bluuebunny/crossref_metadata_2025 huggingface dataset:
Graves’ Disease Presenting After 25 Years of Stable Thyroid Hormone Replacement Therapy
Authors: Wyne Kathleen
Published: May 2021

Background: Autoimmune thyroid disease may present with a wide range of symptoms. When the presentation is hyperthyroidism due to Graves’ Disease the symptoms generally subside over the subsequent two years but may recur at any time months to years later. When the initial presentation is hypothyroidism that person usually remains hypothyroid, requiring thyroid hormone replacement therapy for the rest of their life. Clinical Case: 67 year old woman presenting with hyperthyroidism after 25 years of stable dose thyroid hormone replacement therapy (THRT). She recalls being diagnosed with hyperthyroidism in her late 30s. She did not take any medication at that time. She is very clear that she was not treated with radioactive iodine or surgery. She recalls presenting with fatigue and weight gain about 2 years later at which time she was initiated on thyroid hormone replacement therapy. After multiple dose changes in the first few years she was stabilized on 90 mg daily of Armour thyroid. After more than 20 years on this dose the hyperthyroid symptoms recurred. Her symptoms persisted after decreasing then, ultimately, stopping the Armour Thyroid. Evaluation for causes of hyperthyroidism revealed the presence of both TRAb and TSI antibodies that have decreased in titer but are now still present more than 4 years after the diagnosis of hyperthyroidism. Symptoms have been controlled over this time period with low dose (5-10 mg/day) methimazole. Conclusion: Hypothyroidism is very common in women, with Hashimoto’s Thyroiditis as the usual etiology. When patients on thyroid hormone replacement therapy (THRT) present with symptoms of hyperthyroidism they are usually managed with dose reduction. However, complete cessation of THRT is unusual, especially after more than 10-20 years of therapy. Dose reduction of more than 50% without contributing factors such as significant weight loss should prompt measurement of TRAb and/or TSI to evaluate for Graves’ Disease regardless of the duration of the THRT.
Graves’ Disease Induced Severe Hypercalcemia
Authors: Lugo Lopez Zahira Marie , Penna Laurianne El Musa , Ortiz Arnaldo Nieves , Rivera Ivan Augusto , Diez Andrea del Toro , Bossolo Alex N Gonzalez , Garcia Michelle Marie Mangual
Published: May 2021

Introduction: Hyperthyroidism is a well-known non-parathyroid hormone-mediated cause of hypercalcemia. Hypercalcemia associated with thyrotoxicosis is usually asymptomatic. Increased osteoclastogenesis is one of the mechanisms underlying this etiology. Hyperthyroidism is associated with mild to moderate levels of hypercalcemia in approximately 20% of patients, but severe hypercalcemia is rare. We report a case of a male with Grave’s disease-induced symptomatic severe hypercalcemia. Clinical Case: A 36-year-old male with type 2 diabetes mellitus and arterial hypertension who was transferred from another institution to our Emergency Department due to suspected primary hyperparathyroidism for Endocrinology Services evaluation. Family history is non-contributory. Patient reports palpitations, irritability, and unintentional weight loss of approximately fifty pounds in nine months. One month ago, he started with constipation, anxiety, depression, abdominal discomfort, nausea, and vomiting for which decided to seek medical attention. Physical examination was remarkable for tachycardia, dry mucous membranes, and goiter. Laboratory tests showed lipase 69 U/L (13-60U/L), albumin-corrected calcium 14.3 mg/dL (8.8-10.3mg/dL), phosphorus 3.30 mg/dL (2.4-4.2mg/dL), magnesium 1.58 mg/dL (1.8-2.2mg/dL), creatinine 1.38 mg/dL (0.90-1.30 mg/dL), alkaline phosphatase 77 IU/L (43-115IU/L), iPTH 4 pg/mL (11-67pg/mL), PTHrp <0.4 pmol/L (≤4.2pmol/L), 25-OH vitamin D 32.1 ng/mL (30-100ng/mL), 1,25-dihydroxyvitamin D <5.0 pg/mL(19.9-79.3pg/mL), hemoglobin 11.6 g/dL (14-18g/dL), negative serum and urine protein electrophoresis, TSH 0.003 uIU/mL (0.45-5.33 uIU/mL), free T4 2.80 ng/dL (0.71-1.85ng/dL), total T3 2.57 ng/mL (0.80-2.00ng/mL), TSI: 486% (<140%), urine calcium 24hr 525mg/day (100-300mg/day). Thoracic and abdominopelvic CT scan without contrast was unremarkable for masses, adenopathies, osseous lesions, or acute abdominal processes. Patient was treated with IV isotonic saline and methimazole 10mg oral daily with resolution of symptoms. Finally, diagnosed with Graves’ disease as the cause of hypercalcemia after ruling out other etiologies. He was discharged home with calcium levels 10.8 mg/dL, normal renal function, methimazole, and follow up with Endocrinology Services. Conclusion: This is a case of an atypical presentation of hyperthyroidism-induced symptomatic hypercalcemia. It is important to consider hyperthyroidism in the differential diagnoses of severe hypercalcemia. Prompt suspicion is essential due to the effective treatments available for Graves’ disease. Early treatment of hypercalcemia is important for quick resolution of symptoms and decreased associated mortality.
Graves’ Thyrotoxicosis and Fulminant Myopericarditis: A Clinical Dilemma!
Authors: Jain Meenu , Puchalski Adam , Hodge MaryBeth
Published: May 2021

