Low Diagnostic Utility of Overnight High-Dose Dexamethasone Suppression Test in ACTH-Dependent Cushing’s Syndrome

ObjectiveOvernight high-dose dexamethasone suppression test (ON-HDDST) is a simple test to localize the source of ACTH in patients with ACTH-dependent Cushing’s syndrome (CS). However, previous studies have reported its varying accuracy. We studied the utility of ON-HDDST in diagnosing Cushing’s disease (CD) in a series of patients with CD and ectopic ACTH syndrome (EAS).MethodsWe conducted a retrospective study of 88 patients with ACTH-dependent CS (plasma ACTH > 20.0 pg/mL), who underwent an ON-HDDST. CD and EAS were diagnosed in 68 and 20 patients, respectively. Patients were investigated using MRI of the sellar region, CT of the thorax/abdomen, Gallium-68-DOTANOC PET scan, and bilateral inferior petrosal sinus sampling as required.ResultsPatients with EAS had a significantly higher serum cortisol after ON-HDDST than patients with CD (median [IQR], 19.9 [12.4-31.1] μg/dL vs 9.9 [5.1-25.0] μg/dL, P <.01). A suppressed ON-HDDST (≥50% fall from baseline) was noted in 44 (65%) patients with CD and 3 (15%) patients with EAS (P <.0001). Among patients with CD, cortisol suppression >50% was noted in 35 (76%) of patients with microadenoma and 7 (44%) with macroadenoma. Among patients with EAS, ON-HDDST was suppressed in 1 of 6 patients (17%) with an occult tumor and 2 of 14 patients (14%) with a localized tumor. The ROC curve plotted for the percentage suppression of cortisol had an area under the curve (AUC) of 0.72 (P =.01). The best test parameters, with 65% sensitivity, 85% specificity, 94% positive predictive value, 42% negative predictive value, and 69% accuracy, were at 50% cutoff level.ConclusionThe ON-HDDST had a poor diagnostic value in differentiating CD and EAS.     

Utility of Adrenocorticotropic Hormone in Assessing the Response to Transsphenoidal Surgery for Cushing’s Disease

ObjectivesTo compare adrenocorticotrophic hormone (ACTH) and cortisol dynamics in subjects with Cushing’s disease (CD) following transsphenoidal surgery (TSS) and to determine the value of early postoperative ACTH levels in predicting subsequent hypocortisolemia.MethodsFollowing TSS for CD, serum cortisol and plasma ACTH were measured every 6 hours in the absence of empiric glucocorticoid coverage.ResultsA total of 26 subjects (25 female) underwent 28 operations. Hypocortisolemia was achieved in 21 (81%) subjects after the initial TSS. Repeat TSS was performed in 2 subjects, resulting in hypocortisolemia in 1. Subjects who achieved hypocortisolemia had significantly lower ACTH levels by 19 hours postoperatively (P = .007). Plasma ACTH fell to < 30 pg/mL in 86% and < 20 pg/mL in 82% of subjects who subsequently achieved hypocorti- solemia. Plasma ACTH declined to < 30 pg/mL by a mean of 10 hours and to < 20 pg/mL by 13 hours prior to hypo- cortisolemia. Follow-up data were available on 25 patients for a median of 23 months. Three subjects who achieved initial surgical remission had disease recurrence at 19, 24, and 36 months; all of these subjects had a postoperative nadir serum cortisol levels < 3 μg/dL and plasma ACTH < 20 pg/mL.ConclusionFollowing TSS for CD, plasma ACTH declined prior to achievement of hypocortisolemia in most subjects. In the majority, the ACTH level reached a nadir of < 20 pg/mL. Low early postoperative ACTH levels predict early hypocortisolemia but may not accurately predict long-term remission. (Endocr Pract. 2014;20:1159-1164)     

Venous Sampling for Cushing Disease: Comparison of Internal Jugular Vein and Inferior Petrosal Sinus Sampling

