Abstract
Background:
Thymic hyperplasia is associated with Graves' disease, particularly in young patients. The degree of thymic transformation is minimal in most but not all patients. In the latter group radiological measurements of thyroid size and their change with treatment have rarely been reported. We present two patients with Graves' disease and relatively rapid resolution of thymic enlargement after successful treatment of their hyperthyroidism.
Summary:
Three patients with thyrotoxicosis secondary to Graves' disease and marked thymic enlargement were seen at our institution during a 2-year period. On computed tomography (CT) studies their volumes were 67, 81, and 54 cm3. Thymic hyperplasia in the setting of Graves' disease was the diagnosis of exclusion. Two of the patients returned for follow-up after successful treatment of thyrotoxicosis as requested. On repeat CT their thymic volumes had decreased by 72% and 78%, respectively. Two types of histological modifications of the thymus have been described in association with Graves' disease, namely, thymic parenchyma hyperplasia and medullary lymphoid hyperplasia. The mechanisms underlying thymic transformation in patients with Graves' hyperthyroidism are not completely elucidated, but autoimmune processes underlying Graves' disease are presumed to play a role. The clinical course of our patients is consistent with earlier literature, indicating that thymic enlargement may occur in conjunction with Graves' hyperthyroidism, and that it usually resolves as hyperthyroidism is treated, but there is little quantitative pre- and posttreatment of hyperthyroidism data.
Conclusion:
Although every patient must be individually considered, it appears that thymic hyperplasia can be diagnosed in most Graves' hyperthyroid patients by considering the clinical context and appropriate radiologic studies such as CT. Raising awareness of the association of thymic hyperplasia in patients with Graves' hyperthyroidism and its resolution with the reversibility of the hyperthyroid state should prevent unnecessary thymic evaluation and surgery with its attendant risks.
Introduction
An association of thymic hyperplasia with Graves' disease has been known for almost a century, but precise volumetric radiological evidence of thymic enlargement with subsequent decrease in size after treatment of the hyperthyroidism has seldom been reported. In this report, we present three patients with overt thyrotoxicosis secondary to Graves' disease, each of whom had an anterior mediastinal mass on presentation. In this report the formula used for the calculations of thymic volume was as follows
Thymic volume = (3.14/6) × anteroposterior × craniocaudal × transverse diameter
Case Presentations
Patient 1
A previously healthy 27-year-old African American man presented to the hospital with acute onset of severe lower extremity weakness, myalgias, and muscle stiffness for the past day, which progressed rapidly to weakness involving his legs. He also complained of chest discomfort, progressive dyspnea on exertion, palpitations, increased appetite, and an indeterminate amount of weight loss for the prior 2 months. Physical examination revealed a thin, anxious looking young man, with a regular tachycardia of 146 beats/min. He had mild lid lag and lid retraction, and his thyroid gland was homogeneously enlarged to an estimated weight of 60 g and had an audible thyroid bruit. Neurological examination revealed weakness in both lower extremities with strength of 3/5 and brisk deep tendon reflexes.
Computed tomography (CT) scan of the chest with and without intravenous (IV) contrast performed at the time of admission to evaluate for possible pulmonary embolism versus malignancy in the setting of weight loss revealed an anterior mediastinal mass extending from the thoracic inlet inferiorly along the right anterior surface of the heart and measuring over 6 cm in maximal dimension. The mass was homogeneous in its attenuation and separate from the thyroid gland. The volume of the thymic mass was calculated to be 67.42 cm3 (Table 1).
Laboratory testing indicated hyperthyroidism, with undetectable TSH of <0.004 μU/mL (reference range 0.45–4.5 μU/mL), free thyroxine (T4) of 4.76 ng/dL (reference range 0.8–1.8 ng/dL), and total triiodothyronine (T3) of 554 ng/dL (reference range 97–219 ng/dL). Thyroid-stimulating immunoglobulin (TSI) was 3.6 (reference range <1.3), and thyroid binding inhibitory immunoglobulin was 78% (reference range <16%). A diagnosis of hyperthyroidism due to Graves' disease was made. The patient also had electrolyte abnormalities, including hypokalemia, with a serum potassium of <2.0 mM (reference range 3.5–5.5 mM) and hypomagnesemia of 1 mg/dL (reference range 1.4–1.9 mg/dL). He received intravenous potassium (80 mEq) and magnesium (4 g) until his electrolytes normalized, followed by complete resolution of his lower extremity weakness. The patient was found to have thyrotoxic periodic paralysis, a known complication of hyperthyroidism.
