CLINICAL FEATURES

Clinical features of PPGLs that secrete excessive catecholamines are variable. The classic triad of headache, palpitations, and excessive sweating is now a more unusual presentation. In earlier stages, some individuals may have minimal, nonspecific symptoms and some may have no symptoms at all. Hypertension is seen in 90% of cases; paroxysmal hypertension in otherwise healthy, young individuals is seen in 50% of cases, and can be the first indication of catecholamine excess. Paroxysmal hypertension can subsequently present as episodic severe acute chest pain due to cardiac vasospasm, and can be mistaken for myocardial infarction or acute aortic dissection. Pheochromocytoma crisis is a rare emergency defined as hypertensive crisis or hypotension with hyperthermia (greater than 104°F), encephalopathy, multiorgan failure, with pulmonary edema and circulatory collapse.

DIAGNOSIS

According to recent Endocrine Society guidelines, the initial screening test is biochemical testing – plasma free or urinary fractionated metanephrines using liquid chromatography with electrochemical or mass spectrometric laboratory methods. ^{, ,} Plasma fractionated metanephrines along with dopamine metabolite 3-methoxy tyramine has higher sensitivity (95%) compared to urinary fractionated metanephrines. Symptomatic PPGL can be excluded if plasma fractionated metanephrine levels are within the normal reference range. ^, Specificities of plasma and urine fractionated metanephrines are 96% and 89%, respectively. When measuring plasma fractionated metanephrines, blood work should be done with the patient in supine position for at least 20 minutes using reference standards using the same position to minimize false positive results. ^{, ,} False-positive test results are more common than true positives. The most common causes of false positives are medications such as levodopa, tricyclic antidepressants, and antipsychotics that falsely elevate fractionated metanephrine levels. Biochemical false positives are also common in extremely stressful conditions such as severe pain, cardiac ischemia, and hypoglycemia, and in patients in intensive care units. Therefore, in these settings if the clinician has a high suspicion for PPGL, computed cross-sectional imaging of the abdomen and pelvis may be indicated.

For appropriate interpretation of test results, one has to take into account the pretest probability of disease and extent of elevation above the upper limit of normal. If levels are elevated more than two fold the upper limit of normal, then it is high likely that the patient has PPGL (assuming interfering medications are excluded). But, if levels are less than twice the upper limit of normal, then it is difficult to distinguish between false positives versus true positives. In those cases, the clinician should consider the medications and conditions that can cause false-positive results. If clinical suspicion is high and plasma normetanephrine is elevated, a clonidine suppression test can be done to exclude a catecholamine-secreting tumor.

IMAGING

After clear biochemical evidence of PPGL is established, the next step is to localize the tumor. A computed tomography (CT) scan is preferred over magnetic resonance imaging (MRI) because of its superior spatial resolution in the thorax, abdomen, and pelvis. ^, An MRI is preferred in those cases with neck or skull base paragangliomas, pregnancy, or concern for metastatic disease. ^, An adrenal lesion with an unenhanced CT attenuation value of less than 10 Hounsfield units (HU) can reliably rule out a pheochromocytoma. Even though a CT scan has higher sensitivity (greater than 90%), it has lower specificity (75% to 80%). A CT scan provides only the anatomic location of the tumor but does not provide any information on the functionality of the tumor. Pheochromocytoma size can vary anywhere from 1 to 15 cm and average approximately 4 to 6 cm upon diagnosis. Smaller tumors consist of solid, homogeneous tissue, whereas in larger tumors it is typical to see central necrosis with a peripheral rim of tumor tissue. Pheochromocytomas are usually spherical in shape, with smooth borders and morphologically can mimic other adrenal masses. Differential diagnosis should include lipid-poor adenoma, adrenal carcinoma, and metastasis. Unlike lipid-rich adenomas, pheochromocytoma attenuation is always 10 HU or higher due to the absence of intracytoplasmic lipids. In targeted adrenal CT protocols, which include late enhancement scans, adenomas express rapid washout. Unfortunately, unenhanced CT attenuation and washout characteristics cannot distinguish between adrenal carcinoma and metastasis.

