Regrowth - The Science of Hair Restoration

Telogen Effluvium (Including Postnatal, Postfebrile, Postpartum,
and Heparinoid Alopecia)

Unit 2-35: TOXIC AND PHYSIOLOGIC ALOPECIA Vol. 1 Section 2: DISEASES OF HAIR

The separation of this form of diffuse hair loss as a distinct pathogenetic disorder has only been accomplished in this century. Appreciation of this condition has been dependent on the establishment of methods for qualitative and quantitative evaluation of statistically significant numbers of hairs from an individual scalp; manual epilation and low-power microscopic examination of approximately 100 hairs as introduced by Van Scott and co-workers1 has proved to be reasonably atraumatic and effective diagnostically and prognostically, particularly in telogen and anagen alopecias.

INCIDENCE

Telogen alopecia (along with male-pattern baldness) surely represents the most common type of alopecia. Postnatal and postpartum alopecias affect virtually all children and probably the majority of parturient women, although the latter may be so minimally affected as to escape clinical notice. Prevalence of postfebrile alopecia is not known, although "epidemics" have been noted, for example, during the 1918 flu epidemic.2 Telogen effluvium also follows discontinuation of oral contraceptives, which is analogous to the well-recognized postpartum shedding. Because this form of hair loss represents in effect an acceleration of a normal and disease states will tend to overlap considerably.

CLINICAL MANIFESTATIONS, CAUSE, AND PROGNOOSIS

The characteristic feature of telogen alopecia is a latent period of several weeks between the inciting event and clinical hair loss. The data of Schiff and Kern3 concerning onset of hair loss following delivery can be represented graphically to follow a reasonable facsimile of a bell-shaped curve, with about one half of 98 cases beginning at 11 to 13 weeks. This agrees well with the often-stipulated 3-month interval (the normal average duration of retention of telogen hair in the scalp), but variation from 4 to 16 weeks should be expected. Onset within a few days of pregnancy, however, suggests the possibility of a concomitant or antecedent process compounding the event.

Complaints of clinical alopecia will vary with the sensitivity of the affected woman to the process and her concern with cosmetic appearance. This may be particularly frustration to the examining physician, because true increase in rate of loss of telogen hairs may be exceedingly difficult to detect. It must be remembered that about 50 hairs are lost from the average scalp per day. If this rate is increased to 150 per day, for example, and the scalp contains 100,000 or more hairs, the amount of hair lost over an entire week will be only about 1%. If these hairs are lost from follicles distributed randomly over the scalp, clinical detection of alopecia may be impossible; yet the patient is losing hair at three times the normal rate and may be justifiably concerned. This is true of all type of telogen alopecia.

The loss of hair is sometimes partially patterned rather than randomly diffuse and tends to follow the frontal distribution typical of male baldness. This is particularly true of the normal postnatal shedding observed in virtually all infants.4 This little-studied and apparently universal phenomenon of infant development is better known to mothers than physicians. Justification for this medical lack of interest presumably is based on the temporary nature of the process and complete restitution of normal scalp hair by the end of the first year of life.

All these processes may be regarded as physiologic and consequent to premature induction of the normal hair cycle termination without apparent pathologic implication. In addition, exogenous administration or accidental ingestion of anticoagulants (heparin, heparinoids, coumarin), gold compounds, and propranolol, causes telogen effluvium. The effect is believed to be related to dose - not duration of therapy.5

Although usually secondary to therapeutic administration, accidental poisoning with warfarin can result in the same process. The clinical features are identical with the other cases of telogen alopecia, that is, a diffuse hair loss with clinical severity dependent on a rate of loss, percentage of hairs converted to telogen, and extent of passive removal by manipulations such as excessive brushing.

Telogen alopecia from medication causes diffuse hair loss or predominantly frontal shedding. The hair may not be shed until 3 months after starting the causative medication.

Some instances of alopecia cannot be related to specific physiologic or toxic events. Many observers have noted severe diffuse alopecia occurring in apparently temporal relation to severe antecedent emotional trauma.

The duration of telogen alopecia is somewhat variable, but complete restitution invariably occurs unless another pathologic process supervenes. In one series of subjects with postpartum alopecia, 56 or 98 patients returned to normal in 5 or 6 months. Apparently a few cases may persist for 1 or more years, but this is a distinct exception. It is difficult to assess reports of post-infectious alopecias persisting for years. In the usual case, assurance of complete return to normal with 1 year is entirely warranted.

