ESAP-ITE 2019 Slide Deck

1. ESAP-ITE 2019Slide Deck

2. ADRENAL

3. ITE 2019 Question 3 A 54-year-old man has had difficult-to-control hypertension for 3 years. He has gained 33 lb (15 kg) in the last 3 years and diabetes mellitus was diagnosed 1 year ago. His medications include metformin, amlodipine, valsartan, and hydrochlorothiazide. On physical examination, his BMI is 35 kg/m2 and blood pressure is 148/92 mm Hg. He has scattered 1- to 2-cm bruises on his extremities. He has no dorsocervical fat pad, striae, or proximal muscle strength weakness. Laboratory test results: Sodium = 139 mEq/L (136-142 mEq/L) (SI: 139 mmol/L [136-142 mmol/L]) Potassium = 3.5 mEq/L (3.5-5.0 mEq/L) (SI: 3.5 mmol/L [3.5-5.0 mmol/L]) Serum aldosterone = 14 ng/dL (4-21 ng/dL) (SI: 388.4 pmol/L [111.0-582.5 pmol/L]) Plasma renin activity = <0.6 ng/mL per h (0.6-4.3 ng/mL per h) Fasting glucose = 165 mg/dL (70-99 mg/dL) (SI: 9.2 mmol/L [3.9-5.5 mmol/L])

4. Abdominal CT with contrast demonstrates a 3.8-cm left adrenal mass and an atrophic right adrenal gland (see image, arrows).

5. Which of the following is the best next step in this patient’s management? • Prescribe spironolactone, 50 mg daily • Measure plasma metanephrines and perform a 1-mg overnight dexamethasone suppression test • Schedule adrenal venous sampling to measure aldosterone and cortisol • Perform left adrenalectomy • Measure serum aldosterone after administration of 2 L normal saline Correct Answer: B Learning objective: Exclude hypercortisolism and pheochromocytoma when evaluating a large adrenal tumor suspected of causing primary aldosteronism.

6. Rationale: This patient was evaluated for primary aldosteronism because of resistant hypertension and low-normal potassium. The screening aldosterone-to-renin ratio is marginally positive, disproportionate to his hypertension. The weight gain, hyperglycemia, central obesity, and bruising are suggestive of hypercortisolism. His adrenal tumor is markedly larger than those that usually cause primary aldosteronism, and the contralateral adrenal gland is somewhat atrophic, suggesting hypercortisolism from the adrenal tumor. When the diameter of adrenal cortical tumors is greater than 2.4 cm, the risk of hypercortisolism rises, and if the tumor is removed without testing cortisol dynamics, adrenal crisis might occur postoperatively. The CT was performed with contrast, so density cannot be used to determine whether the tumor is lipid-rich and thus unlikely to be pheochromocytoma. Hypercortisolism and pheochromocytoma must be excluded before performing left adrenalectomy (Answer D) to avoid perioperative complications. With a large adrenal tumor, measuring plasma metanephrines and performing a 1-mg overnight dexamethasone suppression test (Answer B) is the correct next step.Spironolactone now (Answer A) would treat the mineralocorticoid excess but not glucocorticoid manifestations, and this patient needs further evaluation before treatment is determined. Confirmatory testing with saline infusion (Answer E) and adrenal venous sampling (Answer C) are customary steps for the evaluation of primary aldosteronism;

7. Rationale Continued: however, this patient’s large adrenal tumor first warrants complete hormonal evaluation. After further laboratory evaluation, a diagnosis of ACTH-independent hypercortisolism was established in this patient. Cortisol excess takes priority over aldosterone and directs treatment with left adrenalectomy and perioperative glucocorticoid coverage. Coproduction of aldosterone and cortisol from adrenal cortical adenomas, particularly larger tumors, is well described. It is possible, although unlikely, that the primary aldosteronism is bilateral and unrelated to the adrenal tumor, so the patient should be rescreened for primary aldosteronism after adrenalectomy. If it persists, spironolactone would be an appropriate treatment. Educational Objective Exclude hypercortisolism and pheochromocytoma when evaluating a large adrenal tumor suspected of causing primary aldosteronism.

8. Reference(s): • Spath M, Korovkin S, Antke C, Anlauf M, Willenberg HS. Aldosterone- and cortisol-co-secreting adrenal tumors: the lost subtype of primary aldosteronism. Eur J Endocrinol. 2011;164(4):447-455. PMID: 21270113 • Morelli V, Reimondo G, Giordano R, et al. Long-term follow-up in adrenal incidentalomas: an Italian multicenter study. J Clin Endocrinol Metab. 2014;99(3):827-834. PMID: 24423350 • Fallo F, Bertello C, Tizzani D, et al. Concurrent primary aldosteronism and subclinical cortisol hypersecretion: a prospective study. J Hypertens. 2011;29(9):1773-1777. PMID: 21720261

9. ITE 2019 Question 12 A 31-year-old man presents with abdominal pain near his umbilicus. He describes symptoms of bloating and central abdominal pain for several months. He has no notable medical history or past surgeries and takes no medications. He does not smoke cigarettes. On physical examination, he is afebrile, blood pressure is 122/80 mm Hg, and pulse rate is 70 beats/min. His height is 69 in (175 cm), and weight is 148 lb (67.3 kg) (BMI = 21.9 kg/m2). He has no signs of Cushing syndrome and there is no palpable abdominal pain or mass. Abdominal CT with intravenous contrast documents a heterogeneously enhancing right adrenal mass measuring 3.4 x 3.2 cm (see images, arrows). The mass is relatively round and confined to the right adrenal gland. The left adrenal gland appears normal.

