Spontaneous conversion of autoimmune hypothyroidism to Graves disease is a rare

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1 AACE Clinical Case Reports Rapid Electronic Articles in Press Rapid Electronic Articles in Press are preprinted manuscripts that have been reviewed and accepted for publication, but have yet to be edited, typeset and finalized. This version of the manuscript will be replaced with the final, published version after it has been published in the print edition of the journal. The final, published version may differ from this proof.. Case Report ACCR FROM FAMINE TO A FEAST: LITTLE ENDOGENOUS THYROXINE TO OVERPRODUCTION Amos Lal, MD 1 ; Nitin Trivedi, MD, FACE, FACP 2, George M Abraham, MD, MPH, FACP, FIDSA 1 Running Title: Little thyroxine to overproduction From: 1 Department of Medicine and 2 Division of Endocrinology and Metabolic Medicine, Saint Vincent Hospital, Worcester, MA Corresponding address: Nitin Trivedi, MD, FACP, FACE Saint Vincent Hospital 123 Summer Street, Worcester, MA Nitin.Trivedi@stvincenthospital.com ABSTRACT: Objective: Spontaneous conversion of autoimmune hypothyroidism to Graves disease is a rare occurrence. We present a case of antibody confirmed autoimmune hypothyroidism, where the

2 patient was on replacement therapy with levothyroxine for 8 years, had spontaneous conversion to Graves disease with positive thyrotropin receptor antibodies (TRAb). Methods/case presentation: A 79-year-old woman was evaluated for persistent fatigue following acute dermatomal herpes zoster. She had developed progressive tremor of the extremities and heat intolerance. Her other problems included Hashimoto s thyroiditis and vitiligo, diabetes mellitus, cerebrovascular disease, coronary artery disease, osteoporosis and hypercholesterolemia. Her medications included metformin, aspirin, lisinopril, atorvastatin, zoledronic acid and levothyroxine. Clinical examination was notable for healed lesions of herpes zoster and hand tremors. Results: Laboratory evaluation revealed T3 levels of 1.83 ( ng/ml), free T4 of 1.53 levels 1.53 ( ng/dl), thyroid stimulating hormone (TSH) ( mciu/ml). Of note, TRAb was positive at 5.37 ( IU/L). Radioactive iodine uptake scan was normal. Conclusion: TSBAb causes hypothyroidism whereas TSAb is responsible for Graves hyperthyroidism resulting from over activation of TSH receptors. Our patient was on stable dose of levothyroxine for 8 years without any complications. We hypothesize that the conversion of blocking to stimulating antibodies was induced by the stress of the herpes zoster infection. Factors that possibly increased her odds for this phenomenon included her gender, thyroid replacement therapy, advanced age and a background of autoimmune hypothyroidism. This case highlights

3 the critical need to recognize that this transition can occur, since it requires a reversal of treatment plans. Abbreviations: TRAb = thyrotropin receptor antibodies; TSH = thyroid stimulating hormone; TSBAb = TSHstimulation blocking antibody; TSAb = Thyroid stimulating antibody; TPOab = Thyroid peroxidase antibody; GD = Graves disease; HT = Hashimoto s thyroiditis; AITD = Autoimmune thyroid disease; BMI = Body mass index; T3 = Triiodothyronine; T4 = Tetraiodothyronine; AST = Aspartate aminotransferase; ALT = Alanine transaminase; HDL = High density lipoprotein; LDL = Low density lipoprotein; VLDL = Very low density lipoprotein; HbA1C = Glycated hemoglobin; HLA = Human leucocyte antigen; TEC = Thymic epithelial cells; FOXP3 = Forkhead box P3; CTLA4 = Cytotoxic T-lymphocyteassociated protein 4; PTPN22 = Protein tyrosine phosphatase, non-receptor type 22; MHC = Major histocompatibility complex. BACKGROUND Graves disease (GD) and Hashimoto s thyroiditis (HT) represents two ends of a spectrum of autoimmune thyroid diseases (AITD) [1]. Spontaneous conversion of HT with hypothyroidism to Graves disease with hyperthyroidism can rarely occur. We present a case of hypothyroidism due to HT who spontaneously converted to hyperthyroidism from GD after being on a stable dose of levothyroxine for 8 years. CASE PRESENTATION

