Endo-Adrenals

Question 1

What hormones does the medulla and cortex produce?

Answer 1

Cortex: Androgens, mineralocorticoids, glucocorticoids

Medulla: Catecholamines

Question 2

What happens to cortisol with Cushing’s syndrome?

Answer 2

Poor suppressibility of cortisol with dexamethasone and loss of normal diurnal variation in cortisol secretion are seen.

Question 3

What is the most common cause of Cushing’s syndrome?

Answer 3

However, iatrogenic hypercortisolism from the administration of exogenous oral, inhaled, intra-articular, or topical glucocorticoids is often seen in clinical practice and is the most common cause of CS overall.

Question 4

What dose equivalents of prednisone are likely to cause Cushing Syndrome through suppression of the HPA axis?

Answer 4

Doses equivalent to prednisone 5 mg/d or less are unlikely to cause clinically significant HPA axis suppression, while those in excess of 10 to 20 mg/d commonly do after 3 weeks or more of consecutive use.

Question 5

What are the two ways that endogenous Cushing’s syndrome occurs? What are the most common etiologies in each?

Answer 5

ndogenous CS can result from ACTH-dependent and ACTH-independent causes.

Dependent: pituitary adenoma, ectopic ACTH source
Independent: adrenal adenomas and carcinomas

Question 6

What are some causes of pseudo-hypercortisolism? Or disease states that produce hypercortisol mimics?

Answer 6

CS must be differentiated from other disorders and clinical states that are associated with physiologic hypercortisolism (pseudo-Cushing syndrome). Causes of pseudo-Cushing syndrome include severe obesity, polycystic ovary syndrome, pregnancy, anorexia nervosa, depression, alcoholism, and extreme physical stress, as in the setting of infection.

Question 7

Clinical symptoms of hypercortisolism?

Answer 7

Clinical findings that are highly specific for CS include centripetal obesity, facial plethora, abnormal fat deposition in the supraclavicular or dorsocervical (“buffalo hump”) areas, and wide (>1 cm) violaceous striae

Question 8

How is Cushing’s syndrome diagnosed?

Answer 8

At least two first-line tests should be diagnostically abnormal before the diagnosis is confirmed. Initial tests include the overnight low-dose dexamethasone suppression test (LDST), 24-hour urine free cortisol (UFC), and late-night (LN) salivary cortisol. All three tests have similar diagnostic utility, but the LDST or LN salivary cortisol tests are more convenient. The 24-hour UFC and LN salivary cortisol tests should be performed at least twice to ensure reproducibility of results.

See figure 6 algorithm

Question 9

Why can’t random cortisol be used for diagonsis?

Answer 9

Because the secretion of cortisol is pulsatile, measurement of random serum cortisol is neither sensitive nor specific for the diagnosis of CS.

Question 10

What is the low dose dexamethasone test and how should it be interpreted?

Answer 10

In the overnight LDST, 1 mg of dexamethasone is administered at 11 PM or midnight, and serum cortisol is measured the next morning at 8 AM. With either test, serum cortisol will typically be suppressed to less than 2 μg/dL (55 nmol/L).

Question 11

When should the low dose dexamethasone test be avoided?

Answer 11

1) proteins are low
2) meds that accelerate dexamethasone metabolism

Standard assays measure total serum cortisol, or that which is bound to cortisol-binding globulin (CBG) and other proteins. Therefore the LDST should not be performed when CBG is likely to be abnormal, such as with malnutrition, cirrhosis, the nephrotic syndrome, and hyperestrogenemia (oral contraceptive pills or pregnancy). There is no clear association between dexamethasone responses and BMI or weight, and therefore the LDST may be used similarly in the obese population. The LDST is best avoided in patients taking medications that could accelerate dexamethasone metabolism, such as antiepileptic drugs (phenytoin, phenobarbital, and carbamazepine), rifampin, or pioglitazone. Concomitant measurement of serum dexamethasone can confirm altered dexamethasone metabolism and patient adherence.