10. Axial View Coronal View

11. He has no history of episodic spells of adrenergic symptoms, including no sensations of palpitations, sweating, anxiety, tremors, pallor, flushing, headaches, or vision changes. He has had no known episodes of hypertension or orthostasis and no history of weight gain, weight loss, excessive virilization, or feminization. Laboratory test results: Serum cortisol following 1-mg dexamethasone suppression test = 0.7 µg/dL (SI: 19.3 nmol/L) Plasma ACTH following 1-mg dexamethasone suppression test = <5.0 pg/mL (SI: <1.1 pmol/L) Plasma renin activity = 1.5 ng/mL per h (0.6-4.3 ng/mL per h) Serum aldosterone = 5.0 ng/dL (4-21 ng/dL) (SI: 138.7 pmol/L [111.0-582.5 pmol/L]) Plasma metanephrine = <39 pg/mL (<99 pg/mL) (SI: <0.20 nmol/L [<0.50 nmol/L]) Plasma normetanephrine = 1245 pg/mL (<165 pg/mL) (SI: 6.8 nmol/L [<0.90 nmol/L]) Urinary free cortisol = 37 µg/24 h (4-50 µg/24 h) (SI: 102 nmol/d [11-138 nmol/d])

12. Which of the following is the most likely diagnosis? • Adrenocortical carcinoma • Hyperfunctioning adrenocortical adenoma • Nonfunctional lipid-poor adrenocortical adenoma • Nonfunctional lipid-rich adrenocortical adenoma • Pheochromocytoma Correct Answer: E Learning objective: Diagnose pheochromocytoma on the basis of radiographic and biochemical characteristics, even if a patient does not have classic adrenergic symptoms or spells.

13. Rationale: Pheochromocytomas (Answer E) are chromaffin-cell tumors that originate in the adrenal medulla. The diagnosis of pheochromocytoma should involve evaluation of clinical symptoms, evidence of hormonal activity, and radiographic appearance.Pheochromocytomas may secrete catecholamines (such as norepinephrine, epinephrine, and, less frequently, dopamine) that induce adrenergic symptoms and signs, such as palpitations, anxiety, sweating, pallor, and elevations in blood pressure and heart rate. However, some pheochromocytomas do not secrete high concentrations of catecholamines, and in some instances, even when high catecholamine concentrations are detected some patients do not exhibit the classic symptoms. Typically, pheochromocytomas that induce clinical symptoms are associated with metanephrine and/or normetanephrine levels that are substantially higher than the upper limit of the reference range—usually 4 times or more (less commonly 2 or 3 times higher). Importantly, mild elevations above the upper limit of the metanephrines reference range (<2 times) are common and are usually attributed to enhanced sympathoadrenergic tone (eg, in a state of anxiety or stress) and/or the use of norepinephrine reuptake inhibitors (eg, some antidepressants medications and cocaine). In this regard, these milder elevations are frequent causes of false-positive values. Metanephrines are inactive metabolites of catecholamines and elevations either suggest the secretion of high circulating concentrations of catecholamines, or that catecholamines are being metabolized in a tumor to inactive metanephrines before secretion.

14. Rationale Continued: The absence of classic adrenergic symptoms in this patient does not exclude a pheochromocytoma; however, the marked elevation in normetanephrine levels (approximately 7.5 times the upper limit of the reference range) strongly suggests that this adrenal tumor is a pheochromocytoma.Once the clinical and/or biochemical characteristics either confirm or strongly suggest a pheochromocytoma, attention should be paid to the radiographic features. Pheochromocytomas are typically 2 cm or larger when a clinical syndrome of adrenergic excess is detected. However, the incidental detection of a pheochromocytoma can occur at any size. Pheochromocytomas tend to be dense and vascular. Therefore, they often have high attenuation on unenhanced CT imaging (>10 Hounsfield units) or high contrast avidity (often with heterogeneous enhancement) on CT imaging done with intravenous contrast, as in this patient’s case, or they have poor delayed contrast washout when CT imaging is performed with an adrenal washout protocol. On MRI, pheochromocytomas tend to display hyperintensity on T2-weighted imaging and have features suggestive of low lipid content (no loss of signal on out-of-phase sequences).The constellation of biochemical and radiographic findings in this vignette argues against a benign or malignant adrenocortical neoplasm (thus, Answers A, C, and D are incorrect). There is no biochemical evidence of aldosterone or cortisol excess (thus, Answer B is incorrect).This patient underwent a laparoscopic right adrenalectomy after preoperative α-adrenergic blockade, and pathologic examination revealed a 3.5-cm pheochromocytoma. Postoperatively, he did report a marked improvement in his overall anxiety level, which he had previously considered to be normal.

