Graves Disease Graves disease, characterized by exophthalmos, goiter, and hyperthyroidism, was first identified as an association of findings in 1835. A heritable specific defect in immunosurveillance by suppressor T lymphocytes is believed to result in the development of a helper T-cell population that reacts to multiple epitopes of the thyrotropin receptor. This activity induces a B-cell– mediated response, resulting in the clinical features of Graves disease (389). The TSHRAb bind to conformational epitopes in the extracellular domain of the thyrotropin receptor and are uniformly detected in patients with untreated Graves disease (390).
Graves disease is a complex autoimmune disorder in which several genetic susceptibility loci and environmental factors are likely to play a role in the development of the disease. Human leukocyte antigen and polymorphisms in the cytotoxic T-lymphocyte antigen 4 (CTLA-4) gene were established as susceptibility loci; however, the magnitude of their contributions seems to vary among patient populations and study groups. Additional loci are likely to be identified by a combination of genome-wide linkage analyses and allelic association analyses of candidate genes. The rate of concordance for Graves disease is only 20% in monozygotic twins and even lower in dizygotic twins, consistent with a multifactorial inheritance pattern highly inﬂuenced by environmental factors. Linkage analysis identified loci on chromosomes 14q31, 20q11.2, and Xq21 that are associated with susceptibility to Graves disease (393).
The classic triad in Graves disease consists of exophthalmos, goiter, and hyperthyroidism. The symptoms associated with Graves disease include frequent bowel movements, heat intolerance, irritability, nervousness, heart palpitations, impaired fertility, vision changes, sleep disturbances, tremor, weight loss, and lower extremity swelling. Physical findings may include lid lag, nontender thyroid enlargement (two to four times normal), onycholysis, dependent lower extremity edema, palmar erythema, proptosis, staring gaze, and thick skin. A cervical venous bruit and tachycardia may be noted. The tachycardia does not respond to increased vagal tone produced with a Valsalva maneuver. Severe cases may demonstrate acropachy, chemosis, clubbing, dermopathy, exophthalmos with ophthalmoplegia, follicular conjunctivitis, pretibial myxedema, and vision loss.
Approximately 40% of patients with new onset of Graves disease and many of those previously treated have elevated T3 and normal T4 levels. Abnormal T4 or T3 results are often caused by protein binding changes rather than altered thyroid function; therefore, assessment of free T4 and free T3 is indicated in conjunction with TSH. In Graves disease, the TSH levels are suppressed, and levels may remain undetectable for some time even after the initiation of treatment. Thyroid autoantibodies, including TSI, may be useful during pregnancy to more accurately predict fetal risk of thyrotoxicosis (368). Autonomously functioning, benign thyroid neoplasms that exhibit
Table 31.14 Potential Causes of Hyperthyroidism