Pretibial myxedema is characterized by brawny, indurated plaques over the pretibial areas. These plaques may be skin-colored or have an unusual brownish-red color (Fig. 36-3A). On biopsy, the skin is infiltrated by mucinous ground substance (Fig. 36-3B). Pretibial myxedema is specific for Graves’ disease, a frequent cause of hyperthyroidism, but occurs in only 3% to 5% of patients with the disease. Pretibial myxedema is often associated with Graves’ ophthalmopathy (bulging eyes or exophthalmos) and acropachy (clubbed nails). Treatment of hyperthyroidism has no effect on pretibial myxedema.

Figure 36-3. Pretibial myxedema. A, Large indurated skin-colored plaques. B, A positive “string sign” of mucin extending from the biopsy site to the surgical glove.

(Panel B courtesy of Scott Freeman, MD.)

Ai J, Leonhardt JM, Heymann WR: Autoimmune thyroid diseases: etiology, pathogenesis, and dermatologic manifestations, J Am Acad Dermatol 48:641–659, 2003.

15. Why does treatment of Graves’ disease have no effect on pretibial myxedema?

Graves’ hyperthyroidism is an autoimmune disease produced by autoantibodies that bind to thyrotropin (TSH) receptors in the thyroid gland, stimulating the thyroid to produce and release thyroid hormone. Pretibial connective tissue also has thyrotropin receptors. Stimulation of these receptors is the proposed mechanism of mucin production in pretibial connective tissue. Treatment of Graves’ disease treats hyperthyroidism but not the underlying autoimmune disease.

Daumerie C, Ludgate M, Costagliola S, Many MC: Evidence for thyrotropin receptor immunoreactivity in pretibial connective tissue from patients with thyroid-associated dermopathy, Eur J Endocrinol 146:35–38, 2002.

16. What are the skin manifestations of hypothyroidism?

• Mild hypothyroidism: The skin is dry, scaly, cold, and pale. Dryness and scale may make the skin pruritic. The nails are brittle.

• Severe and long-standing hypothyroidism: There may be yellow and diffusely thickened skin (Fig. 36-4), loss of the outer third of the eyebrows and enlarged and thickened lips and tongue.

17. Why do hypothyroid patients have yellow skin?

The yellow skin is due to excess serum carotene that is deposited in the stratum corneum. Carotenemia results from impaired hepatic conversion of carotene to vitamin A in patients with hypothyroidism.

18. Why do hypothyroid patients have thickened skin?

There is increased dermal mucopolysaccharide or mucin within the skin (myxedema).

19. How does the myxedema of hypothyroidism differ from pretibial myxedema of Graves’ disease?

Myxedema of hypothyroidism has smaller quantities of mucin with a generalized distribution over the entire surface area of skin. Pretibial myxedema often has dermal pools of mucin and is localized to the anterior legs.

20. Are the skin changes of hypothyroidism reversible with thyroid replacement?

Yes.

21. What are the skin manifestations of hyperthyroidism?

They are the opposite of hypothyroidism. Hyperthyroid skin is moist, warm, smooth, and erythematous. The nails may separate from the nailbed (onycholysis). The skin may be pruritic. Because itchy skin may occur with either high or low thyroid hormone, patients with itchy skin of unknown cause should have thyroid disease excluded.

22. Which hormone gives the skin a darkened or tanned appearance?

Adrenocorticotropic hormone (ACTH) darkens the skin by stimulating melanocytes to produce melanin. In contrast to normal tanning, the darkening is often accentuated in palmar creases and mucous membranes. (A note of caution: dark skin creases and mucous membranes may be a normal variant in more darkly pigmented races.) The most common cause of elevated ACTH levels is Addison’s disease, in which hypofunctioning adrenals and deficient serum cortisol remove the negative feedback inhibition of the pituitary gland that increases ACTH production.

Figure 36-4. Patient with severe generalized myxedema demonstrating intensive periocular edema and very yellow skin.

