bluuebunny/crossref_metadata_2025 huggingface dataset:
PD-1 Inhibitors Induced Primary Hypoadrenalism
Authors: Tan Zi , Ahmed Ammar , Zainal Abir , Salama Amr , Alweis Richard , Bingham Robert James
Published: May 2021

Background: Primary adrenal insufficiency is known to be induced by certain medications, including anesthetics, antimycotic and antiparasitic medications. However, it is rarely being reported that caused by antitumor immune checkpoint inhibitors PD-1. Clinical Case: A 82-year-old female with a significant history of lung adenocarcinoma status post of recent Pembrolizumab therapy. She presented with multiple complaints, including increasing confusion, mainly memory loss, generalized aches, and pains who was found to have recurrent hyponatremia with a sodium level of 122, treated with water restriction and sodium tablets. Initial screening labs were suggestive of adrenal insufficiency: level of ACTH was within the normal range (11 pg/dL, normal range 7.2–63 pg/dL), level of cortisol was low (1.6 ng/dL, normal range 3–23 pg/dL). MRI brain without contrast ruled out metastatic disease. An ACTH-stimulating test was performed, with the results revealing an inadequate cortisol response at 0, 30, and 60 minutes(1.4 ug/gl, 8.5 ug/dl, 11.9 ug/dl, normal range 18–20 ug/gl). Therefore, a diagnosis of primary adrenal insufficiency was made. The patient was prescribed a daily oral dose of 5 mg of hydrocortisone. Her symptoms improved after a few days, and her hydrocortisone gradually increased to 15 mg daily, and her energy and memory were back to baseline after six months.

Conclusion: This is a rare case of primary adrenal insufficiency caused by Pembrolizumab using for non-small lung cancer treatment. With the growing use of Pembrolizumab, it is necessary to be aware of possible adrenal insufficiency that could be associated with receiving pembrolizumab therapy amid any clinical suspicion. Reference: Chang, L.S., et al., Endocrine Toxicity of Cancer Immunotherapy Targeting Immune Checkpoints. Endocr, Rev, 2019. 40(1): p. 17–65
Primary Hyperaldosteronism in Pregnancy: A Case Report
Authors: Li Jefferson , Kubbar Alaa , Kim Eunice , Pelaez Dennis Nunez , Rodriguez Giovanna , Bahtiyar Gul
Published: May 2021

Background: Primary aldosteronism (PA) is a renin-independent hypersecretion of aldosterone that remains an underdiagnosed etiology of hypertension. Less than 50 cases of primary hyperaldosteronism in pregnancy have been reported in literature that are associated with pregnancy complications including preeclampsia.

Clinical Case: A 41-year-old female G9P4 at 32 weeks gestation was admitted for suspected preeclampsia due to elevated blood pressure during a routine prenatal visit. Her comorbidities include type 2 diabetes, uncontrolled hypertension, and preeclampsia in a previous pregnancy. Home medications included Lisinopril 10 mg once daily which was discontinued upon pregnancy and switched to Labetalol 400 mg twice daily and Nifedipine ER 30 mg daily. She was on a total of 220 units of insulin daily.

On presentation, patient complained of anxiety but denied any headache, nausea, visual disturbances, chest pain, palpitations, muscle cramps, or fatigue. Her blood pressure was 180/100 mmHg with heat rate of 73. Laboratory values was notable for potassium: 2.8 mmol/L (n 3.5–5 mmol/L), bicarbonate: 28 mmol/L (n 24–31 mmol/L), and magnesium: 1.4 mEq/L (n 1.3–1.9 mEq/L). Liver function test and platelet count were normal. Spot protein-creatinine ratio was 0.3 (n 0–0.2). ECG was normal sinus rhythm with a heart rate of 82 without decreased T wave amplitude or U waves. She received three doses of oral 40 mEq potassium chloride over twelve hours and potassium level post repletion was 3.0 mmol/L.

Initially, her hypokalemia was attributed to high insulin dose requirements. Despite down titration of insulin, patient continued to have hypokalemic episodes (nadir 2.7 mmol/L) refractory to oral and parenteral potassium supplementation. She remained hypertensive despite Labetalol 600 mg every 8 hours, Nifedipine ER 30 mg every 12 hours, with as needed hydralazine 10 mg IV pushes, and underwent urgent cesarean delivery. Uncontrolled hypertension persisted postpartum with recurrent episodes of hypokalemia. Further investigations revealed a plasma aldosterone concentration (PAC) and plasma renin activity (PRA) levels of 43.5 ng/dL (n <10 ng/dL) and 1.67 ng/mL/hr (n 0.17–5.38 ng/mL/hr) respectively, potassium at time of testing was 3.6 mmol/L. PAC to PRA ratio was greater than 20:1 with an absolute PAC greater than 15 ng/dL, which is highly suggestive of PA.

Conclusion: We present a case of suspected PA with spontaneous hypokalemia potentially masked by the use of ACE inhibitors uncovered during pregnancy. Given the changes to the renin-angiotensin-aldosterone system (RAAS) during pregnancy, the diagnosis of PA is difficult to establish during gestation. Still, little is known on how to optimally treat these patients.

