Elevated Total T4 Research Articles

FRI473 Central Hypothyroidism Following Neonatal Graves Presentation

Abstract Disclosure: E. Metzinger: None. K. Halpin: None. Background: Neonatal Graves’ disease is a rare disorder of neonatal autoimmune hyperthyroidism secondary to the transplacental passage of thyroid-stimulating hormone receptor antibodies. Although neonatal Graves’ disease is transient, it is associated with cardiac dysfunction, intrauterine growth restriction, prematurity, craniosynostosis, and developmental delay and can be life-threatening. Additionally, infants with neonatal Graves’ disease can rarely present with primary or central hypothyroidism later in infancy or childhood. This is suspected to be due to the disruption in the hypothalamic-pituitary-thyroid axis or development of the thyroid gland. Clinical Case: Here we describe a case of neonatal Graves’ disease that has been complicated by persistent central hypothyroidism requiring levothyroxine treatment. This was a preterm infant with tachycardia, biventricular heart failure, and hepatomegaly who was transferred to a higher level of care NICU for cardiac and respiratory failure. Pregnancy was complicated by history of maternal Graves’ disease status post radioiodine ablation. Maternal TRAB and thyroid levels were unavailable. Initial thyroid studies on DOL 1 were notable for suppressed TSH of <0.02mcIU/mL, elevated free T4 6.9ng/dL, and elevated total T4 >24.9mcg/dL. Total T3 was normal at 161ng/dL (50-452ng/dL) on DOL 2, and TSI was elevated at 4.8 (TSI Index, normal </= 1.3) on DOL 3. For neonatal thyrotoxicosis, the infant was treated with methimazole, potassium iodide (KI), propranolol, and hydrocortisone. Hydrocortisone was discontinued as the infant clinically improved, and KI was discontinued after 1 week. TFTs were closely followed during admission and methimazole dosing was adjusted as needed. He was discharged from the NICU on DOL 19 on methimazole and propranolol with close outpatient lab monitoring and follow-up. Propranolol was discontinued by 1.5 months of life, and methimazole was discontinued by 2 months of life as TFTs normalized. TSI was negative by four months of life. TSH remained low with decreasing free T4 levels. Ultimately, he was started on levothyroxine at 8.5mcg/kg/day at 2.5 months of age for central hypothyroidism. At that time, TSH was 0.06mcICU/mL and FT4 was 0.7ng/dL. TSH remained low through the first 14 months of treatment with normal free T4 levels on levothyroxine. He has been continued on levothyroxine (average 20mcg/day). Conclusion: This case highlights the severity of neonatal Graves’ disease and the possibility of the subsequent development and persistence of central hypothyroidism following neonatal Graves’ diagnosis despite the resolution of hyperthyroidism and normalization of TSI antibody. Due to the risk of the development of hypothyroidism, it may be worthwhile to continue to trend TSH and FT4 to ensure that the infant has not developed hypothyroidism. Presentation: Friday, June 16, 2023

Abstract #1406613: Recurrent Thyroiditis in a Patient with Multiple sclerosis on Natalizumab

Thyroiditis, or self-limiting inflammation of the thyroid gland consists of 3 phases: hyperthyroidism, from release of hormone from damaged cells; hypothyroidism, when thyroid stores are depleted and euthyroidism with restoration of thyroid function. Etiology can include infectious, drug-induced or autoimmune causes such as multiple sclerosis (MS). In fact, 20-25% of untreated MS patients have autoimmune thyroiditis [1]. Moreover, drugs used to treat MS such as alemtuzumab and interferon have been reported to cause thyroid disease [2]. A 42-year-old female with MS on natalizumab for 10 years presented with right sided neck pain radiating to her jaw for 3 months and difficulty swallowing. Family history was pertinent for hypothyroidism in her father, and MS in her brother. She was exposed to nuclear radiation at age 3 from the Chernobyl disaster. On presentation, vital signs and physical exam were unremarkable. Thyroid ultrasound noted an ill-defined 4.2X1.3X1.9 cm hypoechoic nodule in the right mid-pole. Fine needle aspiration of the nodule showed subacute granulomatous thyroiditis (SAH). Labs showed TSH 0.02mIU/L [0.4-4.5], FT4 1.5ng/dL [0.8-1.8] and elevated total T3 204ng/dL [76-181]. TSI< 89 [140%]. Naproxen was given for pain control. Repeat labs 1 month later showed TSH 0.83mIU/L, FT4 1.1 ng/dL and total T3 196ng/dL, consistent with resolution of thyroiditis and clinically correlated with resolution of her pain. However, a month later she presented with worsening left sided neck pain and left thyromegaly associated with speech difficulty, diaphoresis, and constipation. Repeat thyroid ultrasound showed decreased size of right thyroid nodule 1.1X1.1X0.9cm and findings consistent with thyroiditis. She was treated with prednisone with complete resolution of symptoms. Labs post treatment showed elevated TSH 6.01mIU/L, total T3 106ng/dL, and FT4 0.8ng/dL consistent with the recovery phase of thyroiditis. Anti-TPO antibody level was < 1 [< 9 IU/mL]. Labs 1 month later showed normal TSH and FT4 levels. Natalizumab, a humanized monoclonal antibody commonly used to treat MS, has rarely been associated with thyroid disease. Alterations in thyroid function are thought to be due to direct toxicity on the thyroid, its blood supply or indirectly mediated by the immune system [2]. Although MS can be associated with thyroiditis, our patient did not present with the typical pattern of thyroiditis. Instead, she reported symptoms consistent with inflammation of one lobe of thyroid followed by resolution, and thereafter developed inflammation and pain of the other lobe, raising suspicion of potential involvement of natalizumab due to her atypical presentation.

