohydrate metabolism is well validated.^40-46 Several large cross-sectional and case-control studies have reported rates of T2DM ranging from 23% to 72% in patients with acrochordons.^41,42,47 The pathophysiology may involve an increase in tissue and epidermal growth factors driven by elevated serum insulin levels, stimulation of IGF-1 receptors, and a localized proliferation of cutaneous tissue in elastin-poor areas.^45,48,49 Interestingly, the quantity of acrochordons has been positively correlated with fasting blood glucose levels. Additionally, the presence of 30 or more acrochordons was found to increase the risk of developing T2DM.⁴¹ Therefore, the presence and number of acrochordons may serve as a convenient indicator of systemic glycemic control and insulin resistance. Screening for T2DM is warranted in individuals without a prior diagnosis who present with multiple acrochordons.

Keratosis Pilaris

Keratosis pilaris (KP) is a benign skin condition characterized by pink-red, erythematous, monomorphic, follicular papules often seen on the extensor arms, thighs, buttocks, and cheeks. Keratosis pilaris is exceedingly common in the general population but occurs more frequently and with more extensive involvement in those with atopic dermatitis and T2DM.^27,50,51 The mechanism underlying the hyperkeratosis and inflammatory change observed in KP is not well understood and is likely multifactorial.^52,53 Hyperandrogenism, as a consequence of hyperinsulinemia, may play an important role in KP, as elevated circulating androgens are known drivers of keratinocyte proliferation of the pilosebaceous unit of hair follicles.^52,54 Support for this theory includes the clinical exaggeration of KP frequently encountered around puberty when androgen levels peak.^55,56 Moreover, one study found a higher incidence of KP among adolescent patients with type 1 diabetes mellitus than among healthy age-matched controls.²⁷ The most effective treatment of KP appears to be laser therapy, particularly the Q-switched Nd:YAG laser. Numerous topical modalities have been employed to treat KP but exhibit limited efficacy, including mineral oil, tacrolimus, azelaic acid, and salicylic acid, among others.⁵⁷

Necrobiosis Lipoidica

Necrobiosis lipoidica (NL) is a chronic granulomatous skin condition of unknown origin that presents with well-demarcated, yellow-brown, atrophic patches and plaques often found exclusively on the shins. There is a strong association with type 1 diabetes mellitus, with reported rates ranging from 11% to 65% in patients with NL.^58-60 In a recent retrospective study of 236 patients with NL, 58.5% of patients had diabetes.⁶¹ Nevertheless, NL is a rare entity that affects less than 1% of the diabetic population.⁶⁰ Given its correlation with diabetes, it has been postulated that the pathogenesis of NL is due to microvascular ischemic changes resulting from prolonged hyperglycemia.⁶⁰ However, studies revealing an increase in blood flow to NL lesions suggest that the condition may instead be attributed to an inflammatory process.⁶² Despite the disfiguring appearance, the lesions of NL often are asymptomatic. Pain or pruritus may develop secondary to ulceration, which occurs in approximately one-third of patients. Although many treatment options have been attempted—including topical and intralesional corticosteroids, immunomodulators, platelet inhibitors, and phototherapy—efficacy is limited.⁶⁰

Bullosis Diabeticorum

Bullosis diabeticorum (BD) is the abrupt onset of noninflammatory vesicles and bullae developing in the setting of diabetes. The prevalence of BD in the diabetic population ranges from 0.16% to 0.5%.^63-66 Bullosis diabeticorum occasionally has been reported to occur prior to the onset of diabetes, warranting screening hemoglobin A_1c in patients without an established diagnosis of diabetes.⁶⁷ Bullae most commonly present over the acral surfaces, but the lower extremities also are routinely affected. Bullae typically are large and painless, contain clear fluid, and may progress from tense to flaccid over the course of several days. Although histologic analysis reveals nonspecific findings, biopsy may be useful in excluding other bullous disorders. Because BD is a benign condition that spontaneously resolves over several weeks, treatment rarely is pursued.^63,64

