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CLINICAL APPLICABILITY OF SERUM STEROID PRECURSORS IN THE DIAGNOSIS OF ADRENAL TUMORS AND CUSHING'S SYNDROME

Ravinder Jeet Kaur, M.B.B.S – Research Fellow, Division of Endocrinology, Mayo Clinic, Rochester MN

Ravinder J Singh, Ph.D. – Professor of Laboratory Medicine and Pathology, Mayo College of Medicine, Mayo Clinic, Rochester,MN

Irina Bancos, MD – Consultant, Division of Endocrinology, Diabetes and Nutrition, Mayo Clinic, Rochester MN

Jolaine Hines, M.S., MT(ASCP) – Development Technologist - Immunochemical Core Laboratory, Mayo Clinic, Rochester, MN

Stefan K Grebe, M.D., Ph.D. – Professor of Laboratory Medicine and Pathology, Mayo College of Medicine, Mayo Clinic, Rochester,MN

Shobana Athimulam, M.B.B.S – Clinical Fellow, Division of Endocrinology, Diabetes and Nutrition, Mayo Clinic, Rochester MN


Objective : Clinical applicability of serum steroid precursors measured by current available assays has not been systematically studied. We aimed to evaluate the diagnostic value and clinical utility of serum steroid precursors in a prospective cohort of patients with adrenal tumors and Cushing syndrome (CS).

Methods :

Patients were prospectively enrolled over 3 years. Inclusion criteria were adults with any type of CS or adrenal mass and available biomaterial. Patients on exogenous steroids were excluded. 11-deoxycortisol (DCORT), 17-Hydroxypregnenolone (17OHPreg), 17-hydroxyprogesterone (17OHProg), Pregnenolone (PREG), and Androstenedione (ANDRO) were measured by LC-MS/MS. Dehydroepiandrostenedione sulfate (DHEAS) and cortisol were measured by automated chemiluminescent competitive immunoassay. For data analysis, steroids were converted into % of upper age- and sex-adjusted normal range.

Results :

A total of 370 patients (230, 62% women), median age of 59(20-95) years were diagnosed with: adrenocortical carcinoma, ACC (n=19),  adrenocortical adenoma (adrenal CS (n-21), mild autonomous cortisol secretion, MACS (n=63), non-functioning adrenal tumors, NFAT(n=128), aldosteronoma (n=34)), pheochromocytoma (n=26), other adrenal malignancies (n=17), other benign adrenal masses (n=22), pituitary CS (n=33), and ectopic CS (n=7). 
Patients with ACC demonstrated between 2.5 and 12 times higher 17OHPreg, 17OHProg, DHEAS, PREG, ANDRO and DCORT concentrations (p<0.0001 for all), when compared to patients with other adrenal tumors. A multivariable model of 17OHPreg, 17OHProg and DCORT accurately predicted ACC (ROC AUC of 0.99, p<0.0001). In patients with CS, MACS and NFAT, 17OHPreg (p=0.03) and DHEAS (p=0.0003) were lowest and DCORT (p<0.0001) was highest in patients with CS when compared with patients with MACS and NFAT. In patients with MACS vs NFAT only, 17OHPreg was a significant predictor of MACS in a multivariable model of age, sex, DHEAS, DCORT and 17OHPreg (P=0.04).Patients with ACTH-independent CS demonstrated lower 17OHPreg and DHEAS (p<0.0001 for both) but no differences in DCORT or 17OHProg when compared to patients with ACTH-dependent CS. In patients with ACTH-dependent CS, patient with ectopic CS had higher DCORT (p=0.005) and 17OHProg (p=0.04), with DCORT being significant predictor of ectopic CS even after correcting for cortisol concentrations (p=0.02).

 

Discussion : Patients with ACC, adrenal adenomas, and different subtypes of CS present with distinctive serum steroid profiles.

Conclusion :

Serum steroid precursors can serve to supplement diagnostic work up of adrenal tumors and CS, especially after validation in larger cohorts of patients.



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ECTOPIC CUSHING'S SYDNROME

Farah Morgan, M.D. – Program Director Endocrinology Fellowship, Associate Professor, Cooper University Hospital

Ashish Shah, MD – Endocrinology Fellow, Cooper University Hospital


Objective : We report a unique case of paraneoplastic Cushing’s syndrome in the setting of poorly differentiated neuroendocrine carcinoma.

Methods : n/a

Results :

A 24yr old female presented to the hospital April 2018 with palpitations, weight loss, and abdominal pain. She was found to have Grave’s disease along with a right adnexal mass, multiple liver/lung lesions, retroperitoneal lymphadenopathy, a right parietal brain lesion, and a right 2cm thyroid nodule. Biopsy of the retroperitoneal lymph node revealed metastatic poorly differentiated carcinoma with neuroendocrine differentiation. FNA of the thyroid nodule confirmed metastasis.

In May 2018, she had the 1st cycle of carboplatin/etoposide and in June 2018 had her 2nd cycle. She was started on high dose Decadron (4mg BID) during her 1st cycle of chemotherapy due to vasogenic edema from her brain metastasis. 2 weeks after her 2nd cycle of chemotherapy, she presented to the hospital with recurrent seizures along with multiple metabolic abnormalities including new onset severe hypokalemia 1.7 mmol/L (3.5-5.0 mmol/L) and severe metabolic alkalosis with a bicarbonate level of 42 mmol/L (22-28 mmol/L) and pH of 7.72 (7.35-7.45). She was persistently hypertensive as well as hyperglycemic requiring insulin therapy. During her hospital stay she required aggressive potassium repletion with potassium chloride 40 mEq TID.. Given the neuroendocrine nature of her poorly differentiated carcinoma, ectopic Cushing’s syndrome was thought to be a cause of her metabolic abnormalities. She was placed on spironolactone 50mg TID with improvement in her potassium. Labs were consistent with Cushing’s syndrome with a 24hr urine free cortisol of  3,132.1 ug/24hr (4-50 ug/24hr) ,midnight cortisol of 51.3 ug/dL (5-23 ug/dL) and 9AM cortisol of 51.1 ug/dL (5-23 ug/dL). An ACTH was 132 pg/mL (6-50 pg/mL). These cortisol values were elevated despite being on high doses of Decadron. After confirmatory testing, she was started on metyrapone 250mg q6hr to control hypercortisolism. She remained on metyrapone for a few days with normalization of potassium and bicarbonate levels. She was discharged from the hospital only on spironolactone (due to inability to get insurance approval for metyrapone) and resumed chemotherapy. After 5 cycles of chemotherapy and decreased size in her metastatic lesions, her potassium and bicarbonate levels remain normal and she is normotensive and euglycemic.

Discussion : n/a

Conclusion : This is a rare case of ectopic Cushing’s syndrome with clinical improvement after treatment of the underlying malignancy. This case shows the importance of evaluating for ectopic Cushing’s syndrome in the setting of unexplained hypokalemia.



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FALSE POSITIVE URINARY METANEPHRINES - A CASE SERIES

Michael Morocco, MD – Attending Physician, Cleveland clinic Akron General

Monisha Priyadarshini Kumar

Monisha Priyadarshini Kumar, MD – Resident Physician, PGY2, Cleveland Clinic Akron General

Nairmeen Haller, PHD – Director of Research, Cleveland Clinic Akron General

Monisha Priyadarshini Kumar, MD – Resident Physician, PGY2, Cleveland Clinic Akron General


Objective :

Despite the rareness of pheochromocytoma, availability of definitive treatment makes early diagnosis crucial to avoid life-threatening hypertension. It is essential for the clinicians to be familiar with the interpretation of 24-hour(hr) urine fractionated metanephrine screening test results to avoid unnecessary workup.