ODP527 To Treat or Not to Treat Pembrolizumab-Induced Thyroiditis: Using Common Terminology Criteria for Adverse Events as a Decision-Making Aid

Abstract Introduction Programmed cell death-1 (PD-1) checkpoint inhibitors are immunotherapeutic agents that are used to treat advanced malignancies including breast cancer. The adverse effects of these medications include thyroid and pituitary dysfunction and may be treated with glucocorticoids, which may cause steroid-induced effects such as hyperglycemia, osteoporosis, and adrenal suppression. The Common Terminology Criteria for Adverse Events (CTCAE) widely used by oncologists for management can support treatment decisions by endocrinologists in patients undergoing treatment with PD-1 checkpoint inhibitors. Case Description A 42-year-old female with stage IIIc high-grade triple negative left breast invasive ductal carcinoma was started on pembrolizumab immunotherapy (PD-1 inhibitor). Prior to starting treatment, the patient's thyroid function tests were normal: free T4 0.93 ng/dL (normal range [NR] 0.89-1.76 ng/dL) and thyroid-stimulating hormone (TSH) 1.42 uIU/mL (NR 0.55-4.78 uIU/mL). Two weeks later, she developed heat intolerance, diarrhea, weight loss, and dysphagia. At that time, thyroid tests were consistent with thyrotoxicosis with elevated total T3 644.6 ng/dL (NR 60-180 ng/dL) and totalT4 &amp;gt;12. 00 ng/dL with suppressed TSH 0. 01 uIU/mL. Despite negative TSH receptor antibody and thyroid-stimulating immunoglobulin, CT scan of the neck showed diffuse enlargement of the thyroid gland and thickening of the extraocular muscles. On physical examination she had mild exophthalmos. The etiology of thyrotoxicosis was initially thought to be Graves’ disease, but thyroiditis could not be ruled out. Treatment with methimazole and beta blockers was initiated. Three weeks after methimazole was started, her symptoms improved significantly, with repeat thyroid function tests: TSH 3.64 uIU/mL and free T4 1.29 ng/dL. Methimazole was held. Four weeks later, the second dose of pembrolizumab was administered. Later that day, repeat thyroid function tests showed high TSH 53.12 uIU/ml, and low T4 0.55 ng/dL with negative thyroid-stimulating immunoglobulin and thyroid peroxidase antibodies, consistent with thyroiditis. Endocrinology and Oncology teams discussed the CTCAE determining that the severity of thyroiditis was grade 2 (moderate symptoms, able to perform activities of daily living, TSH persistently above 10 uIU/L). Pembrolizumab was continued and hypothyroidism was treated with levothyroxine. Discussion CTCAE is used by oncologists to aid in treatment decisions in patients treated with PD-1 inhibitors. Endocrinologists should consider using the CTCAE grading (severity) scale for each adverse event. Adoption and utilization of the CTACE severity scale by endocrinologists may lead to a more standardized and systematic approach for treatment of thyroid disorders associated with PD-1 inhibitor immunotherapy Presentation: No date and time listed

ODP501 New-Onset Graves’ Disease in a Patient with Recent Diagnosis of Covid-19 Infection

Abstract Background Thyroid disorders have been described in patients with Covid-19 infection. Although thyrotoxicosis secondary to thyroiditis is mostly reported in several publications worldwide in patients infected with Covid-19, new-onset Graves’ disease is rarely reported. Clinical Case A 41-year-old female without significant past medical history presented to emergency room with nausea, vomiting, palpitations and syncope. She was diagnosed with COVID-19 infection five days prior to her presentation. On admission, patient was normotensive, tachycardic with heart rate of 135 beats/min, and oxygen saturation &amp;gt;90% on room air. Thyroid exam was unremarkable. Initial labs showed suppressed TSH, elevated free T4 of 2.58 ng/dL (0.76–1.70 ng/dL) and elevated total T3 of 210 ng/dL (80–175 ng/dL). The computed tomography pulmonary angiogram (CTPE) was negative for pulmonary embolism. Transthoracic echocardiogram (TTE) showed moderate cardiac effusion without tamponade. Patient had no prior history of thyroid disease, but her mother had hypothyroidism. With Burch-Wartofsky score of 50, treatment for thyroid storm was initiated: Hydrocortisone, propranolol, and propylthiouracil (PTU), followed by cholestyramine, and super saturated potassium iodide (SSKI). Shortly after, patient developed hypotension requiring norepinephrine infusion and transfer to intensive care unit. Repeat TTE showed ejection fraction of 50%, moderate pericardial effusion without tamponade, and global hypokinesis suggestive of myocarditis. Propranolol was held. Although patient's blood pressure improved overnight, patient developed shock liver with AST elevated at 4,095 IU/L (8-30 IU/L), ALT at 2,837 IU/L (&amp;lt;35 IU/L), and total bilirubin at 1.6 mg/dl (0.2-1.2 mg/dl) compared to normal values on admission. PTU was discontinued after two doses due to elevated liver enzymes. Thyroid scan showed diffuse mildly increased radiotracer uptake suggestive of autoimmune thyroid disease. Thyroid stimulating immunoglobulin (TSI) was elevated at 6.5 IU/L (&amp;lt;0.55IU/L) with thyrotropin receptor antibody (TRAb) of 8.39 IU/L (0. 00 - 1.75 IU/L) suggestive of Graves’ disease. On discharge, patient was asymptomatic. At outpatient follow up, patient had improvement in liver enzymes and mild hyperthyroidism, methimazole was started with the plan for close monitoring of liver enzymes and thyroid function tests. Conclusion New-onset Graves’ disease can occur in the setting of Covid-19 infection. It is crucial to report this type of cases to gain more insights in the exact relationship between thyroid disease and Covid-19 infection. Physicians should be aware of the possibility of Graves’ disease in addition to thyroiditis in the setting of thyrotoxicosis and Covid-19 infection. Making the right diagnosis is essential as treatment and course of disease are very different. Presentation: No date and time listed

