bluuebunny/crossref_metadata_2025 huggingface dataset:
A Case of HCG-Mediated Hyperthyroidism Related to Metastatic Choriocarcinoma
Authors: Sovich Samantha C , Garg Dave K , Yu Run
Published: May 2021

Introduction: We present a clinical case of a non-seminomatous germ cell choriocarcinoma producing human chorionic gonadotrophin (HCG) and inducing hyperthyroidism.

Clinical Case: A 21-year-old male with recently diagnosed metastatic non-seminomatous germ cell choriocarcinoma presented with persistent tachycardia and anxiety. At diagnosis, his β- human chorionic gonadotrophin (β-HCG) was elevated to 6,435 mIU/mL (normal <1 in male) and thyroid-stimulating hormone (TSH) was within normal limits. At presentation, however, his β-HCG increased to 103,229 mIU/mL, TSH was suppressed <0.02 mcIU/mL (normal 0.3-4.7), and free thyroxine was elevated (FT4) 2.6 ng/dL (normal 0.8-1.7). His thyrotoxicosis improved with initiation of methimazole; however, his TSH remained undetectable due to persistently elevated β-HCG levels. His course was complicated by hemorrhagic shock and acute liver injury in the setting of a presumed intraluminal gastric metastasis, necessitating the discontinuation of methimazole. He was continued on steroids to try to minimize T4 to T3 conversion, but ultimately his thyroid hormones uptrended. He became stable enough to tolerate 5 days of chemotherapy, after which his FT4 quickly normalized. Unfortunately, he continued to suffer from vasodilatory shock and ultimately passed away.

Discussion: It has been demonstrated that HCG can bind to the TSH receptor and has thyrotropic activity. The development of hyperthyroidism requires HCG levels >200,000 mIU/mL that are sustained for several weeks (1). It is unknown what the prevalence of hyperthyroidism is in choriocarcinoma, but it has been shown to greatly increase when serum HCG levels are greater than >50,000 mIU/mL (2).

Conclusion: Hyperthyroidism can be difficult to recognize in patients suffering from cancer as many of the typical symptoms can also be seen with active malignancy. Patients with HCG-secreting tumors should be evaluated for hyperthyroidism and may benefit from treatment until the underlying cause can be managed.

References: (1) Hershman, Jerome M. “Physiological and Pathological Aspects of the Effect of Human Chorionic Gonadotropin on the Thyroid.” Best Practice & Research Clinical Endocrinology & Metabolism, Baillière Tindall, 19 May 2004, www.sciencedirect.com/science/article/abs/pii/S1521690X0400020X.(2) Oosting, S F et al. “Prevalence of paraneoplastic hyperthyroidism in patients with metastatic non-seminomatous germ-cell tumors.” Annals of oncology: official journal of the European Society for Medical Oncology vol. 21,1 (2010): 104-8. doi:10.1093/annonc/mdp265
A Case of Thyrotoxic Periodic Paralysis
Authors: Mahali Lakshmi Priyanka , Pechman Amanda
Published: May 2021

Introduction: Thyrotoxic periodic paralysis (TPP) is an uncommon disorder characterized by simultaneous thyrotoxicosis, hypokalemia, and paralysis. It is a rare complication of hyperthyroidism with a prevalence of 1 in 100,000. It has a higher prevalence in young Asian males, with much fewer cases reported in Hispanic patients. The majority of cases are seen in hyperthyroidism due to Grave’s disease, however other causes of thyrotoxicosis have been associated with TPP. Hypokalemia occurs when thyroid hormone stimulates the sodium-potassium-ATP pump by binding to the thyroid response elements upstream of the genes for this pump, increasing its activity and thereby causing a transcellular shift of potassium into the intracellular fluid. Attacks usually begin with proximal muscle weakness of the lower extremities and may progress to tetraplegia, with the degree of muscle weakness corresponding to serum potassium levels. Interestingly, no correlations with serum T3 or T4 levels have been found.

Clinical Case: A 38-year-old Hispanic man with a history of GERD presented to the emergency department with an inability to move his extremities. Initial labs were significant for profound hypokalemia to 2.0 mEq/L (3.5-5) and hyperthyroidism, with TSH<0.05 uU/mL (0.3-4.2) and free T4 2.4 ng/dL (0.6-1.5). Additional workup revealed a positive thyroid stimulating immunoglobulin and a positive thyrotropin binding inhibitor, and thyroid ultrasound demonstrated a hyperemic thyroid with numerous subcentimeter hypoechoic nodules, all of which was suggestive of Grave’s disease. His symptoms resolved with potassium repletion, suggesting thyrotoxic periodic paralysis secondary to hyperthyroidism. Upon further evaluation, the patient endorsed several months of hyperthyroid symptoms such as tremors, heat intolerance, and weight loss. He also endorsed alcohol use, a high carbohydrate diet, and recent life stressors, a combination of which likely precipitated his thyrotoxic periodic paralysis. He was discharged on methimazole 10 mg daily and propranolol 40 mg BID, with a decrease in his free T4 and improvement in his symptoms. He has been educated to avoid alcohol consumption and high-carbohydrate meals to avoid precipitating another episode of periodic paralysis, and once his hyperthyroidism is under better control he plans to undergo radioactive iodine ablation (RAI) for definitive management.

Conclusions: Thyrotoxic periodic paralysis is a rare but dangerous complication of hyperthyroidism, and should be considered in the differential diagnosis when young individuals present with otherwise unexplained hypokalemia and paralysis. Acute management is potassium repletion, long term management involves treatment of thyrotoxicosis and avoiding precipitating factors, and definitive therapy is RAI or thyroidectomy.
A Killian-Jaimeson Diverticulum Masquerading as a Thyroid Nodule
Authors: Patel Reema , Abdulla Maha , Rao Jianyu , Elliot Abemayor , Cheung Dianne
Published: May 2021

Background: A Killian-Jaimeson diverticulum is a rare outpouching in the cervical esophagus, just below the cricopharyngeus muscle, that can be easily mistaken for a thyroid nodule on ultrasonography (1).

