Alopecias




Abstract


Alopecia can reflect the loss of hair follicles, loss of hair shafts, or loss of both. Hair follicle loss may be due to follicular agenesis, dysgenesis, or destruction while loss of hair shafts can result from shedding, plucking, miniaturization, or breakage. Although alopecia may be present since birth, it is more often acquired. In alopecia of the scalp, the distribution can be diffuse, patterned, or circumscribed/focal, with androgenetic alopecia and telogen effluvium being the most common forms of alopecia. Scalp alopecia is also subdivided into scarring forms (e.g. lichen planopilaris) and non-scarrring forms (e.g. alopecia areata). In addition, a distinction is made between excessive shedding as in telogen effluvium and hair shaft fragility as in trichorrhexis nodosa due to cumulative cuticular damage or inherited hair shaft abnormalities. Alopecia can also occur in other sites, either in conjunction with or independent of scalp alopecia. This chapter provides a framework for classification of the alopecias that will facilitate accurate clinical diagnosis and patient management.




Keywords

androgenetic alopecia, alopecia areata, alopecia totalis, alopecia universalis, cicatricial alopecia, scarring alopecia, congenital alopecia, inherited alopecia, anagen effluvium, telogen effluvium, female pattern hair loss, male pattern hair loss

 




Introduction


In this chapter, the major non-cicatricial (non-permanent) alopecias will be reviewed first, followed by a discussion of cicatricial alopecias and a review of structural hair shaft abnormalities. Chapter 68 reviews the structure and function of the hair follicle as well as regulation of the hair cycle. Table 69.1 outlines the historical information of importance in the evaluation of alopecias while Figs 69.1 and 69.2 depict a clinical approach and the diagnostic tests that can be performed in addition to the clinical examination. The decision to perform scalp biopsies, hair shaft analysis, and blood tests is guided by the differential diagnosis.



Table 69.1

Clinical assessment of alopecia.

Chemotherapy-induced anagen effluvium is usually a straightforward diagnosis.



















CLINICAL ASSESSMENT OF ALOPECIA
The clinical history should be directed toward establishing the diagnosis, detecting precipitating factors where relevant, identifying associated comorbidities, and obtaining information pertinent to the proposed treatment
Establishing the diagnosis and detecting precipitating factors



  • Determine if patient has increased hair shedding (suggestive of telogen effluvium) or a reduction in hair density with visible balding or both; the latter is suggestive of patterned hair loss



  • If increased hair shedding, is the hair “coming out by the roots”? (suggestive of telogen effluvium) vs breaking near the scalp? (suggestive of acute alopecia areata, anagen effluvium) vs breaking near the ends? (suggestive of hair shaft abnormalities such as trichorrhexis nodosa)



  • If increased hair shedding and hair “coming out by the roots”, a duration <3 months suggests acute telogen effluvium whereas >6 months is diagnostic of chronic telogen effluvium; recurrent episodes of acute telogen effluvium without a clear trigger is a common prodrome to female pattern hair loss



  • In patients with acute telogen effluvium, search for triggers such as high fever, surgery, or serious illness that occurred 2–3 months prior to onset whereas in patients with chronic telogen effluvium, consider hypo- or hyperthyroidism, drugs, chronic illnesses, exposures (e.g. thallium), and rarely diffuse alopecia areata



  • If visible balding, determine if congenital or acquired and then if patchy (suggestive of alopecia areata, tinea capitis, lichen planus), diffuse (suggestive of acute or postpartum telogen effluvium, anagen effluvium, diffuse alopecia areata), or patterned (suggestive of androgenetic alopecia, frontal fibrosing alopecia, central centrifugal cicatricial alopecia)



  • Determine if any associated symptoms such as pain, burning, pruritus, or dandruff as: trichodynia may accompany telogen effluvium or female pattern hair loss with excessive shedding; localized pain can indicate pustules; diffuse pain and pruritus may accompany a cicatricial alopecia; there may be altered or crawling sensations in patients with trichotillomania; and dandruff can be a feature of seborrheic dermatitis, psoriasis, or tinea capitis



  • A positive family history may point to common disorders such as alopecia areata or androgenetic alopecia or rare hair shaft abnormalities

Identifying associated comorbidities



  • Organ-specific autoimmune diseases in patients with alopecia areata



  • Hyperandrogenism (e.g. hirsutism, acne, irregular menses) and metabolic syndrome in women with androgenetic alopecia



  • Personal or family history of ischemic heart disease and prostate cancer in men with androgenetic alopecia

Obtaining information pertinent to the proposed treatment



  • Review previous treatments including duration and if used correctly



  • Determine expectations (e.g. halting progression, preventing relapse, hair regrowth)



  • Determine commitment to repeated or long-term therapies




Fig. 69.1


Clinical approach to scalp alopecia.

Androgenetic alopecia is also referred to as female or male pattern hair loss.



Fig. 69.2


Bedside diagnostic tests for the assessment of alopecia.

Additional investigations include fungal culture, Wood’s lamp examination, scalp biopsy, hair shaft analysis, and blood tests.




