bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Pesticide Chlorpyrifos Promotes Obesity by Inhibiting Diet-Induced Thermogenesis
Authors: Wang Bo , Zhang Shuman , Llanos Andrea , Tsakiridis Evangelia E , Desjardins Eric M , Yabut Julian M , Green Alexander E , Day Emily A , Smith Brennan K , Lally James S V , Raphenya Amogelang R , Srinivasan Krishna A , McArthur Andrew G , Kajimura Shingo , Patel Jagdish Suresh , Wade Michael Gordon , Morrison Katherine Mary , Holloway Alison , Steinberg Gregory R 
Published: May 2021

Abstract
Obesity is a major risk factor for type 2 diabetes (T2D), non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease that arises from a caloric surplus of as little as 10–30 kcal per day. And while increased consumption of energy dense foods and reduced physical activity are commonly thought to be the major contributors to this caloric imbalance, diet-induced thermogenesis is a quantitatively important component of the energy balance equation. In adult humans, recent studies have indicated that diet-induced thermogenesis requires the activation of brown adipose tissue (BAT), however, the determinants regulating this process and why they may differ between individuals are not fully understood. We hypothesized that environmental toxicants commonly used as food additives or pesticides might reduce diet-induced thermogenesis through suppression of uncoupling protein 1, the defining protein of human BAT thermogenesis. Through a screening approach of pesticides/toxicants chosen from the Toxcast chem Library, we discovered that the organophosphate insecticide chlorpyrifos potently suppressed the expression of uncoupling protein 1 (UCP1) and mitochondrial respiration in brown adipocytes at concentrations as low as 1 pM. Chloropyrifos-induced suppression of brown adipocyte thermogenesis was also observed in mice fed a diet high in fat and housed at thermoneutrality where it promoted greater obesity, non-alcoholic fatty liver disease and insulin resistance. Reductions in thermogenesis by chlorpyrifos were associated with impaired activation of the β3-adrenergic receptor and protein kinases critical for regulating UCP1 and mitophagy. These data indicate that the commonly used pesticide chlorpyrifos, at doses found within the food supply, suppresses the activation of brown adipose tissue, suggesting that its use may contribute to the obesity epidemic.
Immune Checkpoint Inhibitor-Induced Hypophysitis in Renal Cell Carcinoma: Two Contrasting Case Presentations
Authors: Okigbo Chinelo , Kirk Deepa 
Published: May 2021

Abstract
Background: Increasing use of immune checkpoint inhibitor (ICI) therapy for malignancy has led to rising incidence of ICI-mediated endocrinopathies. We describe two varying cases of patients with renal cell carcinoma (RCC) who presented with ICI-mediated hypophysitis.
Cases: Patient A: A 72 year old female with RCC (T1bN0M0) diagnosed after an incidental renal mass was found on CT scan following a motor vehicle accident. After nephrectomy, she received 5 cycles of nivolumab (6/2019 to 10/2019). One month later, she presented in severe DKA and was diagnosed with ICI-mediated diabetes (low c-peptide, negative autoantibodies). ICI therapy was stopped. In 4/2020, she experienced a drastic reduction in her insulin requirement (~30 units/day of basal/bolus insulin to ~6 units/day of basal insulin only). She had a primary care visit for fatigue, nausea, and anorexia. Biochemical evaluation showed hyponatremia, normokalemia, normoglycemia, and no acid-base disorder. One week later, she presented to the emergency department (ED) with worsening symptoms. She was hypotensive (94/56 mmHg), hyponatremic (129 mmol/L), normokalemic, and azotemic. Cosyntropin stimulation test (CST) showed an inappropriate response [ACTH &lt;5 pg/ml; cortisol response of 0.4 to 8.1 µg/dl]. Brain MRI showed a partially empty sella. She was diagnosed with secondary adrenal insufficiency (AI) due to hypophysitis and started on steroid replacement. A repeat CST after 3 months did not show HPA axis recovery. Her presentation is unique because she developed secondary AI six months after nivolumab therapy.