The relationship of postpartum alopecia to recurrent pregnancies is of prognostic (and possibly pathogenetic) interest. Schiff and Kern stated that a new pregnancy established in the early postpartum period (prior to second menses) was not followed by alopecia.

ETIOLOGY AND PATHOGENESIS

Postpartum hair loss represents an apparent delay during the third trimester in the normal rate of anagen-telogen conversion. Those hairs that would have normally converted during this period apparently do so only after release from the hormonal alterations of pregnancy, resulting in a temporary increase in the number converted to telogen hairs during the postpartum period. This interpretation is based on the observation by Lynfield7 of an increased percentage of anagen hairs before delivery and a significant decrease (or increase in telogen) after delivery. The precise hormonal mechanism is unknown, although Lynfield cites the know influence of estrogen on prolonging the anagen stage.

The mechanism of postfebrile alopecia is unknown. Although clinical impressions would suggest that a major elevation of temperature is necessary there is no good quantitative evidence to support this supposition. Similarly, the induction of telogen alopecia by heparin and related compounds occurs by an unknown mechanism. The ability to produce telogen alopecia by purposeful prescription of known agents that in proper doses do not cause serious systemic toxicity provides unique opportunity for studies of pathogenesis. The interesting observation of an inconstant perivascular collagenous degeneration similar to that notes in alopecia areata8 and certain cicatricial alopecias9 requires additional investigation for appropriate interpretation.

DIAGNOSIS

The diagnosis of telogen alopecia, although reasonably evident from history in most cases, can be directly confirmed by identification of all shed hairs as morphologically normal telogen hairs by observation of a greatly increased number of telogen hairs (decreased anagen - telogen ratio) in the scalp, as reflected in a sample of epilated hairs. It must be emphasized, however, that even an anagen-telogen count must be interpreted with caution. A count late in the course of anagen alopecia when most growing hairs have already been lost would reveal a high proportion of telogen hairs by epilation: both experience and constant referral to the person are mandatory.

DIFFERENTIAL DIAGNOSIS

Diffuse nonpatterned alopecia will not normally be confused with any of the patchy or cicatricizing processes. In telogen effluvium the scalp skin is entirely normal, as are the hair shafts. Differentiation from (acute) anagen alopecia is generally not difficult. When all anagen hairs are severely damaged, 90% or more of the scalp hairs may be lost in a short time. Telogen alopecia by contrast rarely results in loss of more than 50% of scalp hair. Even this gross loss may be remarkably unspectacular clinically, particularly if the remaining hair is long and tends to mask the thinning. Observations of the hair roots will reveal characteristic differences in anagen or telogen alopecias. Hairs damaged in anagen will show specific morphologic dysplastic alterations. Hairs lost in telogen alopecia are morphologically normal resting hairs.

The situation may be more confusing when an agent responsible for anagen alopecia is delivered slowly rather than rapidly, as for example chronic ingestion of small amounts of a toxin. Similarly, smaller doses of a cancer chemotherapeutic agent may result in entirely reversible matrix inhibition or only a small percentage of visibly affected hairs. The magnitude of hair loss in such instances may be more similar to that in telogen alopecia than to gross loss of acute toxic anagen alopecia. Careful observation of spontaneously and manually epilated hairs should detect characteristic constrictions, breaks, or atrophic hairs in the latter instances.

Telogen alopecia resulting in male-pattern hair loss can be readily overlooked in the male; in the female it is less likely ignored. The etiology of male-pattern baldness in women is often obscure, but search for causes of underlying telogen alopecia is appropriate.

TREATMENT

There is no effective treatment for telogen alopecia. Careful explanation of cause and favorable prognosis, together with instructions to preserve as many telogen hairs in the scalp as possible by avoidance of manipulation until new growth has progressed, should be routine.

Anagen Alopecia (Toxic Effluvium)

The greater sensitivity of actively growing (anagen) hairs, in contrast to resting hair, to a variety of toxic chemical or physical agents has been appreciated for many decades. Indeed, x-ray (or thallium) epilation to rid the scalp of fungus infections was standard therapy. The development of pharmaceutical agents with known toxicity manifest primarily on rapidly proliferating tissues will produce anagen alopecia for many years to come. In addition, accidental exposure to poisons or natural products provides occasional cases.

