bluuebunny/crossref_metadata_2025 huggingface dataset:
A Rare Case of Rhabdomyolysis in a Patient With Pembrolizumab Induced Hypothyroidism
Authors: Idriss Setana , Shaikhoun Mazin , Ramineni Srivyshnavi , Elnigomy Sheikan , Apedo Margaret
Published: May 2021

Introduction: Although reported in previous literature, Rhabdomyolysis due to hypothyroidism,without an obvious precipitating factor, is rare. We report a case of severe hypothyroidism leading torhabdomyolysis. Case Report: A 70-year-old man with a history of progressive weakness, myalgia x1 month, statinallergy, pancreatic adenocarcinoma, metastatic melanoma, and acquired hypothyroidism afterreceiving Pembrolizumab for 6 months. He was non-adherent to the levothyroxine, prescribed 1month before hospitalization. He presented to the ED after slipping from his bed onto the floor in aseating position and being unable to get up due to his weakness. Initially, he was afebrile, hypoxic,tachypneic, tachycardic, hypotensive, lethargic, oriented x2, and had a global muscular weakness. Labs were significant for CK of 10,180 (n < 166 IU/L), TSH 136.18(n 0.34-5.6 mU/L), FT4 < 0.25 (n0.6-1.10 ng/dl), FT3 1.4 (n 2.5-3.9 Pg/ml), AKI, leukocytosis, abnormal electrolytes and LFTs. IV fluidsand antibiotics failed to improve the patient’s clinical status in 48 hours. He was started on IVthyroxine and stress steroids with improved weakness and overall clinical picture. Discussion: 4.6 % of people have hypothyroidism per the United States National Health andNutrition Examination Survey. Rhabdomyolysis is defined as the rapid breakdown of skeletal muscle,which may also develop due to hypothyroidism. Most patients with hypothyroidism who developrhabdomyolysis are found to have a clear precipitating risk factor, such as the use of statins orstrenuous exercise. Still, none of these risk factors were present in this case. Our patient acquiredhypothyroidism after a few months of receiving Immunotherapy. It is reported that hypothyroidismoccurs in (9% to 18%) of patients receiving Pembrolizumab. Although the patient was prescribedthyroid replacement therapy, he was not adherent to the medication for 1 month prior topresentation. Although mechanical injury is reported to cause elevated CK levels, mostrhabdomyolysis cases are related to crush injuries. We believe that the fall was probably related tohis progressive generalized weakness due to his noncompliance with medical therapy leading tomyxedema coma and rhabdomyolysis. Conclusion: Screening for hypothyroidism in patients with elevated muscle enzymes should behighly considered since an early diagnosis. Prompt treatment of hypothyroidism is essential toprevent rhabdomyolysis and its consequence.
Acute Inflammatory Demyelinating Polyneuropathy (AIDP) Masked by Autoimmune Thyroiditis
Authors: Wirtshafter Stephanie , Iqbal Iqra
Published: May 2021

Hashimoto’s thyroiditis and Guillain-Barre syndrome (GBS) are autoimmune disorders that are both well-known in their own right. Hashimoto’s is one of the most common causes of primary hypothyroidism, and GBS involves immune mediated damage to the peripheral nervous system. The association between the two is a rare clinical entity. This case demonstrates that these entities can occur together and could be related in similar pathophysiology.

A 37 year old male presented with complaints of bilateral hand and feet numbness for one month. The numbness started in the hands, then involved the feet, and was mostly felt in tips of extremities. He also complained of weakness in arms and legs. Neurology exam showed bilateral patellar, ankle, and biceps hyporeflexia. Muscle strength was 5/5 in all extremities, but decreased grip strength was noted in the hands. Initial lab work including complete blood count, comprehensive metabolic profile and urinalysis were all in normal range. Computerized tomographic scan (CT) head was normal while CT abdomen/pelvis showed hepatic fatty infiltration. Other lab tests including HIV, syphilis, Hepatitis B, Hepatitis C, glycosylated hemoglobin A1c, lipid panel, anti-nuclear antibody, anti-neutrophil cytoplasmic antibodies, serum/urine protein electrophoresis, alcohol level, vitamin B1, B6, folate, copper, and creatine kinase were all negative or within normal range. Lab abnormalities included elevated thyroid stimulating hormone (TSH) of 20.2 mIU/l and low normal B12 level of 289 pg/ml. His triiodothyronine (T3) and thyroxine (T4) hormone levels were in normal range. A thyroid peroxidase antibody level came back as high as 966 IU/ml. A diagnosis of Hashimoto’s thyroiditis leading to subclinical hypothyroidism was made. Patient was discharged on vitamin B12 and 112mcg of Synthroid. Instead of getting better, he returned 1 week later with worsening numbness and tingling which was now ascending upward to bilateral knees and elbows. Meanwhile TSH improved to 10 mIU/l and vitamin B12 increased to 1162 pg/ml. A magnetic resonance imaging (MRI) of the cervical/thoracic spine was unremarkable. A lumbar puncture showed negative xanthochromia, 0 WBC, 0 RBC, 0 neutrophils, 0 lymphocytes, 0 monocytes, glucose 63 mg/dl, elevated protein of 57 mg/dl, and culture was negative. Guillain-Barre syndrome was then the working diagnosis, more specifically its most common subtype, acute inflammatory demyelinating polyneuropathy (AIDP). Patient received five days of intravenous immunoglobulins and his symptoms improved. He was then discharged to follow up with endocrinologist.