Reference: Morton, A., 2015. Primary Aldosteronism and Pregnancy. Pregnancy and hypertension. An International Journal of Women’s Cardiovascular Health, Volume 5 Issue 4, 259–262.
Primary Macronodular Adrenal Hyperplasia Associated With Autosomal Dominant ARMC5 Mutation
Authors: Kerut Sarah Elizabeth , Subauste Angela
Published: May 2021

Background: Primary macronodular adrenal hyperplasia (PMAH) is an uncommon cause of Cushing’s syndrome. In some cases, this is an inherited disorder due to a mutation in the armadillo repeat-containing 5 (ARMC5) gene. Clinical Case: A 43-year-old African American woman presented to clinic with weight gain, worsening type 2 diabetes mellitus, and symptomatic hypertensive cardiomyopathy. Physical exam was significant for central obesity, bilateral supraclavicular fat pads, acanthosis nigricans and wide striae over the abdomen. Her serum cortisol was 13.8 mcg/dL after 1 mg of dexamethasone (n<1.8 mcg/dL), urinary cortisol was 180 mcg in 24 hours (n=3.5–45 mcg/24h) and two midnight salivary cortisol tests were 227 and 118 ng/dL (n<100 ng/dL). Her ACTH was 2.4 pg/mL (n=7.2–63.3 pg/mL). Computed tomography (CT) of the abdomen showed nodularity, diffuse thickening and low-density (<10 Hounsfield units) of the bilateral adrenal glands. She underwent bilateral adrenalectomy for a diagnosis of PMAH. Pathology showed nodular adrenocortical hyperplasia; the right and left adrenal glands measured 75 grams and 68 grams, respectively. She was started on hydrocortisone and fludrocortisone postoperatively. Over the following two years, she had a 68-pound weight loss, an 86% reduction in her daily insulin requirement and a 10% improvement in her left ventricular ejection fraction. Approximately two years later, the patient’s brother was referred for bilateral macronodular hyperplasia incidentally discovered on a CT of the abdomen. He had a history of hypertension and type 2 diabetes mellitus with cushingoid features on exam. His serum cortisol was 20.7 mcg/dL after 1 mg of dexamethasone, urinary cortisol was 65.1 mcg in 24 hours, two midnight salivary cortisol tests were 232 and 404 ng/dL and ACTH was 2.0 pg/mL. Upon obtaining further family history, the patients reported clinical features of Cushing’s syndrome in their paternal grandmother but denied features in either parent. The second patient had genetic testing which showed a mutation in the ARMC5 gene, c.1777C>T, p.R593W, a mutation previously described. Due to clinical signs of Cushing’s syndrome, he underwent bilateral adrenalectomy in which pathology showed right and left nodular adrenocortical hyperplasia measuring 110 and 73 grams, respectively. He is doing well postoperatively. The patients recently reported their aunt was diagnosed with PMAH and mild Cushing’s syndrome. She had a unilateral adrenalectomy of the larger adrenal gland and is doing well postoperatively. Conclusion: In some cases, Cushing’s syndrome is an inherited disorder. Autosomal dominant mutations in the ARMC5 gene are occasionally seen in PMAH, which causes less than 2% of endogenous Cushing’s syndrome. For all patients diagnosed with PMAH, clinicians should consider screening their family members with a dexamethasone suppression test.
Rare Case of Huge Adrenocortical Carcinoma in Surprisingly Asymptomatic Patient
Authors: AlJedaani Samia Mohammad , Al-Obaydi Sarah , Shah Aesha , Fan Chris , Manni Andrea
Published: May 2021

Introduction: Adrenal Carcinoma (AC) is a rare endocrine malignancy of the adrenal glands. It can affect up to 3–10% of the human population. It is common in children as secondary malignancies or as a manifestation of a tumor syndrome. Typically patients with AC start to become symptomatic after extensive tumor development- 10–13 cm. The presentation of AC includes signs of hormone excess. The most common hormone in excess is cortisol. Thus individuals with AC typically present with symptoms of hypercortisolism or Cushing’s Syndrome. In chronic cases the high concentration of glucocorticoids can start stimulating aldosterone receptors causing hypertension and hypokalemia. Furthermore, patients with AC also have symptoms of tumor growth, such as abdominal pain, flank pain, and early satiety. Currently prognostic factors for AC are undefined. AC generally has a poor prognosis as a majority of patients are diagnosed during advanced stage of disease (stage IV). Furthermore, it was found that patients with stage IV disease had a survival of less than one year. Currently the only curative treatment is complete tumor resection. Medical management with chemotherapy can be utilized in cases of extensive metastasis and poor prognosis. A common chemotherapeutic agent is mitotane, which is a steroidogenesis inhibitor. Case Presentation:Patient is a 19 year old female, who initially presented to her primary care provider’s (PCP) office for an annual wellness visit during August 2020. She was subsequently discovered to have elevated blood pressure. At this time she was not symptomatic. She was advised on lifestyle modifications. She was also stopped on her birth control medication. Furthermore, she later presented to her PCP with continued elevated blood pressure, still not symptomatic. In an outpatient cardiology office, she presented with blood pressures in the 200s/100s range and a new murmur. She was sent to the ED for evaluation (11/2020). On her presentation to the ED, she still did not have any symptoms. She also denied any fatigue or unintentional weight changes. Her only concern was mild edema in the lower legs after standing for extended periods of time. Her medical history was insignificant. Her family history was significant for her paternal essential HTN diagnosed in the early 20s. Laboratory evaluation revealed unremarkable electrolyte levels and CBC. Furthermore, her TSH level was also normal. A chest ray revealed multiple pulmonary nodules ranging from 3–5 mm. A renal ultrasound revealed a large mass in the RUQ (16.9x9.6x12 cm). She was also found to have mildly elevated cortisol levels at 22.9, suppressed ACTH levels, and normal levels of aldosterone and metanephrines. Subsequent CT imaging and biopsy revealed adrenal carcinoma with extensive metastasis to the lungs and liver. Patient was referred to Oncology service to start Chemotherapy.
Severe Cyclical Hypercortisolism Due to Metastatic Neuroendocrine Cancer Initially Diagnosed as Colon Cancer
Authors: Liu John Chen , Patel Richa , Gundluru Rajani , Parimi Joseph Theressa Nehu , Gusov Timur , Naha Sowjanya , Syed Hasan
Published: May 2021

Case Description: A 65 year-old male with initial diagnosis of metastatic colon cancer based on liver biopsy presented for evaluation of severe hypercortisolism with 24-hour urinary free cortisol (UFC) of 1184 mcg/day after presenting to his Oncologist in December 2019 requesting evaluation for muscle weakness and weight gain. On re-evaluation in March, his cortisol had dramatically improved with 24-hr UFC of 120 mcg/day and ACTH of 84 pg/mL and had resolved with 24-hr UFC of 32.6 mcg/day by May.

