Joshua D. Safer
The skin characteristics associated with thyroid dysfunction are classic. The term “myxedema,” the original name for hypothyroidism, refers to the edema-like associated skin condition caused by increased glycosaminoglycan deposition in the skin. In 1878, Ord published the first comprehensive description of myxedematous skin (1). Horsley connected myxedema to the thyroid in 1885 (2). Still the classic cutaneous sign of hypothyroidism, generalized myxedema is caused by deposition of dermal acid mucopolysaccharides, especially hyaluronic acid. The entire skin is firm to the touch, appearing swollen, dry, pale, and waxy. Despite its edematous appearance, the skin does not pit with pressure. There is also a typical facial appearance manifested by a broad nose, swollen lips, macroglossia, and puffy eyelids (3).
More generally, skin manifestations of hypothyroidism may be divided into three categories (Table 52.1): (a) direct action of thyroid hormone on skin tissues, (b) skin manifestations of direct thyroid hormone action on nonskin tissues, and (c) autoimmune skin disease associated with hypothyroidism of autoimmune etiology.
TABLE 52.1. SKIN MANIFESTATIONS OF HYPOTHYROIDISM
Directed thyroid hormone action on skin tissues
Epidermal changes
Coarsened, thin, scaly skin
Dermal changes
Nonpitting edema (myxedema)
Edema (hands, face, eyelids)
Carotenemia
Pallor
Hair and nail changes
Dry, brittle, coarse hair
Alopecia
Loss of laternal third of eyebrows
Coarse, dull, thin, brittle nails
Sweat gland changes
Dry skin (xerosis)
Decreased sweating
Skin manifestation of thyroid hormone action on other tissues
Cold intolerance
Pallor
Purpura
Drooping of upper eyelids
Nerve entrapment syndromes
Associated autoimmune phenomena
Urticaria, pruitis
Vitiligo
Pernicious anemia
Bullous disorders
Eczema
Connective tissue diseases
DIRECT THYROID HORMONE ACTION ON SKIN TISSUES
Thyroid hormone acts directly on skin, mediating its effect through the thyroid hormone receptor (TR). The TR has been identified in both epidermis and dermis. Hair, which has important relationships with both epidermis and dermis, is a site where TR has also been identified. Immunohistochemical localization and quantitative polymerase chain reaction (PCR) have demonstrated all three thyroid hormone–binding TR isoforms in skin tissues (4,5,6,7). TRs have been detected in epidermal keratinocytes, skin fibroblasts, hair arrector pili muscle cells, other smooth muscle cells, sebaceous gland cells, vascular endothelial cells, Schwann's cells, and cell types composing the hair follicle (see Fig. 30.1). Several thyroid hormone responsive genes have been identified in skin (see Chapter 30).
Epidermal Changes
Thyroid hormone is an important regulator of epidermal growth, differentiation, and homeostasis. Epidermal manifestations of thyroid hormone deficiency are evident in that the skin in hypothyroidism is rough and covered with fine superficial scales, especially on the extensor extremities (8). Xerosis may be severe enough to resemble an acquired ichthyosis. The dryness of the palms and soles may be extensive (9). Histologic examination reveals epidermal thinning and hyperkeratosis (10).
In the 1970s, investigators reported conversion of thyroxine (T4) to either triiodothyronine (T3) or rT3 in skin cultures, thus demonstrating indirectly the presence of thyroid hormone deiodinases in skin (11,12,13). RNA expression of both deiodinase types II and III has been found in human skin (14). In one study in goats, investigators found that deiodinase type III was most active in skin (15) followed by deiodinase type II. An in vivo study in humans (16) provided further evidence that deiodinase type III is functionally dominant in skin. Women receiving supraphysiologic doses of T4 in a topical cream did not have detectable changes in circulating TSH, T4, or T3 concentrations. Only serum rT3 levels increased significantly, strongly suggesting the dominance in skin of type III (inner ring) deiodinase activity.
In tissue culture studies, thyroid hormone stimulates growth of both epidermal keratinocytes and dermal fibroblasts (4,17,18). However, thyroid hormone–mediated inhibition of keratinocyte growth has been observed when keratinocytes were cocultured with dermal fibroblasts (18).