Androgenetic Alopecia




Synonyms


▪ Male pattern and female pattern hair loss (MPHL and FPHL) ▪ Common balding ▪ Hereditary balding or thinning



Key features





  • Genetically determined sensitivity of scalp hair follicles to adult levels of androgens



  • Miniaturization of hairs in a symmetric “pattern” on the crown, vertex, and frontal regions



  • Antiandrogen medications can be used for successful treatment




Introduction


Androgenetic alopecia (AGA) is an androgen-dependent, hereditary physical trait resulting from the conversion of scalp terminal hairs into miniaturized vellus hairs in a characteristic pattern. The frequency and severity increase with age, and at least 80% of Caucasian men and ~50% of women show evidence of AGA by age 70 years .


Pathogenesis


High concordance of MPHL amongst monozygotic twins indicates a strong genetic predisposition. The inheritance is polygenic and a number of genetic loci have been implicated, including those that encode the androgen receptor (MPHL; see Ch 157 ), estrogen receptor-β (FPHL), and the aromatase which converts testosterone to estradiol (FPHL) . Androgens clearly initiate and promulgate MPHL in genetically susceptible individuals, and while inhibition of androgen biosynthesis or action will arrest the progression of MPHL, this will only partially reverse the hair miniaturization. Additional implicated genes in MPHL include those that encode histone deacetylases (HDAC) 4 and 9 and the WNT molecule WNT10A . The WNT signaling pathway is known to play a key role in hair follicle development (see Ch. 68 ).


In men, the expression of AGA is specifically related to the androgen hormone dihydrotestosterone (DHT). Testosterone is converted to DHT by the enzyme 5α-reductase, of which there are three isoenzymes (types I, II, and III); the latter are encoded by separate genes and differ in their expression and activity in various tissues. For example, Type I 5α-reductase is present predominantly in sebaceous glands and the liver, whereas type II 5α-reductase dominates in scalp, beard and chest hair follicles, as well as in the liver and the prostate ( Fig. 69.3 ). Type III is found throughout the epidermis and dermis, but its functional role has yet to be elucidated. Of note, the genetic absence of type II 5α-reductase prevents development of male AGA.




Fig. 69.3


5α-reductase isoenzyme activity in adult human tissues.

Type III 5α-reductase is found throughout the epidermis and dermis, but its functional role has not yet been elucidated.


Investigators have localized androgen-metabolizing enzymes to various regions of the hair follicle ( Fig. 69.4 ). In scalp biopsy specimens obtained from men with AGA, 5α-reductase activity and DHT levels are increased compared to non-balding scalp skin . DHT is implicated in the appearance of miniaturized hair follicles and hair shafts, and decreased levels in both the skin and the blood have been associated with a reversal of miniaturization.




Fig. 69.4


Localization of androgen-metabolizing enzymes in the normal hair follicle.

Courtesy, Maria K Hordinsky, MD.


In women, a similar androgen-related pathophysiology is postulated . Women who develop balding shortly after puberty often have a positive family history for pattern hair loss in both male and female family members. In women who develop pattern alopecia during the perimenopausal period and menopause, it may be due to a genetic predisposition as well as alterations in androgen metabolism at the level of the hair follicle and systemic hormonal changes .


Rarely, AGA develops in prepubertal children (ages 6–10 years) . Affected boys and girls demonstrate a FPHL pattern without bitemporal recession, and they have a strong family history of AGA (present in at least one parent). No evidence has been found for abnormal circulating testosterone levels or precocious puberty.


Utilizing gene expression arrays of scalp biopsies from men with AGA, enhanced expression of the gene that encodes prostaglandin D2 synthetase was observed in bald scalp as compared to haired scalp ; prostaglandin D2 synthetase converts prostaglandin H2 (PGH2) to PGD2. Increased levels of PGD2 were also found in balding scalp, and in explants of human hair follicles, PGD2 was shown to inhibit hair growth. This inhibition of hair growth by PGD2 required interactions with one of its receptors, raising the possibility of a potential therapeutic target.


Clinical Features


MPHL is symmetric and progressive with some pattern variation. Hamilton and then Norwood first classified the patterns of male AGA based upon frontoparietal and frontal recession as well as vertex thinning (see Fig. 157.2 ). Occasionally, a “male type” pattern with frontotemporal and vertex thinning is seen in women, and then they too can be classified with the Hamilton or Norwood system.


However, the most common pattern of FPHL is diffuse central thinning of the crown with preservation of the frontal hairline which can be assessed by the Ludwig grading scale (see Fig. 157.3 ). Often there is frontal accentuation of the hair loss, creating a “Christmas tree” pattern . Examination of the central part width can also be used to classify the severity of FPHL via the Sinclair scale ( Fig. 69.5 ) and it can be compared to the occipital part width ( Fig. 69.6 ) . The findings by trichoscopy are shown in Fig. 69.7 . A history of increased hair shedding may precede the clinical appearance of central thinning, but this is not specific for FPHL (see below).




Fig. 69.5


The Sinclair scale for female pattern hair loss.

Stage 1 – normal; Stage 2 – widening of the central part line; Stage 3 – widening of the part line with translucency of the hairs at its border; Stage 4 – development of a bald area anteriorly along the part line; and Stage 5 – advanced hair loss.



Fig. 69.6


Female androgenetic alopecia.

Comparison of the part line on the crown ( A ) and the occiput ( B ).



Fig. 69.7


Trichoscopy.

