Joint Program in Nuclear Medicine

Graves' Disease

Gabriel Soudry, MD
Kevin J. Donohoe, MD

September 13, 1994

Presentation

A 27 year old female presented with symptoms and signs of hyperthyroidism. Thyroid function tests confirmed the diagnosis of hyperthyroidism. Thyroid scan with uptake was performed to determine the etiology of the hyperthyroidism.

Imaging Findings

Thyroid scintigraphy (RAO, anterior and LAO views, 14k bytes) shows an enlarged gland with a focal region of decreased uptake in the right lower pole (thick arrows, 14k bytes). The is visualization of a pyaramidal lobe (thin arrows). The thyroid uptake was markedly elevated at 72%%.

Because of the hypofunctioning right lower pole nodule, a total right thyroidectomy and a subtotal left thyroidectomy was performed. Pathology showed a follicular adenoma with atypical characteristics and thyroid hyperplasia.

Differential Diagnosis

The association of thyrotoxicosis and bilateral ophthalmopathy is pathognomonic of Graves' disease. Other causes of thyrotoxicosis an be differentiated by radioiodine uptake which can be high in single toxic nodules and toxic multinodular goiter, and low in excess thyroxine intake (thyrotoxicosis medicamentosa, factitious) and thyroiditides (sub-acute, silent, postpartum).

Discussion

History:

Caleb Hillier Parry, a private practitioner in Bath, England, saw his first patient with a diffuse goiter and hyperthyroidism in 1786. His report of eight patients, however was not published until 1825, which was 3 years after his death (1). In 1835, Robert James Graves in Dublin described the same disease in six pregnant women. The disease was named after him in both the former British empire and in the United States (2). Carl A von Basedow described the disease a third time in three women in 1840 (3) and his name rather than Graves is applied to the disease in Europe.

Prevalence:

Graves' disease has been estimated to occur in 0.4%% of the population of the United States with a lifetime risk of 1%%. It is most commonly manifest in the third or fourth decade of life and the female to male ratio is 7:1 to 10:1 in published series.

Pathogenesis:

The thyroid abnormalities characteristic of Graves' disease result from the action of immunoglobulin of the IgG class on the gland. These antibodies may be directed against components or regions of the plasma membrane that include the receptor for thyroid simulating hormone (TSH) itself. The principal destabilizing factor resulting in autoimmune thyroid disease appears to be an organ specific defect in suppressor T-lymphocytes. Hyperthyroidism itself appears to have an adverse effect on generalized suppressor T-cell function, and this may be a self-perpetuated or potentiating factor in Graves' disease.

For many years, the common procedure for testing serum for Graves' related IgG was to administer IgG to a mouse whose thyroid had been prelabeled with radioactive iodine and to seek evidence of subsequent enhancement of thyroid hormone secretion in the blood. Unlike the stimulation produced by TSH which peaks at about 2 hours, that of Graves' IgG peaks at about 16 hours. The IgG responsible for this activity was named long-acting thyroid stimulator (LATS) and is demonstrable in 50%% of patients with active Graves' disease.

More recently, two types of assays have been developed. The first one measures the ability of Graves' IgG to inhibit the binding of I-125 labeled bovine TSH to specific binding sites of the thyroid membranes. Those antibodies called TSH-binding inhibitory immunoglobulin (TBII) are present in more than 90%% of patients with active Graves' disease. In another assay, Graves' IgG is tested for its ability to stimulate hormonal secretion in human thyrocyte preparations. These antibodies, designated thyroid-stimulating immunoglobulins (TSI) are present in approximately 80%% of patients with active Graves' disease. These two assays are referred to as measurements of TSH receptor antibody (TRAb) in the endocrinology literature (4).

Natural history:

The course of the thyrotoxic component in untreated Graves' disease is often erratic and most patients exhibit exacerbations of varying frequency and duration followed by a 'burn out" phase (5).

Clinical picture:

Graves' disease is characterized by the association of thyrotoxicosis, diffuse goiter, infiltrative ophthalmopathy and occasionally infiltrative dermopathy. The infiltrative ophthalmopathy follows a course independent from the thyrotoxic component and is not influenced by the treatment. It occurs in 50 to 100%% of patients depending on whether clinical examination alone or orbital ultrasound is used to evaluate the orbital involvement. Beta-mode ultrasonographic examination reveals swelling of extra-ocular muscles and increased retro-orbital fat (6). Infiltrative ophthalmopathy may occur in the absence of thyrotoxicosis. This entity is called euthyroid ophthalmic Graves' disease. Infiltrative dermopathy occurs in 5 to 10%% of patients and for unknown reasons is found only in patients with ophthalmopathy. It is characterized by plaques of confluent areas of violaceous pretibial induration.