A 2 cm pancreatic lesion was noted during cancer staging; a second opinion was obtained on the liver biopsy which was interpreted as metastatic neuroendocrine tumor, possibly of pancreatic origin. The patient was started on FOLFINIRNOX in December 2019. This was transitioned to carboplatin and etoposide after the revised diagnosis and was continued through May with regression of liver lesions on followup imaging. A 68 Ga-DOTATATE PET CT confirmed uptake in the pancreas, retroperitoneal lymph nodes, and thyroid. A thyroid ultrasound was obtained which did not meet FNA criteria.

Given the chronologic association between cortisol levels and chemotherapy response we were suspicious for ectopic Cushing’s syndrome due to metastatic neuroendocrine cancer and the patient was followed for recurrence. In September, the patient endorsed leg weakness and hyperglycemia and was found to have a 24-hr UFC of 4731 mcg/day and an 8 am cortisol of 102 mcg/dL.

The patient developed severe hypokalemia requiring admission and was restarted on chemotherapy with moderate improvement in cortisol levels and symptoms. Given the degree of cortisol elevation, we recommended bilateral adrenalectomy, for which the patient established care at a more specialized center.

Discussion: Ectopic Cushing’s syndrome is an uncommon variety of ACTH-dependent Cushing’s syndrome caused by CRH or ACTH-producing tumors. The more aggressive form is associated with small-cell lung cancer while the chronic form is associated with indolent tumors.

Cyclical Cushing’s syndrome is a rare cause of hypercortisolism characterized by cyclical variations in cortisol levels. The pathophysiology of the cyclical variation is unclear. About half of cases are caused by pituitary corticotrophs but up to 26% can be attributed to ectopic ACTH production, typically due to indolent tumors rather than aggressive malignancies.

We present a case of cyclical hypercortisolism with an initial diagnosis of colon cancer. On further review, the cyclical hypercortisolism was likely associated with chemotherapy response. Reevaluation of surgical pathology was consistent with metastatic neuroendocrine cancer, the likely source of ectopic ACTH.

Our case highlights the importance of maintaining a broad differential when considering cases of cyclical cortisol elevation, including consideration of concurrent chemotherapy for seemingly unrelated malignancies.
Severe Hyponatremia With Partial Hypoadrenalism in Acute Porphyria
Authors: Marcus-Perlman Yonit , Lahav Meir , Shefer Gabi , Stern Naftali , Greenman Yona
Published: May 2021

Background: Hyponatremia is the most common electrolyte-abnormality in hospitalized-patients, it increases likelihood of hospital death up-to 50% when serum Na<120mEq/L. Syndrome of inappropriate ADH secretion (SIADH) is the most common cause of hyponatremia in hospital inpatients. Clinical Case: 29 years-old woman, hospitalized several times due to severe hyponatremia of 103mEq/L; Admissions were accompanied by severe abdominal-pain and vomiting. She complained of severe premenstrual syndrome with severe abdominal pain and was hospitalized twice after intrauterine insemination. She was euvolemic and due to high urinary-sodium was diagnosed with SIADH. Brain MRI, chest x-ray, thyroid-function test, and 1-mcg ACTH-test were normal. Insulin Tolerance Test for hypoadrenalism was abnormal with cortisol levels of 14.2mcg/dl and 40mg/dl glucose. She was instructed to take strong analgesics and prednisone during attacks, this did not prevent hyponatremia. Finally, due to recurrent abdominal pain, porphyria workup was done and was positive. There are 30 case-reports of porphyria and SIADH. Porphyrias are a group of 8 inherited metabolic-disorders of heme biosynthesis, often classified as hepatic or erythropoietic according to the organ in which heme precursors accumulate. Acute intermitted porphyria is estimated in ~1/75000 people of European descend, yet clinical disease is seen in ~10% of carriers. Attacks present with severe abdominal-pain, nausea, vomiting, constipation, occasionally excretion of red colored urine and signs of increased sympathetic activity. Hyponatremia due to SIADH develops in 40% of patients and can lead to convulsions. Porphyria can exacerbate by several drugs, infectious processes, alcohol, and menstruation-induced hormonal-changes. Diagnosis is made by excess of urine porphobilinogen and 5-aminolaevulinic-acid. Treatment should include avoidance of precipitating factors and hemein infusions. Conclusions: SIADH is considered responsible for the hyponatremia seen in porphyria patients. Our patient showed an abnormal cortisol response to Insulin induced hypoglycemia, in accordance to (1) that demonstrated decreased output of cortisol and metabolites in porphyria patients secondary to decreased hemoproteins, as p450 cytochromes. Importantly, levels of endogenous hormones, particularly progesterone, can trigger an attack especially in luteal phase and in clomiphene citrate administration.1. Pozo et al Orphanet Journal of Rare Diseases 2014
Surgically Treated Resistant Hypertension Due to Bilateral Adrenal Hyperplasia
Authors: Ganesan Kavitha , Sallar Anthony Selase , James Deirdre
Published: May 2021