15. Reference(s): • Lenders JW, Duh QY, Eisenhofer G, et al; Endocrine Society. Pheochromocytoma and paraganglioma: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(6):1915-1942. PMID: 24893135 • Fassnacht M, Arlt W, Bancos I, et al. Management of adrenal incidentalomas: European Society of Endocrinology clinical practice guideline in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol. 2016;175(2):G1-G34. PMID: 27390021

16. ITE 2019 Question 31 A 46-year-old man is referred for evaluation of resistant hypertension. Chlorthalidone was discontinued 1 month ago due to hypokalemia. He is currently treated with amlodipine, benazepril, carvedilol, and hydralazine. On this regimen, he was screened for primary aldosteronism 1 week ago. Laboratory test results: • Sodium = 139 mEq/L (136-142 mEq/L) (SI: 139 mmol/L [136-142 mmol/L]) • Potassium = 2.9 mEq/L (3.5-5.0 mEq/L) (SI: 2.9 mmol/L [3.5-5.0 mmol/L]) • Serum aldosterone = 8 ng/dL (4-21 ng/dL) (SI: 221.9 pmol/L [111.0-582.5 pmol/L]) • Plasma renin activity = 0.8 ng/mL per h (0.6-4.3 ng/mL per h)

17. Which of the following should be your next step on the basis of these test results? • No further testing; primary aldosteronism has been excluded • Rescreen after correcting hypokalemia • Rescreen after stopping hydralazine • Rescreen after substituting doxazosin for amlodipine • Proceed to adrenal venous sampling Correct Answer: B Learning objective: IDENTIFY CAUSES OF FALSE-NEGATIVE SCREENING FOR PRIMARY ALDOSTERONISM.

18. Rationale: Although many medications interact with the renin-angiotensin-aldosterone axis, most antihypertensive agents act by vasodilation or volume depletion, which tend to raise plasma renin activity. Thus, when the renin is low (<1 ng/mL per h), the aldosterone-to-renin ratio is generally valid. β-Adrenergic blockers can lower renin, but aldosterone falls in parallel. The aldosterone-to-renin ratio in this case is 10, which is intermediate between a clearly positive screen (>20) and a normal screen (<4). During proper preparation for screening, however, it is important to first correct hypokalemia, as low potassium impairs aldosterone production. Thus, in a setting of high clinical suspicion and an unusual result with a very low potassium level, the screen cannot be dismissed as normal and should be repeated after correcting the hypokalemia (thus, Answer B is correct and Answer A is incorrect). Hydralazine and amlodipine do not significantly interfere with screening because the plasma renin activity is less than 1 ng/mL per hour. Thus, rescreening after stopping hydralazine (Answer C) or amlodipine (Answer D) is incorrect). Adrenal venous sampling (Answer E) is a localizing study that is conducted after confirming the diagnosis and performing cross-sectional imaging.

19. Reference(s): • Raizman JE, Diamandis EP, Holmes D, Stowasser M, Auchus R, Cavalier E. A renin-ssance in primary aldosteronism testing: obstacles and opportunities for screening, diagnosis, and management. Clin Chem. 2015;61(8):1022-1027. PMID: 26106077Funder JW, Carey RM, Mantero F, et al. The management of primary aldosteronism: case detection, diagnosis, and treatment: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016;101(5):1889-1916. PMID: 26934393

20. ITE 2019 Question 37 A 59-year-old woman is referred for evaluation of possible Cushing syndrome after bilateral adrenal nodules were found incidentally 6 months earlier. She has gained 150 lb (68.2 kg) over the past 15 years and has developed hypertension, type 2 diabetes mellitus, hyperlipidemia, sleep apnea, and depression. She has progressive weakness and relies on a wheelchair. On physical examination, she is a morbidly obese woman. Her blood pressure is 135/82 mm Hg. Her height is 67 in (170.2 cm), and weight is 359 lb (163.2 kg) (BMI = 56.2 kg/m2). She has facial rounding, plethora, acanthosis nigricans on her neck, multiple skin tags, and a marked increase in supraclavicular fullness and dorsocervical fat accumulation. Cutaneous wasting is present with multiple ecchymoses on her arms and hands. She has 2+ pretibial edema and proximal muscle weakness.

21. Laboratory test results: Electrolytes, normal Complete blood cell count, normal Hemoglobin A1c = 8.3% (4.0%-5.6%) (67 mmol/mol [20-38 mmol/mol]) Aldosterone = 4.4 ng/dL (4-21 ng/dL) (SI: 122.1 pmol/L [111.0-582.5 pmol/L]) Plasma renin activity = 9.1 ng/mL per h (0.6-4.3 ng/mL per h) Urinary free cortisol (2 measurements) = 31 µg/24 h (4-50 µg/24 h) (SI: 85.6 nmol/d [11-138 nmol/d]) (second measurement: 41 µg/24 h [SI: 113.2 nmol/d]). Creatinine measurements on each sample confirm these were both full 24 hour collections. Late-night salivary cortisol (4 measurements): 0.43 µg/dL (<0.13 µg/dL) (SI: 11.9 nmol/L [<3.6 nmol/L]) (second, third, and fourth measurements: 0.17 µg/dL [SI: 4.69 nmol/L], 0.30 µg/dL [SI: 8.28 nmol/L], and 0.24 µg/dL [SI: 6.62 nmol/L]) Cortisol after overnight 1-mg dexamethasone suppression test = 8.3 µg/dL (SI: 229.0 nmol/L) Basal plasma ACTH = 53 pg/mL (10-60 pg/mL) (SI: 11.7 pmol/L [2.2-13.2 pmol/L])