Since thymic hyperplasia is an uncommon but known manifestation of Graves' disease, medical treatment of Graves' disease was started with methimazole 20 mg orally twice daily and propranolol 80 mg orally four times daily. Approximately a month after admission, thyroid function tests indicated that he was biochemically euthyroid with a free T4 of 1.04 ng/dL, total T3 of 147 ng/dL, and normal electrolytes. TSH was still suppressed at <0.01 μU/mL.
A CT scan of the chest without IV contrast was repeated 15 weeks after the patient's initial presentation and it showed an interval reduction in size of the previously described anterior mediastinal mass. It was described as a small area of homogeneous soft tissue density seen in the anterior mediastinum measuring up to 2.0 cm, with small areas extending over the anterior mediastinum bilaterally, findings being most compatible with thymic hyperplasia. The volume of the hyperplastic thymus had reduced from 67.42 cm3 initially to 19.77 cm3 (Table 1).
Patient 2
A previously healthy 45-year-old African American woman presented to the hospital with progressively worsening palpitations for the past month, dyspnea on exertion, worsening lower extremity edema, and fatigue. She admitted to increased appetite, a 25-pound weight gain within the past 2 months, and increased frequency of her bowel movements. On physical examination the patient was found to have an irregular heart beat at 150 beats/min, noticeable eye proptosis, and lid lag retraction, as well as a fine hand tremor. Her thyroid was diffusely enlarged and nontender, with an approximated weight of 50 g by palpation. The remainder of the physical examination was only significant for decreased breath sounds on the right lower lung base, bibasilar pulmonary crackles, and bilateral pitting edema of her lower extremities.
CT of the chest with IV contrast performed for further evaluation of the unilateral pleural effusion diagnosed on the chest X-ray revealed a homogenous, smooth marginated soft tissue mass into mediastinum, separated from the thyroid that was consistent with thymic hyperplasia versus thymoma versus lymphoma. The volume of the anterior mediastinal mass was 80.9 cm3. Laboratory data revealed a TSH <0.004 μU/mL (reference range 0.4–4.0 μU/mL), free T4 5.93 ng/dL (reference range 0.8–1.9 ng/dL), total T3 384 ng/dL (reference range 80–200 ng/dL), thyroperoxidase antibodies 62.1 IU/mL (reference range <35 IU/mL), and an elevated TSI to 3.5 (reference range <1.3). The electrocardiogram confirmed atrial fibrillation with rapid ventricular response of 150 beats/min. Transthoracic echocardiography revealed mild to moderate left ventricular dysfunction with an estimated ejection fraction of 45%. A diagnosis of Graves' disease thyrotoxicosis with secondary atrial fibrillation and subsequent high-output heart failure was made.
The initial medical management included esmolol drip intravenously for heart rate control, propranolol 40 mg orally twice daily, methimazole 40 mg orally three times a day, potassium iodine, and hydrocortisone 100 mg intravenously three times a day. No further investigations of the thymic mass were done as it was considered to be thymic hyperplasia in the setting of Graves' disease with hyperthyroidism.
The patient was discharged in a stable condition on methimazole 40 mg orally daily, propranolol 160 mg orally daily, prednisone taper dose, and cardizem 90 mg orally every 6 hours. A successful total thyroidectomy was performed 6 days after hospital discharge, and the patient was further initiated on thyroid hormonal therapy with levothyroxine.
Two months after thyroidectomy, a clinical and laboratory evaluation of the patient revealed an euthyroid state, with the following thyroidal hormonal levels: TSH 0.5 μU/mL, free T4 1.28 ng/dL, and total T3 91.4 ng/dL.
A CT of the chest with IV contrast to evaluate for the anterior mediastinal mass was performed and revealed interval regression of the mass seen on the previous CT. It was described as soft tissue within the anterior mediastinum consistent with thymic tissue, decreased in size when compared with previous examination. The volume of the thymic mass has reduced from 80.9 to 8.16 cm3 (Table 1).
Patient 3
A 19-year-old previously healthy African American man presented with a 2-month history of progressive midsternal chest pain that was characterized as constant, nonradiating, worsened by deep inspiration, and associated with shortness of breath and palpitations. He also admitted to increased appetite, diarrhea, heat intolerance, an agitated state, and fever.
