bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of a PTHrP Chemiluminescent Immunoassay to Assess Humoral Hypercalcemia of Malignancy
Authors: Ashrafzadeh-Kian Susan Louise , Bornhorst Joshua , Algeciras-Schimnich Alicia
Published: May 2021

Background: Measurement of parathyroid hormone related peptide (PTHrP) is helpful in the diagnosis and clinical management of patients suspected of humoral hypercalcemia of malignancy (HHM). In these patients uncontrolled release of PTHrP by tumor cells is responsible for the hypercalcemia and PTH concentrations are typically suppressed.

Objective: Develop a sensitive and specific assay for quantitation of PTHrP in plasma.

Method: Calibrators (PTHrP 1-86) and samples (50uL) were incubated with an anti-PTHrP goat polyclonal acridinium ester labeled antibody. Complexes were transferred and incubated in a microplate coated with an anti-PTHrP polyclonal rabbit antibody. After washing, the acridinium ester generated signal, which is directly proportional to the amount of PTHrP in sample, was quantified.

Results: In this assay PTHrp was stable for 24 hours ambient, 3 days refrigerated, 34 days frozen and through 3 freeze/thaws. Intra and inter-assay imprecision in EDTA plasma (~0.16-35.0 pmol/L) ranged from 2.2-8.6% and 5-15%, respectively. The limit of detection was 0.04 pmol/L and the limit of quantitation was 0.16 pmol/L (15% CV). The analytical measuring range was 0.39-50.5 pmol/L (slope of 1.07 and r2 of 0.99). Average spike recovery was 98% (range 85-108%). The assay was not affected by hemoglobin of ≤500 mg/dL, triglycerides of ≤2000 mg/dL, or bilirubin of ≤50mg/dL. No hook effect was noted up to 500 pmol/L. PTH (1-84) did not cross-react in the assay. C-terminal PTHrP(107-139), and N-terminal PTHrP(1-36) had no significant cross-reactivity (≤1.1%). Mid-PTHrP(38-94) had 8.3% cross-reactivity. Comparison with an in-house PTHrP assay (n=267) showed an r2 of 0.96, and slope of 2.25 by Passing-Bablok regression fit. The 97.5% reference interval for PTHrP (n=114) was ≤0.7 pmol/L, however a higher concentration (≤4.2 pmol/L) was identified as a more specific clinical cut-off. A retrospective clinical validation study showed that using ≤4.2 pmol/L resulted in a 91% clinical sensitivity and a 98% clinical specificity.

Conclusion: We have developed an analytically and clinically sensitive and specific PTHrP immunoassay. A cutoff of ≤4.2 pmol/L is clinically useful in the evaluation of patients suspected of hypercalcemia of malignancy.
Growth Hormone Receptor Inhibition Sensitizes Human Pancreatic Cancer to Chemotherapy Treatments
Authors: Basu Reetobrata , Kopchick John Joseph , Ortiz Silvana Duran , Qian Yanrong , Kulkarni Prateek
Published: May 2021

Human growth hormone (GH) and its cognate growth hormone receptor (GHR) have been established to have a distinct role in promoting the progression of several types of human cancers. We had earlier described a newfound role of the GH-GHR axis in driving chemoresistance in melanoma by upregulating drug efflux by ABC multidrug transporter expression and a phenotype switch by induction of epithelial-to-mesenchymal transition (EMT). Here we present an in-depth analysis of this role of GH-GHR in the highly therapy resistant human pancreatic cancer which has a 5-year survival rate of only 10% in 2020. Using human and mouse pancreatic cancer cells and RNA and protein expression analyses by RT-qPCR, ELISA, and western-blot, we identified that (i) GH upregulates specific ABC-transporter expressions in a drug-context specific manner, (ii) GH upregulates EMT transcription factors, (iii) GH activates specific oncogenic signaling pathways, and (iii) GH action increases cytochrome P450 members involved in hepatic drug metabolism. The GH antagonist, Pegvisomant, significantly inhibited these effects. Additionally, we confirmed the effects of these molecular changes by specific assays. For example, GH increases basement membrane invasion, viability of circulating tumor cells, and drug efflux; while inhibition of GHR by pegvisomant in pancreatic cancer cells reversed this aggressive tumor phenotype and sensitized the tumor cells to chemotherapy. Cell viability assays confirmed a decreased IC50 of gemcitabine, doxorubicin, and erlotinib in pancreatic cancer cells treated with pegvisomant and an increase in IC50 cells treated with GH. We further verified our results using in silico analyses of TCGA datasets for pancreatic cancer - which provided robust confirmation of our experimental findings. Presently we are validating our observation in nude mice with human pancreatic cancer cell xenografts. In conclusion, our in vitro results confirm that GHR antagonism can drastically sensitize human pancreatic cancer cells by blocking mechanisms of drug resistance, thus providing a valuable window for improved efficacy of available chemo- and targeted therapy.
A Case of Paraneoplastic Hypoglycemia From Squamous Cell Carcinoma of Undetermined Primary
Authors: Murati Jonila , Reddy Niyoti , Knapp Philip E , Alexanian Sara
Published: May 2021