Objective: Because magnetic resonance imaging (MRI) fails to detect many adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas, inferior petrosal sinus sampling (IPSS) is considered the gold standard to differentiate Cushing disease (CD) from ectopic ACTH secretion syndrome (EAS). Some authors have suggested internal jugular vein sampling (IJVS) as an alternative to IPSS.Methods: We simultaneously compared IJVS to IPSS in 30 consecutive patients referred for ACTH-dependent Cushing syndrome and equivocal MRI exams. Five sites were simultaneously sampled in each patient (right and left IPS, right and left IJV, and femoral vein) before and after the administration of corticotrophin-releasing hormone or desmopressin. The test was considered consistent with CD when the IPS to peripheral ratio was >2 at baseline or >3 after stimulus and the IJV to peripheral ratio was >1.7 at baseline or >2 after stimulus.Results: In 27 of 30 patients, IPSS results were consistent with a central source of ACTH. Two of the other 3 patients had EAS (one lung carcinoid and one occult), and 1 patient had pathology-proven CD. The sensitivity of IPSS was 96.4%. Only 64.2% of these patients had results meeting criteria for a central source of ACTH by IJVS criteria. Twenty patients with centralizing IPPS have undergone pituitary surgery. Of these, the central origin of excessive ACTH was confirmed with certainty in 16 patients. Among these 16 patients, the IPSS sensitivity was 93.8%, whereas 5 patients had false-negative IJVS (68.7% sensitivity).Conclusion: These results do not support the routine use of IJVS in establishing if the pituitary is the source of excessive ACTH.Abbreviations:ACTH = adrenocorticotropic hormoneCD = Cushing diseaseCRH = corticotrophin-releasing hormoneCS = Cushing syndromeDDAVP = desmopressinEAS = ectopic ACTH secretionIJVS = internal jugular vein samplingIPSS = inferior petrosal sinus samplingJVS = jugular venous samplingMRI = magnetic resonance imaging     

Bilateral Adrenalectomy: Lifesaving Procedure in Severe Cushing Syndrome

ObjectiveTo discuss the role of bilateral adrenalectomy in Cushing syndrome, as illustrated in a case of severe hypercortisolism that was unresponsive to combination agent medical therapy.MethodsWe report the clinical, laboratory, imaging, and pathologic findings in a patient with ectopic Cushing syndrome attributable to an adrenocorticotropic hormone (ACTH)-secreting neuroblastoma. In addition, we provide a literature review regarding olfactory neuroblastoma and discuss current and emerging therapeutic options for Cushing syndrome.ResultsA 59-year-old man presented with nasal congestion and neck swelling and was noted to have hypokalemia, hypertension, and hyperglycemia. A nasal biopsy demonstrated a poorly differentiated carcinoma with neuroendocrine features. He was subsequently diagnosed as having ACTH-dependent Cushing syndrome, but despite high-dose combination medical therapy, his condition rapidly deteriorated. Urgent bilateral adrenalectomy provided rapid control of the hypercortisolism, and the patient was later able to undergo an uncomplicated total macroscopic resection of his locally metastatic primary tumor.ConclusionThis report describes the challenges in the diagnosis and management of ACTH-dependent Cushing syndrome and highlights the important role that bilateral adrenalectomy can still have in patients with severe hypercortisolism causing life-threatening complications. (Endocr Pract. 2012;18:e85-e90)     

Etiology-, Sex-, and Tumor Size-Based Differences in Adrenocorticotropin-Dependent Cushing Syndrome

ObjectiveTo examine demographic, clinical, and biochemical differences in patients with adrenocorticotropin (ACTH)-dependent Cushing syndrome (CS) based on etiology, sex, and tumor size.MethodsThis was a single-center study of 211 patients with ACTH-dependent CS followed for 35 years. Patients were stratified into 3 groups based on etiology: Cushing disease (CD)/transsphenoidal surgery, Cushing disease/total bilateral adrenalectomy (CD/TBA), and ectopic ACTH secretion (EAS). Patients were also stratified based on sex and tumor size (nonvisualized, microadenoma, and macroadenoma).ResultsCD was the commonest cause of ACTH-dependent CS (190; 90%). Most patients presented in the third decade (median age, 29 years). Clinical features, cortisol, and ACTH were significantly greater in the EAS group. The CD/TBA group had more nonvisualized tumors (22% vs 8%; P = .000) and smaller tumor size (4 vs 6 mm; P = .001) compared with the CD/transsphenoidal surgery group. There was female predominance in CD (2.06:1) and male predominance in EAS (2:1). Men had shorter duration of symptoms (2 years; P = .014), were younger (23 years; P = .001), had lower body mass index (25.1 kg/m²; P = .000), and had more severe disease (low bone mineral density, hypokalemia). Macroadenomas were frequent (46; 24.2%), and ACTH correlated with tumor size in CD (r = 0.226; P = .005).ConclusionOur cohort presented at an earlier age than the Western population with a distinct, but slightly lower, female predilection. Patients with CD undergoing TBA had frequent negative imaging. Men had a clinical profile suggesting aggressive disease. Microadenoma and macroadenoma were difficult to distinguish on a clinicobiochemical basis.     

Pituitary Mri Findings in Patients With Pituitary and Ectopic Acth-Dependent Cushing Syndrome: Does A 6-Mm Pituitary Tumor Size Cut-Off Value Exclude Ectopic Acth Syndrome?