Physical examination revealed an agitated man with an asthenic build (body mass index 19.9 kg/m2) and regular tachycardia (heart rate 107 beats/min). He had smooth and moist skin, and a fine hand tremor was noted. The eye examination was significant for inferior lid retraction bilaterally, without proptosis or lid lag. He had diffusely enlarged and tender lymph nodes in the submandibular, cervical, supraclavicular, and axillary regions. The thyroid gland was enlarged and nontender, with lateral edges to the level of the sternocleidomastoid muscles, having an estimated weight of ∼150 g by palpation and a thyroid bruit was present bilaterally.
CT of the chest with IV contrast performed to evaluate for possible pulmonary embolism or other compressive intrathoracic pathology revealed a hyperplastic anterior mediastinal mass with a calculated volume of 53.5 cm3 and enlarged right hilar lymph nodes (Table 1). Laboratory tests included a TSH of <0.004 μU/mL (reference range 0.40–4.0 μU/mL), free T4 >6 ng/dL (reference range 0.80–1.90 ng/dL), total T3 of 395 ng/dL (reference range 80–200 ng/dL), thyroperoxidase antibodies 47 IU/mL (reference range <35 IU/mL), and an elevated TSH receptor antibody (TSI) of 3.9 (reference range <1.3). On the basis of the clinical and biochemical presentation, Graves' disease with hyperthyroidism was diagnosed.
A cervical lymph node biopsy to evaluate for lymphoma showed sheets of lymphocytes with reactive changes, but the cytology was negative for malignancy, and cytometry studies performed on the biopsy aspirate were negative for lymphoma.
The patient was started on medical therapy for Graves' disease, with propranolol 40 mg orally three times a day, methimazole 30 mg orally twice daily, and a short course of prednisone 60 mg daily, followed by a rapid steroid taper regimen. Five days after initiation of treatment, free T4 was 3.26 ng/dL and total T3 129 ng/dL and TSH was still suppressed at <0.01 μU/mL. The rapid decrease in thyroid hormone levels was considered to be secondary to iodine-mediated inhibition of hormonal release from the iodine use with the contrast dye, as well as secondary to decrease T4 to T3 hormonal conversion by the steroid. After discharge, he failed to return for follow-up as recommended.
Discussion
Thymic hyperplasia in patients was first reported in association with Graves' disease by Halsted in 1914 (2). Michie and Gunn demonstrated the presence of histological modifications in the thymus in 38% of patients with thyrotoxicosis (3). Typically, however, these findings are minimal and radiologic evidence of a thymic mass is seldom reported (4,5).
The thymus seems to play a primary role in the development of the myasthenia gravis, and thymectomy is a major treatment. In contrast, in Graves' disease thymic hyperplasia seems to be an effect rather than a cause of the disease. In support of the latter statement are experimental studies in rats showing thymic enlargement after administration of thyroid hormone (6) and reduction in thymic size after thyroidectomy (7).
Several case reports describe regression of thymic enlargement after thyroidectomy or medical therapy alone (5,8). Strong evidence that thymic transformation is a result of the hyperthyroidism was provided by Murakami et al. (9), who studied thymic size and density by CT in 23 untreated patients with Graves' disease. An increase in size and density of the thymus was found in untreated patients with Graves' disease when compared to their age-matched control subjects, and thymic size and density decreased significantly after treatment with antithyroid drugs (9).
In their recent review on the management of the anterior mediastinal masses in patients with Graves' disease, Yacoub et al. (10) presented 21 cases from the literature of patients with Graves' disease and anterior mediastinal masses who underwent thymectomy or observation alone while on antithyroid therapy. The histologic findings in seven out of the eight cases who underwent thymectomy were consistent with thymic hyperplasia. Most importantly, all of the 13 patients who were observed had regression of the thymus with medical treatment alone.
In patients with Graves' disease and thymic enlargement undergoing thymectomy, histologic analysis of the thymus showed two morphologic transformations of the thymus gland, namely, thymic hyperplasia and lymphoid hyperplasia (4). Expansion of both the cortical and medullary component was observed on thymic biopsy by Michie and Gunn in their study of 40 patients with thyrotoxicosis, and involution of cortical tissue with a relative persistence of medullary expansion was found after prolonged treatment with antithyroid drugs (11). These findings suggest two separate pathogeneses for thymic enlargement in hyperthyroid patients. While thymic cortical tissue expansion seems to be dependent on a hyperthyroid state, lymphoid hyperplasia appears to be correlated more with the immune abnormalities underlying Graves' disease.
