COMMENTARY

Iron deciency and hair loss: The jury is still out

Elise A. Olsen, MD Durham, North Carolina

rost, Bergfeld, and Calogeras in this issue of the Journal of the American Academy of Dermatology1 give a thoughtful and erudite discussion of the diagnosis and treatment of iron deficiency. These authors further clarify which test for iron deficiency to do and when and how to evaluate the response to therapy. Given that iron deficiency is common, readily diagnosable, and treatable, and that it has potential implications for dermatologic conditions, dermatologists must be cognizant of this information. Iron deciency has been implicated in skin, nail, and hair disorders. Iron deciency has been associated with generalized pruritus including documentation of improvement with replacement of iron.2-5 Koilonychia, glossitis, and angular stomatitis, either alone or as part of the Plummer-Vinson (PattersonKelly) syndrome characterized by dysphagia and postcricoid esophageal web, have been associated with iron deficiency.6,7 The need for iron greatly increases with chronic erythroderma, the desquamating skin cells of patients with chronic erythrodermic psoriasis accounting for up to 38% of total body iron loss.8 In their thorough review of the topic, Trost, Bergfeld, and Calogeras provide references that support a potential relationship between iron deciency and the most common types of hair loss including androgenetic alopecia or diffuse alopecia in women, telogen efuvium, or alopecia areata.9-19 These are very disparate types of hair loss with quite different etiologies and should be evaluated individually, rather than collectively, as to their association with iron deficiency. For example, acute

From the Division of Dermatology, Duke University Medical Center. Funding sources: None. Conflicts of interest: None identified. Reprints not available from the author. Correspondence to: Elise A. Olsen, MD, Division of Dermatology, Duke University Medical Center, Box 3294, Durham, NC 27710. E-mail: olsen001@mc.duke.edu. J Am Acad Dermatol 2006;54:903-6. 0190-9622/$32.00 2006 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2005.10.038

telogen effluvium is less a specific disorder than a reaction pattern to a multitude of noxious stimuli or types of physical/emotional distress. If acute telogen effluvium is related to iron deficiency, it most likely occurred in the setting of acute blood loss secondary to an acute injury, surgery, or pregnancy, and the correction of the iron deficiency usually occurs concomitant with the correction of the anemia. Thus, there may be a relationship of iron deficiency to an acute telogen effluvium, but it probably cannot be teased out as an isolated causative event independent of anemia. In contradistinction to acute telogen efuvium, patients with chronic telogen efuvium (CTE) may have developed iron deciency without any precipitous or obvious loss of blood or documented anemia. CTE is loosely dened as telogen efuvium of uncertain origin that persists for more than 6 months.9,20 Considerable overlap of CTE, diffuse alopecia in women, and late onset female pattern hair loss is likely. Each is a more diffuse scalp hair loss than is typical of early onset female pattern hair loss or androgen-related hair loss in women but is collectively characterized by an increased percentage of hairs in telogen and a clinical decrease in hair density.21 That deficiency of an essential nutrient can cause CTE has been shown conclusively with zinc and biotin deficiency. Although not usually thought of as a CTE, infants with enzymatic abnormalities in absorption of zinc (acrodermatitis enteropathica) or biotin (multiple carboxylase deficiency) may develop a persistent telogen effluvium.22 That these deficiencies are the direct cause of the CTE has been shown by reversal of the associated hair loss with dietary supplementation of zinc or biotin, respectively. What precludes proof that any of these nutritional decienciesiron, zinc, or biotinis a causative factor in adults with CTE/diffuse alopecia are (1) a reliable screening test as well as common agreement on a threshold level for deficiency utilizing this screening test and (2) proof that reversing the deficiency reverses the hair loss. In the studies noted in this issue of the Journal, the definition of iron deficiency used in studies of women with CTE or diffuse hair loss ranged from a serum ferritin of \ 20 903