Abstract 117: Uncommon presentation of a common disease

Background: Autoimmune thyroid disorders, particularly Graves’ disease presenting as generalized pruritus is uncommon.Case Report: This is a case report of 42 y old male driver presented with generalized pruritus at the primary care clinic. His symptoms didn’t resolve on taking antihistamines. The patient was referred to higher center. Pruritus was not associated with any food or fabric allergy, no past history of bronchial asthma, eczema, renal or hepatic disease. On examination, he is not looking jaundiced or pale. Apart from superficial scratch marks on his trunk and all 4 limbs, there were neither skin eruptions, burrows, vesicles, nor scaly lesions to suggest scabies orfungal infection. Incidental findings of tachycardia and a goiter led to the investigations of his thyroid status. There was no exophthalmos, organomegaly or dermopathy. General laboratory investigations were performed and elevated total T4 and suppressed TSH hormone values were found in his thyroid function tests. Tc 99 thyroid scintigraphy showed diffuse increased uptake. He was diagnosed with Graves’ disease and treated with carbimazole. His itching subsided on follow up.Conclusion: A thorough and complete physical examination is of paramount importance in making an accurate diagnosis.

Abstract #1088797: Graves' Disease Induced Vasospastic Angina and NSTEMI: An Unusual Link Between Endocrinology and Cardiology

A common link between Endocrinology and Cardiology is T3, the active form of thyroid hormone. Approximately 5-25% of patients with hyperthyroidism have atrial fibrillation, but a far less common cardiovascular disease (CVD) associated with thyrotoxicosis is myocardial infarction (MI). There are few reported cases of hyperthyroidism causing STEMI, NSTEMI, coronary vasospasm, and autoimmune myocarditis. We present a previously healthy 58-year-old female seen at the emergency department (ED) for nighttime/early morning chest pain, dyspnea and diaphoresis. She denied prior episodes or family history of CVD. EKG showed incomplete right bundle branch block and anterior T-wave inversions. Troponin peaked at 13 ng/mL. Echocardiogram was unremarkable. Left heart catherization demonstrated non-obstructive coronary artery disease concerning for vasospasm. Pertinent laboratories showed decreased TSH (< 0.005 μU/mL) and elevated total T3 and free T4 (2.19 ng/dL). Differentials for thyrotoxicosis included primary hyperthyroidism, spurious results (patient was taking supplement with biotin and iodine), and stress-induced thyroid function alteration. Further workup revealed negative Thyroid Stimulating Immunoglobulin (TSI) and positive TSH Receptor Antibodies (TRAb). Chest pain resolved and she was discharged, but returned days later with same complaints and elevated troponin. Cardiac differentials were myocarditis in the setting of autoimmune thyroiditis vs vasospastic angina. Serial EKGs had no signs of myocarditis. She denied prior viral infection, autoimmune conditions, recreational drugs, appetite suppressants, ephedrine, or migraine medications. Cardiac MRI was not consistent with myocarditis, instead suspicion was raised for subacute MI with nonobstructive coronary arteries (MINOCA). Based on Coronary Vasomotion Disorders International Study Group (COVADIS) criteria, she had nitro-sensitive vasospastic angina. In the setting of thyrotoxicosis and positive TRAb, she was diagnosed with coronary vasospasm NSTEMI triggered by Graves'. Autoimmune thyroid disease may be undiagnosed 50% of the time, unknowingly contributing to CVD. T3 has direct and indirect cardiovascular effects. It promotes catecholaminergic stimulation and acts as a positive ionotrope and chronotrope. Excess T3 creates a hypermetabolic state that can rarely trigger severe coronary vasospasm. MI with < 50 % stenosis is defined as MINOCA, accounting for 6% of acute infarctions that undergo angiography. Non-atherosclerotic etiologies of MINOCA include coronary vasospasm, embolism/thrombus, anemia, hypotension, and thyrotoxicosis. Our patient had two of these, and to the best of our knowledge, this is the first reported case of a troponin >0.5 ng/mL secondary to Graves’ disease induced MINOCA.