Supportive evidence for an immunology-based pathogenesis of thymic hyperplasia was published by Wortsman et al. (12). They demonstrated direct binding of circulating immunoglobulin G from a patient with Graves' disease to thymocytes and exhibition of a blastogenic response. Further immunologic studies of the hyperplastic thymocytes demonstrated immature T cell function by expression of T cell-specific CD molecules, as well as mitogenic activity in response to T cell-dependent concanavalin. Murakami et al. demonstrated the presence of TSH receptors in the nonneoplastic human thymus by polymerase chain reaction amplification, Northern blot, and Western blot analysis, as well as by immunohistochemistry studies of the thymic epithelial cells (9).
Thymulin, a thymic protein with a role in lymphocyte differentiation and function, has been described to be elevated in patients with hyperthyroidism and decreased in those with hypothyroidism, and may play a role in the development of lymphoid hyperplasia (13). Medullary lymphoid follicle formation can be part of a generalized hyperplasia of the lymphoreticular system that can be seen in Graves' disease. Peripheral lymphocytosis, diffuse lymphadenopathy, and splenomegaly have been described in hyperthyroid patients (14). Experimental animal studies also demonstrated spleen enlargement after administration of thyroid hormone in rats, as early as 3 weeks after hormonal therapy (6).
Further studies are needed to establish the exact pathophysiology of thymic hyperplasia in the setting of Graves' disease and the role of autoimmunity in thymic transformation. It appears that thymic hyperplasia is more likely to occur in the presence of high-titer TSH receptor antibodies that bind to the TSH receptor in thymic cells and cause proliferation. Why this phenomenon occurs and is recognized in only a small percentage of patients with Graves' disease is not completely understood, but future studies should take note that thymic hyperplasia seems to occur more frequently in younger patients with Graves' disease.
Thymomas appear to be associated with autoimmune processes, such as myasthenia gravis or Graves' disease (15). If the CT scan is suggestive of a thymoma or the patient has associated muscle weakness suggestive of myasthenia gravis, further consideration of a thymoma should be given. Close follow-up is important since in the majority of patients with Graves' hyperthyroidism and thymic hyperplasia, thymic enlargement will diminish in size with treatment of the hyperthyroidism.
In our first patient, muscle weakness was the manifestation of thyrotoxic periodic paralysis, not a thymus-related condition. Thyrotoxic periodic paralysis is an uncommon disorder that completely resolved after treatment of hypokalemia. Muscle paralysis is thought to be the result of hypokalemia that occurs secondary to thyroid hormone-induced adrenergic response and insulin release and its stimulation of the sodium–potassium ATPase activity with a shift of potassium from the extracellular space (16).
Once the diagnosis of Graves' disease is made in association with thymic enlargement, our recommendation is to monitor radiologically the thymic mass for regression during treatment of hyperthyroidism; otherwise, no interventional diagnostic or therapeutic procedure is needed in most cases. All aspects need to be monitored and considered for the possibility of a more aggressive process, however.
The observation period before consideration of other etiologies of a thymic mass, such as lymphoma, thymoma, or thymic carcinoma, deserves comment. In our first two patients we noted a relatively rapid and dramatic regression of the thymic mass, over a 15-week and 2-month period, respectively (Table 1). In the literature, however, reduction in thymic size may take place over 2 years with an average of 6-month period (10).
Precise volumetric changes of the thymic gland in response to the treatment of hyperthyroidism are infrequently reported. To our knowledge, this is only the second report of precise measurements of the thymic volume before and after treatment of Graves' hyperthyroidism (17). The 10-fold decrease in the thymic volume in patient 2, from 80.9 to 8.16 cm3 within a 2-month period (Table 1), might be explained by abrupt reversal of the hyperthyroid state that was achieved by thyroidectomy.
In summary, reversibility of thymic hyperplasia with the treatment of Graves' disease is clearly established in the literature and supported by the present report. In most patients it spares the need for thymic biopsy or surgical removal and thus eliminates the risk of surgical complications.
Footnotes
Disclosure Statement
The authors declare that no competing financial interests exist.