Background: Treatment resistant hypertension (TRH) may affect about 15% of patients with hypertension. While primary hyperaldosteronism is a known etiology of TRH, clinicians must consider the possibility of elevations of other adrenal hormones. Early identification of an etiology may prevent or delay the onset of complications. Case Report: Endocrinology was consulted on a 46 years-old man for evaluation of TRH. His past medical history is significant for TRH, nonischemic cardiomyopathy, congestive heart failure (Ejection Fraction 45–50%), and chronic kidney disease. Physical examination was unremarkable except for a blood pressure of 193/124 mmHg while on furosemide, isosorbide mononitrate, hydralazine, carvedilol, spironolactone, and clonidine. Chart review revealed mild hypokalemia. Computed tomography (CT) of the abdomen without contrast showed bilateral enlarged nodular adrenal glands with an increase in size over the last three years (left adrenal gland: 6.3 cm, right adrenal gland: 5.6 cm). Initial workup showed normal free plasma metanephrine, normetanephrine, aldosterone renin ratio, 17-hydroxyprogesterone, and undetectable random adrenocorticotropic hormone (ACTH) with random cortisol of 29 mcg/dl. Subsequent evaluation revealed elevated deoxycorticosterone (3030 ng/dL), 11-deoxycorticosterone (42 ng/d) and 18-Hydroxycorticosterone (640 ng/dL). He subsequently developed Cushing’s syndrome and diabetes mellitus. The patient underwent laparoscopic left adrenalectomy and subtotal right adrenalectomy. Pathology showed macro-nodular adrenal cortical hyperplasia. He was started on hydrocortisone for postoperative adrenal insufficiency. On his most recent follow-up, his blood pressure was well controlled on bumetanide, carvedilol, metolazone, and nifedipine. (Hydralazine, isosorbide mononitrate, spironolactone, and clonidine were stopped). After surgery, Corticosterone (92.10 ng/dL), 11-Deoxycorticosterone (<5.00 ng/dL) and ACTH(9 pg/mL) normalized. Conclusion: Determining the etiology of TRH should not be stopped after ruling out the “usual suspects” since malignant hypertension with end-organ dysfunction can develop, if not appropriately treated. In our patient, TRH was due to elevated 18-Hydroxycorticosterone (precursor of aldosterone), which improved after adrenalectomy.
Testosterone Use and Adrenal Hemorrhage
Authors: Sattar Moin U , Mahali Priyanka L , Chamorro-Pareja Natalia , Suda Nisha , Bloomgarden Noah
Published: May 2021

Background: Testosterone supplementation has been associated with a variety of side effects, such as polycythemia, and can potentially increase the risk of cardiovascular disease. Testosterone use has also been associated with increased thrombotic events, especially in patients with underlying hypercoagulable state. Clinical Case: A 57-year-old man presented with abdominal pain and distention. He had history of previous intramuscular (IM) and oral testosterone use for ten years. For 8 weeks prior to initial presentation, he reported using weekly IM 500mg Testosterone injections. Computed Tomography (CT) of the abdomen and pelvis revealed multiple thrombi of the portal, splenic, superior mesenteric and inferior mesenteric veins. He was started on Warfarin and discharged home. A few weeks later, he presented with similar symptoms with labs now showing an International Normalized Ratio (INR) of 10.2. Repeat CT was significant for presence of bilateral adrenal hemorrhage, measuring 2.9cm on the right and 2.4cm on the left, which were not seen on previous imaging done one week prior. During the hospital course, he was found to be hypotensive with low platelet count so Intravenous Immunoglobulin therapy was initiated for suspected catastrophic antiphospholipid syndrome (CAPS). Morning cortisol was 5.82 ug/dL (6.2–29.0) so this critically-ill patient was started on stress dose hydrocortisone, which was subsequently tapered to physiological dose after clinical improvement. Cosyntropin stimulation test was performed after withholding the prior dose of hydrocortisone. The baseline cortisol was 0.88 ug/dL (6.20–29.00ug/dL), after administration of 250mcg of Cosyntropin 30- and 60-minute cortisol levels were 1.5 ug/dL (4.3–22.4ug/dL) and 1.6 ug/dL (4.3–22.4ug/dL) respectively. Baseline ACTH of 121.0 pg/mL (7.2–63.3pg/mL), consistent with primary adrenal insufficiency. Dehydroepiandrosterone Sulfate (DHEA-S) level was 15.7 ug/dL (80.0–560.0ug/dL). Hypercoagulability workup was significant for the presence of lupus anticoagulant and antibodies positive for heparin induced thrombocytopenia, so patient was diagnosed with Antiphospholipid syndrome. Conclusion: This is a case of hypercoagulability in a patient with history of anabolic steroid misuse who developed extensive intraabdominal venous thrombosis, adrenal hemorrhage, and primary adrenal insufficiency. Adrenal vein thrombosis and hemorrhage can be life threatening sequalae of testosterone misuse and should be considered in the differential for patients with history of testosterone misuse and adrenal insufficiency.
The Development of Hypogonadotropic Hypogonadism After Starting Low Dose Mifepristone for Cushing’s Syndrome
Authors: Rowell Jennifer Voigt
Published: May 2021

Background: Mifepristone is an antiprogesterone that has been studied in females and has shown central effects including suppressing LH surges. There is a paucity of information about how it effects males. Clinical Case: 65-year-old male with bilateral adrenal macronodular hyperplasia noted on a past surveillance CT scan presented to endocrinology. He had a history of coronary artery disease, type 2 diabetes, obesity, and treated sleep apnea. He had progressively worsening abdominal weight gain, supraclavicular fat pads, thin bruising skin, and hypertension. He had several abnormal 1 mg overnight dexamethasone suppression tests (ACTH 3 & <1 pg/ml and cortisol 10 ug/dL & 11.1 ug/dL). He had several abnormal midnight salivary cortisol tests (109 ng/dL, 147ng/dL, and 152 ng/dL, reference <100 ng/dL). He elected to have medical treatment for his Cushing’s Syndrome after worsening hypertension and several episodes of hypertensive urgency. He was deemed a non-surgical candidate. He was started on mifepristone 300 mg/day and spironolactone 12.5 mg/day given eGFR 47 mL/min/1.73sq m. His mifepristone dose was dropped to 300 mg every other day after he had several episodes of orthostatic hypotension, nausea, and hot flashes. On lower dose mifepristone, his hypertension control improved without orthostatic hypotension or nausea. His hot flashes remained and he developed breast enlargement and tenderness. A repeat testosterone was found to be low, but the rest of his evaluation for gynecomastia was negative otherwise. His pre-treatment am testosterone was 281 ng/dL (normal 250–1100 ng/dL) and post mifepristone treatment am testosterone level was <7 ng/dL. He had suppressed gonadotrophins (LH <0.2 mIU/mL; normal 1.4–7.77 mIU/mL, FSH <0.2 mIU/mL; normal 2.5–17.1 mIU/mL), normal prolactin (PRL 11 ng/mL; normal 2.6–12 ng/mL) and a normal pituitary MRI.

