Reclassifying TRAb-negative hyperthyroidism: Unveiling hyperthyroidism due to thyroid volume enlargement

1. Introduction

The thyroid gland, a butterfly-shaped endocrine gland located in the neck, plays an important role in producing hormones such as thyroxine (T4) and triiodothyronine (T3). These hormones are essential for regulating growth, metabolism, and various bodily functions that determine energy expenditure, including heart rate and body temperature. Thyroid disorders are highly prevalent, affecting approximately 5% of the population worldwide, making them the most common endocrine disorders after diabetes mellitus. In the United States alone, an estimated 20 million people are affected by some form of thyroid disorder, with women being five to eight times more likely to be diagnosed than men. Hyperthyroidism is a condition characterized by excessive production of thyroid hormones. It can result from various underlying causes, including toxic adenomas, thyroiditis, gestational factors, iodine excess, and Graves' disease. Autoimmune hyperthyroidism (Graves' or Basedow's disease) is the result of an autoimmune stimulatory activity to the thyroid gland and probably to some extrathyroid tissues like retrobulbar tissue [1]. is typically diagnosed by the presence of thyrotropin receptor antibodies (TRAb). SAbs tend to dominate in thyrotoxic GD. TRAbs are heterogeneous and may either have a stimulating effect (TSH-receptor stimulating antibody, TSAb) or an inhibitory effect (TSH-receptor blocking antibody, TBAb) on the TSH receptor. TSAbs tend to dominate in thyrotoxic GD. Binding to TSH receptors on thyroid follicular cells, TSAbs induce over-production of the thyroid hormones thyroxine (T4) and triiodothyronine (T3). The systemic effects of elevated T3/T4 manifest as an increased metabolic rate and its associated symptoms. The autoimmune process can damage tissue and cause inflammation of the orbit and skin, resulting in thyroid eye disease and the skin resulting in pretibial myxoedema [2].

1.2 Justification

A subset of patients presents with clinical features of hyperthyroidism that are consistent with Graves' disease but lack detectable thyroid-stimulating hormone receptor antibodies (TRAb), posing a diagnostic challenge. This subgroup, commonly referred to as "TRAb-negative Graves' disease" or "TRAb-negative hyperthyroidism," does not conform to the conventional diagnostic criteria for Graves' disease, which rely heavily on the presence of TRAb. This discrepancy highlights the need for a reevaluation and refinement of the classification of this distinct subgroup of patients.

This study aims to investigate the characteristics of this unique group and proposes renaming the condition as "Hyperthyroidism due to thyroid volume enlargement" to better reflect its underlying pathophysiology. The suggested terminology emphasizes that the disorder may be more strongly associated with thyroid gland enlargement, which leads to excessive thyroid hormone production, rather than the autoimmune mechanisms that define Graves' disease.

Furthermore, these patients typically lack the extrathyroidal manifestations commonly observed in Graves' disease, such as orbitopathy. They also exhibit significant variability in thyroid function test results and can often be managed effectively with minimal doses of antithyroid medications. Another notable distinction is the prolonged duration of disease progression before hyperthyroidism becomes clinically evident, compared to the more rapid onset observed in Graves' disease.

To further explore these differences, this study evaluates the relationship between thyroid gland size and patient body weight. The findings suggest that the increased thyroid volume, relative to body weight, may play a pivotal role in the pathogenesis of hyperthyroidism in this subgroup. These differences underscore the importance of unacceptable explanation for distinguishing of TRAb-negative hyperthyroidism from Graves' disease in clinical practice.

2. Methods

2.1. Study design

The study was a single-center prospective cross-sectional study that included 100 patients who underwent thyroid evaluation at the head and hand neck Surgery Department of the tertiary care facility located within the SMART Health Tower in Sulaimani, Iraq, over a period of 1 year. Patients included in the study met predefined inclusion criteria. Prior to participation, informed consent was obtained from all subjects. Data pertaining to demographic characteristics, complications, and imaging findings were collected utilizing Microsoft Excel software.

2.2. Setting

The study will include two groups of participants, the first group will be the case group and the second group will be the control group. The cases will be taken in a estimation time of 2 month (from 20/4/2024 to 20/6/2024) and for each case, one control counterpart will be chosen in the same geographical and socio-demographical background. The patients will be received and managed in the same settings.

2.3. Inclusion criteria

All patients with the clinical diagnosis of hyperthyroidism who were, Presented with a confirmed clinical diagnosis of hyperthyroidism. Tested negative for thyroid receptor antibodies (TRAB). Exhibited a large volume of the thyroid gland as confirmed by ultrasound (US) examination. Were considered candidates for inclusion.

2.4. Exclusion criteria

Several factors served to exclude potential participants from the study, Patients were diagnosed with thyroiditis, an inflammatory condition affecting the thyroid gland. Individuals who tested positive for thyroid receptor antibodies (TRAB), indicating a potential autoimmune cause of hyperthyroidism. Patients with a small thyroid gland size identified by ultrasound (US) examination, as this did not align with the specific focus of the study.

2.5. Data collection and analysis

Data will be received from the ques- tionnaire and the patient records. Microsoft Excel Version 2013 (Microsoft Corporation, Redmond, WA) will be used for data collection, entry, and coding. Statistical Package for the Social Sciences (SPSS) Version 25 (IBM Corp, Armonk, NY) will be used for conducting Data analysis. Continuous variables will be compared by the Student's t-test, and discrete variables will be analyzed using the χ2 test.

1.6. Follow Up

The typical duration of follow-up for patients who have undergone follow up ranges from one to two months up to 6 months. During this period, patients are consistently monitored through both clinical assessments, lab tests and radiological evaluations as part of regular follow-up protocols.

References:

1. Paunkovic N, Paunkovic J. The diagnostic criteria of Graves’ disease and especially the thyrotropin receptor antibody; our own experience. Hell J Nucl Med. 2007;10(2):89-94.

2. Matthews DC, Syed AA. The role of TSH receptor antibodies in the management of Graves' disease. European journal of internal medicine. 2011;22(3):213-6.