In patients with suspicion for metastatic PPGL, functional imaging is the next step. ^, Functional imaging is not necessary if patients are over 40 years of age, have no family history, an adrenal tumor size less than 3 cm mainly secreting metanephrines, or have negative genetic testing. In extra-adrenal tumors, regardless of tumor size or genetic testing, functional imaging is needed to stage the tumor and determine if there are additional paragangliomas. Iodine-123-metaiodobenzylguanidine ( ¹²³ I-MIBG) scintigraphy and gallium 68 (68-Ga) 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-octreotate (DOTATATE) positron emission tomography (PET) CT can be used to identify additional PPGLs and stage the known PPGL. ^{, 18} F-fluorodeoxyglucose ( ¹⁸ F-FDG) PET CT is also useful in detecting sites of metastatic disease and is preferred over ¹²³ I-MIBG scintigraphy in patients with known metastatic PPGL.

GENETIC TESTING

Approximately 40% of PPGLs are inherited or familial and are associated with pathogenic variants in 15 susceptibility genes. The most commonly mutated genes are RET proto-oncogene (multiple endocrine neoplasia type 2), von Hippel–Lindau ( VHL ), succinate dehydrogenase subunits B ( SDHB ), C ( SDHC ), D ( SDHD ), and neurofibromatosis type 1 ( NF1 ) ( Table 12.1 ). SDHB pathogenic variants are associated with aggressive metastatic disease (40% to 60%).

Genetic testing is recommended for all patients with PPGLs, especially those with a positive family history, bilateral adrenal tumors, paraganglioma, and of younger age. ^, It is also recommended to counsel family members for the possibility of genetic PPGLs and recommend the evaluation of first-degree relatives.

PREOPERATIVE MEDICAL MANAGEMENT

Preoperative medical management and preparation for surgery is essential to minimize the risks of a catecholamine surge during surgery, which can be fatal. Focus is aimed at controlling volume expansion, hypertension, and tachycardia to avoid intraoperative hemodynamic instability. An electrocardiogram should be done as part of the preoperative evaluation; an echocardiogram should be ordered if there are any concerns about cardiac function. Perioperative α-adrenergic blocking agent starting at least 7 to 14 days prior to surgery is recommended. The period of α-adrenergic blockade should be longer in patients with organ damage due to long-standing catecholamine excess.

The most commonly used α-adrenergic blocking agents are phenoxybenzamine and doxazosin. Phenoxybenzamine is a noncompetitive, nonselective α-adrenergic blocking agent that binds to alpha-1 and alpha-2 receptors, has a long half-life (24 to 48 hours), and is not easily overcome by catecholamine tumor burden. The initial dose is 10 mg once or twice orally daily and can be increased by 10 to 20 mg every 2 to 3 days. The final dose is usually 1 mg/kg per day but can be as high as 240 mg/day. Side effects include orthostasis, tachycardia, dizziness, fatigue, and retrograde ejaculation in males, and severe nasal congestion. Phenoxybenzamine is slightly better in controlling systolic blood pressure than selective alpha-1 blockade, and it can be associated with postoperative hypotension 24 to 48 hours following treatment discontinuation; therefore, vasopressor support and intravenous fluids may be needed following surgery.

Doxazosin, prazosin, and terazosin are selective alpha-1 blocking agents, which preferentially bind to alpha-1 receptors, subsequently causing vasodilation. Because these agents do not bind to alpha-2 receptors, tachycardia occurs less often compared to phenoxybenzamine. Due to their short half-life, the last dose should be given on the morning of surgery as they have a risk of inadequately controlling catecholamine release intraoperatively. Conversely, compared to phenoxy­benzamine, postoperative hypotension is less likely. Side effects include vertigo, headache, gastrointestinal symptoms, and postural hypotension. Doxazosin has a 12-hour half-life and is usually administered one to two times daily with the initial dose being 1 to 2 mg/day and the maximum dose being 16 mg/day. Prazosin is initiated as a 0.5- to 1-mg dose every 4 to 6 hours and titrated to an average of 2 to 5 mg two to three times a day with a maximum total of 20 to 24 mg/day. Terazosin can be initiated at a dose of 1 mg/day, with an average of 2 to 5 mg/day and maximum dose of 20 mg/day.