Conclusion: This is the first case demonstrating severe hypogonadotropic hypogonadism in a male using low dose mifepristone treatment for mild ACTH independent Cushing’s Syndrome.

Reference: Escudero, E. and et al. Mifepristone Is an Effective Oral Alternative for the Prevention of Premature Luteinizing Hormone Surges and/or Premature Luteinization in Women Undergoing Controlled Ovarian Hyperstimulation for in Vitro Fertilization. J Clin Endocrinol Metab. 2005; 90(4):2081–2088.
Modified GRAS Score for Prognostic Classification of Adrenocortical Carcinoma: An ENSAT Multicentre Study
Authors: Elhassan Yasir , Altieri Barbara , Berhane Sarah , Cosentini Deborah , Calabrese Anna , Haissaguerre Magalie , Kastelan Darko , Fragoso Maria C , Bertherat Jerome , Baudin Eric , Haak Harm , Boudina Maria , Canu Letizia , Loli Paola , Sherlock Mark , Kimpel Otilia , Marta Laganà , Kroiss Matthias , Arlt Wiebke , Terzolo Massimo , Berruti Alfredo , Deeks Jonathan , Libe Rossella , Fassnacht Martin , Ronchi Cristina Lucia
Published: May 2021

Background: Adrenocortical carcinoma (ACC) has an aggressive but heterogeneous behaviour. ENSAT stage and Ki67 proliferation index are used to predict clinical outcome but are limited in distinguishing patients with different risk of disease progress. We aimed to validate the prognostic role of a previously proposed points-based score (mGRAS) in a large ACC cohort.

Methods: We included ACC patients who underwent adrenalectomy between 2010 and 2019, had complete clinical and histopathological data, and did not participate in our previous studies (Libe et al. Ann Oncol 2015; Lippert et al. JCEM 2018). The mGRAS score was calculated as follows: age (<50yr=0; ≥50yr =1), symptoms (no=0; yes=1), ENSAT stage (1–2=0; 3=1; 4=2), resection status (R0=0; RX=1; R1=2; R2=3), and Ki67 (0–9%=0; 10–19%=1; ≥20%=2 points), generating scores from 0 to 9 and four mGRAS groups (scores 0–1, 2–3, 4–5, and 6–9). Progression-free survival (PFS) and disease-specific survival (DSS) were the primary and secondary endpoints, respectively. The discriminative performance of mGRAS was investigated using the Harrell’s C-index and Royston-Sauerbrei’s R2D statistic.

Results: A total of 942 ACC patients from 14 ENSAT centres were included (38% men; median age 50yrs (interquartile range 38, 61)). The four mGRAS groups showed superior prognostic discrimination compared to the individual clinical and histological parameters for both PFS and DSS (C-index 0.71, R2D=0.30 and 0.77, R2D=0.46, respectively); ENSAT staging was the second best discriminator (C-index 0.67, R2D 0.21 and 0.72, R2D=0.35, respectively). An even better prognostic discrimination was observed using the ten mGRAS scores individually (C-index 0.73, R2D=0.30, and 0.79, R2D=0.45 for PFS and DSS, respectively). The superiority of mGRAS was confirmed when separately considering patients treated or untreated with adjuvant mitotane (n=481 vs 314). In mitotane-treated patients, the four mGRAS groups showed better performance in predicting PFS than Ki67 index (C-index 0.66, R2D 0.18 vs C-index 0.62, R2D 0.12).

Conclusion: The prognostic performance of mGRAS is superior to that of ENSAT staging and Ki67. This simple score may guide personalised treatment decisions in patients with ACC, e.g. regarding the need for adjuvant therapy and frequency of monitoring.
1-25OH2D Mediated Hypercalcemia Secondary to DISR From Immune Checkpoint Inhibitors
Authors: Disanti Domenic , Marr Alissa , Goldner Whitney Sears
Published: May 2021

Background: Drug induced sarcoid like reactions (DISR) have recently been described as a potential consequence of immune checkpoint inhibitor therapy. However, hypercalcemia associated with DISR has not been reported.

Clinical Case: A 72 year old male presented with metastatic melanoma. He initiated therapy with Ipilimumab/Nivolumab (Ipi/Nivo). Three weeks after his first cycle he developed symptomatic hypercalcemia (calcium 14.4 mg/dL), and acute kidney injury (creatinine 3.45mg/dL), PTH 12 pg/mL, 25OHD 51, and PTHrp 0.5. He received IV fluids and IV bisphosphonates and calcium normalized to 9.1 mg/dL and creatinine 1.85 mg/dL. His Ipi/Nivo were stopped due to concern for neurotoxicity. He subsequently switched to Q3week Pembrolizumab (Pembro) and after 2 infusions, he again developed hypercalcemia (calcium 11.8 mg/dL). FDG PET demonstrated a complete radiographic response. Labs showed a 1,25OH2D of 103 pg/mL (reference range 19.9–79.3 pg/mL), PTH of 4 pg/mL and calcium of 11.4 mg/dL. He was treated with prednisone 20 mg QD. After 9 days on prednisone, 1,25OH2D was 26 pg/mL and calcium 9.4 mg/dL. He took prednisone for 3 weeks total. Repeat labs off prednisone for one week were 1,25OH2D of 38 pg/mL and calcium 9.1 mg/dL. He continued on Pembro. After being off steroids for 5 weeks, he developed body aches and swelling of the hands. 1,25OH2D increased to 100 pg/mL and calcium to 10 mg/dL. He restarted prednisone and stopped Pembro. Labs one month later showed a 1,25OH2D of 45 pg/dL while still on prednisone 10 mg qd and a normal calcium in the mid 9’s. Follow up FDG PET showed hypermetabolic bilateral hilar and mediastinal lymphadenopathy not seen on previous imaging. Ultrasound-guided lymph node biopsy revealed granulomatous lymphadenitis. He was diagnosed with DISR, secondary to immunotherapy with checkpoint inhibitors. He continues on prednisone 10 mg per day and calcium and 1,25OH2D levels have remained normal.