Patient B: A 43 year old female with RCC (T4N1M1) who received 4-cycles of ipilimumab and nivolumab (11/2019 to 1/2020). One month later, she presented to the ED with hypotension, anorexia, and fatigue. Biochemical evaluation showed severe DKA. She was diagnosed with ICI-mediated diabetes (low c-peptide, negative autoantibodies) and started on basal/bolus insulin. Her ICI-therapy was stopped. One month later, she was readmitted for hypotension and severe headaches and found to have hyponatremia (131 mmol/L), normokalemia, hyperprolactinemia (29 ng/ml), cortisol 4.5 µg/dl (previous random cortisol a month earlier was 33 µg/dl). Pituitary gland was normal on MRI. She was presumed to have secondary AI due to hypophysitis and started on steroid replacement. A CST performed after 3 months showed ACTH &lt;5 pg/ml and cortisol response of 3.5 to 4.5 µg/dl. Her case was a usual presentation of ICI-mediated secondary AI as it occurred within 1-2 months of stopping ICI therapy.
Conclusion: As we continue to learn about ICI-mediated endocrinopathies, it is imperative to document the variation in timing of presentation. ICI-mediated hypophysitis can present at any time after the initiation of therapy. Given this variation, there is need for routine screening and early treatment of hypophysitis to reduce ED visits and readmission rates.
Interesting and Rare Case of Central Diabetes Insipidus in a Patient With Acute Myeloid Leukemia
Authors: Sherpa Chheki , Shrestha Bishow Chandra , Rijal Swarup S , Gabriely Ilan , Nallala Deepika , Singh Vinita 
Published: May 2021

Abstract
Introduction: Central Diabetes Insipidus (CDI) is the lack of antidiuretic hormone (ADH) leading to impaired urinary concentration and manifests with extreme thirst and excessive urination. Patients unable to drink fluids are at risk of severe dehydration and hypernatremia. CDI can be a rare complication of acute myeloid leukemia (AML). The occurrence of AML with CDI is extremely rare with only few case reports published. This combination of AML with CDI has been reported to be associated with monosomy 7 and inversion (3) (q21q26) and portends an overall a very poor treatment response resulting in poor outcomes.
Case Presentation: 66-year-old female with hypertension, polycythemia vera diagnosed in 2006 with transformation to AML in 2020. FISH studies revealed monosomy 7. Cytogenetic studies showed inv (3)(q21q26.2). Remission induction chemotherapy was initiated. Subsequently, neutropenic fever and sepsis secondary to Clostridium difficile colitis lead to hospitalization. Her sodium (Na) level gradually trended up and reached a peak of 157 mmol/l (range 136-145) and elevated serum osmolality at 311 mOsm/K with low urine osmolality 135 mOsm/K, low urine sodium at 13 and low urine specific gravity 1.006 concerning for CDI. She developed polyuria and received desmopressin (DDAVP) leading to improvements in urine osmolality to 267 mOsm/K, 30 minutes indicating CDI diagnosis. Her Na gradually normalized to 144 mmol/l, urine osmolality improved to 580 mOsm/K and urine specific gravity to 1.025. She is now on DDAVP 0.05 mg oral twice daily and her Na is in normal range. MRI pituitary did not show any evidence of metastatic lesion with intact pituitary bright spot. Her other pituitary hormonal workup was normal except for hypogonadotropic hypogonadism.
Discussion: The pathophysiology of AML and CDI is unclear. Leukemic cells infiltration of the neurohypophysis; thrombosis of small vessels in hypothalamic nuclei and the posterior pituitary; alterations of the neutrophil migration placed on the chromosome 7 leading to glycoprotein gp 130 production, a cell surface marker on granulocytes are some of hypothesis suggested. CDI has a variable onset in the course of myeloid malignancies. MRI pituitary can be normal in most of the cases.