4 A 79-year-old woman was evaluated in the office with persistent fatigue of 2 months duration following acute dermatomal herpes zoster. She had also noticed progressively worsening hand tremor and heat intolerance. She reported no neck pain or eye symptoms. Her medical problems, in addition to hypothyroidism due to HT for 8 years, included diabetes mellitus, cerebrovascular disease, coronary artery disease, osteoporosis, hypertension, vitiligo and hypercholesterolemia. Her medications included metformin, aspirin, lisinopril, atorvastatin and zoledronic acid. Her hypothyroidism was treated with a stable dose of levothyroxine 25 mcg daily for past 8 years and had no recent change in medications. She did not use any over-thecounter. She stopped using oral biotin 4 years before her current presentation. At the time of examination, she had normal blood pressure of 132/80 mm Hg, and was noted to have a heart rate of 76 beats per minute. She weighed 59 kilograms and had a BMI of 24.4 kg/m 2. Clinical examination was notable for healed lesions of herpes zoster in the thoracic region, a fine tremor of the outstretched hands. Examination of the neck revealed no goiter, bruit or tenderness of the thyroid gland. No lid lag or proptosis were noted on eye examination. Rest of her systemic examination was unremarkable. INVESTIGATIONS Laboratory evaluation revealed T3 levels of 1.83 ( ng/ml), free T4 of 1.53 ( ng/dl), thyroid stimulating hormone (TSH) ( mciu/ml). Other laboratory data including complete blood count and chemistry was unremarkable. Liver function tests were normal with a total protein of 7.3 g/dl ( ), albumin levels 4.4 g/dl ( ), AST levels were 22 (0-55 u/l), ALT levels were 22 (0-32 U/L), alkaline phosphate levels were 55 ( u/l) and total bilirubin levels were 0.3 mg/dl ( ). Ultrasound of the thyroid showed a diffusely heterogeneous thyroid gland without nodules. A thyrotropin receptor antibody titer was 5.37 (normal IU/L) and a 24-hour radioactive iodine uptake was 15% (10-35%). A

5 glycated hemoglobin (HbA1C) was 6.2 %. She also had a normal lipid profile with total cholesterol of 170 mg/dl ( ), triglyceride levels of 164 mg/dl (0-149), high density lipoprotein (HDL) levels of 40 mg/dl (40-59), low density lipoprotein (LDL) levels of 97 mg/dl (0-99) and very low density lipoprotein (VLDL) levels of 33 mg/dl (5-40). Unfortunately an HLA status was not evaluated for the patient. DIFFERENTIAL DIAGNOSIS Graves disease Hashitoxicosis Levothyroxine overdose Euthyroid sick syndrome Central hypothyroidism Assay artifact from biotin use TREATMENT In light of her abnormal clinical and laboratory findings, levothyroxine was promptly discontinued. Upon review of her records we noticed that initially the patient was started on 10 mg/d of methimazole and was subsequently tapered down. At the time of submission of this case report, the patient has been taking methimazole for 14 months. The decision to continue methimazole treatment beyond 1 year was based on the presence of thyrotropin receptor antibodies in high titers at one year of the initial diagnosis. The patient reported marked improvement in her symptoms in the 2 weeks following initiation of methimazole treatment.