Calcium channel blocking agents such as nicardipine, amlodipine, nifedipine, and verapamil can also be used as an add-on therapy in controlling blood pressure preoperatively. ^, Calcium channel blockers inhibit norepinephrine-mediated transmembrane influx of calcium into smooth muscle cells/myocardium and therefore significantly assist in controlling hypertension and tachy­arrhythmia, without the burden of causing hypotension during a normotensive state. They are useful as adjunct therapy for patients with inadequate blood pressure control to prevent the need for increasing α-adrenergic blockade agents. Calcium channel blockers can be used as an alternative for those patients who cannot tolerate α-adrenergic blockade due to its side effects or in patients with intermittent hypertension. Calcium channel blockers are also very useful in preventing catecholamine-driven coronary vasospasm. ^,

β-Adrenergic blockers can be used to counteract tachycardia induced by α-adrenergic blocking agents but should never be used before the initiation of α-adrenergic blockade as an unopposed α-adrenergic effect could cause severe vasoconstriction with subsequent acute cardiac failure, hypertensive crisis, and pulmonary edema. Metoprolol (starting at 12.5 mg extended release once daily and titrated for a target heart rate of 80 beats per minute) and atenolol (starting at 12.5 mg daily) are cardio-selective β-adrenergic antagonists and have less side effects than nonselective β-adrenergic antagonists.

Target blood pressure should be low-normal for age and comorbidities. For example, in a 20-year-old, a systolic blood pressure of 100 mm Hg is reasonable, whereas in a 75-year-old patient with chronic kidney disease, a systolic blood pressure of 130 mm Hg would be a reasonable target. Orthostatic hypotension is not a goal of therapy, but rather a side effect of adrenergic blockade. Orthostasis can be reversed in part by a high sodium diet (5000 mg/day). There is a risk of postoperative hypotension from α-adrenergic blocking agents, hence a high-sodium diet (mentioned previously) and increased fluid intake to increase volume is recommended to decrease perioperative morbidity and mortality. ^,

ACUTE MEDICAL MANAGEMENT OF PPGL CAUSING HYPERTENSIVE EMERGENCY

Hypertensive emergency due to PPGL should be managed in the intensive care unit setting with intravenous drugs with a short half-life. The drug of choice for hypertensive emergency due to PPGL is the α-adrenergic blocker phentolamine (half-life of 19 minutes), which can be initiated as a 5-mg intravenous bolus, and additional boluses can be given every 10 minutes to reduce blood pressure to the target level. In addition, an intravenous calcium channel blocker (e.g., intravenous nicardipine) may be used due to its peripheral and coronary vasodilation properties and ability to prevent coronary vasospasm. The initial infusion rate of intravenous nicardipine is 5 mg/hour, increased by 2.5 mg/hour every 15 minutes, with a maximum dose of 30 mg/hour. Clevidipine is also a calcium channel blocker available for intravenous use (initial dose 1 to 2 mg/hour), which has a shorter half-life; however, it is expensive and less widely available, but can achieve tighter blood pressure control with less risk of overshoot hypotension. Finally, IV sodium nitroprusside is a vasodilator with a rapid onset and short duration of effect and can be initiated at a very low rate (0.3 μg/kg per minute) and titrated every few minutes until target blood pressure is achieved; the maximum recommended infusion rate is 10 μg/kg per minute. ^,

SURGERY

The best surgical approach for pheochromocytomas is minimally invasive laparoscopic adrenalectomy, unless the tumor is greater than 6 cm or is invasive, in which case open resection is recommended. Posterior retroperitoneoscopic adrenalectomy is the most favorable and direct approach to the adrenal gland with the shortest surgery time due to the elimination of intraperitoneal dissection. Patient satisfaction is higher, and recovery is quicker with the retroperitoneal approach. This is due to less pain and avoidance of the major intraabdominal dissection (such as liver dissection on the right side, or spleen and colon on the left side) required to reach the adrenal glands if surgery is performed through the abdominal transperitoneal approach. Nevertheless, if there are any concerns over the possibility of malignant pheochromocytoma, based on radiologic studies, surgery should be performed through the abdominal approach, starting with laparoscopic and conversion to open if necessary. For paragangliomas, open resection is usually recommended. Partial adrenalectomy (cortical sparing) is suggested for patients with bilateral disease, or hereditary pheochromocytomas, such as MEN2 syndrome, due to a high possibility of bilateral tumors. ^, By sparing healthy adrenocortical tissue, it may be possible to avoid life-long glucocorticoid and mineralocorticoid replacement.