Generalized Granuloma Annulare

Generalized granuloma annulare (GA) is an idiopathic inflammatory cutaneous disorder characterized by pink-red, arciform and annular, nonscaly, beaded papules and plaques. Granuloma annulare can be localized or generalized with perforating, patch, and palmoplantar variants. Although the pathogenesis is poorly understood, some studies have demonstrated a correlation between GA and type 1 diabetes mellitus.^68-71 Generalized GA appears to be most strongly associated with diabetes, and approximately 10% to 15% of cases occur in this population.^70,72 Because GA has been reported to precede the diagnosis of diabetes, patients with generalized or recurrent localized GA should be screened for persistent hyperglycemia with a hemoglobin A_1c test.^71,73 Although some GA is self-resolving, treatment options for persevering GA include topical and intralesional steroids, isotretinoin, dapsone, tacrolimus, antimalarials, biologic medications, and psoralen plus UVA therapy.⁷⁴

Final Thoughts

Mechanistic links between common cutaneous conditions and persistent hyperglycemic and hyperinsulinemic states are slowly emerging. Hyperglycemia promotes nonenzymatic glycation of the vascular endothelium as well as formation of AGEs that impair cross-linking of collagen in the skin. The consequent microangiopathic damage may lead to cutaneous conditions such as DD, NL, and BD. In addition to microvascular compromise, impaired collagen cross-linking may result in ichthyosiform skin changes and SD. Hyperinsulinemia causes increased circulating levels of IGF-1, which leads to the overactivation of IGF-1 receptors present on fibroblasts and keratinocytes. This aberrant IGF-1 signaling drives cellular hyperproliferation and differentiation, which may be responsible for cutaneous findings such as AN, KP, and/or acrochordons. An insulin-dependent increase in IGF-1 and androgenic signaling may have implications for hormonally driven inflammatory skin disorders such as acne vulgaris and hidradenitis suppurativa, warranting further investigation.

Physicians should be aware of these dermatologic manifestations and their proposed underlying pathophysiologic mechanisms related to impaired glucose tolerance and insulin resistance. A diagnosis of T2DM is not a prerequisite for metabolic disturbance, and the skin may serve as the first clue to underlying systemic disease. Early identification of these cutaneous conditions may lead to timely patient counseling, lifestyle modification, and/or medical management, preventing the long-term sequelae associated with metabolic disorders.

Nutritional dermatoses are classically associated with dietary nutrient deficiencies; however, cutaneous disease as a consequence of nutrient excess often is overlooked. Chronic hyperglycemia and hyperinsulinemia resulting from excess carbohydrate intake may be implicated in a number of cutaneous pathologies, of which every dermatologist should be aware.^1-3

Although diabetic patients exhibit many cutaneous manifestations of excess carbohydrate consumption, the absence of a diagnosis of type 2 diabetes mellitus (T2DM) does not necessarily preclude them.^4-6 Emerging evidence now highlights the development of insulin resistance well before a patient ever meets the diagnostic criteria for T2DM.^7,8 Cutaneous disease can provide early insight into a patient’s glucose tolerance and may be the first sign of metabolic derangement. Prompt recognition of these cutaneous alterations and management of the patient’s underlying systemic disease can improve their quality of life and help prevent severe systemic complications associated with insulin resistance and impaired glucose tolerance.

The aim of this review is to highlight both common and rare cutaneous manifestations associated with the persistent consumption of high glycemic load diets, resultant hyperglycemic and hyperinsulinemic states, and the pathophysiologic mechanisms that underlie them.

