bluuebunny/crossref_metadata_2025 huggingface dataset:
Is Metformin Use Associated With Decreased Thyroid Cancer Risk in Patients With Acromegaly?
Authors: Kadioglu Pinar , Sulu Cem , Tay Kubilay , Guzel Suleyman , Sahin Serdar , Durcan Emre , Ozkaya Hande Mefkure
Published: May 2021

Context: Acromegaly has long been blamed to portend an increased risk for benign and malignant thyroid neoplasia. Growth hormone (GH) and consequent insulin-like growth factor 1 (IGF-1) hypersecretion are implicated in cancer promotion. Metformin, a biguanide derived from the French lilac, is gaining considerable interest because of its plausible anti-tumor properties. Besides, metformin has been shown to inhibit somatotroph proliferation and decrease GH secretion in in vivo studies. Patients with acromegaly have high incidence of diabetes and were thereof treated with metformin. We hypothesized metformin use may be linked to decreased thyroid cancer incidence in patients with acromegaly. Study Design and Methods: The medical records of 508 patients with acromegaly followed at our tertiary referral center between 1969 and 2019 were retrospectively reviewed. The inclusion criteria were having a follow-up duration for at least 12 months and being regularly screened for nodular thyroid disease and thyroid cancer by ultrasonography as indicated in respective guidelines. Patients with acromegaly were evaluated based on ongoing or prior history of metformin use or thyroid cancer diagnosis. Metformin exposure was defined as use of metformin for at least 12 months on a regular basis between initial date of acromegaly and time prior to cancer diagnosis date. Considering the long patency period of cancer of interest, we excluded exposures in the year immediately prior to index cancer date. We evaluated the effect of metformin exposure on risk of thyroid cancer using Kaplan-Meier analysis. Results: Final analysis included 377 patients with acromegaly. Mean age at acromegaly diagnosis was 41.6 ± 11.7 and 60.5% of the patients were female. Three hundred twenty-two patients (85.4%) had undergone transsphenoidal surgery as primary therapy, 73 patients (19.4%) needed radiotherapy and 178 patients (46%) received post-operative medical therapy. Median follow-up duration was 73.5 months (IQR [31.0-137.7]). One hundred twenty patients (31.9%) had an ongoing or prior use of metformin, and total of 19 patients (5%) had thyroid

cancer. Age at acromegaly diagnosis, gender distribution, baseline GH and IGF-1 levels, pituitary tumor size and invasiveness, biological aggressiveness, curative therapy options, treatment responses didn’t differ between metformin users and non-users, as well as between those having and not having thyroid cancer. Kaplan-Meier estimates for 1 year, 3 years and 5 years of metformin exposure showed decreased probability of thyroid cancer incidence (p<0.05 for all). Conclusion: Although our results imply decreased thyroid cancer risk upon metformin exposure, prospective study designs with larger cohorts are obliged in order to fully elucidate the effect of metformin use on thyroid cancer.
Concurrent Papillary and Follicular Thyroid Cancer Presenting as Shoulder Pain
Authors: Santiago Carrion Ada Marie , Agosto-Vargas Yanerys
Published: May 2021

Differentiated thyroid cancer arises from thyroid follicular epithelial cells. It accounts for more than 90% of thyroid cancers. In areas of sufficient iodine nutrition, about 85% of differentiated thyroid cancers are papillary, 10% are follicular and 3% are Hurthle cell carcinomas. The coexistence of different types of thyroid cancer in a single patient is a rare condition.

This is the case of a 56 year-old man with medical history of arterial hypertension who presented to clinics with right shoulder pain. Imaging of the right shoulder showed a osteolytic lesion involving the right humerus with associated cortical disruption consistent with pathological fracture secondary to metastatic disease. Bone biopsy showed papillary thyroid carcinoma. Subsequently, ultrasound-guided fine needle aspiration biopsy to a right lobe nodule was performed, which confirmed the presence of papillary thyroid carcinoma. There was also evidence of cervical lymph node involvement. Patient proceeded to total thyroidectomy with neck dissection, and surgical pathology revealed the presence of 2.5 cm right lobe papillary carcinoma and 1.5 cm left lobe follicular carcinoma. Postoperatively, he was found with persistent elevated thyroid-stimulating hormone (TSH) and elevated quantitative thyroglobulin with elevated thyroglobulin antibodies. Patient received therapeutic radioiodine (I-131) for ablation of thyroid cancer. Whole body iodine scan demonstrated residual functioning thyroid tissue within post-thyroidectomy bed, with or without residual carcinoma, and large expansile uptake lesion involving the right humeral head and neck. Therefore, patient will receive a second dose of radioactive iodine. He has been started on thyroid hormone replacement with a goal of TSH <0.1 uIU/mL for high risk American Thyroid Association (ATA) stratification, and has remained clinically euthyroid.

Thyroid carcinoma is the most common endocrine malignancy and one of the most rapidly increasing cancers in the United States. This increase in incidence is largely due to incidental detection on diagnostic imaging. Here we present an uncommon case of two distinct thyroid malignancies occurring simultaneously in a patient presenting with a pathological fracture. Synchronous occurrence of two types of differentiated thyroid cancer is a rare event, and has only been reported in case series. Bone metastasis from differentiated thyroid cancer can occur in 2-13% of patients. Despite the therapy for papillary thyroid carcinoma and follicular thyroid carcinoma remain the same, proper identification will lead to prompt therapy and increased survival. Physicians should be aware of this variety.
Hurthle Cells Adenoma With Distant Metastases Refractory to Radioiodine
Authors: Rosario Pedro Weslley , Mourão Gabriela Franco
Published: May 2021