Is It the COVID-19 and Untreated Panhypopituitarism a Deadly Combination: A Case Report?
Authors: Burekovic Azra , Divanovic Anida 
Published: May 2021

Abstract
Background: The possible long-term consequences of coronavirus disease (COVID-19) on the endocrine system are still not known. With the number of cases rising we have reported the first possible implications of COVID-19 on panhypopituitarism in Bosnia and Herzegovina. Clinical Case: A 59-year-old man was referred to the Endocrinology Counseling Center on 12/10/2020. For 15 years he did not take thyroid and adrenal replacement therapy. As a child, he was treated for short stature, as well as his two sisters. He had signs and symptoms of myxedema. He was urgently hospitalized to the Department of Endocrinology. His condition has worsened in the last month, more intensely in the last 10 days. He complained of general weakness, malaise, drowsiness, shortness of breath, fatigue, constipation, swelling of the lower legs. The patient was enormously adipose and moved harder with help of a walking stick. The thyroid gland appeared smaller on palpation. Laboratory investigations showed low and borderline levels of the following hormones TSH 0.590 (0.3-4.2 mU/L), FT4 1.44 (12.0-22.0 pmol/L), FT3 0.858 (3.1-6.8 pmol/L), ACTH at 8 am 2.59, ACTH at 16 pm 8.44 (7.20-63.3 pg/ml), GH 0.090 (0.0-14.0), FSH &lt;0.7 (1.6-9.7 IU/L), LH &lt;0.7 (0.7-7.8 IU/L), prolactin &lt;30.8 (78-380 uIU/ml), testosterone 1.01 (above 50 years 2.5-21.6 nmol/l), cortisol at 8 am 557, cortisol at 16 pm 674, cortisol at 11 pm 674 (morning: 123-626 nmol/L, afternoon 46-389 nmol/L), DHS 1.87 (2.17-11.7 nmol/L). On 12/10/2020 he tested negative for SARS-CoV-2 infection. On 14/10/2020 his condition worsened. He was somnolent, and even though he was admitted to diuretic therapy, he had decreased urine output. His D-dimer was 3.93 (0-0.055 mcg/mL). CT findings of thoracic organs described cardiomegaly, atherosclerotic altered thoracic aorta, and changes in the pulmonary parenchyma on both sides. On 16/10/2020 the patient was transferred to the cardiology department. SARS-CoV-2 test was repeated, and it was positive. The patient exited due to pulmonary arrest on 17/10/2020. Conclusion: There are several possible mechanisms that may describe that COVID-19 infection exacerbates the symptoms of myxedema and panhypopituitarism, and consequently leads the patient to severe acute respiratory failure.
Isolated Central Adrenal Insufficiency Due to Nivolumab: A Case Report
Authors: Rjoob Hani , Khan Tayyab S 
Published: May 2021

Abstract
Background: Immune checkpoint inhibitors are immunomodulatory antibodies directed against programmed cell death 1 (PD-1), Nivolumab, or cytotoxic T-lymphocyte antigen-4 (CTLA-4) Ipilimumab. They have improved outcomes in patients with advanced cancers including renal cell carcinoma, non-small cell lung cancer and melanoma. Several immune related adverse events (irAEs) have been recognized with use of immune checkpoint inhibitors, including those involving the endocrine system. We present a case of a patient presenting with isolated central adrenal insufficiency in the context of Nivolumab use. Clinical Case: Our patient is a 54-year old man with pre-existing primary hypothyroidism and metastatic renal cell carcinoma treated with Nivolumab. After receiving a total of 14 cycles of Nivolumab, he presented to the Emergency room with his sister, who found him confused and lethargic. On presentation, he was found to be hypoglycemic (random glucose was 2.2 mmol/L). On physical examination, his vital signs were stable and he appeared euvolemic. He was disoriented without focal neurological deficits. Initial blood work revealed sodium 134 mmol/L, (Normal 135-145mmol/L), potassium 4.5 mmol/L (Normal 3.5-5 mmol/L), and TSH being 12.6 mIU/L (Normal 0.4-4 mIU/L). He was resuscitated with IV Dextrose 50% bolus then admitted to hospital and kept on an IV dextrose infusion. While his glucose improved, he was found to have hyponatremia, and confusion persisted. His nadir sodium was 116 mmol/L without seizures or loss of consciousness and required treatment with hypertonic saline. Giving hypoglycemia and hyponatremia, morning cortisol and ACTH were checked and came back 4 nmol/L (Normal 133-537 nmol/L) and undetectable (&lt; 0.7 pmol/L, Normal 1.6-13.9 pmol/L) respectively. The diagnosis of central adrenal insufficiency was made likely secondary to Nivolumab. He was started on Dexamethasone 8 mg daily. Sodium level normalized and glucose level improved with steroids. He was discharged home on prednisone 50 mg and then switched to hydrocortisone. Further
