Anagen Effluvium

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Background

Normal human hairs can be classified according to the three phases of their growth cycle: anagen, catagen, and telogen. Anagen hairs are in a growing phase, during which the matrix cells of the hair follicle undergo vigorous mitotic activity. These hairs have long, indented roots covered with intact inner and outer root sheaths, and they are fully pigmented.

Toward the end of the anagen phase, the amount of pigment decreases at the base of the follicle, which expands to form a keratinized club. Then, the hair enters the catagen phase, a transitional phase in which mitotic activity decreases. The follicle separates from the dermal papilla and the capillary plexus and moves upward within its connective tissue sheath toward the epidermis. The resulting telogen hairs, or club hairs, are in a resting phase. These hairs have short, club-shaped roots that anchor them in the follicle. They lack root sheaths and show depigmentation of the proximal part of the shaft.

The hairs continue in this resting state until the follicle spontaneously re-enters the anagen phase. At this point, the club hairs are forced out by growing hairs underneath them, and the cycle begins anew. The cycle is not synchronous throughout the scalp. The length of each phase of the cycle, as well as the length of the entire cycle, varies with the site and the age of the patient. In the scalp, for example, the average length of the anagen phase is 1000 days; the catagen phase lasts only a few days; and the telogen phase lasts 100 days.

Of the 100,000 hairs on the average scalp, 10-15% are in the catagen or telogen phase at any time. Most hair follicles are in the anagen stage at any given time. This process is different from chronic telogen effluvium, postulated to be a result of a reduction in the variance of anagen duration.[1]

Pathophysiology

Hair loss can be classified according to the stage of the hairs shed. Telogen effluvium is defined as the early and excessive loss of normal club hairs from normal resting follicles in the scalp. This hair loss usually results from trauma to the normal hair as a result of a stressor such as parturition, surgery, or fever that causes an abnormally large percentage of hairs to move into the catagen and telogen phases. When anagen restarts 2-4 months later, the club hairs are pushed out and lost, causing a temporary diffuse thinning of the scalp hair.

Anagen effluvium occurs after any insult to the hair follicle that impairs its mitotic or metabolic activity. The hair loss is usually the result of an exposure to chemotherapeutic agents such as antimetabolites, alkylating agents, and mitotic inhibitors that are used to treat cancer, although it is not the only type of chemotherapy induced-hair loss in these patients.[2]

The inhibition or arrest of cell division in the hair matrix can lead to a narrow, weakened segment of the hair shaft that is susceptible to fracture with minimal trauma. It can also result in complete failure of hair formation. The hair bulb itself may be damaged, and the hairs may separate at the bulb and fall out. Only actively growing anagen follicles are subject to these processes. This form of alopecia is more common and severe with combination chemotherapy than with the use of a single drug, and the severity is generally dose dependent. Anagen effluvium also occurs in persons with alopecia areata as the result of the inflammatory insult to the matrix.

The characteristic finding in anagen effluvium is the tapered fracture of the hair shafts. The hair shaft narrows as a result of damage to the matrix. Eventually, the shaft fractures at the site of narrowing.

Anagen effluvium is an uncommon symptom of pemphigus vulgaris.[3] The hair follicle is a preferential target for pemphigus autoantibodies because the desmosomal proteins are overexpressed in the follicular epithelium. The ensuing intercellular cleavage causes the anagen hairs in lesional and perilesional areas to fall out.

Etiology

Chemotherapeutics used to treat cancer are the most common causes of anagen effluvium.[4, 5, 6, 7] A study of 384 patients with chemotherapy reactions showed the most common overwhelmingly was anagen effluvium (78.6%).[8]  The most severe alopecia is caused by doxorubicin, the nitrosoureas, and cyclophosphamide. Other causative agents include bleomycin, dactinomycin, daunorubicin, fluorouracil, methotrexate, and azathioprine.[9, 10] Anagen effluvium was also linked with a Ganoderma lucidum–induced aplastic crisis.

Other medications that can cause anagen effluvium include bismuth, levodopa, colchicine, cyclosporine, and, possibly, strontium ranelate and pegylated interferon alfa-2a/ribavirin therapy.[11, 12, 13] Anagen effluvium with permanent alopecia has been described in patients treated with taxanes.[14]

Exposure to chemicals such as thallium, boron, and arsenic can precipitate anagen effluvium.[15]

Causes of anagen arrest also include radiation therapy, endocrine diseases, alopecia areata, cicatrizing disease, and trauma or pressure.[16]

Pemphigus vulgaris is reported to be a cause of anagen effluvium.

Acute vesiculobullous hand dermatitis and anagen effluvium can occur in Ganoderma lucidum –induced aplastic crisis.[17]

Prognosis

Anagen effluvium is entirely reversible, with hair regrowth typically occurring after a delay of 3-6 months.[2] Upon the cessation of drug therapy, the follicle resumes its normal activity within a few weeks. Mitotic inhibition apparently stops the reproduction of matrix cells, but it does not permanently destroy the hair. In some cases, hair regrows despite continued or maintenance therapy. On occasion, the color and texture of the hair that regrows after chemotherapy-induced alopecia is different from those of the original hair.