Case: A 57 year old man with squamous cell carcinoma (SCC) of the tongue with complete response to chemoradiation was found unresponsive with a reading of “low” by a POC glucometer. He was treated with an IV dextrose bolus but had recurrent hypoglycemia requiring a continuous dextrose infusion. He was diagnosed with COVID-19 pneumonia, acute hepatitis (elevated liver enzymes), and acute kidney injury (elevated serum creatinine 1.2 mg/dL). Other labs: elevated TSH 8.44 uIU/mL, normal AM cortisol 16.4 ug/dl. A 5.1 cm mass was discovered in the left lung with bilateral nodules, biopsi revealed SCC of unclear origin (either lung or metastatic disease from prior tongue cancer). He was malnourished from prior cancer related dysphagia and nutritional supplements were added. Despite this and improvement in liver and kidney function, he had persistent hypoglycemia. He became hypoglycemic within 4-hrs while performing a 72-hr fast with labs: serum glucose 45 mg/dL, insulin < 2 uU/mL, c-peptide < 0.1 ng/mL, proinsulin < 4 pmol/L, beta hydroxybutyrate 0.17 mmol/L, IGF1 < 16 ng/mL (ref: 50 - 317), IGF2 147 ng/mL (ref: 267-616), negative hypoglycemia panel and insulin antibody. This was consistent with a paraneoplastic hypoglycemia known as non-islet cell tumor hypoglycemia (NICTH). To discontinue the dextrose infusion, he was started on prednisone 20 mg daily titrated up to 60 mg daily, intermittent tube feeds and palliative chemotherapy. With this, hypoglycemia improved, and the dextrose infusion was discontinued. Unfortunately, he had ischemic bowel perforation leading to cardiac arrest and death. Discussion: Our patient had NICTH as suggested by the 72-hr fast (non-insulin mediated hypoglycemia, IGF2/IG1 ratio > 10) and the presence of a tumor. It is mediated by tumor-produced IGF-2 causing increased glucose utilization, decreased gluconeogenesis, glycogenolysis and ketogenesis. Curiously, IGF-2 may not be elevated if the tumor produces a partially processed “big IGF-2” for which there is no commercial assay. Instead, an IGF2/IGF1 ratio close to or more 10 is indicative of NICTH. Mesenchymal and hepatic tumors are the most common cause of this rare entity with an incidence of one per million people years. A literature search showed very few reports of SCC-mediated-NICTH, with one case of esophageal SCC. Our patients’ primary tumor was undetermined (lung vs tongue) - but in either case this could be a novel association. A multidisciplinary approach is required centered around the tumor (surgery, chemotherapy, or radiation). High dose prednisone 30 to 60 mg daily can be used in the interim as it decreases IGF-2 but is not always successful. Recombinant hGH and glucagon are alternatives or can be combined with steroids. In summary IGF2/IGF1 ratio should be calculated, palliative tumor directed therapy should be initiated with prednisone and supplemental nutrition as adjuncts.
ACTH Producing Mediastinal Tumor - Multidisciplinary Approach
Authors: do Amaral Camila Lopes , Veras Victor Rezende , Araújo Jéssica Silveira , Amancio Samuel Aguiar , Da Rocha Duilio Reis , Alves Newton de Albuquerque , Alencar Renata Carvalho , Quidute Ana Rosa
Published: May 2021

Introduction: Ectopic ACTH syndrome is rare but is frequently a severe condition because of the intensity of the hypercortisolism. Patient management is complex and demands both strategies: the diagnosis and treatment of Cushing syndrome, and the specific management of neuroendocrine tumors. Therefore, management should be performed ideally by experienced endocrinology teams in collaboration with surgeons, oncologists, nuclear medicine, specialized hormonal laboratory and modern imaging platforms.

Clinical Case: Female patient, born in 2000, at the age of 15 was diagnosed with Cushing’s syndrome secondary to ACTH secretion by mediastinal tumor. At diagnosis, ACTH 1152pg/ml was found (reference value <46pg/ml). Turkish seat resonance was normal, and chest tomography described a 4.5x3.6x3.8cm mediastinal lesion. Underwent a mediastinal surgical approach in 2015, with clinical and laboratory remission of hypercortisolism. The analysis of the lesion revealed a well-differentiated neuroendocrine carcinoma, with Ki67 5%. Progression of the mediastinal lesion was observed, without an exuberant clinic or laboratory, and a new surgery was performed in 2017, with a remaining macroscopic tumor, due to technical difficulties in resection due to contact with vascular structures. The immunohistochemistry of the resected lesion in this approach showed Ki67 30%, which reflects loss of differentiation. Octreoscan was performed, with no uptake. She evolved without exuberant Cushing’s syndrome until May 2019, when the clinical condition decompensated due to hypercortisolism, and was submitted to a new hospitalization. She was assisted by the thoracic surgery and oncology teams. From this moment a follow-up with endocrinology team started. Ketoconazole was introduced and PET-DOTATOC was requested. She underwent chemotherapy with Oxaliplatin and Capecitabine. In March 2020, DOTATOC uptake was checked and a somatostatin analogue was started. She showed considerable clinical and laboratory improvement. The patient remains clinically stable, with control of hypercortisolism using Ketoconazole 600mg daily and Octreotide 30mg every 28 days. The patient remains under clinical and laboratory surveillance. Awaiting PET-FDG. Mediastinal radiotherapy, lutetium, new mediastinal surgical approach, and bilateral adrenalectomy are also considered as possible therapeutic alternatives.

Clinical Lesson: The reported case shows a rare location of an ACTH-producing tumor, emphasizing the severity of the presentation, the evolution of tumor de-differentiation, the different results identified in octreoscan and PET-DOTATOC, and the importance of multidisciplinary management.
A Tale of Two Cities: Do They Have the Same Destination: Asymptomatic Pheochromocytomas: Biochemically Functioning vs Non Functioning
Authors: Paniagua Gabriela Zuniga , Vimarni Samarth , Broutin Dominique , Martinez Suzanne , Suryanarayanan Sowmya K
Published: May 2021