Thyroid imaging:

The thyroid scintigram typically shows a symmetrically enlarged gland with homogeneous tracer distribution and a prominent pyramidal lobe (7). However, variation in pattern of distribution is not unusual, and may be accounted for by the presence of patches of thyroiditis. The radioiodine uptake is usually elevated to the range of 50%% to 80%%.

Therapy:

There is no curative therapy for Grave's disease. Treatment is designed to reduce the thyroid's ability to produce hormones. Three options are available: Medical therapy, radioactive iodine and surgery.

Medical Therapy:

The agents used in the US are propylthiouracil (PTU) and methimazole (Tapazole). They both inhibit the organic binding of iodide. In addition, propylthiouracil inhibits the peripheral conversion of T4 to T3. The half-life of propylthiouracil is 1.5 h while that of methimazole is 6 h. The initial dose of propylthiouracil is 200 to 300 mg up to 1200 mg daily every 8 to 12 h or 4 to 6 h when large doses are required. The usual regimen of methimazole is 20 to 40 mg daily in one to three divided doses. A latent period between onset of treatment and therapeutic response has to be expected as these agents inhibit the synthesis but not the release of hormone stored. Some improvement is usually noted at 2 weeks with normalization of the metabolic state at approximately 6 weeks.

Therapy is usually prescribed for 12 to 18 months. The incidence of lasting remission has been reported to be around 30%% with higher remission rates associated with longer treatment (8) or higher doses (9). Whether this reflects the natural history of the disease or a modulation of the immune processes involved in Graves' hyperthyroidism is not completely elucidated. Indeed, treatment with antithyroid drugs is consistently associated with a decrease in TRAb, serum microsomal antibody titers, and thyroglobulin antibody titers. In addition, the number of circulating activated T lymphocytes and the helper/suppressor T-lymphocyte ratio is reduced (8, 10, 11). The major complications include agranulocytosis (0.4%%) and very rarely hepatitis; skin rash is considered a minor complication.

Radioactive Iodine Therapy:

I-131 therapy is designed to administer a sufficient radiation dose to partially destroy the thyroid parenchyma. Biologic effects of I-131 include pyknosis and necrosis of the follicular cells and, later, vascular and stromal fibrosis. The studies directed at evaluating the safety of radioiodine therapy have failed to show any significant carcinogenic, leukemogenic or teratogenic effect in doses used to treat hyperthyroidism (12-15). Interestingly, the prevalence of thyroid carcinoma may be lower in patients who received therapeutic doses of radioiodine as compared to the general population. This is in contrast with the increased prevalence of benign and malignant thyroid nodules in patients who received low dose external beam irradiation or irradiation from atomic bomb or nuclear accidents (15).

The I-131 dose (in uCi) to deliver is calculated with the following formula:

The weight of the gland is estimated by palpation, the 24 h iodine uptake is measured using a tracer dose of I-123. The dose of I-131 that is used for treatment of Graves' disease ranges from 70 to 215 uCi/gm (16). Higher doses are associated with less relapse but will be associated with a higher incidence of hypothyroidism during the first few years following treatment (17). Waxman used 86 uCi/gm (for a total thyroid dose of 7000 rads) and was able to bring 80%% of patients to a euthyroid range with 10%% of patients requiring a second treatment and 10%% remaining hypothyroid (18).

Surgery:

The usual surgical treatment of Graves disease consists of sub-total thyroidectomy leaving 3 to 5 grams of residual thyroid tissue attached to an intact inferior thyroid artery (19). Review of the series published since 1987 reveals that reoperation for hemorrhage has been necessary in 0%% to 1.3%% of patients, recurrent nerve palsy occurrence ranged from 0%% to 4.5%%, permanent hypocalcemia was seen in 0%% to 0.6%% of patients, recurrent hyperthyroidism was observed in 1.3%% to 17.8%% and the incidence of hypothyroidism has been 21%% at one year and 31%% to 36%% at 5 years (19).

Choice of therapy:

The choice of therapy may be influenced by cost, age (14), the size of the goiter (20), the degree of thyrotoxicosis (21), pregnancy status, patient preferences, and response to initial treatment. Surgery, because of the potential complications and the cosmetic effect has only a minimal role in the treatment of Graves' disease and will be recommended only in patients for whom other therapies are contraindicated or refused.

In 1990, a survey of the 235 clinically active members of the American Thyroid Association revealed that for management of uncomplicated Graves' disease, radioactive treatment was the first choice for 69%%, thiourea was the main line treatment for 30%% and surgery was chosen by only one respondent (22).