Question 12

Explain how a LN salivary test is performed

Answer 12

The LN salivary cortisol test is performed between 11 PM and midnight. The normal evening nadir in cortisol secretion is lost in patients with CS, while it is preserved in patients with pseudo-Cushing syndrome. Both emotional and physical stress (for example, exercise) can cause a physiologic increase of salivary cortisol. False-positive results are seen with cigarette smoking or use of chewing tobacco. LN salivary cortisol testing should not be performed in patients with erratic sleep schedules (for example, shift-workers).

Question 13

How can you distinguish between pseudo-hypercortisolism and real Cushing’s syndrome?

Answer 13

The normal evening nadir in cortisol secretion is lost in patients with CS, while it is preserved in patients with pseudo-Cushing syndrome. Both emotional and physical stress (for example, exercise) can cause a physiologic increase of salivary cortisol.

Question 14

After Cushing’s syndrome has been confirmed, how do you tell the difference between ACTH dependent or independent causes?

Answer 14

After CS has been confirmed biochemically, further testing is required to distinguish ACTH-dependent or -independent causes, and consultation with an endocrinologist is recommended. The first step is to measure plasma ACTH on two separate occasions. With adrenal (ACTH-independent) CS, plasma ACTH is usually less than 5 pg/mL (1.1 pmol/L), whereas values greater than 20 pg/mL (4.4 pmol/L) are typically seen with ACTH-dependent causes

Question 15

After Cushing’s syndrome has been determined, and then ACTH independence has been established… what next?

Answer 15

The next step in the evaluation of ACTH-independent CS is with imaging of the adrenal glands, such as dedicated adrenal imaging with thin-section CT or MRI. Both studies have equal sensitivity; however, MRI is more costly. Adrenal adenomas and carcinomas can usually be distinguished from one another radiographically

Question 16

What is the treatment for ACTH independent Cushing syndrome?

Answer 16

Surgery is considered first-line treatment for adrenal adenomas and nonmetastatic adrenocortical carcinomas (ACCs). When surgery is delayed for patients with overt CS, adrenal enzyme inhibitors (metyrapone, ketoconazole, and etomidate) can be used to reduce cortisol levels and decrease the risk of complications, such as opportunistic infections and cardiovascular events.

Following adrenalectomy, patients with adrenal CS will often develop acute adrenal insufficiency because of HPA axis suppression and contralateral adrenal atrophy from long-standing elevated cortisol levels. All patients should therefore be treated with stress-dose glucocorticoids during the perioperative period and continued on physiologic replacement until HPA axis recovery has been confirmed. Following successful surgery, the physical changes associated with CS can take up to 1 year to resolve.

Question 17

How is a pheochromocytoma diagnosed?

Answer 17

The diagnosis of pheochromocytoma and paraganglioma is based on confirmation of the excessive secretion of catecholamines or their metabolites, as measured in the plasma or urine.

Question 18

What most u test for if you incidentally find an adrenal mass?

Answer 18

Pheochromocytoma!

Question 19

How do you diagnose a pheo? What are tests and how are they best used?

Answer 19

The sensitivity of plasma free metanephrines is the highest of any screening test (96%-100%); however, its specificity is relatively low (85%-89%). Therefore, plasma free metanephrines will reliably exclude a pheochromocytoma when negative, but further testing is needed to confirm the diagnosis unless the result is markedly abnormal (above 4 times the upper limit of normal). The sensitivity and specificity of 24-hour urine fractionated metanephrines and catecholamines are 91% to 98%. Due to the lower frequency of false-positive results, 24-hour urine measurements are recommended when the pre-test probability of disease is relatively low (adrenal mass without typical radiographic appearance), while measurement of plasma free metanephrines is preferred when clinical suspicion is higher (known hereditary syndrome).

Question 20

After biochemical test confirmation, what is next in the diagnostic workup of a pheo?

Answer 20

Following the biochemical diagnosis of pheochromocytoma or catecholamine-secreting paraganglioma, radiographic localization is needed. Because most catecholamine-secreting tumors are located in the abdomen, CT or MRI of the abdomen and pelvis is the best initial study. If negative, iodine 123 (123I)-metaiodobenzylguanidine (MIBG) scanning can be performed. Adjunctive diagnostic tests are CT or MRI of the chest or head and neck region.

