Joshua D. Safer
Skin findings in thyrotoxicosis are classic and numerous. Indeed, most patients with thyrotoxicosis have cutaneous manifestations. In a review of thyrotoxicosis, hyperhydrosis, or heat intolerance, was the second most common finding (1). Even in cases of thyrotoxicosis in elderly patients, in whom clinical findings are often masked, 40% of patients were noted to have “fine skin” (2). Although certain signs are specific to Graves' disease, thyrotoxicosis of any cause often includes skin sequelae.
Skin manifestations of thyrotoxicosis may be divided into three categories (Table 30.1): (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 thyrotoxicosis of autoimmune etiology.
TABLE 30.1. SKIN MANIFESTATIONS OF THYROTOXICOSIS
Direct Thyroid Hormone Action on Skin Tissues
Smooth, thin skin
Hair and Nail Changes
Fine hair (“loses wave”)
Shiny, soft, friable nails (onycholysis, Plummer's nails)
Skin Manifestations of Thyroid Hormone Action on Other Tissues
Increased sweating (hyperhydrosis)
Associated Autoimmune Phenomena
Dermopathy (pretibial myxedema)
DIRECT THYROID HORMONE ACTION ON SKIN TISSUES
Thyroid hormone acts on skin tissues both directly and indirectly. Direct action is mediated through the thyroid hormone receptor (TR). All three isoforms of TR have been identified in skin tissues (3,4,5,6). TRs have been detected in epidermal keratinocytes, skin fibroblasts, hair erector pili muscle cells, other smooth muscle cells, sebaceous gland cells, vascular endothelial cells, Schwann's cells, and several cell types that constitute the hair follicle (Fig. 30.1).
FIGURE 30.1. Cartoon of classic human skin anatomy. The epidermis is composed of keratinocytes, which differentiate from the basal layer through the spinous and granular layers (in which the nucleus and other organelles are lost) to the flattened superficial layer termed the stratum corneum. The dermis is hypocellular and comprises fibroblasts surrounded by a number of extracellular proteins (including collagen, hyaluronic acid, chondroitin sulfate, and dermatan sulfate). Hair arises from keratinocyte-lined hair follicles within the dermis. The skin also includes melanocytes, vascular endothelial cells, nerves, and smooth muscle cells (not shown).
In patients with thyrotoxicosis the epidermis is thin but not atrophic. Relatively little formal study has been done to explain the clinical findings, such that although the histologic appearance of the skin in hypothyroidism is documented (7,8), the literature regarding skin characteristics in thyrotoxic states is less clear. Clinical observations have been further complicated by the fact that most thyrotoxicosis results from Graves' disease, which may include autoimmune-mediated glycosaminoglycan deposition and thickened dermis (see dermis and autoimmune phenomena sections below). There is one report of thickened epidermis in biopsies of thyrotoxic humans (9). An investigation of rats made thyrotoxic with systemic thyroxine (T4) administration noted modest epidermal thinning (10), whereas an investigation of rats receiving a topical triiodothyronine (T3) treatment noted increased epidermal thickness and hair growth (11).
A study meant to reconcile these seemingly contradictory claims suggested that thyroid hormone has two effects on skin proliferation (12). The direct effect of T3 is as a stimulator of skin cell proliferation. On a systemic basis, in contrast, thyrotoxicosis may inhibit keratinocyte proliferation. In tissue culture studies, thyroid hormone has been shown to stimulate growth of both epidermal keratinocytes and dermal fibroblasts (3,12,13). However, thyroid hormone–mediated inhibition of keratinocyte growth has been observed when keratinocytes were cocultured with dermal fibroblasts (12). Thus, in vivo, skin proliferation directly stimulated by T3 may be offset by inhibiting factors dependent on the systemic T3.
Indirect evidence of the presence of thyroid hormone deiodinases in skin tissues dates to the 1970s (14,15,16). In goat skin, deiodinase type 3 is most active, followed by deiodinase type 2 (17). RNA expression of deiodinase types 2 and 3 mRNA has been found in human skin (18), but the one in vivo investigation in humans only showed deiodinase type 3 (19).
Thyroid hormone may play a role in establishing the barrier function of the epidermis by increasing the activity of enzymes of the cholesterol sulfate cycle (20) and by acting on the development of lamellar granules (21). T3 is reported to act on transglutaminase, the enzyme involved with the formation of the cornified envelope, and on plasminogen activator, an enzyme potentially involved in the shedding of corneocytes (22).