Objective: Expert opinion and a consensus statement on Cushing syndrome (CS) indicate that in a patient with a clinical presentation and biochemical studies consistent with a pituitary etiology, the presence of a pituitary tumor ≥6 mm is highly suggestive of Cushing disease (CD). The purpose of the present study was to determine the optimal pituitary tumor size that can differentiate between patients with CD and ectopic adrenocorticotrophic hormone (ACTH) secretion (EAS) and obviate the need for inferior petrosal sinus sampling (IPSS).Methods: We performed a retrospective study of 130 patients seen between 2000 and 2012 including 104 patients with CD and 26 patients with EAS.Results: A pituitary lesion was reported in 6/26 (23%) patients with EAS and 71/104 (68.3%) patients with CD, with median (range) sizes of 5 mm (3–14) and 8 mm (2–31), respectively. All tumors in the EAS group measured ≤6 mm except for 1 that measured 14 mm. The presence of a pituitary tumor >6 mm in size had 40% sensitivity and 96% specificity for the diagnosis of CD. ACTH levels >209 pg/mL and serum potassium <2.7 mmol/L were found in patients with EAS. All patients with EAS had a 24-hour urine free cortisol (UFC) >3.4 times the upper limit of normal (×ULN)Conclusion: Pituitary incidentalomas as large as 14 mm in size can be seen in patients with EAS. However, the 6-mm tumor size cut-off value provided 96% specificity and may be a reasonable threshold to proceed with surgery without the need for IPSS when the biochemical data support a pituitary etiology.Abbreviations: ACTH = adrenocorticotropic hormone CD = Cushing disease CRH = corticotropin-releasing hormone CS = Cushing syndrome EAS = ectopic ACTH secretion IPSS = inferior petrosal sinus sampling HDDST = high-dose dexamethasone suppression test LDDST = low-dose dexamethasone suppression test MRI = magnetic resonance imaging UFC = urine free cortisol ULN = upper limit of normal     

Atypical Clinical Presentation of Acth-Dependent Cushing's Syndrome in a Patient Treated with Retinoic Acid

ObjectiveThe leading signs and symptoms of Cushing’s syndrome (CS) in adolescents, which depend on the duration and the severity of hypercortisolemia, are: a decrease in growth velocity with an increase in body weight, redistribution of fat tissue (round face), and less commonly, acne due to hyperandrogenization. A widely used antiacne drug, retinoic acid, can change the clinical presentation of CS and delay the diagnosis.MethodsWe report an atypical presentation of adrenocorticotropic hormone (ACTH)-dependent CS in a patient treated with retinoic acid due to severe acne.ResultsThree months after the discontinuation of retinoic acid treatment (at a dose of 40 mg daily for 6 months, with a 4 month break and then for an additional 6 months), a 17.5-year-old male presented with short stature (− 3.0 SD), muscle weakness, difficulty concentrating, insomnia, and depressed mood. Body weight (body mass index, 22 kg/m²), fat tissue distribution, pubertal status (testicular volume equal to 20 mL, pubarche V, axillarche present), and blood pressure were normal, and the patient’s bone age was equal to his chronologic age. His bone mineral density was decreased (Z-score, − 3.5 SD). The morning serum cortisol level was normal (8:00 am, 171.9 ng/mL) and did not decrease in the evening (8:00 pm, 178.9 ng/mL) or after 1 mg of dexamethasone (100.4 ng/mL). The patient’s urinary free cortisol was elevated on 3 occasions (274.5, 217.3, and 253.7 μg/day). Increased ACTH levels in the morning (97.5 to 141.1 pg/mL) and postcorticoliberine (577.6 pg/mL) pointed to ACTH-dependent CS. A magnetic resonance imaging scan of the pituitary gland confirmed the presence of a microadenoma.ConclusionRetinoic acid treatment may alter the clinical presentation of ACTH-dependent CS and consequently delay the diagnosis. (Endocr Pract. 2014;20:e119-e122)     