Conclusion: This is the first case of 1,25OH2D mediated hypercalcemia as a consequence of DISR induced by immune checkpoint inhibitor therapy. Hypercalcemia in the setting of malignancy is more commonly due to humoral hypercalcemia of malignancy from PTHrp or bone metastasis, but DISR needs to be a consideration in persons with hypercalcemia on immune checkpoint inhibitor therapy, with elevated 1,25OH2D levels and low PTH and PTHrp levels.
A Unique Case of Primary Hyperparathyroidism
Authors: Lucier Jessica , Shakil Jawairia
Published: May 2021

Background: Primary hyperparathyroidism is the most common cause of hypercalcemia. It is more commonly seen in postmenopausal women, but can develop in younger individuals. Brown Tumors are an uncommon finding that can be seen in sever hyperparathyroidism. These bone findings are most often seen in the maxilla or mandible, though can affect any bone. Bone changes are reversible after parathyroidectomy.

Clinical Case: An 18 year old male with a PMH of nephrolithiasis presented with a two day history of flank pain and hematuria. Endocrinology was consulted for hypercalcemia and elevated PTH. He had a family history of nephrolithiasis in his maternal uncle and grandfather, but no known family history of hypercalcemia or thyroid cancer. He was not on any medications or supplements. His initial labs were significant for a calcium of 15.0, PTH of 644, and a Vitamin D 25 of 11.7. He had no known history of hypercalcemia. He was treated with aggressive hydration, 4mg of zometa, 30mg of sensipar and two doses of 200mg calcitonin, with improvement in his calcium levels. Imaging of the abdomen and pelvis revealed multifocal solid-cystic lesions in the right superior pubic ramus and the distal femur, with smaller enhancing lesions in the left subtrochanteric, consistent with Brown Tumors. SpectCT was obtained and significant for a 2.1 by 1.4cm lesion in the anterior superior mediastinum. His overall presentation was consistent with primary hyperparathyroidism secondary to an ectopic parathyroid adenoma. Due to his relative young age at presentation and degree of primary hyperparathyroidism, there was concern for MEN1 or possible parathyroid carcinoma. MRI of the pituitary was obtained and showed a 4mm microadenoma in the right side of the pituitary. Prolactin, thyroid hormones, IGF-1, plasma metanephrines and calcitonin were all within normal limits. CDC73, a genetic marker for parathyroid carcinoma, was negative. Genetic work up for MEN1 was also negative. Endocrine surgery was consulted and he underwent a resection of the ectopic parathyroid adenoma.

Discusion: Though most patients with primary hyperparathyroidism are asymptomatic, nephrolithiasis and Brown Tumors can be seen with more severe cases. It is important to rule out possible genetic causes for primary hyperthyroidism in patients with abnormal presentations, as it will change the overall long term management.
Atypical Parathyroid Adenoma in a Young Man
Authors: Bowen Elizabeth R , Dillon Joseph Stephen
Published: May 2021

Patient is a 38-year-old man who developed sudden onset of pain in the upper left arm while carrying a case of water. The pain recurred periodically over the next few months. He presented to the emergency department where imaging showed a pathologic fracture in the proximal left humerus through a lytic lesion. Laboratory testing showed: calcium 13.8 mg/dL (8.5–10.1 mg/dL), 25-OH vitamin D 8 ng/mL (31–100 ng/mL), parathyroid hormone 1583.1 pg/mL (18.5–88 pg/mL). Neck ultrasound showed a complex nodule in the left neck measuring 4.2 x 1.7 x 2.5 cm. Subsequent biopsy of the left arm lesion showed a Brown tumor. The patient was referred to endocrinology. There was concern for parathyroid carcinoma given the elevated parathyroid hormone and large neck lesion. Technetium-99m sestamibi scan showed a 4.1 x 2.6 x 2.5 cm mass posterior to the left thyroid lobe. He subsequently underwent left hemithyroidectomy and parathyroidectomy. Pathology revealed a 3.1 cm parathyroid mass with scattered fibrous bands, foci of prominent nucleoli and foci of sheet-like trabecular and spindled architecture. It was without necrosis, lymphovascular invasion, perineural invasion, increased mitotic activity, atypical mitoses or invasion into adjacent structures. Thus, it was classified as an atypical parathyroid adenoma.

Primary hyperparathyroidism is the third most common endocrine disorder, but fewer than 2% occur as a result of an atypical parathyroid adenoma. Patients with an atypical parathyroid adenoma tend to have a more dramatic clinical presentation compared to those with classic adenoma. We see higher calcium and parathyroid hormone levels. Atypical parathyroid adenomas are classified as such due to other features which place the lesion at a higher risk for malignant behavior including higher mitotic activity, adherence to adjacent structures, banding fibrosis and a growth pattern that is either solid or trabecular. In contrast to parathyroid carcinoma, atypical parathyroid adenomas do not show invasion into the surrounding tissues or lymphatic/vascular vessels, and there should be no evidence of metastatic disease. The exact definition of an atypical parathyroid adenoma varies among institutions, and recognition of the defining features (or lack thereof) necessitates an experienced endocrine pathologist.

Due to their uncertain malignant potential, patients with an atypical parathyroid adenoma should undergo routine surveillance for recurrence. Routine follow-up of calcium, parathyroid hormone and imaging is indicated to detect for recurrence. A CDC73 germline mutation is associated with recurrence compared to CDC73-negative patients. Parafibromin expression is also thought to play a role although studies so far have had discrepant results.
Atypical Presentation of Familial Hypocalciuric Hypercalcemia: Case Report
Authors: Ali Dalal S , Dandurand Karel , Khan Aliya Aziz
Published: May 2021

Background: Differentiation between familial hypocalciuric hypercalcemia (FHH) and primary hyperparathyroidism (PHPT) can be challenging in certain cases in the absence of DNA analysis of the calcium sensing receptor gene. The distinction between those two clinical entities with overlapping biochemical features therefore relies on the calcium to creatinine clearance ratio (CCCR), which is expected to be low in FHH (<0.01 in 80% of cases and between 0.01 and 0.02 in approximately 20% of patients)1. Patients with PHPT usually have a CCCR of>= 0.02. A lower CCCR between 0.01 and 0.02 can be seen in approximately 20% of patients1,2and is more commonly seen in the presence of vitamin D insufficiency, impaired renal function, low calcium intake or being of African descent. It is advised to stop drugs which can contribute to hypercalcemia and lower the CCCR such as thiazide diuretics prior to evaluating the CCCR.