Background: Pheochromocytomas (PHEOs) are enterochromaffin tumors arising from the adrenal gland. Their diagnosis and preoperative preparation is crucial due to high morbidity and mortality rates with unrecognized, undiagnosed PHEOs. Case 1: 62-year-old male with a medical history of HCC, noted to have right adrenal adenoma measuring 1.7 x 1.6 cm. Denied any symptoms and normotensive on exam. A PET scan done showed a hypermetabolic right adrenal nodule concerning for malignancy. Serum metanephrines were 45 pg/ml (nl <57 pg/ml) and total plasma metanephrines were 172 pg/ml (nl <205 pg/ml). A CT guided biopsy was consistent with a PHEO. Other labs included: 24 hour urine metanephrines: 155 mcg (nl 90–315), total metanephrines: 520 (nl 224–832) and vanillylmandelic acid was 3.6 (nl <6.0). 24-hour urine epinephrine: 10 mcg (nl 2–24), norepinephrine:57 mcg (nl 15–100) and dopamine: 421 (normal 52–480). Case 2: 55 year old male with UTI and flank discomfort, noted to have incidental 8cm Right adrenal mass noted concerning for malignancy. Also denied any symptoms and normotensive. Plasma fractionated metanephrines 938 (ref <206), metanephrine 279,Normetanephrine 659(ref <148), 24 hr urine metanephrines=1176mcg/24 hr (90–315), Normetanephrines 1487 (122–676), 24 hr urine total metanephrines 2663 (224–832). He is refusing α and β blockade due to normotension in preparation for surgery. Discussion: It is important to suspect, confirm, localize, treat, and PHEOs for several reasons. Most of these tumors hypersecrete catecholamines, and if untreated, cardiovascular morbidity and mortality are high. Another reason to encourage case detection is that, for familial disease, detection of a tumor in the proband may result in earlier diagnosis and treatment in other family members. Alpha-blockade is usually used prior to resection of Pheochromocytomas. However, the data available in the literature regarding alpha blockade for “truly asymptomatic” functioning or non functioning Pheochromocytomas is scarce. However what is unique to our cases is that they both are normotensive and asymptomatic and refusing preoperative preparation. Conclusion: Asymptomatic PHEO are becoming more common presentation given Pheochromocytomas are rare. Are the genetics and biochemical nature any different than classic pheos? Are we supposed to manage them the same way? Would we rethink current guidelines for managing normotensive or nonfunctioning pheochromocytomas pre operatively? We also would like guidelines on how to prepare such truly asymptomatic patients prior to surgery. We refer to Endocrine Society guidelines for management of such tumors.
Adrenal Insufficiency in an Adolescent Boy With Type 1 Diabetes Mellitus - the Importance of Considering X-Linked Adrenoleukodystrophy
Authors: Wiersma Rebecca , Gupta Ashish , Lund Troy C , Orchard Paul J , Miller Bradley Scott
Published: May 2021

Background: Primary adrenal insufficiency (PAI) is the rare, life-threatening failure of the adrenal glands to produce sufficient glucocorticoids and mineralocorticoids, presenting with fatigue, weakness, weight loss, hyperpigmentation, hypoglycemia, and hypotension. In adults, PAI is primarily autoimmune, occurring independently or in conjunction with thyroiditis and/or Type I diabetes mellitus (T1DM) as a component of Autoimmune Polyglandular Syndrome-2 (APS-2, Schmidt syndrome). APS-2 is rare (prevalence 1 in 20,000) and more common in females with a peak incidence in the third and fourth decades of life. In children, PAI is most often due to congenital adrenal hyperplasia (CAH), followed by autoimmune disease, but as many as 50% of cases of non-CAH pediatric PAI are not autoimmune. PAI is often the first documented clinical finding in boys with X-linked adrenoleukodystrophy (X-ALD), a rare disorder (prevalence 1 in 15,000) in which deficiency of a peroxisomal membrane protein leads to very long chain fatty acid (VLCFA) accumulation and progressive destruction of the adrenal cortex. A subset of boys with X-ALD develop cerebral ALD (cALD), characterized by progressive central demyelination, neurocognitive decline, and death. 70–80% of boys with X-ALD present with PAI prior to demonstrating neurologic symptoms. Diagnostic workup for X-ALD in pediatric patients presenting with PAI is crucial as timely intervention with hematopoietic stem cell transplant (HSCT) can stop progression of cerebral disease. Clinical Case: An eleven-year-old male was diagnosed with PAI after presenting with poor school performance, growth delay and skin hyperpigmentation. Medical history was significant for well controlled T1DM diagnosed at eight years old. Given his history of T1DM, his PAI was presumed to be autoimmune and further diagnostic testing was not performed. Eleven months later, a brain MRI performed for complaints of visual disturbance and chronic headaches revealed extensive demyelination with gadolinium enhancement consistent with cALD. Elevated VLCFAs and a mutation in the ABCD1 gene confirmed the diagnosis of X-ALD. Unfortunately, the extent of cerebral involvement was so severe that HSCT would not be of significant clinical benefit. In these situations, progressive neurological decline that leads to disability and ultimately death would be expected. Clinical Lessons: This case illustrates that VLCFA testing should be performed in all boys with PAI to rule out X-ALD. In boys, PAI should not be assumed to be autoimmune, even with co-existing autoimmune diseases since APS-2 (Schmidt syndrome) is rare and more likely to occur in adult women. PAI presents early and precedes neurologic symptoms in a majority of boys with cALD. Early identification of X-ALD through VLCFA testing prior to development of severe cALD is critical to allow early intervention with lifesaving HSCT.
Bilateral Adrenal Incidentalomas, Uncommon Presentation and Very Rare Pathology
Authors: Ibraheem Hamad Mohammad Khair Ahmad , Saleh Ahmed Osman , Naem Emad
Published: May 2021

Background: Adrenal incidentaloma is an adrenal mass larger than 1cm accidentally discovered by radiological examination. The incidentalomas should be evaluated for malignancy and functionality. The prevalence of adrenal incidentaloma is 4–10%,1 and around 10–15% of incidentally discovered adrenal masses can be bilateral.2 We present a patient with bilateral adrenal masses due to primary adrenal lymphoma. Clinical Case: 74-year-old gentleman, with past medical history of type-2 Diabetes mellitus, hypertension, presented to our hospital with 2 months history of right-sided flank pain, 20 kg weight loss, loss of appetite and dizziness. Otherwise, no fever, night sweats, bleeding per rectum or urinary symptoms. On physical examination, vital signs were within normal, no remarkable findings other than tenderness over the right flank. Complete blood count and chemistry panel were within normal. Abdominal CT scan was done for evaluation of the abdominal pain which showed two large masses replacing the adrenal glands measure about 10cm in diameter with patchy areas of enhancement. Adrenal insufficiency was suspected based on the symptoms and the CT scan findings. Short syncatin test (high-dose test 250mcg) was done, which showed a cortisol baseline 152nmol/L, 30 minutes 168nmol/L, and 60 minutes 169nmol/L. This was suggestive of adrenal insufficiency, so he was started on hydrocortisone. Screening for pheochromocytoma was done as the patient developed uncontrolled BP readings prior to a scheduled adrenal biopsy. 24-hour urine metanephrines and normetanephrine were negative. CT-guided adrenal mass biopsy showed findings suggestive of large B-cell lymphoma. FDG PET-CT scan showed huge bilateral intense FDG uptake in the adrenal glands with no extra-abdominal manifestations noted. He was started on R-CHOP chemotherapy and after 4cycles, a PET scan showed a significant decrease in the size of previous adrenal masses.