Addison’S Disease in Evolution: An Illustrative Case and Literature Review

ObjectiveTo present a case of symptomatic autoimmune adrenal insufficiency with initially normal serum cortisol and to caution about limitations of the current diagnostic algorithm for adrenal insufficiency, which does not reflect the pathophysiology of early disease.MethodsWe describe the clinical presentation and relevant investigations of a patient ultimately found to have Addison’s disease, which is followed by a focused review of the literature.ResultsA 41-year-old Caucasian woman with autoimmune hypothyroidism, premature ovarian failure, and microscopic colitis presented with nausea, salt craving, increased skin pigmentation, and postural hypotension. Initial bloodwork revealed a normal morning cortisol of level of 19.2 μg/dL (normal, 7.2 to 25 μg/dL) but an adrenocorticotropic hormone (ACTH) level 10 times normal, at 513.6 pg/mL (normal, < 52.5 pg/mL). Her potassium was normal, but her aldosterone level was 4.12 ng/dL (normal, 12.3 to 62.5 ng/dL) and her renin activity was increased (23.0 mg/dL/hour; normal, < 6.0 mg/dL/hour). Six weeks after initial presentation, she was found to have anti-adrenal antibodies. It was not until 10 weeks after her initial symptomatic presentation that her morning cortisol level was found to be subnormal and a formal diagnosis of adrenal insufficiency was made.ConclusionThe present case and literature review reveal that common diagnostic approaches will miss patients with (possibly symptomatic) early adrenal insufficiency. We suggest that serum ACTH level testing or tests of mineralocorticoid function be included in the initial step of investigation for suspected primary adrenal insufficiency. (Endocr Pract. 2014;20:e176-e179)     

Results of repeated transsphenoidal surgery in Cushing's disease. Long-term follow-up

ObjectiveTranssphenoidal surgery (TSS) is the treatment of choice for Cushing's disease (CD). However, the best treatment option when hypercortisolism persists or recurs remains unknown. The aim of this study was to analyze the short and long-term outcome of repeat TSS in this situation and to search for response predictors.Patients and methodsData from 26 patients with persistent (n = 11) or recurrent (n = 15) hypercortisolism who underwent repeat surgery by a single neurosurgeon between 1982 and 2009 were retrospectively analyzed. Remission was defined as normalization of urinary free cortisol (UFC) levels, and recurrence as presence of elevated UFC levels after having achieved remission. The following potential outcome predictors were analyzed: adrenal status (persistence or recurrence) after initial TSS, tumor identification in imaging tests, degree of hypercortisolism before repeat TSS, same/different surgeon in both TSS, and time to repeat surgery.ResultsImmediate postoperative remission was achieved in 12 patients (46.2%). Five of the 10 patients with available follow-up data relapsed after surgery (median time to recurrence, 13 months). New hormone deficiencies were seen in seven patients (37%), and two patients had cerebrospinal fluid leakage. No other major complications occurred. None of the preoperative factors analyzed was predictive of surgical outcome.ConclusionsWhen compared to initial surgery, repeat TSS for CD is associated to a lower remission rate and a higher risk of recurrence and complications. Further studies are needed to define outcome predictors.     

Paradoxical Results after Inadvertent Use of Cosyntropin [Adrenocorticotropin Hormone (1-24)] Rather than Acthrel (Ovine Corticotropin Releasing Hormone) during Inferior Petrosal Sinus Sampling

ObjectiveThe use of ovine corticotropin releasing hormone (oCRH) maximizes the diagnostic accuracy of inferior petrosal sinus sampling (IPSS) in patients with adrenocorticotropin hormone (ACTH)-dependent Cushing’s syndrome (CS). oCRH is marketed as ACTHrel and, understandably, may be confused with cosyntropin [ACTH ^(1-24)]. The inadvertent substitution of synthetic ACTH^(1-24) for oCRH (ACTHrel) during IPSS may cause unexpected and misleading results. The aim of this report is to raise awareness of the potential confounding results created when synthetic ACTH^(1-24) is mistakenly used during IPSS.MethodsWe present 3 patients treated at 3 different centers with ACTH-dependent CS in whom ACTH^(1-24) was mistakenly substituted for oCRH (ACTHrel) during IPSS.ResultsIn all patients, there was an abrupt and unexpected decrease in plasma ACTH in the inferior petrosal sinus (IPS) samples after presumptive stimulation with oCRH. Re-evaluation of the patients’ pharmacy records confirmed that synthetic ACTH^(1-24) had been used rather than oCRH during each procedure. Because “sandwich” immunometric assays for ACTH measure the entire pool of endogenous ACTH, the administration of synthetic ACTH^(1-24) artifactually decreases the endogenous plasma ACTH^(1-39) measurement by binding only to the N-terminal antibody raised against ACTH^(1-17) and not to the C-terminal antibody raised against ACTH^(34-39). This results in a lack of a detectable sandwich complex and explains the apparent reduction in ACTH concentration.ConclusionAn abrupt decrease in ACTH during IPSS suggests that synthetic ACTH^(1-24) rather than oCRH (ACTHrel) has been administered. The labeling of oCRH as ACTHrel poses a potential patient safety problem about which endocrinologists, interventional radiologists, and pharmacists should be aware. (Endocr Pract. 2014;20: 646-649)     

Cushing Disease in Children and Adolescents: Twenty Years’ Experience in A Tertiary Care Center in India