This subtle presentation of GBS/AIDP masked by Hashimoto’s thyroiditis and vitamin B12 deficiency suggests a close association of autoimmune etiology between these disorders. Although rare, endocrinologists should consider this rare association in cases of paresthesias with unexplained symptoms.
Amiodarone Induced Thyrotoxicosis: A Case of Refractory Disease Treated With Thyroidectomy
Authors: Mushref Malek , Tofil Kathrin Sandra , Hermayer Kathie Lynn
Published: May 2021

Amiodarone induced thyrotoxicosis (AIT) is a challenging diagnosis that affects 3-5% of patients taking amiodarone in the United States. Type I AIT is seen in patients with preexisting thyroid disease and is generally treated with thionamides while type II AIT represents a destructive thyroiditis that responds to glucocorticoids. A mixed type exists and is associated with higher mortality, especially in older adults with cardiovascular disease. Thyroidectomy is considered a last resort option for patients intolerant or refractory to medical treatment.

A 70 year-old male with a history of coronary artery disease, ventricular tachycardia (VT), and heart failure was referred to the endocrine clinic for abnormal thyroid function tests that showed TSH <0.0023 uIU/mL (0.4-4.7), Free T4 2.51 ng/dL (0.7-1.48) and Free T3 5.37 pg/mL (1.71-3.71). He endorsed palpitations, excessive sweating, tremors, and reported taking amiodarone for 3 years prior to presentation. Vitals showed normal pulse and blood pressure. Thyroid autoantibodies including TSI and TBII were within normal limits. Thyroid ultrasound showed mild thyromegaly with normal vascularity and no nodules. AIT was suspected and he was started on methimazole 20 mg daily, prednisone 30 mg daily and continued on his home metoprolol 100 mg daily. Methimazole and prednisone were both up titrated in a week because his labs did not improve. One month later, he presented to the hospital with acute exacerbation of heart failure. His TFTs showed (TSH <0.0021 uIU/mL, FT4 >5.0 ng/dL, FT3 4.61 pg/mL). Thyroid RAIU showed severely decreased uptake secondary to the high iodine content of amiodarone. He remained thyrotoxic despite using higher doses of prednisone (60 mg daily) and methimazole (90 mg daily). He was changed to PTU (900 mg daily) and started on cholestyramine, with no improvement in overall status. Several weeks after admission, a total thyroidectomy was performed. His postoperative course was unremarkable except for hypoparathyroidism. He was clinically and biochemically euthyroid one week after his procedure. At 6 months follow up, he remained stable on levothyroxine 100 mcg/day but continued to require calcitriol and calcium supplementation.

We present an interesting case of mixed type AIT refractory to medical therapy associated with cardiovascular compromise. This case highlights the challenges in the diagnosis and management of such patients. Thyroid autoantibodies, thyroid ultrasound and RAIU were more indicative of Type II AIT, however, lack of response to high dose steroids was inconsistent with the diagnosis. While receiving the treatment for both Type I and II AIT, our patient had persistent clinical and biochemical thyrotoxicosis and required thyroidectomy. Although most AIT patients are treated medically, thyroidectomy is reserved for those most severe and refractory cases and is considered a viable option in such patients.
An Unusual Etiology of Graves’ Disease: Alemtuzumab
Authors: Santiago Carrion Ada Marie , Agosto-Vargas Yanerys
Published: May 2021

Cluster of differentiation 52 (CD-52) is a glycoprotein expressed on the surface of most lymphocytes and it is the most prevalent marker in T cells, B cells, natural killers and monocytes. Alemtuzumab, a CD-52 monoclonal antibody, is one of the initial therapies approved for patients with relapsing-remitting multiple sclerosis. It acts by inducing rapid and prolonged depletion of lymphocytes with a consequent immunosuppression. Although not clearly understood, Alemtuzumab has been associated with the development of autoantibodies. These have been reported to cause thyroid injury resulting in 10-15% incidence of new-onset Graves’ disease.

This is the case of a 38 year-old man with medical history of relapsing-remitting multiple sclerosis who came to the Endocrinology clinic to establish care due to abnormal thyroid function tests. Patient has received Alemtuzumab since the past two years. Three months prior to arrival, he was found with weight loss, hyperdefecation and tremors by his Neurologist. Patient was found with suppressed TSH for which Methimazole was commenced. Thyroid ultrasound showed normal size and homogenous right and left thyroid lobes, and no evidence of cystic or solid masses. Thyroid stimulating immunoglobulins were found elevated which correlated with Graves’ disease. Moreover, thyroid scintigraphy showed 34% radioiodine uptake at 24 hours indicating de novo synthesis of thyroid hormone in this patient with hyperthyroidism. As Alemtuzumab was identified as a precipitating cause of Graves’ disease, therapy was discontinued and plasmapheresis will be given for the treatment of relapsing-remitting multiple sclerosis.

Monoclonal antibody use has increased since the past decades. It has been well described in literature that monoclonal antibodies against programmed cell death receptor 1 (PD-1) and programmed cell death ligand 1 (PD-L1) may cause autoimmune thyroid disease. Nonetheless, it is important to recognize that other monoclonal antibodies may have similar adverse effects. Alemtuzumab is a monoclonal antibody and antineoplastic agent used for relapsing multiple sclerosis, some hematologic malignancies, and as an induction agent for solid organ transplantation. Its main effects include autoimmunity with thyroid being one of the most described targets. In these patients, expert clinicians should recognize the possibility of thyroid disease for prompt treatment which will improve quality of life.
Antineutrophil Cytoplasmic Antibodies in Patients Treated With Methimazole
Authors: Rosario Pedro Weslley , Andrade Gabriela Costa , Maia Flavia Coimbra Pontes
Published: May 2021