Myocarditis is a rare presentation of Graves’ disease, fulminant myocarditis is even rarer. We report a woman with Graves’ disease with fulminant myopericarditis as the presenting clinical feature. A 23-year-old healthy woman presented with acute onset pleuritic chest pain, palpitations, diaphoresis, heat intolerance, and dyspnea. There was no history of fever, upper respiratory tract infection, diarrhea, or weight loss. Physical exam revealed sinus tachycardia and palpable non-tender thyroid. Blood work was pertinent for TSH <0.01uIU/ml(0.3-4.5), free T4 2.8ng/dl(0.6-1.5), free T3 > 32.6pg/ml (2.4-4.2) and positive TSI (thyroid-stimulating immunoglobulin) 12.4 IU/L (<0.54). She had a diffusely enlarged vascular thyroid on ultrasound, all findings consistent with hyperthyroidism due to Graves’ disease. Electrocardiogram showed sinus tachycardia with diffuse PR depression and ST-segment elevation, troponin was 0.85 which increased to 17.5 within 12 hours, an echocardiogram showed normal ejection fraction (EF) with mild pulmonary hypertension but no pericardial effusion. She improved symptomatically with beta-blockers, methimazole, and colchicine but unfortunately had a witnessed ventricular fibrillation cardiac arrest in the next 12 hours with return to spontaneous circulation achieved after 90 minutes of bystander cardiopulmonary resuscitation. Coronary angiogram revealed normal coronaries with post-cardiac arrest EF of 5%. She subsequently developed acute respiratory distress syndrome secondary to massive pulmonary hemorrhage requiring extracorporeal mechanical support for worsening cardiogenic shock, succumbing to her illness a few hours later. Graves’ disease affects 0.5% of the population and causes hyperthyroidism in 50-80% of cases. Thyrotoxicosis may be associated with supraventricular arrhythmias and cardiomyopathy due to long-standing untreated hyperdynamic heart failure, but myopericarditis is an unusual presentation of Graves’ thyrotoxicosis with fulminant myopericarditis being even rarer. Fulminant myocarditis can present with ventricular tachyarrhythmias and can rapidly deteriorate into shock which may be difficult to distinguish from other causes of cardiogenic shock such as acute coronary syndromes or stress-induced cardiomyopathy. Myopericarditis associated with Graves’ is thought to be due to autoimmunity against functional TSH receptors identified in human cardiomyocytes. Fulminant myocarditis is a common cause of sudden cardiac death in young healthy adults, which is also the same population that gets Graves’ disease. It is critical to recognize the unusual presenting features of Graves’ disease such as fulminant myopericarditis, as timely aggressive intervention can reduce the risk of sudden cardiac death.
The Burden of Illness of Congenital Adrenal Hyperplasia (CAH) in Adults: Results: of a Structured Literature Review
Authors: Woods Matthew Stephen , Coope Helen , Maskin Kamran , Parviainen Lotta Elisabet , Porter John , Withe Michael , Sabar Uzmah
Published: May 2021

Objectives: Congenital adrenal hyperplasia (CAH) is a group of rare autosomal-recessive disorders that arise from genetic deficiencies in key enzymes involved in cortisol synthesis. The burden of CAH has never been comprehensively reviewed; this literature review was conducted to summarise the existing burden of illness evidence available for these patients. Methods: A structured, comprehensive literature review was conducted to identify articles describing the burden and treatment landscape of CAH. Literature databases (MEDLINE, Embase, the Cochrane Library and EconLit), websites and conference proceedings were searched. Searches were performed in 2016 and updated in June 2020; eligible articles presented evidence for patients with CAH or paediatric patients with adrenal insufficiency (AI), for ≥1 topic of interest (epidemiology; natural history; clinical characteristics; humanistic, caregiver and economic burden; treatment options; or clinical guidelines). The evidence presented here focusses on the humanistic and economic burden of CAH in adults. Results: A total of 3,711 citations were identified and 336 were included; 84 references reported humanistic or economic burden data relevant to adult patients with CAH. 51 publications were identified reporting patient symptoms, comorbidities and cardiometabolic risk factors; 38 reporting on the impact of CAH on health-related quality of life (HRQL); 5 reporting patient views and 2 reporting economic burden associated with CAH. Compared to the general population, adult patients with CAH were found to be significantly shorter, have poorer bone health, increased levels of obesity, impaired male and female fertility, higher blood pressure and cholesterol levels, have more psychiatric and neurological disorders and have poorer cognitive performance. Adult patients with CAH were also found to have greater insulin resistance and higher levels of type 2 diabetes (T2D). CAH patients are also at risk of adrenal crisis, which contributes to excess mortality. The reported HRQL in adults with CAH varies, with increased impairment observed in more severe forms of CAH, and challenges due to living with a chronic disease impacting HRQL varying according to sex. “Sick day rules” where patients need to double or triple treatment doses, have a significant impact on patients’ HRQL and also have an impact on patients’ resource use, with a UK study reporting that CAH patients will implement these rules 171 times over their lifetime, and be hospitalised for adrenal crises on 11 occasions. CAH was also found to have a significant economic impact, with significantly higher annual healthcare costs compared to matched controls (p=0.007 for patients aged 18–40 years; p<0.001 for patients aged ≥40 years). Conclusions: This comprehensive review highlights that CAH in adults is associated with a significant humanistic and economic burden.
Percutaneous Ethanol Injection as Treatment for Thyroid Cystic Nodules
Authors: Rios Paola , Ambut Jonathan , Manzano Alex
Published: May 2021

Background: Thyroid cystic nodules are common and frequently benign. Aspiration of thyroid cyst decreases compression symptoms and volume. However, they commonly recur, and usually, surgery is required for definitive treatment. A less invasive approach, done less frequent, is percutaneous ethanol injection (PEI), which has shown fewer recurrences than simple aspiration and is well-tolerated with few side effects. We present 2 patients that where treated in our clinic with PEI.