Methods : This is a retrospective, descriptive report of case series of two patient who had false positive urinary metanephrine during the endocrinology office visit.

Results :

Case 1: A 64-year-old female with the history of hypothyroidism and fibromyalgia presented with complaints of diaphoresis and palpitations. Her physical exam was unremarkable. Initial workup for hyperhidrosis resulted in normal thyroid function test (TFT), tryptase and 5-hydroxy indoleacetic acid (5-HIAA) level. Her 24-hr urine test showed metanephrines 69ug/24-hr (52-341), normetanephrine 760ug/24-hr (88-444) and total metanephrines 829ug/24-hr (140-785). On further questioning, she reported taking duloxetine for fibromyalgia. Considering the potential interference between antidepressant use and 24-hr urinary metanephrine testing, the test was repeated two weeks after discontinuation of the duloxetine with a normal result. Her repeat TFT showed suppressed TSH and symptoms resolved with subsequent levothyroxine dose reduction.


Case 2: A 73-year-old female presented with complaints of generalized hyperhidrosis, palpitations, and frequent loose stools. Initial workup resulted in normal TFT, and thyroid ultrasound. Endocrinopathy workup showed normal tryptase, 5-HIAA level, but elevated 24-hr fractionated urinary metanephrine 135ug/24-hr (52-341), normetanephrine 863ug/24-hr (88-444) and total metanephrine 998ug/24-hr (140-785). On review, the patient reported quetiapine use for insomnia. Repeat 24-hr urine fractionated metanephrine testing two weeks after discontinuation of the atypical antipsychotic (AAP) resulted normal. Thus, the abnormally elevated urine metanephrine was determined to be due to drug interference.

Discussion : Clinical practice guidelines recommend discontinuation of interfering medications, such as tricyclic antidepressant, levodopa, and adrenergic drugs, prior to 24-hr urinary fractionated metanephrine testing. AAP and serotonin-norepinephrine reuptake inhibitors are widely used but overlooked medication that leads to misleading test results and subsequent unnecessary imaging. Both cases discussed here had a false positive test as a result of medication interference.

Conclusion : The 24-hr urinary metanephrine test is widely used for pheochromocytoma screening and this report underscores the importance of reviewing home medications prior to testing in order to avoid unnecessary workup.



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Elevated Catecholamines: Drugs versus Pheochromocytoma

Rashmi G. Dhakal, MD – Fellow, University at Buffalo, SUNY

Adel Hanna, MD – Fellow, University of Buffalo

Antoine Makdissi, MD – Associate Professor, University at Buffalo

Manav Batra, MD – Assistant Professor, University at Buffalo,SUNY


Objective : Medications like tricyclic antidepressants and other psychoactive medications can cause elevation in serum catecholamine levels which poses challenge in diagnosing neuroendocrine disorders such as pheochromocytoma. We report a case of pheochromocytoma in a patient who was taking multiple psychoactive medications which can increase catecholamines, metanephrine and normetanephrine levels. 

Methods : N/A

Results :

45 year old female with history of hypertension, depression and schizophrenia was found to have 5 cm vascular heterogeneous right adrenal mass on CT scan during work up for abdominal pain. She had off and on abdominal pain associated with nausea but no vomiting, headache, flushing, blurring of vision, pheo spells, easy bruising, weight gain or striae. 

Laboratory testing showed normal renal and hepatic function panel but elevated plasma metanephrine 125 pg/ml (0-62), plasma normetanephrine 1898 pg/ml (0-145),24 hr urine metanephrine 350 ug/24 hr (45-290) and 24 hr urine normetanephrine 3244 ug/24 hr (82-500). Plasma Aldosterone, renin, dehydroepiandrosterone sulphate, testosterone and 24 hour urine free cortisol levels were normal. She was on multiple psychoactive agents (mirtazapine, buspirone and doxepin) that can block the re-uptake of normetanephrines leading to elevated levels. However, she was unwilling to hold those medications due to concern for mental illness. She was started on Doxazosin and labetalol for suspected pheochromocytoma and uncontrolled hypertension. Repeat lab showed elevated plasma metanephrine 105, plasma normetanephrine 1328 pg/ml, 24 hr urine normetanephrine 2480 ug/24 hr but normal 24 hr urine metanephrine 273 ug/24 hr. She was prepared for surgery with Doxazosin and labetalol.

Patient underwent uncomplicated laparoscopic right adrenalectomy which revealed 5.5 x 3.8 x 2.5 cm mass adherent to inferior venacava. The tumor was positive for synaptophysin and chromogranin. S100 was positive in sustentacular cells. Ki-67 proliferation index was 1-2%. There was no invasion of periadrenal soft tissue, vascular invasion, necrosis or increased mitotic activity. She continues to do well. 

Discussion : N/A

Conclusion : Our case illustrates the dilemma of diagnosing pheochromocytoma in patient taking multiple psychiatric medications which can potentially elevate serum catecholamine levels. Our patient underwent resection of the mass which turned out to be pheochromocytoma. It is therefore very important to be vigilant about the clinical symptoms and have high suspicion for pheochromocytoma in such conditions.



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Melanoma Which Cannot Be Forgotten: Metastasis in Adrenal

Omolola Olajide, MD – Program Director, Marshall University Joan C.Edward School of Medicine

Le Yu Khine, MD – Endocrinology Fellow, Marshall University Joan C.Edward School of Medicine


Objective :

Adrenal metastases are found in  about 50% of cases of malignant melanoma and are often clinically and biochemically silent. We present a case of adrenal metastasis recurring 12 years after the primary diagnosis. 

Methods :

Case Presentation

 

Results : A 69 year old lady with history of hypertension and type 2 diabetes mellitus presented with right flank pain radiating to the back for two months. She had also lost 30 lbs in this same time frame. She was diagnosed with melanoma on her right arm 12 years prior which was subsequently  removed surgically but she refused chemotherapy. She denied episodes of headache, dizziness or palpitations. No reported history of Hypokalemia . CT and MRI abdomen showed complex cystic and solid right suprarenal mass ( 16.1 cm x 13 cm ) with a differential diagnosis of a hematoma vs an adrenal cortical carcinoma. Hormonal work up was negative for Cushing’s syndrome, pheochromocytoma and hyperaldosteronism. DHEA-sulfate level was normal. She subsequently had an open adrenalectomy and the pathology showed malignant melanoma. Post-operatively, her early am cortisol and electrolytes were normal

Discussion :

Melanoma is known to metastasize to the adrenal glands because of their rich supply of sinusoidal blood supply. They can present years after treatment of the primary lesion. An adrenal mass greater than 5 cm in diameter, with central or irregular areas of necrosis/hemorrhage is characteristic of a metastasis from malignant melanoma. Pre-operative evaluation of DHEA-S, primary aldosteronism, Cushing’s syndrome  and pheochromocytoma needs to be performed. Detailed imaging ( CT, MRI and PET ) should be obtained. Biopsy of potentially resectable lesions is contraindicated, because of the resulting tumor spill. Open adrenalectomy is the preferred approach for known or suspected adrenocortical carcinoma. Ipilimumab, a checkpoint inhibitor was the first agent to demonstrate improved objective survival in patients with metastatic melanoma. Pembrolizumab and nivolumab have also been approved for treating patients with ipilimumab-refractory cases.

 

Conclusion :

Adrenal metastases are not uncommon with malignant melanoma and can still occur many years after the diagnosis.   Our case highlights the importance of long term follow up in these cases.

