Clinical Challenge: Rash on Shin and Ophthalmopathy

Graves disease is a syndrome characterized by hyperthyroidism, Graves ophthalmopathy, and pretibial myxedema originally described in 1835 by Robert James Graves.1 The disease is the most common underlying cause of hyperthyroidism with a reported incidence of new cases estimated at 20 to 50...

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Graves disease is a syndrome characterized by hyperthyroidism, Graves ophthalmopathy, and pretibial myxedema originally described in 1835 by Robert James Graves.¹ The disease is the most common underlying cause of hyperthyroidism with a reported incidence of new cases estimated at 20 to 50 per 100,000 individuals per year.² Graves disease can occur at any age, but the peak of disease occurs between the ages of 30 to 50 years, affecting women more often than men.³ Hyperthyroidism is confirmed by measurement of the serum thyrotropin concentration, which is usually undetectable due to negative feedback of thyroid hormones on the anterior pituitary, along with elevated free thyroxine.⁴

Graves disease is triggered by circulating autoantibodies directed against the thyrotropin receptor that mimic the actions of thyrotropin. Activation of thyroid follicular cells leads to secretion of thyroid hormones that induce thyroid growth and vascularization.⁵  Symptoms associated with the disease include anxiety, fatigue, nervousness, weight loss, moist skin, hair loss, muscle weakness, and palpitations.⁶ The extrathyroidal symptoms include localized dermopathy, acropachy, and ophthalmopathy.

Almost half of the patients with Graves hyperthyroidism experience Graves ophthalmopathy, also known as thyroid-associated ophthalmopathy or thyroid eye disease.⁷ The common clinical features arise from soft-tissue enlargement in the orbit that leads to increased pressure within the bony cavity.⁸ The clinical signs may include upper eyelid retraction, edema, erythema of the conjunctivae, and proptosis.⁷

Graves ophthalmopathy is associated with the presence of antithyrotropin-receptor antibodies.⁹ Histologic studies of the extraocular muscles demonstrate amorphous accumulation of granular material consisting primarily of collagen fibrils and glycosaminoglycans, among which hyaluronan predominates.¹⁰

Pretibial myxedema, also called thyroid dermopathy, is a dermatologic manifestation of Graves disease characterized by accumulation of glycosaminoglycans in the reticular dermis.¹¹ It results from a localized autoimmune response within connective tissue likely caused by antibodies against receptors of thyroid-stimulating hormone.¹² Lesions are typically asymptomatic and rarely painful or pruritic, occurring most frequently in the pretibial region. They have sharply demarcated pink or purple-brown papules or nodules overlying a nonpitting thickening and induration.¹³ Approximately 20% of patients with thyroid dermopathy have thyroid acropachy, which manifests as clubbing of the fingers and toes.⁷

Therapies used to treat Graves hyperthyroidism are drugs that inhibit thyroid hormone production (methimazole and propylthiouracil), radioactive iodine to induce shrinkage of thyroid tissue, and surgical removal of the gland.¹⁴ Along with these, beta blocking agents are useful for symptom control of moderate to severe thyrotoxicosis.⁴

Treatment of Graves ophthalmopathy depends on the severity and includes immunosuppressive therapy, orbital irradiation, and surgery via endoscopic orbital decompression.⁶ Thyroid dermopathy may remit spontaneously; intralesional steroids can hasten resolution but results are variable.^11,15

Alexandra Stroia, BS, is a medical student at the Lake Erie College of Osteopathic Medicine. Stephen Schleicher, MD, is director of the DermDox Dermatology Centers, associate professor of medicine at Geisinger Commonwealth Medical College, and clinical instructor of dermatology at Arcadia University and Kings College.

References

1. Graves RJ. Newly observed affection of the thyroid gland in females. Clinical lectures. Lond Med Surg J. 1835:7:516-517.
2. Smith TJ,  Hegedüs L. Graves’ disease. N Engl J Med. 2016;375(16):1552-1565. doi:10.1056/nejmra1510030.
3. Piantanida E. Preoperative management in patients with Graves’ disease. Gland Surg. 2017;6(5):476-481. doi:10.21037/gs.2017.05.09
4. Gilbert J. Thyrotoxicosis — investigation and management. Clin Med (Lond). 2017;17(3):274-277. doi:10.7861/clinmedicine.17-3-274
5. Lin JD, Yang SF, Wang YH, et al. Associations of melatonin receptor gene polymorphisms with Graves’ disease. PLoS One. 2017;12(9):e0185529. doi:10.1371/journal.pone.0185529
6. Łacheta D, Miśkiewicz P, Głuszko A, et al. Immunological aspects of Graves’ ophthalmopathy. Biomed Res Int. 2019;2019:7453260. doi:10.1155/2019/7453260
7. Bahn RS. Graves’ ophthalmopathy. N Engl J Med. 2010;362(8):726-738. doi:10.1056/NEJMra0905750
8. Otto AJ, Koornneef L, Mourits MP, Deen-van Leeuwen L. Retrobulbar pressures measured during surgical decompression of the orbit. Br J Ophthalmol. 1996;80:1042-1045.  doi:10.1136/bjo.80.12.1042
9. Khoo DH, Eng PH, Ho SC, et al. Graves’ ophthalmopathy in the absence of elevated free thyroxine and triiodothyronine levels: prevalence, natural history, and thyrotropin receptor antibody levels. Thyroid. 2000;10(12):1093-1100. doi:10.1089/thy.2000.10.1093
10. Smith TJ, Bahn RS, Gorman CA. Connective tissue, glycosaminoglycans, and diseases of the thyroid. Endocr Rev. 1989;10:366-391. doi:10.1210/edrv-10-3-366
11. Ramos LO, Mattos PC, Pertoti de Figueredo GL, Maia AAA, Romero SAR. Pre-tibial myxedema: treatment with intralesional corticosteroid. An Bras Dermatol. 2015;90(3 Suppl 1):143-146. doi:10.1590/abd1806-4841.20153651
12. Fatourechi V. Pretibial myxedema — pathophysiology and treatment options. Am J Clin Dermatol. 2005;6:295-309. doi:10.2165/00128071-200506050-00003
13. Lause M, Kamboj A, Fernandez Faith E. Dermatologic manifestations of endocrine disorders. Transl Pediatr. 2017;6(4):300-312. doi:10.21037/tp.2017.09.08
14. Kahaly GJ. Management of Graves thyroidal and extrathyroidal disease: an update. J Clin Endocrinol Metab. 2020;105(12):3704-3720. doi:10.1210/clinem/dgaa646
15. Lan C, Li C, Chen W, Mei X, Zhao J, Hu J. A randomized controlled trial of intralesional glucocorticoid for treating pretibial myxedema. J Clin Med Res. 2015;7:862-872. doi:10.14740/jocmr2303w