Clinical Case: A 65-year-old woman underwent a thyroid ultrasound after her primary care physician noted left-sided thyromegaly. The ultrasound described a 33 mm solid, hypoechoic, wider-than-tall nodule in the left mid gland with an obscured posterior margin as well as macro- and microcalcifications. Given the size and highly suspicious features on ultrasound, she was referred to endocrinology clinic for a fine needle aspiration (FNA). She underwent ultrasound-guided FNA of what appeared to be the previously described thyroid nodule. Surprisingly, the pathology report noted degenerative changes with amorphous debris and possible foreign materials (vegetable or food) without any thyroid tissue. She was sent for an MRI neck, which showed the left neck mass communicating with the esophagus, favoring a left lateral projecting Killian-Jamieson esophageal diverticulum with internal debris. She was referred to head and neck surgery. Given only minimal symptoms of dysphagia, there are no current plans for surgery.

Conclusion: This case illustrates the possibility of mistaking a Killian-Jaimeson diverticulum as a thyroid nodule. Recognition of this rare disease process in the differential diagnosis of thyroid nodules with high risk ultrasound characteristics may prompt more advanced imaging with MRI or CT, and lead to an accurate diagnosis prior to subjecting patients to unnecessary and potentially harmful FNAs (2).

References: (1) Kim HK, Lee JI, Jang HW, et al. Characteristics of Killian-Jamieson diverticula mimicking a thyroid nodule. Head Neck. 2012;34(4):599-603. doi:10.1002/hed.21575. (2) Bonacchi G, Seghieri M, Becciolini M. Killian-Jamieson diverticulum: real-time sonographic findings. J Ultrasound. 2016;19(4):295-298. Published 2016 Apr 21. doi:10.1007/s40477-016-0208-3.
A Rare Phenomenon of Hashimotos Thyroiditis Converting to Graves Disease
Authors: Caseja Ahl Jeffrey , Nakhle Samer
Published: May 2021

Introduction: Hashimotos thyroiditis and Graves disease are two distinct autoimmune disorders of the thyroid. Conversion of hypothyroidism to hyperthyroidism is even more rare. We report a case of an established Hashimotos thyoiditis patient who converted into Graves disease.

Case Description: 67-year old female with a past medical history of iron-deficiency anemia, dyslipidemia, and depression presented with a six-month history of fatigue, cold-intolerance, hair loss, and weight gain in September of 2015. Laboratory tests confirmed diagnosis of Hashimotos thyroiditis with an elevated TSH 80.7 (0.40-4.50 mIU/L), FT4 0.2 (0.8-1.8 ng/dL), and positive thyroid antibodies TPO 24 (0.0-8.9 IU/mL). She was started on Levothyroxine 88 mcg daily. Gradually she had a decreased requirement of Levothyroxine; from February 2016 to March 2017 she maintained a normal TSH range while on 50 mcg/day with resolution of her symptoms.

The patient was then lost to follow-up until she presented in the clinic in September 2018 with complaints of several weeks of easy fatigability, 10lb-weight loss, and periorbital edema. She was found to have a suppressed TSH 0.01, and elevated FT4 2.3, and FT3 8.4 (2.3-4.2 pg/mL). Her Levothyroxine 50 mcg/day was discontinued for four days and labs were repeated which still showed suppressed TSH and elevated FT4 and FT3. She was found to have a positive TRAB and a positive TSI which are consistent with hyperthyroidism. Thyroid ultrasound was performed which showed a heterogeneous thyroid gland with increased vascularity, confirming the diagnosis of Graves disease. She was started on Methimazole 10 mg daily. Her Methimazole dose was adjusted according to her thyroid function test until she had a total thyroidectomy in October 2019. She was started on levothyroxine post-operatively and as of March 2020 is on Levothyroxine 50 mcg/daily.

Conclusion: Despite the rarity of Hashimotos thyroiditis converting to Graves disease, it is possible that those affected can be encountered by primary care providers and hospitalists and could easily be mistaken for over-replacement of levothyroxine. Close monitoring of the patient along with regular thyroid function tests will be required for ongoing follow-up.
Selective Serotonin Reuptake Inhibitors Increase Urinary Free Cortisol in Patients with Carney Complex and Primary Pigmented Nodular Adrenocortical Disease
Authors: Chrysavgi Kamilaris Crystal Dawn , Sinaii Ninet , Stratakis Constantine A
Published: May 2021

Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of ACTH-independent Cushing syndrome predominantly associated with Carney Complex (CNC), a multiple endocrine neoplasia syndrome primarily caused by inactivating defects in PRKAR1A. PPNAD, which has neuroendocrine features, demonstrates cortisol production in response to serotonin as well as increased expression of tryptophan hydroxylase type 2, a serotonin synthesizing enzyme, and the serotonin (5-HT) receptors types 4, 6, and 7. This creates an autocrine/paracrine serotonergic regulatory loop that activates cortisol production. PPNAD can be diagnosed through a 6-day Liddle test (LT) showing a paradoxical increase of >50% from baseline in 24-h urinary free cortisol (UFC) on the 2nd day of high-dose dexamethasone administration (Day 6). Selective serotonin reuptake inhibitors (SSRIs) inhibit the reuptake of serotonin and are widely used for the treatment of depression. We performed a retrospective cohort study of patients with CNC and PPNAD that underwent a LT to evaluate the effect of SSRIs on UFCs, with the hypothesis that SSRI use leads to an exaggerated increase in UFC through presumed activation of the described serotonergic regulatory loop. Of the 34 patients (4–65 y) with CNC and PPNAD that underwent a LT at our institution between 2004 and 2018, 4 took an SSRI during testing. No differences were observed between the SSRI (S) group and the non-SSRI (NS) group in baseline UFCs and the percent increase in UFC on D6. Specifically, the median (IQR) baseline UFC in the S group was 36 (13–252) mcg/24h (nl 4–56) vs 35 (13–98) mcg/24h in the NS group (P=0.95). The percent change in UFC was 208 (93–683)% in the S group and 185 (28–364)% in the NS group (P=0.89). However, there was a difference for overall UFC measurement (across days 1–6 of the LT) in the S group vs the NS group (P=0.03). Age <18 vs 18+ and sex did not have an effect on the outcomes (P=0.17 and P=0.74, respectively). Thus, we conclude that though the percent change in UFC during the LT was similar in both groups, there was a significant difference in overall UFC in the S group when compared to the NS group. These data support an effect of SSRIs and serotonin on UFC and consequently cortisol production in PPNAD. This interesting observation has to be confirmed in more patients with CNC and PPNAD to further elucidate the effects of SSRIs on cortisol production in patents with PPNAD-caused Cushing syndrome, as this may have significant diagnostic and therapeutic implications.
Intravascular Lymphoma in Patient With Celiac Disease With Multi Glandular Involvement
Authors: Alam Mustafa , Horani Mohamad Hosam
Published: May 2021