 



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A CASE OF ADRENAL CORTICAL CARCINOMA PRESENTING AS LIVER DYSFUNCTION AND UNCONTROLLED DIABETES

Yumiko Tsushima, MD – Resident, Icahn School fo Medicine at Mount Sinai Beth Israel

Maria Brito – Assistant Professor, Icahn School fo Medicine at Mount Sinai Beth Israel

Esra Kalkan, Fellow – Fellow, Icahn School fo Medicine at Mount Sinai Beth Israel

Mariana Rivera – Resident, Icahn School fo Medicine at Mount Sinai Beth Israel


Objective :

To recognize the importance of evaluating causes of secondary diabetes mellitus in uncontrolled diabetics through detailed history and physical exam.

Methods : n/a

Results :

n/a

Discussion :

A 57 year-old woman with PMH of uncontrolled type 2 diabetes mellitus (DM2) was initially admitted to the hospital for altered mental status secondary to UTI. Elevated liver enzymes at presentation prompted a RUQ US which revealed an 8cm mass concerning for an adrenal etiology for which Endocrinology was consulted. At initial encounter, the patient reported generalized fatigue and weakness but denied any changes in weight or distribution of fat, striae, easy bruising, hirsutism, headache, palpitations, and flushing. Menopause was 1 year ago. DM2 was diagnosed at least 9 years prior and treated with two oral agents and insulin aspart 70-30 mix 20 units BID with HbA1c of 12.3%. Vitals were normal and physical exam was significant for mild hirsutism, buffalo hump, and 2+ edema in the bilateral lower extremities. Labs showed T. Bil 0.6 mg/dL (N: 0.1-1.2 mg/dL), ALP 330 U/L (N: 38-126 U/L), AST 37 U/L (N:<36 U/L), ALT 133 U/L (N: <46 U/L). Midnight salivary cortisol was 0.43 µg/dL and 0.73 µg /dL (N:<0.01-0.09 µg/dL) and post-1mg dexamethasone cortisol was 17.0 µg/dL. ACTH, DHEAS, normetanephrines, metanephrines, renin, and aldosterone were all normal. CT revealed a large adrenal mass invaginating into the liver. No metastatic lesions were found. The patient underwent R adrenalectomy. The tumor was 13cm and 380g and pathology confirmed adrenal cortical carcinoma (ACC). Liver enzymes normalized after surgery and she was discharged on glargine 3 units and premeal lispro 3 units for the DM2.

ACC is a rare disease affecting 1-2 people per million per year. Sixty percent are hormone-producing and most present with Cushing’s syndrome. Our case is unique in that hypercortisolism manifested most prominently as uncontrolled DM2 (as evidenced by the rapid decline in insulin requirement post-surgery) and had only mild physical findings suggestive of Cushing’s syndrome. While not all patients with poor glycemic control warrant biochemical screening tests for Cushing’s syndrome, a detailed history and physical exam can help determine the next step.

Conclusion :

Even hormone-secreting ACCs can be asymptomatic. Although uncontrolled DM2 can be due to multiple factors, taking the extra time to conduct a thorough history and physical exam on patients with sudden or progressively worsening glycemic control for symptoms and signs of Cushing’s syndrome is extremely beneficial.



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AN OCCULT SOURCE OF ANDROGENS: UNDIAGNOSED CONGENITAL ADRENAL HYPERPLASIA CAUSING INADEQUATE RESPONSE TO ANDROGEN DEPRIVATION THERAPY IN PROSTATE CANCER

Hanford Yau, MD, FACP, FACE – Endocrinologist, The University of California, San Francisco, Fresno, CA

Mustafa Kinaan, MD – Endocrinology Fellow, University of Central Florida College of Medicine/HCA GME Consortium

Kenneth Simon, DO – Oncologist, Division of Hematology and Oncology, Orlando VA Medical Center.

Akin Eraslan, MD – Endocrinologist, Division of Endocrinology, Orlando VA Medical Center.


Objective : This case highlights the importance of testosterone level monitoring in prostate cancer patients after medical or surgical castration.

Methods : This is a case report. Please see details under discussion section.

Results :

This is a case report. Please see details under discussion section.

Discussion :

We present the case of a 73-year-old Caucasian male with history of adenocarcinoma of the prostate (pT2CN0M0 with Gleason score of 9) undergoing androgen deprivation therapy. The patient underwent radical prostatectomy upon initial diagnosis and was later started on androgen deprivation therapy following local recurrence of tumor with involvement of pelvic lymph nodes. Despite treatment with leuprolide, he continued to have total testosterone levels as high as 294.4 ng/dL as well as elevated prostate specific antigen (PSA).  During routine surveillance CT scan for cancer restaging, patient was found to have incidental bilateral adrenal nodular hyperplasia. He was referred to our endocrinology clinic for further evaluation of adrenal nodular hyperplasia and failure to suppress his testosterone levels. Given concerns about overproduction of adrenal androgens, the levels of androstenedione and dehydroepiandrosterone were obtained and both were elevated. Consequently, an adrenocorticotropic hormone (ACTH) stimulation test was performed demonstrating significant elevation in 17-hydroxyprogesterone at baseline (19,910 ng/dL) with increase to (>20,000 ng/dL) at 30 and 60 minutes. Cortisol level, however, remained unchanged at ~5 mcg/dL throughout the stimulation test.  Based on these results, genetic testing for congenital adrenal hyperplasia was pursued revealing a common and rare mutation of the CYP21A2 gene. The first mutation was located in intron 2 and is usually associated with simple virilizing or salt wasting phenotypes of classic congenital adrenal hyperplasia. The second common mutation detected was in the I172N sequence and is associated with the simple virilizing phenotype. The patient had no salt-wasting features and was clinically diagnosed with simple virilizing, classic congenital adrenal hyperplasia. The patient was started on dexamethasone and had marked decrease in his adrenal androgens, testosterone, and PSA levels. 21-hydroxylase deficiency comprises nearly 95% of all congenital adrenal hyperplasia cases with an incidence of 1 in 10,000 in Western countries. Males with the simple virilizing subtype are at risk of not being diagnosed because they are phenotypically normal at birth. 

Conclusion : Inadequate responses to androgen deprivation therapy should trigger further evaluation for congenital adrenal hyperplasia, a condition that is often overlooked.



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MULTIFOCAL PARAGANGLIOMA WITH A NOVEL GERMLINE MUTATION IN FUMARATE HYDRATASE GENE

Anery Patel, MD – Endocrine Physician, UNMC

Preethi Polavarapu, MD – Fellow, University of Nebraska Medical center


Objective :

Paragangliomas ( PGL) are the neuroendocrine tumors of the sympathetic and parasympathetic ganglia. The common mutations for PGL are SDHA, SDHB, SDHD, NF1. We report a case of multifocal paraganglioma with a novel germline mutation in Fumarate Hydratase( FH) gene.

Methods :

64 y/o male initially admitted to the hospital for rectal bleeding and NSTEMI. He was found to have multi-vessel disease on cardiac cath. He was unable to undergo colonoscopy for GI bleeding due to ongoing cardiac issues. A PET scan obtained showed hypermetabolic enlarged retroperitoneal lymph nodes concerning for malignancy.  He underwent an EUS and EGD to biopsy the abdominal lymph node, which showed paraganglioma and stained positive for chromogranin and synaptophysin. The patient did not have any symptoms of palpitation, uncontrolled hypertension. Labs revealed elevated normetanephrine at 2.15nmol/l, metanephrine at 0.39 nmol/l, 24-hour urinary normetanephrine at 87ug/ d. DOTATATE scan showed radiotracer soft tissue mass at left periaortic nodal region consistent with paraganglioma and radiotracer avid lymph nodes in the abdomen.