Patient Education

Drug-induced alopecia can be psychologically devastating to a patient. Patients have even refused possibly palliative or life-saving treatments because they could not accept the temporary or prolonged baldness.

Patients must be warned of the potential for hair loss when they undergo treatment with any of the medications responsible for anagen effluvium.

Patients should also be reassured that the hair loss is temporary. Normal hair growth resumes a few weeks after the termination of treatment, although the color or texture of the regrowing hair may differ from those of the original hair.

History

Patients present with diffuse hair loss after an exposure to drugs or toxic chemicals. Chemotherapeutic agents are most commonly responsible for hair loss. The most severe hair loss occurs in association with doxorubicin, the nitrosoureas, and cyclophosphamide. Hair loss usually begins 7-14 days after a single pulse of chemotherapy.[18] The hair loss is clinically most apparent after 1-2 months.

The patient's full dermatologic, systemic, and family histories should be obtained to rule out other causes of hair loss, including malnutrition, iron deficiency, endocrine and metabolic disorders, collagen disease, infections (eg, syphilis), and widespread skin disease.

Anagen effluvium may be an uncommon symptom in a patient with pemphigus vulgaris.

A variety of medications may cause hair loss, stimulate hair growth, or induce changes in hair shape and color. Drug-induced hair loss is usually a consequence of a toxic effect of the drug on the hair matrix. Although many drugs have been occasionally described to produce hair loss, the relationship between drug intake and hair loss has only been proven for a few agents. The type of hair loss (ie, telogen effluvium, anagen effluvium, or both) depends on the medication, its dosage, and patient susceptibility.

Tamoxifen is associated with anagen effluvium, producing diffuse hair loss starting shortly after initiation, becoming most prominent after 6 weeks of it, with hair growth rate returning to baseline within three months of tamoxifen being stopped.[19]

Physical Examination

Anagen effluvium is a nonscarring alopecia that leaves the follicular ostia intact. Most hair follicles are in the anagen stage at any given time; therefore, anagen alopecia affects a large percentage of the scalp. Some chemotherapeutic agents can also induce telogen effluvium. The combination of telogen effluvium and anagen effluvium can result in complete baldness.

The diffuse alopecia of anagen effluvium can be distinguished from androgenetic alopecia, which is characterized by frontotemporal thinning followed by hair loss in the crown.

The hair and scalp should be thoroughly inspected to rule out local disease. Any erythema, scale, pustules, bogginess, sinus tract formation, or obliteration of the follicular openings should be noted. Any of these findings may indicate another cause of the alopecia.

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Anagen effluvium. Courtesy of DermNet New Zealand (https://www.dermnetnz.org/assets/Uploads/hair-nails-sweat/anagen-effluvium-01.jpg).

Laboratory Studies

A few select laboratory studies may be performed, as indicated by features of the history or physical findings. Serologic tests may include the following:

Serum and urine amino acid levels may be determined.

If tinea capitis is a concern in the differential diagnosis, microscopic examination for fungal elements and culture for fungi may be performed.[25]

Other Tests

Phototrichography, trichoscanning, trichoscopy, and reflectance confocal microscopy may be used to evaluate hair loss from anagen effluvium.[26, 27]

Procedures

Anagen effluvium can be distinguished from telogen effluvium by means of the pull test. To perform this test, firmly grasping 40 hairs between the thumb and forefinger and slowly pull on them to remove them, causing only mild discomfort to the patient. Then, a trichogram is used to quantify the ratio of terminal anagen hairs to telogen hairs. Anagen and telogen hairs can often be identified with the naked eye, but any doubts can be resolved by means of light microscopy. Anagen hairs have long indented roots covered with intact inner and outer root sheaths, and they are fully pigmented. Telogen hairs have short, club-shaped roots. They lack root sheaths and show depigmentation of the proximal part of the shaft. Fewer than 4-6 telogen hairs are typically present. A greater number of telogen hairs indicates a shift toward the telogen phase and suggests a probable diagnosis of telogen effluvium.

An alternative to is perform a gentle pull test or examine hairs removed by combing. The presence of tapered fractures is diagnostic of anagen effluvium.

Anagen effluvium can be distinguished from other forms of alopecia on the basis of the histologic changes on horizontal sections. A 4-mm punch biopsy sample of the scalp contains 25-50 follicles for inspection. Less than 15% of the follicles are normally in the telogen phase. A normal anagen-to-telogen ratio in a patient with hair loss is characteristic of anagen effluvium. A finding of greater than 15% of follicles in the telogen phase indicates a significant shift toward telogen in most individuals. This finding suggests telogen effluvium. The follicles should show no signs of inflammation, dystrophic changes of the inner sheath, or traction. These features permit the distinction of anagen effluvium from alopecia areata, androgenetic alopecia, and traction alopecia.