A Case of T3 Thyrotoxicosis With Concomitant Follicular Thyroid Carcinoma

Introduction: The coexistence of hyperthyroidism and thyroid cancer is considered a rare event. In these cases, the follicular thyroid carcinoma subtype is an even more rare finding. It is highly unlikely to find follicular carcinoma in a hyperactive thyroid nodule. Clinical Case: We report a case of an 85-year-old female with a past medical history of atrial fibrillation presenting to the clinic after she has noticed enlargement of her neck two weeks prior. The patient was seen by her primary care physician who ordered a CT neck that revealed a goiter and the patient was subsequently referred to our clinic. On further questioning, the patient denied palpitations, sweats, difficulty swallowing, heat or cold intolerance, weight changes, bowel changes, or any other complaints. The patient denied any prior history of thyroid disease or exposure to goitrogens. Her past medical history was not significant for any auto-immune related diseases. She denied any family history of thyroid disease or malignancy. On physical examination, the patient had a normal eye exam and mild goiter with a small palpated right thyroid nodule. Initial thyroid ultrasound revealed a heterogenous right lobe measuring 7.1 cm x 7.3 cm x 5.9 cm with one superior nodule measuring 1.3 cm x 0.7 cm x 0.8 cm and a heterogenous left lobe measuring 2.0 cm x 1.5 cm x 1.1 cm. Laboratory blood work up revealed total T4 of 10.5 μg/dL(normal: 5.0 to 12.0μg/dL), elevated total T3 at 322 ng/dl (normal: 80-220 ng/dL), suppressed TSH <0.01 uIU/mL (normal: 0.40-4.00 uIU/mL), markedly elevated thyroglobulin 2828 ng/mL(normal: 1-84 ng/mL), as well as elevated anti-TPO Ab 63.5 IU/mL (10.0-35.0 IU/mL). The patient underwent a thyroid uptake scan that revealed increased uptake in the right lobe. Three months after presentation, the patient underwent fine-needle aspiration (FNA) which was benign (Bethesda classification II). A decision was made to start the patient on Methimazole and the subsequent thyroid profile showed an improvement in her T3 and TSH, but thyroglobulin continued to uptrend despite treatment. The patient then underwent another thyroid ultrasound one year later that revealed increased right lobe size to 10.3 cm x 6.3 cm x 6.4 cm with enlargement of the superior nodule to 8.5 cm x 4.6 cm x 6.4 cm. The left lobe was also enlarged from the prior scan measuring 3.9 cm x 1.2 cm x 1.0 cm. The patient underwent a second FNA from that nodule which also revealed benign hyperplastic nodule (Bethesda classification II). Despite the benign FNA finding, a decision was made to perform genetic testing given the rapid progressive enlargement of the nodule. The genetic testing revealed TERT promoter gene mutation with a high risk for malignancy. The patient then underwent total thyroidectomy and the pathological analysis showed a 9 cm follicular thyroid carcinoma of the right nodule. The patient then underwent successful I-131 radioactive Iodine ablation. Subsequent thyroid ultrasounds were negative and TSH continued to downtrend while the patient continued to take thyroid hormone replacement. This patient’s presentation is unique in many aspects. The patient presented with a hyperactive hot nodule while follicular carcinoma of the thyroid gland is typically associated with clinical euthyroidism and a scan showing a cold nodule(1). In a study of 425 hyperthyroid patients, thyroid cancer was diagnosed in 7 (1.65%) hyperthyroid patients, and histological examination revealed the presence of papillary carcinoma in 5 cases and follicular carcinoma in only 2 cases (2). Our patient also had two negative FNAs despite the presence of follicular carcinoma. Hence, we are shedding the light on the importance of genetic testing in the setting of negative FNA for rapidly enlarging thyroid nodules. Conclusion: We urge physician’s awareness that on rare occasions, follicular thyroid carcinoma can be present in a hyperactive thyroid with a hot nodule. In the presence of negative FNA, hyperfunctioning rapidly growing thyroid nodules should be carefully evaluated by further genetic testing for the presence of concurrent malignancy.

Coexistence of Thyroid Hormone Resistance and Autoimmune Thyroid Disease: Not a Mere Coincidence

Introduction: The coexistence of thyroid hormone resistance and autoimmune thyroiditis was initially thought to be a chance event. In a large cohort study, Barcoff et al. demonstrated an increased likelihood of thyroid autoantibodies in patients with thyroid hormone resistance (RTH). We report a unique case to epitomize the coexistence of these two conditions and discuss the postulated mechanisms.Clinical Case: A 22-year-old woman with a history of Hashimoto’s thyroiditis, attention deficit hyperactivity disorder, and migraine presented to the endocrinology clinic with symptoms of weight loss, fatigue, decreased appetite, and heat intolerance for 4 months. She was diagnosed with Hashimoto’s thyroiditis at age 12 with elevated TSH only and had been on levothyroxine 25 mcg since diagnosis. Physical exam demonstrated a body mass index of 34.14 kg/m2, blood pressure of 138/91 mmHg, pulse of 77 bpm, and an enlarged palpable thyroid gland. Laboratory investigations revealed elevated thyroid peroxidase (TPO) antibody at 234 IU/mL (<9) and thyroglobulin Antibody at 3 IU/mL (<1) with elevated free T4 of 3.76 ng/dL (0.61-1.36), elevated total T4 of 21.58 mcg/dL (6.09-12.23), increased T3 uptake of 51.2% uptake (32-48.4), and upper normal TSH of 3.99 uIU/mL (0.44-5.33). Elevated free T4 was confirmed by the equilibrium dialysis method at 6.2 ng/dL (0.9-2.2) with upper normal TSH at 3.77 uIU/mL. Thyroid ultrasound demonstrated thyromegaly and hypervascularity of the gland. TSH secreting pituitary adenoma was ruled out with a normal alpha subunit of 0.2 ng/ml (0.1-0.6) and molar ratio of the alpha subunit to TSH ratio <1 along with a normal pituitary MRI. She was not taking other medications or supplements. She was diagnosed with thyroid hormone resistance and is undergoing genetic testing to differentiate the THRB genetic mutations from Non-TR-RTH. Her symptoms improved after discontinuing her levothyroxine.Clinical Lesson: Our case highlights the importance of evaluating thyroid disorders properly before starting treatment and illustrates the coexistence of autoimmune thyroiditis with thyroid hormone resistance. Barcoff et al. demonstrated that there was an increased likelihood of thyroid autoantibodies with odds ratio = 2.36 (p = 0.002) in a large patient cohort with RTH, compared to their unaffected first-degree relatives. However, since there was no correlation in increased antibody with increased age and the duration of the disease, the proposed hypothesis did not substantiate chronic TSH stimulation inducing autoimmune response. The proposed mechanism is that the elevated TSH in RTH stimulates the immune system at the TRα level which was demonstrated in murine models with increased activation of thymic function in correlation with TSH level. More research is needed to understand the underlying mechanism of their coexistence.