work up confirmed preserved other anterior pituitary hormones. MRI of Sella did not show pituitary enlargement or inflammation. Conclusion: Our patient presented with hypoglycemia and hyponatremia; both could be the presenting manifestations of central adrenal insufficiency. Nivolumab has been commonly associated with thyroid dysfunction and thyroiditis. Given lack of expression of PD-1 in the pituitary, PD-1 inhibitors are less likely to be associated with hypopituitarism in general, or central adrenal insufficiency in particular. However, our report adds to the growing body of literature associating it with central adrenal insufficiency, which can be isolated. In so doing, it underscores the need for early recognition this association with Nivolumab, so as to avoid the potentially life threatening consequences of this condition.
Isolated Macroprolactinomas in Four Young Adult Males Harboring a Variant of the Aryl Hydrocarbon Interacting Protein (AIP) Gene: Isn’t It Too Much of a Coincidence?
Authors: Chaves Carolina Marques , Chaves Mariana M , Anselmo Joao 
Published: May 2021

Abstract
Background: Germline mutations in the Aryl hydrocarbon receptor-Interacting Protein (AIP) gene are associated with pituitary adenomas in young patients usually in the setting of Familial Isolated Pituitary Adenomas (FIPA). The majority of these adenomas are somatotropinomas followed by prolactinomas, and rarely non-secreting adenomas. AIP-mutation-related prolactinomas predominantly affect men, as opposed to sporadic prolactinomas, that typically affect women. Clinical Case: We previously described an AIP gene mutation in two patients affected by prolactinomas. During the past years, we continued our study and have identified two more male patients with macroprolactinomas originally from the same small village and harboring the same AIP gene mutation. These male patients aged 19 to 44 years at the time of diagnosis. Two of them had neurological manifestations as the first clinical manifestation of the disease, one was studied because of hypogonadism and two patients had visual field defects. All of them had prolactin levels above 1000 ng/dl (mean 2946.5±948.7 ng/dl, reference range 10-21). In the imaging exams (CT/MRI) they presented pituitary adenomas larger than 20 mm (macroprolactinomas) and in two of the cases, the adenomas were even larger than 40 mm (giant prolactinomas). In order to exclude mutations most often associated with prolactinomas, DNA samples were obtained and analyzed by Next Generation Sequencing (NGS) using TruSightCancer Gene Set (Illumina) methodology. Investigation of significant deletions and/or duplications was performed using the MLPA (Multiplex ligation-dependent probe amplification) technique. None of the patients were positive for mutations of Multiple Endocrine Neoplasia type 1 (MEN1) gene. A variant of the AIP gene c.47G&gt;A, expecting to lead to a substitution of arginine by histidine at position 16 (p.Arg16His) of the AIP was found in these four patients, including a father and his son. Seven asymptomatic carriers were identified among their first-degree relatives. In silico analysis and the information available in the literature, as well as in databases is not in agreement with the pathogenicity of this variant of the AIP gene. However, our findings point to a founder effect transmitted as a dominant trait with incomplete penetrance (4 out of 11 patients, 36%). Conclusion: The variant of the AIP gene identified in our patients behaved as a pathogenic mutation and was only associated with prolactinomas, including two giant prolactinomas.