6 At the time of her follow up visits her dose of methimazole was sequentially reduced to 2.5 mg daily and at her 12 months follow up she was taking 2.5 mg of methimazole once a day with normalization of her thyroid functions. Her thyroid function test repeated at 12 months revealed a normal free T4 of ng/dl ( ), normal T3 of 111 ng/dl (58-159) and normal TSH of 3.75 mciu/ml ( ). OUTCOME AND FOLLOW-UP Until her last follow up at 12 months of treatment the patient remained clinically and biochemically euthyroid with low dose methimazole (2.5 mg per day) and no requirements for beta-blockers. DISCUSSION GD and HT share similar pathophysiologic mechanism but different clinical manifestations. The auto-antibodies in GD and HT are different in these disorders; thyroid-stimulating hormone receptor antibody (TRAb) in GD and thyroid peroxidase antibody (TPOAb) in HT [2]. Interconversion of these disorders due to change in the type of antibody can rarely occur. Our patient was diagnosed with HT with hypothyroidism with laboratory values confirming elevated thyroid stimulating hormone (TSH) levels and elevated TPOab. During her treatment, she remained clinically and biochemically euthyroid on a stable dose of levothyroxine replacement for 8 years, before converting to GD with a positive thyrotropin receptor antibody. Spontaneous

7 conversion of autoimmune hypothyroidism to Graves disease is a rare occurrence and has been mostly reported as isolated cases or a small case series [3]. Spontaneous conversion of HT can occur within a few months to a few years. Cases have been described where the antibody conversion occurred even after a decade of hypothyroidism [4]. The switch from one antibody to the other triggers the change of thyroid functional status from hypothyroidism to hyperthyroidism and vice versa [5]. Both thyroid stimulating antibody (TSAb) and TSH stimulation blocking antibody (TSBAb) act on the TSH receptors. Thyroid stimulating antibody (TSAb) is responsible for Graves hyperthyroidism resulting from over activation of TSH receptors. Transition from hypothyroid state to GD is determined in such patients by factors such as presence of TSAb, activity of TSBAb and responsiveness of the thyroid gland to the stimulating antibodies [5]. Risk factors associated with such a shift in spectrum from hypothyroidism to hyperthyroidism include female sex, older age, prolonged treatment with levothyroxine and stress [6]. Our patient was being treated with a stable dose of levothyroxine for more than 8 years. The conversion of blocking to stimulating antibodies may have been induced by the stress of the herpes zoster infection. Although any kind of stress, either emotional (grief over the loss of a loved one) or physical (acute illness like in our case) can act as a trigger, it is postulated that viral infections can augment autoimmunity by triggering a nonspecific secretion of interleukin-2, or by encouraging MHC class II expression on thymic epithelial cells (TEC) [6, 7]. Studies have shown that the immune-regulatory genes that predispose to AITD (FOXP3, CD25, CD40, CTLA-4, and the HLA genes, PTPN22, among other emerging immunoregulatory genes), play an important role in the evolution of an effective immune response [8].

8 The findings in our patient is most consistent with Graves disease. Patients with euthyroid sick syndrome usually have low T3 along with or without low free T4 and modestly reduced TSH levels. The TSH level in our patient was markedly low. Hashitoxicosis, unlike our patient, is characterized by transient initial phase of hyperthyroidism followed by hypothyroidism [9, 10]. Hashitoxicosis is a possibility. However, absence of goiter, persistence of TRAB and continued need for methimazole treatment to maintain euthyroidism favors Graves' disease rather than Hashitoxicosis. Normal radioactive iodine uptake with suppressed TSH is considered inappropriately normal. Normally, the uptake of radioactive iodine is primarily driven by TSH. Thus, a subject with low TSH should have virtually negligible radioactive iodine uptake in the thyroid gland unless something else, such as thyrotropin receptor antibodies in our case, is driving the uptake. Low TSH from pituitary disease should be accompanied by low thyroid hormone levels and low radioactive iodine uptake. Finally, the patient responded nicely to methimazole treatment. We have followed the patient up to 12 months from her initial presentation with low TSH. She is currently stable on low dose methimazole. Her thyrotropin receptor antibodies titer after 9 months of methimazole treatment was 4.10 IU/L (normal ). However, her normal BMI and completely normal fasting lipid profile results negate the differential. Viral infections such as herpes zoster are known to trigger autoimmune thyroid disease particularly in genetically predisposed subjects, perhaps through the phenomenon of molecular mimicry between the thyroid antigens and viral proteins [11, 12]. Although the change in our patient s thyroid status was preceded by an episode of herpes zoster infection, her genetic predisposition is not entirely clear. HLA haplotyping, which was not performed in this patient, would have been useful in defining her genetic predisposition. Finally, a plausible hypothesis would be an overdose of exogenous levothyroxine. But there are no plausible