A Androgenetic alopecia (AGA): a diversity of hair shaft diameters affects >20% of the hairs. Brown halos around hair shafts (peripilar sign) is a subtle clue. B Telogen effluvium: the hair shafts are of equal diameter (unlike AGA). C Alopecia areata (AA): yellow dots, exclamation point hairs, and dystrophic hairs are characteristic features; the color of the yellow dots may vary from yellow to yellow–pink. Note some vellus-like hair shafts. D Trichotillomania: hair shafts of different lengths, broken hairs, and black dots. E Tinea capitis: comma hairs are a clue to the diagnosis. Zigzag hairs can also be seen. F Temporal triangular alopecia: vellus-like, depigmented hair shafts, but no yellow dots or dystrophic hairs as are seen in AA. G Discoid lupus erythematosus (DLE): follicular red dots are a characteristic sign and they correspond histopathologically to dilated vessels, extravasated erythrocytes, and keratin plugs. H Lichen planopilaris: discrete white dots due to loss of melanin over scarred fibrotic tracts and perifollicular fibrosis. The fibrosis in DLE is more diffuse. I Monilethrix: the presence of broken hair shafts plus hairs with a beaded appearance allows a bedside diagnosis. J Trichorrhexis invaginata (bamboo hairs) in a patient with Netherton syndrome: broken hair shafts and nodose swellings.

E, G, H, Courtesy, Antonella Tosti, MD.


Pathology


Scalp hairs exist as clusters (follicular units) composed of three to five shaft-producing follicles serviced by a single arrector pili muscle. One by one, as follicles miniaturize, the follicular units within thinning regions of the scalp begin to produce only one or two terminal hairs. Once all the follicles within a follicular unit miniaturize, baldness is observed. Histopathologic findings of MPHL and FPHL are described in Table 69.2 and are illustrated in Figure 69.9 as well as compared to normal hair follicles ( Fig. 69.8 ).



Table 69.2

Histologic features of various forms of alopecia.

Trachomalacia is characterized by pleated or twisted hair shafts within follicular infundibula.




































































HISTOLOGIC FEATURES OF VARIOUS FORMS OF ALOPECIA
Male and female pattern hair loss (androgenetic alopecia) (see Fig. 69.9 )



  • Normal total number of follicles and no significant inflammation



  • Increased number and percentage of vellus hairs



  • Numerous fibrous “streamers”



  • Slightly increased telogen count



  • Uninvolved scalp (e.g. occiput) appears normal

Telogen effluvium



  • Normal total number of hairs



  • Normal number of terminal (large) hairs



  • Increase in the telogen count to >20% (>15% is suggestive); telogen count seldom exceeds 50%; >80% is inconsistent with telogen effluvium



  • Absence of inflammation and scarring

Trichotillomania



  • Follicles are normal size



  • Total number of hairs (both terminal and vellus) is normal



  • Incomplete, disrupted follicular anatomy



  • Increased number of terminal catagen and/or telogen hairs



  • Trichomalacia and pigment casts



  • No significant inflammation

Alopecia areata (see Fig. 69.9 )
Early, progressive disease (“acute” and “subacute”)



  • Normal total number of hairs



  • Peribulbar mononuclear cell infiltrate (with occasional eosinophils), predominantly affecting terminal anagen and catagen hair bulbs



  • Occasional exocytosis of inflammatory cells into bulbar epithelium



  • Degenerative changes of hair matrix



  • Increased number of terminal catagen and telogen hairs



  • Increased number of miniaturized hairs



  • Trichomalacia and marked narrowing of hair shafts

Longstanding and stable disease (“chronic”)



  • Majority of hairs in catagen or telogen phases



  • Numerous miniaturized, “arrested”, rapidly cycling hairs, referred to as nanogen hairs



  • Mild peribulbar mononuclear cell infiltrate around those nanogen hairs possessing anagen-like or catagen-like bulbs

Postoperative (pressure-induced) alopecia



  • Early stage includes vascular thrombosis and inflammation within the dermis and superficial fat



  • Necrosis of the epidermis and eccrine coils when severe



  • In conjunction with alopecia, synchronized conversion of most or all of the terminal hair follicles to the catagen/telogen phase ( without hair miniaturization)



  • Pigment casts, incontinent pigment within collapsed root sheaths, and trichomalacia (but not distorted follicular anatomy)

Psoriasiform alopecia



  • Psoriasiform epidermal changes may or may not be present



  • Marked increase in percentage of catagen/telogen hairs, associated with hair miniaturization



  • Occasional miniaturized follicle showing peribulbar chronic inflammation; plasma cells rare or absent



  • Marked diminution in number of sebaceous glands

TNF-α inhibitor-induced psoriasiform alopecia



  • Psoriasiform dermatitis often present



  • Increase in catagen/telogen hairs and miniaturization of hairs, similar to alopecia areata



  • Some peribulbar and superficial perivascular inflammation present, often with several eosinophils and plasma cells in the infiltrate

Central centrifugal cicatricial alopecia



  • Premature desquamation of the inner root sheath



  • Eccentric epithelial atrophy (thinning) with hair shafts in close proximity to the dermis



  • Concentric lamellar fibroplasia (onion skin-like fibrosis) of affected follicles



  • Variably dense lymphocytic perifollicular inflammation, primarily at the level of the upper isthmus and lower infundibulum



  • Occasional fusion of infundibula (polytrichia)