Postoperatively, the patient should be monitored closely for hemodynamic instability and hypoglycemia for 24 to 48 hours. Intravenous infusion of normal saline with dextrose as well as vasopressors/inotrope agents may be needed for volume expansion. Sudden catecholamine withdrawal following tumor removal also leads to rebound hyperinsulinemia and subsequent rebound hypoglycemia. Frequent blood glucose monitoring in the first 24 hours after surgery is needed.

PATHOLOGY

All PPGLs have malignant potential. About 10% of pheochromocytomas and 20% of catecholamine-secreting paragangliomas become metastatic. The most utilized scoring system to stratify malignancy risk is the Pheochromocytoma of Adrenal Gland Scales Score (PASS) proposed by Thompson in 2002. A PASS score of greater than or equal to 4 suggests malignant lesion. One point is given for capsular invasion, vascular invasion, profound nuclear pleomorphism, or hyperchromasia, and two points are given for invasion of periadrenal adipose tissue, focal or confluent necrosis, high cellularity, large nests or diffuse growth, spindling of tumor cells, 4+ mitotic figures per 10 high-power field (hpf), atypical mitotic features, or cellular monotony.

FOLLOW-UP

Plasma or 24-hour urine fractionated metanephrines should be measured at 2 to 6 weeks postsurgery to confirm whether the tumor has been resected successfully. In the case of persistently elevated fractionated metanephrines, further imaging is recommended. The European Society of Endocrinology Clinical Practice Guideline recommends following up on plasma or urine fractionated metanephrine levels every year for at least 10 years. However, many experts recommend life-long follow-up. A metaanalysis showed the risk of recurrence is around 5% during 5-year follow up.

CLINICAL FEATURES

Patients with PA can present with nonspecific symptoms such as fatigue, muscle weakness, muscle cramps, nocturia, and headaches. Clinically, patients will have hypertension but not always hypokalemia. PA can rarely present as a hypertensive emergency, with uncertain prevalence, as there are few cases reported. Early diagnosis of PA is essential, as long-standing PA causes an increase in fibrosis and collagen production at the cardiac intraventricular septum and peripheral vasculature and is subsequently associated with left ventricular hypertrophy, cardiovascular disease, myocardial infarction, and stroke (the most common causes of mortality).

The Endocrine Society recommends screening for PA in patients who meet one of the following criteria:

• 1.
  

  Sustained blood pressure above 150/100 mm Hg in three separate measurements taken on three different days

  
  
• 2.
  

  Resistant HTN (greater than 140/90 mm Hg) on three conventional antihypertensive medications, one including a diuretic

  
  
• 3.
  

  Controlled HTN (less than 140/90 mm Hg) with four or more medications

  
  
• 4.
  

  HTN associated with hypokalemia or adrenal incidentaloma or sleep apnea

  
  
• 5.
  

  HTN and family history of early onset of HTN or stroke before 40 years of age

  
  
• 6.
  

  HTN with first-degree relatives with PA

DIAGNOSIS

Screening for PA includes measurement of the plasma aldosterone and renin levels in the morning hours in an ambulant patient in the seated position. Plasma aldosterone concentration (PAC) greater than 10 ng/dL associated with a suppressed plasma renin concentration less than 1 ng/mL per hour or a renin concentration below the lower limit of the reference range is a positive case detection test for PA.

However, case detection testing lacks sensitivity and specificity. All patients with positive case detection testing should have PA confirmed with an additional test. Confirmatory testing can be completed using one of the four recommended methods: oral sodium loading with measurement of 24-hour urine aldosterone excretion, the saline infusion test (SIT) over 4 hours, the fludrocortisone suppression test (FST), or the captopril challenge test (CCT). No test is superior to another, and the test is usually chosen based on patient preference, cost, and local expertise. However, in patients with spontaneous hypokalemia with undetectable renin levels and PAC greater than 20 ng/dL, further confirmatory testing is not needed. ^,

For the oral sodium loading test, salt intake is increased to 5 g/day for 3 days (confirmed by 24-hour urine sodium content greater than 200 mmol) and slow-release potassium chloride is given to maintain plasma potassium in the normal range. Urinary aldosterone is measured in the 24-hour urine collection between the mornings of day 3 to day 4. An aldosterone level greater than 12 µg/24-hour in a patient with suppressed renin confirms the diagnosis of PA. The SIT should be done in the seated position with 2 L of normal saline infused over 4 hours starting at 8:00 a.m. Levels of renin, aldosterone, cortisol, and plasma potassium are drawn at time 0 and 4 hours. PAC greater than 10 ng/dL confirms PA and levels above 5 ng/dL but less than 10 ng/dL represent a gray zone and are highly suggestive of PA. ^,