9 explanations as to why our patient who was on a stable dose of levothyroxine for over 8 years would suddenly have overdose of exogenous levothyroxine despite being on the same dose and no changes in other parameters or without introduction of any other drugs that may interact with levothyroxine. Eventually the prompt response that the patient showed in terms of resolution of her symptoms and her current continual requirement of low dose methimazole cemented our hypothesis. Potential factors that could have increased her odds for this phenomenon include her gender, thyroid replacement therapy, advanced age and a background of autoimmune hypothyroidism. This case highlights the critical need to recognize that such a transition can occur, since it may require an absolute reversal of therapy. Close monitoring is warranted with judicious testing for appropriate antibodies, especially for patients who present with change in symptomatology and have some of the above- mentioned risk factors. LEARNING POINTS/TAKE HOME MESSAGES Spontaneous conversion of Hashimoto s thyroiditis to Graves disease can occur at any time in the disease. In case there is change in symptomatology of the patient who has been stable on the treatment for a long time, it is prudent to consider this possibility, along with ruling out other causes like levothyroxine overdose. Any physical or emotional stress can be a trigger for change in auto-antibodies and thus the disease spectrum. This requires reversal of treatment strategy.

10 REFERENCES [1] Jacobson DL, Gange SJ, Rose NR, Graham NM. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clinical immunology and immunopathology. 1997;84: [2] Ramos-Levi AM, Marazuela M. Pathogenesis of thyroid autoimmune disease: the role of cellular mechanisms. Endocrinologia y nutricion : organo de la Sociedad Espanola de Endocrinologia y Nutricion. 2016;63: [3] Takasu N, Yamada T, Sato A, et al. Graves' disease following hypothyroidism due to Hashimoto's disease: studies of eight cases. Clinical endocrinology. 1990;33: [4] Steel NR, Bingle JP, Ramsay ID, Kendall-Taylor P. Myxoedema followed by TSAbinduced hyperthyroidism: report of 2 cases. Postgraduate medical journal. 1985;61: [5] McLachlan SM, Rapoport B. Thyrotropin-blocking autoantibodies and thyroidstimulating autoantibodies: potential mechanisms involved in the pendulum swinging from hypothyroidism to hyperthyroidism or vice versa. Thyroid : official journal of the American Thyroid Association. 2013;23: [6] Weetman AP. Graves' disease. The New England journal of medicine. 2000;343: [7] Weetman A, DeGroot LJ. Autoimmunity to the Thyroid Gland. In: De Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, et al., editors. Endotext. South Dartmouth (MA): MDText.com, Inc.; [8] Lee HJ, Li CW, Hammerstad SS, Stefan M, Tomer Y. Immunogenetics of autoimmune thyroid diseases: A comprehensive review. Journal of autoimmunity. 2015;64:82-90.

11 [9] Wasniewska M, Corrias A, Salerno M, et al. Outcomes of children with hashitoxicosis. Hormone research in paediatrics. 2012;77: [10] Unnikrishnan A. Hashitoxicosis: A clinical perspective. Thyroid Research and Practice. 2013;10:5-6. [11] Benvenga, S., et al. "Homologies of the thyroid sodium-iodide symporter with bacterial and viral proteins." J Endocrinol Invest. 1999; 22: [12] Benvenga, S. and F. Guarneri. Molecular mimicry and autoimmune thyroid disease. Rev Endocr Metab Disord. 2016;17: