Diet and hair loss: effects of nutrient deficiency and supplement use

Patients presenting with hair loss should be screened by medical history, dietary history and physical exam for risk factors for nutrient deficiency. If warranted, laboratory studies may be performed. In patients with no risk factors, further laboratory evaluation searching for nutritional deficiencies is not warranted. For patients with nutritional deficiencies, it is clear that those deficiencies should be corrected. Further research is required to determine whether any benefit exists for nutrient supplementation in the absence of documented deficiency. At this time, patients must be informed that such research is lacking and that in fact some supplements carry the risk of worsening hair loss or the risk of toxicity.


Introduction
Patients with hair loss often inquire whether nutritional supplements can help restore hair growth or prevent further hair loss. In fact, many will start dietary supplements without consultation in the hope that the supplements will help.
The unregulated supplement industry also capitalizes on this population's vulnerability. While hair follicles are among the most metabolically active in the body, and hair growth may be impacted by calorie and protein malnutrition as well as micronutrient deficiency, the links are complex.
Nutritional deficiency may impact both hair structure and hair growth. Effects on hair growth include acute telogen effluvium (TE), a well-known effect of sudden weight loss or decreased protein intake [1], as well as the diffuse alopecia seen in niacin deficiency [2]. Studies have also reported potential associations between nutritional deficiency and chronic TE, androgenetic alopecia (AGA), female pattern hair loss (FPHL), and alopecia areata (AA) [3,4].
Given this well-recognized link, many patients seeking treatment for hair loss ask about dietary recommendations.
Specifically, is it necessary to test for nutrient deficiency in a patient presenting with hair loss? Are there risk factors that should prompt testing? In the absence of such risk factors, is there any evidence to support the use of micronutrient supplementation?
Physicians must be prepared to answer these questions.
Hair loss is common, with close to 50% of men and women Diet and hair loss: effects of nutrient deficiency and supplement use Patients presenting with hair loss should be screened by medical history, dietary history and physical exam for risk factors for nutrient deficiency. If warranted, laboratory studies may be performed. In patients with no risk factors, further laboratory evaluation searching for nutritional deficiencies is not warranted. For patients with nutritional deficiencies, it is clear that those deficiencies should be corrected. Further research is required to determine whether any benefit exists for nutrient supplementation in the absence of documented deficiency. At this time, patients must be informed that such research is lacking and that in fact some supplements carry the risk of worsening hair loss or the risk of toxicity.
Vegans and vegetarians are also at higher risk for ID, as their requirements for dietary iron are considered to be 1.8 times higher than for meat consumers [18]. Non-heme iron, found in plants, has a lower bioavailability than heme iron, found in meat and fish [19].  [16,20]. There are few intervention trials, and they are limited by small numbers, lack of controls in some, and variable ferritin levels. These have utilized different interventions, including iron alone [21], iron with L-lysine [8,22], and iron with spironolactone [23].
One study used a control population that excluded patients at risk for ID [24] and found no statistically signifi-

Zinc
Zinc is an essential mineral required by hundreds of enzymes and multiple transcription factors that regulate gene expression [26]. While the exact mechanism of action is unclear, one possibility centers on zinc's role as an essential component of numerous metalloenzymes important in protein synthesis and cell division [27]. Another possibility is zinc's role in the Hedgehog signaling pathway [28], a critical component in the pathways that govern hair follicle morphogenesis [29].
Zinc deficiency may be either inherited or acquired and affected by pattern hair loss by age 50 [5].

Iron
Iron deficiency (ID) is the world's most common nutritional deficiency and is a well-known cause of hair loss. What remains unclear is what degree of ID may contribute to hair loss.
While the mechanism of action by which iron impacts hair growth is not known, hair follicle matrix cells are some of the most rapidly dividing cells in the body, and ID may contribute to hair loss via its role as a cofactor for ribonucleotide reductase, the rate-limiting enzyme for DNA synthesis [14]. In addition, multiple genes have been identified in the human hair follicle [15], and some may be regulated by iron [16]. In a mouse model, reversal of ID led to restoration of hair growth [17].
Certain populations are at higher risk for ID, and a medical and dietary history may reveal risk factors. Premenopausal women are at higher risk due to menstrual blood loss, while postmenopausal women and men may present due to gastrointestinal blood loss. Other risk factors include malabsorption disorders (such as celiac disease) as well as achlorhydria or the use of H2 blockers, as iron requires an acidic pH for absorption.
In a review of the literature, no studies regarding niacin levels in patients presenting only with hair loss were identified.