Factitious Total Triiodothyronine(T3) Elevation in a Euthyroid Patient With Paraproteinemia

Background: We report a rare case of a patient treated with levothyroxine for hypothyroidism who also had paraproteinemia and was found to have a clinically inconsistent elevation of T3 by RIA. Clinical Case: A 72 Year old African American female with a history of hypothyroidism and IgG kappa Multiple Myeloma (MM) was admitted to the hospital for altered mental status. Her hypothyroidism had been well controlled for years on a stable dose of levothyroxine 0.075mg daily. Review of systems were negative pertinent to thyroid dysfunction. Family history: negative for thyroid disease. On physical exam, an elderly female clinically euthyroid without palpable thyromegaly but was confused and disoriented. Initial Vital signs: BP 117/67, HR 62, RR 14, T 98, SpO2 99% on room air. BMI 19. EKG: normal sinus rhythm, CXR: normal, TSH: 6.27 (0.55-4.78 uIU/mL), total T3: >600 (60-181ng/dL), total T4: 4.5 (3.2-12.6 ug/dL), FT4: 1.22 (0.89-1.76 ng/dL), hemoglobin: 6.6 (12-16 g/dL), hematocrit: 20.9 (38-47 %), Na: 132 (136-145 mmol/L), K: 4.0 (3.5-5.1 mmol/L), Cl: 104 (98-10/ mmol/L), BUN: 45 (20-31 mmol/L), creatinine: 2.8 (0.6-1.0 mg/dL), total protein: 10.1 (5.7-8.2 g/dL), albumin: 1.8 (3.4- 5.0 g/dL), A:G ratio: 0.22 (0.60-1.50 mmol/L). Serum protein electrophoresis revealed Gamma Globulin 5.8 (0.8-1.7 g/dL), Kappa 9270 mg/L (3.3 -19.4 mg/L) Lambda 9.3 (5.7-26.3mg/L), K/L 996.7 (0.26 -1.65), B2 - macroglobulin: 17.9 (ref: <or= 2.51mg/L) which is consistent with an M- spike migrating in the gamma globulin region. Serum TPO, TG, TSI antibodies were negative. Further testing again reported Total T3 >600 with normal reverse T3 21(8-25 ng/dL). Conclusion: Rare cases of factitious elevations of thyroid hormone have been reported in patients with elevated abnormal IgG or IgA proteins having high binding affinity for thyroid hormone.[1] This hypothyroid patient was clinically and biochemically euthyroid except for a dramatic but clinically inconsistent elevated total T3. She also had multiple myeloma with paraproteinemia (IgG Kappa M spike). The few cases reported to date have shown factitious elevation of either or both total T4 and total T3. In our case the factitious elevation was limited to total T3. We alert clinicians to be aware of factitious elevation of thyroid hormones due to high affinity binding to immunoglobulins. In our case this caused spurious elevation of total T3, but not total T4, in a patient with multiple myeloma and an IgG kappa M spike paraprotein. Reference: 1: Marianna Antonopoulou, Arnold Silverberg, “Spurious T3 Thyrotoxicosis Unmasking Multiple Myeloma”, Case Reports in Endocrinology, vol. 2013, Article ID 739302, 3 pages, 2013. https://doi.org/10.1155/2013/739302

MON-481 Remarkable Euthyroid Hyperthyroxinemia Mistaken for Thyrotoxicosis

CLINICAL CASEA 46 year old caucasian female with past medical history of menorrhagia was referred from primary care for evaluation of thyrotoxicosis. Thyroid function was assessed in the context of menometrorrhagia. She did not have any history of thyroid disorder or abnormal thyroid function tests. Per outside records, recent labs demonstrated TSH 0.88 uIU/mL (0.36-3.74), Free T4 > 8.00 ng/dL (0.76-1.46), Free T3 2.9 pg/mL (2.18-3.98). All other labs were within normal limits. Thyroid ultrasound revealed normal parenchyma and volume. She did not take any medications or supplements including biotin. She denied heat intolerance, anxiety, palpitations, dyspnea, tremors, hyperdefecation, or change in hair, skin, or mood. No epiphora, diplopia, or eye irritation was reported. Her father had been diagnosed with hyperthyroidism, mother with hypothyroidism.Repeat labs at our visit revealed normal TSH of 1.05 uIU/mL (0.358- 3.74), normal Free T3 2.58 pg/mL (2.18- 3.98), normal Total T3 136 ng/dL (80-200), elevated Free T4 >8.00 ng/dL (0.76-1.46) and elevated Total T4 11.6 ug/dL (4.5-10.5). These lab values were not consistent with patient’s euthyroid clinical status, prompting assessment of Free T4 by dialysis, normal at 1.5 ng/dL (0.9-2.2) and T3 uptake, high at 40% (24-39%). This picture was consistent with Familial Dysalbuminemic Hyperthyroxenemia (FDH). The decision was made not to treat the patient with anti-thyroid medications and to perform a confirmatory genetic testing to test for mutations in the ALB (albumin) gene.DISCUSSIONThe free T4 assay used by our institution is performed on the Siemens Dimension Vista platform using a two-step chemiluminescent immunoassay. While in theory two-step assays should not yield abnormal results in FDH, several two-step assays are known to yield falsely high results in patients with FDH (1, 2, 3).Other potential etiologies for discordant Free T4 levels include thyroid hormone autoantibodies, heterophile antibodies, biotin use, and anti-streptavidin antibodies (3).CONCLUSIONRecognition of laboratory error in the workup of thyroid disease is essential. Clinicians must ensure thyroid function labs are consistent with each other and with the patient’s presentation. In such cases misdiagnosis of hyperthyroidism or thyroid hormone resistance may lead to unnecessary testing and inappropriate treatment (3).