ObjectiveTo analyze the clinical presentation, diagnostic evaluation, treatment modalities, and follow-up of pediatric patients with Cushing disease.MethodsIn this retrospective analysis, we reviewed records of children (younger than 20 years) with Cushing disease who had undergone transsphenoidal adenomectomy in a tertiary health care center in India during the period of 1988 to 2008. Endogenous hypercortisolism was identified by a serum cortisol value ≥ 1.8 μg/dL during a low-dose dexamethasone suppression test (LDDST) with or without elevated midnight serum cortisol (≥ 3.2 μg/dL). Corticotropin dependence was defined by a basal plasma corticotropin concentration ≥ 5 pg/mL. Patients with normal pituitary imaging underwent bilateral inferior petrosal sinus sampling (BIPSS). Those with persistent or recurrent disease after surgery were treated with second-line interventions on a case-by-case basis.ResultsTwenty-nine boys and 19 girls were included. Mean age was 14.85 (± 2.5) years. Weight gain (98%), round facies (98%), and growth arrest (83%) were the most common manifestations. LDDST and midnight cortisol had 100% sensitivity for detecting endogenous hypercortisolism, while midnight corticotropin measurement had 100% sensitivity for defining corticotropin dependence. Magnetic resonance imaging and unstimulated BIPSS had 71% and 89% sensitivity, respectively, for diagnosing Cushing disease. Twenty-seven patients (56%) achieved remission after the first transsphenoidal operation with higher remission rates in those with microadenoma (75%). Basal serum cortisol < 5 mg/dL on the fifth postoperative day predicted cure. Eight patients received postoperative radiotherapy, with 4 achieving remission.ConclusionsClinical presentation and diagnostic yield with various tests were similar to those previously reported in the literature. Remission rates were poor after first transsphenoidal operation in patients with macroadenoma and outcome was dismal with a second transsphenoidal operation. Serum cortisol concentration < 5 mg/dL on the fifth postoperative day predicted cure. (Endocr Pract. 2011;17:369-376)     

Unusual Recurrence of Hypercalcemia Due to Concurrent Parathyroid Adenoma and Parathyroid Sarcoidosis with Lymph Node Involvement

ObjectiveTo describe a patient presenting with the rare findings of synchronous parathyroid adenoma and parathyroid sarcoidosis.MethodsWe describe the clinical history, physical examination findings, laboratory values, imaging findings, and pathologic data of a man who developed recurrent se- vere hypercalcemia after successful parathyroidectomy.ResultsA 67-year-old man had the following initial blood test results: calcium, 11.1 mg/dL (reference range, 8.5-10.6 mg/dL); albumin 4.0 g/dL (reference range, 3.2-5.2 g/dL); intact parathyroid hormone, 166 pg/mL (refer- ence range, 10-69 pg/mL); creatinine, 1.9 mg/dL; 25-hy- droxyvitamin D, 15 ng/mL (reference range, 30-80 ng/ mL); and 1, 25-dihydroxyvitamin D, 44 pg/mL (reference range, 16-72 pg/mL). Chest x-ray was normal, and delayed images from a technetium Tc 99m sestamibi scan showed increased activity in the right lower pole of the thyroid. Two months after successful parathyroidectomy, the pa- tient was admitted to the hospital with a serum calcium concentration of 17 mg/dL. Pathologic examination of the resected gland confirmed the diagnosis of parathyroid ad- enoma, and subsequent review disclosed the presence of noncaseating granulomas within the adenoma.ConclusionsSarcoidosis with parathyroid involve- ment causing severe hypercalcemia is unique to this case.Recurrent hypercalcemia after successful resection of a parathyroid adenoma may require consideration of poten- tial causes other than the initial diagnosis. (Endocr Pract. 2010;16:463-467)     

Hypercalcemia Secondary to Gastrointestinal Stromal Tumors: Parathyroid Hormone-Related Protein Independent Mechanism?

ObjectiveHypercalcemia is a common paraneoplastic manifestation of many malignancies like breast, ovarian, and squamous-cell cancers of head and neck; however, there have been only a few case reports of hypercalcemia associated with gastrointestinal stromal tumors (GISTs). We report a case of GIST presenting with hypercalcemia without any osseous metastasis and provide a literature review regarding the mechanisms of hypercalcemia and therapeutic strategies.MethodsWe present a report of case and a review of the relevant literature.ResultsA 52-year-old woman with history of localized breast cancer in remission and a pelvic 13 × 12 cm GIST with peritoneal, liver, and lung metastases presented with hypercalcemia of 14.3 mg/dL (8.5-10.5 mg/dL). Parathyroid hormone-related protein (PTHrP) was undetectable, intact parathyroid hormone (PTH) was appropriately low at 1 pg/mL (10-65 pg/mL), and 1,25 dihydroxy vitamin D (1,25 OH₂ vit D) was elevated at 131 pg/mL (18-78 pg/mL) with normal renal function. Calcium responded transiently to tyrosine kinase inhibitor therapy and bisphosphonates but within a year, she expired due to tumor progression.ConclusionGIST is a rare cause of hypercalcemia. In addition to PTHrP expression, direct tumor production of 1,25(OH)₂ vit D or 1-α hydroxylase enzyme resulting in activation of 25-hydroxy vitamin D may be an alternative mechanism in GIST-related hypercalcemia. Therapy with tyrosine kinase inhibitors and bisphosphonates is recommended, though prognosis is poor. Further investigations are needed to characterize the etiology and management of hypercalcemia in these patients. (Endocr. Pract. 2013;19: e158-e162)     