Acanthosis Nigricans

Acanthosis nigricans (AN) is a highly prevalent cutaneous finding in individuals with insulin resistance that clinically presents as thickened, hyperpigmented, velvety plaques on the intertriginous and flexural surfaces. The most frequently involved sites include the neck, axillae (Figure), and inframammary and inguinal folds. Black and Hispanic patients most commonly are affected. Although classically associated with T2DM, AN also can be observed in normoglycemic individuals.^7-9 One recent study reported the rate of AN to be 36% in a cohort of middle-aged patients (N=320) with normal fasting blood glucose levels, while the rate of AN in matched patients with hyperglycemia (prediabetes and T2DM) was approximately 50%.⁷ Quantification of insulin resistance was performed using the homeostatic model assessment of insulin resistance index. Interestingly, the specificity for insulin resistance in normoglycemic and hyperglycemic subjects with AN was 85% and 90%, respectively.⁷ These findings suggest that AN may serve as a convenient surrogate marker for subclinical insulin resistance, a conclusion that has been reported in a series of previous studies.^8-10

Although the pathogenesis of AN has not been fully elucidated, it is known that persistently elevated blood glucose triggers continual secretion of insulin and insulinlike growth factor 1 (IGF-1), which results in the overstimulation of insulin and IGF-1 receptors on keratinocytes and dermal fibroblasts through direct and indirect pathways.^11,12 The resultant cellular proliferation can be observed histologically in the forms of orthokeratotic hyperkeratosis and papillomatosis, as occurs in AN.^11,13 Further supporting the association between elevated insulin and AN are reports of AN developing at sites of repeated insulin injection as well as genetic mutations in the insulin receptor resulting in severe AN in children.^14-16

The treatment of AN ultimately focuses on improving glycemic control and reducing insulin resistance through lifestyle modification and pharmacotherapy with agents such as metformin.^11,13 Dermatologic treatment with oral and topical keratolytic agents such as isotretinoin and other retinoids, salicylic acid, urea, or ammonium lactate may be used, but their efficacy generally has been limited.^11,13,17,18

Diabetic Dermopathy

Diabetic dermopathy (DD), commonly known as shin spots, refers to the red-brown, atrophic, circinate macules and patches that often appear on the lower extremities in patients with T2DM. Although the pretibial area is the most frequently involved site, other areas of bony prominence such as the forearms can be affected. The prevalence of DD in the diabetic population can be exceedingly high, with some studies reporting incidence rates greater than 50%, particularly in those with poorly controlled T2DM.^19-21 Interestingly, DD also has been documented in patients without T2DM and has been postulated to be an early sign of insulin resistance.^20,22

The pathogenesis of DD remains uncertain, but one proposed mechanism is through microvascular damage caused by hyperglycemia-induced, nonenzymatic glycation, possibly in conjunction with mild trauma, that leads to the deposition of hemosiderin and melanin in the skin.^20,23 A recent study identified increased vascularization of dermopathy lesions when compared with surrounding tissue.²⁴ Subcutaneous nerve ischemia and degeneration secondary to diabetic neuropathy also have been postulated as causative.^20,23 Given the lack of effective therapies and the asymptomatic nature of DD, treatment typically is not pursued. However, DD is associated with other diabetic microvascular complications, including diabetic nephropathy, retinopathy, and neuropathy. For this reason, identification of DD warrants further characterization and management of a patient’s underlying diabetes.^19,20

Scleredema Diabeticorum

Scleredema diabeticorum (SD) refers to the slowly progressive, painless thickening and woody induration of the neck, shoulders, and upper back in individuals with long-standing, poorly controlled diabetes. The condition is almost exclusively seen in the diabetic population, with prevalence rates reported to be as high as 14%.^25-27 Although SD generally is asymptomatic, some individuals may experience restricted mobility and decreased sensation in affected areas.^25,27,28 The diagnosis of SD frequently is missed or ignored clinically. Biopsy can provide diagnostic confirmation of this entity, as histopathology reveals a thickened reticular dermis with an accumulation of collagen and adjacent mucinous infiltrate with no edema or sclerosis.^28,29