  • In advanced lesions, total destruction of the follicular epithelium with retained hair shaft fragments and granulomatous inflammation



  • In pustular lesions (“folliculitis decalvans”), intrafollicular and perifollicular infiltrates rich in neutrophils and lymphocytes

Lichen planopilaris (see Fig. 69.9 )



  • Band-like mononuclear cell infiltrate obscuring the interface between follicular epithelium and dermis; vacuolar alteration at the interface and hypergranulosis within affected infundibula is typical



  • Colloid or Civatte bodies are occasionally found as part of the interface alteration



  • Inflammation affects the upper portion of the follicle (infundibulum and isthmus) most severely



  • Occasionally, epidermal changes of lichen planus are found



  • Over time, perifollicular fibrosis becomes prominent and the lymphocytic infiltrate seems to “back away” from the follicle



  • An artifactual cleft between epithelium and stroma is often found, with epithelium “floating” within the cleft (Max-Joseph spaces)



  • Grouped globular immunofluorescence (usually IgM) adjacent to the follicular epithelium is the characteristic pattern

Discoid lesions of lupus erythematosus



  • Vacuolar interface alteration of the epidermis and follicular epithelium; epidermis may be spared



  • The interface change in follicles is usually vacuolar rather than lichenoid (less inflammation)



  • Chronic inflammation (often including plasma cells) of the eccrine sweat glands and arrector pili is sometimes present



  • Increased dermal mucin is often present



  • Granular deposits of IgG and C3 (less commonly IgM or IgA) at the dermal–epidermal junction and/or the junction of the follicular epithelium and dermis are typical

Acne keloidalis



  • Perifollicular, chronic inflammation (lymphocytic and plasmacytic), most intense at the level of the isthmus and lower infundibulum



  • Lamellar fibroplasia, most marked at the level of the isthmus



  • Loss of sebaceous glands



  • Total follicular destruction in advanced disease

Dissecting cellulitis of the scalp



  • Moderately dense, perifollicular lymphocytic inflammation affecting the lower half of the dermis and extending down into the subcutaneous fat



  • Numerous intact and seemingly undamaged follicles with intact sebaceous glands surrounded by an infiltrate of acute and chronic inflammation (early disease)



  • Increased percentage of catagen/telogen hairs



  • Initially, lymphocytes dominate the infiltrate, but eventually neutrophils become more numerous, especially in longstanding, fluctuant lesions



  • Vascular proliferation accompanies the infiltrate as the disease evolves, and the deep dermis and subcutaneous fat begin to exhibit the histologic findings of granulation tissue



  • Eventually, chronic abscesses become lined with squamous epithelium derived from the overlying epidermis, and true sinus tracts are formed



  • When inflammation subsides, there is dense fibrosis of the dermis and the superficial fat with loss of follicles

“End-stage” cicatricial alopecia



  • A decreased total number of hairs, especially terminal hairs



  • Loss of the sebaceous glands in zones of follicular loss



  • Residual, “naked” hair shafts surrounded by mild, granulomatous inflammation



  • Follicular streamers (stelae) without overlying follicles



  • Cylindrical columns of connective tissue representing the sites of former follicles

Traction alopecia (end-stage)



  • The total number of terminal hairs is markedly reduced



  • Distinct columns of connective tissue replace some follicles, leaving obvious “blank spaces”



  • The sebaceous glands associated with the remaining hair follicles are still intact and sebaceous glands often persist in follicular units that seem to have lost all of their hair-producing epithelium



  • No significant perifollicular inflammation



  • Rarely, retained “naked” hair shafts are seen in otherwise typical cases of end-stage traction alopecia; the significance of the finding is unclear




Fig. 69.8


Vertical and horizontal sections of a hair follicle cut at different levels (from bottom to top).

Bulb : the hair bulb embraces the dermal papilla and is composed of matrical cells admixed with pigmented melanocytes; the nucleated hair shaft is surrounded by: (1) the early inner root sheath (IRS); (2) a pale outer root sheath (ORS); and (3) a dermal fibrous sheath in continuity with the dermal papilla. Suprabulbar area : the hair shaft is nucleated and is surrounded by (moving outwards): (1) the hair cuticle – a single layer of overlapping elongated cells; (2) the Huxley layer of the IRS – 3–4 layers of cuboidals cells with keratohyaline granules; (3) Henle layer of the IRS – single layer of elongated cells; and (4) the pale ORS. Sub-isthmus : the IRS is completely keratinized, the hair shaft is no longer nucleated, and the ORS is less pale and more pink, resembling epidermis. Isthmus : upon entering the isthmus, abrupt disintegration of the keratinized IRS occurs and is replaced by tricholemmal keratinization by the ORS. Infundibulum : the epithelium has reached maturation and is identical to, and in continuity with, the epidermis.

Courtesy, Catherine M Stefanato, MD, FRCPath.



Fig. 69.9


Histologic features of androgenetic alopecia, alopecia areata, and lichen planopilaris.