Case Presentation: The patient is a 60 year old male with a past medical history of celiac disease, paroxysmal Afib, iron deficiency, and CAD who presented with lightheadedness, dizziness, and fatigue. Notable workup revealed that the patient had Afib with RVR, a TSH of 0.189, Free t4 0.51an LDH of 2726, hemoglobin of 8.7, AST of 155, ALT of 19, WBC of 4.5, and serum iron of 20. The patient’s cardizem dose was adjusted and repeat transthoracic echocardiogram was unremarkable compared to history. The patient presented again with complaints of abdominal distension, postural dizziness, occasional night sweats, and fevers. Repeat workups revealed pancytopenia, proteinuria, hypotension, and anasarca most pronounced in the lower extremity and scrotum. Ultimately, a kidney biopsy revealed an intravascular B cell non-Hodgkin lymphoma (IVBCL). Notable repeat labs include a CRP of 44 and a failed ACTH stimulation test. A brain MRI revealed a 6mm pituitary microadenoma. The patient placed on an R-CHOP regiment and is scheduled for repeat MRI to rule out pituitary involvement.

Discussion: IVBCL’s are a rare form of diffuse B cell lymphoma and remain a diagnostic challenge due to the variety of involved systems including skin, CNS, and endocrine. IVBCL is also known to not produce a mass or lymphadenopathy. Celiac disease is a known risk factor for non-Hodgkin’s lymphoma. A literature search reveals a few case reports with common themes of increased LDH and inflammatory markers, anemia, and hepatic and renal dysfunction. Postural hypotension can also be a presenting symptom due to IVBCL’s ability to infiltrate neurovascular tissue to cause autonomic neuropathy. However, in this case, the patient’s history of primary adrenal insufficiency makes this unlikely. Hypothyroidism secondary to pituitary and thyroid involvement was suspected due to TSH level suppressed enough for central hypothyroidism. Repeated MRI showed resolution of Pituitary Microadenoma post Chemo therapy.

Sylvain Raoul Simeni Njonnou, Bruno Couturier, Yannick Gombeir, Sylvain Verbanck, France Devuyst, Georges El Hachem, Ivan Theate, Anne-Laure Trepant, Virginie De Wilde, Frédéric-Alain Vandergheynst, “Pituitary Gland and Neurological Involvement in a Case of Hemophagocytic Syndrome Revealing an Intravascular Large B-Cell Lymphoma”, Case Reports in Hematology, vol. 2019, 6 pages, 2019. https://doi.org/10.1155/2019/9625075

Catassi C, Fabiani E, Corrao G, et al. Risk of Non-Hodgkin Lymphoma in Celiac Disease. JAMA. 2002;287(11):1413

Khan MS, McCubbin M, Nand S. Intravascular Large B-Cell Lymphoma: A Difficult Diagnostic Challenge. J Investig Med High Impact Case Rep. 2014 Mar 6;2(1):2324709614526702.

Pearce C, Hope S, Butchart J. Intravascular lymphoma presenting with postural hypotension. BMJ Case Rep.

Published 2018 Jan 29.
Plasmapheresis as First Line Therapy for Thyrotoxicosis in a Critically Ill Patient
Authors: Sheskier Rachel , Sajan Alen , Mathias Priyanka , Tabatabaie Vafa
Published: May 2021