Fatty Acids
Deficiency of the polyunsaturated essential fatty acids linoleic acid (an omega-6 fatty acid) and alpha-linolenic acid (an omega-3 fatty acid) can result from inappropriate parenteral nutrition and malabsorption disorders such as cystic fibrosis.
Hair changes include loss of scalp hair and eyebrows as well as lightening of hair [3,4]. Unsaturated fatty acids may modulate androgen action by inhibition of 5α-reductase, similar to the drug finasteride [42]. Additionally, arachidonic acid, an omega-6 fatty acid, may promote hair growth by enhancing follicle proliferation [43].
However, limited information is available on supplementation. In one patient with essential fatty acid deficiency, topical application of safflower oil, high in linoleic acid, resulted in growth of hair [44].
While results from a trial utilizing a supplement were reported, limited conclusions may be drawn, as this supplement combined multiple fatty acids and antioxidants [45].

Selenium
Selenium is an essential trace element that plays a role in protection from oxidative damage as well as hair follicle morphogenesis. Rats deficient in selenium display sparse hair growth [46], while knockout mice lacking specific selenoproteins exhibit progressive hair loss after birth [47].
Risk factors for deficiency include living in areas with low selenium soil content (particularly in parts of China, Tibet, and Siberia), long-term hemodialysis, HIV, and malabsorption disorders [48].
There is limited research on selenium deficiency and alopecia in humans. One case report in a child described sparse hair, which improved after dietary supplementation [49].
Given the lack of human research, it is surprising that some hair loss supplements are marketed as containing selenium. This is concerning, as selenium toxicity from nutritional supplementation is well documented [9][10][11]. Toxicity can result in generalized hair loss, as well as blistering skin lesions, gastrointestinal symptoms, and memory difficulties.

Vitamin D
Data from animal studies suggests that vitamin D plays a role in hair follicle cycling [50]. In a study of mice treated to model vitamin D-dependent rickets, the resultant animals developed hair loss [51]. In vitro studies have shown increase in vitamin D receptor expression in the outer root sheath keratinocytes during the growing phases of the hair cycle [52]. may affect multiple organ systems. Patients may experience diarrhea, immunological effects, and delayed wound healing.
Abnormalities in taste and smell may occur. Cutaneous effects include acral and periorificial dermatitis, while hair changes include TE and brittle hair.
The autosomal recessive disorder, acrodermatitis enteropathica, results in decreased absorption of zinc, while acquired zinc deficiency may occur in malabsorption syndromes, such as inflammatory bowel disease [30] or following gastric bypass surgery. Other groups at risk include patients with malignancy, those with liver or renal dysfunction, pregnant women [31], and patients with alcoholism [32]. Drugs that can affect zinc levels include valproic acid [33] and certain antihypertensives [34].
Dietary risk factors include vegetarianism, as bioavailability of zinc is lower in vegetables than meat [35]. Additionally, vegetarians typically consume more legumes and whole grains, which contain phytates that bind to zinc and inhibit absorption [35].
Serum zinc, the most commonly measured index of zinc status, may be impacted by several variables, and the functional effects of deficiency may be observed before serum levels decrease below normal [36].
Screening in those with risk factors is indicated, as hair loss due to zinc deficiency can be reversed. A case series demonstrated reversal of hair loss following oral supplementation in five patients with TE and zinc deficiency [37].
A study of 312 patients with AA, male pattern hair loss (MPHL), FPHL, or TE showed that all groups had statistically lower zinc concentrations as compared to 30 healthy controls [38]. In patients with AA and low serum zinc levels, supplementation has been shown to have therapeutic effects [39].
However, there is currently limited information on the effects of zinc supplementation on hair growth in those without documented deficiency. One report described a single patient with alopecia, without clear deficiency, who experienced improvement following oral zinc therapy [40].
A major point when considering supplementation in the absence of known deficiency is that zinc toxicity can occur with excess supplementation. Acute adverse effects include pain, vomiting, and diarrhea, while chronic effects include interaction with iron and reduced immune function [18].

Niacin
Pellagra, due to a deficiency of niacin, results in the wellknown triad of photosensitive dermatitis, diarrhea, and dementia. Alopecia is another frequent clinical finding [2].
Pellagra became rare in many developed countries after niacin fortification of food was introduced. Alcoholism is now considered the most common cause of pellagra in developed countries [41]. Other causes include malabsorption disorders or drug-induced cases, such as with isoniazid [41].
No significant difference in serum folate levels was seen in 91 patients with diffuse hair loss as compared to controls [58]. In fact, another study of 200 women with chronic TE showed 28.5% had elevated serum folic acid, although methodology of the study was not included and therefore limited conclusions may be drawn [8].