Introduction: Adenoma of the thyroid is defined as an encapsulated follicular tumor that is well delimited in relation to the adjacent parenchyma and whose cells do not exhibit the nuclear alterations of papillary thyroid carcinoma (PTC), and in the absence of capsular and vascular invasion. Adenoma, including the of Hurthle cells, is considered a benign tumor. No additional treatment is recommended after resection of the tumor. Case: A 64-year-old man was submitted to total thyroidectomy because of a nodule measuring 3.5 cm with indeterminate cytology (predominance of Hurthle cells). Histology revealed an Hurthle cells adenoma of 3.2 cm. The tumor did not exhibit vascular or capsular invasion, the cells did not contain nuclei of PTC, and no necrosis or mitoses were observed. Five years after surgery, serum thyroglobulin (Tg) was elevated (25 ng/ml) during euthyroidism (TSH 0.6 mUI/l) and in the absence of anti-Tg antibodies. Serum calcitonin was undetectable. The patient developed a progressive increase in Tg and neck ultrasonography (US), chest computed tomography (CT), and FDG-PET/CT were performed. US revealed atypical lymph nodes (the largest with 12 mm) and cytology showed abundance of Hurthle cells. Chest CT detected multiple nodules, the largest measuring 15 mm, and FDG-PET/CT revealed areas of cervical and pulmonary uptake corresponding to the lesions seen on US and CT. The patient received 100 mCi radioactive iodine and post-therapy whole-body scanning showed mild uptake only in the thyroid bed. The patient continues to show progressive increase in Tg (last measurement > 1,000 ng/ml), as well as progression of metastases. He remains under follow-up and on therapy with tyrosine kinase inhibitor. The histology result was revised by two pathologists with broad experience in thyroid pathology who confirmed the initial findings compatible with adenoma. Conclusion: The present case shows that, although rare, Huthle cells tumors can develop metastases even when the tumor is < 4 cm and unequivocally without nuclei of PTC or capsular and vascular invasion, thus considered benign (adenoma). As observed in this case, these metastases can be macrometastases, distant, and refractory to radioiodine. Reference: Lloyd RV, Osamura RY, Klöppel G, Rosai J, ed. WHO Classification of Tumours of Endocrine Organs. 4th edition Lyon: IARC; 2017
Predictive Accuracy of Delta Cortisol on Recovery of Adrenal Function in Patients With Drug Induced Cushing’s Syndrome With Secondary Adrenal Insufficiency
Authors: San Bo Bo
Published: May 2021

There is a growing concern upon the finding of many drug induced Cushing’s syndrome because of inadvertent use of glucocorticoids (GC) either prescribed or as alternative medicine in Myanmar. These patients are presenting with diversity of clinical problems ranging from hypertension, diabetes to acute adrenal crisis due to hypothalamic-pituitary-adrenal (HPA) axis suppression and secondary adrenal insufficiency (AI). The present study aimed to assess the delta cortisol (the degree of cortisol increments) during the first short Synacthen test (SST) as a factor predictive of adrenal function recovery in patients with drug induced Cushing’ syndrome with secondary AI and to determine the proportion of patients who recovered from AI within six-month follow-up. This was a hospital based prospective analytical study that enrolled a total of 52 patients with drug induced Cushing’s syndrome with secondary AI from January 2018 to June 2019. Secondary AI is defined by morning basal serum cortisol ≤ 400 nmol/L with Synacthen stimulated peak cortisol level ≤ 550 nmol/L and serum ACTH < 60 pg/ml. The follow-up SSTs were performed at three-month and six-month after first SST, and the patients with morning basal serum cortisol > 400 nmol/L (or) Synacthen stimulated peak serum cortisol > 550 nmol/L during follow-up SSTs are defined as recovered adrenal function group. In this study, a total of 52 patients were treated with modified regimen of physiological dose of prednisolone with tapering schedule or stress dose GC based on the basal serum cortisol levels up to six months. Among them, nearly half (n=25 / 48.1%) of the patients with drug induced Cushing’s syndrome with secondary AI achieved normal adrenal function within six-month follow-up. It was found that mean values for delta cortisol were not statistically significant between recovered and non-recovered groups, 118.6 nmol/L (SD 72.3) and 97.2 nmol/L (SD 64.2) respectively. The delta cortisol during the first SST could not predict strongly (AUC - 0.6, 95% CI - 0.44 to 0.76, P = 0.2) the recovery of adrenal function in patients with drug induced Cushing’s syndrome with secondary AI and it was inconsistent with previous studies. The older age of the patients, oral route of administration of drugs causing Cushing’s syndrome and comorbid hypertension were found to be more significant in the non-recovered group. In conclusion, the present study did not support the evidence that the delta cortisol during the first SST could predict adrenal function recovery in patients with drug induced Cushing’ syndrome with secondary AI.

Reference: (1) Baek et al., 2016; Recovery of Adrenal Function in Patients with Glucocorticoids Induced Secondary AI. Endocrinol Metab.31, pp. 153–160. (2) Pofi et al., 2018; The Short Synacthen Test Can Be Used to Predict Recovery of HPA Axis Function. J Clin Endocrinol Metab.103(8), pp. 3050–3059.
Leukocytosis and PTHrP-Mediated Hypercalcemia: Ominous Signs in an Indolent Thyroid Nodule
Authors: Gerwer Johanna Elizabeth , Thomas Robert L , Orosco Ryan K , Choe Charles , McCowen Karen C
Published: May 2021