A Androgenetic alopecia with the characteristic miniaturization of hair follicles (vertical section). B Normal scalp (horizontal section). C Androgenetic alopecia with variation in hair follicle size (horizontal section; compare to B). D Androgenetic alopecia at the level of the isthmus with miniaturized vellus-like hair follicles and no significant inflammation (horizontal section). E Alopecia areata with miniaturized, vellus-like hair follicles, one of which has a peribulbar lymphocytic infiltrate (vertical section). A clue to the diagnosis is the dilatation of the follicular infundibula which corresponds to the yellow dots by trichoscopy (asterisks) . F Alopecia areata with the characteristic peribulbar lymphocytic infiltrates (horizontal section). G Alopecia areata at the level of the isthmus demonstrating exclusively telogen follicles (horizontal section). H Lichen planopilaris. Focal hypergranulosis at the acrotrichium and a dense perifollicular lymphocytic infiltrate. Note the Max-Joseph spaces between the hair follicle and the perifollicular sheath.


Differential Diagnosis


The diagnosis of MPHL is straightforward unless it is coincidentally associated with other non-scarring hair diseases such as alopecia areata or telogen effluvium. Initial recognition of FPHL may coincide with a superimposed telogen effluvium. Early-onset or severe patterned hair loss in women should suggest the possibility of pathologic hyperandrogenism, and appropriate screening laboratory tests (total and free testosterone, dehydroepiandrosterone sulfate, and 17 hydroxy-progesterone) should be performed (see Ch. 70 ).


Treatment


Male pattern hair loss


Topical formulations of minoxidil (2% solution, 5% solution, 5% foam) and oral finasteride have been approved by the US Food and Drug Administration (FDA) for the treatment of men with male AGA. Minoxidil is considered to be a biological response modifier and 1 ml is applied to the affected area twice a day. The most frequently reported adverse reactions are mild scalp dryness and irritation, and, rarely, allergic contact dermatitis. Minoxidil-induced hair growth is commonly associated with shedding of telogen hairs and a paradoxical worsening of hair loss ~4 to 6 weeks following initiation of treatment. This resolves with continued treatment.


Oral finasteride (1 mg daily), a type II 5α-reductase inhibitor ( Fig. 69.10 ), has been found to be effective in the treatment of balding in men . It halts hair loss in 90% of patients, and partial hair regrowth occurs in 65% of those receiving finasteride. Continued use of the product is necessary to sustain regrowth, which is also true for topical minoxidil; halting the medication will be associated with resumption of hair loss.




Fig. 69.10


Mechanisms of action for antiandrogens and 5α-reductase inhibitors.


Possible finasteride side effects include reversible loss of libido, reduced volume of ejaculate fluid, and erectile dysfunction, which occurs in ~2% of men. There are reports of long-lasting sexual dysfunction (post-finasteride syndrome), but its incidence is unknown. While the overall incidence of prostatic carcinoma is reduced among elderly men who take finasteride 5 mg daily for benign prostatic hypertrophy, patients should be informed that this higher dose has been associated with an increased risk of the diagnosis of high-grade prostatic carcinoma . It is uncertain if the latter represents overdiagnosis due to enhanced screening or whether it is predictive of an increased risk of metastasis and a higher mortality rate . With regard to the effects of finasteride (1 mg/day) on lowering serum concentrations of prostate-specific antigen (PSA), the recommendation is to adjust the measured serum PSA concentrations upwards by 40–50% for the purposes of prostate cancer screening .


Surgical hair replacement, specifically hair transplantation and scalp reduction, are alternatives for the treatment of male androgenetic alopecia (see Ch. 157 ). Potential therapies such as the oral PGD2 receptor antagonist setipiprant await further studies.


Female pattern hair loss


In the US, topical minoxidil (2% solution, 5% foam) is approved for the management of FPHL. There is a low-to-moderate level of evidence to support its effectiveness . FPHL can develop in the setting of hyperandrogenemia, and women may benefit from oral contraceptives (to suppress ovarian androgen production), spironolactone ( Fig. 69.11 ), or, if appropriate, finasteride therapy . If oral finasteride or spironolactone is used in women with childbearing potential, appropriate contraception should be utilized (given the risk of feminization of the male fetus), with oral contraceptives being the rational choice. While finasteride (1 mg per day) appears to be ineffective in postmenopausal women , when given at higher daily doses of 2.5 and 5 mg, it can improve FPHL . However, the level of evidence in support of the use of finasteride for FPHL was recently judged to be low .




Fig. 69.11


Female pattern hair loss in a 10-year-old girl.

A Prior to treatment. B Obvious improvement following 5 years of therapy with oral spironolactone and topical minoxidil.


Dutasteride is a combined type I and type II 5α-reductase inhibitor. A dose of 0.5 mg/day leads to a greater reduction in serum and scalp DHT levels than does finasteride at 5 mg/day. This suggests that dutasteride may be a more effective therapy. While there are case reports of dutasteride leading to improvement of FPHL, the potential teratogeni­city and prolonged biologic half-life preclude its use in women of childbearing age . Hair transplantation can also be offered to women with severe FPHL.




Telogen Effluvium




Key features





  • Increased shedding of otherwise normal telogen hairs in response to a pathologic or normal physiologic change in health status



  • A chronic form with no discernible precipitating factor is observed in some women



  • Laboratory evaluation is directed by history, physical examination, and microscopic evaluation of shed or plucked hairs




Introduction


In the normal scalp, there are ~100 000 hair follicles of which ~90% will be in the anagen phase, and the remaining 10% in telogen (see Table 68.3 ). Telogen typically lasts for three months. Daily, ~50–200 hairs undergo exogen and are shed (see Fig. 68.4 ). Only 500–1000 follicles are in the transitional catagen phase on any given day. The biologic clock that determines the end of the anagen phase and the beginning of the catagen/telogen phase is a complex phenomenon whose molecular basis is beginning to be understood (see Ch. 68 ).