Macroprolactinoma Presenting With Hyponatremia; A Rare Case Report
Authors: Ibrahim Safa , Wenkert David 
Published: May 2021

Abstract
Background: Hyponatremia is a common electrolyte abnormality, investigating the etiology can be challenging to the clinician, especially when the cause has rarely been associated with hyponatremia. Macroprolactinoma has rarely been reported as a cause of hyponatremia. We are reporting a case of macroprolactinoma presenting with hyponatremia.
Care Report: A 67 year old female previously healthy female, presented with a fall due to syncopal episode. Patient reported lightheadedness for a week prior to presentation. On physical examination, patient had bilateral periorbital ecchymoses, and swelling of the nose. Remaining of physical exam was unremarkable. Lab work showed hyponatremia with high urine osmolality and high urine sodium, consistent with syndrome of inappropriate antidiuretic hormone (SIADH). CT head showed Intrasellar soft tissue mass represents a pituitary macroadenoma. Pituitary hormonal workup showed high prolactin: 2,808 ng/mL, the rest of pituitary profile was normal, including pituitary-adrenal axis evaluation. Pituitary MRI confirmed a large pituitary macroadenoma measuring 1.7 x 2.9 x 2.5 cm, which displaces and compresses the optic chiasm and invades the right cavernous sinus. She was treated with fluid restriction and salt tablets with improvement of sodium level to normal. Cabergoline 0.25 mg twice a week was started with improvement of prolactin level to 156 ng/mL over 9 months period.
Discussion: Pituitary macroadenoma rarely associated with hyponatremia, and when reported it is usually secondary to hypopituitarism (low ACTH or low TSH). However, there are few cases reported of SIADH related hyponatremia in the presence of normal pituitary function. Although the exact mechanism of exaggerated production of arginine vasopressin (AVP) is not fully understood, the likely theory thought to be related to the mechanical pressure on the axonal terminal of AVP neurons by the large pituitary tumor.
Conclusion: Hyponatremia due to SIADH has been linked in few cases with nonfunctioning pituitary adenoma. Only two cases found in the literature reporting SIADH secondary to prolactin producing pituitary adenoma, with our case being the third reported case.
Panhypopituitarism Presenting as Progressive Visual Acuity Deterioration Secondary to Suprasellar Germinoma
Authors: Young Po Rainer Wandrew , Cating-Cabral Monica Therese B 
Published: May 2021

Abstract
Background: Overall the incidence of germ cell tumors worldwide is 0.1% with 60% comprising of germinomas. These may present in the suprasellar region a third of the time and thus impart variability in its presenting characteristics. Clinical Case: A 27-year male presented with progressive blurring of vision with incongruent visual acuity and refraction grade with optic disc pallor assessed with normal angiography. Patient also presented with increasing docility, sluggishness and more withdrawn behavior paired with polyuria, polydipsia and cold intolerance. Progressive worsening of vision led to cranial CT revealing an enhancing hyper density in the right caudate head later elucidated via MRI with several interspersed non-enhancing foci in the right caudate nucleus, both internal capsules with associated mild mass effect. The largest component located in the right capsular region with measurement of 21 x 21 x 16 mm with enhancing lesions in the hypothalamus and pituitary stalk. Endocrine evaluation revealed low serum cortisol at 91.03nmol/L (NV 138-685 nmol/L), responsive to ACTH stimulation test (65.94nmol/L to 387nmol/L), high prolactin at 856.9 mIU/L (42.4-296.8mIU/L) and low FT4 8.62pmol/l (9.01-19.05 pmol/L) despite normal TSH 1.528uIU/ml (0.35-4.94 uIU/mL). Optic nerve atrophy was now attributed to compressive intracranial mass. Secondary adrenal insufficiency was managed