Background
Understanding the pathophysiology of telogen effluvium requires knowledge of the hair growth cycle. All hair has a growth phase, termed anagen; a transitional phase, termed catagen; and a resting phase, termed telogen. On the scalp, anagen lasts approximately 3 years and telogen roughly 3 months, though these times can vary widely from one individual to another. During telogen, the resting hair remains in the follicle until it is pushed out by growth of a new anagen hair.
Telogen effluvium is a form of nonscarring alopecia characterized by diffuse hair shedding, often with an acute onset. [1, 2] It can affect hair on all parts of the body, but in general, only loss of scalp hair is symptomatic. A chronic form of telogen effluvium with a more insidious onset and a longer duration also exists, [3] though it has been suggested that this may not be a truly distinct condition. [4] Telogen effluvium is a reactive process caused by a metabolic or hormonal stress or by medications. Generally, recovery is spontaneous and occurs within 6 months, unless a background of pattern alopecia is present. [5]
Anagen effluvium is a nonscarring alopecia that leaves the follicular ostia intact. Most hair follicles are in the anagen stage at any given time; consequently, 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.
Pathophysiology
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 reenters 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.
Telogen effluvium
In most people, 5-15% of the hair on the scalp is in telogen at any given time. Telogen effluvium is triggered when a physiologic stress or hormonal change causes a large number of hairs to enter telogen at one time. Shedding does not occur until the new anagen hairs begin to grow. The emerging hairs help to force the resting hairs out of the follicle. Evidence has suggested that the mechanism by which a telogen hair is shed is an active process that may occur independent of the emerging anagen hair. The interval between the inciting event in telogen effluvium and the onset of shedding corresponds to the length of the telogen phase, 1-6 months (average, 3 mo).
In 1993, Headington described the following five functional subtypes of telogen effluvium, defined according to which portion of the hair cycle is abnormally shortened or lengthened [6] :
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Immediate anagen release
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Delayed anagen release
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Immediate telogen release
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Delayed telogen release
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Short anagen phase
These subtypes represent variations on the principles discussed above. It is rarely possible to distinguish these subtypes clinically.
Anagen effluvium
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, though it is not the only type of chemotherapy induced-hair loss that can occur in these patients. [7]
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. [8] 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
Telogen effluvium
Physiologic stress is the cause of telogen effluvium. These inciting factors can be organized into several categories (see below). Evidence from murine studies has indicated that psychological stress can induce catagen (the transition phase from anagen to telogen), mainly by exerting effects on neurotransmitters and hormones. [9] In humans, however, the role these effects play in hair loss remains to be determined. Although substance P has been extensively studied in human hair follicles in vitro, in-vivo studies have not been performed. [10] In HIV disease, [11] apoptosis may be related to HIV-1 viral protein R. [12]
The following have been identified as inciting factors for telogen effluvium:
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Chronic illnesses, such as malignancy (particularly lymphoproliferative malignancy), as well as any chronic debilitating illness, such as systemic lupus erythematosus, end-stage renal disease, or liver disease
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Hormonal changes, such as pregnancy and delivery (can affect both mother and child), thyroid dysfunction [15] (particularly hypothyroidism; see the image below), and discontinuance of estrogen-containing medications
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Changes in diet, such as crash dieting, anorexia, low protein intake, and chronic iron deficiency [16, 17, 18] ; one study examining the possible role of iron deficiency in female-pattern hair loss found that although iron deficiency was common in women, it was not significantly greater in patients with female-pattern hair loss or chronic telogen effluvium than in control subjects [19]
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Heavy metals, such as selenium, arsenic, and thallium
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Allergic contact dermatitis of the scalp [23]
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Psychological stress [18]
Several studies have reported increased rates of telogen effluvium associated with COVID-19 infection. [24, 25] A multicenter study from South Korea supported this association but did not find a significant association between COVID-19 vaccination and telogen effluvium. [26]
Anagen effluvium
Chemotherapeutics used to treat cancer are the most common causes of anagen effluvium. [27, 28, 29, 30] A study of 384 patients with chemotherapy reactions showed that by far the most common reaction was anagen effluvium (78.6%). [31] The most severe alopecia is caused by doxorubicin, the nitrosoureas, and cyclophosphamide. Other causative agents include bleomycin, dactinomycin, daunorubicin, fluorouracil, methotrexate, and azathioprine. [32, 33]
Additional medications that can cause anagen effluvium include bismuth, levodopa, colchicine, albendazole, cyclosporine, and, possibly, strontium ranelate and pegylated interferon alfa-2a/ribavirin therapy. [34, 35, 36, 37, 38] Anagen effluvium with permanent alopecia has been described in patients treated with taxanes. [39]
Exposure to chemicals such as thallium, boron, and arsenic can precipitate anagen effluvium. [40]
Causes of anagen arrest also include radiation therapy, endocrine diseases, alopecia areata, cicatrizing disease, and trauma or pressure. [41]
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. [42]
COVID-19-related anagen effluvium has been described. [43]
Epidemiology
Telogen effluvium is quite common, but its exact prevalence remains to be defined. A large percentage of adults have experienced an episode of telogen effluvium at some point in their lives.
Telogen effluvium can occur at any age. It is not uncommon for infants in the first months of life to experience an episode of telogen effluvium.
Acute telogen effluvium can occur in either sex if the proper inciting conditions are present. Because hormonal changes in the postpartum period are a common cause of telogen effluvium, women may be more likely to experience this condition. In addition, women tend to find the hair shedding more troublesome than men do and thus are more likely to seek medical attention for it. Chronic telogen effluvium has been reported mainly in women. [44]
No racial predilection has been recognized.
Prognosis
Mortality has not been reported with telogen effluvium. Morbidity is limited to mild cosmetic changes. However, telogen effluvium can have substantial impact on those affected. [45, 46] In acute telogen effluvium, the prognosis is good for recovery of normal hair density. In chronic telogen effluvium, a good cosmetic outcome can be expected, even if hair shedding continues.
Anagen effluvium is entirely reversible, with hair regrowth typically occurring after a delay of 3-6 months. [7] Upon 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 are 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. They 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.
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Telogen effluvium secondary to hypothyroidism.
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Anagen effluvium. Image from DermNet New Zealand (https://www.dermnetnz.org/assets/Uploads/hair-nails-sweat/anagen-effluvium-01.jpg).
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