Introduction: Antithyroid drugs (ATDs) are widely used for the treatment of hyperthyroidism. Most side effects of these medications are mild and emerge within the first months of treatment. In contrast, antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis is a severe adverse event whose occurrence increases with increasing time of treatment. Vasculitis is more frequently associated with propylthiouracil than with methimazole, but the latter has also been related to the occurrence of ANCA and even to clinically manifest vasculitis. Many patients develop ANCA during treatment with methimazole but do not exhibit signs/symptoms of vasculitis. Objective: We previously reported a relatively high frequency (20%) of ANCA in patients exposed to methimazole but none of them exhibited clinical manifestations of vasculitis on that occasion. We continued to follow up these patients with ANCA and report here their evolution after 2 years. Methods: Seventeen patients exposed to methimazole were followed for 2 years after antibodies detection (ANCA). Results: Eight patients had ANCA but had not used methimazole for at least 6 months. During the following 24 months, continuing without ATD, none of the patients developed clinically apparent vasculitis. In the last assessment, five patients no longer had ANCA, while these antibodies persisted in three. Nine patients had ANCA and had been on methimazole for at least 6 months. The medication was not immediately discontinued in these patients when the antibodies were detected. After this detection, treatment with methimazole was continued in these patients for more 3 months (n = 1), 6 months (n = 2), 9 months (n = 1), 12 months (n = 2), 18 months (n = 2), and 24 months (n = 1). During the 2 years of follow-up after the detection of ANCA, none of the 9 patients developed signs/symptoms of vasculitis. In the last assessment, ANCA were negative in two patients who had received methimazole for more 3 and 6 months and who were therefore without receiving the drug for 21 and 18 months, respectively. The other 7 patients remained ANCA positive. Conclusion: Although vasculitis is necessarily associated with the presence of ANCA, the inverse frequency is undefined and appears to be low. Thus, measurement of ANCA would not be recommended in asymptomatic patients during methimazole treatment and immediate discontinuation of this drug, if these antibodies are detected eventually, may not be required. Reference: Antineutrophil cytoplasmic antibodies in patients treated with methimazole: a prospective Brazilian study. Andrade GC, Maia FCP, Mourão GF, Rosario PW, Calsolari MR. Braz J Otorhinolaryngol. 2019; 85:636-41.
COVID-19 Infection Causing Atypical Thyroiditis
Authors: Katkar Rujuta Baban
Published: May 2021

Introduction: Coronavirus disease 2019 (COVID-19) has caused significant health burden across the world. Identification of factors contributing to severe disease is important to enable stratification of risk, optimize the reallocation of hospital resources, and guide public health recommendations and interventions. Subacute thyroiditis is an inflammatory thyroid disease characterized by neck pain and is usually preceded by an upper respiratory tract infection. It may be caused by a viral infection or a post-viral inflammatory reaction, and many viruses have been linked to the disease. We present case of atypical thyroiditis associated with COVID-19 infection. Case Report: 27-year-old female with no significant past medical history apart from recent COVID-19 infection is referred to endocrinology for evaluation of abnormal thyroid function test. Patient states around three months ago she was experiencing the symptoms like unintentional weight loss, nausea, palpitation, insomnia, anxiety, fatigue similar to symptoms she experienced 9 years ago while she was pregnant with her daughter so she thought she is pregnant again and visited her gynecologist. But patient had pregnancy test was done and she was found to be negative but her thyroid function test showed low TSH 0.32mIU/ml (0.47-4.68mIU/ml). Patient states around same time she was diagnosed with COVID-19 infection and she lost 5 pounds during that time but even after recovery from the infection she continued to lose weight and lost a total of 18 pounds in 3 months. Patient states during the time of COVID-19 infection she was having difficulty swallowing and painful swallowing but following infection patient denied any current difficulty swallowing or breathing, headache, vision changes, cold or heat intolerance, diarrhea or constipation, tremors, proximal muscle weakness, bulging of her eyes. Patient continue to have regular monthly menstrual cycles. Three months following infection patients repeat thyroid function tests were done and it showed normal TSH 0.56mIU/ml(0.47-4.68mIU/ml),free T4 1.05ng/dL(0.78-2.19ng/dL) and negative thyroid antibodies like TSI index<1.0, Thyroid peroxidase Antibodies 1.4 IU/mL, Thyrotropin Receptor Ab <1.00 IU/L. Patient also had normal thyroid ultrasound. Patient had complete resolution of hyperthyroid symptoms and did not require any medications. Conclusion: In conclusion, physicians should be engaged in close monitoring of thyroid disease in patients with suspected COVID-19, for timely detecting signs of disease progression. Finally, the presence of thyroid disease shall be regarded as an important factor in future risk stratification models for COVID-19.
Diagnostic Dilemma: A Case of Undetectable TSH
Authors: Mimms Remy , Sirisena Imali
Published: May 2021

Introduction: Under steady-state conditions, measurement of TSH is accepted as the best assessment of thyroid function. The widely used TSH chemiluminometric assays have very low limits of detection and can help distinguish between the various causes of subnormal TSH. However, when evaluating a patient with abnormal thyroid tests but without thyroid symptoms, an appraisal of the test should be considered.

Clinical Case: A 63-year-old South Asian man was referred to endocrinology for evaluation of a non-detectable TSH (<0.01 µIU/mL) that was reproduced on repeat testing, both using Siemens ADVIA Centaur TSH3-UL immunoassay. The patient was clinically euthyroid and denied taking biotin supplements. Testing of thyroid hormone showed normal values for free T3, total T3, free T4, and total T4. Additional labs included normal studies for free thyroxine by equilibrium dialysis, thyroid stimulating immunoglobulin, and heterophilic antibodies. Thyroid uptake and scan showed uniform uptake of 5.1% and 15.1% at 2-hours and 24-hours, respectively, with no dominant nodules. Hypothalamic-pituitary hormonal testing and MRI pituitary were both normal as well. When TSH testing was repeated on a separate platform, Roche’s eCLIA immunoassay, detectable values were obtained (TSH 6.48 µIU/mL).