A small number of thyroid hormone–responsive genes have been identified, including the keratin genes, the “hairless” (hr) gene, and ZAKI-4 (23,24,25,26,27). The keratin genes encode the intermediate filaments, making up about 30% of the protein of the epidermis. Thyroid hormone can exert direct control over specific keratin genes at the nuclear level through thyroid hormone response elements in their upstream promoters (23,24). Although thyroid hormone stimulates expression of proliferation-associated keratin genes both in vivo and in vitro (28), to date only negative thyroid hormone response elements have been identified for these genes (23). It is not known whether the above reflects thyroid hormone induction of indirect keratin gene–stimulating pathways or the existence of unidentified positive thyroid hormone response elements for the keratin genes.
Mutations in the hr gene are associated with atrichia/alopecia phenotypes in mice (29), and mutations in the human homologue gene are associated with similar syndromes in humans (30,31,32,33). “Hairless” mice with mutant hr genes have 20-fold decreased expression of hr protein. Thompson (25,26) reported that hr is regulated by TR in brain and that the promoter region of the hr gene contains a thyroid hormone response element. Hypothyroid mice have reduced hr expression in brain relative to euthyroid mice. Addition of exogenous T3 results in restoration of hr expression. In contrast, hr expression in skin has been reported to be the same in both hypo- and euthyroid mice. The connection between the hr gene, thyroid hormone, and normal skin physiology remains to be elucidated (33a).
Thyroid hormone associations with constituents of dermis are well established (34). In thyrotoxic patients, most dermal findings derive from autoimmunity rather than direct thyroid hormone action. The autoimmune manifestations are discussed under that subheading below.
In tissue culture studies, thyroid hormone stimulates proliferation of dermal fibroblasts (3,12). Other reported thyroid hormone actions on cultured skin fibroblasts include inhibition or synthesis of hyaluronic acid, fibronectin, and collagen (35,36,37). The net effect of thyroid hormone on dermal thickness and collagen thickness synthesis remains the subject of debate, however. In 1967, investigators (10) reported skin thinning in rats made thyrotoxic with intraperitoneal T4. They used proline-14C uptake as a surrogate for collagen production to demonstrate decreased collagen production in the thyrotoxic animals. Increased collagen catabolism in thyrotoxic rats also has been reported (10,38). More recent investigations suggested increased dermal thickness in mice treated with T3, whether topically or intraperitoneally administered (11,12). There is also a report of increased dermal thickness in mice treated topically with the thyroid hormone analogue triac (39). Further, topical triac restored collagen in human skin where collagen had been diminished by topical steroids (39a).
Although the studies noted above have suggested a marked dermal response to direct thyroid hormone administration, data on supraphysiologic doses of thyroid hormone in wound healing are contradictory. Although some researchers have reported improved rates and quality of wound healing in response to thyroid hormone (28,40,41,42,43,44,45,46), others have reported no apparent thyroid hormone–mediated changes in wound healing (47,48,49). There are two reports (40,41,42) that exogenous thyroid hormone improved the rate and quality of wound healing in euthyroid rats. Additionally, a recent study found in high doses of thyroid hormone speeded the rate of wound healing in hypothyroid mice (28). One study found no change in wound healing with euthyroid hamsters receiving intraperitoneal (IP) T4 (47).
Hair and Nail Changes
The hair in thyrotoxicosis may be fine and soft. A diffuse, nonscarring alopecia also may be observed. Nail changes may also occur, characterized by a concave contour accompanied by distal onycholysis (Plummer's nails).
Few systematic analyses of thyroid hormone action on hair growth have been done. Thyrotoxic rats have decreased resting phase and decreased growing phase in their hair growth cycle (50). Mice and rats treated for short periods with topical T3 have increased hair counts, but mice made thyrotoxic with systemic T3have decreased hair counts (11,12). Thyrotoxic goats have increased mohair length but decreased fiber diameter (51).
In vitro studies on human tissue suggest an increased hair growth rate in thyrotoxicosis. DNA flow cytometry studies of dissected anagen hairs from thyrotoxic patients (compared with follicles taken from normal subjects) demonstrated a 30% increase in the S and G2 + M phases of the cell cycle (52). A topical mixture including T4, insulin, and growth hormone increased hair counts over a 6-month treatment period in men with androgenic alopecia (53).
SKIN MANIFESTATIONS OF THYROID HORMONE ACTION ON OTHER TISSUES
The skin of patients with thyrotoxicosis is often described as the texture of an infant's skin: warm, moist, and smooth. Although the smooth skin is an epidermal finding, the warmth is caused by increased cutaneous blood flow, and the moisture is a reflection of the underlying metabolic state (54) (see also Chapter 38). Increased blood flow in the skin and peripheral vasodilatation may be responsible for facial and palmar erythema. The increased skin perfusion of thyrotoxicosis has been confirmed experimentally by laser Doppler techniques (55) and nailfold capillaroscopy (56).