22. Pituitary MRI findings are normal. Abdominal CT performed 6 months earlier is reviewed. Bilateral adrenal nodules (8 Hounsfield units on the right side and 4 Hounsfield units on the left side) are identified (see image, arrows).

23. Which of the following diagnostic studies should you recommend next? • Bilateral adrenal venous sampling for cortisol and aldosterone • Measurement of plasma free fractionated metanephrines • Bilateral inferior petrosal sinus sampling for ACTH • Dexamethasone–corticotropin-releasing hormone test • CT-guided percutaneous biopsy of the right adrenal nodule Correct Answer: C Learning objective: Recommend bilateral inferior petrosal sinus sampling for ACTH as the diagnostic test of choice in patients with ACTH-dependent hypercortisolism and a normal pituitary imaging study.

24. Rationale: The diagnosis and differential diagnosis of endogenous Cushing syndrome is the one of the most challenging problems in clinical endocrinology. The clinical and biochemical findings in this patient certainly support the diagnosis of true Cushing syndrome. Several late-night salivary cortisol measurements are well above the normal reference range and results from an overnight 1-mg dexamethasone suppression test are abnormal. In light of the clinical findings in this patient, the diagnosis of endogenous hypercortisolism is secure. Although the 24-hour urinary free cortisol excretion is in the normal range, it has become increasingly appreciated that urinary free cortisol is an insensitive diagnostic test in the evaluation of patients with suspected hypercortisolism. The sensitivity of urinary cortisol is only 70% for the diagnosis of Cushing syndrome. Longitudinal studies in patients after pituitary surgery for Cushing disease have shown that an increase in late-night cortisol secretion is the earliest biochemically detectable abnormality during recurrence and that urinary free cortisol elevation is a much later event. The sensitivity of late-night salivary cortisol and the overnight 1-mg dexamethasone suppression test for Cushing disease is 94% to 98%. Because the clinical and biochemical data in this patient demonstrate unequivocal Cushing syndrome, no other studies to confirm the diagnosis, including a dexamethasone–corticotropin-releasing hormone test (Answer D), are required.

25. Rationale Continued: After the clinical and biochemical diagnosis of Cushing syndrome has been established, the initial differential diagnostic test should be measurement of basal plasma ACTH. This patient’s plasma ACTH elevation clearly suggests an ACTH-secreting neoplasm as the cause of her cortisol excess. The imaging studies in this woman could certainly cause diagnostic confusion. Because ACTH-dependent Cushing syndrome is expected, a pituitary MRI is the initial imaging study of choice. In light of her ACTH elevation, the low-attenuation adrenal nodules most likely represent ACTH-dependent nodular adrenal hyperplasia. Chronic ACTH stimulation causes nodular adrenocortical hyperplasia in at least 15% to 20% of patients. Since pheochromocytoma has been associated with ectopic ACTH production, it may seem reasonable to measure plasma free and fractionated metanephrine levels (Answer B) to exclude this possibility. However, this patient has very low-attenuation nodules (<10 Hounsfield units), which would be incompatible with pheochromocytoma. Adrenal nodules are usually associated with ACTH-independent hypercortisolism. Bilateral inferior petrosal sinus sampling for ACTH (Answer C) is always the diagnostic test of choice in patients with ACTH-dependent hypercortisolism and a normal pituitary imaging study. Corticotropin-releasing hormone is administered during this study, and a basal central-to-peripheral ACTH gradient greater than 2 or a post–corticotropin-releasing hormone central-to-peripheral ACTH gradient greater than 3 is consistent with an ACTH-secreting pituitary tumor. Because corticotroph adenomas usually express vasopressin receptors, desmopressin acetate (DDAVP) may be substituted if corticotropin-releasing hormone is not available.

26. Rationale Continued: Bilateral adrenal venous sampling for cortisol and aldosterone (Answer A) is not needed in patients with ACTH-dependent Cushing syndrome. CT-guided percutaneous biopsy (Answer E) of adrenal nodules is not indicated in patients with low-attenuation nodules. The only indications for CT-guided percutaneous biopsy of an adrenal nodule would be the presence of bilateral adrenal enlargement and primary adrenal insufficiency or in the setting of a known primary malignancy with potential metastasis to the adrenal gland where a clinical diagnosis may alter the treatment protocol or the prognosis. 