Results :

He was started on alpha blockade with phenoxybenzamine before surgery and was added on beta blocker later. He underwent retroperitoneal mass resection with lymph node dissection. Pathology was consistent with benign multifocal paraganglioma with largest tumor dimension of 3.8 cm. Post resection, plasma normetanephrine levels normalized at 0.83 nmol/l. Genetic testing revealed that the patient has a mutation variant of unknown significance (VUS) in the FH gene while other genetic testing revealed no mutation.

Discussion :

30 % of the PGL is hereditary; hence all the patients should be tested for genetic mutations, especially in patients with multifocal, malignant and recurrent tumor. Diagnosis is usually established by genetic testing which tests for 20 hereditary cancer. In our patient, we have found germline mutation variant in FH gene whose significance is not known.  Based on the study by Castro-Vega et al., mutations in the FH gene accounted for 0.83 % of the cases with PGL or pheochromocytoma. Studies have found that the FH gene inactivation causes epigenetic dysregulation similar to SDHB gene deficiency.  Since succinate and fumarate are generated by sequential enzymatic reaction in the same metabolic signaling pathway, SDH and FH deficient genes likely will have the same oncogenic mechanism. These results suggest that germline mutation in FH gene can cause multifocal, malignant PGL/PCC.

Conclusion :

Mutations in the FH gene can predispose to malignant, multifocal PGL in addition to renal cell cancer and leiomyomatosis, hence close follow up is required in these patients.



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A CASE OF PERSISTENT HYPOKALEMIA IN A NORMOTENSIVE PATIENT WITH PRIMARY ALDOSTERONISM

James K. Burks, Professor of Medicine – Endocrinology Fellowship Program Director, Texas Tech Health Science Center of the Permian Basin

Amanda N. Cantu, MD – Endocrinology Fellow, PGY-4, Texas Tech University Health Sciences Center at the Permian Basin


Objective :

Primary aldosteronism (PA) is characterized by hypertension, hypokalemia, suppressed renin activity and increased aldosterone and was first described by J. W. Conn in 1955. The common form of PA includes arterial hypertension and hypokalemia.  Brooks et al., in 1972 challenged the view that PA exists only in patients with resistant hypertension and can exist in normotensive patients.  Thirty cases of normotensive PA have been reported, of which most patients were middle-aged and predominantly women (81%). We report a case of a young patient with no history of hypertension with persistent hypokalemia found to have PA.

Methods : n/a

Results : n/a

Discussion :

The patient is a is a 27-year-old female with no past medical history who was evaluated in endocrinology clinic for a hospital follow up due to persistent hypokalemia.  She presented to the emergency department with complaints of paresthesias, bilateral lower extremity weakness, cramps, and difficulty ambulating.  She was not taking any medication or herbal supplements and was found to have a potassium level of 2.1 mmol/L (3.4-4.9) prompting hospital admission. The patient did not present with nausea, vomiting, or diarrhea, and creatinine level was 0.7mg/dL.

The patient’s blood pressure (BP) upon arrival to the emergency department was 146/71mmHg, yet during the next two days of hospitalization her BP remained between 109-134mmHg systolic. Although the aldosterone/renin ratio (ARR) was elevated during the initial hospitalization, multiple doses of oral and IV potassium supplementation were given.  In theory this could lead to increased aldosterone secretion.  The patient was discharged on potassium supplementation.

Repeat labs in the outpatient setting showed K level: 3.3 mmol/L, plasma aldosterone concentration (PAC): 25.7 ng/dl (n1ng/ml), and ARR: of 51.4 (n < 25). Urine studies showed 24Hr U K: 101.8, mmol/day, 24 U Aldosterone: 40.8mcg/day (1.2-28.1), and 24Hr U Na: 249 mmol/day. PA was confirmed, and an aldosterone-antagonist was added to her therapy. Adrenal CT was ordered which showed a right adrenal adenoma and adrenal venous sampling (AVS) is now planned to confirm lateralization.

Conclusion :

Excess or inappropriate aldosterone activity has been associated with cardiac fibrosis, inflammation and remodeling, insulin resistance, kidney injury, and increased mortality.  Current guidelines recommend screening patients with sustained BP above 150/100 mm Hg as well as in patients with hypertension and spontaneous or diuretic-induced hypokalemia.  Persistent hypokalemia should prompt evaluation for PA in patients with no apparent etiology regardless of the presence of hypertension.



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A THIRST FOR ANSWERS: WHEN HYPOKALEMIA PRESENTS AS NEPHROGENIC DIABETES INSIPIDUS

Rani Bhatia, MD – Internal Medicine Resident, Baylor College of Medicine, Houston, TX

Mercy Misoi, MD – Internal Medicine Resident, Baylor College of Medicine, Houston, TX

Mikel Etchegaray, MD – Internal Medicine Resident, Baylor College of Medicine, Houston, TX

Mohita Singh, MD – Internal Medicine Chief Resident, Baylor College of Medicine, Houston, TX

Madhuri Vasudevan, MD, MPH AACE member – Endocrinologist, Baylor College of Medicine, Houston, TX


Objective : Adrenocortical carcinoma is a rare tumor that may be functional, causing adrenal-related hormonal syndromes such as Cushing’s, Conn’s, and androgen abnormalities. Severe symptomatic hypokalemia demonstrated by generalized weakness, rhabdomyolysis, and diabetes insipidus may be seen.

Methods : n/a

Results : n/a

Discussion : A 60-year-old woman with established adrenocortical carcinoma of the right adrenal gland, previously treated with mitotane and cisplatin, presented with three weeks of nausea, vomiting, increasing thirst, polyuria, polydipsia, and progressive weakness. Physical exam was remarkable for hypertension 172/84, cachexia, dry mucous membranes, and diffuse 3/5 extremity strength. There were no Cushingoid features. EKG showed low amplitude T waves. Labs were remarkable for potassium <2 mEq/L, magnesium 1.1 mg/dL, calcium 7.2 mg/dL, phosphorus 1.7 mg/dL, bicarbonate 41 mEq/L, creatinine kinase 13,000 U/L, aldosterone 2600 ng/dL, plasma renin activity <0.6 ng/ml/hr, early morning cortisol 50.4 mcg/dL, DHEAS 429 mcg/dL, sodium 151 mEq/L, serum osmolality 303 mOsm/kg, and urine osmolality 178 mOsm/kg H2O. Computed Tomography revealed interval enlargement of right adrenal mass (13 x 9.6 cm) with liver and inferior vena cava invasion. Aggressive electrolyte repletion improved her strength and diabetes insipidus resolved.  She initiated high dose spironolactone and angiotensin receptor blocker therapy. Severe hypokalemia and hypomagnesemia precluded ongoing cisplatin therapy, and she started neoadjuvant carboplatin and etoposide followed by transcatheter right hepatic arterial embolization, terminating the vascular supply to the tumor.

Conclusion : This case demonstrates the importance of considering a broad differential diagnosis with a unifying etiology when approaching a patient with acute onset of severe electrolyte derangements. In this patient, adrenocortical carcinoma production of aldosterone and cortisol, exacerbated by recent cisplatin therapy, led to severe hypokalemia, generalized weakness, cardiac instability and nephrogenic diabetes insipidus, due to decreased expression of aquaporin channels in the collecting duct. Aggressive electrolyte repletion can reverse nephrogenic diabetes insipidus and dramatically improve debilitating complications of profound hypokalemia. The numerous clinical manifestations of hypokalemia, including rare but known presentation of diabetes insipidus, should be considered and aggressively managed in any patient presenting with severe hypokalemia.