SAT-518 Progression of Graves Disease to Hashimoto’s Thyroiditis Following Alemtuzumab Therapy for Multiple Sclerosis

Introduction: Alemtuzumab, an anti-CD52 monoclonal antibody used in the treatment of relapsing-remitting multiple sclerosis is most commonly associated with Graves disease, but autoimmune hypothyroidism may also be seen. We present an unusual case where both were present in the same patient and progression from hyperthyroidism to hypothyroidism was seen within only a few months. Clinical Case: A 33-year-old female referred to Endocrinology clinic for evaluation of hyperthyroidism. She was complaining of palpitations, tremors, increased sweating, heat intolerance, and unintentional weight loss for 3 months. She received 2 cycles of alemtuzumab treatments over the last 21 months for her multiple sclerosis. Last treatment was 8 months before she developed hyperthyroid symptoms. Patient had no prior history of thyroid disorder. Thyroid stimulating hormone (TSH) level was within normal range before alemtuzumab was administered. TSH was monitored periodically and was normal till 8 months after receiving alemtuzumab therapy. Physical exam was remarkable for diffuse enlarged thyroid, not tender, without palpated thyroid nodules but with thyroid bruit. No proptosis was present.Thyroid function tests obtained by her primary care physician were consistent with hyperthyroidism. Patient found to have suppressed TSH <0.015 IU/mL [0.465 - 4.680IU/mL], elevated total T3 372ng/dL [97-169ng/dL], and elevated total T4 >24.9 ug/dL [5.5 - 11.0 ug/dL].Further workup revealed elevated Free T3, 10.90 [2.77 - 5.27 pg/mL] and elevated free T4 > 6.99 ng/dL [0.78 - 2.19 ng/dL]. Thyrotropin receptor antibody (TR Ab) was elevated as well at 3.43 IU/L [<1.75 IU/L]. Pregnancy test was negative. Thyroid ultrasound demonstrated goiter with no focal thyroid nodules seen. She was started on methimazole 10 mg daily.One month later, TSH was elevated at 31.58 though she only took methimazole for one week and then discontinued due to rash and pruritus. At that time, she reported severe fatigue and 25 lbs weight gain. Repeated labs one month later showed elevated TSH, 60.978 IU/ML, low free T4 0.08 pg/mL and low free T3 0.72 ng/dL. Thyroid peroxidase Antibody (TPO Ab) was obtained and was 5308.8 IU/mL [0.0 - 5.5 IU/mL]. She was started on levothyroxine 100 mcg daily. Two months later, levothyroxine dose was increased to 112 mcg daily due persistent TSH elevated. At subsequent visit, patient was euthyroid with normal TSH 3.191IU/mL and normal free T4 1.48 ug/dL. Conclusion: This case was unique in that the patient developed both TR Ab and TPO Ab after alemtuzumab therapy which resulted in Grave’s disease followed by Hashimoto’s thyroiditis. The case highlights the importance of continuous monitoring of thyroid function in patients treated with alemtuzumab given the unpredictable autoimmune phenomena which may occur.

SUN-507 Fueling the Fire: A Case of Hypokalemic Periodic Paralysis Associated with Type I Renal Tubular Acidosis and Thyrotoxicosis in Pregnancy

Background: Hypokalemic periodic paralysis (HPP) related to thyrotoxicosis, though rare, is more often seen in Asian males. Type 1 renal tubular acidosis (T1 RTA), which can also cause HPP, is typically managed with alkali therapy and potassium supplementation, though there are no well-established guidelines for management in pregnancy.Clinical Case: A 27-year-old Puerto Rican woman, at 32 weeks gestation, presented to the hospital with sudden onset muscle weakness, and was found to have 1/5 muscle strength in her lower extremities. She had no personal or family history of similar illness. Laboratory analysis revealed hypokalemia (potassium 2.0 mmol/L, range: 3.5 – 5); non-gap metabolic acidosis (sodium 137mmol/L, range 136 – 145; chloride 113 mmol/L, range 98- 107; and bicarbonate 8 mmol/L, range 22 – 29); and an arterial pH of 7.09. Urine studies demonstrated a urine pH of 6.5 and a urine sodium of 32 mmol/L which was diagnostic of T1 RTA in the context of her metabolic derangements. She was treated emergently with potassium and bicarbonate infusions, with improvement in her symptoms. Subsequent thyroid function testing revealed: a low TSH of 0.01 uIU/ml, normal free T4 of 1.66 (range: 0.9 - 1.7) ng/dl, normal free of T3 3.7 (range: 2.0 -4.4) pg/ml and elevated total T4 of 16.5 (range: 4.5 - 11.7) ug/dl. Renal ultrasound demonstrated medullary nephrocalcinosis. She was discharged on potassium and sodium citrate tablets. At 37 weeks, the patient was readmitted for induction of labor due to pre-eclampsia, and delivered a healthy male baby. Several months later, she presented to the Endocrinology clinic with symptoms of increased frequency bowel movements, palpitations and heat intolerance, which had been ongoing since pregnancy. On review, a metabolic panel prior to pregnancy had demonstrated non-gap acidosis and mild hypokalemia. Further testing demonstrated the following: TSH < 0.01 uIU/ml, Free T4 1.71 ng/dl, Free T3 4.8 pg/ml, TSI 280%, and a thyroid uptake scan with homogenous radiotracer uptake, with a 24-hour uptake of 40%. She was started on methimazole therapy, and continued on potassium and sodium citrate tablets with clinical and biochemical improvement.Conclusion: Thyrotoxicosis can augment hypokalemia in T1 RTA, and can increase the risk of HPP. Our patient had biochemical evidence of RTA prior to pregnancy, though without episodes of HPP, and we believe that her hyperthyroidism, triggered by pregnancy, may have been the additional insult that precipitated her paralysis. This is the first reported case of HPP related to co-existing thyrotoxicosis and T1 RTA in a pregnant individual.Reference:1. Tu ML, Fang YW, Leu JG, Tsai MH. An atypical presentation of high potassium renal secretion rate in a patient with thyrotoxic periodic paralysis: a case report. BMC Nephrol. 2018;19(1):160. Published 2018 Jul 4. doi:10.1186/s12882-018-0971-9

Thyroid Hormone Alterations Among Women with Posttraumatic Stress Disorder Due to Childhood Sexual Abuse

Research on thyroid activity among male combat veterans with posttraumatic stress disorder (PTSD) has consistently shown elevations in total triiodothyronine (TT3) and inconsistent elevations of other thyroid variables. This study is the first large scale investigation of thyroid function in women with PTSD. Thyroid function was measured in 63 women with PTSD due to childhood sexual abuse (PTSD-CSA) in comparison with a community sample of 42 women without current PTSD-CSA. Clinical measures included the Clinician Administered PTSD Scale (CAPS), the Evaluation of Lifetime Stressors, the Trauma Assessment for Adults and the Beck Depression Inventory. Women with PTSD-CSA showed significant elevations in Total T3 and the TT3/free thyroxine (TT3/FT4) ratio, the FT3/TT3 ratio, and modest reductions in thyroid stimulating hormone relative to our community sample. These findings could not be explained by the influence of prior trauma, lifetime PTSD or depressive symptoms. Altered thyroid activity, especially elevated Total T3 levels, was found in women with PTSD associated with childhood sexual abuse.