Conclusions: Testing of serum TSH by commercially available immunoassays is based on the sandwich method in which one antibody binds to the β-subunit of TSH and the other to the α-β interface. Most assays use monoclonal antibody pairs to achieve high selectivity. Immunoassay tests are prone to interferences, particularly by way of altering the measurable concentration of the analyte or by altering antibody binding (1). In this case, the presence of detectable TSH depended on the platform by which it was measured. This finding suggests a TSH-β variant with impaired immunoreactivity but functionally normal bioactivity. Such a mutation has been previously reported to occur five times more frequently among South Asian individuals than the general population (2). Genetic testing was offered to the patient to confirm this suspicion but was declined.

It is incumbent on the clinician to reconcile a test result that is discordant with the clinical presentation. Having a fundamental understanding of the principles of the testing platform can assist in identifying potential sources of error. Failing to recognize a possible interference can lead to unnecessary healthcare expenditures, misdiagnosis and inappropriate management, potentially at a cost to the patient’s wellbeing. When faced with an undetectable TSH with otherwise normal thyroid hormones and unremarkable clinical picture, it is best to repeat the TSH test using a different available platform.

References: (1)Favresse J et al. Endocr Rev. 2018;39(5):830-850(2)Pappa T et al. Thyroid. 2015 Aug;25(8):869-76
Graves Disease in Infancy
Authors: Beliard Kara A , Shyamkumarb Srinidhi , Yau Mabel , Mintz Cassie , Rapaport Robert
Published: May 2021

Background: Graves disease (GD) is the most common cause of hyperthyroidism worldwide. The usual age of presentation is between 20-30 years, and it is more common in females. Transient hyperthyroidism does occur in infants born to mothers with GD, however, the novo GD in infants is extremely rare. We are aware of only four cases of GD in children under the age of 2 years old previously reported in the literature, with the youngest being of 18 months. Although rare, the complications can be devastating, so identifying and treating GD in infants is vital. We describe an infant who presented at 12 months of life with poor weight gain.

Patient Findings: A 12-month old female patient presented with weight loss, tachycardia, diaphoresis and hypertension. She had a palpable thyroid gland without ocular changes. She was found to have an undetectable Thyroid Stimulating Hormone (TSH) with an elevated free T4 of 2.1 ng/dL (normal 0.80 - 1.50 ng/dL). She was stabilized in the intensive care unit with beta-blocker and methimazole. The diagnosis of GD was subsequently confirmed with an extremely elevated elevated Thyroid Stimulating Immunoglobulins (TSI) titer of 263 Iu/L (normal 0.00-0.55 IU/L), her TSH receptor gene was normal. At 34 months of age, her TSI titer is still elevated at 34 IU/L and she still requires methimazole to maintain a euthyroid state. She is growing and developing appropriately.

Conclusion: To our knowledge, this report describes the youngest child to be diagnosed with GD in the English literature. Only four patients between the ages of 18 - 24 months have been described. Autoimmune diseases are rare in infants, the reason for which GD developed at such a young age remains unclear. Clinical signs and symptoms of hyperthyroidism in infants can be subtle and easily missed: increased growth velocity, failure to gain weight, autonomic changes, and irritability. Most patients have an enlarged thyroid gland, and some have ocular changes. The major long-term complications of undiagnosed hyperthyroidism include craniosynostosis and permanent neurocognitive damage. A high index of suspicion is needed for the recognition and prompt treatment of GD in infants, leading to better clinical outcome.
Significance of Discordant Results: between Confirmatory Tests in Diagnosis of Primary Aldosteronism
Authors: Fukumoto Tazuru , Umakoshi Hironobu , Ogata Masatoshi , Yokomoto-Umakoshi Maki , Matsuda Yayoi , Motoya Misato , Nagata Hiromi , Nakano Yui , Iwahashi Norifusa , Kaneko Hiroki , Wada Norio , Miyazawa Takashi , Sakamoto Ryuichi , Ogawa Yoshihiro
Published: May 2021

Context: Current clinical guidelines recommend confirmation of positive result in at least one confirmatory test in the diagnosis of primary aldosteronism (PA). Clinical implication of multiple confirmatory tests has not been established, especially when patients show discordant results. Objective: The aim of the present study was to explore the role of two confirmatory tests in subtype diagnosis of PA. Design: Retrospective cross-sectional study. Setting: The study was conducted at two referral centers. Participants and Method: We identified 360 hypertensive patients who underwent both captopril challenge test (CCT) and saline infusion test (SIT) and exhibited at least one positive result. Among them, we studied 193 patients with PA whose data were available for subtype diagnosis based on adrenal vein sampling (AVS). Main Outcome Measure: The prevalence of bilateral subtype on AVS according to the results of the confirmatory tests. Results: Of patients studied, 127 were positive for both CCT and SIT (double-positive), while 66 were positive for either CCT or SIT (single-positive) (n = 34 and n = 32, respectively). Altogether, 135 were diagnosed with bilateral subtype on AVS. The single-positive patients had milder clinical features of PA than the double-positive patients. The prevalence of bilateral subtype on AVS was significantly higher in the single-positive patients than in the double-positive patients. (63/66 [95.5%] vs. 72/127 [56.7%], P < 0.01). Several clinical parameters were different between CCT single-positive and SIT single-positive patients. Conclusion: Patients with discordant results between CCT and SIT have a high probability of bilateral subtype of PA on AVS.
Inadvertent Excessive Soy Intake as Part of a Weight Loss Program Leading to Rapid Growth of Multinodular Goiter
Authors: Thrupthi Komandur , Leung Vivien
Published: May 2021