During the anagen phase, each human hair will grow for a few months to years before it becomes a telogen hair and is shed. Scalp hair grows longer than hair on other parts of the body because its anagen phase is longer. Unlike mammals that molt, hair cycling in humans is asynchronous such that shedding of each follicle is independent of surrounding follicles. Consequently, a fairly uniform density of hair is maintained at all times. Various metabolic alterations such as pregnancy, malnutrition, and other stresses are capable of adjusting the biologic clock within hair follicles, and it is possible for abnormally large numbers of hairs to enter the telogen phase simultaneously. When this happens, the hair loss is termed a telogen effluvium .


Pathogenesis


Depending on the cause of telogen effluvium, the period of excessive shedding can vary. Telogen effluvium is by far the most common form of hair loss due to medications or in association with systemic diseases or altered physiologic states. The causes of telogen effluvium are listed in Table 69.3 . However, a fair number of women have been found to have a persistent telogen effluvium without any discernible precipitating cause . This chronic telogen effluvium primarily affects women between the ages of 30 and 60 years and is a diagnosis of exclusion. Computer modeling of hair cycle kinetics has suggested that chronic telogen effluvium results from a reduced variance in the duration of anagen rather than a shortened anagen phase per se .



Table 69.3

Causes of telogen effluvium.

For a complete list of associated drugs, see ref. 32.







CAUSES OF TELOGEN EFFLUVIUM



  • Shedding of the newborn (physiologic)



  • Postpartum (physiologic)



  • Chronic telogen effluvium (no attributable cause or illness)



  • Postfebrile (extremely high fevers, e.g. malaria)



  • Severe infection



  • Severe chronic illness (e.g. HIV disease , systemic lupus erythematosus)



  • Severe, prolonged psychological stress



  • Postsurgical (implies major surgical procedure)



  • Hypothyroidism and other endocrinopathies (e.g. hyperparathyroidism, hyperthyroidism)



  • Crash or liquid protein diets; starvation/malnutrition



  • Drugs:




    • discontinuation of oral contraceptives



    • retinoids (acitretin, isotretinoin) and vitamin A excess



    • anticoagulants (especially heparin)



    • antithyroid (propylthiouracil, methimazole)



    • anticonvulsants (e.g. phenytoin, valproic acid, carbamazepine)



    • interferon-α-2b



    • heavy metals



    • β-blockers (e.g. propranolol)




If there is a definable precipitating event, hair loss begins approximately 3 months after this event, since it takes that amount of time for a hair follicle to progress through the telogen phase and then finally be shed. There is neither clinical nor histologic evidence of inflammation in “pure” telogen effluvium.


Most drugs that have been associated with hair loss, with the exception of antineoplastic agents, cause hair loss via telogen effluvium. While numerous medications have been associated with hair loss, only a subset of these are common causes of telogen effluvium (see Table 21.19 ). The most prominent offenders are retinoids (acitretin and isotretinoin) , anticonvulsants, antithyroid medications, anticoagulants, lithium, and interferons. More complete lists of medications associated with alopecia are readily available .


Clinical Features


Thinning of the hair involves the entire scalp and may also be noted on other hairy regions of the body (e.g. pubic and axillary hair). A gentle hair pull may be positive for two or more normal telogen hairs ( Fig. 69.12 ). A forcible hair pluck (trichogram) will show a mixture of anagen and telogen hairs with the percentage of telogen in excess of 20% (see Fig. 69.2 ). While a telogen count of 15–20% is suggestive of abnormal shedding, >20% is diagnostic. In an active telogen effluvium, a 60-second timed hair count will usually be in excess of 100 hairs (the mean normal value is 10 hairs) . This method, which involves combing the hair forward for 60 seconds over cloth of a contrasting color before shampooing, can be used to follow the progression and eventual resolution of a telogen effluvium. In an attempt to assist patients in describing the amount of daily hair shedding they are experiencing, a visual scale that depicts varying numbers of hairs has been proposed ( Fig. 69.13 ) . The histopathologic findings in telogen effluvium are outlined in Table 69.2 .




Fig. 69.12


Microscopic features of anagen and telogen hairs.

A Telogen shaft showing a club-shaped bulb. B Anagen shaft with attached root sheaths, demonstrating a pigmented and distorted bulb. M, matrix; I, inner root sheath; O, outer root sheath. C Ruffled cuticle of loose anagen hair.

C, Courtesy, Julie V Schaffer, MD.



Fig. 69.13


Visual shedding scale.

The patient chooses the photograph that best correlates with the amount of daily hair shedding in the setting of daily washing. Grades 1–4 are considered normal while grades 5 and 6 reflect excessive shedding.

Adapted with permission from ref 35.


Eventually complete hair regrowth is expected. The prognosis for women with chronic telogen effluvium is relatively good, for although hair shedding can continue for many years, this does not appear to lead to baldness . The prognosis for telogen effluvium associated with systemic disease is excellent if the precipitating cause is eliminated.