Conclusion: Bilateral adrenal incidentaloma should be evaluated the same as unilateral adrenal mass. Although adrenal involvement is common in non-Hodgkin lymphoma, primary adrenal lymphoma is extremely uncommon.

References

1.Bovio S, Cataldi A, Reimondo G, Sperone P, Novello S, Berruti A, Borasio P, Fava C, Dogliotti L, Scagliotti GV, Angeli A, Terzolo M. Prevalence of adrenal incidentaloma in a contemporary computerized tomography series. J Endocrinol Invest. 2006 Apr;29(4):298–302. doi: 10.1007/BF03344099. PMID: 16699294.

2.Angeli A, Osella G, Alì A, Terzolo M. Adrenal incidentaloma: an overview of clinical and epidemiological data from the National Italian Study Group. Horm Res. 1997;47(4–6):279–83. doi: 10.1159/000185477. PMID: 9167965.
Ectopic ACTH-Producing Pheochromocytoma as a Rare Cause for Rapid Progressing Cushing Syndrome: A Case Report
Authors: Salazar Daniela , Costa Cláudia Fernandes , Oliveira Joana , Violante Liliana , Cunha Ana Luísa , Fernandes Manuel , Santos Ana Paula , Torres Isabel
Published: May 2021

Background: Cushing syndrome due to ectopic CRH or ACTH secretion can be rarely caused by pheochromocytoma, commonly as part of genetic conditions. Case: A 21 year-old male, previously healthy, with no usual medication, went to the physician assistant for hematuria. The kidney US revealed, besides lithiasis, a highly vascularized mass in the right adrenal gland with 10 cm. In his first evaluation the patient had no complaints or pheochromocitoma/hypercortisolism stigmata, other than hand tremor and slight rounding of the face. Blood pressure was 149/88 mmHg, and heart rate 86 bpm. There was no family history of endocrine disease. He rapidly developed increased appetite, insomnia, and severe myalgias, with filling of supraclavicular fossae, facial plethora, and cervical and truncal acne. Laboratory analysis showed abnormal overnight dexamethasone suppression test (57.4 µg/dL, N < 1.8), elevated ACTH 378 pg/mL (N 9.0–52.0), 24h-urinary free cortisol (UFC) (5334.0 µg/24h, N 4.3–176.0), and late-night salivar cortisol (1.44 µg/dL, N < 0.32), hypokalemia (2.8 mEq/L, N 3.8–5.0), and leukocytosis (22.4*109/L, N 4.0–11.0); DHEA-S 962 µg/dL (N 80–560), 4-androstenedione 380 ng/dL (N 70–360), 17-OH progesterone 4.5 ng/mL (N 0.59–3.44), cromogranine A 6063 ng/mL (N 0–100), and markedly elevated urinary amines (adrenaline 173 nmol/24h, N 0–109; noradrenaline 5033 nmol/24h, N 89–473; normetanephrine 334605 nmol/24h, N 480–2424; metanephrine 15998 nmol/24h, N 264–1729; dopamine 4808 nmol/24h, N 424–2612). Hypercalcemia with hypophosphatemia and supressed PTH level was also detected. 68Ga-DOTANOC PET revealed a mass of the right adrenal gland with overexpression of somatostatin receptors (likely pheochromocytoma), without evidence of other tumor lesions of neuroendocrine origin. Pituitary MRI showed normal pituitary gland. Potassium supplementation, alpha-blockade with phenoxybenzamine, and metyrapone were initiated. Due to severe back pain, a CT scan of the spine was performed detecting compressive osteoporotic fractures in the mid dorsal and low dorsal segments. The patient was submitted to right adrenalectomy. Histology revealed pheochromocytoma with 11.2*9mm, with capsular and vascular invasion, extra-adrenal extension, necrosis, and atypical mitosis, with Ki67 of 9.5% and PASS score of 16. Postoperative analysis showed ACTH 45.6 pg/mL (N 7.2-63,3), late-night salivar cortisol < 0,0544 µg/dL (N < 0,32) and free urinary cortisol 41.4 µg/24h (N 4.3–176.0). Discussion: Ectopic cushing syndrome caused by pheochromocytoma is a rarely described entity. In this young patient, it caused rapid clinical progression of hypercortisolism with important hydroelectrolytic disturbances and compressive vertebral fractures, requiring prompt surgical intervention for clinical remission and improvement.
Exogenous Cushing Syndrome Associated With Homeopathic Cream (Boswellia Serrata)
Authors: Mejía Maria Gimena , Jimenez-Canizales Carlos Eduardo , Trespalacios Ruben Fuentes , Niebles Oscar
Published: May 2021