Quantitative Trait Loci Associated with Elevated Thyroid-Stimulating Hormone in the Wistar-Kyoto Rat

Thyroid hormones are essential for the regulation of developmental and physiological processes. The genetic factors underlying naturally occurring variability in mammalian thyroid function are, however, only partially understood. Genetic control of thyroid function can be studied with animal models such as the inbred Wistar-Kyoto (WKY) rat strain. Previous studies established that WKY rats have elevated TSH, slightly elevated total T3, and normal total T4 levels compared with Wistar controls. The present study confirmed a persistent 24-h elevation of TSH in WKY rats compared with the Fisher 344 (F344) rat, another inbred strain. Acute T3 challenge (25 microg/100 g body weight ip) suppressed serum TSH and T4 levels in both strains. Quantitative trait locus analysis of elevated TSH in a reciprocally bred WKY x F344 F2 population identified one highly significant locus on chromosome 6 (LOD=11.7, TSH-1) and one suggestive locus on chromosome 5 (LOD=2.3, TSH-2). The confidence interval of TSH-1 contains the TSH receptor and type 2 deiodinase genes, and TSH-2 contains the type 1 deiodinase gene. The WKY alleles of each gene contain sequence alterations, but additional studies are indicated to identify the specific gene or genes responsible for altered regulation of the thyroid axis. These findings suggest that one or more genetic alterations within the TSH-1 locus significantly contribute to the altered thyroid function tests of the WKY rat.

Genetic immunization of outbred mice with thyrotropin receptor cDNA provides a model of Graves' disease.

We performed genetic immunization of outbred NMRI mice, using a cDNA encoding the human thyrotropin receptor (TSHr). All mice produced antibodies capable of recognizing the recombinant receptor expressed at the surface of stably transfected Chinese hamster ovary (CHO) cells, and sera from most of the immunized mice blocked TSH-dependent stimulation of cAMP accumulation in cells expressing the TSHr. Five out of 29 female mice showed sign of hyperthyroidism including elevated total T4 and suppressed TSH levels. The serum of these mice contained thyroid-stimulating activity, as measured in a classic assay using CHO cells expressing recombinant TSHr. In contrast, only 1 male out of 30 had moderately elevated serum total T4 with undetectable TSH values. The hyperthyroid animals had goiters with extensive lymphocytic infiltration, characteristic of a Th2 immune response. In addition, these animals displayed ocular signs reminiscent of Graves' ophthalmopathy, including edema, deposit of amorphous material, and cellular infiltration of their extraocular muscles. Our results demonstrate that genetic immunization of outbred NMRI mice with the human TSHr provides the most convincing murine model of Graves' disease available to date.

Familial Dysalbuminemic Hyperthyroxinemia: Cumulative Experience in 29 Consecutive Patients

The syndrome of familial dysalbuminemic hyperthyroxinemia (FDH), an inherited abnormality characterized by the presence of a variant serum albumin with preferential affinity for T4, is recognized with increasing frequency as a cause of elevated total and free T4 serum values in clinically euthyroid patients with normal TSH levels. Hyperthyroxinemia caused by this syndrome is occasionally confused with hyperthyroidism or thyroid hormone resistance syndromes, which may prompt unnecessary treatment. To better define the clinical and biochemical characteristics of patients with FDH, we undertook a retrospective analysis of the experience at our institution with this condition. We reviewed our cumulative experience in 29 consecutive patients with FDH diagnosed between 1970 and 1991. FDH was diagnosed in 18 males and 11 females (mean age, 42.7 years) on the basis of clinical euthyroidism, increased total T4 and increased/normal free T4 serum values, normal T3 and TSH serum values, increased T4 binding to serum albumin, and low/normal T4 binding to T4-binding globulin and serum prealbumin. Clinical thyroid examination revealed no abnormalities except for goitre in five patients, and the results of radioiodine uptake studies were normal. Patients with subsequently documented FDH were referred for evaluation of "unusual" findings on thyroid function tests or FDH was detected on routine thyroid function tests or identified on family screening. Euthyroid hyperthyroxinemia in combination with a family history compatible with FDH correctly suggested FDH in seven patients. Clinical euthyroidism in conjunction with a normal basal sensitive TSH value in a hyperthyroxinemic patient differentiates euthyroid hyperthyroxinemia from thyrotoxicosis, obviating unnecessary therapy. Detection of excessive thyroxine binding to serum albumin establishes the diagnosis of FDH and allows it to be differentiated from thyroid hormone resistance syndromes. After a diagnosis of FDH has been established, family screening is advisable. Hyperthyroxinemia in clinically euthyroid patients ("euthyroid hyperthyroxinemia") is recognized with increasing frequency and should prompt a careful diagnostic evaluation. The differential diagnosis of this condition may be difficult because it includes various common and unusual syndromes, including quantitative or qualitative changes in thyroid hormone-binding proteins, circulating antibodies against thyroid hormones, resistance to thyroid hormones, influences from drugs, and acute somatic or psychiatric illness (1). The recently recognized syndrome of familial dysalbuminemic hyperthyroxinemia (FDH), an inherited abnormality with autosomal dominant transmission, is characterized by the presence of a variant serum albumin with preferential affinity for T4 (2-4). Typically, FDH is detected incidentally or patients are referred to endocrinologists on the basis of "unusual" results on routine thyroid function testing, revealing consistently elevated total T4 and elevated or normal free T4 values in a clinically euthyroid patient with normal TSH levels (1,5). Unfortunately, hyperthyroxinemia due to FDH may be confused with hyperthyroidism or thyroid hormone resistance syndromes, prompting repeated unnecessary laboratory testing and possibly even inappropriate treatment (1,3,6,7). Herein, we describe the clinical and biochemical characteristics of 29 consecutive patients with documented FDH.