Introduction/Background: Anaplastic thyroid cancer is a rare thyroid malignancy with a bad prognosis. There are few systemic markers, as thyroglobulin is not usually synthesized in these poorly differentiated malignancies. Clinical Case - Diagnostic Evaluation, Treatment, and Follow Up: A 70-year old man presented in 2016 with a right thyroid nodule, slowly growing since 2012. The nodule was 10cm on neck CT and ultrasound showed a hyperechoic mass with central hypoechoic area, and coarse calcifications. Fine needle biopsy showed a follicular neoplasm. By 2019, neck CT showed enlargement of the nodule to 13 cm. Repeat thyroid biopsy was benign. Lobectomy was recommended due to size but not performed. In 2020, he developed neck discomfort and painful thigh swelling. WBC was significantly elevated at 27,000 (4000-10000) /mm3. Ultrasound showed no evidence of necrosis or abscess in the nodule. WBC rose progressively to 96,000/mm3 (ANC 94,200). CT chest showed further enlargement of the thyroid mass, a soft tissue shoulder mass and lung nodules suspicious for metastases. Laryngoscopy revealed a distorted larynx from external compression, and possible vocal-fold involvement (motion impairment) without airway compromise. Biopsy of the shoulder mass, lung nodule, and thigh masses all showed metastatic anaplastic thyroid cancer. Full infectious disease evaluation and molecular testing for BCR-ABL and JAK2 mutations were negative. Thus, leukocytosis was determined to be reactive in the setting of malignancy. Serum calcium of 14.7 mg/dL (8.5 - 10.6mg/dL) prompted hospital admission. Bone metastases were not visible on imaging. Hypercalcemia was treated effectively (to 8.3mg/dL) with IV fluids, calcitonin and IV bisphosphonates. Workup revealed suppression of PTH to 4 pg/mL (15-65 pg/mL) and low 25 Vitamin D of 21 ng/mL (30-80ng/L). Subsequently PTHrP was elevated at 53.4 pmol/L (<2.3pmol/L) and 1,25 Vitamin D inappropriately normal at 48.9 pg/mL (20- 79.3pg/mL), suggested humoral hypercalcemia of malignancy. The patient declined further treatment beyond hospice care. Clinical Lesson/Conclusion: Significant, sudden leukocytosis and hypercalcemia prompted further evaluation of his long-standing apparently benign thyroid nodule leading to a diagnosis of anaplastic thyroid cancer. Presumably this mass had been a follicular thyroid cancer, misdiagnosed on cytology, that subsequently de-differentiated. There are uncommon reports of leukocytosis complicating anaplastic thyroid cancer, where elevated GCSF and IL-6 were noted. We suspect this same etiology here. Hypercalcemia is extremely rare other than one report of PTHrP-secreting anaplastic thyroid cancer. Thus, high, rising calcium and PTHrP levels may reflect level of disease activity in anaplastic thyroid cancer.
Medullary Carcinoma of Thyroid Due to GLP-1 Receptor Agonist
Authors: Vemula Hasitha , Villanueva Fiorella Sotomayor , Nguyen Huong Diem , Mohan Akhila , Potluri Sriravali
Published: May 2021

Introduction: The first GLP-1 receptor agonist (GLP-1 RA) was approved for the treatment of type 2 Diabetes mellitus in 2005. This class has gained popularity due to its anti-glycemic effect, weight loss and reduction in Cardiovascular disease outcomes1. The effects of this drug class on human thyroid cells are not well known. We hereby report a case of a woman who developed medullary carcinoma of thyroid (MTC) after using Dulaglutide.

CaseA 63-year-old female with T2DM for 3 years, taking dulaglutide for 2 years, who presented with a lump in the neck. She had no personal or family history of MEN 2 syndrome, radiation exposure or cancer. Examination showed a 2cm firm nodule in the left lower neck. Thyroid ultrasound revealed a large nodule in the left upper lobe of thyroid. Lab work showed TSH of 1.55mIU/L (0.27-4.2 mIU/L) and serum calcitonin level of 1903 pg/ml (0.0-5.1 pg/mL). FNA biopsy of the nodule showed MTC. She tested negative for RET MEN 2 gene mutation. She underwent total thyroidectomy and neck dissection. Pathological examination confirmed MTC. Post-op calcitonin improved to 2.1 pg/ml.

Discussion: GLP-1 RAs provide glycemic control by many mechanisms, including increase in insulin secretion, reduction in postprandial glucagon secretion, delaying gastric emptying, increasing satiety and weight loss. Although they have proved effective in T2DM management, the potential effects on thyroid C-cells should not be ignored. Several in-vitro studies have shown GLP-1 receptors on the rat thyroid tissue C-cells. Stimulation of these receptors resulted in increased production of calcitonin in a dose dependent manner and increased risk of C-cell tumor formation at 104 weeks. Studies initially done by Knudsen et al2 showed that this effect was not seen in humans due to lower expression of GLP-1 receptors in human thyroid tissue C cells. However, a study conducted by Gier et al showed the expression of GLP-1 receptor in some patients with C-cell hyperplasia as well as papillary and medullary carcinoma3. FDA adverse event reporting system database suggested an increased risk of thyroid cancer associated with GLP-1 RAs. It is unclear whether dulaglutide contributed to the development of MTC in this patient. She had not had a baseline calcitonin level prior to the initiation of dulaglutide. The consequence of long-term use of GLP-1 RAs in the thyroid gland in humans still remains unknown and further studies to determine if they increase the risk of MTC are warranted.