Question 21

What is the preoperative management of someone with a pheochromocytoma?

Answer 21

1) alpha blockade: phenoxybenzamine
2) beta blockade

Preoperative pharmacologic treatment is mandatory for pheochromocytomas and paragangliomas to prevent life-threatening cardiovascular complications related to the massive release of catecholamines during surgery. Preoperative blockade of α-adrenoceptors, usually with phenoxybenzamine, is first-line medical therapy. The dosage is titrated to achieve a blood pressure below 130/80 mm Hg seated and greater than 90 mm Hg (systolic) standing. Commonly used but non-FDA approved alternatives include calcium channel blockers and selective α1-blockers (terazosin or doxazosin). β-Adrenoceptor blockers (metoprolol or propranolol) are added later to treat reflex tachycardia, but should never be started before adequate α-blockade has been achieved due to the risk of hypertensive crisis from unopposed α-receptor stimulation. A heart rate of 60 to 70/min seated and 70 to 80/min standing can be targeted in most patients.

Question 22

Once resected laparoscopically, what next for people who have had a pheo? What is their follow-up?

Answer 22

Pheochromocytomas and paragangliomas require lifelong surveillance for recurrence with annual plasma free metanephrine measurement.

Question 23

What do you see on a BMP with primary hyperaldosteronism?

Answer 23

Additional signs of PA include hypokalemia and metabolic alkalosis. Without treatment, excess cardiovascular morbidity and mortality are seen.

Question 24

What are the most common causes of hyperaldosteronism?

Answer 24

Aldosterone-producing adrenocortical adenomas (APA; aldosteronomas) cause approximately 40% of PA, whereas nearly all other cases are due to bilateral adrenal hyperplasia. Unilateral adrenal hyperplasia and aldosterone-secreting adrenocortical carcinomas (ACCs) are rare. Familial hyperaldosteronism is also uncommon.

Question 25

How is primary hyperaldosteronism initially screened for?

Answer 25

Initial screening for PA is with the simultaneous measurement of midmorning ambulatory plasma renin activity (PRA) and plasma aldosterone concentration (PAC), in a volume replete normokalemic patient. Testing is positive if PAC is frankly elevated (>15 ng/dL [414 pmol/L]), PRA is suppressed, and PAC/PRA ratio is greater than 20.

Question 26

If being treated for primary hyperaldosteronism, what medications should be discontinued?

Answer 26

Many medications, including common antihypertensive agents, can affect measurements of PAC, PRA, or both (Table 22). However, because patients undergoing screening often have drug-resistant hypertension, discontinuing all potentially offending medications can be unsafe. Stopping mineralocorticoid receptor antagonists (spironolactone and eplerenone) for 4 to 6 weeks prior to testing is recommended. Diuretics should also be discontinued prior to testing to assure euvolemia. Most other medications can be continued, but results must be interpreted in context. For example, if PRA is suppressed despite treatment with an ACE inhibitor or angiotensin receptor blocker, PA is likely. If results are difficult to interpret, repeat testing after eliminating potential interfering medications is advised. Verapamil, hydralazine, and α-blockers (doxazosin) can be substituted for blood pressure control if necessary.

Question 27

How is confirmatory testing performed for primary hyperaldosteronism?

Answer 27

Confirmatory testing is performed except when initial testing is diagnostic for PA, as in cases of spontaneous hypokalemia with undetectable PRA and PAC greater than 30 ng/dL (828 pmol/L). Confirmatory tests include oral and intravenous salt loading and the fludrocortisone suppression and captopril challenge tests

Question 28

Once diagnosis of primary aldosteronism has been confirmed biochemically, what next in the diagnostic algorithm?

Answer 28

Once the diagnosis of PA has been confirmed biochemically, radiographic localization with abdominal CT is indicated.

Question 29

What are the main treatment goals for primary aldosteronism?

Answer 29

The goals of treatment include improvement in blood pressure (resolution of hypertension is unlikely), normalization of serum potassium (this is very likely), and reduction in plasma aldosterone because hyperaldosteronemia is associated with a blood pressure–independent increase in cardiovascular events. The treatment of choice for PA due to APA or unilateral adrenal hyperplasia is laparoscopic adrenalectomy. For patients who are unable or unwilling to have surgery, medical treatment including a mineralocorticoid receptor antagonist is the preferred treatment option.