Calcium Challenge to Confirm Secondary Hyperparathyroidism Caused by Decreased Calcium Intake

ObjectiveSecondary hyperparathyroidism commonly occurs in the setting of mid-to low-normal serum calcium levels, often in the setting of chronic kidney disease, phosphate loading, vitamin D deficiency, or insufficient calcium intake or absorption. In this article, we report 9 patients who had adequate kidney function (estimated glomerular filtration rate >60 mL/min/1.73 m²) and normal 25-hydroxy vitamin D level (≥30 ng/dL) and whose secondary hyperparathyroidism resolved after starting adequate oral calcium intake.MethodsOur retrospective case series included 8 women and 1 man; the mean age was 69.0 ± 12.2 years (mean ± standard deviation). The initial intact parathyroid hormone (iPTH) level was 80.6 ± 13.4 pg/mL (reference range [ref], 10-65 pg/mL), corrected serum calcium level was 9.2 ± 0.2 mg/dL (ref, 8.5-10.5 mg/dL), serum phosphate level was 3.6 ± 0.4 mg/dL (ref, 2.5-4.9 mg/dL), 25-hydroxy vitamin D level was 42.2 ± 10.5 mg/dL (ref, 20-50 ng/mL), and estimated glomerular filtration rate was 72.6 ± 14.4 mL/min/1.73 m². Patients were treated clinically with oral calcium 600 mg twice a day.ResultsiPTH was retested after a mean duration of 17.6 ± 12.7 days of calcium supplementation; the iPTH level decreased to 51.0 ± 10.6 pg/mL, with all patients achieving iPTH in the normal range with normocalcemia, consistent with hyperparathyroidism being because of insufficient calcium intake or absorption. All patients were normocalcemic after supplementation.ConclusionSecondary hyperparathyroidism can result from insufficient oral calcium intake. Calcium challenge is an efficacious and cost-effective tool for confirming and treating secondary hyperparathyroidism in the setting of normal vitamin D levels and kidney function.     

Severe Ectopic Cushing Syndrome Caused by Adenoid Cystic Carcinoma of a Salivary Gland

ObjectiveWe present a rare case of Cushing syndrome due to ectopic adrenocorticotropic hormone (ACTH) secretion (EAS). To our knowledge only two similar cases have been previously reported.MethodsThis is a case report of EAS by a metastatic lingual adenoid cystic carcinoma (ACC).ResultsThe patient was diagnosed of a Cushing syndrome caused by tumoral EAS two years after initial cancer diagnosis. Clinical presentation included asthenia, insomnia, hypertension, acne, and hyperpigmentation developing in a period of two months. Laboratory and imaging testing revealed hypokalemic metabolic alkalosis, hypercortisole- mia, high ACTH, nonsuppresion by 8 mg dexamethasone, and a normal pituitary magnetic resonance imaging (MRI). With a high clinical suspicion of EAS, combined medical treatment was started but was unsuccessful. Bilateral adrenalectomy could not be performed given the patient’s rapid deterioration. Immunostained tissue from the original tumor was positive for synaptophysin.ConclusionThis rare case of EAS illustrates the challenge that this condition may confer regarding diagnosis and management. (Endocr. Pract. 2013;19:e118-e121)     

Cushing's Syndrome Due to Ectopic Adrenocorticotrophic Hormone Production by Olfactory Neuroblastoma

ObjectiveTo review a case of olfactory neuroblastoma (ON) with Cushing’s syndrome (CS) due to ectopic production of adrenocorticotrophic hormone (ACTH) and compare the histopathologic diagnosis, treatment modality, and prognostic factors with the literature.MethodsWe report the clinical presentation, biochemistry, imaging, histopathology, treatment, and outcome of a patient with ON. We conducted an English language literature review of CS due to ectopic ACTH production and ON.ResultsCS due to ectopic ACTH production is uncommon, and CS due to ON is extremely rare. A 19-year-old Hispanic man presented with right nasal obstruction, involuntary weight gain, and intensely pruritic skin rash. Examination revealed large, wide purple striae on both arms and the abdomen. Head magnetic resonance imaging (MRI) revealed a right ethmoid sinus enhancing mass extending into the orbit, nasal cavity, and maxillary and sphenoid sinuses. Laboratory results showed a pm cortisol level of 26 mcg/dL, a 24-hour urinary free cortisol level of 7,507 mcg, an ACTH level of 83 pg/mL, and nonsuppression of cortisol with an overnight dexamethasone suppression test (1 and 8 mg). A biopsy revealed ON, and immunohistochemistry (IHC) was positive for ACTH. He underwent chemotherapy followed by surgical debulking and adjuvant radiation therapy, with no disease recurrence through the last follow-up in February 2012. Plasma and urinary cortisol levels normalized following surgery.ConclusionThis is the first case reported of a Hispanic male with an uncommon tumor (ON) and an even more uncommon presentation, ectopic ACTH production causing CS. The extremely high ACTH levels and plasma and urine cortisol levels dramatically dropped following multimodality management. So far, he has had 2.5 years of disease-free survival. (Endocr Pract. 2014;20:e47-e52)     

Bone Marrow Uptake in Parathyroid Scintigraphy is A Consequence of Extremely High Parathyroid Hormone Levels

ObjectiveWe retrospectively evaluated patients with end-stage renal disease (ESRD) who were referred to our department for parathyroid scintigraphy. The aim of this study was to investigate the causes of bone marrow uptake observed on parathyroid scintigraphy.MethodsWe included 18 ESRD patients (10 F, 8 M; mean, 52 ± 13 years old; range, 45-59) in the study. The disease duration of the patients was mean 7.7 ± 4.7 years. The patients’ mean plasma calcium and parathormone (PTH) levels were 9.7 ± 1.4 mg/dL and 1,553.3 ± 691.7 pg/mL, respectively. Dual-phase technetium-99m 2-methoxyisobutyl-isonitrile (Tc-99m MIBI) parathyroid imaging and, if necessary, additional Tc-99m pertechnetate scintigraphy were performed. Quantification of the planar early phase parathyroid images was performed for various regions (sternum, humerus, ribs) with the same size rectangular region of interest (ROI, 176 × 176 pixels). Average counts were compared with paired samples Student’s t tests, and P <.05 was considered statistically significant.ResultsTc-99m MIBI parathyroid imaging revealed parathyroid hyperplasia, adenoma, and ectopic adenoma in 7, 3, and 2 patients, respectively. The other 7 patients had normal scintigraphy results with regard to parathyroid pathologies. Bone marrow uptake in the sternum, ribs, and humerus was observed in 6 patients. The difference between the average quantitative value obtained from the ROIs drawn on the sternum and humerus was also statistically significant compared to patients without bone marrow uptake (P<.05). All 6 patients’ exhibited extremely high PTH levels (>2,000 pg/mL; mean, 2,413.7 ± 150 pg/mL) compared to the other 12 patients (mean, 1,342.8 ± 249 pg/mL).ConclusionOur results show that bone marrow uptake on parathyroid scintigraphy is a consequence of extremely high PTH levels in ESRD patients; no further analysis is required. (Endocr Pract. 2013;19:202-205)     

Calcium,Parathyroid Hormone,and Vitamin D in Patients with Primary Hyperparathyroidism: Normograms Developed from 10000 Cases

ObjectiveTo better define the typical and atypical biochemical profiles of patients with surgically proven primary hyperparathyroidism.MethodsIn this single-center, prospectively conducted study of consecutive patients with surgically proven primary hyperparathyroidism over a 7-year period, we analyzed serum calcium, parathyroid hormone, and 25-hydroxyvitamin D concentrations.ResultsA total of 10 000 patients were included, and more than 210 000 calcium, parathyroid hormone, and 25-hydroxyvitamin D values were evaluated. Both calcium and parathyroid hormone levels demonstrated a Gaussian distribution with the average calcium concentration being 10.9 ± 0.6 mg/dL and the average parathyroid hormone concentration being 105.8 ± 48 pg/mL. The average highest calcium and parathyroid hormone concentrations were 11.4 ± 0.7 mg/dL and 115.3 ± 50 pg/mL, respectively. At least 1 calcium value of 11.0 mg/dL was seen in 87% of patients, but only 21% had 1 or more calcium value above 11.5 mg/dL. Only 7% had a single serum calcium level reaching 12.0 mg/dL. Normocalcemic hyperparathyroidism was seen in just under 3% of patients who had identical findings at surgery. An average parathyroid hormone concentration less than 65 pg/mL was seen in 16%, with 10% of patients who had no high parathyroid hormone values. The average 25-hydroxyvitamin D concentration was 22.4 ± 9 ng/mL, with levels decreasing as calcium levels increased (P < .001); 36% had 25-hydroxyvitamin D levels below 20 ng/mL.ConclusionsPatients with PHPT present with a number of distinct biochemical profiles, but as a group, they present with a near-normal Gaussian distribution of both calcium and parathyroid hormone levels. Either serum calcium or parathyroid hormone remained normal in 13% of patients, yet the findings at surgery are similar to those of patients with elevated calcium or parathyroid hormone. Low 25-hydroxyvitamin D is an expected finding in patients with PHPT, decreasing as serum calcium levels increase. (Endocr Pract. 2011;17:384-394)     