Slominski A, Tobin DJ, Shibahara S, Wortsman J: Melanin pigmentation in mammalian skin and its hormonal regulation, Physiol Rev 84:1155–1228, 2004.

23. What skin disease is associated with insulin-dependent diabetes, hypothyroidism, and Addison’s disease?

Vitiligo. This is a trick question. Vitiligo is not caused by deficient hormones but is an autoimmune disease that results in the destruction of melanocytes and is associated with the autoimmune endocrinopathies. Vitiligo presents clinically as white macules, most commonly on the face and hands. Vitiligo is present in 4% of patients with insulin-dependent diabetes, 7% of patients with Graves’ disease, and 15% of patients with Addison’s disease. There is also a familial predisposition to this group of diseases.

24. What skin findings are associated with glucocorticoid excess or Cushing’s disease?

The skin is generally thin and atrophic. Wound repair is inhibited, and striae developed in sites such as the abdomen, upper chest, and buttocks, where the skin is normally stretched. These striae are often large and purple in color, in contrast to idiopathic or pregnancy-induced striae (Fig. 36-5). The skin has a ruddy appearance, and telangiectasias may be prominent. The skin bruises and tears easily. Other skin changes include hypertrichosis, dryness, fragility of the skin, and facial acne. These changes may also be seen in skin that has been treated with high-strength topical steroids for long periods of time. Broadened facial features (moon facies), increased subcutaneous fat on the upper back and neck (buffalo hump), and truncal obesity are also characteristic.

25. Are the skin changes caused by excess glucocorticoids reversible?

Partially. Striae and telangiectasias may fade but often do not disappear.

26. Which hormones have the greatest effect on sebaceous glands and hair?

The androgens. Androgens at the time of puberty induce sebaceous gland activity and the development of acne. Excess androgen in women may cause acne, hirsutism (increased facial hair), and/or alopecia. Associated signs may include hyperpigmentation of genital and areolar skin and clitoromegaly. Possible causes of hirsutism and acne in women include adrenal and ovarian tumors, prolactin-producing pituitary tumors, polycystic ovarian disease, adrenal enzyme deficiencies, and familial acne and hirsutism that may be related to increased end-organ sensitivity to normal circulating levels of androgens. Most acne and hirsutism in women is benign and familial. Screening tests for tumors include serum prolactin; dehydroepiandrosterone sulfate (DHEAS), which is an androgen produced by the adrenal glands; and free testosterone.

27. Are there medications and nutritional supplements that may cause acne?

Yes. Supplements and medications that have androgen effects and can cause acne may not appear in the patient’s list of medications. New-onset acne in a recreational weightlifter, either male or female, may result from the abuse of androgens. New-onset acne in a young woman may be from birth control pills that are low in estrogen. The progesterone-like hormone in many birth control pills and in all long-acting depository forms may have androgen effects. New onset acne in a perimenopausal woman may result from small amounts of testosterone added to some estrogen supplements. High-dose glucocorticoid therapy can also cause acne. The acne that occurs from changing hormone levels takes 4 to 6 weeks to appear.

Figure 36-5. Cushing’s syndrome (excess glucocorticoids), showing truncal obesity and abdominal striae.

(Courtesy of James E. Fitzpatrick, MD.)

Hartgens F, Kuipers H: Effects of androgenic-anabolic steroids in athletes, Sports Med 34:513–554, 2004.

28. What hormonal methods are available to treat acne?

Estrogens often antagonize the effects of androgens. High-dose estrogen birth control pills that use progesterone-like hormones with few androgen effects have been approved for the treatment of acne in women. Spironolactone, an aldosterone antagonist that acts as a relatively weak antiandrogen, has been used to treat hormone related acne in women over the age of 35. Additionally, it has been used for treatment of hirsuitism, androgenic alopecia, and hydradenitis suppurativa due to its antiandrogen effects.

Shaw J: Antiandrogen and hormonal treatment of acne, Dermatol Clin 14:803–811, 1996.