Introduction: The role of plasmapheresis (TPE) in thyrotoxicosis management is not well established. Its use may be determined on an individualized basis (1). We report a case of a critically ill patient where TPE was utilized as first-line therapy for refractory thyrotoxicosis. Clinical Case: A 33-year-old woman with Graves’ disease complicated by medication non-adherence presented with rapidly ascending paralysis and bulbar weakness. Primary work up was consistent with acute inflammatory demyelinating polyneuropathy (AIDP) based on EMG findings of motor fiber polyneuropathy with demyelinating features. Laboratory evaluation revealed uncontrolled hyperthyroidism (TSH <0.05 uU/mL, N 0.3-4.2 uU/mL; fT4 3.9 ng/dL, N 0.6-1.5 ng/dL; tT3 318, N 60-160 ng/dL). Initially, there was low concern for thyrotoxicosis based on a Burch-Wartofsky score of 15 (2). Standard dose methimazole and aggressive beta-blockade were initiated. Hospital course was complicated by hypoxic respiratory failure due to progressive paralysis requiring intubation and septic shock from Klebsiella pneumonia requiring initiation of pressors and broad-spectrum antibiotics. Biochemical evaluation showed increasing fT4 (3.8 ng/dL) and tT3 (419 ng/dL) levels. Burch-Wartofsky score increased to 55, consistent with a thyrotoxic crisis. Due to the patient’s critical condition, TPE was rapidly initiated along with standard therapy for thyrotoxic crisis (high dose methimazole, esmolol drip, stress dose corticosteroids, cholestyramine, and potassium iodide) as a bridge to definitive management with thyroidectomy. Rapid clinical improvement with a decline in fT4 levels (3.8 to 2.1 ng/dL) was noted after initiation of TPE with normalization in fT4 (1.5 ng/dL) and tT3 (54 ng/dL) after three sessions. Thyroidectomy was pursued after clinical stabilization. Surgical pathology showed diffuse papillary hyperplasia consistent with Graves’ disease. Due to persistent respiratory failure, the patient underwent tracheostomy placement. Repeat EMG revealed severe myopathic dysfunction without demyelinating features favoring a diagnosis of acute thyrotoxic myopathy over AIDP. Patient was ultimately discharged to a long term acute care facility due to slow neurological recovery. Conclusion: TPE should be considered as first line management in conjunction with conventional medical therapy in critically ill patients with thyrotoxicosis as a bridge to thyroidectomy due to rapid time to effect and patient stabilization. References: (1) Padmanabhan A, et al. J Clin Apher. 2019 Jun;34(3):171-354. (2) Bahn Chair RS, et al. Thyroid. 2011 Jun;21(6):593-646.
Severe Hyperbilirubinemia Associated With Thyrotoxicosis: Importance of Early Recognition
Authors: Villavicencio Camila Alejandra , Franco-Akel Alberto , Belokovskaya Regina , Agarwal Sanket , Homsy Nicholas F , Park Hansang , Joanna Lenik , Bohidar Amelia
Published: May 2021

Thyroid storm (TS) is a rare and life-threatening condition due to a profound hypermetabolic state, leading to decompensation of homeostasis. It is commonly associated with a precipitating factor such as surgery, trauma, or infection. Occasionally, the clinical presentation may be non-specific, thus causing a potential delay in diagnosis. This could be problematic due to the condition’s high mortality rate, especially if not recognized early. Thyrotoxic jaundice presenting with a pattern of cholestatic hyperbilirubinemia (HBR) has been reported in the literature, although uncommon. We present the case of a 71-year-old woman with unexplained jaundice and direct HBR who was diagnosed with impending TS in the setting of toxic multinodular goiter (TMNG). This is a case of a 71-year-old woman with a remote history of hypothyroidism who presented with acute onset right upper quadrant abdominal pain, jaundice, a non-tender asymmetric nodular large goiter, and bilateral non-pitting leg edema. Ancillaries were significant for total and direct HBR of 4.3 and 3.5 mg/dL, respectively. An abdominal sonogram, abdomen CT and ERCP, all ruled out an obstructive biliary etiology. Unfortunately, the patient developed post-ERCP pancreatitis, with subsequent worsening of direct HBR. TSH was found to be suppressed, free T4 was significantly elevated at 4.3 ng/dL. A Burch-Wartofsky score of >40 was highly suggestive of TS. In addition, elevated thyroglobulin levels ruled out exogenous thyrotoxicosis, the absence of orbitopathy, pretibial myxedema, and negative TRAb pointed towards TMNG as the most likely etiology of hyperthyroidism. This diagnosis was confirmed through neck ultrasound, showing multiple nodules and the absence of high vascularity of the thyroid gland. The patient was managed in the ICU with beta-blockers, methimazole, potassium iodide solution, glucocorticoids, and bile acid sequestrants, leading to satisfactory and significant clinical improvement of thyrotoxicosis and bilirubin levels. Hepatic dysfunction has been described in patients with hyperthyroidism since the nineteenth century. Although the underlying mechanism remains unclear, it may be multifactorial. Different hypotheses have been proposed suggesting that the hypermetabolic state secondary to decompensated hyperthyroidism causes a supply-demand mismatch between hepatic oxygen consumption and hepatic blood flow, decreasing the oxygen tension in the centrilobular region resulting in cholestasis. Furthermore, hepatic hypermetabolism in response to excess thyroid hormone leads to the saturation of the bile flow rate. A possible direct toxic effect of T4 in the hepatocytes has been described although further research is needed. This case highlights the importance of considering decompensated hyperthyroidism as a differential diagnosis of cholestatic HBR.
When Your Thyroid Causes Muscle Paralysis
Authors: Gandhi Anand , Al-Maradni Ahmad , Vinales Karyne Lima , Correa Ricardo Rafael
Published: May 2021