with hydrocortisone 50mgIV every 8 hours, and central hypothyroidism was managed with levothyroxine 75mcgtab 1tab once a day. Increased urinary output assessed as diabetes insipidus was given desmopressin 60mcg/tab ½ tab 2x a day at this time. Stereotactic biopsy of the brain revealed a germinoma of the right caudate lobe. Given the nature of the intracranial mass with high sensitivity to chemotherapeutic and radiotherapy, a multidisciplinary approach to treatment was taken with radiotherapy, hormonal and steroid replacement. Patient underwent external beam radiation therapy of the brain and spine for a total of 51 treatments allowing for improvement of visual acuity to counting, with polyuria less than 2-3 diaper changes per day. Conclusion: Optic disc pallor is a clinical sign that indicates optic nerve atrophy reflective of the optic tract. This may be an important clinical sign to increase clinical suspicion for intracranial mass lesion especially with correlation to manifestation of pituitary hormone deficiencies.
Pituitary Hyperplasia: To Operate or Not to Operate, That Is the Question
Authors: Rajwani Aakash , Ghalib Luma 
Published: May 2021

Abstract
Pituitary hyperplasia is defined as an absolute increase in the number of one or more adenohypophyseal cell subtypes, manifesting radiologically as pituitary enlargement beyond what is considered normal. It has been noted in certain physiological conditions like pregnancy however can also be seen in pathological conditions with end organ insufficiency like severe hypothyroidism.
21- year old female with a past medical history of Primary Hypothyroidism secondary to Hashimoto’s thyroiditis presented initially for evaluation of worsening headache and blurry vision. She was diagnosed with hypothyroidism at 10 years of age and had an extensive family history of hypothyroidism. At the time of presentation, she was 11 months post- partum and had been on and off her levothyroxine supplementation, having stopped it completely for a few months after delivery. MRI brain showed an 18 mm homogeneously enhancing intrasellar mass with suprasellar extension. She was referred to Neurosurgery for further evaluation. Workup revealed a TSH &gt;100 (0.27 - 4.2 mIU/L) and FT4 &lt;0.4 (0.8 - 2 ng/dL). In the context of severe untreated hypothyroidism and MRI findings consistent with pituitary hyperplasia with abutment but no mass effect on the optic apparatus, initial plan was to treat the hypothyroidism medically and observe closely. Patient was started on levothyroxine supplementation. Her TSH improved to 3.367 (0.550 - 4.780 uIU/mL) and FT4 to 2.00 (0.89 - 1.76 ng/dL), ηοωεϖερ she continued to have worsening of visual symptoms. Surgery was considered to decompress the optic nerve, but pre-operative MRI showed a significant decrease in size of the pituitary gland with decreased suprasellar bulging and no mass effect on the optic chiasm. Surgery was subsequently cancelled.
Prolonged primary hypothyroidism leads to pituitary hyperplasia due to loss of negative feedback from lack of circulating T4 and T3, leading to excessive TRH secretion from the hypothalamus. The high TRH can lead to thyrotroph as well as lactotroph hyperplasia. Subsequently patients can present with headache, vision changes along with signs and symptoms of hypothyroidism and increased prolactin secretion. It is important to differentiate hyperplasia from other sellar lesions like pituitary macroadenoma or hypophysitis. Patients with hypothyroidism, who have pituitary enlargement diagnosed on brain imaging, should be promptly diagnosed and treated with thyroid hormone replacement. With a higher frequency and improved quality of imaging techniques, we are increasingly coming across scenarios of abnormal findings on imaging. Correlation of radiographic imaging results with a thorough history and biochemical testing is essential prior to proceeding with surgical intervention.