From Deficit to Excess: A Rare Case of Hypothyroidism Transitioned to Graves Thyrotoxicosis

Abstract

Autoimmune thyroid diseases such as Hashimoto’s thyroiditis and Graves’ disease represent two ends of a dynamic immunological spectrum. While hypothyroidism typically follows Graves’ thyrotoxicosis due to disease progression or treatment, the reverse transition from hypothyroidism to hyperthyroidism is exceedingly rare and poses diagnostic and therapeutic challenges. We report a case of a 47-year-old female with a known history of hypothyroidism, previously managed with levothyroxine, who presented with unexplained weight loss and symptoms suggestive of hyperthyroidism. Laboratory investigations revealed suppressed TSH and elevated free T3 and T4 levels, along with a positive TSH receptor antibody (TRAb) titer. A thyroid uptake scan confirmed the diagnosis of Graves’ thyrotoxicosis. The patient was treated with methimazole and propranolol regimen, and subsequently prepared for radioiodine therapy. This case underscores the importance of recognizing autoimmune thyroid disease as a spectrum that may evolve over time. Shifts in thyroid function, driven by a changing balance of thyroid-stimulating (TSAb) and blocking (TBAb) antibodies, can result in transitions between hypothyroid and hyperthyroid states. Factors such as levothyroxine therapy and immune modulation may influence this transition. The conversion from hypothyroidism to Graves’ hyperthyroidism, though rare, is a clinically significant phenomenon. Routine monitoring, awareness of atypical presentations, and individualized management strategies are essential. Further research is needed to understand the immunological mechanisms underlying such transitions and to develop predictive tools for early detection.

Keywords

Introduction

Graves’ disease and Hashimoto’s thyroiditis represent the two most prevalent autoimmune thyroid disorders, with a significantly higher incidence observed in females compared to males. [1] The development of hypothyroidism from Graves thyrotoxicosis is common. But the transition of Graves thyrotoxicosis after a period of hypothyroidism is very rare phenomenon, however, it has garnered growing recognition in recent medical literature. [1,2]

Joplin and Fraser were the first to report this occurrence in 1959. [3] Subsequently, Doniach et al. [4] also reported a similar case in 1960 followed by few others including Gavras and Thomson. [5] Thyroid-stimulating hormone receptor antibodies (TRAbs) play a crucial role in this alternating disease pattern. TRAbs are of two types: thyroid-stimulating antibodies (TSAb) and TSH receptor-blocking antibodies (TBAb) possess both stimulatory and inhibitory effects respectively, which can influence whether a person experiences a hyperthyroid or hypothyroid state. [6] The etiology is multifaceted, with a pathogenesis that remains incompletely elucidated. It is recognized that an interplay of environmental, infections, hormonal, and genetic variables significantly influences the disease process.[7]

Graves’ disease is typically managed using antithyroid drugs, including carbimazole, methimazole, and propylthiouracil. However, these drugs can lead to various side effects including pancytopenia and agranulocytosis. In spite of well-documented incidence and management of agranulocytosis, there is lack of evidence-based guidelines. In a recent study, using Lugol’s solution in combination with beta blockers was an effective approach to prepare patients with Graves’ disease for thyroidectomy. [2]

CASE PRESENTATION:

A 47-year-old female presented to the outpatient department with primary complaints of unexplained weight loss. She was a known case of hypertension and hypothyroidism, for which she had been prescribed levothyroxine therapy approximately five years prior. At the time of evaluation, she was not on any thyroid medication.

On clinical examination, her vitals were stable: blood pressure 120/84 mmHg, pulse rate 84 /minute. Physical examination of neck revealed a mild, diffuse thyromegaly without tenderness. Comprehensive laboratory investigations demonstrated supressed TSH levels at 0.008 μIU/mL, elevated free thyroxine (T4) at 1.81ng/dL, and elevated free triiodothyronine (T3) at 5.24 pg/mL. Serum calcium was within normal limits 9.8 mg/dL. TSH receptor antibody (TRAb/TSI) 2.36 IU/L strongly suggesting autoimmune thyroid stimulation.

A thyroid uptake scan revealed asymmetrical enlarged thyroid gland, with the left lobe appearing larger than the right with diffusely increased radiotracer uptake in both lobes. Overall thyroid radioiodine uptake was 1.2%, within normal physiological range. The thyroid to parathyroid ratio was noted to be 3:1 and suggestive of diffuse toxic goitre. These findings supported the definitive diagnosis of Graves Thyrotoxicosis.

The patient was initiated on propranolol 40mg postprandially to manage adrenergic symptoms along with methimazole 10 mg once daily for hyperthyroidism and advised radioiodine therapy subsequently. The patient was also counselled regarding the potential adverse effects of methimazole, including fever, rashes, sore throat and was advised to discontinue methimazole 4 days prior to planned radioiodine therapy.