References: 1. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016;375(4):311. Epub 2016 Jun 13. 2. Glucagon-like Peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation. Endocrinology. 2010;151(4):1473. Epub 2010 Mar 3. Glucagon Like Peptide-1 Receptor Expression in the Human Thyroid Gland
Radiofrequency Ablation: A Novel Treatment Option for Neck Recurrence in Medullary Thyroid Carcinoma
Authors: Aljammal Jules , Ahmad Shahzad , Hussain Iram , Zulfiqar Fizza
Published: May 2021

Background: Medullary thyroid carcinoma (MTC) is an aggressive cancer with cervical lymph node metastases typically found at presentation. The recurrence rate after resection is high (~ 50%)(1), and patients often need multiple surgeries. Radiofrequency ablation (RFA) has been used in treatment of recurrent thyroid cancer when surgery is contraindicated or declined by patients in both Asia and Europe (2). We present the first case of an MTC recurrence treated successfully with RFA in North America.

Clinical Case: A 43-year-old female with sporadic metastatic MTC, status post total thyroidectomy and multiple neck surgeries, presented with elevated calcitonin level of 630 pg/mL (normal: < 10 pg/mL). Neck ultrasound showed left tracheoesophageal groove mass, measuring 12 mm X 12 mm X 17 mm, consistent with metastatic MTC on cytopathology with calcitonin washout of 16590 pg/mL (normal: < 10 pg/mL). She had no dysphagia, shortness of breath or hoarseness of voice. Computed tomography (CT) scan of chest confirmed presence of mass, in proximity with left recurrent laryngeal nerve. Serial imaging showed rapid enlargement, with concern for impending aerodigestive tract invasion. Surgical intervention had a high risk of vocal cord paralysis due to the lesion’s location. A multidisciplinary tumor board agreed that thermal ablation aimed at shrinking the mass, as a bridge to systemic therapy, would be the best option. RFA was performed as an outpatient with conscious sedation, after informed consent and observing standard aseptic techniques. Under continuous ultrasound guidance, D5W was injected into left tracheoesophageal groove behind the mass and a continuous infusion of D5W at 15 mL/hr was maintained to protect the nerve from thermal injury. Using a trans-isthmic approach, an 18 G monopolar RFA probe with 5 mm active tip was advanced into the malignant mass and ablation was performed with 35 W power until the entire mass was hyperechoic. Vocal response was monitored throughout the procedure and voice remained normal after RFA. A neck ultrasound at her 6 months follow-up showed ablated lesion measuring 7 mm X 11 mm X 10 mm, representing a 68.6% reduction in volume. Repeat CT scan thorax showed disappearance of mass in left neck region.

Conclusion: RFA is a minimally invasive and effective treatment for recurrent cervical MTC lesions, and a viable alternative to surgery, as shown in our case. Future studies should focus on long term follow-up and comparison with surgery with regards to safety and efficacy.

References: 1.Skoura E. Depicting medullary thyroid cancer recurrence: the past and the future of nuclear medicine imaging. Int J Endocrinol Metab. 2013;11(4):e8156. 2.Garberoglio R, Aliberti C, Appetecchia M, Attard M, Boccuzzi G, Boraso F, et al. Radiofrequency ablation for thyroid nodules: which indications? The first Italian opinion statement. J Ultrasound. 2015;18(4):423-30.
Relationship Between rhTSH Administration and Thyroid Cancer Progression: A Case Report
Authors: Mejia Maria G , de Bogotá, C Hospital San José , Veronesi Luz Amaya , Concha Diana Carolina
Published: May 2021

Introduction: The relationship between the administration of recombinant TSH (rhTSH) and the progression of thyroid cancer has been described in some case reports (1). There are scant data suggesting that rhTSH acts as a growth factor that stimulates metastatic tumor expansion. Case Report: A 55 year old male patient who 3 years ago reported an evident mass at cervical level. The ultrasound documented a large thyroid mass with an endothoracic component. The FNA reported BETHESDA IV, suspicious for follicular neoplasia. Extension studies showed lytic left parietal bone lesion and liver metastatic compromise. The pathology of the total thyroidectomy showed a follicular carcinoma with a micronodular pattern and capsular invasion, of 19x9x7 cm, vascular and esophageal involvement T4BN0M1. He was sent to radioiodine therapy with 100 MCI with previous suspension of LT4 (Preablative TGL> 300 ng / ml (<50 ng / ml) Abs-TGL 2 IU / ml (<2 IU / ml) TSH 31.3 mIU / L (0.37-4.7 mIU / L) and body scan documenting uptake of the radiotracer at the left parietal, the anterior costal grating, and liver. A second dose of iodine was applied, with 150 MCI after stimulation with thyrotropin (Preablative TGL> 300 ng / ml, Abs-TGL 1.76 IU / ml, TSH 83 mIU / L) Immediately after the administration of rhTSH, the patient described the appearance of alopecic plaques on the scalp, sensation of mass at the right upper quadrant of the abdomen and bone pain in the right rib cage and at the right hip, which progressively worsened the following days until they were incapacitating. The scan report showed a new uptake in dorsal vertebrae, the MRI showed new bone injury at the innominate bone, as well as increase in the sum of its maximum dimensions by 22%, indicative of progression. The cerebral angio-MRI showed hypervascularized metastasis at the left parietal level. Bone scintigraphy documented foci of hyper uptake in both parietals, manubrium and sternal body, 5-8 right anterior costal arches, right scapula, both humeral heads, vertebral bodies T3-T5-T7L4, right acetabulum, left proximal femur and the entire length of the right femur. The clinical and imaging worsening of the bone lesions after the application of rhTSH was striking, for this reason radiotherapy and embolization of the liver lesion was performed. The patient was not a candidate for neurosurgical management due to the vascular component of the cranial lesions. Conclusion: rhTSH is a very well-tolerated method that avoids symptoms associated with severe hypothyroidism. However, it has been associated with neoplastic progression. This is one of the few cases documented in the literature where there is a direct association between the administration of rhTSH and the progression of bone metastases.