When the cause is unclear, the evaluation of a patient with telogen effluvium includes thyroid and chemistry panels, sedimentation rate, hematocrit, and ferritin (as a reflection of total body iron storage). According to literature recommendations, ferritin levels should be at least 40 ng/dl, but the significance of abnormal values is uncertain . In persistent cases of telogen effluvium, i.e. those lasting beyond 6 months, a scalp biopsy specimen submitted for horizontal sectioning can prove useful in excluding early AGA; the ratio of terminal to vellus hairs counted at the level of the isthmus allows distinction . However, there does remain the possibility of the coexistence of both disorders. Trichoscopy findings are shown in Fig. 69.7B .




Alopecia Areata




Key features





  • Non-scarring patterned alopecia, most commonly presenting as circular areas of alopecia



  • Organ-specific autoimmune disease involving T cells



  • Can lead to total scalp hair loss (alopecia totalis) or complete scalp and body hair loss (alopecia universalis)




Introduction


Celsus is credited with describing patterns of hair loss using the Greek word alopekia , meaning fox mange, and Sauvages coined the term “alopecia areata”. Alopecia areata is a non-cicatricial alopecia that is postulated to be a hair-specific autoimmune disease, with genetic factors playing a role in disease susceptibility and severity. A concordance rate of 55% has been found in identical twin studies, implicating both genetic and environmental factors.


In the acute progressive stage of alopecia areata, lymphocytic infiltrates are seen around, and sometimes within, the hair bulb region of anagen follicles. Despite the presence of this inflammatory infiltrate, the follicle retains its potential to produce hair, implying that the follicular stem cells remain viable.


The chronic relapsing nature of alopecia areata and its profound effect on physical appearance make the development of this condition a distressing and life-changing event for many affected individuals .


Epidemiology


The prevalence of alopecia areata in the US is ~0.1% to 0.2% of the population . The average lifetime risk of developing alopecia areata is estimated to be 1.7%. Overall, one in five patients with alopecia areata reports that another family member has the disease.


Pathogenesis


There are multiple hypotheses regarding the pathogenesis of alopecia areata, ranging from an environmental insult such as a viral infection to a genetic susceptibility to T-cell-driven autoimmunity . The latter could result from a primary attack of the immune system against the hair follicle or a breakdown in the hair follicle’s immune privilege which leads to a secondary attack by the immune system (see Ch. 68 for details). Of course, it is most likely that there is an interplay of several factors and depending upon the particular patient or subtype, one factor may play a more important role.


With regard to genetic susceptibility, genome-wide association studies have identified several loci which are involved in immune regulation, including that of regulatory T cells . Examples of these genes include those that encode HLA alleles, interleukin (IL)-2 and -21, the IL-2 receptor A, and cytotoxic T lymphocyte-associated protein 4 (CTLA-4; Table 69.4 ) . Additional associated genes point to a role for oxidative stress and disrupted autophagy/apoptosis.



Table 69.4

Alopecia areata: disease and genetic associations.

PRDX5 encodes an anti-oxidant enzyme and STX17 is associated with the gray hair phenotype in horses. CTLA4 , cytotoxic T lymphocyte-associated antigen 4 gene; IL2RA , interleukin 2 receptor subunit alpha gene; ULBP , UL16-binding protein genes.

















ALOPECIA AREATA: DISEASE AND GENETIC ASSOCIATIONS
Associated diseases



  • Atopy (allergic rhinitis, atopic dermatitis, asthma); >40% in some studies



  • Autoimmune thyroid disease (e.g. Hashimoto thyroiditis), vitiligo, inflammatory bowel disease



  • Autoimmune polyendocrinopathy syndrome type 1 (autosomal recessive; due to mutations in the autoimmune regulator gene [ AIRE ]; up to 30% of patients have alopecia areata)



  • Type 1 diabetes increased in relatives of patients with alopecia areata

HLA associations



  • HLA-DQB1*0301 (DQ7), HLA-DQB1*03 (DQ3), and HLA-DRB1*1104 (DR11); HLA-DQB1*03 appears to be a susceptibility HLA marker for all forms of alopecia areata, whereas the HLA alleles DRB1*0401 (DR4) and HLA-DQB1*0301 (DQ7) are considered markers for severe longstanding alopecia totalis/universalis

Additional genome-wide associations



  • Function of Treg cells: CTLA4, IL-2/IL-21, IL2RA, Eos , LLRC32 / GARP



  • Expressed within the hair follicle: PRDX5, STX17 , BCL2L11 ( BIM )



  • ULBP gene cluster – encodes activating ligands of NK cell receptor NKG2D



Evidence in support of a T-cell-driven autoimmune process includes the observation that CD8 + T cells are the initial intrafollicular lymphocytes to appear in alopecia areata. In mouse models, it is also possible to induce alopecia within transplanted human skin by transferring CD8 + T cells, but this does not occur if T cells are depleted . Cytotoxic CD8 + NKG2D + T cells, which produce interferon (IFN)-γ, are thought to play a key role in pathogenesis (see Ch. 68 for details). Involvement of IFN-γ and the γ-chain cytokines (IL-2, IL-7, IL-15, IL-21) implicates downstream signaling via the JAK (Janus kinase)/STAT pathway (see Fig. 128.10 ). These findings represented the rationale for cytokine-targeted therapy and indeed the JAK inhibitors tofacitinib and ruxolitinib did promote hair regrowth in separate uncontrolled clinical studies.