Clinical Case: 41-year-old female with a history of primary hypothyroidism on Levothyroxine, with neck discomfort, and no risk factors for thyroid cancer had a cystic thyroid nodule 1.5 x 1.8 x 2.8 cm over the right thyroid lobule. Cytology results reported as Bethesda II. One year later, her thyroid nodule was 1.9 x 2.6 x 3.3 cm. Underwent FNA and 6 cc of dark brown liquid was drained from the cyst which was reported again as Bethesda II. The patient was monitored with thyroid ultrasound after a year, and the cystic nodule was 2.2 x 2.9 x 3.1 cm. PEI was decided as the next approach. After six cc was aspired, 0.5 cc of desiccated ethanol was injected into the remained cystic. Eight months after PEI, cystic size was 0.7 x 0.9 x 0.8 cm. The second case is a 40-year-old female who presented complaining of neck discomfort without changes in her voice. The patient did not have any risk factors for thyroid cancer. Thyroid ultrasound was done, which showed a 2.3 x 2.7 x 3.3 cm cyst on her right thyroid lobe. PEI was arranged and 9 cc of dark fluid was aspirated with a posterior injection of 0.5 cc of desiccated ethanol. Symptoms resolved, and the patient was lost to follow up. Five years later, she was seen again. Neck ultrasound showed a cyst of 0.4 x 0.6 x 0.8 cm on her right thyroid lobe. Neither of the two patients had a side effect associated, and the procedure was well tolerated.

Conclusions: Percutaneous ethanol injection is a good alternative in the treatment for cystic thyroid nodules due to decrease in cystic size, which we observed that continued for five years of follow up in one of our patients. These will avoid frequent cystic aspiration secondary to recurrence or invasive surgical management.
Profound Hypothyroidism 21 Days After Methimazole Initiation in a Patient With Graves’s Disease and Liver Cirrhosis
Authors: Hammami Safa , Schuff Kathryn Graham , Hettinger Barbara Diane
Published: May 2021

Introduction: Methimazole is the first line treatment of nonpregnant Grave’s disease (GD) patients with Grave’s ophthalmopathy. It usually results in euthyroidism within 4 to 12 weeks, and it is recommended to check FT4 every 4 to 6 weeks after initiation of therapy. We report a patient with GD who developed profound hypothyroidism 21 days after starting methimazole. Clinical Case: 51-year-old male with decompensated EtOH/NASH liver cirrhosis, Gilbert’s syndrome, and GD presented with severe hypothyroidism 21 days after initiating methimazole treatment. He initially presented to the emergency department (ED) with atrial fibrillation with a HR of 140 and found to have bilateral exophthalmos and lid lag. Labs: TSH <0.01 uIU/L (normal range (nl) 0.27-4.20), FT4 2.6 ng/dl (nl 0.7-1.7), TT4 6.2 ug/dl (nl 4.5-12), TT3 125 ng/dl (nl 71-180), TBG 14 ug/ml (nl 13-39), TSI 344 IU/l (nl 0-0.5), AST 55 IU/L (nl 14-44), ALT 27 IU/L (nl 9-57), Alk Phosphatase 497 IU/L (nl 45-129), Tbili 7.1 mg/dl (nl 0.2-.1), and albumin 2.1 g/dl (nl 3.4-5). He was started on methimazole 40 mg daily and propranolol 20 mg BID. Three days later, FT4 decreased to 1.3 ng/dl, so methimazole was decreased to 20 mg day. Ten days later, FT4 was 0.2 ng/dl and methimazole was reduced further to 10 mg daily. Eight days later, he presented to the ED with severe lethargy and found to have HR of 38 and oral temperature (T) of 94. TSH was 3.49 uIU/L and FT4 <0.1 ng/dl. Sixteen hours after 200 mcg IV levothyroxine, he had normal mental status, HR of 49, and T of 97.9. FT4 increased to 0.5 ng/dl within 48 hours of thyroxine initiation. Urine drug screen was only positive for tetrahydrocannabinol and other work up for severe lethargy and hypothermia was unremarkable. He was discharged on 100 mcg of PO levothyroxine. Conclusion: Only 21 days after starting methimazole, the patient developed severe lethargy associated with hypothermia, bradycardia, and undetectable FT4, with no alternative etiology and prompt response to IV levothyroxine, consistent with profound hypothyroidism. Although the half-life of T4 is shortened in hyperthyroidism, the particularly fast and profound effect of methimazole in this patient was unusual and likely due to a limited extra-thyroidal pool of thyroxine caused by low TBG level. As cirrhosis is usually associated with increased TBG level, he may have a contributing congenital etiology. Reduced levels of other T4 binding proteins, albumin and pre-albumin may also have contributed. Although methimazole clearance can be decreased in liver impairment, no dose adjustment is generally recommended, and even this would not have explained the observed rapid decrease in FT4 level. Methimazole should be used with caution and FT4 should be checked early and more frequently when treating hyperthyroid patients with liver disease and possible alteration in thyroid binding proteins.
Skin Deep: A Rare Case of Thyrotoxic Periodic Paralysis in an African American Patient
Authors: Banerjee Ela
Published: May 2021