The FST requires hospitalization for 4 days and is rarely performed anymore. ^,

For the CCT, the patient receives 25 or 50 mg of captopril orally while seated. Plasma renin, aldosterone, and cortisol levels are drawn at time 0 and 2 hours after captopril administration. In patients with PA, aldosterone remains elevated and renin remains suppressed following the challenge. ^,

IMAGING

After the diagnosis of PA is confirmed, all patients should undergo an adrenal CT scan to localize the tumor as an initial subtype testing. The CT scan also provides details about the size of the adrenal adenoma and any characteristics of malignancy such as irregular borders, delayed washout, local invasion, etc. In bilateral adrenal hyperplasia, the CT scan may show normal-appearing adrenal glands or nodular changes, whereas unilateral APA usually present as microadenomas (less than 1 cm) and may not be visible on CT. Hence, the CT scan can be inaccurate in nearly half of the cases with risk of missing APA or BAH. If a nodule is found on a CT scan, it may be nonfunctioning and unrelated to the diagnosis of PA. Multiple studies have demonstrated that the CT or MRI scan should be used in conjunction with adrenal venous sampling (AVS) to localize the source of PA accurately. Hence, in almost all patients, AVS is a prerequisite before proceeding to surgery. Even though there was an exception not to use AVS in patients younger than 40 years of age with confirmed PA and hypokalemia with normal kidney function, more recent reports recommended to use AVS in all patients with PA.

ADRENAL VENOUS SAMPLING

AVS should be done by an experienced interventional radiologist. It can be done either simultaneously or sequentially with or without cosyntropin administration. Cosyntropin increases the blood supply to the adrenal glands, and therefore the adrenal veins can be more easily catheterized. AVS test results are interpreted by measuring adrenal vein aldosterone to cortisol (A/C) concentration in bilateral adrenal veins and A/C concentration in the peripheral vein. The A/C ratio of the dominant to nondominant side is termed the aldosterone lateralization index (LI). If AVS is done following cosyntropin, an LI of greater than 4 indicates a unilateral source of aldosterone hypersecretion. If the LI is less than 2, then there is no lateralization, which indicates bilateral adrenal hyperplasia. If AVS is done without cosyntropin, then an aldosterone LI ratio of greater than 2 is used as positive lateralization by some experts. When the nondominant adrenal A/C is lower than the peripheral vein A/C, it is called contralateral suppression and is typically found in patients with unilateral adrenal disease. When the aldosterone LI is between 2 and 4, if there is contralateral suppression, patients would likely benefit from unilateral adrenalectomy. ^{, ,}

TREATMENT

Treatment is based on multiple factors including the patient’s preference, comorbidities, age, and unilateral versus bilateral PA. For unilateral adrenal hyperplasia or unilateral APA, laparoscopic unilateral adrenalectomy is preferred if the patient is willing to undergo surgery with an acceptable risk. The anterior laparoscopic approach is the most commonly performed method, although some specialized centers also perform retroperitoneoscopic approaches, which is the most direct approach to the adrenal gland with a shorter surgery time and quicker patient recovery (see prior section on surgical treatment of PPGL). In nearly half of all patients, HTN is cured after unilateral adrenalectomy and HTN improved in 100% of patients. ^,

For BAH or poor surgical candidates, medical therapy with mineralocorticoid receptor (MR) antagonists is recommended. ^, Spironolactone and eplerenone are two available MR antagonists. The starting dose for spironolactone should be 12.5 mg to 25 mg daily; gradual titration upward is needed to find the lowest effective dose. The starting dose for eplerenone should be 25 mg twice daily. The dose of the MR antagonist should be titrated for a target serum potassium concentration of 4.5 mmol/L without the aid of potassium supplementation. With each change in the dosage of the MR antagonist, serum potassium and creatinine should be checked 7 to 10 days later. Caution should be used if MR antagonists are used in patients with chronic kidney disease and should be avoided in patients with stage IV or higher kidney disease due to the risk of life-threatening hyperkalemia. ^{, ,} Hypervolemia can be prohibitive in the use of MR antagonists as monotherapy, and in approximately 50% of patients, a second agent, such as low-dose thiazide diuretic, calcium channel blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers, have been employed as secondary agents in PA. ^{, ,}