Background: Periodic paralysis represents a spectrum of disorders characterized by ion channel dysfunction, mainly Na-K-ATPase channels. Thyrotoxic periodic paralysis (TTP) is defined by the presence of hypokalemia and diffuse muscular paralysis in a pre-existing hyperthyroid state. Diagnosis can be challenging, especially in cases of undiagnosed hyperthyroidism due to the non-specific presentation of this illness. We present a case of a young male who presented with recurrent, spontaneous paralysis found to have Graves’ disease. Clinical Case: A 38-year-old Asian male presented with sudden onset diffuse weakness, numbness, and tingling. The weakness was so severe that he could barely walk more than a few steps. However, his symptoms resolved in less than 24 hours without any intervention. Five months later, the patient experienced a recurrent episode of this similar constellation of diffuse muscle weakness and paresthesia. The patient was taken to a nearby hospital, where he was provided with intravenous fluid resuscitation. Initial laboratory workup was notable for hypokalemia to 1.4 mmol/L (n: 3.6 - 5.3 mmol/L), hypophosphatemia to 0.6 mmol/L (n: 2.4 – 4.8 mmol/L), and elevated creatinine kinase to 807 U/L (n: 22 – 198 U/L). Additionally, TSH was <0.001 mU/L (n: 0.45 – 4.5 mU/L) along with free T4 3.4 ng/dL (n: 0.80 – 1.70 ng/dL. The patient denied any other symptoms or a family history of similar symptoms. Lumbar puncture and brain/spine MRIs were unremarkable. Symptoms gradually improved throughout hospitalization with fluid and electrolyte repletion. Hyperthyroidism was treated with methimazole 5mg twice daily, later changed to PTU 50mg every eight hours due to recurrent headaches. Thyroid uptake scan showed diffuse bilateral uptake to 39.11% at 4 hours and 61.8% at 24 hours. Follow up labs revealed: TSH 0.3 mU/L, free T4 1.44 ng/dL, free T3 3.5 pg/mL (n: 2.3 – 4.1 pg/mL). Patient denied recurrent episodes of weakness or paresthesia. Definitive hyperthyroidism treatment with RAI was planned. Conclusions: The prevalence of TPP is higher in Asian males compared to other ethnic groups. TPP manifests as a sporadic onset of muscle weakness ranging from mild weakness to flaccid paralysis. It has been described that thyroid hormone itself augments the activity of the Na-K-ATPase channel and increases its responsiveness to beta-adrenergic stimulation. In addition, hyperthyroidism is associated with insulin resistance leading to hyperinsulinemia. Both beta-agonism and insulin promote potassium to be driven into cells resulting in hypokalemia. As such, activities which increase beta adrenergic stimulation, like stress and exercise, and promote the secretion of insulin, such as heavy carbohydrate intake, are well described triggers of TPP. Treatment revolves around acutely treating hypokalemia followed by preventing subsequent attacks via regulation of the altered thyroid state.
Physiologic Effects of Levothyroxine and Liothyronine in the in Older Individuals With Persistent Subclinical Hypothyroidism: A Randomized, Double-Blind, Cross-Over Study
Authors: Meizlik Paige , Cucchiara Andrew , Kannan Lakshmi , Mays Jarvis , Jolivert Jennifer , Scattergood Theresa , Cappola Anne Rentoumis
Published: May 2021

Background: Subclinical hypothyroidism is common in older individuals, but the physiologic responses to treatment with levothyroxine (LT4) and liothyronine (LT3) are not well defined in this age group. Methods: We conducted a randomized, double-blind, cross-over study of LT4 and LT3 treatment in men and women aged 70 years and over without anti-thyroid peroxidase antibodies with persistent subclinical hypothyroidism, defined as having a TSH level between 4.5 and 19.9 µIU/mL with a normal free thyroxine (FT4) level at two consecutive time points. Physiologic outcome measures assessed after achieving a TSH level of 0.5-1.5 µIU/mL with each therapy included vital signs, weight and body composition, bone mineral content and bone density, lipids, resting energy expenditure (REE), cognitive function, quality of life, and thyroid symptoms. Results: Thirteen participants [mean (SD) age 77 (5) years], 4 women and 9 men, completed the study. Baseline mean TSH was 4.84 (1.29) µIU/mL. The mean LT4 dose was 105 (36) µg/day [1.4 (0.5) µg/kg/day] and LT4 dose was 34 (9) µg/day [0.4 (0.1) µg/kg/day]. Mean time on LT4 was 200 days and on LT3 was 231 days, with a 28 day washout period. Compared with baseline, participants had an average weight loss of 1.1 kg on LT4 (p<0.02) and 2.5 kg on LT3 (p<0.001), which was significantly different between the two treatments (p=0.01). Fat mass decreased by an average of 0.7 kg on LT4 (p=0.03 vs. baseline) and 1.5 kg on LT3 (p<0.01 vs. baseline) and differed between treatments (p=0.01). There was a significant difference in total cholesterol of 13.3 mg/dL (p<0.001) and in low-density lipoprotein cholesterol (LDL) of 10.8 mg/dL (p<0.001) between LT4 and LT3 treatment arms; for both, the levels were lower on LT3 than LT4. No differences were seen in the other assessed outcomes. Conclusions: In a cross-over study of treatment of LT4 or LT3 in persistent subclinical hypothyroidism, participants lost fat mass and weight after each treatment, with a greater decrease after treatment with LT3. These findings support different physiologic responses to LT4 compared with LT3.
Thyroid Hormone and Estrogen Promote Endocrine Resistance, Proliferation, Dedifferentiation, and Cancer Stem Cells in Steroid Receptor-Positive Breast Cancers
Authors: Wahdan-Alaswad Reema S , Thor Ann D
Published: May 2021

Background: Breast cancer (BC) and thyroid disease are well-recognized comorbidities. Hyperthyroidism and supraphysiologic thyroid hormone (TH) have been shown to promote BC incidence. We recently reported that thyroid hormone replacement therapy (THRT) was significantly and independently associated with shortened disease-free and overall survival, as well as endocrine resistance only in patients with steroid receptor-positive (SR+) BC (1). TH markedly upregulated estrogen and cell cycle signaling in vivo and in vitro and promoted dedifferentiation to basaloid and pre-stem phenotypes. Metformin (Met) attenuated this shift. Mechanisms of TH-mediated endocrine therapy resistance in ER+ BC are the focus of this report.

Design: Two clinical cohorts of early-stage lymph node-negative (LN-) SR+ BC patients (n=820 and n=160) were used to determine the effect of THRT on overall survival using Kaplan-Meier methods. Bi-directional cross-talk between TH and E2 was tested using different BC cell lines, ER+ PDX in vivo models, in vitro methods, and publically available in silico data for modeling.

Results: Our results show that E2+TH increases cell proliferation, enhances cell cycle, and hormone-associated oncogenic signaling in SR+/ER+ BC. Given that high expression of THRA is associated with poor prognosis in SR+ BC, knockdown of THRA and ESR1 reduced cell proliferation in ER+ BC cells. ER+ PDX tumors were implanted into NSG mice containing E2 pellet and subsequently treated with TH, Tamoxifen (Tam), Fulvestrant (ICI) or Met. Our data show that TH-mediated endocrine resistance only in the E2+TH+Tam treated tumors (P<0.0001 vs E2+Tam alone). Both ICI and Met provided significant attenuation of tumor growth in vivo. RNAseq analysis of E2+TH+Tam tumors show an increase in pro-oncogenic signaling (Wnt/Fizzled, MMPs, and TCL/LEFT). Our data suggest that the use of Tam did not dampen tumor growth whereas a full ER-antagonist (ICI) or Met attenuated E2-TH mediated cross-talk and tumor growth.