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PREVALENCE OF HYPERCORTISOLISM IN PATIENTS WITH TYPE 2 DIABETES MELLITUS WITH INCIDENTALLY FOUND ADRENAL ADENOMAS: AN INTERIM ANALYSIS

Paria Zarghamravanbakhsh, MD – Resident Internal Medicine, NYC Health + Hospitals/Queens

Rupak Mahendhar – Research Assistant, NYC Health + Hospitals

Isaac Sachmechi, MD, FACP,FACE – Chief of the Division of Endocrinology, NYC Health + Hospitals/Queens

Mina fransawy Alkomos, MD – Research Assistant, NYC Health + Hospitals

Isaac Sachmechi, MD, FACP,FACE – Chief of the Division of Endocrinology, NYC Health + Hospitals/Queens

Kiruthi Palaniswamy, PharmD – Medical Affairs, Corcept Therapeutics


Objective : Adrenal adenomas frequently are discovered incidentally during imaging, with 5% to 30% secreting cortisol. Presented are the interim results of an investigator-initiated study on the prevalence of hypercortisolism in patients with type 2 diabetes mellitus (T2DM) with incidentally discovered adrenal adenomas at the NYC Health + Hospitals Queens Diabetes Center of Excellence. 

Methods : Electronic medical records (EMR) were analyzed for patients 18 years or older with T2DM and adrenal adenomas incidentally found from October 2014 to October 2017. The study had 2 cohorts: (1) patients with existing biochemical results (of a 1-mg DST and ACTH assay) and (2) patients requiring biochemical workup. All patients were to have a repeat CT scan to assess any change in nodule size. Target study enrollment was 30 patients.

Results :

Twenty-two patients with T2DM and adrenal adenomas were identified through EMR database. Eight of 22 patients had complete evaluations (CT scans and biochemical evaluations). The adrenal nodules in these 8 patients ranged in size from 1 cm to 2.4 cm and remained stable over time, and HbA1c was greater than 7%. Of these 8 patients, 4 had an abnormal 1-mg DST value >1.8 µg/dL. Average ACTH in these 4 patients was 20.27 pg/mL.

Fourteen of 22 patients require either biochemical evaluation or repeat imaging. Three of the 14 patients with incidentally discovered adrenal nodules who have not yet undergone repeat imaging had a positive 1-mg DST, with an average ACTH of 15 pg/mL. Adrenal nodules in this cohort were < 1.2 cm. One subject withdrew consent.

Discussion : n/a

Conclusion : In our interim analysis, 7 of 22 patients (32%) with T2DM and incidental adrenal adenomas had hypercortisolism using the diagnostic criteria of 1-mg DST >1.8 µg/dL. Full data analysis of the remaining 11 patients is required to determine hypercortisolism prevalence at our clinic, but our interim data suggests a high prevalence of hypercortisolism in patients with T2DM with incidentally discovered adrenal adenomas.



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SIMULTANEOUS OCCURRENCE OF SUCCINYL DEHYDROGENASE B MUTATION AND TUMOR PROTEIN P53 MUTATION IN A PATIENT WITH METASTATIC PHEOCHROMOCYTOMA

Ewa Gniado, MD – Endocrinology Fellow, University of Cincinnati Medical Center

Colin Carracher, M.D. – Assistant Professor, Division of Endocrinology Department of Internal Medicine UC College of Medicine

Sona Sharma, M.D. – Associate Professor of Clinical Medicine, Division of Endocrinology, Diabetes and Metabolism University of Cincinnati College of Medicine


Objective : Pheochromocytomas are catecholamine-secreting neuroendocrine tumors that arise from chromaffin cells of the adrenal medulla. Approximately 10 percent of the pheochromocytomas are malignant as defined by the presence of distant metastases. SDHB mutations are known to cause the development of pheochromocytomas and paragangliomas, which are more likely to be malignant than in other gene mutations. Germline mutations in TP53 occur in Li–Fraumeni syndrome, which is associated with an increased risk of developing various cancers, including adrenocortical carcinomas, at an early age. We describe a case of a metastatic malignant pheochromocytoma who was found to have both SDHB and TP53 mutations occurring together.

Methods : N/A

Results : N/A

Discussion : A 39-year-old male with a 3-year history of hypertension presented to the hospital with neck pain and a non-healing fracture of the cervical spine. MRI of the neck revealed a C3 vertebral body collapse and an underlying C3 lesion. Computed tomography (CT) of the thorax, abdomen, and pelvis showed multiple lesions in the axial and appendicular skeleton, a sternal body mass, bilateral pulmonary nodules, bilateral adrenal masses, and an aortocaval lymph node conglomerate. Serum epinephrine was 200 pg/ml (N 10-200), norepinephrine 28,241 pg/ml (N 80-520), and dopamine 250 pg/ml (N 0-20). He underwent biopsy of the protruding sternal mass which revealed metastatic pheochromocytoma. Genetic testing revealed both SDHB and TP53 mutations. He was started on alpha-, beta- and calcium channel blockers to control hypertension and tachycardia. Two months after the diagnosis, CT of the abdomen and pelvis showed progression of disease, with enlargement of the right adrenal mass as well as the aortocaval LN conglomerate, with mass effect on several surrounding structures. His plasma metanephrines were significantly elevated. He was started on systemic chemotherapy with Cyclophosphamide, Dacarbazine, and Vincristine. He required several antihypertensive medications, including metyrosine, to control his blood pressure and more specifically to prepare for chemotherapy.

Conclusion :

SDHB mutations are known to lead to the development of pheochromocytomas, however, to date, there are scarce and inconsistent data connecting TP53 gene mutation in the pathogenesis of such tumors. To our knowledge, this is the first reported case of these two gene mutations occurring together in the same individual. Our case demonstrates a highly aggressive clinical course of pheochromocytoma and raises the possibility that the simultaneous occurrence of these two mutations modified their clinical expression and the behavior of his tumor.



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OUTCOMES IN PATIENTS WITH ADRENAL INSUFFICIENCY DIAGNOSED BY SYNACTHEN TEST

Yi-Chun Lin, Medicine, Endocrinology and Metabolism – Attending physician, Taipei Veterans General Hospital

Ting-Yu Chen


Objective : We initiated a research retrospectively on those who had accurate diagnosis of adrenal insufficiency (AI) according to their cortisol levels after synacthen test. We aimed to elucidate the risk on hospitalization and mortality in subjects with AI.

Methods :

AI will be confirmed if the plasma cortisol level is less than 18.5 ug/dL during 60 minutes after synacthen intravenous stimulation tests performed between January 1st, 2011 and December 31th, 2015 in a single tertiary medical center . We retrospectively analyzed the prognostic factors regarding primary outcome of hospitalization rate and secondary outcome of mortality.

Results : A total of 202 subjects received synacthen test consecutively from January 1st, 2011 to December 31th, 2015. The mean follow up was 34.5 months. Among them, 50.5% (102/202) were diagnosed as adrenal insufficiency, 49.5% have normal cortisol response during synacthen test (control group). The two groups had similar baseline characteristics, except the AI group had older age (62.8±17.0 vs 52.0±20.5 years, p<0.01), and higher prevalence of diabetes mellitus (DM) (22.5% vs 11%, p=0.03) than the control group. The Kaplan-Meier survival curve for disease-free events showed that AI group had a significant higher hospitalization rate. In unadjusted model, primary outcome of hospitalization rate is significant higher in the AI group than the control group (48% vs 31%, p=0.013), death occurred in 9 out of 102 (8.8%) patients in the AI group and 3 out of 100 (3%) in the control group with borderline significance (p=0.08). In the cox regression model, after adjusting DM comorbidities, AI had a significant independent HR of 1.63 (95% confidence interval: 1.03-2.57, p=0.037) for hospitalization than the control group.