Background: Over the past few decades consumption of soy products has gained popularity in the U.S. in part due to reports of potential health and weight loss benefits. However, concerns have emerged regarding soy as a potential endocrine-disrupting chemical (EDC) leading to thyroid dysfunction amongst other health issues. Studies have shown a potential association of high soy intake with risk of hypothyroidism and simple goiter (1), but less is known regarding its impact on multinodular goiter. Clinical Case: A 33-year-old female originally from Bolivia without significant medical history presented to our endocrine clinic with complaints of right-sided neck swelling. The swelling was insidious in onset, had gradually increased in size over the past 3-4 months, and become uncomfortable. She denied dysphagia, cough, or shortness of breath. Prior to the onset of symptoms, she had enrolled in a commercial weight loss program. The diet program consisted of limiting caloric intake to multiple meal replacement bars during the day followed by a light dinner of fish and non-starchy vegetables. Examination revealed a palpable right-sided thyroid mass and enlarged thyroid gland. Lab work showed normal TSH, fT4, and T3 levels, positive anti-thyroid peroxidase antibody (anti-TPO Ab) 588 (<=35.0 IU/ml), and negative thyroid-stimulating immunoglobulins (TSI). Ultrasound of the thyroid confirmed the presence of a 4 cm dominant right thyroid nodule and multinodular goiter. Subsequent fine-needle aspiration of thyroid nodule was consistent with benign nodular goiter. Upon further investigation, it was discovered that the meal replacement bars contained a significant amount of soy protein resulting in an excessive intake of 20-40 grams of soy protein daily. We discussed treatment options, and the patient declined thyroid surgery in favor of surveillance following discontinuation of the weight loss products. The patient was advised to consume a varied diet and given follow-up appointments for monitoring. Conclusion: Inadvertent excessive soy intake via meal replacement bars may have triggered the rapid growth of a multinodular goiter in our patient despite reported adequate dietary iodine intake. Soy products often contain isoflavones that may exert an adverse effect on the thyroid by inhibition of TPO, disruption of iodine metabolism, and/or estrogenic activity. We advise that caution be exercised with high soy protein consumption especially in patients with underlying risk factors for multinodular goiter. References: Messina, M. and Redmond, G., 2006. Effects of soy protein and soybean isoflavones on thyroid function in healthy adults and hypothyroid patients: a review of the relevant literature. Thyroid, 16(3), pp.249-258.
Iodoral-Induced Iatrogenic Hypothyroidism
Authors: Kwak Leigh , Gruntmanis Ugis , De Castro Alicia , Radovanovic Natasa , Ammana Hima Reddy
Published: May 2021

Background: Iodine is essential for the formation of thyroid hormones. Therefore, the thyroid gland is generally able to maintain normal hormone synthesis despite changes in iodine availability. When there is an increase in iodide load, the thyroid gland is able to inhibit the formation of organic iodide via the Wolff-Chaikoff effect (WCE). This prevents the formation of large quantities of thyroid hormones, thus preventing hyperthyroidism1. Continued exposure to excess iodine is also overcome by the “escape” phenomenon and hormone synthesis resumes in a normal fashion2. However, some patients may lack this autoregulation and develop hypothyroidism. Clinical Case: An 86-year-old male with a history of subclinical hypothyroidism initially presented to his PCP for evaluation of cognitive decline. Workup revealed a TSH of 10 mcIU/mL (0.34 – 5.6 mcIU/mL), a normal FT4 and a negative TPOAb. It was subsequently revealed that the patient was started on Iodoral 12.5 mg daily, an iodine/potassium iodide supplement, 1 month prior to presentation by a naturopathic doctor. Prior to all this, his TSH had always ranged between 4 – 6 mcIU/mL for many years. It was recommended that he discontinue Iodoral and repeat thyroid labs in the future. Despite this, the patient continued on varying doses of Iodoral supplementation. Repeat labs obtained 8 months later revealed an elevated TSH of 99 mcIU/mL and a low FT4 of 0.43 ng/mL (0.6 – 2.6 ng/mL). Despite these numbers, he was asymptomatic and did not exhibit any overt signs of hypothyroidism. He was referred to Endocrinology and finally stopped taking Iodoral.7 weeks post-discontinuation, his repeat labs showed a resolution of hypothyroidism and return to his baseline subclinical disease with a TSH of 8.2 mcIU/mL and a normal FT4. A urine iodine/creatinine was normal at 244.2 ug/g (35 – 540 ug/g) indicating that there was no residual iodine excess from the Iodoral. Conclusion: As far as we are aware, we present the first reported case of Iodoral-induced iatrogenic hypothyroidism. As with past cases of iodine-induced hypothyroidism, our patient had underlying thyroid disease in subclinical hypothyroidism which could explain why he was unable to escape from the WCE. The half-life of Iodoral is unknown but it is generally understood that the effects of iodide are reversed between 2 to 4 weeks after withdrawal. Our patient did not repeat his thyroid function tests until 7 weeks post-discontinuation but did demonstrate a return to baseline with no other intervention. Reference: 1. Markou K, Georgopoulos N, Kyriazopoulou V, Vagenakis AG. Iodine-Induced hypothyroidism. Thyroid. 2001 May;11(5):501-10. doi: 10.1089/105072501300176462. PMID: 11396709.2. Torti JF, Correa R. Potassium Iodide. 2020 Oct 12. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan–. PMID: 31194460.
Survival Benefit of Corticosteroid Replacement in Critically Ill Patients: One Treatment Effect or Two?
Authors: Laies Slavita M , Qualls Clifford R , Dorin Richard I
Published: May 2021

Survival benefit of corticosteroid replacement in critically ill patients: one treatment effect or two?