References: (1)Braga M. Ringel M. Cooper DS. Sudden Enlargement of Local Recurrent Thyroid Tumor after Recombinant Human TSH Administration. J Clin Endocrinol Metab. 2001; 86(11):5148–51.
Biopsy Confirmed Subacute Thyroiditis Associated With COVID-19
Authors: Maldonado Francisco Javier López , Cota Arreola Rene Arturo
Published: May 2021

Subacute thyroiditis is a transient inflammatory disease of the thyroid associated with anterior neck pain, and systemic symptoms. The diagnosis is generally reserved for a specific type of thyroiditis characterized by granulomatous inflammation and the presence of giant cells. We hereby present a case of a woman with a COVID-19 diagnosis, and a compatible biopsy result for subacute thyroiditis.

On 06/03/2020, a 28 year old woman with previous history of ankylosing spondylitis managed with certolizumab pegmol, presented with fatigue, headache, odynophagia, and fever (38.1°C). 2 days later an oropharyngeal swab (PCR) for SARS-CoV-2 turned out positive. On the 4th day the fever spiked to 39°C with added malaise. Acetaminophen 1 gr PO TID was prescribed. The patient denied dyspnea, and thorax CT-Scan was normal. Complete remission was achieved in 3 weeks. On 08/01/20 she returned to work after a negative swab test. On 08/04/20, she presented with fever (38.7°C), malaise, distal tremors, anorexia, tachycardia, myalgias, arthralgias, and fatigue. 2 days later anterior neck pain that radiated to the jaw, and diffuse goiter was noticed. A thyroid function panel reported Total T4: 24 µg/dL (4.5-12.5), fT4 5.2 ng/dl (0.8-1.8), TSH: 0.001 mUI/L (0.37-4.7), thyroglobulin 135 ng/ml (3-42). TPO-Ab <35 IU/mL and TgAb <20 IU/mL.

A neck US showed increased volume in the right lobe with multiple hypoechoic regions on both lobes, and diminished vascularization at color Doppler. I-131 scan showed no uptake. A biopsy of the right lobe reported fibrosis with inflammatory infiltrate composed of lymphocytes, plasma cells, histiocytes, and scarce neutrophils. Some cells with epithelioid appearance and a multinucleated giant cell were also found. Residual thyroid follicles showed colloid depletion and degenerative changes to the epithelium, which was consistent with a diagnosis of subacute thyroiditis.

Treatment was initiated with prednisone 10 mg PO QD, propranolol 20 mg PO BID for 2 weeks, and acetaminophen 1 gr PO TID PRN. Fever and pain were intermittent for 6 weeks, but the rest of the symptoms subsided within 2 weeks. On 11/15/20, the patient attended a check-up with lab results that were consistent with hypothyroidism, negative IgM, and positive IgG SARS-CoV-2. Replacement therapy with levothyroxine 88 mcg per day was initiated.

This case, which confirms the diagnosis of subacute thyroiditis via biopsy, among the others reported worldwide suggests that there’s an increased risk for women for subacute thyroiditis associated with COVID-19. Further research is needed to confirm risk factors for the development of the disease.
Differentiating Recurrent Thyroiditis From Graves’ Disease on a Background of Lithium Use
Authors: Subbiah Kasi , Kumar Jesse , Sivappriyan Siva , Anandappa Samantha
Published: May 2021

A 26-year-old female presented with severe thyrotoxic symptoms 4 months post-partum following an uncomplicated pregnancy; investigations showed a FT4 39.4 pmol/L (n 12 – 22 pmol/L), FT3 8 pmol/L (n 3.1 – 6.8 pmol/L), FT4:FT3 ratio 4.9, TSH <0.02 mU/L (n 0.27 – 4.2 mU/L), TSH receptor antibody (TRAb) < 0.9 IU/L (n < 0.9 IU/L) with normal blood flow on ultrasound doppler and a low (0.2%) Tc99 uptake isotope scan suggesting thyroiditis. 2 years previously she had an episode of thyroiditis (investigations showed FT4 31.2 pmol/L, FT3 7 pmol/L, FT4:FT3 ratio 4.4, TSH <0.02 mU/L and imaging showed low (0.4%) Tc99 uptake) when on lithium 1gm/day for more than a year to treat bipolar disorder.

On recurrence, despite compliant treatment with Propranolol and Prednisolone 30mg once daily, thyroid function deteriorated and 2 months later repeat thyroid function testing showed a FT4 > 100 pmol/L, FT3 30.2 pmol/L, FT4:FT3 ratio 3.3 and TSH < 0.02 mU/L. A repeat Tc99 uptake scan showed increased uptake at 13% and ultrasound showed a very vascular bulky thyroid gland. These investigations were suggestive of either a rebound hyperthyroidism (post-thyroiditis) or Graves’ disease. At this stage, TRAb titers were repeated and were now elevated at 4.5 IU/L therefore carbimazole 40mg daily was started. Due to the severity of symptoms, she underwent urgent thyroidectomy. Histopathology showed features of diffuse hyperplasia of the thyroid gland with variably sized follicles lined by cuboidal epithelial cells and a mild patchy chronic inflammatory cell infiltrate in the stroma. Post thyroidectomy she is stable on L-thyroxine therapy.

Points for discussion:

1. Lithium is typically used as a mood stabilizer and as thyroid dysfunction is known to exacerbate mood disturbances it is vital that patients are appropriately screened, monitored and treatment is commenced promptly for thyroid disease.

2. Lithium can increase clinical manifestations of thyroid autoimmunity and may influence thyrotoxicosis either due to thyroiditis or Graves’ disease. Differentiating these etiologies is important from the treatment perspective.

