HYPOKALEMIC PERIODIC PARALYSIS IN A PATIENT WITH EUTHYROID GRAVES DISEASE AND CELIAC DISEASE. Aman Rajpal, MD 1 ; Ajay Sood, MD 2

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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 HYPOKALEMIC PERIODIC PARALYSIS IN A PATIENT WITH EUTHYROID GRAVES DISEASE AND CELIAC DISEASE Aman Rajpal, MD 1 ; Ajay Sood, MD 2 From: 1 Endocrine Section, Medical Service, Louis Stokes Cleveland VA Medical Center and Case Western Reserve University, Cleveland, OH 44106, USA; 2 Endocrine Section, Medical Service, Sacramento VA Medical Center and University of California at Davis, Sacramento, CA Running title Thyrotoxic Periodic Paralysis Address correspondence to: Aman Rajpal, MD Endocrine Section, Medicine Service Louis Stokes Cleveland VA Medical Center East Blvd Cleveland, OH aman.rajpal@va.gov

2 Keywords Hypokalemia Paralysis Hyperthyroidism Graves Celiac Word count Abstract: 235, Text: 1796 The authors have nothing to declare

3 Abstract: Objective: Thyrotoxic periodic paralysis (TPP) is a sporadic form of hypokalemic periodic paralysis (HPP) that is most commonly seen in patients with Graves disease in association with acute thyrotoxicosis. A very few cases of HPP have been reported in patients with Graves disease when patient is euthyroid. Case Presentation: We describe a case of a 62 year-old Caucasian male with a history of Graves disease, who presented with acute progressive bilateral lower extremity weakness. He was found to have severe hypokalemia, with no evidence of diarrhea or increased urinary potassium excretion. He was diagnosed as having HPP. He remained clinically and biochemically euthyroid during the admission. There was no history of high-carbohydrate meal intake, intense exercise, recent steroid exposure or unusual stress. His symptoms improved gradually over the next 3-4 days with potassium supplementation. Nine months later, he progressed to overt hyperthyroidism and was treated with 25 mci of I-131 and following that he has been on levothyroxine replacement for post-ablative hypothyroidism. Other unusual features in this patient were hypocalcemia, hypomagnesemia and vitamin D deficiency during the acute presentation. Serum calcium and magnesium normalized 2 days after admission, while serum vitamin D continued to be low. He was later diagnosed to have celiac disease.

4 Conclusion: Our case adds a rare presentation of hypokalemic paralysis in a euthyroid patient with a known history of Graves disease with associated celiac disease, hypomagnesemia and hypocalcemia to the literature. Abbreviations; TPP = Thyrotoxic periodic paralysis; HPP = Hypokalemic periodic paralysis; TSH = Thyroid stimulating hormone; MMI = Methimazole; Free T4 = free thyroxine; Free T3 = free triiodothyronine; TSI = Thyroid stimulating immunoglobulin.

5 Introduction: Hypokalemic periodic paralysis (HPP) is a rare disorder characterized by episodic muscle weakness associated with hypokalemia (1). It can be familial (autosomal dominant inheritance) or associated with thyrotoxicosis, barium poisoning, renal tubular acidosis (RTA), primary hyperaldosteronism, licorice ingestion, or severe diarrhea. Thyrotoxic periodic paralysis (TPP) is a sporadic form of HPP that is seen in patients with thyrotoxicosis, most commonly Graves disease. TPP can also occur with subclinical thyrotoxicosis (2). Very few cases of HPP have been reported in patients with Graves disease while being euthyroid (3-6). We describe a case of a Caucasian male with a known history of Graves disease who presented with hypokalemic paralysis while he was euthyroid. He later developed overt hyperthyroidism. Case report: A 62 year-old male with history of Graves disease and testicular cancer (seminoma, in remission) was admitted to the hospital for acute progressive bilateral lower extremity weakness. He denied a family history of thyroid disorder, periodic paralysis or any autoimmune diseases. Graves disease was diagnosed 3 years ago when the patient had weight loss, tremors, suppressed TSH (< uiu/ml, normal: ), elevated TSI (670 %, normal: 0-139) and increased (33%) homogenous uptake on I-123 scan. He was treated with methimazole (MMI) and propranolol with significant clinical and biochemical improvement. After 2 years of treatment, MMI