Discussion :

This study showed that AI diagnosed by synacthen test had higher hospitalization rate than the normal cortisol response group. By the report of the NHANS data in USA, it also showed that patients with AI had higher admission rate along with increased mortality up to 2 times than non-AI population. However, most of the study designs were based on International Classification of Disease diagnosis codes rather than the plasma cortisol level of patients after synacthen injection.

Conclusion : Synacthen tests identified subjects with diagnosis of AI who had higher hospitalization rate than the normal cortisol response individuals.



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ADRENAL GANGLIONEUROMA: A RARE INCIDENTALLY-FOUND LESION

Ahmed S. Ahmed – Internal Medicine Resident PGYII, EVMS

David C. Lieb, MD, FACE, FACP – Associate Professor, Eastern Virginia Medical School

Marybeth Hughes – Chief of Surgical Oncology, EVMS

Mc Anto Antony, M.D – Fellow, Eastern Virginia Medical School


Objective : To present a rare tumor that should be included in the differential for a large incidentally-found adrenal mass.

Methods : Review of patient records and pertinent literature on Pubmed

Results : A 40-year-old male was referred for evaluation of an incidental left adrenal mass. The patient had undergone MRI to further evaluate a hepatic lesion that was determined to be a hemangioma. MRI demonstrated a 4 cm left adrenal mass of ‘indeterminate nature’. CT imaging showed a 4.8 cm left adrenal mass of intermediate attenuation, with delayed phase imaging inconsistent with a lipid-rich adenoma. The right adrenal gland was normal. Patient reported chronic abdominal pain of unclear etiology, with intermittent episodes of diaphoresis and diarrhea over years. His weight was stable. He was not hypertensive. Plasma metanephrines were normal (55 pg/mL, nl 0-62) and normetanephrines were elevated (201 pg/mL, nl 0-145). 24-hour urine fractionated catecholamines and metanephrines were within normal limits. His cortisol appropriately suppressed to < 1 mcg/dL after dexamethasone given the prior evening. Total testosterone was normal at 412 ng/dL (nl 264-916). Given the lesion’s size and atypical appearance, surgical excision was recommended. He underwent a laparoscopic left adrenalectomy, with final pathology demonstrating a 7 cm ganglioneuroma involving the left adrenal gland.

Discussion :

The differential for a large incidentally-discovered unilateral solid adrenal mass includes adrenal carcinoma, benign adenoma, pheochromocytoma, myelolipoma and ganglioneuroma (GN). GNs are benign, often asymptomatic tumors that originate from the neural crest. They may arise anywhere along the sympathetic chain. GNs are grouped among the peripheral neuroblastic tumors which also include malignant neuroblastoma. GNs are commonly located in the retroperitoneal space, posterior mediastinum, and occasionally the adrenal medulla. Adrenal GNs occur most frequently in the fourth and fifth decades of life, whereas other GNs tend to occur in a younger age group. These tumors are often found incidentally as they tend to be hormonally silent and asymptomatic. Up to 30% of patients with GNs may have elevated plasma and urinary catecholamine levels, but without exhibiting any symptoms of catecholamine excess. Ultimately, surgery with laparoscopic adrenalectomy constitutes the gold standard for the treatment of primary adrenal GNs. Postoperatively, there is no need for adjuvant treatment and the overall prognosis is excellent.

Conclusion :

Though uncommon, adrenal ganglioneuromas must be included in the differential for a large incidentally-discovered adrenal mass.



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A CASE OF SECONDARY ADRENAL INSUFFICIENCY FOLLOWING NIVOLUMAB IMMUNOTHERAPY IN A PATIENT WITH METASTATIC MELANOMA.

Kajal Shah, MBBS – PGY2 Resident , Department of Internal Medicine, LIJ Forest Hills Hospital Northwell Health, NY ; Hofstra Northwell School of Medicine , NY.

Rifka Schulman, MD, FACE, CNSC – Assistant Professor, Hofstra Northwell School of Medicine; Director of Inpatient Diabetes ,Long Island Jewish Medical Centre, Division of Endocrinology, Long Island Jewish Medical Hospital, Hofrsta Northwell School of Medicine , NY.


Objective : Cases of adrenal insufficiency (AI) secondary to Programmed Cell Death Protein 1 receptor ( PD-1 ) inhibitor have been increasingly recognized. We report a case of secondary AI due to nivolumab, a PD-1 inhibitor.

Methods : Case Report.

Results : A 48 year old postmenopausal female with metastatic melanoma, on nivolumab for 3 months, presented with fever, chills, abdominal pain, fatigue, and weight loss for one month. Physical examination showed a cachectic female with dry mucosa and perioral hypopigmentation. Body weight was 62 Kg ( BMI-22.1 kg/m2 ) and blood pressure was 87/58 mm hg. Initial laboratory findings showed sodium 128 (normal, 135-145 mmol/L ) and glucose 78 ( normal, 70-99 mg/dl ). Her morning serum cortisol was 0.1 (normal, 6.0-18.4 mcg/dl ). Cosyntropin stimulation showed an inappropriate response: cortisol increased from 0.2 to 3.6 mcg/dl after one hour. Adrenocorticotropic hormone was < 5 (normal, 0-46 pg/ml), which was consistent with secondary AI. Further workup showed that Thyroid Stimulating Hormone (4.08, normal 0.20-4.20microIU/ml), Free Thyroxine (1.2 , normal 0.9-1.8 ng/dl ) , Follicle Stimulating Hormone (FSH , 43.9 , normal 25.8-134.8IU/L) , Luteinizing hormone (LH , 62.9 , normal 7.7-58.5IU/L ) , Estradiol ( < 5, normal < 5 - 138 pg/ml ) , and Prolactin (12.9 , normal 3.4-24.1 ng/ml ) were within normal limits for a postmenopausal female. Insulin like Growth Factor-1 (IGF-1 , 55 , normal 57-95 ng/ml ) was borderline low. The patient was started on hydrocortisone, which improved her clinical status and lab findings. Nivolumab was discontinued. Five months later, a decline was seen in IGF-1, LH, FSH levels, but with sparing of the thyroid axis. MRI sella showed a normal pituitary gland, but was limited by lack of intravenous contrast. The patient had a complicated course with multiple hospital admissions and expired a year later.

Discussion : Nivolumab is a monoclonal antibody that binds to PD-1 receptor, allowing immune cells to mount a response against cancer cells. Nivolumab is currently used for treatment of metastatic melanoma. Endocrine abnormalities seen with nivolumab and other immunotherapy agents, include hyperthyroidism, hypothyroidism, AI (isolated primary or secondary), and hypophysitis. In our case, the patient developed secondary AI but later also developed decreased LH/FSH and IGF-1 function, but with normal thyroid function and pituitary imaging.

Conclusion : An increasing trend of endocrinopathies observed amongst oncology patients treated with immunotherapeutic agents necessitates a high clinical suspicion for diagnosis. We present a case of nivolumab induced secondary AI with later progression to hypopituitarism sparing the thyroid axis.