ACUTE MEDICAL MANAGEMENT OF HYPERTENSIVE EMERGENCY CAUSED BY PRIMARY HYPERALDOSTERONISM

The choice of therapy in the case of hypertensive emergency depends on the end organ damage involved. Close monitoring in the intensive care unit setting is necessary and continuous infusion of titratable, short-acting intravenous antihypertensive agents are used to reduce blood pressure in order to limit further end organ damage. Intravenously administered nicardipine (5 to 30 mg/hour) is a calcium channel blocker that can prevent vasospasm and is useful in cases of hypertensive encephalopathy and hemorrhagic stroke. Labetalol (20 to 80 mg administered as an intravenous bolus every 10 minutes or a continuous infusion at a rate of 0.5 to 2 mg/minute) or nitroprusside (0.25 to 10 µg/kg per minute) are also preferred agents. In the setting of acute myocardial infarction, nitroglycerin (5 to 100 µg/minute), labetalol (20 to 80 mg intravenous bolus every 10 minutes or continuous infusion 0.5 to 2 mg/minute), or nitroprusside (0.25 to 10 µg/kg per minute) could be used to increase coronary perfusion and decrease afterload. Lowering the diastolic blood pressure to less than 60 mm Hg can risk a decrease in coronary and renal perfusion and worsening of myocardial ischemia and acute kidney injury, respectively. For acute left ventricular heart failure, nitroglycerin (5 to 100 µg/minute), nitroprusside (0.25 to 10 µg/kg per minute), or enalaprilat (1.25 to 5 mg every 6 hours) are used to decrease afterload. In acute heart failure, β-adrenergic blockers should be avoided. ^,

CLINICAL PRESENTATION

Clinical features vary from patient to patient, which may include central adiposity, moon faces, supraclavicular fat distribution, wide purple-red striae, proximal muscle weakness, osteoporosis, glucose intolerance, HTN, dyslipidemia, obesity, easy bruising, psychiatric disturbances, amenorrhea, hirsutism, and decreased libido. HTN is prevalent in 75% to 80% of cases of CS. Proposed mechanisms for HTN include increased production of deoxycorticosterone, increased sensitivity to catecholamines, angiotensin II, enhanced cardiac output, increased hepatic production of angiotensinogen, and mineralocorticoid effects of cortisol. Hypertension in CS is significantly correlated with the duration of hypercortisolism and early recognition is important. Cardiovascular disease, infections, and venous thrombosis are the most common causes of mortality in CS. Very rarely, CS presents with hypertensive emergency, which may be associated with acute pulmonary edema and hypertensive encephalopathy, with only a few cases reported.

DIAGNOSIS

Screening for CS should be considered in patients with signs and symptoms consistent with hypercortisolism. In addition, all patients with incidentally discovered adrenal masses should be screened for autonomous glucocorticoid secretion. The Endocrine Society recommends one of four tests as an initial screening test: 1-mg overnight dexamethasone suppression test (DST); 24-hour urine free cortisol (UFC, two measurements); late-night salivary cortisol (LNSC, two measurements); and formal 2-day low-dose DST (0.5 mg dexamethasone every 6 hours × 8). The overnight DST requires the administration of 1 mg of dexamethasone between 11:00 p.m. and midnight and the cortisol level to be drawn at 8:00 a.m. the following morning. LNSC can be performed at home using a designated lab cotton Salivette (multiple manufacturers) for the patient to collect a saliva sample at 11:00 p.m. at night on two separate nights. Serum cortisol at 8:00 a.m. after the 1-mg DST greater than 1.8 μg/dL, LNSC greater than 145 ng/dL, or 24-hour UFC level above the upper limit of normal are considered positive case detection results. If one of the aforementioned test results are positive, consider performing one or two other tests and repeating the abnormal test. False-positive test results can be seen in pregnancy, depression, alcohol dependence, poorly controlled diabetes mellitus, physical stress, intense exercise, etc. If two tests are positive, then further testing to establish the cause of CS is recommended. The first step is to check serum ACTH. Suppressed ACTH levels (less than 10 pg/mL) suggest ACTH-independent CS caused by primary adrenal gland pathology. A CT or MRI of the abdomen is performed in such cases to identify unilateral or bilateral adrenal lesions and to help differentiate between benign versus malignancy. ACTH-independent CS is caused by a unilateral cortisol-secreting adrenal adenoma in 60% and adrenocortical carcinoma (ACC) in 40% of cases, and very rarely by primary pigmented nodular adrenal disease (PPNAD) and bilateral macronodular adrenal hyperplasia (BMAH). On CT, cortisol-secreting adrenal adenomas are typically round to oval with smooth borders and are frequently lipid poor (greater than 10 HU). Features of ACC on a CT scan include: large size (mean diameter 9 cm) with irregular borders; intratumoral necrosis; hemorrhage and calcifications (30% of cases); and lipid poor (greater than 20 HU). In 9% to 19% of cases, ACC may invade the renal vein or inferior vena cava. On contrast-enhanced CT, an absolute contrast washout of greater than 60% and relative contrast washout of greater than 40% indicate adrenal adenoma with high sensitivity and specificity. PPNAD presents as normal or slightly enlarged adrenal glands with multiple small nodules of less than 6 mm, whereas BMAH presents with massively enlarged and multinodular adrenal glands.