INCIDENCE

Anagen alopecia is far less common than the telogen form, which occurs as a nearly normal physiologic event in postnatal and postpartum periods (although not necessarily clinically manifest). Since all the clear-cut anagen alopecias represent exposure to exogenous substances or events, their occurrence will be sporadic and in proportion to exposure. Accidental exposure is particularly likely to occur in children. Although one could probably demonstrate a statistical predilection for females if all ages were considered, this would almost undoubtedly reflect the relative psychologic importance of scalp hair to women and their desire to seek medical help. Obviously, the high prevalence of male baldness would correspondingly decrease clinically demonstrable anagen alopecia in the population of older men.

ETIOLOGY AND PATHOGENESIS

A large number of elements or compounds are known to affect anagen hairs, and alopecia results from exposure to toxic chemicals encountered iatrogenically, accidentally, occupationally, or in cosmetics.10,11 Anagen effluvium follows poisoning by thallium, mercury, and borates as well as treatment for anticancer medications, vitamin A, retinoids, and cantharidin, which act by cytotoxic inhibition of the highly proliferative hair matrix. Salts of lead, mercury, selenium, and arsenic are also incriminated. Methotrexate has been shown to cause a reversible atrophy of anagen hair bulb proportionate to dose,1 and the effect is impressed on the hair shaft as a progressive construction.12 Systematic investigation of x-ray- and antimetabolite-induced anagen alopecia must be credited primarily to Van Scott, 1,13 although anagen (and telogen) hair sensitivity to x-irradiation was documented as early as 1926 and the anatomic peculiarities of affected anagen hairs described in 1906. These historical aspects of x-ray alopecia are reviewed by Flesh.2 Temporary epilation after 300 R but permanent alopecia after 500 R or more has been attributed to damage to the mesodermal hair papilla with the larger doses. Graded response to doses of x-ray less than 300 R was demonstrated quantitatively by Van Scott and co-workers,1 who indicated that the number of affected (dysplastic) hairs was proportionate to dose and length of time after exposure. The morphologic alterations included diminution of diameter of the matrix, which generally progressed to severe atrophy and death of the hair root. Occasionally, a hair could be found whose matrix had recovered and was producing a new hair shaft, with the constricted area being propagated outward in advance of apparently normal hair development. This reversible effect after x-ray is distinctly uncommon, with lesser doses being reflected in smaller number of hairs affected rather than lesser degree of dysplasia. This situation may be contrasted to the effect of the antifollic acid compound methotrexate which was found to result in reversible atrophy of the hair bulb in proportion to the dose of the drug. With recovery of the hair root, the defect was propagated distally as a construction in the shaft. More severe constrictions resulted in breakage of the hair shaft, producing a characteristic and recognizable defect readily, distinguishable from the progressively atrophic root after irradiation. The rate of hair growth, if affected at all, also returned to normal. Thus the approximate date of drug effect could be calculated by dividing the distance between the hair root and the construction by the normal daily growth rate.13

Although this type of damage to the anagen hair has been frequently quoted as prototypical of anagen toxicity, in fact no exactly analogous situation has since been reported. Probably all antimitotic, antifoliative, or radiomimetic drugs are potentially capable of anagen toxicity; several have been documented.12 It would be useful if differences in types of morphologic or biochemical damage could be detected after different agents. Anagen effluvium is inducible by lithium,14 indomethacin, allopurinol, cholesterol-lowering agents, and overdosage of antithyroid medication. Although thallium is presumably no longer used therapeutically, it is a common ingredient of various insect and small animal poisons and still causes a substantial amount of human morbidity. Acute poisoning in young children is not likely to go unrecognized, since abrupt loss of hair will be accompanied by pain and anorexia, or more severe central nervous system gastrointestinal, or renal manifestations. Chronic thallotoxicosis in all age-groups may be much less obvious and may be far more common than generally realized.15 Evidence supporting the primary involvement of anagen hairs in thallium toxicity is well summarized by Flesch.2 Some investigators believe that the tapered end of a broken hair with a dark zone near the break, said to be caused by entrapped air bubbles, is characteristic (if not pathognomonic) of thallium alopecia. However, dysplastic atrophied hair roots may not be significantly different from those observed after the administration of certain cancer chemotherapeutic drugs.12 In animal experiments, thallium toxicity can be blocked by cystine or methionine. Incorporation of these amino acids is a vital part of normal hair growth and consolidation and can be modified by diet in both animals16 and humans.17 Since other sulfhydryl compounds do not block thallium toxicity, it is possible that the element interferes with normal cystine incorporation in the growing hair. An analogous process may be operative in the toxic anagen alopecia induced in humans by ingestion of the nuts of the monkeypot tree, coco de mono (Lecythis ollaria) a deciduous tree widely distributed in Central and South America. Many other plants are responsible for producing alopecia, including Stanleya, Astragalus pectinatus (locoweed), Leucaena, Melilotus (yellow sweet clover), Colchicum autumnale, Gloriosa, and Saptaceae (several Brazilian woods of this family).18 Kerdel Vegas19 had described from Venezuela an acute gastrointestinal syndrome followed by reversible hair loss. The active principle was isolated and characterized as selenocystathionine. In vitro, cytotoxicity of this compound could be blocked by (natural) l-cystine but not d-cystine or sulfhydryl compounds, a situation comparable to that reported for thallium.2 A similar syndrome of gastrointestinal symptoms and hair loss has been reported to follow the administration of synthetic d,l-selenocystine20 in humans, and hair loss among Indians has been associated with selenium poisoning.