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ng/mL,9 \30 ng/mL,10 \40 ng/mL,11,16 or even\70 ng/mL,12 or a serum iron less than \60 ug/dL.13 If one uses a ferritin level of 30 ng/mL as the cutoff for iron deficiency, the sensitivity is 92% and the specificity is 98%.23,24 If one uses a ferritin level of 40 ng/mL as the cutoff, both the sensitivity and specificity are 98%. Guyatt et al,25 in a review of 55 articles on the laboratory diagnosis of iron deficiency, noted that the likelihood of iron deficiency in the general population does not start to drop off until the ferritin values are [ 40 ng/mL. They noted that ferritin need not be abandoned as an indicator of iron deficiency in those who have underlying inflammatory or liver disease, but rather threshold levels must be raised to approximately 70 ng/mL in this population. What is the signicance of merely showing an increased incidence of iron deciency in a given disorder as many of the referenced studies seek to prove? To show any relatedness, not causality, of a given nding (such as iron deciency) to a condition (such as hair loss), one must have an adequate number of control subjects and consideration of factors that could independently account for the nding in both the control group and the condition in question. For example, in the case of women and iron deciency, one must take into account the following variables in both groups that could effect the iron status: age, menses, recent pregnancy, diet, iron supplements (including iron in oral contraceptive pills), and concurrent medical problems or drugs that could lead to blood loss (eg, systemic steroids, anticoagulants, nonsteroidal anti-inammatory drugs). Patients who take increased amounts of zinc in over-the-counter preparations, those who drink large amounts of tea that contains tannins and manganese, or women who take their calcium with meals or with their iron supplements may develop iron deciency.26-30 Each of these variables might explain some increased risk for iron deficiency in the hair loss group and must be taken into account with properly matched controls. It is also possible that the hair loss could lead to changes in behavior, which in turn could result in iron deficiency. For example, patients who are depressed about their hair loss may fail to eat well and develop iron deficiency post facto. It is important that all these factors, and possibly others as well, should be considered in choosing a control group. Of all the studies noted, those by Rushton et al11 and Aydingoz et al10 come closest to doing this. In the study by Rushton et al, of 100 women with diffuse alopecia and 20 controls without complaints of hair loss, they excluded from both groups those who had been pregnant, were on oral

contraceptive pills, or had any known underlying medical illness and any obvious androgen excess. However, although they noted that the hair loss group had not taken iron, there was no mention of this for the control group, and, conversely, they noted that the control group had not had menstrual abnormalities but not whether the hair loss group had. This omission could have been just an oversight in the methods section and both groups had all of these factors accounted for, but it is also possible that the patients with diffuse alopecia had menstrual irregularities leading to increased blood loss and did not take iron, giving them two reasons for a higher incidence of iron deficiency. In general, to denitively link iron deciency to hair loss, the control group necessary to account for all these variables will probably need to be of considerable size. The size of the control groups without hair loss in the referenced articles on iron deciency and hair loss ranged from zero (CTE/androgenetic alopecia9 and alopecia areata14) to 11 (various types of hair loss15) to 20 (diffuse alopecia11). Only Aydingoz et al10 had a relatively large (n = 46), age-matched control group with exclusion of pregnancy, thyroid problems, acute febrile disease, hyperandrogenism, chronic disease, or use of medications likely to affect iron status. In this study of 43 women with diffuse or androgenetic alopecia, there was no association of iron deficiency and hair loss. Further work is necessary to determine whether there truly is a relationship of any kind of iron deciency to hair loss that is unrelated to some other factor present at the onset or occurring during the time that hair loss has developed. It may be that adequate amounts of iron, like adequate thyroid hormone, are necessary for normal hair growth, and without sufcient amounts of iron, agents capable of treating the specic etiology of the hair loss in question may not be effective. This conclusion is suggested by the study by Rushton and Ramsay16 in women with androgenetic alopecia with low serum ferritin treated with cyproterone acetate who did not respond as well as those with higher serum ferritin. However, Vexiau31 more recently showed a disparity of response of women with androgenetic alopecia to cyproterone acetate on the basis of presence or absence of hyperandrogenism which offers another possibility for the disparity in hair growth between the treated groups. If in fact normal iron is a permissive factor for hair growth, its role should be accounted for in all studies of hair loss involving women and could account, for example, for why postmenopausal women with presumed androgenetic alopecia did not respond to finasteride 1 mg per