27. Reference(s): • Aron DC, Findling JW, Fitzgerald PA, et al. Pituitary ACTH dependency of nodular adrenal hyperplasia in Cushing’s syndrome: report of two cases and review of the literature. Am J Med. 1981;71(2):302-306. PMID: 6266251 • Alexandraki KI, Grossman AB. Is urinary cortisol of value in the diagnosis of Cushing’s syndrome? CurrOpin Endocrinol Diabetes Obes. 2011;18(4):259-263. PMID: 21681089

28. ITE 2019 Question 44 A 61-year-old man undergoes right adrenalectomy, right nephrectomy, and partial hepatectomy for adrenocortical carcinoma. Eight months earlier, he was discovered to have a 16-cm right adrenal mass with evidence of liver and pulmonary metastases. He had no clinical evidence of Cushing syndrome, although no steroid profile was obtained. He was referred to an oncologist. The patient received 6 cycles of adriamycin, cisplatin, and etoposide. Mitotane was also prescribed, and he has taken 3 to 6 g daily since his diagnosis and this has resulted in therapeutic mitotane levels. The adrenal mass regressed to 12 cm, his pulmonary metastases were no longer visible, and his liver metastases were stable. Eight hours after surgery, he develops shock with a blood pressure of 60/30 mm Hg, a pulse rate of 118 beats/min, and a temperature of 104oF (40oC). He is intubated after a bolus of etomidate, 10 mg intravenously, and mechanical ventilation is started. Urine output diminishes to less than 20 mL/h. Aggressive fluid resuscitation with isotonic fluids is initiated along with vasopressors (dopamine and norepinephrine infusion). A rapid ACTH-stimulation test is performed and then hydrocortisone, 100 mg intravenously every 8 hours, is immediately initiated.

29. Which of the following patterns of laboratory test results would you most likely expect from the rapid ACTH-stimulation test in this patient? Correct Answer: B. B Learning objective: Predict the pattern of laboratory test results in a patient with mitotane-induced primary adrenal insufficiency.

30. Rationale: Adrenocortical carcinoma (ACC) is a rare malignancy with incompletely understood pathogenesis and a very poor prognosis. Approximately 60% of patients with ACC present with steroid hormone excess (Cushing syndrome is the most common) or local mass effect. Even in the absence of clinical Cushing syndrome, all patients with ACC should have careful assessment of adrenal function before and during therapy. Cytotoxic chemotherapy in ACC with a combination of etoposide, doxorubicin, cisplatin, and mitotane provides the best outcomes. The response rate is as high as 50%; however, the median progression-free survival is short (only 5 months). Mitotane is the only adrenal-specific agent available for treatment of ACC, and its specific cytotoxic effects produce focal degeneration of the fasciculata and reticularis zones of the adrenal cortex. The efficacy of mitotane in patients with ACC is a matter of controversy with some studies showing clinical benefit and others not demonstrating any positive impact. Adverse effects are common.  Because of its adrenolytic activity, mitotane inevitably induces primary adrenal insufficiency. Mitotane also increases the metabolic clearance of glucocorticoids (by its induction of CYP3A4), increases corticosteroid-binding globulin, and may further reduce the free fraction of cortisol and cause confusion when measuring total cortisol concentrations. All patients receiving mitotane should be expected to develop primary adrenal insufficiency and should receive glucocorticoid support. Most patients on therapeutic mitotane require 40 to 60 mg of hydrocortisone daily in divided doses. Monitoring of ACTH and cortisol levels is important. 

31. Rationale Continued: Further confounding the adrenal function in this patient was the use of etomidate before mechanical ventilation. Like ketoconazole, etomidate is an imidazole derivative and abruptly inhibits adrenal steroid biosynthesis by inhibiting both 11β-hydroxylase and side-chain cleavage enzymes. Accordingly, this patient had mitotane-induced primary adrenal insufficiency further aggravated by the use of etomidate. Therefore, elevated basal ACTH and absent cortisol response to ACTH (Answer B) is the pattern of laboratory test results would you most likely expect. If the patient had a cortisol-producing adrenocortical tumor (previously untreated with adrenolytic or adrenostatic therapy), its removal may be associated with secondary adrenal insufficiency due to its autonomous cortisol production with suppression of the hypothalamic-pituitary secretion of corticotropin-releasing hormone and ACTH. However, this patient did not have any clinical evidence of preexisting Cushing syndrome and had been treated for many months with an adrenolytic agent (therefore, Answer A is incorrect). Answer C is incorrect because a plasma ACTH concentration of 365 pg/mL (80.3 pmol/L) would provoke a maximum cortisol response and further administration of ACTH would not cause any additional increase in cortisol concentration. Furthermore, the adrenolytic effect of mitotane would limit the adrenocortical secretion of cortisol regardless of the magnitude of ACTH secretion. Answers D and E are incorrect because they represent a normal cortisol secretory response and are not consistent with the clinical picture of adrenal insufficiency. 

32. Reference(s): • Else T, Kim AC, Sabolch A, Raymond VM, Kandthil A, Caoili EM, et al. Adrenocortical carcinoma. Endocr Rev. 2014;35(2):282-326. PMID: 24423978 • Terzolo M, Fassnacht M, Ciccone G, Allolio B, Berruti A. Adjuvant mitotane for adrenocortical cancer--working through uncertainty. J Clin Endocrinol Metab. 2009;94(6):1879-1880. PMID: 19494162 • Terzolo M, Baudin AE, Ardito A, Kroiss M, Leboulleux S, Daffara F, et al. Mitotane levels predict the outcome of patients with adrenocortical carcinoma treated adjunctively following radical resection. Eur J Endocrinol. 2013;169(3):263-270. PMID: 23704714

33. ITE 2019 Question 64 A 68-year-old man is referred to you after a retroperitoneal mass was incidentally identified on abdominal CT performed to investigate intermittent abdominal pain (see image, arrow). He has a 6-year history of poorly controlled hypertension, but no other notable medical history. His current medication regimen consists of hydrochlorothiazide and lisinopril. His brother was recently treated for a kidney tumor.

34. On physical examination, his height is 72.5 in (184.2 cm) and weight is 202 lb (91.8 kg) (BMI = 27 kg/m2). Fundoscopic examination reveals grade II hypertensive changes only (silver wiring, arteriovenous nicking). The rest of the examination findings are normal. Laboratory test results: • Urinary catecholamine fractionation: • Dopamine = 480 µg/24 h (<700 µg/24 h) (SI: 3132 nmol/d [<4567 nmol/d]) • Epinephrine = 25 µg/24 h (<35 µg/24 h) (SI: 136 nmol/d [<191 nmol/d]) • Norepinephrine = 568 µg/24 h (<170 µg/24 h) (SI: 3359 nmol/d [<1005 nmol/d])

35. Which of the following genes should be tested first to search for a pathogenic variant? • VHL (von Hippel–Lindau tumor suppressor) • SDHB (succinate dehydrogenase complex, subunit B) • SDHC (succinate dehydrogenase complex, subunit C) • SDHD (succinate dehydrogenase complex, subunit D) • Genetic testing is not indicated Correct Answer: B Learning objective: Determine the optimal sequence of genetic testing in paraganglioma/pheochromocytoma on the basis of clinical, imaging, and biochemical findings at presentation.

36. Rationale: This vignette describes an abdominal paraganglioma that is secreting excess norepinephrine (as is the case with approximately 50% of abdominal paragangliomas). At least one-third of all patients with paraganglioma have a disease-causing pathogenic variant. Thus, while it was previously common practice to restrict genetic testing to patients presenting with pheochromocytoma or paraganglioma at a young age (ie, younger than 50 years), the Endocrine Society now recommends that genetic testing be offered to all patients with paraganglioma (therefore, Answer E is incorrect). Since 1990, 14 different pheochromocytoma and paraganglioma susceptibility genes have been identified. Most cases of familial paraganglioma are caused by mutations in the succinate dehydrogenase (SDH; succinate:ubiquinone oxidoreductase) subunit genes (SDHB, SDHC, SDHD, SDHAF2, SDHA), which compose portions of mitochondrial complex II. However, paraganglioma has also been reported in the setting of von Hippel–Lindau syndrome, and pathogenic variants in the SDHAF2 gene, TMEM127 gene (transmembrane protein 127), and MAX gene (Myc-associated factor X) have recently been described in familial paraganglioma. Such pathogenic variants are rare and the mechanism behind tumor formation in these circumstances remains unclear.

37. Rationale Continued: Genotyping of the main pheochromocytoma/paraganglioma susceptibility genes has been reported in a series of studies that include 3000 patients. Germline pathogenic variants were documented in 33.8% and were most common in SDHB (10.30%), SDHD (8.09%), VHL (6.80%), RET (5.00%), and NF1 (2.40%). Pathogenic variants in SDHC, SDHA, MAX, and TMEM127 collectively occur in less than 2% of such cases. With this in mind, and given the costs of genetic testing, it is recommended that a stepwise approach be applied to genetic testing on the basis of clinical and biochemical features at presentation. The current algorithm recommended by the Endocrine Society is outlined in the Figure. The gene most likely to harbor a pathogenic variant in this man with an extra-adrenal, norepinephrine-producing tumor is SDHB (Answer B). In addition, the family history of possible renal cancer further supports this answer because SDHB pathogenic variants are associated with renal carcinoma. Although SDHD testing (Answer D) should be performed if no germline pathogenic variants are found in the SDHB gene, this should not be the initial gene of choice. Pathogenic variants in SDHD are most commonly associated with head and neck paragangliomas, which are usually (in 95% of cases) nonfunctional. Pathogenic variants in SDHC (Answer C) are very rare in paraganglioma and this gene should only be screened if no pathogenic variants are found in SDHB or SDHD. The absence of any other clinical features of von Hippel–Lindau syndrome, as well as the lower frequency of VHL pathogenic variants (Answer A) in hereditary paraganglioma, make this a less likely genetic cause of paraganglioma.

38. Rationale Continued: Figure. Algorithm outlining optimal sequence of genetic testing in patients with pheochromocytoma or paraganglioma. Adapted from Lenders JW, Duh QY, Eisenhofer G, et al; Endocrine Society. 2014 Pheochromocytoma and paraganglioma: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(6):1915-1942.

39. Reference(s): • Galan SR, Kann PH. Genetics and molecular pathogenesis of pheochromocytoma and paraganglioma. Clin Endocrinol (Oxf). 2013;78(2):165-175. PMID: 23061808 • Lenders JW, Duh QY, Eisenhofer G, et al; Endocrine Society. 2014 Pheochromocytoma and paraganglioma: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(6):1915-1942. PMID: 24893135

40. ITE 2019 Question 69 A 22-year-old woman is sent for evaluation of irregular menses and hirsutism. She reports that she developed pubic hair and body odor at age 4 years and was diagnosed with “premature adrenarche,” but no testing was performed. She was tall relative to her peers until sixth grade, when she stopped growing. She had menarche at age 10.5 years, and she developed acne, facial hair, and menstrual irregularities starting at age 14 years. Her last menstrual period was 3 months ago. She has a brother who was also a tall child but stopped growing in the sixth grade and a sister who had normal growth and development and now has regular monthly menses. On physical examination, her blood pressure is 115/70 mm Hg and BMI is 23 kg/m2. She has coarse terminal hair stubble on her chin, upper lip, and sides of her face and acne on her cheeks and forehead. She has no moon facies, dermal atrophy, myopathy, striae, or acanthosis nigricans. Pelvic examination findings are normal, including typical external genitalia. Laboratory test results: • Serum testosterone = 60 ng/dL (8-60 ng/dL) (SI: 2.1 nmol/L [0.3-2.1 nmol/L]) • Serum DHEA-S = 545 µg/dL (44-332 µg/dL) (SI: 14.8 µmol/L [1.19-9.00 µmol/L]) • Serum 17-hydroxyprogesterone = 300 ng/dL (<80 ng/dL [follicular]; <285 ng/dL [luteal]; <51 ng/dL [postmenopausal]) (SI: 9.1 nmol/L [<2.42 nmol/L (follicular)]; [<8.64 nmol/L (luteal)]; [<1.55 nmol/L (postmenopausal)])

41. Which of the following is the most appropriate next step in this patient’s evaluation? • ACTH-stimulation test measuring 17-hydroxyprogesterone and cortisol • ACTH-stimulation test measuring 17-hydroxypregnenolone and DHEA • Adrenal-directed CT • Plasma ACTH measurement • No further testing Correct Answer: A Learning objective: Guide the biochemical evaluation of adrenal androgen excess.

42. Rationale: If cortisol production is normal and the history indicates androgen excess in childhood, then nonclassic 21-hydroxylase deficiency (21-OHD) should be considered. (Note that “premature adrenarche” is a descriptive term that requires the exclusion of 21-OHD, which was not previously done.) A morning 17-hydroxyprogesterone concentration less than 200 ng/dL (<6.1 nmol/L) excludes nonclassic 21-OHD, and a value greater than 1000 ng/dL (>30.3 nmol/L) establishes the diagnosis. Serum 17-hydroxyprogesterone varies with time of day and across the menstrual cycle. Given the suspicious history and an equivocal random value of 300 ng/dL (9.1 nmol/L), a formal ACTH-stimulation test for 17-hydroxyprogesterone and cortisol (Answer A) is warranted. Adrenal-directed CT (Answer C) is recommended if the testosterone concentration is markedly elevated (>150 ng/dL [>5.2 nmol/L]). Nonclassic 3β-hydroxysteroid dehydrogenase/isomerase deficiency is exceedingly rare and is only considered in unusual cases after nonclassic 21-OHD has been excluded. Furthermore, the best parameter for this diagnosis is the 17-hydroxypregnenolone-to-cortisol ratio, which must be measured together (thus, Answer B is incorrect). Plasma ACTH measurement (Answer D) will not aid in this patient’s diagnosis. In a patient with childhood-onset androgen excess sufficient to advance bone age, a diagnosis should be pursued. Thus, no further testing (Answer E) is incorrect.

43. Reference(s): • Auchus RJ. The classic and nonclassic congenital adrenal hyperplasias.EndocrPract. 2015;21(4):383-389. PMID: 25536973 • Witchel SF. Nonclassic congenital adrenal hyperplasia. CurrOpin Endocrinol Diabetes Obes. 2012;19(3):151-158. PMID: 22499220 • Carbunaru G, Prasad P, Scoccia B, et al. The hormonal phenotype of nonclassic 3beta-hydroxysteroid dehydrogenase (HSD3B) deficiency in hyperandrogenic females is associated with insulin-resistant polycystic ovary syndrome and is not a variant of inherited HSD3B2 deficiency. J Clin Endocrinol Metab. 2004;89(2):783-794. PMID: 14764797

44. ITE 2019 Question 82 A 54-year-old woman with a history of HIV infection and asthma presents with polyuria, polydipsia, and a blood glucose value of 317 mg/dL (17.6 mmol/L). She has no history of hyperglycemia or diabetes mellitus. HIV was diagnosed 20 years ago and is well controlled, with a recent CD4 cell count greater than 500 and an undetectable viral load. Her medication regimen includes darunavir (protease inhibitor), ritonavir (protease inhibitor), etravirine (nonnucleoside reverse transcriptase inhibitor), emtricitabine (nucleoside reverse transcriptase inhibitor), inhaled fluticasone (250 mcg twice daily), salmeterol (50 mcg twice daily), atorvastatin, and lisinopril. On physical examination, she has several features of Cushing syndrome, including moon facies, dorsocervical fat pad, central adiposity, lipoatrophy of the arms and legs, and violaceous striae.