References

1. Parry CH. Collections from the unpublished medical writings (vol II). London: Underwoods, 1825:111-120. (Cited by Major RH. Classic descriptions of disease with biographical sketches of the authors. Springfield, IL: CC Thomas, 1978: 275-279).

2. Graves RJ. Newly observed affection of the thyroid gland in females. From the clinical lectures delivered by Robert J. Graves, MD, at the Meath Hospital, during the session of 1834-35. London Medical and Surgical Journal 1835; 7:516-517. (Cited by Major RH. Classic descriptions of disease with biographical sketches of the authors. Springfield, IL: CC Thomas, 1978: 279-281).

3. von Basedow CA. Exophthalmos durch hypertrophie des zellgewebes in der augenhohle. Wochenschrift fur die gessamte heilkunde, Berlin, March 28, 1840. (Cited by Major RH. Classic descriptions of disease with biographical sketches of the authors. Springfield, IL: CC Thomas, 1978: 282-285).

4. Larsen PR, Alexanders NM, Chopra IJ, et al. Revised nomenclature for tests of thyroid hormones and thyroid related proteins in serum. J Clin Endocrinol Metab 1987; 64: 1089-1092.

5. Larsen PR, Ingbar SH. The thyroid gland. In:Wilson JD, Foster DW, editors. Williams textbook of endocrinology. Philadelphia: WB Saunders, 1992: 357-487.

6. Forrester JV, Sutherland GR, McDougall IR. Dysthyroid ophthalmology: orbital evaluation with beta-scan ultrasonography. J Clin Endocrinol Metab 1977; 45: 221-224.

7. Palmer EL, Scott JA, Strauss HW. Endocrine imaging. Practical Nuclear Medicine. Philadelphia : WB Saunders, 1992:311-341.

8. Orgiazzi J: Management of Graves' hyperthyroidism. Endocrinol Metab Clin North Am 1987;16:365-389.

9. Romaldini JH, Bromberg N, Werner RS, et al: Comparison of effects of high and low dosage regimens of antithyroid drugs in the management of Graves' hyperthyroidism. J Clin Endocrinol Metab 1983;57:563-574.

10. Volpe R. Immunoregulation in autoimmune thyroid disease. N Engl J Med 1987;316:44-46.

11. Tētterman TH, Karlsson FA, Bengtsson M, Mendel-Hartvig I. Induction of circulating activated suppressor-like T cells by methimazole therapy for Graves' disease. N Engl J Med 1987;316:15-22.

12. Saenger EL, Thoma GE, Thomkins EA. Incidence of Leukemia following treatment of hyperthyroidism : Preliminary report of the cooperative Thyrotoxicosis Follow-up Study. JAMA 1968;205:147-152.

13. Holm LE, Dahlqvist I, Israelson A, et al. Malignant thyroid tumors after iodine-131 therapy: A retrospective cohort study. N Engl J Med 1980;303:188-192.

14. Hamburger JI. Management of hyperthyroidism in children and adolescents. J Clin Endocrinol Metab 1985;60:1019-1024.

15. Henneman G, Krenning EP, Sankaranarayanan K. Place of radioactive iodine in treatment of thyrotoxicosis. Lancet 1986;1:1369-1372.

16. Nordyke RA, Gilbert FI Jr. Optimal iodine-131 dose for eliminating hyperthyroidism in Graves' disease. J Nucl Med 1991;32:411-416.

17. Hershman JM. The treatment of hyperthyroidism. Ann Intern Med 1966;64:1306-1314.

18. Clinical Nuclear Medicine Syllabus, April 1994, Cambrige, MA.

19. Feliciano DV. Everything you wanted to know about Graves' disease. Am J Surg 92;164:404-411.

20. Laurberg P, Buchholtz-Hansen PE, Iversen E, et al. Goitre size and treatment outcome of medical treatment of Graves' disease. Acta Endocrinol(copenh)1986;111:39-45.

21. Takamatsu J, Kuma K, Mozai T. Serum triiodothyronine to thyroxine ratio: A newly recognized predictor of the outcome of hyperthyroidism due to Graves' disease. J Clin Endocrinol Metab 1986;62:980-988.

22. Solomon B, Glinoer D, Lagasse R, Wartofsky L. Current trends in the management of Graves' disease. J Clin Endocrinol Metab 1990;70:1518-1524.

Click here to go to Joint Program in Nuclear Medicine home page and Copyright notice.

J. Anthony Parker, MD PhD, Tony_Parker@bidmc.harvard.edu