Background: In the comparison of placebo versus corticosteroid replacement therapy (CRT) among ill patients, the treatment effect (difference in 28-day mortality rate between placebo and CRT) tends to vary according to mortality in the placebo group. In this context, we treat 28-day mortality in the placebo group as a surrogate for severity of illness [1]. Hypothesis: In the present era of physiologic CRT, critical illness related corticosteroid insufficiency (CIRCI) may be defined operationally by the difference in clinical outcomes, such as 28-day mortality, between placebo and CRT treatment groups. In this simulation analysis, we examined the hypothesis that treatment effects of CRT observed in various randomized, placebo-controlled clinical trials may be explained by heterogeneous population consisting of two strata, S1 and S2, having discrete conditional probabilities of mortality when treated with CRT vs. placebo. Methods: Using published Randomized Controlled Trial (RCT) data, the relationship between treatment effect and severity of illness was analyzed using a least squares solution weighted by sample sizes. A probability model included likelihoods for outcomes (28-day mortality with placebo vs. CRT) in two population strata: (i) a minority stratum (S1) having treatment effect > 0 and (ii) a majority stratum (S2) having a treatment effect ≤ 0. In a simple simulation scenario we varied the treatment effect in S1 as function of the placebo group mortality in S2 in order to fit the relationship obtained from published RCT data. The potential impact of sensitivity and specificity on diagnostic tests to identify S1 was also addressed. Results: A hyperbolic function (y = [Mx/(K+x)] - A) provided a good fit for published RCT trials of physiologic CRT (treatment effect [y] vs. placebo group mortality rate [x]). Pooling results for S1 and S2 having population frequencies of 0.2 and 0.8, respectively, approximated the observed

hyperbolic function of treatment effects and severity of illness. A significant treatment effect was maintained when S1 was identified by diagnostic tests having 75% sensitivity-specificity. Conclusions: Population heterogeneity has not been excluded as an explanation for the relatively modest treatment effect of CRT in critically ill patients. Given the possibility of harm of CRT in the majority population (S2), our model further suggests that clinical or laboratory measures that would distinguish S1 and S2 with reasonable accuracy would significantly improve clinical outcomes and reduce numbers needed to treat. Our findings also support the more general hypothesis that the treatment effects of CRT vary according to severity of illness (1).

References: 1.Briegel, J., V. Huge, and P. Mohnle, Hydrocortisone in septic shock: all the questions answered? J. Thorac. Dis, 2018. 10(Suppl 17): p. S1962-S1965.
Lenvatinib-Induced Destructive Thyroiditis in a Patient With Hepatocellular Carcinoma
Authors: Pandya Anjani , Shakil Jawairia
Published: May 2021

Lenvatinib is an antineoplastic oral agent that acts as a multi-kinase inhibitor against vascular endothelial growth factor (VEGF). This drug is commonly known for its use against radioiodine-refractory differentiated thyroid cancer, but it is also approved for unresectable hepatocellular carcinoma (HCC). Side effects such as fatigue, hypertension, palmar-plantar erythrodysesthesia, diarrhea, decreased appetite, and hypothyroidism are frequently reported adverse effects. However, the incidence of hyperthyroidism is a less known phenomenon. This case describes a patient with HCC on lenvatinib therapy who develops destructive thyroiditis. A 69-year-old man with hepatitis c cirrhosis complicated by progressive hepatocellular carcinoma (Child-Pugh class A6) presented with generalized weakness, unintentional weight loss, heat intolerance, palpitations, and tremors. He had been started on chemotherapy with lenvatinib 12 mg/day four weeks prior to presentation. Endocrinology was consulted due to abnormal thyroid function tests (TFTs). He had no previous history of thyroid function abnormalities or family history of thyroid disease. Laboratory tests revealed a hyperthyroid state [total thyroxine (T4), 14.3 µg/dL (normal range 4.5-11.7); free thyroxine (FT4), 1.9 ng/dL (normal range 0.9-1.7); thyroid-stimulating hormone (TSH), 0.07 µIU/mL (normal range 0.27-4.20), and negativity for antibodies [anti-thyroid peroxidase antibody (TPO Ab), 0.8 IU/mL (normal range 0.0-9.0); thyroglobulin antibody (Tg Ab), < 0.9 IU/mL (normal range 0.0-4.0); thyroid stimulating immunoglobulin (TSI), 90% (normal range < 122)]. Ultrasonography revealed a mildly prominent thyroid gland, a homogenous echo texture, and no suspicious thyroid nodules. In addition, a 99m-technetium (99mTc) scintigraphy demonstrated reduced radioactive uptake that was consistent with thyroiditis. Therefore, this patient was diagnosed with lenvatinib-induced destructive thyroiditis. Palpitations improved with a beta-blocker and the patient was resumed on a lower dose of lenvatinib, 8 mg/day, one week later. About six weeks after the initial dose of lenvatinib, his TFT results normalized. Lenvatinib disrupts cell proliferation which can affect many organs, including the thyroid gland. Although several theories have been proposed, the exact underlying mechanism by which this occurs remains unknown. It is important to note that in addition to hypothyroidism, lenvatinib may also cause hyperthyroidism in the form of a transient destructive thyroiditis. This emphasizes the need to routinely check TFTs prior to the initiation of lenvatinib and throughout the course of therapy.
Non-MAS Non-APS Rare Case: Co-Occurrence of Graves’ Disease (GD), Latent Autoimmune Diabetes in Adult (LADA), Systemic Lupus Erythematosus (SLE), and Ulcerative Colitis (UC)
Authors: Harris Laura , Tahapary Dicky L , Wisnu Wismandari , Purnamasari Dyah , Yunir Em , Waspadji Sarwono
Published: May 2021