Biotin
Biotin, or vitamin H, serves as a cofactor for carboxylation enzymes. In isolated sheep hair follicles, incubation in biotincontaining solutions resulted in increased DNA concentration and protein synthesis [59].

Amino Acids and Proteins
Protein malnutrition, such as in kwashiorkor and marasmus, can result in hair changes that include hair thinning and hair loss [64].
One study examined the role of L-lysine, an essential amino acid that may play a role in iron and zinc uptake.
Addition of L-lysine to iron supplementation resulted in a significant increase in mean serum ferritin concentration in some women with chronic TE who failed to respond to iron supplementation alone [8]. Although interesting, there is limited data available, and the role of L-lysine should be investigated further.
In terms of other amino acids and proteins, no clear con- Risk factors for vitamin D deficiency include inadequate sun exposure, dark skin, obesity, gastric bypass, and fat malabsorption [53].
One study of eight females with TE or FPHL showed that serum vitamin D2 levels were significantly lower than in controls. Furthermore, vitamin D2 levels decreased with increased disease severity [54]. However, data on the effects of vitamin D supplementation in hair loss is lacking.

Vitamin A
Vitamin A is a group of compounds including retinol, retinal, retinoic acid, and provitamin A carotenoids. In murine studies, dietary vitamin A has been shown to activate hair follicle stem cells [55], although its role is recognized as complex and "precise levels of retinoic acid are needed for optimal function of the hair follicle" [56].
While deficiency has not been linked to hair loss, high levels of vitamin A have. In fact, one study found that in a mouse AA model, reduction of vitamin A in the diet actually delayed hair loss onset [56].
In humans, hypervitaminosis A may result from oversupplementation and has a strong known link to hair loss with other effects such as skin, vision, and bone changes [4,8].

Vitamin E
Tocotrienols and tocopherols are members of the vitamin E family and are potent antioxidants. Deficiency results in hemolytic anemias, neurologic findings, and skin dryness.
Vitamin E deficiency is rare, but may occur with fat malabsorption disorders.
Minimal information in the literature exists regarding benefits of vitamin E supplementation on hair loss. One study of 21 volunteers who received tocotrienol supplementation (100 mg of mixed tocotrienols daily) showed significant increase in hair number as compared to a placebo group [57].
However, excess supplementation may result in hypervitaminosis E, which can increase the risk of bleeding and decrease thyroid hormone production. Additionally, there is some evidence for an adverse effect on hair growth, as seen in volunteers taking 600 IU per day for 28 days, a dosage around 30 times the daily recommended intake [8]. This group had significant decreases in thyroid hormone levels [8].

Folic Acid
Folic acid is found in leafy greens and many foods are fortified with folic acid, making deficiency uncommon. Deficiency mainly results in megaloblastic anemia, without manifestation of hair loss.

Iron
• Chronic diffuse telogen hair loss with iron deficiency anemia [20]. • In the absence of anemia, studies are not clear whether there is a significant link between ID and hair loss [16,20,24].
• Insufficient evidence to recommend iron supplementation to all hair loss patients with iron deficiency in the absence of anemia [20]. Approach on a case-by-case basis. • Excess supplementation can cause hemochromatosis [25].

Zinc
• Statistically lower serum zinc concentrations in a study of 312 patients with AA, MPHL, FPHL, or TE compared to 30 healthy controls [38].
• A case series demonstrated reversal of hair loss following oral supplementation in five patients with TE and zinc deficiency [37]. • Limited information on effects of zinc supplementation improving hair growth in the absence of deficiency. • One case report with a patient with dry brittle hair and alopecia, without clear zinc deficiency, who experienced improvement in alopecia following oral zinc therapy [40]. • Excess supplementation can cause acute toxic effects including epigastric pain, nausea, vomiting diarrhea, and headache and chronic toxic effects including reduced copper status, interaction with iron, reduced immune function, and decreased concentrations of HDL cholesterol [18].
Niacin (Vitamin B3) • Diffuse hair loss with pellagra due to severe deficiency [2]. • No known studies regarding serum niacin levels in patients with hair loss.
• Limited information on effects of niacin supplementation improving hair growth in absence of deficiency.
• Limited information on effects of fatty acid supplementation improving hair growth in absence of deficiency.