Another naturally occurring amino acid analog, mimosine, is apparently responsible for causing hair loss in humans or some animals who ingest seeds of the shrubby tree Leucaena glauca. This species is widely established in Hawaii (where it was once planted as fodder for grazing animals) and can be found growing wild in southern Florida. Although originally said to be a substituted alanine, the compound acts as an inhibitor of tyrosine decarboxylase and tyrosinase. Only growing hairs are affected, establishing mimosine as another cause for anagen alopecia.

Several other heavy metals, including arsenic, lead, and bismuth, can cause alopecia, presumably of the anagen type. Some of these may act indirectly by induction of iron deficiency, a condition frequently reported to be associated with hair loss. These reports are largely of a testimonial nature, and it is difficult to assess accurately their importance. Certainly chronic poisoning should be considered in patients of all ages with diffuse alopecia of inapparent cause.

Alopecia as an occupational disease occurs in the synthetic rubber industry following exposure to chloroprene dimers, which are chemicals related to Vitamin A.21

Following tick bite of the scalp a patch of alopecia may develop, with its center presumably caused by direct necrotizing effect of the tick saliva and its radial spread attributed to the action of diffusing toxin.22

The high degree of metabolic and mitotic activity of the anagen hair root renders it (along with the bone marrow and gastrointestinal epithelium) unusually susceptible to competitive analogs, growth inhibitors, and metabolic poisons. It is unnecessary in most cases to assume specific clinical affinity of hair roots for a given compound. Essentially all the substances that can cause anagen hair loss can also cause severe generalized toxicity or death when larger amounts are present. Although the specific mechanisms of cytotoxicity may differ, it is the capacity to inhibit highly proliferative tissues in general that results in anagen hair loss.

CLINICAL MANIFESTATIONS

Approximately 90% of scalp hairs are in anagen; therefore, severe toxicity causes marked and extensive hair shedding.6 The hairs are atrophied and are easily extracted, or they break. Anagen hair loss occurs much earlier than telogen hair loss and is usually reversible.

The clinical features of anagen hair loss depend on the degree of toxicity evoked by the causative agent and the cycle state of the hair population in a given area. Although the male beard area represents a high population of anagen hairs, a daily shaving habit will tend to obscure hair loss in the area. Similarly, preexistent male-pattern baldness will obscure what might be severe anagen alopecia. Loss of eyebrow hair may be lessened because of the smaller proportion of eyebrow hairs in the growing phase as compared with scalp hairs. Constriction of hair shafts of anagen hairs as a result of recovery of the partly inhibited hair root will occur to varying degrees and may be so slight as to result in breakage of hairs only after moderately severe trauma. Excessive cosmetic manipulation will result in more hair loss in a person so predisposed than in one who rarely combs the hair.

The loss will occur earlier after the toxic insult than in telogen alopecia, since extremely atrophied hairs will leave the scalp with the gentlest of rubbing, whereas telogen hair roots are more likely to be retained in the scalp for several weeks. Any patterning of the hair loss in anagen alopecia will simply reflect the preexisting pattern of anagen - telogen ratio in a given area. Most acute anagen alopecias are entirely reversible, the obvious exception being those produced by high-dosage irradiation that causes extensive dermal alteration. The prognosis in diffuse hair loss of long duration associated with chronic poisoning is less clear and permanent thinning may occur.