Clinical Case: A 56-year-old lady was referred for evaluation of persistent hypercalcemia post parathyroidectomy and fatigue. She had mildly elevated ionized serum calcium (iCa) and a mid-normal PTH with a CCCR of 0.024. She had a normal BMD with no prior fragility fractures and passed a kidney stone prior to her presentation. Physical exam was unremarkable. She had previously travelled to Tampa and had a subtotal parathyroidectomy 3 glands (RU, LU, RL) for a possible diagnosis of PHPT, tissue biopsy showed hyperplastic parathyroids. Her MEN1 gene analysis was negative for MEN1 mutation and MRI of the abdomen was unremarkable. Her mother had a diagnosis of PHPT and osteoporosis. The iCa remained mildly elevated at 1.43 mmol/L (1.15–1.3) with a 24 hr urinary CCCR at 0.024 and a mid-normal PTH of 4.4 pmol/L (1.6–6.9). Her eGFR was 104 mls/min, 25 vitamin D 82 nmol/L (75–250), 1,25 dihydroxy vitamin D 122 pmol/L (60–206), PO4 0.90 mmol/L (0.8–1.45) and alkaline phosphatase 46 U/L (35–120) were all normal. She continued to have mild symptoms of hypercalcemia and her bone scan was negative for underlying skeletal pathology.

DNA studies for mutations in the CaSR gene were completed. This confirmed the presence of a heterozygous loss of function mutation in the CASR gene at c493-2A>G which appears to be pathogenic.

Conclusion: The CCCR is useful in differentiating PHPT from FHH however in certain cases of FHH the CCCR may be higher then expected and we have now confirmed the presence of FHH with a molecular diagnosis in a patient with a CCCR as high as 0.02.

References: 1 Gunn, IR, Gaffney, D. Clinical and laboratory features of calcium-sensing receptor disorders: a systematic review. Ann Clin Biochem 2004; 41:441–58 2 Stephen J. Marx, Letter to the Editor: Distinguishing Typical Primary Hyperparathyroidism From Familial Hypocalciuric Hypercalcemia by Using an Index of Urinary Calcium, The Journal of Clinical Endocrinology & Metabolism, 2015
Denosumab Induced Severe Prolonged Hypocalcemia in Metastatic Prostate Cancer
Authors: Mehmood Hassan , Hasan Farhad
Published: May 2021

Background: Denosumab is a RANK-l inhibitor that, in addition to the treatment of osteoporosis, is used in patients with advanced cancer and metastatic bone disease to prevent skeletal-related events. Although denosumab is generally safe and effective, it can cause hypocalcemia which in some patients can be severe and life threatening. We present a case of severe prolonged hypocalcemia after a single dose of denosumab in a patient with metastatic prostate cancer. Case: A 78-year-old male with a past medical history of stage 4 prostate cancer on antiandrogen treatment with GnRH antagonist presented with severe hypocalcemia. Physical exam revealed a blood pressure 125/80 mm Hg, pulse 115 per min and weight 135 lb with negative Chvostek’s and Trousseau’s signs. The electrocardiogram showed supraventricular tachycardia with prolonged QTc interval of 503 ms (<430 ms). Labs showed serum calcium 4.9mg/dL (8.5–10.5), albumin 2.5g/dL (3.6–5.1), corrected calcium 5.7 mg/dL, ionized serum calcium 0.64mmol/L (1.05–1.3), creatinine 1.10mg/dL (0.7–1.2), eGFR >60, phosphorus 2.0mg/dL (2.5–4.5), magnesium 1.9 mg/dL (1.6–2.6), 25-OH vitamin D 29.7 ng/mL (30–100), 1,25 dihydroxy vitamin D 174 pg/mL (18–64), iPTH 244.0 pg/mL (11–68) and PSA 1860 ng/mL. Three weeks prior to presentation, the patient received 120 mg of subcutaneous denosumab. Pre-treatment serum calcium was 9.2 mg/dL (8.5–10.5), and Tc-99m bone scan showed multiple osteoblastic osseous metastatic lesions involving both axial and appendicular skeleton. The patient was diagnosed with denosumab-induced severe hypocalcemia and started on intravenous (IV) calcium gluconate infusion, oral phosphate 250 mg twice daily, and ergocalciferol 50,000 IU twice weekly. He required IV calcium gluconate up to 10 g per day in addition to oral calcium carbonate 2 g t.i.d. for 2 weeks to resolve hypocalcemia and normalize QTc interval. Patient was discharged to nursing home on calcium carbonate 2 g q.i.d. with IV calcium gluconate as needed to keep corrected calcium >8.0 mg/dL. After discharge he required up to 4 g of IV calcium and 8 g of oral calcium per day. Unfortunately, he presented again with severe hypocalcemia 5 weeks after discharge. In addition to current regimen of oral and IV calcium boluses, low dose calcitriol was started. We were only able to maintain his serum calcium>8.0 mg/dL by administering high daily dose of oral calcium carbonate 8 g /day and calcitriol 2 mcg daily. Due to poor prognosis, he was transitioned to hospice care and died 2 weeks later. Discussion: There are not many case reports on severe prolonged hypocalcemia secondary to denosumab in cancer patients but normal kidney function. Our patient remained on high dose of calcium even 101 days after denosumab administration. Reference: 1. Milat F et al. Prolonged hypocalcemia following denosumab therapy in metastatic hormone refractory prostate cancer. Bone. 2013 Aug 1;55(2):305–8.
Ectopic Atypical Parathyroid Adenoma Presenting With Pancreatitis
Authors: Shiu Paul , Tashdjian Caroline , Kaur Tarandeep
Published: May 2021