3. FT4:FT3 ratios, TSH receptor antibodies, Tc99 uptake scans and ultrasound doppler of the thyroid will assist in diagnostic accuracy. However, in certain rare circumstances, during the recovery phase of thyroiditis, the Tc99 scan can demonstrate diffusely increased activity, which is representative of a rebound phenomenon thus posing a diagnostic dilemma.

4. Finally, TRAb titers may help differentiate the above, but sometimes may change from undetectable to high suggesting changes in thyroid autoimmunity.
Difficulties in Differential Diagnosis of Thyrotoxicosis: Clinical Case
Authors: Volkova Natalia I , Davidenko Ilya , Dzherieva Irina , Ganenko Lilia , Reshetnikov Igor , Sorokina Julya , Zibarev Alexander , Degtyareva Yulya , Chernova Anastasya , Gizatullina Gulnara
Published: May 2021

Introduction: Thyrotoxicosis (T) develops as a result of persistent excess of thyroid hormones (TH). There are two groups of diseases that are fundamentally different in pathogenesis. The first group includes those in which the production of TH increases. Diseases of the second group are accompanied by T caused by destruction of the thyroid gland tissue. Therapeutic approaches for different pathogenetic types of T are different, therefore, a careful differential diagnosis of T is necessary, even if at first glance the diagnosis seems obvious. Clinical Case: A 35-year-old patient consulted a physician complaining of weakness, weight loss by 11 kg in 1.5 months, tremors, palpitations, which first appeared about a month ago. The examination revealed TSH <0.0083 mU/l (0.4-4.0), and an endocrinologist’s consultation was recommended. On examination, the thyroid gland is no larger than the distal phalanx of the subject’s thumb, BMI=24 kg/m2, HR=100 bpm, BP=115/80 mm Hg. Laboratory examination: TSH <0.0083 mU/l, free T4 =28.29 pmol/l (9.0-19.05). Ultrasound of the thyroid gland: signs of diffuse changes in tissue, the total volume=16.8 ml3. For differential diagnosis of T, antibodies to TSH receptors were determined, the titer of which turned out to be slightly increased 1.43 IU / L (<1). A diagnosis of Graves’ disease (GD) was made and treatment was prescribed (Tyrozol 30 mg, Bisoprolol 2.5 mg per day). After 3 weeks, the patient noted an improvement in well-being, but weakness, tremor, an increase in free T4 (23.33 pmol/l) and total T3 (3.26nmol / l at a rate of 0.98-2.33) remained. The lack of achievement of the target values of TH levels was regarded as inadequacy of the received dose of Tyrozol, in connection with which it was decided to increase the dose to 40 mg per day. After 2 weeks, an increase in free T4 (27.26 pmol/L) and total T3 (3.84 nmol/L) remained. The lack of positive dynamics called into question the diagnosis of GD. With a more thorough collection of anamnesis, it was found that 1.5 years ago, the patient took amiodarone for 6 months as prescribed by a cardiologist (he does not remember the dose). In this connection, to establish the cause of T, scintigraphy was performed: revealed a weak accumulation of a radiopharmaceutical with diffuse uneven distribution. Based on the data obtained, amiodarone-induced T type 2 was verified. Treatment was corrected: Tyrosol withdrawal and Prednisolone administration, 40 mg/day with positive dynamics from treatment. Conclusion: Clinical case demonstrates how important it is to carefully collect the patient’s history and follow the algorithms for differential diagnosis. Errors in diagnosis lead to incorrectly prescribed treatment, lengthening the duration of symptoms, which affects not only the patient’s quality of life, but also reduces the level of his trust in medical professionals.
High-Dose Thyroid Hormone Replacement in Bexarotene-Induced Central Hypothyroidism
Authors: Mathews Tony , Gigliottie Benjamin
Published: May 2021

Background: Central hypothyroidism is a rare disorder characterized by a defect in thyroid hormone production by an otherwise normal thyroid gland due to decreased stimulation by TSH. Medications are an uncommon cause. Case Presentation: A 72-year-old man was referred for evaluation of a low TSH. He had a long history of hypothyroidism, euthyroid on levothyroxine, and was diagnosed with cutaneous T cell lymphoma (CTCL). Due to disease progression on dapsone, PUVA and TAR baths, he was started on bexarotene. Soon after, he developed recurrent symptoms of hypothyroidism including fatigue, cold intolerance, dry skin, and myalgias. Workup revealed a TSH of <0.01 ulU/mL (0.27-4.20) with a free T4 of 0.6 ng/dl (0.9-1.7). After evaluation, his levothyroxine dose was increased. Repeat labs 3 months later showed a TSH of <:0.01 with a free T4 0.8 ng/dl and T3 43 ng/dl (80-200). Over several months, levothyroxine titration to a supraphysiologic dose of 800 mcg daily was required, despite optimal administration, to normalize FT4. Given persistent hypothyroid symptoms and a low T3 level, liothyronine 5 mcg BID was added and resulted in clinical and biochemical euthyroidism. Clinical Lessons: Unlike in primary thyroid disorders, the TSH assay is unreliable in central hypothyroidism since values can be low, normal, or even mildly elevated; regardless, TSH has subnormal bioactivity. Ineffectual TSH leads to a low T4, which is a required for diagnosis. Bexarotene, a derivative of Vitamin A, is a retinoid X receptor (RXR) selective ligand approved for the treatment of CTCL. The exact mechanism of bexarotene-induced thyroid dysfunction is not clear, although it involves both central and peripheral effects. Bexarotene inhibits TSH gene expression by decreasing the activity of the thyrotropin β subunit gene promoter in a dose-dependent and thyroxine-independent manner; TSH levels drop as early as 4-8 hours after exposure. Bexarotene also directly lowers T4 and T3 levels, even in athyreotic patients, by negatively impacting deiodinase activity and hepatic conjugation. Stopping bexarotene is often not possible given its effectiveness in CTCL. Therefore, thyroid hormone should be initiated with the goal of achieving a normal FT4, although as the current case demonstrates, massively supraphysiologic doses and/or the addition of liothyronine may be necessary to achieve clinical euthyroidism.
The Majority of Inpatient Short Synacthen Tests Are Performed Incorrectly, Due to Imprecise Timing, Incorrect Sampling and Failure to Interrupt Steroid Administration
Authors: McCarthy Aonghus , McKenna Susan , Hall Keira , Niland Aileen , Boran Gerard P , Moran Carla M
Published: May 2021