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day (ie, they may have had concomitant iron deficiency).32 Iron status was not evaluated in that study. There is published data, although small numbers, on whether those women with hair loss and documented iron deciency will grow hair with correction of the iron deciency. Those with telogen efuvium looking for a primary explanation of the hair loss merely require making sure that some other factor that could explain the hair loss is not at play and then seeing whether the hair loss improves with rd treatment of the iron deciency. Ha 13 used serum iron alone to diagnose iron deficiency and reported on 39 women with telogen effluvium (defined by positive hair pull alone) who had iron deficiency, 19 of whom had concomitant anemia. He made the observation that, in this group of women, hair regrowth followed iron therapy and hair loss began again after iron therapy was stopped. No explanation was given for the iron deficiency, and no history was given to address all of the variables noted previously that could be important. Furthermore, nothing can essentially rule out that some of these patients did not have anemia of chronic disease since total ironbinding capacity also was not done. A more definitive study, although of small numbers, is that by Sinclair9 in which he found no increased incidence of iron deficiency in 77 women with chronic telogen loss/CTE nor any decrease in shedding or increased hair density on effective treatment with iron of the 5 with concomitant iron deficiency. Where do we go from here? To fully dene the relationship of iron deciency with any specic type of hair disorder, we need the following: (1) a uniform denition of iron deciency that can be made readily by blood tests done in the absence of iron supplementation, (2) evaluation for iron deciency in women with well-dened types of hair loss with recording of the multiple variables necessary to sort out related conditions or explanations for the iron deciency, (3) larger control groups that also take into account these variables, and (4) well-controlled therapeutic trials including objective measures of hair growth such as static target area hair counts, phototrichogram, or trichogram in women with documented iron deciency and hair loss both preand postcorrection of the iron deciency, and (5) funding . Are any sponsors willing to step up to the proverbial plate on this important issue?

REFERENCES 1. Trost LB, Bergfeld WF, Calogeras E. The diagnosis and treatment of iron deficiency and its potential relationship to hair loss. J Am Acad Dermatol 2006;54:824-44. 2. Bernhard JD. Itch: mechanisms and management of pruritus. New York: McGraw-Hill, Inc; 1994. pp. 245-8.