Inappropriately normal or elevated ACTH levels greater than 20 pg/mL in a patient with hypercortisolism are consistent with ACTH-dependent CS. Serum ACTH levels of 10 to 20 pg/mL are considered indeterminate and could be from cyclical or mild CS or falsely detectable due to lab error or heterophile antibodies.

Dehydroepiandrosterone sulfate (DHEA-S) is an adrenal androgen that is regulated by ACTH. Hence, serum DHEA-S concentrations are normal or high in CD, whereas it is low in the benign causes of ACTH-independent CS. Measuring DHEA-S level is particularly useful in patients with subclinical hypercortisolism (SH) with adrenal incidentalomas or indeterminate ACTH levels. SH is a condition with hypercortisolism but without the typical symptoms and signs of hypercortisolism. In one study, DHEA-S was found to be significantly low in SH patients compared to age-matched controls, and low DHEA-S levels (less than 40 μg/dL) can be used as a diagnostic marker for SH.

Once ACTH-dependent CS is confirmed, the clinician must localize the source of ACTH secretion. Pituitary-dependent CS typically occurs in women and is slow in onset and relatively mild in degree of signs and symptoms and cortisol excess (e.g., 24-hour UFC less than 500 μg), whereas ectopic ACTH-dependent CS occurs equally in men and women and is typically more rapid in onset, with more severe signs and symptoms and cortisol excess (e.g., 24-hour UFC greater than 1000 μg). A pituitary-directed MRI scan is the first step in distinguishing pituitary-dependent CS from ectopic ACTH. When a clear-cut pituitary adenoma is detected in a woman with slow onset and mild-to-moderate CS, no further localization studies may be needed, whereas if a small pituitary adenoma is detected in a patient with severe CS, it may be a nonfunctioning pituitary tumor and additional testing is needed. ^, Bilateral inferior petrosal sinus sampling (BIPSS) is the gold-standard test to distinguish between pituitary-dependent CS and ectopic ACTH syndrome; sensitivity and specificity are greater than 95%. Based on BIPSS results, if there is a central to peripheral ACTH gradient of 2.0 or greater before corticotrophin-releasing hormone (CRH) administration and 3.0 or greater post-CRH, CD is confirmed. ^,

CT or MRI of chest and abdomen and pelvis is the first step in imaging to localize the source of ectopic ACTH secretion (EAS). CT or MRI do not reveal any source in around 50% of cases and functional imaging with an octreotide scan or ⁶⁸ Ga-DOTATATE PET/CT is the next step. ^{, 68} Ga-DOTATATE PET/CT imaging has shown promising results in identifying source of EAS in 18 of 22 patients in a recent study. ^,

TREATMENT

Medical Therapy

Medical therapy is a second-line option of treatment in patients where surgery was not curative or for those who are poor surgical candidates. Available medical treatments include: steroidogenesis inhibitors (e.g., ketoconazole, metyrapone, mitotane, etomidate); somatostatin receptor agonists; dopamine agonists; and glucocorticoid receptor antagonists (e.g., mifepristone). Combination therapy is required in some cases at low doses to achieve cortisol control. Patients treated with medical therapy are at risk of adrenal insufficiency and should be counseled about the risks of adrenal crisis and emergency use of glucocorticoids. Table 12.2 shows different medications, their mechanism of action, dosage, and effect on cortisol and blood pressure.

TABLE 12.2

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