As noted previously, collapse of the hair follicle’s immune privilege may play a role in the pathogenesis of alopecia areata . Normally, anagen hair follicles express low levels of MHC class I molecules (thereby minimizing presentation of autoantigens), upregulate immunosuppressant molecules such as TGF-β1 and α-MSH, and do not activate natural killer (NK) cells by expressing UL16 binding protein 3, an NKG2D ligand. In that hair matrix immune privilege is restricted primarily to the anagen phase, it has been postulated that an autoantigen from melanocytes, which are active during the anagen phase, could be responsible for initiating the immune response against the hair follicle.


Clinical Features


Alopecia areata commonly presents as round or oval patches of non-scarring hair loss ( Fig. 69.14A ). Short “exclamation point” hairs (i.e. distal end broader than the proximal end) can often be seen, particularly at the margins of areas of alopecia ( Fig. 69.14B ). Other presentations include alopecia totalis (loss of all scalp hair), alopecia universalis (loss of all scalp and body hair; Fig. 69.14C ), an ophiasis pattern (band-like pattern of hair loss along the periphery of the temporal and occipital scalp; Fig. 69.14D ), and alopecia involving the beard area ( Fig. 69.14E ). The reticular variant is characterized by recurrent patchy disease, in which the patient experiences hair loss in one area while at the same time undergoing spontaneous regrowth in other sites. The rare diffuse variant of alopecia areata can manifest with widespread thinning or may primarily affect the top of the head. Non-pigmented hairs may initially be spared, and, as a result, some patients with diffuse involvement will appear to develop rapid graying of the hair. With regrowth, the hairs may initially be gray or white, but repigmentation is usually observed within a few weeks or months .




Fig. 69.14


Alopecia areata.

A Circular area of alopecia in a child. B Diffuse variant with multiple exclamation point hairs characterized by a distal end that is broader than the proximal end. C Total alopecia of the scalp, eyebrows, and eyelashes in a patient with alopecia universalis. D Ophiasis with a band-like pattern of hair loss along the periphery of the temporal and occipital scalp. E Alopecia areata with just beard involvement. F Trachyonychia in a patient with alopecia areata.

B, F, Courtesy, Julie V Schaffer, MD.


In addition to the hair follicle, nails may be involved. The most common abnormality is nail pitting, but other changes described include trachyonychia (sandpaper-like roughness due to excessive longitudinal ridging; Fig. 69.14F ), brittle nails, onycholysis, koilonychia and, rarely, onychomadesis (see Ch. 71 ).


Disease associations are listed in Table 69.4 . The histopathologic features of alopecia areata (see Fig. 69.9 ) are described in Table 69.2 , and trichoscopy findings are shown in Fig. 69.7C .


Differential Diagnosis


Tinea capitis, trichotillomania, temporal triangular alopecia, traction alopecia, secondary syphilis, and loose anagen syndrome need to be considered in the differential diagnosis of alopecia areata as well as pressure-related alopecia, aplasia cutis, and “burnt-out” cicatricial alopecia. The diffuse variant may initially be confused with telogen effluvium and androgenetic alopecia. Usually, the history and clinical examination (including trichoscopy) is sufficient to distinguish between these conditions, but performing a scalp biopsy may prove useful for less distinctive presentations.


Treatment


Treatment studies are difficult to perform because the disease has an unpredictable course and may improve on its own. Nevertheless guidelines have been established to facilitate research .


Numerous therapies are available for the management of alopecia areata ( Table 69.5 ), and several can be utilized in combination. The treatment of patchy alopecia areata may include topical or intralesional corticosteroids , topical minoxidil (2% or 5%), topical anthralin (0.5–1% cream applied daily; see Ch. 129 ), and combination therapy. The concentration of intralesional corticosteroid is usually 2.5–5 mg/ml of triamcinolone acetonide , and injections can be repeated every 4–8 weeks. This medication should be injected at the level of the mid dermis to target the diseased, miniaturized hair bulbs.



A dependable and safe treatment for extensive disease (totalis or universalis) has yet to be found, although spontaneous recovery is possible (albeit rarely), even in longstanding disease. Approximately 80% of patients will respond to high-dose systemic corticosteroids (e.g. 40 mg triamcinolone intramuscularly monthly, or daily oral prednisolone or dexamethasone tapered over 6–8 weeks); however ~50% will relapse with dose reduction or cessation of therapy . Long-term maintenance therapy with oral corticosteroids is rarely justified and steroid-sparing agents such as azathioprine and methotrexate are unreliable.


Topical immunotherapy (with diphencyprone or squaric acid dibutyl ester) is a non-FDA-approved treatment for extensive disease. Clinicians interested in using topical immunotherapy should carefully review the published protocols ( Table 69.6 ). PUVA, potent topical corticosteroids under plastic occlusion, and systemic targeted immunomodulators (“biologics”) have all been tried with less success. More recently, promising results with oral JAK/STAT pathway inhibitors (e.g. tofacitinib , ruxolitinib ) have been reported, but relapse following discontinuation is an issue. Of note, patients with the ophiasis pattern of hair loss are more resistant to therapy than are other patients with similar amounts of hair loss.


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Sep 15, 2019 | Posted by in Dermatology | Comments Off on Alopecias

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