Background: Cushing syndrome (CS) includes the signs and symptoms associated with prolonged exposure to abnormally elevated plasma levels of glucocorticoids, which can be either exogenous or endogenous (cortisol). Exogenous CS has been associated with homeopathic and allopathic products with anti-inflammatory properties, has been demonstrated in many of them, that there are steroid contributions in these drugs which are not reported in their inserts and in prolonged exposure generate BMS. Clinical Case: We present the case of a 23-year-old female with a history of polycystic ovarian syndrome in management with ciproterone acetate and metformin 500 mg dia, who has gained 12 kilos of weight in two months, Progressive appearance of violaceous stretch marks on the thighs, arms and abdomen, associated with diaphoresis, hyporexia, acneiform, rash and hirsutism. The symptoms were related to the use of natural anti-inflammatory cream, for joint pains in knee and shoulders based on natural extracts of Boswellia Serratia during the last three months. It presents paraclinics with post-dexamethasone serum cortisol levels in 1. 25, ACTH 1. 5, Urinary cortisol 20. 24 ug/24h, urinary volume 0. 88 L/24H, DHA -S 27. 1Ug/dl, Free testosterone <0.24 pg/ml, TSH 2. 59 ng/dl, Free-T4: 1. 16 ng/dl, Prolactin: 31 Ng/ml (0–23), Somatomedin C: 109 Ng/ml, (92.9–342.0), HBAC1: 5. 37%, preprandial and postprandial glycemia: 90–133 mg/dl, Am Cortisol:1.11 mcg/dl (6–18 Mcg/dl), Basal Insulin: 74 uUI/ml., Postprandial Insulin: 57 uUI/ml. Clinical findings and dynamic biochemical studies of the adrenal axis, with a positive dexamethasone suppression test and no findings suggesting ectopic production; it was confirmed that the diagnosis of exogenous CS is associated with the use of topical anti-inflammatory. With the of the drug’s suspension, clinical findings have improved, and cortisol levels have decreased. Conclusion: Exogenous hypercortisolism associated with the use of topical anti-inflammatory drugs is not frequent. The first case reported an association with the use of a topical drug based on Boswellia Serrata. In conclusion, with the presence of signs and symptoms of CS the recent use of herbal products by any route of administration and by excluding other causes of endogenous hypercortisolism (central or ectopic) and exogenous, the use of homeopathic products should be suspected as an etiology. Nowadays, there are no reports of exogenous Cushing by BS. The first case is described, without omitting the possibility of unknown compounds in the topical preparation.
Large Bilateral Adrenal Myelolipomas in the Setting of Congenital Adrenal Hyperplasia
Authors: Anderson Karolina E , Solorzano Carmen , Bao Shichun
Published: May 2021

Adrenal myelolipomas (AMLs) are rare benign adrenal tumors containing adipose and hematopoietic tissue, with a reported incidence of 0.08 to 0.4% on autopsy. AMLs are the second most common primary adrenal incidentaloma. Congenital adrenal hyperplasia (CAH) is associated with 10% of analyzed AML cases, half of which are bilateral in CAH patients.

This is a 40-year old male with CAH diagnosed shortly after birth, due to 21-hydroxylase deficiency. He was doing well on a maintenance dose of hydrocortisone 20mg PO qAM and 10mg PO qPM and fludrocortisone 0.2mg PO daily until two years ago when he was incidentally found to have large bilateral AMLs while undergoing abdominal MRI and CT scans. These measured 6.6x3.6x7.7cm on the right (R) and 12.3x8.4x6.8cm on the left (L) at the time. He was asymptomatic, denying flank and abdominal pain. Follow up adrenal CT a year later revealed his AMLs increased in size to 8.7x4.2x6.6cm (R) and 13.9x6x8cm (L). Repeat CT another year later showed further rapid enlargement of his AMLs, measuring 11.1x6.1x7.9cm (R) and 17.1x7.8x10.8cm (L). He also exhibited a rising 17-hydroxyprogesterone level of 11,547ng/dL, despite an increased hydrocortisone dose (20mg BID). Although he remained asymptomatic, due to the precipitous growth of the masses and his increasing steroid requirement, a surgical approach was recommended. Open bilateral adrenalectomy was performed by an experienced endocrine surgeon and patient was discharged from the hospital with maintenance hydrocortisone and fludrocortisone therapy as well as strict sick day instructions.

AMLs were first described in 1905 by Gierke. In the past, they were often discovered on autopsies, but more recently, due to the increase in imaging, have been incidentally diagnosed on more patients. Mostly, they occur unilaterally and are small (<4 cm) in size. Individuals with hormonal dysfunction such as those with Cushing’s Syndrome, Conn’s syndrome and CAH, particularly with difficult-to-control corticotropin levels, may be at a greater risk of developing AMLs concurrently, however this phenomenon is still not well understood. Small asymptomatic AMLs can be monitored with serial imaging over time. Spontaneous rupture of AMLs was found in 4.5% of cases, mostly occurring in tumors > 10cm, some resulting in retroperitoneal hemorrhage or even hemorrhagic shock. Although there is no clear consensus on surgery, development of symptoms or significant growth (to >10cm), as in our case, is a reason to pursue surgical evaluation especially in a young, otherwise relatively healthy adult.
Primary Hyperaldosteronism From Adrenocortical Adenoma Presenting as Seizures and Stroke
Authors: Parihar Aisha
Published: May 2021

Background: Primary hyperaldosteronism, which is unregulated secretion of aldosterone from the adrenal gland, is a common cause of resistant hypertension. Hyperaldosteronism can lead to life threatening cardiovascular and neurological complications emphasizing the crucial need for timely identification and management. We present a case of a young patient who suffered complications as a result of primary hyperaldosteronism.