Background: Advancement in medical technology has allowed us to diagnose complicated autoimmune diseases. There is a growing report of multiple autoimmunity co-occurence. Multiple Autoimmune Syndrome (MAS) is a combination of at least three autoimmune diseases, whereas Autoimmune Polyendocrine Syndromes (APS) comprise autoimmunity that involves multiple endocrine gland. Case Illustration: A 47-year old female came with chief complaint of palpitation. She had a history of systemic lupus erythematosus in the last three years, after suffering from malar rash, alopecia, and polyarthritis. Her 24-hour urine protein was 1575 mg. She routinely consumes methylprednisolone, hydroxychloroquine, and mycophenolic acid. She also experienced hematochezia and the biopsy from colonoscopy revealed chronic colitis with crypt destruction. She was diagnosed with ulcerative colitis and was treated with mesalazine. Since last year, her blood glucose was consistently high, accompanied with polydipsia and polyuria. She was treated with metformin, despite persistent increase in her A1C, as well as fasting and random blood glucose. We performed GAD65 test which came back positive, hence we diagnosed her with latent autoimmune diabetes in adult. In the past three months, she experienced palpitations, tremor, diarrhea, diaphoresis, and unexplainable weight loss. No exophthalmos was found, but she complained of an enlargement around her neck. We run thyroid hormone test, her TSHs was <0.003 (0.35-4.94 μIU/mL) and FT4 was 4.17 (0.70-1.48 ng/mL). Her ultrasound revealed diffuse enlargement of both thyroid with increased vascularization. We diagnosed her with Graves’ disease and treated her with methimazole and propranolol. Discussion: This case highlighted the rare co-occurrence of four autoimmune diseases. The underlying genetic predisposition of individual with autoimmune disease, will make them prone to develop multiple defect in their self-tolerance mechanism. However, the strict criteria of APS or MAS constrained us from putting all her autoimmunities into one big umbrella. Based on epidemiological data, hyperthyroidism in female productive age, with diffuse thyroid enlargement, is commonly due to Graves’ disease. However, this diagnosis needs to be further evaluated with thyroid scintigraphy and confirmed with TSH-receptor antibody test. Conclusion: Improvement in medical diagnostic tools as well as better understanding of the underlying pathophysiology will make it inevitable to find more autoimmunity co-occurrence in the future. In order to keep up with this progress, the traditional classification of APS or MAS should be reviewed to allow clinician to see the case in one big entity. Keywords: GD, LADA, SLE, UC
Overt Hypothyroidism Induced by Prolonged Therapy With Imatinib
Authors: Wang Ally W , Nosova Emily V
Published: May 2021

Background: Imatinib, a tyrosine kinase inhibitor (TKI), is commonly used to treat chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors. TKI-induced thyroid dysfunction is recognized as an adverse class effect with most cases occurring between six to twelve months after treatment initiation.

Clinical Case: 76-year-old man with hypertension and CML on Imatinib that had been started twenty months prior was admitted for confusion. The patient also reported constipation, cold intolerance, and weight gain despite no change in diet, appetite, or physical activity. On evaluation, his responses to questioning were noticeably delayed, however he was not lethargic. His vital signs were normal and he was otherwise euthyroid on physical exam. He had no known history of thyroid dysfunction. Labs showed a TSH of 94.7 (0.4 - 4.2 uIU/mL), Free T4 0.4 (0.8 - 1.5 ng/dL), and Total T3 30 (87 - 178 ng/dL). Thyroglobulin antibody was 1016 (0.0 - 4.1 U/mL) and TPO antibody was >2000 (0.0 - 5.6 IU/mL). A TSH checked two months before admission was 1.1. Antibody levels had not been checked previously. Thyroid ultrasound demonstrated a hyperemic and heterogeneous thyroid, consistent with thyroiditis. Levothyroxine at a dose of 50 mcg daily was advised, due to patient’s advanced age as well as history of arrhythmia. The patient’s confusion resolved on hospital day three. Repeat thyroid function tests will be checked four to six weeks after Levothyroxine initiation.

Discussion: As a class, tyrosine kinase inhibitors are known to cause thyroid dysfunction with the most common medication being Sunitinib. Data related to the effects of thyroid function during Imatinib treatment are limited. Previous cases of Imatinib-induced thyroid dysfunction report only hypothyroidism in thyroidectomized patients and no clinically significant change in thyroid function among patients who were euthyroid prior to therapy initiation. Our case reports a patient with no prior thyroidectomy who developed overt hypothyroidism while on Imatinib for nearly two years. The mechanism for TKI-induced thyroid dysfunction has not been elucidated. Due to relatively acute onset and markedly positive TPO and thyroglobulin antibodies, we suspect that TKI may alter HLA recognition on thyroid follicular cells, thereby inducing autoimmunity. Our case showcases the need to maintain awareness and continuous surveillance for thyroid dysfunction when patients are on long term TKI as overt hypothyroidism may be induced by prolonged treatment.
Rapidly Progressive Cognitive Decline and Varicella Zoster Blisters Associated With Teprotumumab in 2 Patients With Graves’ Orbitopathy
Authors: Hoang Thanh Duc , Chou Eva , Nguyen Nguyen T , Shakir Mohamed K M
Published: May 2021