Question 30

If someone is not a surgical candidate, then how is primary hyperaldosteronism managed?

Answer 30

For patients with bilateral adrenal hyperplasia or those with unilateral causes of PA who are not surgical candidates, medical therapy with a mineralocorticoid antagonist is indicated. Spironolactone is the most commonly used medication due to its proven efficacy and cost-effectiveness.

Question 31

Summary, treatment for:

• Primary hyperaldosteronism (unilateral adrenal hyperplasia, aldosteronoma): laparoscopic adrenalectomy
• Bilateral adrenal hyperplasia or cases of unilateral primary hyperaldost who are not surgical candidates: medical therapy with a mineralocorticoids, like spironolactone

Answer 31

The treatment of choice for primary hyperaldosteronism due to an aldosteronoma or unilateral adrenal hyperplasia is laparoscopic adrenalectomy; for patients with bilateral adrenal hyperplasia or those with unilateral causes of primary hyperaldosteronism who are not candidates for surgery, medical therapy with a mineralocorticoid antagonist such as spironolactone is indicated.

Question 32

What are the clinical hallmarks of primary adrenal failure?

Answer 32

Hyperpigmentation is a clinical hallmark of this disorder that is not seen with secondary cortisol deficiency.. also get fatigue, weakness, hypotension,

Question 33

What are the most common causes of primary adrenal failure?

Answer 33

• autoimmune adrenalitis
• Addison’s disease: infiltration of the adrenal gland by TB
• Bilateral adrenal hemorrhage: DIC, blood thinners

Question 34

Describe when an adrenal crisis may occur and what the symptoms are.

Answer 34

Adrenal crisis may occur when onset of adrenal failure is abrupt (bilateral adrenal hemorrhage) or when increased stress occurs in the setting of chronic adrenal failure. Manifestations of adrenal crisis include shock, hypotension, fever, nausea, vomiting, abdominal pain, tachycardia, and even death.

Question 35

What is a way to diagnose primary adrenal failure?

Answer 35

The diagnosis of primary adrenal failure is based on demonstrating inappropriately low serum cortisol levels. Because most assays measure total cortisol, abnormalities in cortisol-binding protein or albumin can trigger spurious results. An early morning (8 AM) serum cortisol of less than 3 μg/dL (82.8 nmol/L) is consistent with cortisol deficiency, whereas values greater than 15 to 18 μg/dL (414.0-496.8 nmol/L) exclude the diagnosis when binding protein abnormalities and synthetic glucocorticoid exposure are excluded.

Question 36

How is ACTH used to distinguish between primary and secondary adrenal failure?

Answer 36

Once the diagnosis of cortisol deficiency has been established, measurement of 8 AM plasma ACTH will differentiate primary and secondary causes. In primary adrenal failure, ACTH is typically greater than 200 pg/mL (44 pmol/L), whereas it will be low or inappropriately normal in secondary cortisol deficiency.

Question 37

How is primary adrenal failure treated?

Answer 37

Most patients require glucocorticoid doses equivalent to 12.5 to 25 mg of hydrocortisone daily. Hydrocortisone is administered 2 to 3 times daily, while once daily dosing of longer-acting glucocorticoids (prednisone or dexamethasone) is acceptable. In contrast to patients with secondary cortisol deficiency (see Disorders of the Pituitary Gland), those with primary adrenal failure also require mineralocorticoid replacement. Usual doses are 0.05 to 0.2 mg per day of fludrocortisone.

Question 38

How should adrenal incidentalomas be evaluated?

Answer 38

The two main goals of evaluation of adrenal incidentalomas are to identify adrenal masses that are likely to be malignant and those that are associated with hormonal hypersecretion so that targeted treatment can be undertaken promptly.

1) test for pheo
2) take a good history and test for other adrenal causing diseases

Adrenal masses that are larger than 4 cm, those with worrisome radiographic findings, and pheochromocytomas should be removed surgically.