Linkage of familial dysalbuminemic hyperthyroxinemia to the albumin gene in a large Amish kindred.

Familial dysalbuminemic hyperthyroxinemia (FDH) is the most common cause of inherited euthyroid hyperthyroxinemia in Caucasians. Transmitted as an autosomal dominant trait, it is always associated with high serum total T4 (TT4) and more rarely with elevated total T3 (TT3) and/or rT3 (TrT3) concentrations. Free T4, by dialysis, and TSH levels are normal, suggesting the presence of a T4-binding protein abnormality. The abnormal serum T4 carrier shares some physical and immunological properties with albumin, suggesting that it may be albumin itself. Here we show linkage between FDH and the albumin gene in a large Amish family of Swiss descent, using as markers a SacI polymorphism in the coding sequence of the albumin gene and the group-specific component (Gc) gene, located less than 1 centimorgan from the albumin gene. Blood samples were obtained from 160 members of this kindred, and 22 had FDH identified by the pattern of T4 binding to serum proteins separated by isoelectric focusing. Serum TT4 values were above the normal range in all subjects expressing the FDH phenotype, and TrT3 levels were above the normal range in only one half. TT4 concentrations correlated positively with TrT3 and TT3. All TT3 values were, however, within the normal range. Free T4 and TSH levels were normal, confirming the euthyroid state in these subjects. FDH was associated with the albumin SacI(+)/Gc 1S haplotype, yielding a LOD (logarithm of the odds ratio) score of 5.53, with a recombination frequency of 0. These data provide strong support that a variant albumin is the cause of FDH in this kindred.

Elevation of Serum Free Triiodothyronine, Total Triiodothyronine, Thyroxine-Binding Globulin, and Total Thyroxine Levels in Combat-Related Posttraumatic Stress Disorder

This study was designed to assess both central and peripheral aspects of thyroid function in combat-related posttraumatic stress disorder (PTSD), with the particular purpose of finding a mechanistic explanation for an imbalance between serum levels of free thyroxine (T4) and total T4 previously observed in pilot work. A total of 96 male combat veterans with PTSD diagnosed by DSM-III-R (72 from the West Haven, Conn, Veterans Affairs Medical Center and 24 from the Menlo Park, Calif, Veterans Affairs Medical Center) were compared with 24 male control subjects. One or more serum samples were analyzed by radioimmunoassays for levels of total T4, free T4, total triiodothyronine (T3), free T3, T4-binding globulin, and thyrotropin. The pilot observation of moderately elevated total T4 levels with no elevation in free T4 levels in patients with PTSD was confirmed, suggesting the hypotheses that (1) there may be an increased peripheral conversion of free T4 by deiodination to T3 or (2) there may be an increased binding of T4 secondary to elevated T4-binding globulin levels. Our findings support both hypotheses. The PTSD groups all showed a marked and sustained elevation in levels of both total T3 and free T3, as well as elevated T3/T4 ratios, supporting the increased T3 conversion hypothesis. The PTSD groups also showed a marked and sustained increase in T4-binding globulin levels, supporting the increased binding hypothesis. Thyrotropin levels did not differ between PTSD and control groups. These findings demonstrate an unusual pattern of thyroid alterations, featuring substantial elevations in total T3, free T3, and T4-binding globulin levels, in combat-related PTSD that differs from established endocrinopathies, such as classic hyperthyroidism, T3 thyrotoxicosis, or chronic T4-binding globulin elevation.

Triiodothyronine Antibodies in a Case of Graves' Disease: Long-Term Follow-Up Under Carbimazole

We present a case of 50-year-old man with Graves' disease who had antibodies against triiodothyronine (T3) resulting in inappropriately elevated total T3 (TT3) and free T3 (FT3) concentrations, during an 8-year period of treatment with carbimazole

A point mutation in transthyretin increases affinity for thyroxine and produces euthyroid hyperthyroxinemia.

In a family expressing euthyroid hyperthyroxinemia, an increased association of plasma thyroxine (T4) with transthyretin (TTR) is transmitted by autosomal dominant inheritance and is secondary to a mutant TTR molecule with increased affinity for T4. Eight individuals spanning three generations exhibited the abnormality. Although five of eight individuals had elevated total T4 concentrations, all affected individuals were clinically euthyroid and all had normal free T4 levels. Purified TTR from the propositus had an affinity for 125I-T4 three times that of control TTR. Exons 2, 3, and 4 (representing greater than 97% of the coding sequence) of the TTR gene of DNA prepared from the propositus' peripheral blood leukocytes were amplified using the polymerase chain reaction (PCR) and were sequenced after subcloning. Exons 2 and 3 were indistinguishable from normal. In 50% of clones amplified from exon 4, a substitution of adenine (ACC) for guanine (GCC) in codon 109 resulted in the replacement of threonine-for-alanine, a mutation confirmed by amino acid sequencing of tryptic peptides derived from purified plasma TTR. The adenine-for-guanine substitution abolishes one of two Fnu 4H I restriction sites in exon 4. PCR amplification of exon 4 of TTR and restriction digestion with Fnu 4H I confirmed that five affected family members with increased binding of 125I-T4 to TTR are heterozygous for the threonine 109 substitution that increases the affinity of this abnormal TTR for T4.