Original Article
Exacerbation of Autoimmune Thyroid Dysfunction after Unilateral Adrenalectomy in Patients with Cushing's Syndrome Due to an Adrenocortical Adenoma
N Engl J Med 1990; 322:1708-1712June 14, 1990
- Abstract
- Abstract
Little is known about the factors that cause exacerbations of autoimmune thyroid dysfunction. One possibility is an alteration in adrenocortical function, since glucocorticoids are known to alter both pituitary—thyroid and immunologic function. We encountered three patients in whom overt autoimmune thyroid disease developed after unilateral adrenalectomy for Cushing's syndrome due to an adrenocortical adenoma. We compared the postoperative changes in thyroid function in these patients with those in 21 other patients with Cushing's syndrome who underwent the same treatment.
After unilateral adrenalectomy, one of the three patients had transient hyperthyroidism and a low thyroid uptake of 131I, indicative of silent thyroiditis. After the same surgical procedure, the second patient had hypothyroidism, whereas the third patient had transient hyperthyroidism at first, and hypothyroidism then gradually developed. All three patients had serum antithyroid antibodies, the titers of which increased after surgery. In the remaining 21 patients (only 2 of whom had antithyroid antibodies initially), the serum concentrations of thyroxine, triiodothyronine, and thyroxine-binding globulin and the secretion of thyroid-stimulating hormone increased after surgery from values that were low or near the lower limit of normal to values still well within the normal range. None of these patients had clinically evident thyroid disease or increased antithyroid-antibody titers.
We conclude that reductions in the secretion of glucocorticoid may exacerbate subclinical autoimmune thyroid disease. Patients with Cushing's syndrome due to adrenocortical adenoma who have thyroid antibodies should be followed closely after treatment, because thyroid dysfunction may develop. (N Engl J Med 1990; 322: 1708–12.)
Article Activity
- Article
CUSHING'S syndrome may be caused by functioning tumors or hyperplasia of the adrenal cortex. It includes the various metabolic abnormalities induced by excessive secretion of glucocorticoid, principally of cortisol. Excess glucocorticoids suppress autoimmune processes, including those affecting the thyroid gland.1 2 3 4 5 Furthermore, in patients with adrenal insufficiency glucocorticoid-replacement therapy has been found to result in several different changes in pituitary—thyroid function6 7 8 9; some patients with both adrenal insufficiency and hypothyroidism had improvement in thyroid function when they were given replacement doses of glucocorticoids.6 , 8 , 9 The interactions between Cushing's syndrome and autoimmune thyroid disease have not been studied, however. We recently encountered three patients who had Cushing's syndrome due to a hyperfunctioning adrenocortical adenoma, in whom autoimmune thyroid dysfunction developed after unilateral adrenalectomy. We studied these patients and 21 other patients with the same adrenal disorder to determine what factors might predict the development of postoperative autoimmune thyroid dysfunction.
Methods
Subjects
We studied 24 patients (16 women and 8 men; mean [±SD] age, 38±12 years), each of whom had Cushing's syndrome due to a hyperfunctioning adrenocortical adenoma. None had a history of thyroid disease. The diagnosis of hyperfunctioning adrenocortical tumor was made on the basis of history, clinical findings, measurements of plasma and urinary steroids before and during the administration of dexamethasone, abdominal CT scanning, and adrenal scintigraphy with 131I-labeled cholesterol. Before surgery, all the tumors were thought to be adenomas on the basis of their radiologic features. The mean estimated duration of the disease was 14±8 months.
All 24 patients subsequently underwent surgery, during which each was found to have a solitary tumor. All underwent unilateral adrenalectomy. The mean tumor weight was 11±8 g. Histologic studies revealed the tumors to be adenomas composed of clear cells, compact cells, or both. These patients were examined postoperatively, and blood samples were collected at regular intervals for at least two years. Thyrotropin-releasing hormone stimulation tests, in which 500 μg of thyrotropin-releasing hormone was given intramuscularly, were performed two to three months after surgery, as well as before it. During this two-year period, symptomatic thyroid dysfunction developed in 3 of the 24 patients; they are described in detail in Results. The other 21 patients had no thyroid dysfunction at any time after adrenalectomy. The size of the thyroid gland was assessed from measurement of its width, estimation of its weight, or both. In normal subjects, the thyroid gland is not usually palpable; when it is palpable, its width is less than 3.5 cm.
The study plan was reviewed and approved by our institutional review committee, and consent was obtained from all patients.