Conclusions: These findings suggest that TH+Tam may enhance oncogenic signaling and is associated with a significantly increase in mortality risk in ER+/SR+ BC tumors. Exogenous TH adversely affects SR+ BC and not SR- BC. Understanding the mechanism of cross-talk between TH and E2 allows us to define novel therapeutic strategies that will facilitate rapid clinical application for ER+ BC patients currently taking THRT and anti-estrogen treatments. Reference: (1) Wahdan-Alaswad et. al. Clin Cancer Res October 23 2020 DOI: 10.1158/1078-0432.CCR-20-264.
A Case of Aldosterone Producing Adrenocortical Carcinoma
Authors: Soe Myat Han , Rao Madhu N
Published: May 2021

Introduction: Adrenocortical carcinomas (ACCs) are rare and aggressive cancers. Approximately 60% of ACCs are functional, presenting with Cushing syndrome and/or virilization. Aldosterone producing ACCs account for about 1-3% of hormonally active ACCs. Despite aldosterone production, their mutational landscape is not different from other functional ACCs - they do not harbor mutations of known aldosterone-producing adenoma (APA) associated genes. They present with uncontrolled hypertension and hypokalemia, as seen in this case. Case: 63 year old Asian female with previously well controlled hypertension experienced resistant hypertension and hypokalemia for over a year. Since the onset of hypokalemia, patient noticed worsening hypertension despite addition of multiple medications. CT abdomen during an episode of severe gastroenteritis revealed a 3.7 cm heterogenous multilobulated left adrenal mass. Hormonal workup showed elevated aldosterone of 35 ng/dl with suppressed plasma renin activity of 0.41 ng/ml/h and serum potassium of 3.4 while patient was on 50 mg of spironolactone. Plasma and urine metanephrine levels were unremarkable. Plasma ACTH was <5 ng/L, cortisol was 12 ug/dl and DHEA-S was 149 ng/dl. 24 hour urine free cortisol result was not available. Repeated CT abdomen revealed a 5.2 cm left adrenal mass (Non-contrast HU of 38, 50% absolute wash out), increasing in size from 3.7 cm in 6 months. The mass was FDG avid with SUV of 13.2. Patient underwent laparoscopic left adrenalectomy and surgical pathology revealed a 4.2 cm, high grade ACC with vascular invasion, Ki67 index of 35% and modified Weiss score of 6. Hypertension and hypokalemia resolved after tumor removal, no longer requiring antihypertensive medications. Plasma aldosterone level also remains normal after surgery. However, postoperative CT (6 weeks after surgery) revealed numerous pulmonary metastases. Germline genetic testing is pending. Genomic interrogation of the primary tumor identified CDKN2A and CDKN2B deletions, along with pathogenic mutations in CTNNB1 and DNMT3A. Copy number analysis revealed numerous large scale chromosomal alterations including many arm level and whole chromosome gains and losses. These somatic mutations affect p53/Rb1 signaling (CDKNs), chromatic remodeling (DNMT3A) and wnt signaling pathway (CTNNB1). Together with noisy pattern of copy number alterations, these genomic alterations likely account for the aggressive nature of this tumor. Clinical Lessons: (1) Clinicians should raise the suspicion of ACC during the workup for primary hyperaldosteronism, especially if an adrenal mass does not have the reassuring radiographic features suggestive of a benign adrenal mass. (2) Metastatic lesions may not necessarily produce aldosterone as the primary tumor does. (3) Mutational analysis of the tumor informs molecular subtypes of ACC, prognosis, and treatment decisions.
A Surprising Outcome of Metastatic Pheochromocytoma Misdiagnosed as Renal Cell Carcinoma: A Case Report
Authors: Monsour Elio Paul , Abdelmasih Randa , Pothen Joshua , Gandhi Rima , Ramharrack Frank
Published: May 2021

Background: Metastatic pheochromocytomas are rare neuroendocrine tumors that carry a poor prognosis. There are no curative treatments; however, current therapeutic strategies to control tumor burden include surgery, radiation, ablative therapy, chemoembolization, and systemic therapies. We describe an interesting case of a patient with metastatic pheochromocytoma misdiagnosed as renal cell carcinoma (RCC) started on axitinib and pembrolizumab, who achieved a partial response to treatment, despite lack of approved indications for these therapies in metastatic pheochromocytoma.

Clinical Case: A 64-year-old man presented to the emergency department (ED) with uncontrolled hypertension and severe headache. A 12 cm left-sided pheochromocytoma was diagnosed 11 years ago, which was surgically resected via adrenalectomy. After surgery, the patient was followed in the endocrine clinic for five years with pheochromocytoma serum biochemical markers and declared free of disease. 2 months before hospital admission, he was worked-up for flank pain and at that time, CT abdomen showed a 3 cm mass in the liver and exophytic solid mass measuring 4.2 cm off the left kidney. Subsequently, a CT guided biopsy of the left renal mass was performed and revealed grade II renal cell carcinoma (RCC). He was referred to oncology and was started on a combination of IV pembrolizumab, an immune checkpoint inhibitor against PD-1/PD-L1, and oral axitinib, a selective VEGF receptor inhibitor. He received 3 cycles of immunotherapy treatment; however, he became significantly hypertensive with intermittent headaches, so he was started on atenolol 25 mg once daily. Despite this, he continued to have uncontrolled hypertension, worsening headaches, and flushing, which prompted him to undergo evaluation in the ED. On arrival, BP was 210/90. Labs were remarkable for Hgb 17.2, WBC count of 17.1, and glucose of 178 mg/dL. CT head was negative for any acute intracranial process. Due to suspected recurrence of pheochromocytoma, atenolol was stopped, adrenal workup was conducted, and the patient was started on doxazosin. Urine metanephrines came back elevated at 1097 (RR: 55-320 μg/24 hrs), urine norepinephrine of 260 (RR: 14-120 μg/24 hrs), and urine normetanephrine of 3305 (RR: 114-865 μg/24 hrs). Re-evaluation of pathology opinion was obtained, which indicated that biopsy stained positive for chromogranin A and synaptophysin markers, consistent with metastatic pheochromocytoma. FDG PET/CT was performed following discharge, which revealed the left renal mass decreased to 2.4 cm and the liver mass shrunk to 1.5 cm.