3. Lewiecki MC, Rahman F. Pruritus, a manifestation of iron deficiency. JAMA 1976;236:2319-20. 4. Valsecchi R, Cainelli T. Generalized pruritus: a manifestation of iron deficiency. Arch Dermatol 1983;229:630. 5. Sneddon IB, Garrets M. The significance of low serum iron levels in the causation of itching. In: Jadassohn W, Schinnen CG, editors. Proceedings of XIII International Congress of Dermatology. Vol 2. Berlin: Springer Verlag; 1968. pp. 1061-3. 6. Bridges KR, Bunn HF. Anemias with disturbed iron metabolism. In: Isselbacher, Braunwald, Wilson, Martin, Fauci, Kasper, editors. Harrisons principles of internal medicine. Vol 2. 13th ed. New York: McGraw-Hill; 1994. pp. 1721-6. 7. Brittenham GM. Disorders of iron metabolism: iron deficiency and overload. In: Hoffman R, Benz EJ, Shattil SJ, et al, editors. Hematology: basic principles and practice. 3rd ed. Philadelphia: Churchill Livingstone; 2000. pp. 397-428. 8. Reizenstein P, Skog E, Stigell P. Radio-iron content of epithelium and cell turnover in psoriasis. Acta Derm Venereol 1968;48: 70-4. 9. Sinclair R. There is no clear association between low serum ferritin and chronic diffuse telogen hair loss. Brit J Dermatol 2002;147:982-4. 10. Aydingoz IE, Ferhanoglu B, Guney O. Does tissue iron status have a role in female alopecia? J Eur Acad Derm Venereol 1999;13:65-7. 11. Rushton DH, Ramsay ID, James KC, Norris MJ, Gilkes JJH. Biochemical and trichological characterization of diffuse alopecia in women. Brit J Dermatol 1990;123:187-97. 12. Rushton DH. Management of hair loss in women. Derm Clinics 1993;11:47-53. 13. Hard S. Non-anemic iron deficiency as an etiologic factor in diffuse loss of hair of the scalp in women. Acta Derm Venereol 1963;43:562-9. 14. White MI, Currie J, Williams MP. A study of the tissue iron status of patients with alopecia areata. Brit J Dermatol 1994; 130:261-3. 15. Kantor J, Kessler LJ, Brooks DG, Cotsarelis G. Decreased serum ferritin is associated with alopecia in women. J Invest Dermatol 2003;121:985-8. 16. Rushton DH, Ramsay ID. The importance of adequate serum ferritin levels during oral cyproterone acetate and ethyinyl oestradiol treatment of diffuse androgen-dependent alopecia in women. Clin Endocrinol 1992;36:421-7. 17. Boffa MJ, Wood P, Griffiths CEM. Iron status of patients with alopecia areata. Br J Dermatol 1995;132:662-4. 18. Rushton DH, Norris MJ, Dover R, Busuttil N. Causes of hair loss and the developments in hair rejuvenation. Intern J Cosm Sci 2002;24:17-23. 19. Rushton DH. Nutritional factors and hair loss. Clin Exper Dermatol 2002;27:396-404. 20. Whiting DA. Chronic telogen effluvium: increased scalp hair shedding in middle aged women. J Am Acad Dermatol 1996;35:899-906. 21. Olsen EA. Female pattern hair loss. J Am Acad Dermatol 2001;45(3 Suppl):S70-80. 22. Fiedler VC, Gray AC. Diffuse alopecia: telogen hair loss. In: Olsen EA, editors. Hair disorders: diagnosis and treatment. 2nd ed. New York: McGrawHill; 2003. pp. 310-1. 23. Mast AE, Blinder MA, Gronowski AM, Chumley C, Scott MG. Clinical utility of the soluble transferrin receptor and comparison with serum ferritin in several populations. Clin Chem 1998;44:45-51. 24. Punnonen K, Irjala K, Rajamaki A. Serum transferrin receptor and its ratio to serum ferritin in the diagnosis of iron deficiency. Blood 1997;89:1052-7.

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25. Guyatt GH, Oxman AD, Ali M, Willan A, McIlroy W, Patterson C. Laboratory diagnosis of iron deficiency anemia: an overview. J Gen Intern Med 1992;7:145-53. 26. Simon SR, Branda RF, Tindle BH, Burns SL. Copper deficiency and sideroblastic anemia associated with zinc ingestion. Am J Hematol 1988;28:181-3. 27. Fiske DN, McCoy HE, Kitchens CS. Zinc-induced sideroblastic anemia: report of a case, review of the literature, and description of the hematologic syndrome. Am J Hematol 1994;46: 147-50. 28. Deur CJ, Stone JJ, Frenkel EP. Trace metals in hematopoiesis. Am J Hematol 1981;11:309-31. 29. Rossander-Hulten L, Brune M, Sandstrom B, Lonnerdal B, Hallberg L. Competitive inhibition of iron absorption by

manganese and zinc in humans. Am J Clin Nutr 1991;54: 152-6. 30. US Department of Health and Human Services. Center for Disease Control and Prevention. Recommendations to prevent and control iron deficiency in the United States. MMWR Morbid Mortal Wkly Rep 1998;47:1-30. 31. Vexiau P, Chaspoux C, Boudou P, Fiet J, Jouanique C, Hardy N, Reygagne P. Effects of minoxidil 2% vs. cyproterone acetate treatment on female androgenetic alopecia: a controlled, 12month randomized trial. Brit J Dermatol 2002;146:992-9. 32. Price VH, Roberts JL, Hordinsky M, Olsen EA, Savin R, Bergfeld W, et al. Lack of efficacy of finasteride in postmenopausal women with androgenetic alopecia. J Am Acad Dermatol 2000;43(5 Pt 1):768-76.