This case underscores the importance of maintaining a high index of suspicion for evolving thyroid dysfunction in patients with a history of hypothyroidism, particularly in the context of autoimmune thyroid disease, where a transition to hyperthyroid states such as Graves' disease, although uncommon, may occur.

DISCUSSION:

This case highlights a rare but increasingly recognized phenomenon: the transition from hypothyroidism to hyperthyroidism, specifically to Graves' thyrotoxicosis. Autoimmune thyroid disorders, including Hashimoto’s thyroiditis and Graves’ disease, represent a dynamic spectrum of immune dysregulation rather than fixed, isolated conditions. In most clinical scenarios, Hashimoto’s thyroiditis leads to permanent hypothyroidism, while Graves’ disease causes sustained hyperthyroidism. While progression from hyperthyroid states such as Graves’ thyrotoxicosis to hypothyroidism is commonly observed often as a result of disease progression, radioiodine therapy, or antithyroid drug use, the reverse transition is distinctly uncommon. However, a switch between these states especially from a hypothyroid to hyperthyroid profile presents both diagnostic and therapeutic challenges. Nevertheless, several case reports and small studies have described similar occurrences, suggesting the need for greater awareness and understanding of this atypical presentation.

Our patient, with a prior diagnosis of hypothyroidism managed on levothyroxine, later presented with signs of hyperthyroidism, confirmed biochemically and supported by imaging and serological findings, notably a positive TSH receptor antibody (TRAb). This case adds to a growing body of evidence suggesting that changes in the dominant activity of TRAbs either stimulating or blocking can drive shifts in thyroid function. The interplay of TSAb (thyroid-stimulating antibodies) and TBAb (thyroid-blocking antibodies) is central to this pathophysiological transformation.

In both autoimmune hypothyroidism and Graves' disease, genetic predisposition constitutes a critical determinant. [7] Graves' disease typically presents with thyroid-stimulating antibodies (TSAb); however, it is now understood that both TSAb and thyroid-blocking antibodies (TBAb) may be present simultaneously. [11] The prevailing theory suggests that the relative levels of these antibodies, along with the thyroid gland's sensitivity to TSAb, play a key role in determining whether the patient presents with hypothyroidism or hyperthyroidism.[12] Multiple mechanisms have been proposed to explain this conversion. One prominent hypothesis involves a shift in the balance between different thyroid-stimulating hormone receptor antibodies (TRAb), specifically from thyroid-stimulation blocking antibodies (TBAb) to thyroid-stimulating antibodies (TSAb). This shift can trigger hyperthyroidism as TSAb stimulate the thyroid gland, leading to excessive hormone production.[7] Another theory suggests autoimmune tissue damage cause hypothyroidism, may later undergo repair and produce TSAb stimulation leading to the emergence of hyperthyroidism. [8] Thyroxine therapy may enhance TSAb activity or trigger its production, regardless of TBAb presence. This may result from increased serum T4 promoting immunostimulatory molecule expression or a shift in dominance from TBAb to TSAb, potentially influenced by antithyroid-induced suppression of autoantibodies which in severe circumstances may cause hypothyroid patients to acquire hyperthyroidism. [9,10]

A reporter mentioned the likelihood of covid vaccine induced such a reaction in the body and specifically affected the thyroid gland is considerable. This is supported not only by established causal associations but also by several reported instances demonstrating the vaccine’s potential to provoke responses at the injection site (topical), within various organs including the thyroid (local), as well as throughout the entire body (systemic). [13] But cannot be determined in this case, as the vaccination was administered two years ago. Additionally, it is hypothesized that people who are genetically predisposed might need an outside stimulus, like infection or neck radiation, to transition from autoimmune hypothyroidism to Graves' illness, which could disrupt the immune balance. [14,15]

Importantly, clinicians should remain vigilant in patients with a history of thyroid disease, even if they appear stable on thyroid hormone replacement. Unexplained weight loss, palpitations, or signs of increased metabolism in such individuals warrant a thorough re-evaluation, including repeat thyroid function tests and antibody profiling. Early identification of this transition is crucial, as inappropriate continuation of levothyroxine therapy in the presence of emerging hyperthyroidism may exacerbate symptoms and delay proper treatment.

Management of Graves’ disease in this context should follow established protocols, incorporating symptom control with beta-blockers and antithyroid medications. Our patient responded well to methimazole and propranolol and was appropriately prepared for definitive radioiodine therapy. Educating and closely monitoring patients for potential side effects of antithyroid medications is essential, particularly for rare yet serious adverse effects such as agranulocytosis. The use of Lugol’s iodine as preoperative preparation, as suggested in recent studies, may be considered in selected cases, especially when surgical intervention is planned. In this case, a careful integration of clinical, biochemical, and radiological data enabled prompt diagnosis and initiation of appropriate treatment.