Background: Thyrotoxic Periodic Paralysis (PP) is a rare form of hypokalemic PP that occurs in association with hyperthyroidism, especially Grave’s disease. This disease is frequently seen in males and is particularly prevalent among Asians with an incidence rate of 2%. In non-Asian populations, the incidence among those with hyperthyroidism is even lower at 0.1 - 0.2% and therefore significantly rare in African populations. Inability to recognize this emergency in the non-Asian population can therefore result in potentially fatal outcomes. Case Presentation: A 27 year old African American male with a history of Grave’s disease presented to the emergency department (ED) with the inability to move his muscles. Patient was initially diagnosed with Grave’s disease in 2017 when he was found to have suppressed TSH with elevated TSI and started on methimazole 40mg daily. The patient ran out of methimazole about 2 weeks prior to presentation and woke up on the day of admission with extreme muscle weakness. At the outside hospital, he was found to have potassium of 1.5mEq/L,TSH of < 0.1uL/ml and Free T4 of 3.4 ng/dL. He was given 1000 mg Propylthiouracil, stress dose hydrocortisone, propranolol and potassium replacement and then transferred to our ED for Endocrine evaluation. On assessment, he complained of nausea, vomiting, full body muscle weakness, tingling in his extremities and irritability. He denied any recent illnesses. On physical exam, Temperature 97.4 F, Respiration 18, Pulse 84, BP 157/72, O2 saturation 99%. His thyroid gland was enlarged however non-tender and without bruit. He had normal respiratory and cardiac exam. He was lying flat in bed and unable to raise his limbs against gravity and also unable to hold up his limbs when raised. He lacked his patellar and ankle jerk reflexes bilaterally. He was otherwise alert and oriented x 3. On labs, TSH was 0.004 uL/ml, Total T3 was 294 ng/dL, Free T4 of 3.01 ng/dL, Potassium was 2.1 mEq/L. His potassium was cautiously replaced and improved to 4.7 mEq/L later in the day, at which time, the patient was able move and sit up in bed. He was restarted on Methimazole 40mg daily for his thyroid disease and arranged for outpatient follow up. Discussion: Thyrotoxic PP is seen in a male-to-female ratio ranging from 17:1 to 70:1 and occurs at an average age of 20-40 years. Thyrotoxic PP is especially rare in the non-Asian population at an incidence rate of 0.1 - 0.2%. Nevertheless, in setting of ever-growing diversity due to immigration and inter-race relationships, it is difficult to predict one’s genetics based on the color of their skin. It is possible that our African American patient may have an Asian ancestor unbeknownst to him. Therefore, we must keep a broad differential regardless of one’s race so as to not miss timely diagnosis of medical emergencies which can result in reduced muscle strength, flaccid paralysis, respiratory failure, cardiac arrhythmias and eventual death.
Subacute Thyroiditis With Very Elevated Thyroglobulin Level in a Patient on Chronic Adalimumab Therapy
Authors: Jobira Beza , Saxon David , Greca Amanda La
Published: May 2021

Background: Viral infections are a well-recognized cause of subacute thyroiditis (SAT), but other etiologies are occasionally seen. Here we present a case of SAT in a patient receiving chronic tumor necrosis factor inhibitor (TNF-i) therapy. Serum thyroglobulin (Tg) levels in healthy individuals have been reported and range 1.40-29.2ng/mL in males and 1.50-38.5ng/mL. There are no known serum Tg levels of reference in SAT.

Clinical Case: A 43-year-old woman with a history of psoriasis treated with adalimumab presented to her primary care physician (PCP) 2 months after her mother had noticed the patient’s new goiter. Patient recalled upper respiratory infection symptoms lasting 1.5 weeks, and subsequent agitation, insomnia, and a low-grade fever preceding the development of goiter. She denied neck compressive symptoms aside from mild dysphagia. She has been treated with adalimumab 40mg subcutaneous injection weekly for psoriasis with good results for the past 3.5 years and was on norethindrone 0.35mg daily for contraception. Her thyroid exam with her PCP revealed a diffuse painless goiter and she was clinically euthyroid. Labs revealed a TSH 1.44mIU/L [0.45-5.33], TT3 104ng/dL [60-181], fT3 3.3pg/mL [2.3-4.2], fT4 0.83ng/dL [0.89-1.76], and Tg 288.7ng/mL [1.6-50]. Thyroid antibodies (Tg, thyroid peroxidase and thyroid stimulating immunoglobulin) were negative. She tested negative for COVID-19. The neck ultrasound showed an enlarged pseudonodular thyroid gland with a heterogenous parenchyma and diffuse hypervascularity bilaterally (right lobe, 7.4 x 2.8 x 3.0 cm; left lobe, 8.4 x 3.2 x 3.6 cm; isthmus, 9 mm). A month later, repeat labs showed TSH 1.56 mIU/L, TT3 85 ng/dL, fT4 0.74 ng/dL, and Tg 231.2 ng/mL. She was subsequently referred to Endocrine Clinic 4 months after her initial presentation. She had a persistent diffuse painless goiter, minimally decreased in size, and she remained clinically euthyroid. Labs included a TSH 1.75 mIU/L and fT4 0.78 ng/dL.

Conclusion: There are known associations of SAT with chronic TNF-i therapy in patients with psoriasis. Viral infections are an identified cause, but other triggers in chronic TNF-i therapy may exist. Serum Tg is elevated during SAT, but in this case Tg elevation was very significant. Although normal serum Tg levels are established in healthy individuals, there are no known reference values during SAT. Tg levels should not be used in acute illness period to evaluate illness severity or the resolution of SAT.
Successful Management of Hyperthyroidism With Lithium and Radioiodine in a Patient With Previous Methimazole-Induced Agranulocytosis
Authors: Fantin Esther H , Goemann Iuri Martin
Published: May 2021

