Thymic hyperplasia in Graves' disease.

Graves' disease is an autoimmune thyroid condition characterized by the production of autoantibodies against the thyrotropin receptor. It is known to be associated with autoimmune conditions such as myasthenia gravis, Addison's disease, type 1 diabetes mellitus, and vitiligo. We present a case of rare autoimmune association of Graves' disease with thymic hyperplasia which regressed after treatment with antithyroid drugs. Exact pathophysiology of thymic hyperplasia in Graves' is not well understood; it is likely to be the result of rather than the cause of Graves' disease.

INTRODUCTION

Graves’ disease is a common autoimmune condition and is commonly associated with other autoimmune conditions such as myasthenia gravis, Addison disease, type 1 diabetes mellitus, and vitiligo.[1] There is also a rare but well-documented association between Graves’ disease and thymic hyperplasia.[2] However, in most cases, thymic enlargement is minimal and radiologically detectable. Massive enlargement of the thymus is infrequently reported. We would like to highlight this association. Clinicians should be aware of the usually benign clinical course of thymic hyperplasia associated with Graves’ disease.

CASE REPORT

A 30-year-old male presented with intermittent fever, weight loss, and dry cough of 2 months duration. He presented to various centers and was extensively evaluated for fever. Basic hematological and biochemical investigations were within normal limits.

He presented to our center as a case of pyrexia of unknown origin (PUO). On enquiry, he also gave history of weight loss of 10 kg (weight 56 kg) over 2 months despite increased appetite, excessive sweating, restlessness, increased anxiety, and frequent episodes of diarrhea. On evaluation, he was found to have thyromegaly and other features of hyperthyroidism such as digital tremors, warm moist palms, tachycardia (110-120/min), blood pressure 140/68, eye signs such as exophthalmos, lid lag, staring look with cardiovascular, and other systemic examinations being normal. His thyroid function tests were suggestive of hyperthyroidism (T3 2.4 ng/ml, T4 19 μg/dl, and TSH 0.09 μIU/ml). 99mTc-pertechnetate scan showed a diffuse thyromegaly with increased tracer uptake. A CECT chest done (as a part of PUO workup) showed an anterior mediastinal mass (5.6 × 2.1 × 6.0 cm) with mild contrast enhancement, suggestive of a thymic mass [Figure 1]. In view of close proximity of the mediastinal mass to the great vessels and other important structures in mediastinum, a FNAC or biopsy was not attempted.

Figure 1

CECT scan chest of the patient showing a 5.6 × 2.1 × 6.0 cm mass in the anterior mediastinum suggestive of thymic hyperplasia

Patient was started on carbimazole 20 mg BD, propranolol 20 mg TDS, and supportive therapy. He gradually improved, became afebrile, gained 5 kg weight over the next 12 weeks and had gradual regression of clinical features of hyperthyroidism. His ATD dosage was titrated and continued. Repeat CECT scan chest at 12 weeks after initiation of ATD showed regression in the size of the mass (2.4 × 1.2 × 3.0 cm) [Figure 2]. Presently, the patient is clinically and biochemically euthyroid.

Figure 2

Repeat CECT scan chest of the patient after treatment with antithyroid drugs showing regression in size of the thymus (2.4 × 1.2 × 3.0 cm)

DISCUSSION

The association between Graves’ disease and thymic hyperplasia was first recognized in 1929 by Hammar.[3] Thymic involvement may range from microscopic abnormalities in the thymus consisting of medullary lymphoid follicles[4] to massive enlargement of the thymus.[56] The exact pathophysiology of thymic hyperplasia in Graves’ is not well understood. The thymic hyperplasia is more likely due to Graves’ disease. Earlier literature suggested that the hyperplastic thymus played an etiologic role in Graves’ disease as it does in myasthenia gravis by playing a central role in determining self versus non-self recognition by T cells.[7] However, most patients with Graves’ disease do not have obvious immune dysfunction except predisposition to autoimmunity. Murakami et al.[8] studied 23 untreated patients with Graves’ disease and 38 control subjects and showed the presence of thyrotropin receptor in non-neoplastic thymic tissue by polymerase chain reaction amplification and northern and western blot analysis indicating that thymic thyrotropin receptor may be involved in developing thymic hyperplasia in patients with Graves’ disease by serving as an autoantigen.

Treatment with antithyroid drugs (ATDs) can induce rapid, although often incomplete, thymic involution. Murakami et al.[8] studied thymic size and density in 23 untreated patients with Graves’ disease with use of computerized tomography. In comparison with 38 age-matched controls, both thymic size and density were higher in patients with Graves’ disease. After treatment with ATDs, both thymic size (852 ± 245 mm2 before and 402 ± 280 mm2 after treatment; P < 0.001) and density (9.1 ± 50.7 Hounsfield unit before and −35.5 ± 36.3 Hounsfield unit after treatment; P < 0.01) were significantly reduced.[9] The decrease in thymic size and density by ATD could be produced, partly due to decreased circulating thyroid hormone levels by ATD and also by immunosuppressive effects of the drugs.[9] Another study involving three patients with Graves’ disease and marked thymic enlargement showed a regression in thymic volumes by 72% and 78% in two of the three patients who presented for follow-up and whose initial volumes were 67, 81, and 54 cm.[10]

An association between thymic hyperplasia and Graves’ disease seems well established, but the precise pathophysiology of thymic hyperplasia in Graves’ disease has not yet been determined. The thymus does not appear to play an obvious etiologic role. However, treatment of Graves’ disease leads to regression of thymic hyperplasia as was seen in our patient. The other differential diagnosis of an anterior mediastinal mass which have to be differentiated from thymic mass are lymphomas, germ cell tumors, congenital cysts, intrathoracic thyroid tissue, and parathyroid lesions which may require histological diagnosis for a confirmation. About 91 cases of thymus hyperplasia and Graves’ disease association have been reported in the literature, of which about 20 were histologically confirmed. Among these 91 cases, 35 cases showed a thymic mass regression under medical treatment alone.[11] Accordingly, surgical procedures are most frequently unnecessary in such associations because of the thymic mass decrease incurred by ATD treatment. In our case too as the thymic enlargement showed a significant reduction in size with antithyroid drugs, any surgical procedure was not planned. It is important for the clinician to recognize this benign association between thymic hyperplasia and Graves’ disease, and its regression with ATD which can spare patients from a major surgical procedure.