Introduction: The short synacthen test (SST) is commonly used to assess adrenal function. Accurate timing and appropriate holding of exogenous steroids are essential to ensure correct interpretation of results.

Aims & Methods: We reviewed all SSTs performed on inpatients in our hospital over a 1-year period, in order to determine accuracy of testing.

Results: 42 patients (Male 15, Female 27), with mean age 68 years (range 43–90), underwent SST. The majority (39/42; 93%) of tests were requested by internal medicine physicians. The indications for testing were; suspected adrenal insufficiency (18), HPA axis suppression (9), fatigue (7), hyponatremia (5), suspected pituitary disease (2) and vomiting (1). 7 (44%) of the 16 patients taking steroids did not have medication appropriately held. 31 (74%) patients did not have serum ACTH measured prior to the test. 28 (66%) tests were not started at the correct time. Only 10 (24%) of the 30 minute samples were completed within the 25-35min sample window. The mean time between the 0min and 30min samples was 42mins (median 62mins; range 0-209mins). 12 (29%) tests involved an unnecessary 60min sample. 8 (19%) tests had no interpretation of results documented in the medical notes. 4 (10%) patients underwent repeat testing, necessitated by an incorrect first test.

Discussion: The vast majority of inpatient SSTs (33/42;79%) were performed suboptimally, with the most common errors pertaining to incorrect timing of the test, inaccurate sampling and inappropriate pre-test steroid administration. Considering these errors, some results may have been interpreted incorrectly. Repeat tests were recognised as required in 10% of patients, with associated inconvenience, cost and discomfort. Improved training and guidelines for performing SSTs should be available to hospital staff to ensure more accurate application of the test.
Epithelial Transcription Factor FOXA1 Regulates Prostate Cancer Immune Response
Authors: Brea Lourdes T , Wang Xiaohai , Yu Jindan
Published: May 2021

Background : While localized prostate cancer (PCa) can be mitigated by surgery and radiation, metastatic PCa remains a challenge to treat. Androgen deprivation therapies and androgen receptor (AR) pathway inhibitors are mainstay treatments for advanced PCa. Yet, resistance often develops leading to castration-resistant prostate cancer (CRPC). Forkhead Box A1 (FOXA1) is a pioneer transcription factor that plays pivotal roles in regulating AR activity and promoting epithelial differentiation. Studies have shown that FOXA1 is frequently downregulated in CRPC tumors. Congruently, FOXA1 loss is reported to induce aberrant AR signaling, epithelial-mesenchymal transition, and PCa de-differentiation. However, the role of FOXA1 in regulating PCa immune response, an area of much interest recently, has not been reported. CRPC has shown poor response to immune checkpoint inhibitors, due to its immunosuppressive nature. A better understanding of the tumor intrinsic mechanisms regulating PCa tumor immunity will inform the design of better targeted immunotherapeutic approaches. Methods: We performed RNA-seq, ChIP-seq, qPCR, western blot, and ELISA analyses to evaluate how FOXA1 regulates inflammatory response genes. We utilized an in vitro macrophage infiltration transwell assay, in which M2-like macrophages were added to the upper chamber and PCa cells were plated in the lower chamber, to examine how perturbations to PCa cells affect macrophage migration. Finally, we performed bioinformatic analyses of patient datasets to confirm the clinical relevance of FOXA1 repression of inflammatory genes in PCa. Results: Through integration of RNA-seq and ChIP-seq data, we uncovered a novel function of FOXA1 in suppressing inflammatory response pathways. In accordance, patient data analyses revealed that inflammatory response genes were upregulated in FOXA1-low PCa tumors. Mechanistically, we showed that FOXA1 proteins bound an intragenic enhancer of Hypoxia-inducible factor 1-alpha (HIF1A) gene to directly repress its expression, such that FOXA1 loss induced HIF1A upregulation. We further showed that Monocyte Chemoattractant Protein-1 (MCP-1/CCL2) became upregulated upon FOXA1 depletion in a HIF1A-dependent manner. This led to infiltration by immunosuppressive, tumor promoting M2-like macrophages. Inhibiting this HIF1A-CCL2 axis with a HIF1A inhibitor or CCL2 neutralizing antibody blocked macrophage infiltration. Future studies using immunocompetent mouse models are needed to confirm the effect of FOXA1 on macrophage infiltration in vivo and evaluate the preclinical potential of targeting the FOXA1-HIF1A-CCL2 axis in CRPC. Conclusion: This study proposes a novel role for FOXA1 loss in promoting macrophage infiltration via the HIF1A-CCL2 axis. Moreover, our findings suggest that targeting this axis may be a promising approach for the treatment of FOXA1-low CRPC tumors.
Management of Pheochromocytoma in a Patient With Severe Aortic Stenosis Undergoing Transcatheter Aortic Valve Replacement
Authors: Chopra Karishma A , Banka Ajaz
Published: May 2021