Introduction: Antithyroid drug (ATD) therapy is the first-line treatment of Graves’ hyperthyroidism. Agranulocytosis, although rare, is a life-threatening condition associated with ATD therapy. For patients who recovered from ATD-induced agranulocytosis, surgery or radioiodine (RAI) therapy are adequate options to restore the patient’s euthyroid state. Here we report a case of ATD-related agranulocytosis where lithium therapy was used before RAI to control thyrotoxicosis and prevent worsening of hyperthyroidism. Case Report: A 74-year-old female with a previous history of hypertension presented with a 2-month history of weight loss (12 lbs), palpitations and shortness of breath. She was afebrile with a heart rate of 110, a blood pressure of 149/80, a fine tremor and a moderate diffuse goiter. She had a normal eye exam. Laboratory evaluation demonstrated TSH <0.01 uIU/mL (0.35-5.5), FT4 3.11 ng/dL (0.51-1.65) and TSH receptor antibody (TRAb) 40 (<1,0 U/L), consistent with thyrotoxicosis due to Graves’ disease. She was started on methimazole (MMI) 15mg and metoprolol. After four weeks, symptoms resolved and thyroid function tests (TFT) improved. However, after two months of treatment, she was hospitalized for fever, diarrhea and abdominal pain. White blood cell count (WBC) was 650/μL, and neutrophil count was 90/μL. A diagnosis of gastroenteritis and agranulocytosis was made and MMI was stopped. After seven days, symptoms resolved, the neutrophil count was 2200/ul and TFT were acceptable (FT4 1.25, ng/dL TT3 1.67 ng/ml, TSH < 0.02 uIU/mL). She was discharged without ATDs and a RAI dose of 20 mCi was scheduled. However, RAI therapy had to be postponed due to COVID-19 pandemic restrictions. After 3 weeks, TFT worsened and therapy with lithium carbonate 300 mg TID was started as the patient refused thyroidectomy. Lithium was initiated 12 days before RAI therapy and was maintained 7 days after the procedure. No side effects associated with lithium treatment were reported. TFT 7 days after RAI were FT4 1.43, ng/dL TT3 2.05 ng/ml and TSH < 0.02 uIU/mL. One month later, the patient was euthyroid without need for thyroid medication and remains on follow up. Discussion: Serum thyroid hormone (TH) concentrations usually increase after RAI therapy for Graves’ disease, a worrisome fact in patients with increased risk for cardiovascular complications. Previous studies report that pre-RAI treatment with lithium prevents changes in serum TH concentrations and enhances RAI therapy’s effectiveness. Here, treatment with lithium was used to control thyrotoxicosis and prevent further increase in TH levels associated with RAI therapy. Lithium is particularly suitable for patients with ATD-related side effects before definitive therapy (radioiodine or thyroidectomy). The antithyroid effect of lithium in this setting should be further studied.
Thyroid Abscess Initially Presenting as Destructive Thyroiditis With Subsequent Hypothyroidism
Authors: Caseja Ahl Jeffrey , Wang Richard L , Nakhle Samer
Published: May 2021

Introduction: Due to its rich vascular supply and high iodine content infection of the thyroid gland is rare and is uncommonly associated with hyperthyroidism. We report a case of a thyroid abscess presenting with hyperthyroidism with subsequent hypothyroidism in an immunocompetent patient.

Clinical Case: A 34-year old female with no past medical history presented with an enlarging neck mass associated with worsening, non-radiating throat pain of three-week duration associated with dysphagia. She reports 15-lb weight loss and palpitations. On presentation vital signs were within normal range. Physical examination revealed a diffusely tender anterior neck mass. Her thyroid function tests revealed TSH 0.01 uIU/mL (0.358-3.74), FT4 2.4 ng/dL (0.76-1.46), TSI <0.10 IU/L (0.00-0.55), TPO 12 IU/mL (0-34). Laboratory workup was also significant for leukocytosis, thrombocytosis, and hyponatremia. Thyroid ultrasound revealed a large, irregularly shaped, multiloculated fluid collection involving both lobes measuring 6.4 x 4.8 x 2.0 cm. She was started on Vancomycin and Ampicillin/Sulbactam, Metoprolol, and Methimazole. Needle aspiration of 30 cc of purulent material was performed with culture showing a heavy growth of streptococcus constellatus sensitive to penicillin. After a 4-day inpatient stay, she was discharged with Amoxicillin/Clauvanate as well as Methimazole 10mg BID. Ten days after being discharged, the patient again presented to the emergency department with complaint that the neck mass had increased in size. CT neck showed a 5.1 x 2.8 x 0.8 cm lobulated fluid collection. CT-guided drainage was performed, cytology and wound culture were found to be unremarkable. Thyroid function tests revealed she was hypothyroid with TSH 31.157 uIU/mL and FT4 of 0.72 ng/dL. Upon discharge, Methimazole was discontinued and she was started on Levothyroxine 75 mcg daily. Due to failure of prior antibiotics, she received a 14-day course of IV Ceftriaxone. Outpatient follow-up eight weeks later showed she was euthyroid on Levothyroxine 75 mcg with ultrasound revealing small thyroid gland with resolution of the abscess.

Conclusion: Hyperthyroidism in the setting thyroid abscess is secondary to destructive thyroiditis. As there is no increase in thyroid hormone synthesis, there is no role for treatment with antithyroid medication. Symptomatic control with beta-blocker, surgical drainage, and IV antibiotics are recommended for cases of thyroid abscesses. If infection persists or extensive necrosis develops, thyroidectomy may be indicated. Hypothyroidism can be a consequence of destructive thyroiditis as was seen in this patient.
Thyroid Hormone Resistance With Concurrent Papillary Thyroid Cancer
Authors: Pahwa Dhivya , Shanik Michael Howard
Published: May 2021

Introduction: Thyroid hormone resistance is a genetic mutation resulting in decreased receptor responsiveness. We present a case of thyroid hormone resistance with concurrent papillary thyroid cancer.

Clinical Case: A 34-year-old man with a history of papillary thyroid carcinoma status post total thyroidectomy and radioactive iodine. He had transferred his care after moving to our area. He presented with persistently elevated TSH despite ongoing treatment with Levothyroxine 400 mcg daily. Upon presentation the patient reported intermittent palpitations and tremor. Vital signs revealed height of 74 inches, weight of 235 pounds, blood pressure of 112/64, and heart rate of 48. Physical examination revealed a well -healed scar on the neck without palpable lymphadenopathy. Bloodwork revealed TSH of 15.28 mIU/L and Free T4 of 2.8 ng/dL. The patient was maintained on Levothyroxine 400 mcg daily and educated on proper administration of the medication. Two months later, bloodwork revealed a TSH of 9.22 mIU/L with a Free T4 of 3.3 ng/dL. MRI of the pituitary revealed a 4mm hyper-intensity which likely represented a microadenoma. Resistance Thyroid Hormone (RTH) Mutation analysis was ordered which revealed a heterozygous mutation for the Thyroid Hormone Receptor (THR)-Beta gene. The mutation was detected at pArg438His indicating a single nucleotide substitution leading to the replacement of arginine by histidine at the p.438 of the translated protein on exon 10. The patient was maintained on Levothyroxine at 400 mcg daily.

