Unilateral Graves' Disease: The Lesser Known.

BACKGROUND: Here, we present a retrospective study conducted from 2009 to 2018, which showed the presence of unilateral uptake of radioactive tracer on 99mTc thyroid scintigraphy scan in 15 patients with Graves' disease.
MATERIALS AND METHODS: All these patients had either clinical features of Graves' disease or elevated thyroid hormone levels along with ultrasonographic features, showing either normal thyroid gland or diffuse thyroiditis. The scintigraphic features revealed increased uptake in one lobe of the thyroid gland with the other lobe being normal.
RESULTS: Of the 15 patients, 13 were females and two were males. The mean age of the patients was 47 years with standard deviation of 3.4 years (range 26-70 years). Eight of the 15 patients had increased uptake on the right lobe and seven had increased uptake in the left lobe.
CONCLUSION: This study shows that there exists an entity called unilateral Graves' disease which should be further evaluated.

Introduction

Graves’ disease is an autoimmune disorder involving thyroid gland. It is believed that Graves’ disease occurs due to circulating autoantibodies directed against thyroid-stimulating hormone (TSH) receptors on the thyroid gland, thus producing the stimulatory effects of TSH. The thyroid gland is generally enlarged or sometimes of the same size in Graves’ disease. Patients usually present with symptoms of hyperthyroidism such as weight loss, palpitations, sweating, and hyperdefecation.

On a 99mTc pertechnetate thyroid scan, the thyroid gland generally appears diffusely enlarged with homogenously increased radiotracer concentration. A symptomatic patient with elevated thyroid profile and increased uptake on 99mTc pertechnetate thyroid scan is usually considered diagnostic for Graves’ disease.

Unilateral uptake on a thyroid scan in a patient with Graves’ disease is a rare entity with less documented cases. It is a condition wherein the patient presents with typical Graves’ symptoms, sometimes with features of Graves’ ophthalmopathy and elevated thyroid hormones but radiotracer concentration being observed only in one lobe of the thyroid gland on scintigraphic evaluation. Although unilateral hemiagenesis of the thyroid gland, large autonomous functioning thyroid nodule in one lobe, and Plummer's disease could be the close differential diagnoses, a normal ultrasound scan or an ultrasound scan showing features of diffuse thyroiditis usually rules out them.

Here, we would like to present an observational study conducted in Sri Venkateswara Institute of Medical Sciences, Tirupati, India, where 15 cases of Graves’ disease with unilateral uptake on thyroid scan were detected over a period of 9 years (from 2009 to 2018).

Materials and Methods

It is a retrospective study performed in Sri Venkateswara Institute of Medical Sciences, Tirupati, India, between 2009 and 2018. Data of all the patients who underwent 99mTc thyroid scintigraphy in the Department of Nuclear Medicine were reviewed. These patients were later followed up for treatment either by reviewing hospital data or on telephonic conversation with the patients.

Inclusion criteria

Patients with either clinical features of hypothyroidism or biochemical evidence of elevated thyroid hormones

No history of prior thyroid gland dysfunction or treatment for hyperthyroidism or hypothyroidism

Ultrasound neck performed in the patients showing normal thyroid gland or features of diffuse thyroiditis. The ultrasound report was verified by a certified radiologist.

Exclusion criteria

Patients with a history of treatment for thyroid dysfunction

Patients with ultrasound documented nodules or anatomical asymmetry.

Results

Of all the patients who have undergone thyroid scintigraphic evaluation in the institute during that period, in 15 patients, 99mTc pertechnetate thyroid scintigraphy findings showed increased radiotracer concentration in single lobe of the thyroid gland. Of the 15 patients, 13 were females and two were males. The mean age of the patients was 47 years with standard deviation of 3.4 years (range 26–70 years). Eight of the 15 patients had increased uptake on the right lobe and seven had increased uptake in the left lobe.