The thyrotoxic patient may have a generalized hyperhydrosis, usually more prominent on the palms and soles. Sweating in thyrotoxicosis is a reflection of the underlying metabolic state. It is thought to be related to the increased sympathoadrenal activity resulting from the synergistic action between catecholamines and thyroid hormone (57). Localized hyperhydrosis has been reported in cases of pretibial myxedema; in these patients peripheral sympathetic nerves may be inappropriately stimulated by perineural infiltration of mucin (58).
Hyperpigmentation has been described in thyrotoxic patients in a localized or generalized distribution similar to that of Addison's disease (creases of the palms and soles, gingivae, buccal mucosa). The hyperpigmentation may be due to increased secretion of corticotropin (ACTA) compensating for accelerated cortisol degradation (59).
ASSOCIATED AUTOIMMUNE PHENOMENA
Patients with Graves' disease may have distinctive cutaneous signs related to autoimmune attack on skin and other tissues (see Chapter 23). Thyroid dermopathy (formerly termed pretibial myxedema) occurs in 0.5% to 4% of patients (60), and acropachy in approximately 1% of patients with Graves' disease (61). Although pruritus is often considered a cutaneous manifestation of thyrotoxicosis, it is more likely secondary to urticaria, which may be associated with thyroid autoimmunity (62).
Paradoxically, patients with Grave's thyrotoxicosis may manifest a localized skin thickening identical to that seen in hypothyroidism. The dermopathy was termed “pretibial myxedema” for many years due to its common identification in the pretibial area. Because the glycosaminoglycan accumulation occurs throughout the body, the term thyroid dermopathy is more precise. The clinical presentation varies from an infiltrative process with a “peau d'orange” appearance to extreme infiltration. The infiltration is due to the accumulation of hyaluronic acid in the dermis and occasionally in the subcutis (63). A satisfactory explanation for the presence of the hyaluronic acid and for the fact that hyaluronic acid is present in both extremes of thyroid dysfunction remains elusive. Aside from the accumulation of hyaluronic acid in the dermopathy, quantitative and qualitative alterations in elastic tissue have been recognized. A decrease in elastin and irregularly shaped microfibrils has been attributed to abnormalities in fibroblast function (64).
Thyroid dermopathy usually occurs in patients with a history of thyrotoxicosis, and it is almost always associated with ophthalmopathy. As such, dermopathy usually reflects severe Graves' disease. The most common locations for thyroid dermopathy are the pretibial area (hence its original name) and the feet. There are reports of involvement of the upper extremities, shoulders, back, ears, nose, and scar tissues. The lesions are raised and waxy, with coloring ranging from light to yellowish brown. The lesions are aggravated by trauma and often recur if surgically removed. Treatment is rarely indicated, but local glucocorticoid therapy, applied nightly and covered with an occlusive dressing has proved effective. Although the vast majority of patients with dermopathy have Graves' disease, it has been reported in Hashimoto's thyroiditis also (65,66).
Acropachy usually occurs in the presence of both ophthalmopathy and dermopathy and is rare (See Section Localized Myxedema and Thyroid Acropachy in Chapter 23). Acropachy manifests as a triad consisting of digital clubbing, soft tissue swelling of the hands and feet, and periosteal new bone formation. Bone manifestations can result in focal uptake of radioisotope on bone scan or a characteristic mid-diaphysis frothy appearance on plain radiographs. Treatment with a glucocorticoid is reported to be effective.
Autoimmune thyroid disease can be associated with other autoimmune diseases. The most common with skin manifestations include alopecia areata, bullous disorders (e.g., pemphigus, bullous pemphigoid, dermatitis herpetiformis), connective tissue diseases (e.g., lupus erythematosus, scleroderma), lichen sclerosus et atrophicus, palmoplantar pustulosis, and urticaria. Thyroid dysfunction is sufficiently common that the identification of one of the above autoimmune dermatologic conditions may warrant screening for autoimmune thyroid disease. A subset of patients with chronic urticaria and angioedema associated with thyroid autoimmunity may have their urticaria abate with the administration of thyroid hormone. The mechanism by which thyroid hormone may alleviate this process is not known (67).
Hypertrichosis is sometimes observed in patients with cases of thyroid dermopathy and may be related to alterations in the proteoglycans associated with the dermal papilla matrix (68). Because of the association of autoimmune thyroid disease with other autoimmune conditions, such as alopecia areata, fine nail pits and trachyonychia may be present (69) independent of nail findings associated with direct thyroid hormone action (Plummer's nails).
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