Discussion: Thyroid hormone resistance describes a constellation of symptoms from decreased tissue responsiveness to thyroid hormones. Literature reveals the prevalence of THR to be 1 in 40,000 individuals. It occurs due to mutation on the thyroid hormone receptor, most often found on the alpha or beta subunit. Frequently patients present with tachycardia and hyperactivity but it can also present with symptoms suggestive of hypothyroidism and goiter. Risk factors include family history of RTH mutation often with an autosomal dominant inheritance pattern. Patients with an elevated Free T4 with a non-suppressed TSH should be investigated with a genetic analysis of Resistance Thyroid hormone. A positive mutation would confirm the diagnosis. Close monitoring of symptoms as well as thyroid function tests should guide treatment. The concurrent diagnosis of thyroid hormone resistance in conjunction with papillary thyroid carcinoma in our patient is unique and makes management a challenge. The literature reveals few cases reported.

Reference: DynaMed. (2018, November 30). Thyroid Hormone Resistance. Retrieved October 2, 2020, from https://www-dynamed-com.arktos.nyit.edu/topics/dmp~AN~T912485

Igata M, et al. Coexistence of resistance to thyroid hormone and papillary thyroid carcinoma. Endocrinol Diabetes Metab Case Rep. 2016;2016:160003. doi:10.1530/EDM-16-0003
Thyroid Tuberculosis Causing Fever of Unknown Origin in a Patient With Multinodular Goiter
Authors: Rauf Mohammad Talha , Nhan Winnie , Daneshvar Farah
Published: May 2021

Introduction: Tuberculosis (TB) involving the thyroid gland is rare and typically results in hypothyroidism. Here we report a case of thyroid TB that presented with hyperthyroidism. Clinical Case: A 54-year-old woman with a history of hyperthyroidism due to toxic multinodular goiter presented to the emergency department with fever of unknown origin associated with sore throat, non-productive cough, night sweats, diarrhea, and right anterior neck pain that worsened with coughing. Her fevers were intermittent, ranging from 38 to 39 degrees Celsius, and would subside with acetaminophen. She reported that her symptoms had started after getting a thyroid [Tc-99m] pertechnetate scan and 24 hour [I-131] sodium iodide uptake study a month prior. The scan at the time revealed hyperfunctioning thyroid nodules in the lower lobes bilaterally. The 24-hour uptake was 20.2% which is within the normal range of 7 to 30%. TSH on presentation was 0.01 mIU/L (Normal range 0.3-5.50 mIU/L), free T4 was 2.05 ng/dL (Normal range 0.76 -1.7 ng/dL), and free T3 was 5 pg/mL (Normal range 1.9-3.9 pg/mL). Exam revealed a multinodular goiter, which was firm with mild tenderness, and no cervical lymphadenopathy. Infectious workup was unremarkable other than a positive interferon-gamma release assay. As for TB risk factors, the patient immigrated to the United States from Albania about 13 years prior. The patient denied any known TB exposure, neither had she been treated for TB. Radiograph and computed tomography (CT) of the thorax were unremarkable other than re-demonstration of the multinodular goiter. Fluorodeoxyglucose-18 positron emission tomography (FDG-PET), which was performed to identify any focus of active TB, had revealed intense, infiltrative, heterogeneous FDG uptake of the nodular thyroid gland with reactive level 3 and 4 cervical lymph nodes. Also, the scan revealed hyper-metabolic hilar, pre-tracheal, and sub-carinal lymph nodes which could represent latent TB. Further workup for any other foci of active TB including broncho-alveolar lavage, sputum cultures, lumbar puncture, and bone marrow biopsy were unremarkable. Thyroid ultrasound revealed 2 right sided and 3 left sided thyroid nodules, mostly solid and hypoechoic. Fine needle aspiration of nodules revealed benign follicular nodules bilaterally, however the left aspirate contained loose aggregates of histiocytes consistent with non-necrotizing granulomas. Acid-fast bacilli stain of the aspirate was negative. The patient was started on therapy for active TB with isoniazid, rifampin, pyrazinamide, and ethambutol. Six weeks after treatment her fevers had resolved. Conclusion: Thyroid TB should be considered when the severity of symptoms cannot be explained by the degree of hyperthyroidism alone in patients with increased risk of TB. Additionally, TB in the thyroid can be challenging to identify in a patient with known underlying thyroid disease.
ThyrotropinomA: Diagnosing a Rare Cause of Hyperthyroidism
Authors: Bhanot Monica , Hendrickson Chase Dean
Published: May 2021