Conclusion: To our knowledge, this is the first case report outside of a clinical trial highlighting partial response to axitinib and pembrolizumab in metastatic pheochromocytoma. Emerging preliminary phase II clinical trial data are currently investigating these medications as future treatment modalities.
Case Series of Metastatic VIPoma With Partial Response to Somatostatin Receptor Ligand and Review of Therapeutic Options
Authors: Wen Lim Sue , Guan Goh Kian , Ho Jin Hui , Khoo Serena Sert Kim , Hussein Zanariah
Published: May 2021

Background: Vasoactive intestinal polypeptide secreting islet cell tumors (VIPoma) are rare neuroendocrine tumors of pancreatic origin, characterized by secretory diarrhoea and electrolyte imbalances. Metastasis, commonly hepatic, frequently occur at diagnosis in up to 80% patients. Surgery of the primary tumour remains the gold standard management and in metastatic tumors, somatostatin receptor ligands (SRL) are the drugs of choice for symptom relief and disease control. Some patients will require other approaches to control symptoms, such as liver-targeted therapy, peptide receptor radionuclide therapy (PRRT) or chemotherapy. We describe a case series of metastatic VIPoma which partially-responded to SRL and review of other treatment modalities to achieve disease and symptom control. Case: We report 3 cases, ages 37 to 58 years, with metastatic VIPoma whom presented with secretory diarrhoea, hypokalaemia, achlorhydria and elevated serum VIP levels. CT and 68Gallium PET-CT imaging identified metastases in liver, bone, lungs, spleen and lymph nodes. One case underwent distal pancreatectomy and splenectomy at diagnosis and two cases were advanced and non-resectable. All received long-acting SRL initially and achieved partial control of the gastrointestinal symptoms. Two cases underwent Peptide Receptor Radionuclide Therapy (PRRT) and one case received cytotoxic chemotherapy. Two patients have progressive disease and one succumbed to advanced disease. For inoperable disease, PRRT is useful adjuvant therapy for symptom relief and may improve progression free survival (PFS). Cytotoxic chemotherapy is an option for patients with progressive or symptomatic unresectable tumor. Chemoembolization or liver-targeted therapy are used in liver metastasis for loco-regional control. Alfa-interferon and targeted therapies such as everolimus and sunitinib are other treatment options that can be considered. Conclusion: Metastatic VIPoma remains a challenging disease to manage, requiring multimodal treatment approaches. With timely diagnosis and advancing therapeutic options, more patients can achieve improved symptom and disease control as well as increased survival.
Never Forget the Family History: MEN2A Syndrome Presenting as Metastatic Medullary Thyroid Cancer and Bilateral Pheochromocytoma
Authors: Rodriguez Lisette Patricia , Perez Jesus B , Wiese-Rometsch Wilhelmine
Published: May 2021

Introduction: MEN 2A is an autosomal dominant hereditary syndrome considered part of the medullary thyroid carcinoma (MTC) syndromes. This is characterized by MTC, pheochromocytoma, and parathyroid hyperplasia or adenomas causing primary hyperparathyroidism (PHPT).

Clinical Case: A 34 year old female was referred to our clinic for multi-nodular goiter diagnosed during routine gynecologic evaluation. A thyroid ultrasound revealed a heterogeneous right thyroid lobe with a hypoechoic 2.5 cm nodule, associated macro calcifications and increased vascularity; and a left nodule measuring 2.3 cm with the same characteristics. Bilateral thyroid nodule biopsies were performed, resulting in MTC confirmed by positive calcitonin staining. Pre-operative studies revealed serum calcitonin and carcinoembryonic antigen (CEA), both of which are considered serologic markers of MTC activity, at 4,340 pg/ml (n <= 5) and 276.2 ng/mL (n <= 2.5 in non-smokers) respectively. The patient reported father with history of unspecified thyroid cancer, and paternal uncle with history of pheochromocytoma with a p.Cys634Trp mutation in RET proto-oncogene. Due to her family history, pre-operative screening for primary hyperparathyroidism (PHPT) resulted in a calcium 10 mg/dL (n 8.6-10.2), PTH 34 pg/mL (n 14-64). Additionally, screening for pheocromocytoma revealed an elevated 24 hour urine metanephrines of 2,276 (n <= 49-290) ug/24h, plasma metanephrines, including fractionated metanephrine (MN) at 163 (n <= 57) pg/ml, fractionated nor-metanephrine (NMN) at 182 (n <= 148) pg/ml, and total, Free (MN+NMN) metanephrines at 345 (n <= 205) pg/ml. CT abdomen revealed bilateral adrenal nodules, right measuring 1.4 x 3.3 cm and left 2.4 x 3.3 cm. The patient underwent posterior retroperitoneoscopic adrenalectomy with cortex sparing prior to thyroidectomy. Adrenal pathology resulted in bilateral pheochromocytoma with peri-adrenal adipose tissue microscopic involvement, and positive synaptophysin and S-100 stain. Subsequently, she underwent total thyroidectomy with extensive cervical lymph node resection, with pathology resulting in MTC with lymph node metastasis, involving 5/18 cervical lymph nodes. Post-operative labs revealed serum calcitonin <= 2 pg/ml, CEA 26.8 ng/mL, MN < 25 pg/ml, NMN 102 pg/ml, and MN+NMN of 102 pg/ml, which suggested initial surgical success. Post-operative genetic test evaluation revealed abnormal RET oncogene testing compatible with MEN 2A, variant 1: c.1902C>G (p.Cys634Trp).