Background: There are few guidelines for the management of patients with both significant cardiac valvular disease and pheochromocytoma. Resection of pheochromocytoma is challenging for surgeons and anesthesiologists due to the potential for sudden releases of catecholamines causing significant hemodynamic effects. The cornerstone of perioperative management of pheochromocytoma involves alpha blockade to prevent the potential for hypertensive crisis from unopposed alpha-adrenergic vasoconstriction. Achieving adequate adrenergic blockade is challenging in patients with aortic stenosis due to the risks of decreased afterload precipitating myocardial ischemia and bradycardia leading to diminished cardiac output [1]. It is difficult to determine whether to proceed first with transcatheter aortic valve replacement or pheochromocytoma resection in patients with both conditions. Clinical Case: An 83-year-old woman with a past medical history of type 2 diabetes, essential hypertension, coronary artery disease, and severe aortic stenosis was found to have a left adrenal mass (10.7 cm) on coronary CTA during pre-operative evaluation for transcatheter aortic valve replacement. She had significantly elevated total urine metanephrines of 16,237 ug/24 hr (n 140–785 ug/24 hr); other hormonal workup was unremarkable. A multi-disciplinary team of interventional cardiology, anesthesiology, and endocrinology specialists determined the safest management plan involved proceeding with transcatheter aortic valve replacement, after adequate alpha and beta blockade and prior to pheochromocytoma resection, to avoid potential for severe heart failure. Due to the potential for unpredictable catecholamine release intra and peri-operatively, the patient was at high risk for hypertensive crisis and mortality. Her home medications of metoprolol 50 mg twice daily, spironolactone 25 mg daily, and verapamil 120 mg daily were continued. She was started on treatment with phenoxybenzamine 10 mg in morning and 10 mg in evening. The phenoxybenzamine dose was titrated to 10 mg in the morning and 20 mg in the evening to achieve a consistent systolic blood pressure of less than 130 mm Hg. She successfully underwent transcatheter aortic valve replacement and remained hemodynamically stable. She was discharged with plan for surgical resection of pheochromocytoma six weeks after her transcatheter aortic valve replacement. Conclusions: This case describes a successful management strategy for achieving alpha blockade in an elderly patient with pheochromocytoma and severe aortic stenosis. Reference: [1] Saran JS, Moalem J, Schoeniger L, Tzimas K. Perioperative Management of Pheochromocytoma Resection in a Patient With Severe Aortic Stenosis. J Cardiothorac Vasc Anesth. 2018 Dec;32(6):2712–2715.
Multifactorial Hyponatremia in a Lung Transplant Recipient: A Case Report of Pseudohyponatremia, SIADH and Secondary Adrenal Insufficiency
Authors: Shayto Rani
Published: May 2021

Background: Lung transplant recipients are prone to developing multifactorial hyponatremia from immunosuppressive therapies and posttransplant lymphoproliferative disorders.

Clinical Case: A 77-year-old male with a history of lung transplantation in 2017 presented for a 3-month history of confusion, decline in executive function and chronic abdominal pain. Vital signs were BP 137/81 mmHg, HR 81 bpm, RR 14 per minute, SPO2 99% and afebrile. The patient was clinically euvolemic with a presenting sodium was 129 mmol/L, and was treated with 2.5L IV 0.9% saline. Home immunosuppression with cyclosporine, azathioprine and prednisone 5 mg/d were continued. Sodium declined to 126 mmol/L on day 4 prompting endocrine consult. Labs prior to fluid administration were consistent with iso-osmolar hyponatremia: sOsm 283 mOsm/kg and uOsm 409 mOsm/kg. Pseudohyponatremia was suspected and electrophoresis and immunofixation revealed a free kappa light chain gammopathy. Evaluation when sodium was 126 mmol/L was now consistent with hypotonic hyponatremia: sOsm 273 mOsm/kg, uOsm 398 mOsm/kg, and urine sodium 56mmol/L. TSH was normal and AM cortisol was 11.9 ug/dL (3.7–19.4 ug/dL), drawn while on maintenance prednisone. Lab findings and improvement of abdominal pain after receiving high dose prednisone for CT contrast-allergy prophylaxis raised our suspicion for SIADH and undertreated secondary AI. Retrospective chart review revealed tacrolimus use after lung transplant before its discontinuation 9 months prior to admission. Chronic hyponatremia was noted a few months post lung transplantation, with a nadir of 120 mmol/L and only mild improvement despite tacrolimus discontinuation and empiric fludrocortisone use. The patient was treated with a 1L fluid restriction, doubling of prednisone to 10 mg/d and cessation of fludrocortisone for lack of concern for primary. Abdominal symptoms resolved, mental status improved, and serum sodium rose to 132 mmol/L over the next few days, later normalizing to 135–140 mmol/L on follow up. The patient was eventually diagnosed with Waldenström macroglobulinemia.

Conclusion: Hyponatremia in lung transplant recipients can be multifactorial. Calcineurin inhibitors and steroids are part of typical immunosuppressive regimens and can lead to hyponatremia through salt wasting nephropathy or SIADH(1), and undertreated secondary AI, respectively. Posttransplant lymphoproliferative disorders occur in up to 9% of cases(2) and must be suspected as an etiology of hyponatremia.

References: 1.Cowan AJ, Johnson CK, Libby EN. Plasma cell diseases and organ transplant: A comprehensive review. Am J Transplant. 2018;18(5):1046–58.2.Aris RM, Maia DM, Neuringer IP, Gott K, Kiley S, Gertis K, et al. Post-transplantation lymphoproliferative disorder in the Epstein-Barr virus-naïve lung transplant recipient. Am J Respir Crit Care Med. 1996;154(6 Pt 1):1712–7.