Case: The patient is a 40-year-old male who presented for evaluation of hyperthyroidism with symptoms including palpitations, increased bowel movements, anxiety, and worsening tremor. With a family history of Graves’ disease and an ultrasound showing a hyperemic thyroid, there was initial suspicion for Graves’ disease. Although a radioactive iodine thyroid scan showed diffuse uptake that was elevated, 21.4% at 4 hours and 33.1% at 24 hours, lab evaluation appeared inconsistent with Graves’ disease revealing: TSH 1.65 µU/mL (upper limit of normal [ULN] 4.5), free thyroxine (FT4) 1.99 ng/dL (ULN 1.17), free triiodothyronine 6.16 ng/dL (ULN 3.98), thyroid stimulating immunoglobulin 92% (ULN 122), and thyroid receptor antibodies less than 1.0 IU/L (ULN 1.75). Lab results were reproducible with elevated FT4 even by equilibrium dialysis at 3.9 ng/dL (ULN 2.4) and high-normal TSH with serial dilution that ruled out assay interreference. Given these findings, our focus turned to rare causes of hyperthyroidism including thyrotropinoma and thyroid hormone resistance (RTH). Unique to the diagnosis of thyrotropinoma is an elevated serum α subunit in 50-85% of cases (1). Therefore, we obtained an α subunit level which was 0.35 ng/mL (ULN 0.55) with a molar ratio of 2.2 (ULN 2.4). Since the α subunit level was normal, the patient obtained genetic testing for mutations in the thyroid hormone receptor β gene seen in 85% of RTH cases (1). However, no sequence variants were identified. Since initial lab and genetic analyses were undifferentiating, additional tests were obtained including an insulin-like growth-factor 1 level of 209 ng/mL (ULN 237) and prolactin level of 10.1 ng/mL (ULN 20) which can be elevated in 30% of mixed thyrotropinoma cases (1). The first evidence to suggest a thyrotropinoma was a mildly elevated sex-hormone binding globulin at 102 nmol/L (ULN 80). Further evaluation with pituitary magnetic resonance imaging showed a 6-milimeter lesion. Although the pituitary lesion is suggestive of a thyrotropinoma, it is not definitive, as they are present in 20% of RTH cases (1). Therefore, with increased suspicion of a thyrotropinoma, we pursued the more robust T3 suppression test which showed 56% suppression of TSH consistent with a thyrotropinoma. The patient had pituitary surgery with pathology confirming weak immunoreactivity for TSH. Post-operatively, his symptoms improved and free thyroid hormones normalized.

Discussion: It is important to distinguish between thyrotropinoma and RTH as the treatment is different with 80% of thyrotropinoma cases achieving euthyroidism after surgery (1). In our case, the diagnosis was initially unclear thus it was important to broaden the lab and genetic evaluation considering the limitations of the studies. One such limitation is the α subunit may not be elevated in microadenomas as occurred in our case.

1. Beck-Peccoz et al. J Endocrinol Invest. 2019; 42:1401-6
Title: Case of Hyperthyroidism in a Patient on Anti-PD-1 (Programmed Cell Death Receptor-1 Blocking Antibody) Therapy Caused by Destructive Thyroiditis Followed by Graves’ Disease
Authors: Reddy Chandrika , Zena Mohsen
Published: May 2021

Introduction: Immune checkpoint inhibitor (ICI) related thyroid dysfunction such as destructive thyroiditis and hypothyroidism can occur with Anti-PD-1 therapy. Graves’ disease (GD) however is considered rare. We report a case of isolated hyperthyroidism in a patient on Pembrolizumab, Anti-PD-1 presenting initially as destructive thyroiditis and later transitioned to GD.

Case: 57 y.o lady was diagnosed with squamous cell carcinoma of cervix, stage 4 in 2016. She was noted to have asymptomatic goiter in 1997. PET scan in 02/2017 showed hypermetabolic activity in the right lobe nodule of 5.6 cm with maximum SUV of 9.8. Baseline TSH was in normal range in 04/2017. US guided fine needle biopsy of the nodule resulted as follicular neoplasm with 15-30%, risk of malignancy. Molecular test showed 40% risk of malignancy. Lobectomy was deferred. Pembrolizumab was initiated for advanced cervical cancer in 07/2018. Repeat PET in 10/2018 showed resolution of metastasis and right thyroid mass was stable. TSH remained in euthyroid range for 4 months until 11/ 2018. In 01/2019, her TSH was low and became undetectable in 03/2019 with high free T4 and total T3. She developed symptoms of hyperthyroidism. TSI was positive and TSHR Ab was negative. RAIU was low. No iodinated contrast study done prior to I123 scan. In 05/2019 to 08/2019, free T4 and total T3 was normal range with detectable but low TSH consistent with transient resolving thyroiditis. In 10/2019, thyroid hormones significantly increased with recurrence of hyperthyroidism. Both TSI and TSHR Ab were elevated confirming diagnosis of GD. Due to overt thyrotoxicosis, Methimazole (MMI) was initiated in 10/2019. She was briefly lost to follow up and stopped MMI. RAIU scan in 12 /2019 showed increased uptake consistent with GD. MMI was resumed in 04/2020. 06/2020 - 09/2020, MMI dose was titrated to achieve euthyroid state. In 09/25/2020, hypothyroidism was noted which improved with MMI dose reduction. Anti- TPO and Anti-Tg were negative. Pembrolizumab was stopped in 07/2020 due to dilated cardiomyopathy. She completed 2-year course of Pembrolizumab with advanced cervical cancer showing excellent response.

Discussion: Observed thyroid dysfunction with ICI, is transient destructive thyroiditis followed by hypothyroidism, which can be permanent. Our patient had an initial low RAIU indicating destructive thyroiditis along with, mildly elevated TSI suggestive of superimposed autoimmune process. The elevated TSI predisposed to later occurrence of GD likely precipitated by Pembrolizumab. MMI provided therapeutic benefit.

Conclusion: Less than 10 cases of GD with ICI and 5 cases of GD with Anti-PD- 1 have been reported. Our patient is a second case of persistent hyperthyroidism due to GD induced by Pembrolizumab. GD should be considered if hyperthyroidism persists or recurs in patients on ICI with destructive thyroiditis, which is mostly transient.
Use of Lugol’s Solution in the Management of Complex Graves’ Disease-a Small Case Series
Authors: Asefa Rufaro , Martin Allison Shane
Published: May 2021

Background: There are currently no clear guidelines for the peri-operative use of Lugol’s solution (LS) as an alternative to conventional anti-thyroid drug (ATD) therapy in patients with complex Graves’ thyrotoxicosis.