Clinical Case: A 35 year old female with a past medical history of resistant hypertension on four anti-hypertensive medications, primary hyperaldosteronism with known adenoma, CKD stage III, and hyperlipidemia presented to the hospital due to multiple seizures. She was found to be encephalopathic and required intubation for respiratory failure. Her systolic blood pressure was elevated to 250 mmhg. CT scan of the head showed a small left temporal hemorrhage and an MRI brain was revealing of bilateral thalamic infarcts. No neurosurgical intervention, antiplatelet or anticoagulation was recommended. She was admitted to the ICU and started on nitroprusside infusion. CT scan of the abdomen showed a 17 mm right adrenal nodule unchanged from prior imaging. Due to concern for pheochromocytoma, she was started on alpha blockade and subsequently beta blockade therapy. After stabilization of patient’s blood pressure, extubation, and improvement in mental status, she was discharged on new anti-hypertensive medications including spironolactone given her hypokalemia. Further endocrine evaluation was pursued. Work up included urine and plasma catecholamines which were not indicative of pheochromocytoma. Morning cortisol level was within normal limits. Plasma aldosterone level was 30, plasma renin was 0.90 with an aldosterone/renin ratio of 33 suggestive of primary hyperaldosteronism. Though the patient had known primary hyperaldosteronism with an adenoma, she had poor follow up and did not comply with initial recommendation of surgical removal of adenoma prior to her stroke. After medical stabilization following her stroke, a laparoscopic right adrenalectomy was performed. Pathology showed an adrenal cortical adenoma with no evidence of pheochromocytoma. Post-surgical systolic blood pressures were less than 120 mmhg. She was able to come off of spironolactone with plans to gradually discontinue other antihypertensive medications.

Conclusion: This case emphasizes the importance of testing for primary hyperaldosteronism particularly in young patients with resistant hypertension. Furthermore, primary hyperaldosteronism should be considered as an underlying etiology for young patients who suffer from strokes particularly in the setting of hypertension. Given the reversibility of primary aldosteronism from an adrenocortical adenoma with surgery, life threatening complications such as cerebrovascular accidents can be prevented.
Spontaneous Bilateral Adrenal Hemorrhage in Pregnancy
Authors: Haeri Nami Safai , Ullal Jagdeesh , Mahmud Hussain
Published: May 2021

Introduction: Spontaneous Adrenal Hemorrhage (SAH) in pregnancy is a rare occurrence with estimated prevalence of 0.03% to 1.8%. SAH usually involves the right gland and can be easily mistaken with other conditions due to its nonspecific symptoms. We hereby report 2 cases of spontaneous bilateral SAH that occurred during the 3rd trimester of pregnancy.

Case 1: 28-year-old female with history of IBS presented during 35th week of her first pregnancy with right-sided abdominal pain. Abdominal MRI revealed a 4.7 x 2.8 cm right adrenal hemorrhage. Due to stability of her vitals, steroids were not initiated and she was discharged. She returned 4 days later with similar pain but this time on the left side. MRI did not reveal adrenal bleeding. Due to Blood Pressure (BP) of 90/70 mmHg, hydrocortisone IV 50mg every 8 hours was started. 36 hour later she became tachycardic and tachypneic. CT angiogram (CTa) ruled out Pulmonary Emboli (PE), but was remarkable for interval development of a 5.3 x 3 cm left adrenal hemorrhage. There were no findings indicative of Primary Adrenal Insufficiency (PAI). Patient was discharged home on physiologic dose of hydrocortisone and delivered a healthy baby 2 weeks later at term.

Case 2: 30-year-old female with history of hypertension and polycystic kidney disease presented at 31st week of her 2nd pregnancy with left-sided abdominal pain. Abdominal CT scan showed a 2.3 x 3.1 cm left adrenal hemorrhage. Due to BP of 85/50 mmHg at presentation, she was started on hydrocortisone IV 50 mg one dose followed by 25 mg every 8 hours, which improved her BP. 3 days later she developed new right flank pain. MRI was remarkable for features indicative of adrenal hyperplasia but did not confirm presence of hemorrhage. 1 day later she developed hypoxia and underwent CTa to rule out PE, which was remarkable for a new right adrenal hemorrhage. She did not have findings indicative of PAI and was discharged home on physiologic dose of hydrocortisone. Unfortunately, the pregnancy resulted in intrauterine fetal death at 36 weeks.

Discussion: Adrenal cortex hyperplasia secondary to physiological elevation of ACTH plus adrenal venous constriction due to increased catecholamine release, have been suggested as possible mechanisms for increased risk of SAH in pregnancy. Common manifestations of SAH include abdominal pain, fever, fatigue, dizziness, anemia and hypotension. Features of PAI such as hyponatremia and hyperkalemia should be expected in cases of over 90% damage of adrenal cortices. Management in pregnancy involves fluid resuscitation, close monitoring for findings suggestive of adrenal crisis, fetal monitoring and glucocorticoid +/- mineralocorticoid replacement if indicated. Possibility for development of bilateral SAH should always be considered in patients who develop unilateral SAH. If left unrecognized, SAH is associated with poor outcomes and high fatality rate for both mother and fetus.
Thymic Hyperplasia Developing After Treatment of Cushing’s Syndrome, Management and Literature Review
Authors: Riaz Aiman , Wagner Lauren , Malhotra Neha
Published: May 2021

Thymic Hyperplasia Developing After Treatment of Cushing’s Syndrome, Management and Literature Review Introduction/ Background: Rebound thymic hyperplasia (RTH) has been described after the resolution of hypercortisolism from multiple conditions. It can potentially lead to a variety of diagnostic dilemmas. We describe a case where thymic enlargement was seen after unilateral adrenalectomy for adrenal Cushing’s syndrome. Thymic hyperplasia developing after treatment of adrenal Cushing’s syndrome has been very rarely reported. Clinical Case: 43 year old female with type 2 diabetes, hypertension, morbid obesity, depression underwent left adrenalectomy for management of Cushing’s syndrome. Two years after adenoma resection, the patient underwent a CT angiogram of the chest as part of a work up for chest pain which revealed a new anterior mediastinal soft tissue attenuation mass (30–40 Hounsfield units) measuring 6.5cm x2.5cm x 3.7cm. It was found to be abutting the inferior margin of the left brachiocephalic vein and anterior margin of the aortic arch. MRI chest demonstarated mild homogeneous postcontrast enhancement and loss of signal on the opposed phase T1 sequence indicating microscopic fat, deemed to be consistent with thymic hyperplasia. Patient had a detailed discussion of risks versus benefits of biopsy/surgery/conservative management with thoracic surgeon and opted to be managed conservatively. MRI Chest done at 3 month follow up showed a decrease in the size of the mass to 5.8 x 2.4 x 5.cm. She has been on chronic hydrocortisone therapy since adrenalectomy and multiple attempts to wean her off of steroids have been unsuccessful. She continues to be followed closely in the outpatient setting for presumed RTH. Clinical Lesson/ Conclusion: This case highlights the importance of recognizing RTH in patients treated for Cushing’s syndrome. Rapid enlargement of the thymus post adrenalectomy can often lead to unnecessary biopsies and surgeries. The underlying mechanism though unclear has been attributed to depletion of thymic lymphocytes caused by high cortisol concentrations of the plasma leading to RTH when the cortisol level declines. Keywords: Thymic Hypertrophy, Cushing’s syndrome, Thymic hyperplasia
Mortality and Specific Causes of Death in Endogenous Cushing’s Syndrome: A Systematic Review, Meta-Analysis and Meta-Regression
Authors: Limumpornpetch Padiporn , Morgan Ann W , Tiganescu Ana , Pujades-Rodriguez Mar , Nyaga Victoria Nyawira , Baxter Paul D , Stewart Paul Michael
Published: May 2021