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INSULIN PUMP FOR ADRENAL INSUFFICIENCY, A NOVEL APPROACH TO THE USE OF INSULIN PUMPS TO DELIVER CORTICOSTEROIDS IN PATIENTS WITH POOR CORTISOL ABSORPTION

Abdurrahman Khalil, MD – Research assistant, Metro Detroit Endocrinology

Farah Ahmed – Clinical Research Coordinator, Metro Detroit Endocrinology Center

Abdurrahman Khalil, MD – Research assistant, Metro Detroit Endocrinology

Opada Alzohaili, M.D, F.A.C.E, M.B.A – Physician- Principle Investigator, Metro Detroit Endocrinology Center


Objective :

Adrenal insufficiency can lead to serious complications including adrenal crisis and death. First line of therapy is oral corticosteroids with or without fluid cortisone. With severe adrenal insufficiency, increasing oral steroid doses can worsen the side effects caused by long term use of steroids without actually improving patient symptoms. Most common side effects are weight gain, acne and purple stretch marks. Patients needing high dose need an alternative treatment method to increased oral doses. An Insulin Pump, often used for Type 1 and Type 2 Insulin Dependent Diabetics, can be used as a delivery system of steroids that can help relieve patient symptoms, reduce frequency of adrenal crisis and hospital visits and lessen side effects by lowering the corticosteroid dose.

Methods : Patients were ruled into the study if they failed oral corticosteroid therapy due to malabsorption or other barriers preventing them from exhibiting an expected cortisol profile during testing. The patients either could not absorb the corticosteroid or simply were not responding to treatment. This provided the study with 6 subjects out of 118 adrenal insufficient patients.  These 6 were switched to an insulin pump but instead using solu-cortef in a pulse fashion. The number of adrenal crisis events 6 months prior to pump treatment and 6 months post treatment was observed. Adrenal Crisis monitoring included hospitalization, emergency room visits, and symptomatic clinical visits. Symptomatic included severe fatigue, dizziness, dehydration and orthostatic symptoms, which required IV/IM steroid injections. Subject’s weight was monitored and cortisol dose was compared pre and post pump initiation.

Results :

Cortisol pumps have shown to reduce the risk of adrenal crisis by 78.5% compared to oral corticosteroids. With gradually tapered hydrocortisone via pump, the mean dose reduction is 62.77 mg compared to the oral therapy.

Discussion : The data shows that patients who once were unable to achieve appropriate treatment on oral cortisone options have been able to alieviate their cortisol related symptoms, lessen the number of adrenal crisises and achieve better quality of life. As well as lower the dose of daily cortisol recieved.

Conclusion :

Continuous plusatile cortisol replacement via pump is an option for management of severe adrenal insufficiency in patients unresponsive to oral therapy. It can reduce adrenal crisis with its bolusing flexibility while at the same time leading to lower daily doses of steroids. Overall this can improve tolerance to doses and decrease the side effects experienced from long term use of steroids and help patients with their symptoms and improving their overall quality of life.



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A CASE OF TYPE 2 AUTOIMMUNE POLYENDOCRINE SYNDROME PRESENTING WITH ADRENAL CRISIS AND DIABETES: CHALLENGES OF MANAGEMENT AND PEARLS

Katherine Hwu, MD – Assistant Professor Pediatrics -Diabetes and Endocrinology, Baylor College of Medicine

Dina Winograd, MD – Clinical Endocrinology Fellow, Baylor College of Medicine

Swashti Agarwal, MD – Pediatric Endocrinology Fellow, Baylor College of Medicine

Naveed K. Khanjee, MD – Internal Medicine Resident, Baylor College of Medicine

Naveed Khanjee, MD – Internal Medicine Resident, Baylor College of Medicine


Objective : We describe a challenging case of autoimmune polyendocrine syndrome type 2 (APS-2) presenting with adrenal crisis and hyperglycemia, whose management was complicated by progression of diabetic ketoacidosis (DKA) and development of acute heart failure upon initiation of steroid treatment and volume resuscitation.

Methods : n/a

Results : Case Presentation: A 16 year old previously healthy boy presented with a history of weight loss and weakness over a period of months, which was followed by acute abdominal pain and lethargy over three days. He was found to be in shock refractory to fluid resuscitation. On exam he was lethargic and notably had skin hyperpigmentation. Glucose was 408 mg/dL with pH 7.31 and ketones of 1.5 mmol/L. A cortisol was 2.1 µg/dl and ACTH 588 pg/mL. He had an anti-glutamic acid decarboxylase-65 (GAD65) of 120 (ref: <5 IU/mL), islet cell auto-antibody of 6.7 (ref: <0.8 U/mL), 21-hydroxylase antibody of 32 (ref: <1 U/mL), and hemoglobin A1c of 12.3%. Echocardiogram on admission showed normal left ventricular function. He was admitted to the intensive care unit, placed on mechanical ventilation, and managed with stress dose steroids, pressor support and intravenous insulin. Following hydrocortisone administration, his DKA worsened (pH 7.14, ketones 3.0mmol/L). After normalization of his metabolic profile and hemodynamic parameters he was taken off mechanical ventilation. However, he acutely decompensated and was found to have pulmonary edema on chest x-ray and severely depressed left ventricular systolic function on repeat echocardiogram. With supportive therapy and continued steroids administration, his cardiac function normalized within two weeks.

Discussion : APS-2 is a an autoimmune condition most commonly associated with the development of adrenal insufficiency (AI), autoimmune thyroid disease and/or diabetes. This case exemplifies the challenges of managing APS in the acute setting. The administration of high dose steroids in our patient led to worsening DKA. The initial absence of severe DKA could be attributed to glucocorticoid deficiency as glucocorticoids stimulate the pathway responsible for the conversion of norepinephrine to epinephrine, which is responsible for ketogenesis. Furthermore, fluid resuscitation to manage severe shock in this case precipitated acute heart failure. Long-standing untreated AI is known to cause structural cardiac changes, and cardiac function should be monitored closely in these patients.

Conclusion : This case exemplifies the challenges of managing patients with APS-2 presenting in the acute setting.



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A RARE CASE OF ACTH DEPENDENT CUSHING SYNDROME IN PATIENT WITH HISTORY OF MCCUNE-ALBRIGHT SYNDROME

Sadia Ejaz, MD – Endocrinology Fellow, University of North Carolina Chapel Hill


Objective : (1) To understand the mechanism of endocrinopathies associated with McCune-Albright syndrome (MAS), (2) to review the treatment options available for life threatening Cushing syndrome in patients with MAS.

Methods : We reviewed the patient's clinical course along with the relevant literature.

Results : We present a case of 50-year-old female with history of McCune-Albright syndrome (MAS). She presented with precocious puberty and bony abnormalities at the age of 7. She was evaluated in our clinic at the age of 47 for symptoms of severe hypokalemia, hyperglycemia, and weight gain. Physical exam showed coarse facial features, asymmetry of jaw, hyperpigmentation of lower inner lip, dark striae on abdomen, upper arms, and thigh, and coast of Maine café-au-lait spot. Her initial labs showed 24-hour urinary free cortisol level of 392 mcg/24h (3.5-45 mcg/24 h), ACTH 101 pg/ml (10-50 pg/ml), IGF-1 325 ng/ml (56-194 ng/ml), FSH 0.7 mIU/ml (1.9-11.6mIU/ml), GH 0.60 ng/ml (0.01-3.61 ng/ml), LH <0.5 mIU/ml (2.6-12.1 mIU/ml), Prolactin 15 ng/ml (3-19 ng/ml). MRI brain didn’t show any pituitary lesion. Bilateral inferior petrosal sinus sampling was not possible due to tortuosity of vessels. She was not deemed appropriate for surgery due to fibrous dysplasia of her skull. Radiation treatment was done, and she was put on ketoconazole. After 2 years of her initial presentation she developed severe sepsis and necrotizing fasciitis of abdomen. She had a prolonged hospitalization for 6 months due to complications of Cushing syndrome including hyperglycemia, hypernatremia, hypovolemia, hypokalemia, and severe sepsis. She was treated with ketoconazole, metyrapone, and etomidate drip. She was re-evaluated after discharge and bilateral adrenalectomy was done.