Background: Atypical Parathyroid Adenoma (APA) and parathyroid carcinomas (PC) are rare parathyroid tumors (<1%) causing primary hyperparathyroidism. We present a case of ectopic APA in the left anterior mediastinum. Case: A 38 year old male with hyperlipidemia admitted for acute pancreatitis noted to have calcium level of 13.4 mg/dl (8.6–10.3mg/dl) in the absence of family history of hypercalcemia or kidney stones. He was treated with zoledronic acid, intravenous fluids and calcitonin for hypercalcemia. Pancreatitis resolved with fluid management. Calcium on discharge was 9.9 mg/dl. 8 week follow-up labs showed PTH of 420 pg/ml (14–64 pg/ml), calcium 10.2 mg/dl, phosphorus 1.9 mg/dl (2.5–4.5 mg/dl), vitamin D 19 ng/ml (30–100 ng/ml), 24-hour urinary calcium 115 mg/24 hour (55–300 mg/24 hour) and calcium to creatinine ratio 0.41. Hence diagnosis of primary hyperparathyroidism was made but given the degree of calcium and PTH elevation there was a concern for PC. Ultrasound of the neck demonstrated no abnormality. Sestamibi scan showed irregular focal accumulation of radiotracer in the left upper mediastinum suggestive of mediastinal ectopic parathyroid adenoma (EPA). CT chest with contrast showed a 3.9 x 2.2 x 3.4cm lobulated, heterogenous, hypodense, minimally enhancing mass in the left anterior prevascular space. Diagnosis of EPA was made and he underwent left video assisted thoracic surgery. Operative findings showed a multilobular mass at the level of the aortic arch between vagus and phrenic nerves. Intraoperative PTH went from 1124 pg/ml pre-incision to 160 at 15-minute post-excision. Postoperative calcium was 9.6 mg/dl and PTH 51 pg/ml. Final pathology showed 3.7 x 2.5 x 2cm, hypercellular parathyroid with prominent fibrous band and parafibromin retention compatible with APA. Discussion: APA is an intermediate form of parathyroid neoplasm with uncertain malignant potential, showing atypical histological features without evidence of invasive growth. This poses a diagnostic challenge of PC as the histopathological features overlap and requires an expert pathologist to make the diagnosis. Inactivating CDC73 mutations, encoding parafibromin, is the most common genetic abnormality. Loss of parafibromin has been seen in 100% cases of PC and predicts poor prognosis. Due to rarity of the disease there are no clear guidelines on follow up. Based on literature, annual follow up is suggested with biochemical testing and imaging for the first 5 years after surgery and every 2–3 years thereafter due to 3% recurrence rate and potential progression to PC. Cetani et al in 2019 reported 672 cases of APA, only 3 were ectopic in the mediastinum thus making our case rare. APA is a rare entity as biochemical profile and histopathological features overlap with PC and can be misdiagnosed. Greater awareness of APA may improve capture of cases, allowing the development of guidelines to recognize and treat it.
Experience With Anti-Sclerostin Antibody for Osteoporosis Patient With End-Stage Renal Disease on Hemodialysis
Authors: Mukaddam Mona Al , Hvisdas Christopher , Sulaj Anisa , Patel Kruti , Tran Richie
Published: May 2021

Background: Romosozumab is a sclerostin inhibitor indicated for treatment of postmenopausal osteoporosis. Sclerostin inhibits Wnt/Beta-catenin signaling pathway. When sclerostin is inhibited, stimulation of this pathway leads to increased bone formation and production of osteoprotegerin, which also decreases bone resorption. Patients with chronic kidney disease (CKD) demonstrate increased levels of sclerostin that negatively correlates with the rate of bone formation; however, data is lacking for use of romosozumab in this patient population. The report herein details the experience of use of romosozumab in a patient with end-stage renal disease (ESRD) on hemodialysis (HD). Clinical Case: A 37-year-old old African American male was referred after multiple rib fractures and severe non-traumatic T8 compression fracture with nerve compression. His past medical history includes lupus nephritis and cerebritis, ESRD on HD since age 22 status post (s/p) failed renal transplant, and tertiary hyperparathyroidism complicated with fracture in iliac brown tumor and mediastinal parathyromatosis s/p three parathyroid surgeries. Bone mineral density by DXA (g/cm2, Z-score) were as follows: lumbar spine (0.700, -4.0) femoral neck (0.676, -3.8), total hip (0.628,-4.0), 1/3 radius(0.443,-6.2). No prior exposure to antiresorptive or osteoanabolic agents. Pertinent labs included serum calcium 8.5 mg/dL (nl 8.9–10.3 mg/dl), albumin 4.2 g/dL, alkaline phosphatase 319 U/L (nl 38–126), Phosphorus 3.1 mg/dL (2.4–4.7), Creatinine 5.62 mg/dl, 25-OH Vitamin D 31 ng/mL (nl 25 - 80), intact parathyroid hormone 17.9 pmol/L (nl 1.6–6.9). Patient was in excruciating pain and not a surgical candidate due to poor bone quality. Osteoanabolic therapy was recommended given the severity of osteoporosis; however, teriparatide and abaloparaitde were contraindicated given comorbidities. The patient was offered off-label use of Romosozumab with clear understanding that the drug is not approved for this indication and safety/efficacy data in ESRD is not known. The boxed warning regarding increased risk of stroke, myocardial infarction and death were discussed and patient was willing to proceed. Repeat DXA after eleven monthly doses of Romosozumab resulted in a remarkable improvement in bone mineral density at all sites: lumbar spine (+47%), femoral neck (+41%), total hip (+28%), 1/3 radius (+20%). Patient tolerated medication with no side effects or fractures. Serum calcium was monitored prior to initiation and before every dose. No doses were held due to abnormal laboratory values or side effects. Conclusion: This case report summarizes successful experience with the use of Romosozumab in one patient with ESRD on HD with favorable outcomes.