Although the pathogenesis of SD is not well established, it is theorized that the binding of advanced glycation end products (AGEs) to collagen fibers impairs proper cross-linking and degradation by collagenase.^29-31 It is well known that hyperglycemic conditions can promote endogenous formation of AGEs, which occur when reducing sugar molecules become glycated through a nonenzymatic reaction.^30-32 The Western diet also is high in preformed AGEs, which are created primarily through certain high-heat cooking methods such as frying and grilling.^31,32 Hyperglycemia-induced stimulation of fibroblasts also has been proposed as a driver of increased collagen deposition observed histologically in SD.^28,29,33 Treatment of SD can be difficult, as there are no consistently reported therapies, and even improvement in glycemic control does not appear to reverse this condition.²⁹ Case reports have demonstrated some efficacy with various phototherapeutic modalities, including psoralen plus UVA and narrowband UVB phototherapy.^34-36

Ichthyosiform Skin Changes

Ichthyosiform skin changes refer to areas of xerosis and scaling that classically present on the anterior distal lower extremities. Although ichthyosiform alterations have been associated with numerous systemic diseases, they often represent an early finding in diabetic patients.^27,37 The development of ichthyosiform skin changes has been linked to the formation and accumulation of AGEs, which can cause defective cell adhesion in the stratum corneum.^37,38 Treatment with topical emollients and keratolytics may prove beneficial for the skin but do not improve the underlying systemic condition.³⁹

Acrochordons

Acrochordons (skin tags) are common benign fibroepithelial polyps that classically present on the face, neck, and trunk. The underlying mechanism responsible for the development of acrochordons is uncertain, but the association with insulin resistance and impaired carbohydrate metabolism is well validated.^40-46 Several large cross-sectional and case-control studies have reported rates of T2DM ranging from 23% to 72% in patients with acrochordons.^41,42,47 The pathophysiology may involve an increase in tissue and epidermal growth factors driven by elevated serum insulin levels, stimulation of IGF-1 receptors, and a localized proliferation of cutaneous tissue in elastin-poor areas.^45,48,49 Interestingly, the quantity of acrochordons has been positively correlated with fasting blood glucose levels. Additionally, the presence of 30 or more acrochordons was found to increase the risk of developing T2DM.⁴¹ Therefore, the presence and number of acrochordons may serve as a convenient indicator of systemic glycemic control and insulin resistance. Screening for T2DM is warranted in individuals without a prior diagnosis who present with multiple acrochordons.

Keratosis Pilaris

Keratosis pilaris (KP) is a benign skin condition characterized by pink-red, erythematous, monomorphic, follicular papules often seen on the extensor arms, thighs, buttocks, and cheeks. Keratosis pilaris is exceedingly common in the general population but occurs more frequently and with more extensive involvement in those with atopic dermatitis and T2DM.^27,50,51 The mechanism underlying the hyperkeratosis and inflammatory change observed in KP is not well understood and is likely multifactorial.^52,53 Hyperandrogenism, as a consequence of hyperinsulinemia, may play an important role in KP, as elevated circulating androgens are known drivers of keratinocyte proliferation of the pilosebaceous unit of hair follicles.^52,54 Support for this theory includes the clinical exaggeration of KP frequently encountered around puberty when androgen levels peak.^55,56 Moreover, one study found a higher incidence of KP among adolescent patients with type 1 diabetes mellitus than among healthy age-matched controls.²⁷ The most effective treatment of KP appears to be laser therapy, particularly the Q-switched Nd:YAG laser. Numerous topical modalities have been employed to treat KP but exhibit limited efficacy, including mineral oil, tacrolimus, azelaic acid, and salicylic acid, among others.⁵⁷