Conclusion: This case illustrates that patients presenting with MTC and reporting family history of thyroid cancer should be screened for familial MTC syndrome. Patients with RET mutation should be screened for pheochromocytoma prior to surgery for MTC to prevent life-threatening hypertensive crisis.
Reversible Catecholamine Induced Cardiomyopathy
Authors: Tofil Kathrin Sandra , Mushref Malek
Published: May 2021

Background: Pheochromocytomas and paragangliomas (PPGL) are rare neuro-endocrine tumors associated with a myriad of poor outcomes as a result of long-term exposure to catecholamines. Although paragangliomas are less commonly associated with increased catecholamine production than adrenal pheochromocytomas, there have been a few reports of catecholamine-induced cardiomyopathy in patients diagnosed with PPGL. We report a case of a PPGL associated with hypercoagulability and cardiomyopathy. Clinical Case: 42-year-old man with uncontrolled hypertension presented to the emergency department with abdominal pain. On CT imaging, he was found to have hepatic lesions, aortocaval lymph node concerning for metastatic disease, left renal infarct, and a left ventricular thrombus. Soon after his admission, he developed acute ataxia, gaze palsies and left hemiparalysis. CTA of the head showed a basilar artery thrombus [FJ1] which was treated with emergent thrombectomy. In addition patient had absent distal pulse of the right foot[FJ2], and found to have thrombus of the popliteal artery, which was treated with thrombectomy. Further workup with abdominal MRI showed retroperitoneal mass[FJ3] and multiple hepatic lesions concerning for metastatic extra-adrenal neuroendocrine tumor. Plasma normetanephrine was 4.5 nmol/L (ULN 0.89), plasma metanephrine 0.3 nmol/L (ULN 0.49) Chromogranin A was 387 ng/ml (ULN 160). Ga-68 DOTATE scan was consistent with an extra adrenal paraganglioma with less prominent radiotracer activity in hepatic lesion concerning for dedifferentiated metastatic disease. In addition, echocardiogram showed reduced LV ejection fraction of 24% with global hypokinesis, and confirmed the LV thrombus. Cardiac MRI showed infiltrative nonischemic cardiomyopathy and mild dilation of left ventricle, as well as patchy delayed enhancement in the basal and inferoseptal walls suggestive of myocarditis. Treatment included rivaroxaban[FJ4], lisinopril, doxazosin, furosemide, and carvedilol. Several months after discharge, his EF improved to 48%. Hepatic lesions concerning for dediffertiated tumor vs unrelated malignancy was biopsied[FJ5] and consistent with neuroendocrine tumor. Future plan for his PPGL include revaluation for resection of retroperitoneal mass or DOTA Lutathera therapy. Conclusions: This case highlights a young man who was incidentally found to have metastatic paraganglioma with catecholamine-induced cardiomyopathy. The patient was asymptomatic until he developed significant heart failure. Cardiomyopathy in this setting is thought to be secondary to uncontrolled hypertension, as well as sympathetic overdrive from overstimulation of norepinephrine. We present the case to highlight the management challenges in a patient with PPGL with significant cardiovascular compromise and limited therapeutic options.
Simultaneous Occurrence of Germline Pathogenic Allele Variants of TMEM127 and TP53 in a Brazilian Family With Li-Fraumeni Syndrome
Authors: Lima Jose Viana , Scalissi Nilza Maria , Ricardo Gustavo Piech , Piech Mr Gustavo , Biscolla Rosa Paula Mello , Chiamolera Maria Izabel , Olivati Caroline , Baratela Wagner , Ferreira Elisa Napolitano , Kater Claudio E
Published: May 2021

Background: We will describe a Brazilian family whose index case had pheochromocytoma and in the evaluation of the genetic panel by Next Generation Sequence (NGS), the germline pathogenic variants in the TMEM127 and TP53 genes were identified. Clinical Case: A 32-year-old female patient with a clinical picture of paroxysms and difficult to control arterial hypertension, with a personal history of stroke and acute myocardial infarction. She had a 6.5 cm tumor in the right adrenal and urine metanephrine levels of 5.5 mg / g creatinine (VR <1 mg / g creatinine) compatible with pheochromocytoma. She underwent laparoscopic right adrenalectomy. There was a reversal of arterial hypertension and paroxysms. 10 years after adrenalectomy, she was diagnosed with bilateral breast cancer, she underwent radical total mastectomy and 2 years ago there was a recurrence of breast cancer and currently undergoing chemotherapy. Germinative genetic panel carried out by NGS had identified pathogenic variants c.1010G> A, p. (Arg337His) in heterozygosity in the TP53 gene and c.117_120del p. (Ile41Argfs * 39) in heterozygosis in the TMEM127 gene. Her 28-year-old daughter diagnosed bilateral breast cancer and meningeoma in the central nervous system and she had the same pathogenic variants germlines. Thus far, there is no clinical, laboratory or radiological picture of pheochromocytoma. Her 11-year-old granddaughter has only the pathogenic allele variant c.117_120del p. (Ile41Argfs * 39) in heterozygosity in the TMEM127 gene and thus far she has no clinical, laboratory and radiological picture of pheochromocytoma. Conclusion: This is the first case report of the simultaneous occurrence of pathogenic germline variants in the TMEM127 and TP53 genes. Reference: 11) Toledo RA et al Consensus Statement on next-generation-sequencing-based diagnostic testing of hereditary pheocromocytomas and paragangliomas. Nature Reviews Endocrinology 13, 233-247 (2017).