Eight patients, later on follow-up, were maintained on antithyroid drugs and biochemically and symptomatically responded well to treatment. One patient, a 43-year-old female, underwent ablation with 10 mCi (37 MBq) of I-131. She attained euthyroid state 1 year after ablation with I-131. Follow-up could not be performed in six patients. Figure 1 shows 99mTc Thyroid scintigraphy image obtained after 20 minutes of administration of radiopahrmaceutical showing increased radiotracer concentration in left lobe with normal uptake in right lobe.

Figure 1

This is a static image obtained 20 minutes after administration of 99mTc pertechnetate showing increased radiotracer concentration in left lobe with normal uptake in right lobe. Ultrasonography of neck for this patient showed normal thyroid gland

Limitations of the study

Absence of thyrotropin receptor antibody test reports of the patients.

Discussion

Robert Graves, a distinguished Irish physician and prolific medical author, gave his name to an autoimmune disorder of the thyroid gland in the 1830s. The disease is generally characterized by hyperthyroidism due to circulating autoantibodies, but the whole spectrum of thyroid dysfunction may be found in these patients. Thyrotoxicosis is associated with thyroid eye disease frequently (both are required for the strict clinical diagnosis of Graves’ disease), but the latter can be mild and difficult to detect. In Graves’ disease, B- and T-lymphocyte-mediated autoimmunity is known to be directed at four well-known thyroid antigens: thyroglobulin, thyroid peroxidase, sodium iodide symporter, and thyrotropin receptor. However, it is the thyrotropin receptor that acts as the primary autoantigen of Graves’ disease and is responsible for the manifestation of hyperthyroidism.[12]

Involvement of only one lobe of the thyroid gland could not be explained by the diffuse autoimmune pathology of Graves’ disease. Unilateral Graves’ ophthalmopathy is however well reported. Side-to-side differences may be due to acquired conditions, e.g., by preceding unilateral bacterial or viral inflammation of the thyroid gland.[3] In some cases, retroviral sequences have been isolated from thyroidal tissue in patients with Graves’ disease.[4] However, the role of such infections has yet to be fully investigated.

The possible explanations for unilateral Graves’ disease could be as follows: Thyroid lobe is derived from different lobes of precursor cells. Each lobe appears to have differential sensitivity to TSH stimulation, as evident from the development of multinodular goiter in longstanding cases of nontoxic goiter. It seems that the clonal heterogeneity exists a priori, i.e., even before any pathology exists in the thyroid gland. This clonal heterogeneity possibly extends to involve three aspects.

Differential expression of antigens triggers T-cell responses. In Graves’ disease, the majority of the autoimmune response is due to locally infiltrating B-lymphocytes, accumulating in the adjacent interstitium, as evident by the massive decline in anti-TSH antibody levels after surgery. The local infiltration of B-cells is stimulated by a prior T-cell-mediated mechanism that is based on recognition of T-cell antigen by the CD4 T-helper cells. Interestingly, the T-cell recognizes a primary sequence of 10–14 amino acid sequences on the antigen as a stimulating epitope. However, once triggered, the T-cells recruit a variety of cytokines such as IL-4, IL-5, and IL-10. These trigger the locally infiltrated B-cells to be converted to plasma cells. These plasma cells recognize the tertiary structure of a large part of the TSH receptor. It is possible that the original 10–14 amino acid sequences that trigger the T-cell response may be differently expressed in the two lobes

Differential expression and function of iodine uptake mechanism like Na/I symporter

Differences in growth and activity in response to TSH receptor stimulation as seen in different parts of a well-established multinodular goiter.

Apart from these possibilities, the occurrence of a mutation anywhere in the signaling pathway of TSH receptor involving only a part of the gland cannot be ruled out.

Conclusion

The incidence of unilateral Graves’ disease among all the patients with Graves’ disease may be minimal and most of the times may not alter the management of the patients. However, the reason for such condition to occur has to be evaluated, and it questions the established autoimmune pathology of the disease.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.