CONCLUSION:

This case illustrates the complexity and variability of autoimmune thyroid disease. Although the transition from hypothyroidism to Graves’ hyperthyroidism is rare, it is a clinically significant event that requires careful attention. A high index of suspicion, routine monitoring of thyroid function test, and a comprehensive understanding of autoimmune pathophysiology are essential for timely diagnosis and effective management. Ultimately, personalized care and ongoing follow-up are key to ensuring optimal outcomes in such evolving endocrine disorders. Further research is warranted to elucidate the immunological triggers underlying this transition and to develop predictive markers for such atypical disease courses.

REFERENCES

1. Ahmad E, Hafeez K, Arshad MF, Isuga J, Vrettos A. Hypothyroidism conversion to hyperthyroidism: it’s never too late. Endocrinol Diabetes Metab Case Rep. 2018;2018. https://dx.doi.org/10.1530/EDM-18-0047
2. Clifford L, Wakil A. Conversion of primary hypothyroidism to hyperthyroidism: A case report. J ASEAN Fed Endocr Soc. 2018;33(2):190–3. https://dx.doi.org/10.15605/jafes.033.02.12
3. Joplin GF, Fraser R. Thyrotoxicosis developing in recurrent nodular goitre with focal thyroiditis. Proc R Soc Med. 1959;52(3):177–8. http://dx.doi.org/10.1177/003591575905200310
4. Doniach D, Hudson RV, Roitt IM. Human auto-immune thyroiditis: clinical studies. Br Med J. 1960;1(5170):365–73. https://www.bmj.com/content/1/5170/365
5. Gavras I, Thomson JA. Late thyrotoxicosis complicating autoimmune thyroiditis. Eur J Endocrinol. 1972;69(1):41–6. https://dx.doi.org/10.1530/acta.0.0690041
6. Watari J, Jassil N. Conversion of hypothyroidism to hyperthyroidism: A rare clinical phenomenon. AACE Clin Case Rep. 2020;6(5):e279–81. https://dx.doi.org/10.4158/ACCR-2020-0076
7. Furqan S, Haque N-U, Islam N. Conversion of autoimmune hypothyroidism to hyperthyroidism. BMC Res Notes. 2014;7(1):489. Available from: https://dx.doi.org/10.1186/1756-0500-7-489
8. Irvine WJ, Lamberg BA, Cullen DR, Gordin R. Primary hypothyroidism preceding thyrotoxicosis: a report of 2 cases and a review of the literature. J Clin Lab Immunol. 1979;2(4):349–52.
9. Yamasaki H, Takeda K, Nakauchi Y, Suehiro T, Hashimoto K. Hypothyroidism preceding hyperthyroidism in a patient with continuously positive thyroid stimulating antibody. Intern Med. 1995;34(4):247–50. https://www.jstage.jst.go.jp/article/internalmedicine1992/34/4/34_4_247/_article
10. McLachlan SM, Rapoport B. Thyrotropin-blocking autoantibodies and thyroid-stimulating autoantibodies: potential mechanisms involved in the pendulum swinging from hypothyroidism to hyperthyroidism or vice versa. Thyroid. 2013;23(1):14–24. https://dx.doi.org/10.1089/thy.2012.0374
11. Diana T, Krause J, Olivo PD, König J, Kanitz M, Decallonne B, et al. Prevalence and clinical relevance of thyroid stimulating hormone receptor-blocking antibodies in autoimmune thyroid disease. Clin Exp Immunol. 2017;189(3):304–9. https://dx.doi.org/10.1111/cei.12980
12. Takasu N, Yamada T, Sato A, Nakagawa M, Komiya I, Nagasawa Y, et al. Graves’ disease following hypothyroidism due to Hashimoto’s disease: studies of eight cases. Clin Endocrinol (Oxf). 1990;33(6):687–98. https://dx.doi.org/10.1111/j.1365-2265.1990.tb03906.x
13. Ushakov AV. Conversion from hypothyroidism to hyperthyroidism and back after anti-SARS-CoV-2 vaccination. J Endocrinol Metab. 2022;12(6):202–8. https://www.jofem.org/index.php/jofem/article/view/833/284284600
14. Lewandowski K, D?browska K, Makarewicz J, Lewi?ski A. Pendulum swings from hypo- to hyperthyroidism: thyrotoxicosis after severe hypothyroidism following neck irradiation in a patient with a history of Hodgkin’s lymphoma. Thyroid Res. 2016;9(1):1. https://dx.doi.org/10.1186/s13044-016-0030-1
15. Al-Sharafi BA, Khardori R. Hyperthyroidism after hypothyroidism. South Med J. 2000;93(7):703–7. https://dx.doi.org/10.1097/00007611-200007000-00013