Necrobiosis Lipoidica

Necrobiosis lipoidica (NL) is a chronic granulomatous skin condition of unknown origin that presents with well-demarcated, yellow-brown, atrophic patches and plaques often found exclusively on the shins. There is a strong association with type 1 diabetes mellitus, with reported rates ranging from 11% to 65% in patients with NL.^58-60 In a recent retrospective study of 236 patients with NL, 58.5% of patients had diabetes.⁶¹ Nevertheless, NL is a rare entity that affects less than 1% of the diabetic population.⁶⁰ Given its correlation with diabetes, it has been postulated that the pathogenesis of NL is due to microvascular ischemic changes resulting from prolonged hyperglycemia.⁶⁰ However, studies revealing an increase in blood flow to NL lesions suggest that the condition may instead be attributed to an inflammatory process.⁶² Despite the disfiguring appearance, the lesions of NL often are asymptomatic. Pain or pruritus may develop secondary to ulceration, which occurs in approximately one-third of patients. Although many treatment options have been attempted—including topical and intralesional corticosteroids, immunomodulators, platelet inhibitors, and phototherapy—efficacy is limited.⁶⁰

Bullosis Diabeticorum

Bullosis diabeticorum (BD) is the abrupt onset of noninflammatory vesicles and bullae developing in the setting of diabetes. The prevalence of BD in the diabetic population ranges from 0.16% to 0.5%.^63-66 Bullosis diabeticorum occasionally has been reported to occur prior to the onset of diabetes, warranting screening hemoglobin A_1c in patients without an established diagnosis of diabetes.⁶⁷ Bullae most commonly present over the acral surfaces, but the lower extremities also are routinely affected. Bullae typically are large and painless, contain clear fluid, and may progress from tense to flaccid over the course of several days. Although histologic analysis reveals nonspecific findings, biopsy may be useful in excluding other bullous disorders. Because BD is a benign condition that spontaneously resolves over several weeks, treatment rarely is pursued.^63,64

Generalized Granuloma Annulare

Generalized granuloma annulare (GA) is an idiopathic inflammatory cutaneous disorder characterized by pink-red, arciform and annular, nonscaly, beaded papules and plaques. Granuloma annulare can be localized or generalized with perforating, patch, and palmoplantar variants. Although the pathogenesis is poorly understood, some studies have demonstrated a correlation between GA and type 1 diabetes mellitus.^68-71 Generalized GA appears to be most strongly associated with diabetes, and approximately 10% to 15% of cases occur in this population.^70,72 Because GA has been reported to precede the diagnosis of diabetes, patients with generalized or recurrent localized GA should be screened for persistent hyperglycemia with a hemoglobin A_1c test.^71,73 Although some GA is self-resolving, treatment options for persevering GA include topical and intralesional steroids, isotretinoin, dapsone, tacrolimus, antimalarials, biologic medications, and psoralen plus UVA therapy.⁷⁴

Final Thoughts

Mechanistic links between common cutaneous conditions and persistent hyperglycemic and hyperinsulinemic states are slowly emerging. Hyperglycemia promotes nonenzymatic glycation of the vascular endothelium as well as formation of AGEs that impair cross-linking of collagen in the skin. The consequent microangiopathic damage may lead to cutaneous conditions such as DD, NL, and BD. In addition to microvascular compromise, impaired collagen cross-linking may result in ichthyosiform skin changes and SD. Hyperinsulinemia causes increased circulating levels of IGF-1, which leads to the overactivation of IGF-1 receptors present on fibroblasts and keratinocytes. This aberrant IGF-1 signaling drives cellular hyperproliferation and differentiation, which may be responsible for cutaneous findings such as AN, KP, and/or acrochordons. An insulin-dependent increase in IGF-1 and androgenic signaling may have implications for hormonally driven inflammatory skin disorders such as acne vulgaris and hidradenitis suppurativa, warranting further investigation.

Physicians should be aware of these dermatologic manifestations and their proposed underlying pathophysiologic mechanisms related to impaired glucose tolerance and insulin resistance. A diagnosis of T2DM is not a prerequisite for metabolic disturbance, and the skin may serve as the first clue to underlying systemic disease. Early identification of these cutaneous conditions may lead to timely patient counseling, lifestyle modification, and/or medical management, preventing the long-term sequelae associated with metabolic disorders.