6 was discontinued, and one month after discontinuing MMI, the patient was euthyroid. Two months after discontinuing MMI he had sudden onset of decreased proximal motor strength in both lower extremities, with severe hypokalemia (K+ 1.9 mmol/l, normal: 3.5-5), with no evidence of diarrhea or increased urinary potassium excretion (< 1 meq/l/day). Prior to admission, the patient was only on propranolol. A diagnosis of HPP was made. He was clinically and biochemically (TSH: 0.81 uiu/ml, free T4: 1.16 ng/dl (normal: ), free T3: 2.7 pg/ml (normal: 2-4.4) and TSI: 92%) euthyroid during the admission. There was no history of high-carbohydrate meal intake, intense exercise, recent steroid exposure or unusual stress. He was also found to have hypocalcemia (corrected serum calcium of 7.6 mg/dl, normal: ) and hypomagnesemia (serum magnesium of 1.2 mg/dl, normal: ). He had concurrent vitamin D levels of 14 ng/ml (normal: 30-75), phosphorus levels of 1.3 mg/dl (normal: ), and parathyroid hormone levels of 147 pg/ml (normal: 18-80), suggestive of vitamin D deficiency. Propranolol was continued, and with potassium supplementation his symptoms improved gradually over the next 3-4 days. During the hospital stay, he received calcium and magnesium supplementation, and started on vitamin D 50,000 units/week. His calcium and magnesium levels normalized two days after start of treatment, although his Vitamin D levels remained low. During the follow up visit 4 weeks later, his motor strength had improved significantly, with stable potassium levels while still on potassium supplementation. At that visit, he had suppressed TSH with normal free T4. Nine months after

7 discharge, the patient developed overt hyperthyroidism (TSH < 0.01 uiu/ml, free T ng/dl, free T3 5.2 pg/ml), with elevated TSI (898%), and was treated with 25 mci of I-131. Subsequently he has been on levothyroxine replacement for postablative hypothyroidism. Serum calcium and magnesium levels were normal without any supplementation. Vitamin D levels continued to be low despite significant supplementation. Tissue transglutaminase IgA antibody was positive and he was diagnosed to have celiac disease. He is currently on gluten free diet and continues to be on vitamin D supplementation. Discussion: We present an unusual case of HPP associated with hypocalcemia and hypomagnesemia in a euthyroid patient with a known history of Graves disease. Most of the cases of TPP have been reported in patients with Graves disease in association with acute thyrotoxicosis. But very few cases of HPP have been reported in patients with Graves disease when patient is euthyroid (3-6). TPP is a triad of acute hypokalemia (without total body potassium deficit), muscle paralysis, and thyrotoxicosis. TPP occurs predominantly in the Asian population. It is rare in North Americans, occurring in around % of thyrotoxic patients (7).

8 There is a male predominance with a male to female ratio ranging from 17:1 to 70:1 (8). The proposed mechanism of hypokalemia in TPP is that thyroid hormone promotes Na+/K+ ATPase mediated cellular uptake of potassium ions (9). The cell membrane Na+/K+ ATPase pump actively transports potassium from the extra to the intracellular compartment in muscles and the outward flow is controlled by K+ inward rectifying (Kir) channels. Although many conditions including thyrotoxicosis can cause the activation of Na+/K+ ATPase pump, but it does not lead to hypokalemia in majority of the patients. It is possibly because in most cases the increased outward potassium flow compensates the increased inward activity. Only if the outward potassium flow is affected as well, hypokalemia and subsequent paralysis will occur. Recent studies have shown that mutations in the KCNJ18 potassium channel genes are associated with TPP and predispose these patients to acute paralytic attacks (10). The KCNJ18 gene encodes the K+ inward rectifying (Kir2.6) channels and the loss of function mutations of the Kir2.6 ion channel leads to a decreased outflow of potassium from the intra-cellular compartments and together with the massive influx of potassium due to the increased Na+/K+-ATPase activity in the skeletal muscle cells leads to extracellular hypokalemia (11). These episodes usually occur in the morning or evening hours, precipitated by strenuous exercise, high carbohydrate meal, emotional stress, drugs such as insulin, steroids or diuretics. The paralysis may last a few hours to a few days (2). Thus, present literature indicates that a combination of genetic predisposition, thyrotoxicosis, and environmental factors causes TPP. Since