Up to 90% of hypothyroid patients may have scaly skin (19). In addition to the thyroid hormone–mediated growth characteristics noted above, in vitro keratinocyte studies have shown that depletion of T3 results in elevated levels of transglutaminase, an enzyme involved in the formation of the cornified envelope. Further in vitro analysis has suggested that T3-depleted keratinocytes have diminished levels of plasminogen activator, a putative enzyme implicated in the corneocyte shedding process (20).
Other contributory factors in the development of xerosis involve epidermal lipids. Studies of thyroidectomized rats have suggested that sterol synthesis is altered in epidermal keratinocytes deprived of thyroid hormone (21). Thyroid hormone accelerates barrier formation by increasing the activity of enzymes in the cholesterol sulfate cycle. Thus, a deficiency of thyroid hormone may hinder the epidermal barrier function (22). Hypothyroidism also may affect the development of the lamellar granules (Odland bodies), which are vital in the establishment of a normal stratum corneum (23).
Dermal Changes
In hypothyroidism, the skin tends to be pale both because of the dermal mucopolysaccharides and increased dermal water content. In addition, increased dermal carotene content may be evident, appearing as a prominent yellow hue on the palms, soles, and nasolabial folds (19).
The seminal histologic evaluation of the skin of a patient with hypothyroidism was done by Reuter in 1931 (10). Reuter was able to demonstrate increased hyaluronic acid in hypothyroid dermis. Gabrilove and Ludwig (24) examined via biopsy the skin of individuals with hypothyroidism before and after treatment. Histologic changes were observed within 3 to 4 weeks of thyroid hormone changes (24).
Hyaluronic acid is the predominant glycosaminoglycan that accumulates in myxedema (25). Its hygroscopic nature allows it to swell to 1,000 times its dry weight when hydrated. Mucin deposition is extensive and involves not only the skin but also the tongue, myocardium, kidney, and most other organs of the body. Although the hygroscopic nature of hyaluronic acid may partly explain the presence of cutaneous edema, increased transcapillary escape of albumin, resulting in extravascular accumulation, may also contribute to the edema. In addition, inadequate lymphatic drainage may further explain the formation of exudates in the serous cavities that are apparent in the myxedematous state (26).
Since the early histologic studies, there have been a number of systematic evaluations of the glycosaminoglycans (GAGs) present in the skin of hypothyroid patients (25). Most researchers record increased hyaluronic acid in the absence of thyroid hormone (27,28,29). In vitro studies suggest that thyroid hormone decreases synthesis of hyaluronic acid by inhibiting action of hyaluronan synthetase. Thyroid hormone also increases hyaluronic acid degradation. Chondroitin sulfate and dermatan sulfate are reported to be unchanged in hypothyroidism. Heparan sulfate is reported to be either stable or decreased. Data are contradictory for thyroid hormone action on collagen synthesis in skin fibroblasts (30,31).
Hypothyroid dermis is further characterized by a scarcity of dermal fibroblasts. Indeed, in vitro studies confirm that thyroid hormone deficiency retards dermal fibroblast proliferation (4,17,18). Among the fibroblasts present, there can be both decreased activity and absence of new collagen deposition. Abnormal fibroblast function may be the cause of decreased and irregularly shaped elastic microfibrils demonstrated in patients with myxedema (32).
Although the data favor a role for thyroid hormone in normal healing (33), the importance of thyroid hormone to wound healing is debated. Diminished wound healing rates have been reported in both hypothyroid mice (33) and rats (34). There are also reports that several hypothyroid patients required thyroid hormone to achieve healing of radiation-induced neck fistulae (35,36). Conversely, Cannon (37) reported that hypothyroidism did not diminish wound strength in pigs, and Ladenson et al (38) reported an absence of wound healing deficits in hypothyroid humans.
Hair and Nail Changes
In hypothyroidism, hair can be dry, coarse, dull, and brittle. The rate of hair growth is slowed (39,40). Similarly, nails may be thickened, brittle, and slow growing (41). Diffuse or partial alopecia may be observed, and loss of the lateral third of the eyebrow (madarosis) is reported. The alopecia associated with hypothyroidism may be mediated by hormone effects on the initiation as well as the duration of hair growth.
In the 1950s and 1960s, Hale and Ebling documented the impact of thyroid hormone on rat hair growth cycles (39). With the addition of thyroid hormone, they demonstrated decreased resting phase of the hair growth cycle (telogen) and decreased growth phase of the hair growth cycle (anagen). Although there was enhanced turnover, the net hair length at any given time was unchanged from that of untreated animals. Importantly, the time to regrowth of hair following epilation was shortened. The induction of hypothyroidism with the antithyroid drug propylthiouracil significantly increased the time to the restoration of hair.
In vitro studies on human tissue suggest slowed hair growth rates in hypothyroidism. DNA flow cytometry studies on dissected anagen hair follicles from hypothyroid patients (compared with follicles taken from euthyroid controls) demonstrated a 15% decrease in the S and G2 + M phases of the cell cycle (40).
There is a report of long, terminal hairs on the backs and extremities of hypothyroid children (42). The hair disappeared following thyroid hormone replacement, but no mechanism was determined.
Hypothyroid patients may sometimes manifest Candida folliculitis. It has been theorized that because the sebaceous glands of hypothyroid patients secrete less sebum than those of euthyroid persons, the hair follicles may develop a flora depleted of lipophilic organisms, which are replaced by Candida albicans (43).
Sweat Gland Changes
The dryness of hypothyroid skin results from decreased eccrine gland secretion. The mechanism for decreased sweating is not clear, although the hypothyroid glands are atrophic on histologic examination. A role may also be played by a periodic acid–Schiff-positive material that can accumulate in the eccrine apparatus of hypothyroid patients (44). Hypothyroidism has been reported to be a cause of increased sweat electrolytes, requiring differentiation from cystic fibrosis (45).
SKIN MANIFESTATION OF THYROID HORMONE ACTION ON OTHER TISSUES
Several dermatologic manifestations of hypothyroidism derive from hypothyroidism in nonskin tissues. Thyroid hormone–mediated changes to the basal metabolic, vascular, and sympathetic nervous systems are evident when the skin is examined (see Chapters 53,60, and 63).
Cool, pale skin may result from decreased skin perfusion in hypothyroidism. The decreased skin perfusion has been documented with both nailfold capillaroscopy (46) and laser Doppler techniques (47). It has been suggested that the diminished skin perfusion is a reflex vasoconstriction compensatory to diminished core temperature. The diminished core temperature itself may be secondary to the reduced thermogenesis of the hypometabolic state (48). Occasionally, purpura may be noted in hypothyroid patients as a result of diminished levels of clotting factors or the loss of vascular support secondary to the dermal mucin (49,50).
Drooping of the upper lids has been attributed to decreased sympathetic stimulation of the superior palpebral muscle (19). Entrapment syndromes, such as carpal tunnel syndrome and facial nerve palsy, have been reported (51).
ASSOCIATED AUTOIMMUNE PHENOMENA
When hypothyroidism is of autoimmune etiology, additional skin findings may be evident that reflect associated autoimmune diseases (52). Although patients with autoimmune thyroid disease are at increased risk for other tissue-specific autoimmune diseases and are even at a slightly increased risk for more generalized autoimmune diseases, screening hypothyroid patients for other autoimmune disease is not cost effective. Conversely, autoimmune thyroid disease is sufficiently common that patients with other autoimmune disease deserve screening for thyroid dysfunction.
A list of autoimmune conditions apparent when examining the skin includes alopecia areata, pernicious anemia, bullous disorders (pemphigus, bullous pemphigoid, dermatitis herpetiformis), connective tissue diseases (lupus erythematosus, scleroderma), lichen sclerosus et atrophicus, palmoplantar pustulosis, and urticaria. Some patients with autoimmune dermatologic diseases may present with pitting nails (53) independent of the dry, brittle nails associated with direct thyroid hormone action. It has been reported that a subset of patients with chronic urticaria and angioedema associated with thyroid autoimmunity may have their urticaria abate with the administration of thyroid hormone (54). The mechanism by which thyroid hormone may alleviate this process remains speculative.
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