45. Her primary care physician had measured morning cortisol, which returned surprisingly low at 1.7 µg/dL (46.9 nmol/L) and prompted further testing (ACTH-stimulation test):

46. Which of the following is the most likely diagnosis? • Primary adrenal insufficiency • Fluticasone-induced secondary adrenal insufficiency • Cortisol-producing adrenal adenoma • Ectopic ACTH secretion and Cushing syndrome • ACTH-secreting pituitary adenoma Correct Answer: B Learning objective: Diagnose secondary adrenal insufficiency in a patient taking ritonavir (a protease inhibitor that inhibits CYP3A4 activity) and glucocorticoids.

47. Rationale: This patient presents with the clinical features of Cushing syndrome; however, her biochemical evaluation reveals a low morning cortisol level with an inappropriately low ACTH, as well as a suboptimal cortisol response to cosyntropin. Collectively, this patient has clinical Cushing syndrome combined with chronic secondary adrenal insufficiency (secondary adrenal insufficiency that has resulted in prolonged ACTH suppression, consequent atrophy of the zona fasciculata, and suboptimal cortisol stimulation to cosyntropin). The main culprit is the combination of ritonavir and fluticasone. Ritonavir is a unique protease inhibitor because it is a potent inhibitor of P450 CYP3A4. CYP3A4 is responsible for the hepatic metabolism of many medications, including glucocorticoids; therefore, ritonavir inhibits the metabolism of glucocorticoids and results in a potentiation of exogenous glucocorticoids. In fact, ritonavir is most commonly used to “boost” the effect of other protease inhibitors in HIV therapy. Since some protease inhibitors cause gastrointestinal adverse effects that limit their tolerability, administering them in smaller and less toxic doses in combination with ritonavir permits tolerability while maintaining adequate blood levels due to CYP3A4 inhibition. However, an undesired consequence of ritonavir use is that exogenous glucocorticoids, including inhaled, topical, and intraarticular glucocorticoids that have small systemic absorption, are potentiated. This patient’s combination of fluticasone (Answer B) and ritonavir most likely resulted in high levels of systemic fluticasone circulation, resultant Cushing syndrome, and hypothalamic-pituitary-adrenal axis suppression. Fluticasone is a synthetic glucocorticoid and is not measured by the cortisol assay.

48. Rationale Continued: This patient’s management is complex. While the fluticasone is most likely being potentiated at supratherapeutic levels and inducing Cushing syndrome and adrenal insufficiency, it is also treating adrenal insufficiency. Cessation of the medication could result in an adrenal crisis. Replacing fluticasone with an oral glucocorticoid taper is also challenging because the concomitant use of ritonavir will decrease glucocorticoid metabolism and result in unpredictable pharmacokinetics. A multidisciplinary discussion is recommended for these challenging cases. This patient’s antiretroviral regimen was changed to avoid the use of ritonavir, her fluticasone was stopped, and she was treated with a gradual low-dosage prednisone taper until her hypothalamic-pituitary-adrenal axis normalized. There is no evidence of primary adrenal insufficiency (Answer A), which would be characterized by very high ACTH and renin activity levels. There is no evidence of ectopic ACTH syndrome (Answer D), an ACTH-secreting pituitary adenoma (Answer E), both of which would be characterized by a high cortisol level combined with an inappropriately high ACTH level. A cortisol-producing adrenal adenoma (Answer C) would be associated with a low ACTH, but there is no evidence of endogenous hypercortisolism here.

49. Reference(s): • Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2016;101(2):364-389. PMID: 26760044

50. ITE 2019 Question 87 A 23-year-old woman is referred for evaluation of weight gain and difficulty sleeping. She has just graduated from college and is having trouble finding a job. She reports a 15.5-lb (7-kg) weight gain over the past 3 months even though she thinks her caloric intake has been low and physical activity has been high. Her current weight is 145 lb (66 kg). At night, she has had difficulty falling asleep and staying asleep. She takes norgestimate-ethinyl estradiol daily for contraception. On physical examination, her blood pressure is 131/92 mm Hg. She has a small dorsocervical fat pad, but no obvious moon facies, supraclavicular fat pads, striae, lipoatrophy, or lipodystrophy. Her primary care physician had performed an evaluation for Cushing syndrome (testing performed at 8 AM following 1-mg of dexamethasone taken at 11 PM the night before): Cortisol = 30 µg/dL (SI: 827.6 nmol/L) ACTH = 45 pg/mL (10-65 pg/mL) (SI: 9.9 pmol/L [2.2-14.3 pmol/L]) On the basis of these lab values, her primary care physician performed both pituitary and adrenal imaging. Pituitary MRI showed a possible 5-mm pituitary adenoma; however, the finding was small enough that confidence for an abnormality was low. Abdominal CT was also performed and demonstrated a 1.1-cm left adrenal adenoma.