Laboratory and Statistical Analysis
Serum concentrations of thyroxine (T4), triiodothyronine (T3), thyroid-stimulating hormone (TSH), thyroglobulin, and thyroxine-binding globulin were determined by radioimmunoassay with use of commercially available kits. The normal ranges for serum concentrations of T4, T3, and thyroxine-binding globulin are 77 to 155 nmol per liter, 1.2 to 2.8 nmol per liter, and 19 to 25 mg per liter, respectively. The normal range for TSH is from less than 0.05 mU per liter (the sensitivity limit of the assay) to 5 mU per liter, and the range for serum thyroglobulin from less than 10 μg per liter to 50 μg per liter. Antithyroid microsomal antibodies and antithyroglobulin antibodies were measured with commercial kits (Fuji Zoki, Tokyo, Japan). Antibodies were considered to be present when positive reactions were obtained with serum dilutions of 1:40 or higher. TSH-receptor antibodies were measured by radioreceptor assay with a commercial kit (R.S.R., Cardiff, United Kingdom). The assay results were expressed in terms of the percent inhibition of 125I-labeled TSH binding to thyroid plasma membranes, as reported elsewhere.10 The range of normal values was from 15 percent to −15 percent (a positive test for TSH-receptor antibody was defined as a value >15 percent, and a negative test a value ≤15 percent). The uptake of 131I by the thyroid was measured 24 hours after the administration of the isotope (normal values, 15 to 40 percent). The plasma Cortisol concentration was measured by radioimmunoassay with a commercial kit. Urinary excretion of 17-hydroxycorticosteroids and 17-ketosteroids was measured as reported previously.11
Statistical analysis was performed by Student's t-test. P values less than 0.05 were considered significant.
Results
In 3 of the 24 patients who had Cushing's syndrome due to a hyperfunctioning adrenocortical adenoma, thyroid dysfunction developed after unilateral adrenalectomy. Patient 1 had transient hyperthyroidism, with low uptake of 131I by the thyroid, presumably because of thyroiditis. Patient 2 had permanent hypothyroidism, and in Patient 3 hypothyroidism developed gradually after an initial period of hyperthyroidism.
Table 1Table 1
Preoperative Adrenal Function in 3 Patients with Cushing's Syndrome Due to an Adrenocortical Adenoma Who Had Postoperative Thyroid Dysfunction and 21 Other Patients with the Same Disease Who Had No Dysfunction. shows the results of the preoperative adrenal-function tests in these 3 patients and the other 21 patients. All had elevated plasma cortisol concentrations, which varied little during the day, increased urinary 17-hydroxycorticosteroid excretion, and normal urinary 17-ketosteroid excretion. The administration of dexamethasone did not reduce either the plasma cortisol concentration or the urinary excretion of 17-hydroxycorticosteroid in any patient. No differences were noted in these respects between the 3 patients in whom thyroid dysfunction later developed and the other 21 patients. All patients received moderate doses of hydrocortisone (10 to 25 mg per day) for one to two months postoperatively. Their symptoms and signs of Cushing's syndrome disappeared promptly, and none of the patients had manifestations of adrenal insufficiency at any time.Patient 1, a 31-year-old woman, had transient hyperthyroidism with low 24-hour uptake of 131I by the thyroid three months after unilateral adrenalectomy (Fig. 1Figure 1
Transient Hyperthyroidism with Low 24-Hour Thyroid 131I Uptake after Unilateral Adrenalectomy for Cushing's Syndrome Due to an Adrenocortical Adenoma (Patient 1).). She had had symptoms of Cushing's syndrome for approximately one year, and her initial physical examination revealed hypertension, central obesity, red striae, and proximal-muscle weakness and atrophy. Before adrenalectomy her thyroid gland was palpable; its width was 3.4 cm, and its weight was estimated to be 27 g. The patient's serum T4, T3, and TSH values were 78 nmol per liter, 1.2 nmol per liter, and 1.0 mU per liter, respectively. Antimicrosomal antibodies were present in serum at a dilution of 1:100, and tests for antithyroglobulin antibodies were negative. After left adrenalectomy, the patient took hydrocortisone for 1 1/2 months. Three months after surgery, she was noted to have moist skin, and her serum T4 and T3 levels had increased. During the next two months she had excessive perspiration, palpitation, finger tremor, and thyroid enlargement. Her serum T4 and T3 levels became abnormally high, and her titers of antimicrosomal antibody and antithyroglobulin antibody increased. Her peak serum T4 and T3 values were 240 nmol per liter and 4.9 nmol per liter, respectively; at that time her 24-hour thyroid uptake of 131I was only 2.2 percent, a test for TSH-receptor antibody was negative (2.0 percent), and the serum thyroglobulin concentration was 120 μg per liter. The patient received no therapy. Her