Background: Endogenous Cushing’s syndrome (CS) refers to an inappropriate hypercortisolism usually caused by either Cushing’s disease (CD) or adrenal CS (ACS). CS results in significant morbidity and excess mortality if untreated. Even in treated cases there is often a significant health burden. Due to the rarity of CS (incidence ~ 1/1M population), single cohort studies have insufficient power for reporting accurate mortality data. Only one previous systematic review and meta-analysis for CS has been reported that limited its scope to the inclusion of specific CD subgroup. Aims: To perform a meta-analysis and meta-regression analysis of all-cause and specific cause -mortality amongst patients with benign endogenous CS. Methods: The protocol was registered in PROSPERO (CRD42017067530). Searches were undertaken of PubMed, EMBASE, CINHAL, web of science and Cochrane Central from start until April 2019. The primary outcomes were proportion of mortality and SMR. The meta-analysis was done with STATA version 16.1 software. The I2 test, subgroup analysis and meta-regression statistics were used to assess heterogeneity among included studies. Results: A total of 11,527 articles, were retrieved. 87 articles with 100 study cohorts containing 17,276 CS patients reporting mortality were included. Fifty-three study cohorts reported Cushing’s disease (CD) patients, 27 study cohorts reported for adrenal CS patients and 20 studies cohorts reported on both types of CS. The overall SMR of all type CS was 2.91 (95% CI 2.41–3.68) with I2 =40.3%. The SMR for CD was 3.27 (95% CI 2.33–4.21) with I2 = 55.6%. The SMR in ACS was 1.62 (95% CI 0.08–3.16) with I2 =0.0%. The overall proportion of death in CS was 0.05 (95% CI 0.03–0.06) with I2 =51.86%; in CD was 0.04 (95% CI 0.03–0.06) with I2 = 62.7% and in ACS 0.06 (95% CI 0.04–0.11) with I2 = 40.3 %. The proportion of death during the 30-day operative period was highest before 1991 at 0.07 and decreased to 0.03 in 1991–2000 to 0.01 in 2001–2010 and zero after 2011. The causes of death reported across 64 studies were cardiac causes (24.7%), infection (14.4%), cerebrovascular diseases (9.4%), malignancy (9.0%), thromboembolism (4.2%), active disease (2.9%), and adrenal insufficiency (2.7%). Conclusion: CS is associated with increase in overall mortality. Advances in operative techniques and care have decreased peri-operative mortality over a 20 year period. The causes of death highlight the need for aggressive management of cardiovascular risk, prevention of thrombo-embolism, infection control and a normalised cortisol level.
A Case of Acute Pancreatitis as a First Presentation of Primary Hyperparathyroidism
Authors: Elmaaz Ahmed , Akel Alberto Antonio Franco , Belokovskaya Regina
Published: May 2021

Introduction: Alcohol use and biliary stones cause the majority of cases of acute pancreatitis (AP). Hypercalcemia is considered a relatively uncommon sole reason for AP. The incidence of hypercalcemia induced AP is about 1.5%. AP as the first presentation of primary hyperparathyroidism (PHPT), in the absence of any other precipitating factors, is extremely rare. We present a case of AP combined with obstructive uropathy as the first clinical manifestations of occult PHPT. The clinical and biochemical recovery of the patient followed parathyroidectomy suggested the correlation between AP and PHPT. Case Presentation: A 63-year-old patient with a history of type 2 diabetes mellitus, hypertension, and coronary artery disease presented to the emergency room with progressive abdominal pain that started two days prior. The pain radiated to his back and was associated with nausea and vomiting. Additionally, he reported black urine and dysuria. He did not report any alcohol or illicit drug use. His surgical history was significant for cholecystectomy. Physical examination showed elevated blood pressure and severe epigastric tenderness. Laboratory findings were significant for calcium level 14.3 mg/dL (8.5–10.5 mg/dL), serum lipase level 679 U/L (13–60 U/L), serum amylase 327 U/L (28–100 U/L), serum PTH 239 pg/mL (15–65 pg/mL), and leukocytosis 11.9K (4-11K) with neutrophilia of 86.4 %, Hemoglobin 13.3 g/dL, and normal platelet count. Vitamin D 25 (OH) level was 12.5 ng/mL (30–80 ng/mL). Urine analysis had moderate hematuria. Lipid panel showed normal triglycerides and cholesterol concentrations. HbA1c was 6.1 % (4–5.6%). Normal levels of metanephrines were found. CT of the abdomen showed acute pancreatitis with peripancreatic edema and right ureteric stone. Thyroid ultrasound revealed a hypervascular mass posterior to the left thyroid lobe. Sestamibi scan further demonstrated abnormal retention of activity in the neck near the left thyroid lobe consistent with parathyroid adenoma. After hydration and a short course of calcitonin, Cinacalcet was started as a bridge to parathyroidectomy. The patient clinically improved with normalization of Calcium levels. The ureteric stone was removed and elective left parathyroidectomy was performed two weeks later. The histopathological exam confirmed a parathyroid adenoma. Postoperatively, intact PTH level was 26 pg/mL with Calcium level of 10.4 mg/dL. The patient was completely asymptomatic. Conclusion: Although AP is a rare presentation of a silent PHTP, it should warrant the measurement of serum calcium and PTH levels in absence of more common causes of AP, especially if combined with urinary stones. Furthermore, MEN type 2 should be considered in the setting of the thyroid mass with PHPT. Medical therapy could improve the clinical condition of the patient; however, the surgical resection of a parathyroid adenoma remains the curative treatment.
Bilateral Basal Ganglia Calcification; An Unusual Initial Presentation of Pseudohypoparathyroidism
Authors: Zare Ahmad , Choudhry Sara
Published: May 2021