29. What are xanthelasma?

Xanthelasma (palpebra) are distinctive yellowish plaques on the eyelids and around the eyes caused by cholesterol deposition within the skin (Fig. 36-6). Although people with xanthelasma may have normal total cholesterol and triglyceride levels, they often have more subtle lipid abnormalities associated with high cardiovascular risk and deposition of cholesterol within blood vessels. As opposed to other xanthomas, treatment of xanthelasma with surgical excision is often successful.

Figure 36-6. Xanthelasma. Characteristic flat yellowish papules of the upper eyelid.

(Courtesy of the Fitzsimons Army Medical Center teaching files).

Elabjer B, Busic M, Sekelj S, Kristovijevic E: Operative treatment of large periocular xanthelasma, Orbit 28:16–19, 2009.

30. What are eruptive xanthomas?

Eruptive xanthomas are multiple, small, skin-colored to yellow-brown papules that occur in crops, most commonly on the buttocks, thighs, or elbows (Fig. 36-7A). On biopsy, there is accumulation of triglyceride within histiocytes and around blood vessels in the skin. These distinctive papules are a cutaneous sign of very high triglyceride levels. These patients are at risk to develop pancreatitis, which may be severe. Often, eruptive xanthomas are precipitated by the new onset of diabetes.

Figure 36-7. A, Eruptive xanthomas demonstrating typical yellow-brown papules. This patient’s triglyceride level was 7760. B, Tuberous xanthoma manifesting as a large nodular xanthoma of the knee.

(Courtesy of James E. Fitzpatrick, MD.)

Naik NS: Eruptive xanthomas, Dermatol Online J 7:11, 2001. (Readers can go to this article online, read case history, see clinical photographs, biopsy, read discussion, and get references.)

31. How do eruptive xanthomas differ from tuberous xanthomas?

Tuberous xanthomas are larger and deeper than eruptive xanthomas and may be palpated as nodules similar to a large radish, a small turnip, or other vegetable tuber or root within the deep dermis or subcutaneous fat (Fig. 36-7B). These xanthoms are the result of cholesterol accumulation within these tissues, in contrast to the smaller, papular, eruptive xanthomas that contain triglyceride. Tuberous xanthomas are a marker of high cholesterol levels, and these patients are at risk for coronary artery disease at a young age. Tendinous xanthomas (e.g., similar lesions attached to large tendons, such as the Achilles tendon) may also be present.

32. What are the cutaneous features of acromegaly?

Acromegaly is the result of excess pituitary growth hormone present after puberty. Bone thickening is prominent and results in coarse facies and enlarged hands. The skin changes are the result of the production of insulin-like growth factors and, thus, overlap with changes due to insulin resistance. The skin is hypertrophied and thickened, and acanthosis nigricans may be present. These changes may be accentuated on the scalp as whorled furrowing (cutis vertices gyrata) in 30% of patients.

Centurión SA, Schwartz RA: Cutaneous signs of acromegaly, Int J Dermatol 41:631–634, 2002.

Key Points: Xanthomas

1. The presence of one or more xanthomas on the skin usually indicates the presence of an abnormality of lipid metabolism or, less commonly, a monoclonal gammopathy.

2. Xanthomas are histologically characterized by the accumulation of lipids in tissue macrophages.

3. The presence of eruptive xanthomas always indicates the presence of high levels of triglycerides.

4. Patients with eruptive xanthomas are at increased risk to develop pancreatitis.

5. Most patients with xanthelasma often have normal serum levels of triglycerides and cholesterol but often have other abnormalities of apolipoprotein metabolism.

33. How does panhypopituitarism affect the skin?

The skin in patients with panhypopituitarism appears pale, and there are fine wrinkles around the eyes and mouth. Body hair and genital hair are sparse. Sweat and sebum production are also diminished. The skin dryness and thickening are not as prominent as in primary hypothyroidism because there is some autonomous thyroid gland function in panhypopituitarism.

34. How do you diagnose endocrine disease from skin findings?