Discussion : McCune-Albright Syndrome (MAS) is a rare genetic disorder caused by postzygotic mutation in GNAS gene leading to activation of the stimulatory G-protein alpha subunit, that is coupled to several cell surface hormone receptors. In addition to typical triad of polyostotic fibrous dysplasia, precocious puberty and café au-lait skin pigmentations, MAS is also associated with several hyperfunctioning endocrinopathies e.g. precocious puberty, hyperthyroidism, Acromegaly, hyperprolactinemia, and hypercortisolism.

Conclusion : Cushing syndrome is a rare but fatal manifestation of MAS. Cushing syndrome has very diverse clinical course in MAS patients ranging from spontaneous resolution to need for bilateral adrenalectomy or even death. Physicians should have low index of suspicion to test for hypercortisolemia in setting of MAS and symptoms of hypercortisolism. Prompt medical therapy and evaluation for bilateral adrenalectomy should be done.



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CLINICAL PRESENTATION AND OUTCOMES OF OPIOID INDUCED ADRENAL INSUFFICIENCY

Taoran Li, MD – Research Trainee, Division of Endocrinology, Diabetes and Nutrition, Mayo Clinic, Rochester MN

Diane M. Donegan, MB, Bch, BAO – Assistant Professor of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Indiana University, Indianapolis, IN

Irina Bancos, MD – Consultant, Division of Endocrinology, Diabetes and Nutrition, Mayo Clinic, Rochester MN


Objective : Opioid induced adrenal insufficiency (OIAI) may develop in patients treated with chronic opioids due suppression of the hypothalamic-pituitary-adrenal axis. Despite the prevalent use of opioids, limited data are available on the clinical presentation and management of OIAI. Our objective was to describe clinical manifestations, biochemical presentation and clinical course of OIAI.

Methods :

A retrospective study of adults diagnosed with OIAI between 2006-2018 at an academic center. Inclusion criteria were: 1) intermittent or continuous opioid ≥90 days, 2) diagnosis of OIAI with initiation of glucocorticoid (GC) replacement. Exclusion criteria were: 1) comorbidity or medication affecting adrenal function within the last 3 months. Opioid daily dose was converted into morphine mg equivalent (MME). 

Results : OIAI was diagnosed in 40 patients (75% women) at a median age of 49 years (38-55). Patients used daily (37, 95%) or as needed (2, 5%) opioids at a daily median MME dose of 105 mg (60-200) and median duration of 96 months (24-120). Patients reported symptoms suggestive of OIAI for a median of 12 months (1-132) prior to diagnosis: fatigue (29, 73%), musculoskeletal pain (21, 53%), weight loss (17, 43%), headache (12, 30%), and nausea (8, 20%). Only 3 patients were identified with OIAI through case detection. No patient presented in adrenal crisis, but 1 patient developed adrenal crisis after the diagnosis of OIAI was made. Biochemical diagnosis of OIAI was based on 1) low morning cortisol (CORT), baseline ACTH and/or DHEAS in 26 (59%) patients or 2) abnormal Cosyntropin stimulation test (CST) in 17/28 (61%) patients. Median serum CORT was 3 (1.4-5) mcg/dL (normal >7), ACTH 9.7 (5.7-15) pg/mL (normal > 10) and DHEAS of 20 (15-32)mcg/dL (normal >50). The median peak CORT of patients with an abnormal CST was 14 mcg/dL (12-16). In addition to OIAI, 9 (21%) patients (7 men), were diagnosed with opioid induced hypogonadism. Hydrocortisone was the most common GC prescribed for OIAI (38, 95%) and among those with follow-up (33, 83%), 14(42%) experienced improvement in symptoms. At last follow-up, opioids were tapered or discontinued in 21 (48%) patients, of whom 8(38%) recovered from OIAI based on follow up testing.

Discussion : OIAI causes significant morbidity including fatigue, pain, and weight loss. Recognition requires a high level of clinical suspicion as only 8% were identified by a case detection strategy.

Conclusion : Appropriate GC treatment is vital to avoid adrenal crisis and can lead to improvement of symptoms. Resolution of OIAI is possible following opioid cessation or reduction and should be recommended if possible.



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A CASE OF UNEXPLAINED ACTH-DEPENDENT CUSHING'S DISEASE

Fatima M. Kazi, MD – Internal Medicine Resident, Advocate Christ Medical Center

Joseph Zapater, MD, PhD – Endocrinology Fellow, University of Illinois at Chicago

Fatima M. Kazi, MD – Internal Medicine Resident, Advocate Christ Medical Center

Tahira Yasmeen, MD, FACE, FACP – Section Chief of Endocrinology Site Director for UIC Endocrinology Fellowship Chair, Glycemic Control Committee, ACMC Associate Professor of Clinical Medicine, UIC, UIC/Advocate

Vallari Kothari, MD – Endocrinology Fellow, University of Illinois at Chicago

Shahnaz Siddiqui, MD – Internal Medicine Resident, Advocate Christ Medical Center


Objective : In critically ill patients, over activation of hypothalamic pituitary axis can cause hypercortisolism with otherwise unexplained Cushing’s disease. We present a case of ACTH dependent Cushing’s disease with possible stress induced hypercortisolism

Methods : N/A

Results : A 62 year old male was transferred from an outside hospital after a prolonged course for necrotic colonic abscess requiring colon resection. Post-operative course was complicated by acute respiratory failure leading to intubation. He was found to have an incidental 2.5cmx4cm left adrenal adenoma. Clinically, patient had central obesity, moon facies, DM type II diagnosed a year ago. Lab work revealed elevated AM cortisol 59mcg/dL, midnight cortisol 57mcg/dL, 24 hour urinary cortisol 621mcg/24 hrs, elevated ACTH 501pg/mL and no suppression on low and high dose Dexamethasone stress test (DST). Aldosterone renin ratio, urine and plasma metanephrines were normal. MRI pituitary showed a 6 mm pituitary microadenoma. Ketoconazole was started to lower the cortisol levels with inadequate response. Repeat imaging showed bilateral adrenal hyperplasia. Highest cortisol level was noted to be 106.9mcg/dL. Metyrapone was arranged and started at 250mg Q6H and increased to 2.5gm/day. Ketoconazole was discontinued due to thrombocytopenia. Ectopic source of ACTH production could not be located on a PET CT or Octreoscan imaging. An improvement in his mental status and blood glucose was noted with lowered cortisol levels with Metyrapone. Lowest cortisol level noted was 46.6mcg/dL. At this point, an IPSS was done to differentiate between pituitary and ectopic origin of ACTH but the results were not interpretable due to a sample collection error. No further evaluation was pursued as the patient decided hospice

Discussion :

Majority of patients with ACTH dependent Cushing’s syndrome have a pituitary corticotroph adenoma rather than ectopic ACTH secretion while ectopic CRH secretion is rare. ACTH secretion by pituitary adenomas is only relatively resistant to negative feedback regulation by glucocorticoids hence results in normal or mildly elevated ACTH. In contrast, most nonpituitary tumors with ectopic ACTH are completely resistant to feedback inhibition, causing significantly elevated ACTH levels. Elevated ACTH levels reflect tumoral secretion that causes bilateral adrenocortical hyperplasia and hyperfunction. In our patient, elevated cortisol and ACTH levels were likely due to an ectopic source, as ACTH levels were not suppressed by high dose DST. Patient’s recent surgery could also have contributed to stress induced hypercortisolism. Advance imaging was unable to locate the ectopic source.Thus, he underwent IPSS

Conclusion : N/A



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