DIAGNOSIS AND CLINICAL AND LABORATORY FINDINGS

The diagnosis is suggested by precipitous effluvium following a relevant exposure to, or intake of, a toxic agent. If the cause is not obvious, the case merits a careful history, physical examination, microscopic inspection of plucked hairs, and laboratory studies, including toxicologic investigation of blood, tissue, hair and nails, as circumstances dictate.

Any instance of diffuse nonpatterned hair loss should immediately arouse suspicion of toxic anagen alopecia. Precipitous hair loss generally indicates a specific exposure or ingestion in the recent past. Mild, chronic, progressive hair loss may not be immediately evident to the consulting physician, often to the consternation of the patient. A careful history, documented evidence of loss of hairs in excess of the normal daily number, adequate physical and general laboratory examination, and microscopic evaluation of spontaneously shed and manually epilated hairs represents the minimal effective diagnostic work-up.

There is no treatment for anagen alopecia except removal of the inciting cause. Nevertheless, establishment of a specific diagnosis is of paramount importance since complete recovery is the rule, and the patient can make decisions as to temporary scalp coverings based on the prognosis.

Morris Waisman

Robert G. Crounse

REFERENCES

Van Scott EJ, Reinertson RP, Steinmuller R: The growing hair roots of the human scalp and morphologic changes therein following amethopterin therapy. J Invest Dermatol 29:197, 1957
Flesch P: Hair growth. In Rothman S (ed): Physiology and Biochemistry of the Skin. Chicago, University of Chicago Press, 1954
Schiff BC, Kern AB: Study of postpartum alopecia. Arch Dermatol 87:609, 1963
Hamilton JB: Patterned loss of hair in man: Types and incidence. Ann NY Acad Sci 53:708, 1961
Tudhope GR, Cohen H, Merkle RW: Alopecia following treatment with dextran sulfate and other anticoagulant drugs. Br Med J 1:1034, 1958
Rook A: Some chemical influences on hair growth and pigmentation. Br. J Dermatol 77:115, 1965
Lynfield YC: Effect of pregnancy on the human hair cycle. J Invest Dermatol 35:323, 1960
Van Scott EJ: Evaluation of disturbed hair growth in alopecia areata and other alopecias. Ann NY Acad Sci 83:480, 1959
Laymon CW, Murphy RJ: The cicatricial alopecias: An historical and clinical review and an histologic investigation. J Invest Dermatol 8:99, 1947
Jaworsky C, Taylor JS, Evey P, Handel D: Allergic contact dermatitis to glutaraldehyde in a hair conditioner. Cleve Clin J Med 54:443, 1987
Rook A, Dawber R: Diseases of the Hair and Scalp, pp 133-145. Oxford, Blackwell Scientific Publications, 1982
Crounse RG, Van Scott EJ: Changes in scalp hair roots as a measure of toxicity from cancer chemotherapeutic drugs. J Invest Dermatol 35:83, 1960
Van Scott EJ: Physical factors which invluence the growth of hair. In Montagna W, Ellis RA (ed). The Biology of Hair Growth. New York, Academic Press, 1958
Orwin A: Hair loss following lithium therapy, Br J Dermatol 108:503, 1983
Hubler WR: Hair loss as a symptom of chronic thallotoxicosis. South Med J 59:436, 1965
Reis PJ: Variations in the sulfur content of wool. In Lyne AG, Short BF (eds): The Biology of Skin and Hair Growth. Sydney, Angus & Robertson, 1965
Koyangi T, Takanohashi T: Cystine content in hair of children as influenced by vitamin A and animal protein in the diet. Nature 192:457, 1961
Mitchell J, Rood A: Botanical Dermatology: Plants and Plant Products Injurious to the Skin. Vancouver. Greengross, 1979
Kerdel Vegas F: Generalized hair loss due to ingestion of "coco de mono" (lycythis ollaria). J Invest Dermatol 42:91, 1964
Weisberger AS, Suhrland LG: Studies on analogues of l-cystine. III. The effect of selenium cystine on leukemia. Blood 11::19, 1956
Taylor JS. In Maibach HI: Occupational and Industrial Dermatology, 2nd ed, p 109. Chicago, Year Book Medical Publishers, 1987
Heyl T: Tick bite alopecia. Clin Exp Dermatol 7:537, 1982