Reduction of False-Negative Results in Inferior Petrosal Sinus Sampling with Simultaneous Prolactin and Corticotropin Measurement

ObjectiveTo investigate the value of prolactin as an independent marker of catheter placement to improve the diagnostic accuracy of inferior petrosal sinus sampling (IPSS) in patients with corticotropin-dependent Cushing syndrome.MethodsIn this retrospective cohort study, we reviewed hospital records of patients who underwent IPSS procedures at the Cleveland Clinic between 1997 and 2009. Serum prolactin and plasma corticotropin levels were measured prospectively in peripheral and inferior petrosal sinus (IPS) samples.ResultsForty-one patients underwent 42 IPSS procedures at our institution during the study period. Among35 patients with Cushing disease, 1 patient had erroneous IPSS results: all pre-corticotropin-releasing hormone (CRH) and post-CRH IPS to peripheral (IPS:P) ACTH ratios were less than 2 and less than 3, respectively. Despite radiologic evidence of appropriate IPS catheter placement, concurrent IPS:P prolactin ratios indicated that successful IPS venous sampling was not achieved. A second case with equivocal IPSS results could also be explained by corresponding IPS:P prolactin ratios. During IPSS, all patients with an identifiable ACTH-staining adenoma localizing to 1 side of the pituitary gland (n = 22) who demonstrated absent IPS:P ACTH gradients (< 2 before or < 3 after CRH administration) on the ipsilateral side of the corticotroph adenoma had corresponding IPS:P prolactin ratios less than 1.3.ConclusionsMeasurement of prolactin during IPSS testing may reduce false-negative results in patients with Cushing disease who do not demonstrate an appropriate central-to-peripheral ACTH gradient. In our series, all false-negative IPS:P ACTH ratios had a corresponding IPS:P prolactin ratio less than 1.3. (Endocr Pract. 2011;17:33-40)     

Hypercalcemia and Acromegaly-Clarifying the Connections: A Case Report and Review of the Literature

ObjectiveHypercalcemia in patients with acromegaly is rare and usually due to co-existent primary hyperparathyroidism. The etiology of hypercalcemia directly related to acromegaly is debated.MethodsWe present a case report of 1,25(OH)2D3-mediated hypercalcemia in a patient with acromegaly and discuss potential pathophysiological mechanisms contributing to the development of hypercalcemia late in the course of the disease.ResultsA 67-year-old female presented with classical features of acromegaly. A review of her previous photographs suggested a disease duration of approximately 10 years, and her serum calcium (Ca) was normal during this period. A biochemical work up confirmed a combined growth hormone (GH-) and prolactin (PRL-) cosecreting tumor with a GH level of 92.03 ng/mL (normal 0-3.61), an insulin-like growth factor-1 (IGF-1) level of 1,498 ng/ mL (59-225), and a PRL level of 223.3 ng/mL (2-17.4). Magnetic resonance imaging (MRI) of the pituitary showed a 1.9-cm macroadenoma. Her preoperative work up revealed new onset hypercalcemia with a corrected serum Ca level of 10.7 mg/dL (8.5-10.5), an ionized Ca level of 1.37 mmol/L (1.08-1.30), a parathyroid hormone (PTH) level of 13.0 pg/mL (10-60), and a high 1,25(OH)2D3 level of 72.6 pg/mL (15-60). She underwent resection of the pituitary adenoma with normalization of GH and PRL levels, and her IGF-1 level decreased to 304 ng/mL. Her serum Ca (9.3 mg/dL), ionized Ca(1.22) and 1,25(OH)2D3 levels (38.6 pg/mL) normalized after surgery.ConclusionWhile overt hypercalcemia in acromegaly is rare, it tends to occur late in the disease course. The hypercalcemia is mediated by elevated 1,25(OH)2D3 levels rather than PTH. (Endocr Pract. 2014;20:e86-e90)