symptoms gradually disappeared, her thyroid gland became smaller, and her serum T4 and T3 levels gradually returned to normal. Twenty-four months after adrenalectomy, she was euthyroid, and her serum T4, T3, TSH, and thyroglobulin values were normal; the antimicrosomal-antibody titer was 1:100, and the antithyroglobulin-antibody titer was negative.Patient 2, a 27-year-old woman, had permanent hypothyroidism after unilateral adrenalectomy. She had had symptoms of Cushing's syndrome for seven months, and her initial physical examination revealed hypertension, central obesity, and moon face. Before adrenalectomy her thyroid gland was palpable, its width was 3.8 cm, and its estimated weight was 30 g. The patient's serum T4, T3, and TSH concentrations were 83 nmol per liter, 1.1 nmol per liter, and 1.6 mU per liter, respectively. Antimicrosomal antibodies were present in a titer of 1:100, and the antithyroglobulin-antibody titer was negative. After left adrenalectomy, the patient took hydrocortisone for two months. Her serum concentrations of T4 and T3 increased (within the normal range) during the first several months after the operation. After six months she noticed thyroid enlargement and weakness. Physical examination revealed firm, symmetric thyroid enlargement (width, 7.4 cm; estimated weight, 70 g). Her serum T4 and T3 concentrations were low (40 nmol per liter and 1.0 nmol per liter, respectively), and the serum TSH concentration was high (16 mU per liter). The titers of antimicrosomal antibody and antithyroglobulin antibody had increased to 1:6400 and 1:1600, respectively; a test for TSH-receptor antibody was negative (2 percent). She was treated with thyroxine. When it was discontinued temporarily six months later, she became hypothyroid again within three weeks. Twenty-four months after surgery, while receiving 75 μg of thyroxine daily, she was euthyroid and her thyroid gland was smaller (width, 4.0 cm). Her serum T4, T3, and TSH values were normal, the antimicrosomal-antibody titer was 1:1600, and the antithyroglobulin-antibody titer was 1:100.
Patient 3, a 40-year-old woman, had transient hyperthyroidism followed by hypothyroidism after unilateral adrenalectomy (Fig. 2Figure 2
Transient Hyperthyroidism Followed by Hypothyroidism after Unilateral Adrenalectomy for Cushing's Syndrome Due to an Adrenocortical Adenoma (Patient 3).). She had had symptoms of Cushing's syndrome for two years before her initial evaluation, at which time physical examination revealed hypertension, central obesity, and moon face. Her thyroid gland was palpable (width, 4.2 cm; estimated weight, 35 g). Her serum T4, T3, and TSH values were 80 nmol per liter, 1.2 nmol per liter, and 1.2 mU per liter, respectively. Antimicrosomal antibodies were present in serum diluted 1:1600, and the antithyroglobulin-antibody titer was negative. A test for rheumatoid factor was positive (1+). After left adrenalectomy, the patient took hydrocortisone for 1 1/2 months. Two and a half months after surgery, she had increased fatigability. Her pulse rate was 92 per minute, and her thyroid gland was enlarged. Finger tremor, palpitation, excessive perspiration, and joint pains then developed. Her serum T4 and T3 values increased to 192 nmol per liter and 4.8 nmol per liter, respectively, but the 24-hour thyroid uptake of 131I was only 3.2 percent. A test for TSH-receptor antibody was negative (0), the antimicrosomal-antibody and antithyroglobulin-antibody titers had increased, and the serum thyroglobulin concentration was 220 μg per liter. The rheumatoid-factor test was more strongly positive (3+). The patient was treated with methimazole for one month, during which time her serum T4 and T3 concentrations returned to their respective normal ranges. Seventeen months after surgery, she had increased intolerance to cold, constipation, fatigability, and pretibial myxedema and was found to have overt biochemical hypothyroidism (serum levels of T4, 50 nmol per liter; T3, 0.9 nmol per liter; and TSH, 22 mU per liter). She was treated with thyroxine. When it was later discontinued temporarily, she became hypothyroid within two weeks (data not shown). At the time of her most recent examination, when the patient was taking 75 μg of thyroxine daily, she was euthyroid. Her serum T4, T3, TSH, and thyroglobulin values were normal, the antimicrosomal antibody titer was 1:1600, and the antithyroglobulin antibody titer was 1:100.Of the remaining 21 patients with a hyperfunctioning adrenocortical adenoma, 2 had positive antimicrosomal-antibody titers (1:100 in both) and negative antithyroglobulin-antibody titers at first. After surgery, the antimicrosomal-antibody titers for these patients did not change, and their thyroid function remained normal. The remaining 19 patients had no symptoms or signs of thyroid disease, no abnormalities in thyroid-function tests, and no thyroid autoantibodies at any time after the operation.