Physiological intracranial calcification occurs in about 0.3–1.5% of cases. Hypoparathyroidism and pseudohypoparathyroidism are the most common causes of pathological basal ganglia calcification.

A 21-year-old female who was initially evaluated by neurology team for headache and diplopia, underwent MRI of brain which revealed Calcifications involving the bilateral basal ganglia, thalami, dentate nuclei as well as juxtacortical frontal lobes. She reported Fatigue and muscle pain, usually in her arms especially after playing sports which had been going on for many years. She had no history of fractures, seizures, psychiatric disorders, developmental delay or obvious cognitive impairments. She denied any family history of calcium disorders or autoimmune diseases. As she had been generally healthy in her whole life, she never had any lab testing done. On examination, Height 5’1”, Chvostek’s sign was positive. Fundoscopy was normal. she had no dysmorphic features or shortened 4th metacarpal. Investigations revealed serum calcium less than 5.0 mg (N 8.3 - 10.1 mg/dl), PTH 205.1 pg/ml (N 18.4 - 80.1 pg/ml), phosphate 7.1 mg (N 2.5 - 5 mg), Vitamin-D 36.2 ng/ml (N 30.0 - 100.0 pg/ml),magnesium 2.0 m (N 1.6 - 2.6 mg/dl) with normal albumin, alkaline phosphatase and renal function test. She was diagnosed with pseudohypoparathyroidism and started on calcium and active vitamin D supplement and was referred for genetic testing study. She reported significant improvement in myalgia after a few weeks of starting calcium and active vitamin D supplementations and repeat lab testing showed improved hypocalcemia and hyperphosphatemia. This case illustrates unusual presentation of PTH resistance with basal ganglia calcification as initial presentation prompting further workup. She likely has pseudohypoparathyroidism type 1b.

Since adequate treatment of hypoparathyroidism may lead to marked clinical improvement, determination of serum calcium, phosphorus, and parathyroid hormone is mandatory in all individuals with calcification of the basal ganglia to rule out hypoparathyroidism.
Diagnostic Dilemma of Elevated FGF23 in a Patient With Osteomalacia: A Case Report
Authors: Bulut Aysegul , Pena Samara
Published: May 2021

Introduction: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome due to FGF23 hypersecretion. It is mostly seen with benign mesenchymal tumors. Establishing the diagnosis could be challenging due to occult nature of the disease.

Case: A 54-year-old female presented with right thigh and upper back pain. On presentation, she had hypophosphatemia (1.8 mq/dl), low 25-hydroxyvitamin D (23 ng/ml), normal ionized calcium and normal iPTH (53 pg/mL). CT scan showed healing right 10th rib fracture and right proximal femoral fracture. DEXA scan was remarkable for osteoporosis. 99m-Technetium nuclear bone scan displayed hyperactivity on bilateral femurs and multiple ribs concerning for stress fractures. Patient was thought to have osteomalacia from vitamin D insufficiency and started on ergocalciferol. Two months later, patient was diagnosed with invasive ductal carcinoma. She had unilateral mastectomy and adjuvant chemotherapy. Surveillance studies were negative for recurrence. Patient lost to follow up for 2 years until she returned with right hip and upper back pain. Her labs showed hypophosphatemia (1.2 mg/dL), normocalcemia, elevated iPTH (131 pg/mL), low 25-hydroxyvitamin D (26 ng/ml), low normal 1,25-dihydroxyvitamin D (25 pg/ml, normal: 18 -72) and elevated FGF23 (285 RU/ml, normal level <180). 24-hour urine studies showed phosphate of 330 mg and fractional phosphate excretion (FEPO4) of 12%. Nuclear bone scan reported subacute fractures in left 11th and right 6th ribs and right proximal femur. TIO was entertained as the unifying diagnosis. She was started on calcium, phosphate, ergocalciferol and calcitriol. Localizing studies with a PET scan showed FDG hyperactivity in the right vocal cord. Subsequent MRI showed asymmetric fat tissue between esophagus and left common carotid artery concerning for lipoma. She lost to follow up again during COVID-19 pandemic.

Discussion: We present a case of elevated FGF23 with renal phosphate wasting concerning for TIO. This case represents the diagnostic dilemma of elevated FGF23 as well as difficulty in discerning the source in TIO. Although exact tumor source remained unclear in our patient, adipose tissue in the thoracic inlet was a potential culprit. Elevated FGF23 leads to urinary phosphate wasting and inhibition of 1α- hydroxylase. Daily urine phosphate excretion > 100 mg or FEPO4 > 5 % strongly suggest renal phosphate wasting. TIO and iron-induced hypophosphatemia are two most common acquired causes of high FGF23. TIO is mostly caused by benign soft tissue and bone tumors. It can take years to establish the diagnosis due to small size and obscure location of the tumors. Advanced investigation with FDG-PET, 68Ga-DOTATATE scan, octreotide scan and venous sampling of FGF23 can aid in diagnosis. Tumor resection is usually curative. Burosumab (anti-FGF23 monoclonal antibody) can be considered when the tumor is not amenable to resect.