9 our patient was not overtly thyrotoxic and had no precipitating factors for TPP, therefore the reason for development of HPP remains unclear. Although TPP is commonly seen in patients with Graves disease with overt hyperthyroidism, thyrotoxic symptoms may be absent at the time of the attack of TPP in 10 25% of the patients (2-6). Misra et al showed that two-thirds of the patients with TPP had subclinical hyperthyroidism at the time of presentation (12). Hegde et al, described a 32-year-old Asian male who presented with acute onset weakness and hypokalemia with no previous history of thyroid disorder or any signs and symptoms suggestive of hyperthyroidism. He was subsequently diagnosed with Graves disease with subclinical hyperthyroidism (2). Our case had an unusual presentation in that although the patient had a known history of Graves disease, he was euthyroid at the time of the acute presentation of TPP. There have been very few reported cases of TPP in euthyroid state. Ferreiro et al reported a case of TPP six weeks after iodine-125 treatment. At the time of presentation, total T4 level was normal, with normal triiodothyronine uptake (26%), and low 24-hour radioactive iodine uptake (1.4%). In this report no free T4 or TSH levels were measured during the attack (3). Coates et al reported a patient with TPP that occurred 7 days after MMI was initiated for thyrotoxicosis. The patient was said to be clinically and biochemically euthyroid, but the T4 and triiodothyronine concentrations were not reported (4). Rone at al reported a patient who had an attack of TPP that occurred after resolution of the hyperthyroidism. The patient was started

10 on MMI two weeks prior to the episode but at the time of presentation, the patient had a normal total T4 and normal free thyroxine index with suppressed TSH levels (5). Cesur at al presented a review of case series of patients with TPP in a Turkish population (6). One of the patients mentioned in their literature review was euthyroid. Since the original article was in Turkish, we were unable to get details about the case. Compared to the patients in the literature, our patient is unusual in various aspects, such as the duration of being euthyroid, absence of current MMI use, no recent exposure to radioactive iodine and availability of all the laboratory results. Our patient was euthyroid for at least 3 months prior to the attack of TPP and was not on MMI for 2 months prior to the attack. Also there was no recent exposure to radioactive iodine, which can cause transient thyroiditis and can potentially precipitate an attack of TPP. Out of the four cases of HPP reported in euthyroid patients, two had reported TSH values. These cases were reported in 1987 and 1991, and it is not clear if TSH in these cases was measured using sensitive third generation TSH assay, which would give a better idea of functional thyroid status of the patient. The variability of TSI in our patient is also interesting. TSI was 672% at the time of initial diagnosis of Graves, and had decreased to 92 % during the acute episode of hypokalemic paralysis when patient was euthyroid, indicating likely decreased autoimmune phenomenon at the time of acute episode of hypokalemic paralysis. TSI increased to 898%, 4 months later before patient developed overt hyperthyroidism

11 again. Though it may not be of any diagnostic importance, but we thought the variability in TSI was an interesting feature. It is also noteworthy that the increase in TSI correlated with the functional thyroid status and not with occurrence of TPP. Our patient was also found to have associated hypomagnesemia during the acute attack of TPP. Crapo et al presented clinical and metabolic features of TPP in 19 patients and they found mild hypomagnesemia in all the patients during paralysis (13). This has been observed in several previous reports as well. Proposed mechanism is that endogenous catecholamines during stress may contribute to hypomagnesemia without depleting total body stores of magnesium by causing an intracellular shift in magnesium (14). Our patient also has associated hypocalcemia during the acute attack, which has not been reported previously. But given elevated parathyroid hormone and low vitamin D levels this could be partially attributed to severe vitamin D deficiency, although it corrected with improvement of muscle weakness without improvement in serum vitamin D levels. The suboptimal response to vitamin D replacement led to the investigation for possible poor absorption of vitamin D, and the diagnosis of celiac disease. There has been one reported case of celiac disease presenting as hypokalemic periodic paralysis that was not in celiac crisis (15). Co-occurrence of autoimmune thyroid disease and celiac disease is well known (16). Also underlying celiac disease could partly explain the long-term requirement of vitamin D replacement in this patient.

12 In conclusion, our case adds to the literature a rare presentation of hypokalemic paralysis in a euthyroid patient with a known history of Graves disease with associated celiac disease, hypomagnesemia and hypocalcemia. Although the most common cause of TPP is Graves disease with overt hyperthyroidism, the diagnosis of TPP should be considered in any patient presenting with acute paralysis and hypokalemia even if the clinical features of hyperthyroidism are absent, or in a patient with a known history of Graves disease who is currently euthyroid. Thus, we suggest that definition of TPP should also include euthyroid patients who have a history of Graves disease and present with HPP. A clinical suspicion of TPP will result in early diagnosis and appropriate management of this disorder.

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