Clinical Cases: Case 1 is a 44- year-old woman who presented with symptoms of hyperthyroidism and a moderately enlarged goiter due to Graves disease. She was treated initially with Methimazole 45 mg, once daily which was reduced to 30 mg once daily after a week. She subsequently presented to the emergency department with severe anxiety, sore throat, and a high fever. A blood panel showed evidence of profound agranulocytosis due to Methimazole. Methimazole was stopped and she was treated with a 10-day course of LS followed by a semi-elective total thyroidectomy.

Case 2 is a 54-year-old old woman who presented with thyrotoxicosis due to Graves’ disease. She was started on Propylthiouracil (PTU) to which she developed hepatotoxicity and the decision was made to stop PTU. Methimazole was substituted to which she developed a severe desquamating rash hence it had to be stopped immediately. She was given a 10 day course of LS followed by semi-elective total thyroidectomy.

Conclusion: In both cases, hyperthyroidism was successfully treated with Lugol’s solution and their surgeries were uneventful with full recovery. Although beneficial, Lugol’s Solution may result in adverse effects such as severe hypothyroidism, escape hyperthyroidism and death. These cases highlight the need for evidence based treatment guidelines for the use of Lugol’s solution in complex hyperthyroid cases.
Identification of Cell Types that Express Dio3 Deiodinase, a Thyroid Hormone-Inactivating Enzyme, Using a Dio3-CreERT2 Reporter System
Authors: Liu Ye , Forrest Douglas
Published: May 2021

Background: Thyroid hormone promotes development, growth and metabolism. The level of thyroid hormone ligand (triiodothyronine, T3) in tissues depends not only on circulating levels but also upon tight regulation by activating and inactivating deiodinases within tissues. Type 3 deiodinase (Dio3) inactivates T3 and its precursor thyroxine (T4) and mediates many functions including in neurodevelopmental, sensory and reproductive systems. Dio3 is subject to genomic imprinting. Despite its critical functions, Dio3 is often expressed transiently and at low levels in restricted cell populations making it difficult to detect in natural tissues. Methods: To visualize Dio3 expression at cellular resolution, we derived a Dio3-CreERt2 knockin allele that expresses tamoxifen-dependent Cre recombinase from the endogenous Dio3 gene. When crossed with Ai6 reporter mice, Dio3-CreERt2-positive cells display fluorescent signals. When tamoxifen-treated at neonatal ages, Dio3-CreERt2 recapitulates endogenous Dio3 expression as previously reported in brain: in the bed nucleus of the stria terminalis and preoptic nuclei. In addition, we uncovered several positive cell groups in the hypothalamus, brain stem, pituitary and other tissues. Drastic differences were observed for Dio3-CreERt2 as a paternally versus maternally inherited allele, revealing imprinting effect in specific cell types. Dio3-CreERT2 activity is enhanced by T3 administration, in accordance with Dio3 as a T3-indicible gene. Conclusion: The Dio3-CreERT2 model sensitively reveals Dio3-expressing cell types in tissues. The model is useful for studying expression patterns, imprinting and lineage tracing of Dio3-positive cells during development and homeostatic challenges.
Postnatal Hypothyroidism Permanently Disrupts Neural Stem Cell Fate in the Murine Subventricular Zone
Authors: Vancamp Pieter , Demeneix Barbara , Remaud Sylvie
Published: May 2021

The subventricular zone (SVZ) of the adult mammalian brain harbors neural stem cells (NSCs) that generate neurons and oligodendrocytes throughout life. Single-cell RNA-Seq analysis on mouse SVZ-NSCs isolated at different developmental stages established they gradually acquire their adult neurogliogenic identity between postnatal day (P) 7 and 20. However, the factors governing this transition remain elusive. As a key factor driving transcriptional responses during brain development, as well as NSC lineage commitment in the adult SVZ, we hypothesized that thyroid hormone (TH) could fulfil this role. TH serum levels rise postnatally and peak around P15. Re-analysis of single-cell data from the P2 and P20 SVZ revealed a dynamically increased expression of the TH transporters Mct8 and Oatp1c1, as well as the TH-(in)activating deiodinases Dio2 and Dio3 in NSCs, signs that local TH action is promoted. Immunostainings showed a concomitant burst in SVZ-neurogenesis between P4 and P21. Then, to study what occurs if TH synthesis is blocked, we fed dams a 0.15% propylthiouracil-enriched diet from embryonic day 15 to P21. Postnatal hypothyroidism decreased PH3-positive mitotic cell numbers at P4 and P21, whereas increased Sox2 expression coincided with a larger proportion SOX2-positive SVZ-NSCs and progenitors. In the dorsal SVZ, the main site of neurogliogenesis, less neuroblasts were detected at P21, while numbers of OLIG2-positive oligodendroglia precursors did not change significantly. Next, we prepared in vitro neurospheres from dissected SVZs of control and PTU-treated mice, and allowed them differentiate with or without exogenous T3. The neuro/glia balance in neurosphere cultures prepared from P4 animals of either condition did not change when T3 was added, suggesting perinatal NSCs are irresponsive to TH. The balance did change in T3-treated neurospheres prepared from control P21 animals, however, not in those from P21 PTU-exposed mice, suggesting hypothyroid NSCs are irresponsive to T3. Lastly, we examined 3-month-old mice that regained a normal diet following developmental PTU exposure. Fewer oligodendroglia precursors in the SVZ resulted in a lasting altered neuro/glia output. A reduced ability to remember earlier-presented odors indicates impaired olfaction, a behavior strongly depending on SVZ-neurogenesis. Taken together the data indicate that developmental hypothyroidism affects postnatal SVZ organization and permanently alters NSC lineage commitment. Our study allows to determine relevant new read-outs to identify adverse outcome events on brain development and will permit comparison with events following exposure to endocrine disruptors.