bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasmapheresis as First Line Therapy for Thyrotoxicosis in a Critically Ill Patient
Authors: Sheskier Rachel , Sajan Alen , Mathias Priyanka , Tabatabaie Vafa 
Published: May 2021

Abstract
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 &lt;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

Abstract
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 &gt;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

Abstract
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 &lt;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

Abstract
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&lt;0.02) and 2.5 kg on LT3 (p&lt;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&lt;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&lt;0.001) and in low-density lipoprotein cholesterol (LDL) of 10.8 mg/dL (p&lt;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

Abstract
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&lt;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

Abstract
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 &lt;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

Abstract
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

Abstract
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.