Resistance to Anti-Thyroid Drugs in Graves’ Disease: Clinical-Biological Characteristics and Alternative Therapy in Tropical Area

Background: Resistance to anti-thyroid drugs (ATDs) is a rare entity recently described. We report two African observations in the treatment of Graves’ disease. Case 1: A 19-year-old Senegalese woman presented on admission with thyrotoxicosis syndrome associated with diffuse goitre and Grave’s orbitopathy. TSH levels were low (0.005 mIU/ml; N = 0.27 - 4.20) and fT4 elevated (60 pmol/L; N = 12 - 22]. Combination therapy with propranolol (40 mg/day) and carbimazole (starting dose of 45 mg/day and increased to 60 mg/day) was initiated. In view of the persistence of symptoms despite good therapeutic compliance, carbimazole was replaced by methimazole with an initial starting dose of 40 mg/day, followed by 60 mg/day. Despite the change in therapy, clinical symptoms of thyrotoxicosis persisted, and fT4 levels remained elevated. The patient was diagnosed with resistance to ATDs in Graves’ disease. Total thyroidectomy 1% Lugol’s solution. Conclusion: Resistance to ATDs complicates the management of Graves’ disease. Total thyroidectomy following preoperative preparation with Lugol’s solution and/or corticosteroids was shown to be success-ful.


Introduction
Graves' disease is an autoimmune disorder marked by the presence of thyroidstimulating hormone receptor antibody (TRAb) [1]. It is the most common cause of hyperthyroidism [1]. The prevalence of Graves' disease in Senegal is estimated to be approximately 4% [2].
The initial management of Graves' disease is based on the administration of an adequate dose of anti-thyroid drugs (ATDs). These molecules have been shown to be effective in restoring euthyroidism [3]. However, exceptional cases of resistance to ATS have been described during the management of Graves' disease [4] [5] [6]. Such cases are characterized by the persistence of thyrotoxicosis and hyperthyroidism in patients on an optimal dose of ATDs for at least 6 months with good patient compliance and at least one substitution of the ATD type. Resistance complicates the management of Graves' disease, especially in Africa, where access to other therapies is often difficult.
The present study describes two cases of resistance to ATDs during the management of Graves' disease at the Endocrinology department of Pikine Teaching Hospital. Clinical-biological characteristics and the alternative therapy used are presented.

Case 1
The first case was a 19-year-old Senegalese woman in preparatory class. She had progressive weight loss with a suppressed appetite, insomnia, and palpitations for 3 months. There was no medico-surgical pathology in the patients' personal history.
On admission, the patient's blood pressure was 140/80mmHg, heart rate 122 beats/minute, and body temperature 36.2˚C. Clinical examination revealed a WHO grade 2 goitre [7] associated with thrill and acquired bilateral orbitopathy. In view of the persistence of symptoms despite good therapeutic compliance, carbimazole was replaced by methimazole at an initial dose of 40 mg/day, followed by 60 mg/day. Despite the change in drug therapy, clinical symptoms of thyrotoxicosis persisted (palpitations, weight loss), and fT4 values remained elevated ( Figure 1).
The diagnosis of resistance to ATDs in Graves' disease was retained. Surgical treatment of total thyroidectomy was undertaken. ATD therapy was stopped, and Lugol's solution 1% was prescribed for 10 days. No intraoperative and postoperative complications were reported. Currently, the patient is on hormone replacement therapy (L-Thyroxine 150 ug/day).

Case 2
A 22-year-old woman was referred for continued management of Graves' disease that had progressed for 2 years. She presented peripheral hyperthyroidism associated with acquired orbitopathy and elevated TRAb (34 UI/mL; N < 1.75).
On admission, the patient's treatment included propranolol 80 mg/day and Carbimazole 80 mg/day. Treatment was ineffective, and thyrotoxicosis symptoms

Comments
ATDs have been used for the treatment of Graves' disease for several decades [3]. They are effective in achieving rapid euthyroidism, as well as a low risk of progressing to permanent hypothyroidism compared to other therapies. Therefore, ATDs are the first choice of treatment in Graves' disease [1] [3]. However, exceptional cases of resistance to ATDs have been described during the management of Graves' disease and are mainly resistant to methimazole [4] [5] [6].
In this study, we reported two new observations of resistance to ATDs. The patients were two young women that presented with Graves' disease and orbitopathy. The clinical-biological monitoring enabled the diagnosis of resistance to several ATDs, despite good patient compliance.
Indeed, clinical symptoms persisted, and fT4 levels were higher in the two patients after at least 6 months of treatment with carbimazole. Despite the substitution of carbimazole with methimazole or PTU, fT4 values remained elevated. Drug intake that interfered with fT4 values, such as amiodarone, were noted taken by the two patients.
TSH was blocked throughout the follow-up period. However, this observation has been described during the follow-up of Graves' disease, apart from resistance to ATDs [1].
The mechanisms behind resistance to ATS are poorly understood [8] [9]. The MDR-1 multidrug resistance gene, which is responsible for resistance to a wide variety of drugs in human cells, is potentially involved [10]. It is the result of a loss-of-function mutation in the P-pg glycoprotein gene involved in the transport of immunosuppressive drugs and chemotherapeutic agents [11]. In Graves' disease, elevated MDR-1 gene expression levels are associated with disease activ- TSHs valu (mUI/L) TSHs ity and treatment resistance [10]. However, testing for an MDR-1 mutation is not currently recommended and was not performed in the patients in this study. In addition, daily events are of major importance in the onset of Graves' disease, its flare-ups, and potentially the drug treatment failure [1]. The two patients in the present study were final class students with a pending major examination.
Recent studies demonstrated that low baseline thyroglobulin autoantibodies are associated with refractoriness of Graves' disease to ATD treatment [8] [9]. Therefore, they could serve as biomarkers to predict the failure of ATD treatment in such patients.
Alternative treatment for ATDs resistance is not codified. Generally, surgery following preoperative preparation is recommended. The risk of an acute thyrotoxic crisis, however, remains.
Total thyroidectomy following preoperative treatment using Lugol's solution, beta-blockers, and, in one case, corticosteroids, was the chosen therapy. In our experience, this regimen facilitated clinical-biological regression of hyperthyroidism without any specific per-or post-operative complications.
Other alternatives have been proposed in such cases, such as cholestyramine and plasma exchange for the rapid development of euthyroidism before surgery [6] [12] [13]. Furthermore, a herbal decoction of Anemarrhena Bounge is potentially effective in patients with resistance to ATDs and is a therapeutic avenue warranting future exploration [5].

Conclusion
Resistance to ATDs is a recently described rare entity. The main hypothesis proposed that explains this drug resistance is of genetic origin. In Graves' disease, the most common cause of hyperthyroidism, the occurrence of resistance to ATDs, complicates treatment, especially in Africa, where access to other therapies is difficult. Rapidly performed thyroid surgery supervised by sound preoperative preparation with Lugol's solution and/or corticosteroids has been successfully in the present study.