Histologic Findings

Anagen hairs have long, indented roots covered with intact inner and outer root sheaths. These hairs are fully pigmented. Telogen hairs have short, club-shaped roots. These hairs lack root sheaths and show depigmentation of the proximal parts of the shaft.

Medical Care

Although topical minoxidil is not effective in preventing chemotherapy-induced alopecia, it shortens the period of baldness by about 50 days.[28]

Scalp cooling may be used, accomplished either with cooling agents applied via a cooling cap that is changed several times or by continuous cooling of the scalp with cold air or liquid.[2]

The application of a pressure cuff around the scalp and local hypothermia retard anagen arrest, if these measures are implemented during the infusion of medication. These measures do not prevent anagen arrest. The pressure cuff and local hypothermia presumably decrease blood flow in the scalp and hinder the delivery of medication to this site. However, because the scalp may act as a sanctuary for circulating malignant cells, patients with leukemia, lymphoma, and other hematologic malignancies are generally not suitable candidates for these procedures.

A medical corrective preparation makeup can be applied to camouflage eyebrow alopecia induced by chemotherapy and to improve self-esteem.[29]

Prevention

The application of a pressure cuff around the scalp and local hypothermia retard anagen arrest, if these measures are implemented during the infusion of the causative medication (see Medical Care).

The discontinuation or avoidance of the causative drug reverses anagen effluvium.

Bleiker et al did not achieve success in a trial of the possible prophylactic effects of pretreatment with calcipotriol before chemotherapy.[30]

Medication Summary

The goal of pharmacotherapy is to shorten the period of alopecia resulting from chemotherapy. Sadly, no treatment appears to be generally effective in preventing this secondary effect of chemotherapy. In rodent models, localized administration of heat or subcutaneous/intradermal injection of geldanamycin or 17-(allylamino)-17-demethoxygeldanamycin induced a stress-protein response in hair follicles and effectively prevented alopecia from doxorubicin (Adriamycin), cyclophosphamide, paclitaxel (Taxol), and etoposide.[31] Hopefully, localized hair-saving treatment can be developed for humans that does not negatively affect chemotherapy efficacy.

Minoxidil topical (Rogaine)

Clinical Context:  Minoxidil relaxes arteriolar smooth muscle, causing vasodilation; hair growth is possibly secondary to vasodilation. Minoxidil topical is available in 2% and 5% solutions; the 5% solution is recommended only for men.

Class Summary

Minoxidil directly dilates the peripheral vessels. Although the exact mechanism of action for promoting hair growth remains unknown, increased blood flow to the hair follicles may affect their metabolism and growth cycle and thereby prevent hair loss.

Author

Robert A Schwartz, MD, MPH, Professor and Head of Dermatology, Professor of Pathology, Professor of Pediatrics, Professor of Medicine, Rutgers New Jersey Medical School

Disclosure: Nothing to disclose.

Coauthor(s)

Pere Gascon, MD, PhD, Professor and Director, Division of Medical Oncology, Institute of Hematology and Medical Oncology, IDIBAPS, University of Barcelona Faculty of Medicine, Spain

Disclosure: Nothing to disclose.

Specialty Editors

David F Butler, MD, Former Section Chief of Dermatology, Central Texas Veterans Healthcare System; Professor of Dermatology, Texas A&M University College of Medicine; Founding Chair, Department of Dermatology, Scott and White Clinic

Disclosure: Nothing to disclose.

Rosalie Elenitsas, MD, Herman Beerman Professor of Dermatology, University of Pennsylvania School of Medicine; Director, Penn Cutaneous Pathology Services, Department of Dermatology, University of Pennsylvania Health System

Disclosure: Received royalty from Lippincott Williams Wilkins for textbook editor.

Chief Editor

Dirk M Elston, MD, Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Disclosure: Nothing to disclose.

Acknowledgements

Günter Burg, MD Professor and Chairman Emeritus, Department of Dermatology, University of Zürich School of Medicine; Delegate of The Foundation for Modern Teaching and Learning in Medicine Faculty of Medicine, University of Zürich, Switzerland

Günter Burg, MD is a member of the following medical societies: American Academy of Dermatology, American Dermatological Association, International Society for Dermatologic Surgery, North American Clinical Dermatologic Society, and Pacific Dermatologic Association

Disclosure: Nothing to disclose.

Bryan D Seiff, MD Staff Physician, Department of Ophthalmology, NY Presbyterian Hospital-Cornell

Bryan D Seiff, MD is a member of the following medical societies: Alpha Omega Alpha

Disclosure: Nothing to disclose.

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Anagen effluvium. Courtesy of DermNet New Zealand (https://www.dermnetnz.org/assets/Uploads/hair-nails-sweat/anagen-effluvium-01.jpg).

Anagen effluvium. Courtesy of DermNet New Zealand (https://www.dermnetnz.org/assets/Uploads/hair-nails-sweat/anagen-effluvium-01.jpg).