Selenium
• In animal studies, rats deficient in selenium display sparse hair growth [46], while knockout mice lacking specific selenoproteins exhibit progressive hair loss after birth, ultimately leading to almost total alopecia [47]. • One case report of selenium deficiency in a young child reported clinical manifestations of dry skin and sparse, light-colored hair, improving after supplementation [49].
• Limited information on effects of selenium supplementation improving hair growth in absence of deficiency. • Toxicity from excess supplementation is well documented and can cause generalized hair loss [9][10][11].
Vitamin D • Serum vitamin D2 levels in a study of eight females with either TE or FPHL were shown to be significantly lower than in 40 agematched female controls, with decreased levels correlating to increased disease severity [54].
• Limited information on effects of vitamin D supplementation improving hair growth in absence of deficiency.
Vitamin A • Deficiency has no known link to hair loss.
• Limited information on effects of vitamin A supplementation improving hair growth in absence of deficiency. • Toxicity from excess supplementation has a strong known link to hair loss, as well as other effects on skin, vision, and bone [4,8].
(Continued next page) oxidative stress may have an important role in the balding phenotype and development of AGA [72]. Additionally, in a study of endogenous antioxidant enzymes and lipid peroxidation in the scalps of patients with AA, excessive free radical generation was shown to occur in the scalps of patients with AA accompanied by high levels of antioxidant enzymes that were unable to protect against the ROS [73].
While dietary antioxidants play a key role in reinforcing our endogenous antioxidant system, high doses of exogenous antioxidants may actually disrupt the balance between oxidation and antioxidation [71]. In vitro studies have shown that while polyphenols have antioxidant properties at low concentrations, they can potentiate ROS generation at higher concentrations [71,[74][75]. Compounds within plant foods, such as from fruits, vegetables, and grains, may be safer and healthier compared to isolated, high doses present in supplements [71].

Conclusion
While multiple nutrient deficiencies may result in hair loss (Table 1), screening for such deficiencies must be guided by the One trial included L-cysteine, a constituent of keratin, in combination with medicinal yeast and pantothenic acid [65].
However, it is difficult to evaluate the results of these trials, as the composition of these nutritional supplements is not disclosed. Marketing materials accessed from one product's website describe the composition as including "vitamins and minerals for hair growth, including iron, zinc, biotin, niacin, vitamin C and an exclusive marine complex derived from fish proteins" [70].

Antioxidants
Antioxidants are compounds that are able to neutralize reactive oxygen species (ROS), preventing oxidative damage.
Many substances can be classified as antioxidants, including zinc, selenium, and vitamins A and E, as described previously in this article, as well as vitamin C and polyphenols [71]. Oxidative stress has been linked to hair loss. In vitro studies of dermal papilla cells from male AGA patients have shown that  [58].
• Limited information on effects of folic acid supplementation improving hair growth in absence of deficiency.
• Limited information on effects of biotin supplementation improving hair growth in absence of deficiency.

Amino Acids and Proteins
• Protein malnutrition can result in hair loss [64].
• L-lysine supplementation in addition to iron supplementation has been shown to significantly increase mean serum ferritin concentration in some women with chronic TE who failed to respond to iron supplementation alone [8]. • Limited information on effects other amino acids and proteins improving hair growth in absence of deficiency. history and physical exam. Nutrient deficiencies may arise due to genetic disorders, medical conditions, or dietary practices.

Key of abbreviations:
If risk factors are identified (Table 2), then laboratory screening for nutrient deficiency may be indicated. In patients with hair loss, but without any known risk factors for nutrient deficiency, laboratory testing for nutrient deficiency is not required.
An area that requires further research is the role of supplementation. It is clear that nutrient deficiencies must be corrected. What is unclear is the ideal range of micronutrient levels to prevent or correct hair loss. In ID and anemia, supplementation is required, but patients with ID in the absence of anemia must be approached on a case-by-case basis. Some authors believe that raising levels of storage iron may improve hair loss, although the research is not conclusive. All patients receiving iron supplementation must be monitored due to toxicity risk.
For other nutrients, such as zinc, supplementation in deficient patients has resulted in hair growth, although, again, patients must be monitored due to toxicity risk (Table 3).
There is very limited research on the role of nutrient supplementation in the absence of deficiency. Despite this, patients often seek nutrient supplements as a treatment for hair loss. In fact, direct-to-consumer advertising promotes the use of supplements for hair loss, and many such products, containing a wide variety of formulations, are easily available for purchase.  Physicians must counsel their patients on the lack of research supporting these products. Since supplements are not regulated by the FDA, it is up to the physician and the consumer to review the efficacy and safety of supplements.
Websites such as the Natural Medicines Comprehensive Database [76] or the National Institutes of Health Office of Dietary Supplements' PubMed Dietary Supplement Subset [77] and Dietary Supplements Ingredient Database [78] may be of help in this exploration. Equally important is a discussion of the potential toxicity of some of these supplements. Over-supplementation of some nutrients may result in multiple toxicities, while over-supplementation of certain nutrients, including vitamin A, vitamin E, and selenium, may actually result in hair loss.