Figure 3Figure 3
Results of Thyroid-Function Testing before (Solid Bars and Circles) and Two to Three Months after (Open Bars and Circles) Unilateral Adrenalectomy in 21 Patients with Cushing's Syndrome Due to an Adrenocortical Adenoma. shows the serum levels of T4, T3, and thyroxine-binding globulin and the serum TSH concentrations, basally and after stimulation with thyrotropin-releasing hormone, in these 21 patients before and two to three months after unilateral adrenalectomy. None of these patients took hydrocortisone during the three weeks before the second measurement. Before adrenalectomy, when the patients' glucocorticoid secretion was excessive, their mean serum levels of T4, T3, and thyroxine-binding globulin and the responses of the TSH concentration to stimulation with thyrotropin-releasing hormone were low or at the lower limit of normal. Two to three months after adrenalectomy, all the patients had normal values.Discussion
We identified three patients who had Cushing's syndrome due to hyperfunctioning adrenocortical adenoma, in whom autoimmune thyroid dysfunction developed after unilateral adrenalectomy. One had transient hyperthyroidism; the second, hypothyroidism; and the third, hyperthyroidism followed by hypothyroidism. In both patients with hyperthyroidism, the probable cause was thyroiditis, because both had low 24-hour levels of uptake of 131I by the thyroid (neither had received any inorganic iodide, iodine-containing drug, or radiocontrast agent for at least two months) and neither had measurable TSH-receptor antibodies in serum, which would have indicated Graves' disease. All had normal adrenal function at the time thyroid dysfunction developed. Only the patients with thyroid autoantibodies at the time of adrenalectomy, and not all such patients, subsequently had autoimmune thyroid dysfunction.
Hyperthyroidism due to thyroiditis is characterized not only by low levels of thyroid uptake of 131I, but also by its transient nature.12 , 13 Serum thyroglobulin values are elevated, as they are in patients with hyperthyroidism due to Graves' disease, subacute thyroiditis, or nodular thyroid disease; they are not elevated in patients with exogenous hyperthyroidism. The transient hyperthyroidism may or may not be followed by hypothyroidism. Patient 2 had permanent hypothyroidism after surgery. These several sequences of events have been recognized best in the postpartum period,14 during which they are thought to be due to a rebound in immune activity after its suppression during pregnancy.
Among these 24 patients with Cushing's syndrome due to a hyperfunctioning adrenocortical adenoma, 5 patients, including the 3 in whom thyroid dysfunction subsequently developed, had increased antimicrosomal-antibody titers. This rate (21 percent) is high as compared with the rate in normal women in Japan (8.5 percent). We suggest that thyroid function in such patients should be followed carefully after surgery, since the risk of autoimmune thyroid dysfunction in patients with Cushing's syndrome who have thyroid antibodies is high after adrenalectomy, as it is post partum in women with thyroid antibodies.14 Glucocorticoids are known to suppress autoimmune reactions, and they have been used to treat patients with autoimmune thyroiditis.1 2 3 4 5 In such patients, glucocorticoid therapy may decrease antithyroid-antibody titers and normalize thyroid function. Our findings suggest that patients with thyroid autoantibodies may be "protected" from autoimmune thyroid dysfunction by the development of Cushing's syndrome. After the removal of an adrenal tumor and the restoration of normal pituitary—adrenal function, the autoimmune process may be exacerbated, and overt thyroid dysfunction may develop.
Another possible mechanism for the exacerbation of autoimmune thyroid dysfunction may be exposure to large amounts of iodine during the workup for Cushing's syndrome. All three patients had CT scanning and scintigraphy with 131I-labeled cholesterol; thus, they received iodinated organic compounds. To protect their thyroid glands, they also received sodium iodide (30 mg per day) for 10 days before the scintigraphy. Although iodide administration may have contributed to the triggering of thyroid dysfunction, we think this possibility unlikely, because the dysfunction developed several months later, and in two patients it seemed to be permanent.
When the group of patients with Cushing's syndrome due to a hyperfunctioning adrenocortical adenoma was taken as a whole, the preoperative mean serum T3 and T4 levels, T3/T4 ratios, thyroxine-binding globulin levels, and TSH levels, basally and after stimulation with thyrotropin-releasing hormone, were low or at the lower limit of normal. When the patients in whom thyroid dysfunction developed later were excluded, all the values increased well into the normal range after unilateral adrenalectomy. The preoperative abnormalities resulted from the inhibition by glucocorticoids of TSH secretion from the pituitary gland,15 , 16 the peripheral conversion of T4 to T3,17 and the secretion of thyroxine-binding globulin.18 , 19 These changes do not explain the mechanism of thyroid dysfunction after adrenalectomy, however.
Source Information
From the Department of Gerontology, Endocrinology, and Metabolism, Shinshu University School of Medicine, Asahi 3–1–1, Matsumoto, Nagano-ken 390, Japan, where reprint requests should be addressed to Dr. Takasu.
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