Introduction: Teprotumumab, an IGF-1R antagonist, was approved for treatment of Graves’ orbitopathy (GO) in 2020. Common side effects include nausea, diarrhea, muscle spasms, hearing impairment, dysgeusia, headache, dry skin, infusion reactions, and hyperglycemia. We report here 2 cases of unexpected adverse effects. Patient #1 is a 76-year-old man with Graves’ disease diagnosed in 2018, treated with methimazole 2.5mg every other day. His GO manifestations included diplopia, proptosis, and exposure keratopathy. Past history was significant for hypertension, hyperlipidemia, and prostate hyperplasia. He lived independently and walked several miles daily. Teprotumumab was initiated. Between the 4th and 5th doses, his family noted 6-weeks of rapidly progressive cognitive decline characterized by behavioral changes, confabulation, memory deficit, delirium/delusions/mania. He was admitted to neurology service and subsequent doses held. Lumbar puncture was unremarkable. TFT was normal before, during and after stopping teprotumumab. Thyroid antibodies were notable for elevated TSI but normal thyrotropin receptor Ab and TPO/TgAb. Other labs: IL2, IL6, ESR, CRP, heavy metals, IgG, IgM, SARS-CoV-2 IgM/IgGs, vitamins B1, B6, and B12 were all normal. His most recent repeat TPO Ab was 14 IU/mL (increased from <6), TgAb 18.4 IU/mL (increased from <1.0). EEG showed no epileptiform activity. Head MRI/MRA showed cerebral amyloid angiopathy without stenosis or aneurysms in the intracranial arterial vasculature. Symptoms progressed with IV glucocorticoids and IV Ig therapy. He subsequently underwent plasmapheresis with resolution of symptoms. Patient #2 is a 48-year-old man with Graves’ disease and GO diagnosed in 2018, initially treated with methimazole and subsequently underwent total thyroidectomy in 2019. Patient is euthyroid on levothyroxine. Ophthalmic signs and symptoms included significant proptosis and retrobulbar pain. He was started on teprotumumab infusions. After his 4th dose, he noted painful vesicles in a dermatomal distribution on his right posterior thigh. Direct fluorescent antibody stain was positive for varicella zoster, and rashes resolved with valacyclovir therapy. Discussion: Paraneoplastic/autoimmune encephalitis syndromes can be associated with antibodies to neuronal cell surfaces/synaptic proteins and may occur in the presence or absence of cancer. The incidence of varicella-zoster virus infection is associated with the immune status of the patient, disease-related immunocompromised, or iatrogenic immunosuppression, with age being the major risk factor for 90% of adult cases. This could be incidental, or related to other disorders, or perhaps teprotumumab may have activated auto-immunity. The exact mechanisms for rapidly progressive cognitive decline and shingles remains unclear.
Severe Rhabdomyolysis and Acute Renal Failure Due to Noncompliance to Levothyroxine Therapy
Authors: Raj Rishi , Ghayur Ayesha , Elahi Qurrat , Patel Chinmaya
Published: May 2021

Background: Noncompliance to levothyroxine (LT4) is common however only rarely it leads to severe side effects. We report a case of rhabdomyolysis leading to acute kidney injury (AKI) requiring hemodialysis (HD) due to noncompliance to LT4 therapy for one month. Clinical Case: A 68-year-old Caucasian male presented with a 2-week history of worsening fatigue and generalized weakness, accompanied by pain in bilateral lower extremities. Medical history included coronary artery disease, heart failure with reduced ejection fraction, hypertension, dyslipidemia, hypothyroidism, type 2 diabetes mellitus, CKD. Home medications included LT4 200 mcg daily, metoprolol 25 mg daily, doxazosin 2 mg daily, amlodipine 5 mg daily, fluocinonide 40 mg daily, fosinopril 40 mg twice daily, metformin 500 mg twice daily and rosuvastatin 40 mg daily. Further history revealed the patient to be not taking LT4 as “he ran out of it for a month” and only resumed taking it 3 to 4 days before coming to the hospital. On examination, he had proximal muscle weakness with power 3/5 in bilateral lower extremities and mild tenderness on thigh muscles. Labs revealed creatinine 13.1 mg/dL (0.60-1.10 mg/dL), BUN 101 mg/dL (0-30 ng/dL), eGFR 4.0 ml/min/1.73m2, CK 69,500 U/L (22-198 U/L), TSH 55.8 uIU/ml (0.45-4.5 uIU/ml), and FT4 0.61 ug/dL (0.8-1.8 ug/dL). ABG showed metabolic acidosis. Routine labs three months prior revealed normal thyroid function tests (TSH 1.6 uIU/ml and FT4 1.3 ug/dL) on LT4 200 mcg and baseline CKD stage 3b (EGFR 51 ml/min/1.73m2 with baseline creatinine 1.4 mg/dL). The patient was diagnosed with severe rhabdomyolysis secondary to noncompliance with LT4 therapy in presence of concurrent statin use, leading to AKI. Rosuvastatin was stopped and he was treated with aggressive intravenous hydration, sodium bicarbonate, and LT4 200 mcg daily. Despite two days of aggressive treatment, CK remains elevated and hence HD was initiated. The patient underwent three sessions of HD during the course of his hospitalization. Due to lack of renal recovery, outpatient HD was arranged. At 4 weeks of outpatient follow-up, the patient was oliguric and HD dependent. At 8 weeks outpatient follow up, CK, TSH, and FT4 was normal on LT4 200 mcg daily and became dialysis independent. Conclusion: Noncompliance to LT4 therapy along with concomitant use of statin can result in severe rhabdomyolysis induced AKI in patients with CKD.