7/18/12 PPY224 Pathophysiology of Endocrinology, Diabetes and Metabolism, Spring 2005 - Tufts OpenCours…

S e a r c h

Adrenal Cortical and Medullary Disease

Authors: Ann Sweeney, M.D., Richard D. Siegel, M.D., Anastassios G. Pittas, M.D. 1. Goals Color Key Important key words or phrases. To understand the pathophysiology of different forms of adrenal insufficiency and be able to distinguish between primary and secondary forms of the disease Important concepts or main ideas. To form a differential diagnosis for an adrenal neoplasm and perform a workup to determine if the neoplasm is hormonally functional or silent To distinguish between ACTH dependent and independent forms of Cushing's syndrome 2. Learning Objectives

The most common form of Addison's disease is autoimmune adrenalitis. It is associated with other autoimmune endocrine and non­ endocrine disorders. The cortrosyn stimulation test is the most commonly used test to diagnose adrenal insufficiency. An adrenocorticotropin (ACTH) level may help to distinguish between primary and secondary forms of insufficiency. Insulin tolerance testing and metyrapone test are more specific for testing the hypothalamic and pituitary parts of the axis. An incidental adrenal mass must undergo a workup for hypersecretion. Surgical removal is indicated if the mass is functional or greater than 4­5 cm in size. The workup for primary hyperaldosteronism includes a determination that aldosterone is being overproduced in the adrenal cortex independently of renin secretion and cannot be suppressed followed by testing to distinguish between an adenoma and bilateral hyperplasia. Surgery is indicated for the former while the latter is treated medically. Pheochromocytoma is an adrenal medullary tumor which hypersecretes catecholamines and can cause paroxysms of hypertension in association with palpitations, headaches and sweats. Biochemical diagnosis should be made first followed by appropriate imaging. Surgical removal is carefully performed after preoperative treatment with specific medications to lower blood pressure and possibly deplete the tumor of catecholamines. The most common form of Cushing's syndrome is exogenous "steroid" (glucocorticoid) therapy. Endogenous Cushing's may be due to a pituitary, adrenal or ectopic etiology. The workup involves the determination that the syndrome is present followed by testing to determine the specific etiology. In its worst form, it can be a devastating catabolic syndrome with both severe medical and psychological complications. Adrenal carcinoma is a rare aggressive malignancy. Tumors may be "silent" or associated with hormonal hypersecretion syndromes. 3. Cortisol and Aldosterone Production and Regulation

Cortisol production is precisely regulated by the hypothalamic pituitary adrenal axis. Adrenocorticotropin hormone (ACTH) secreted by the pituitary stimulates the adrenal gland to secrete cortisol which in turn feeds back and inhibits ACTH and cortisol releasing hormone (CRH). ACTH is the sole stimulator of cortisol production. Daily cortisol production is between 15­25 mg and the majority is produced between 5 and 9 am.

Aldosterone production Regulated mainly through the renin­angiotensin system­ low renal perfusion pressure stimulates renin production→ angiotensin I→ angiotensin II→aldosterone secretion Elevated extracellular potassium concentation also stimulates aldosterone secretion ACTH is responsible ~15% of aldosterone secretion

Figure 1. Hypothalamus diagram

Vance, ML. Hypopituitarism. New England Journal of Medicine. 1994; 23: 1651, 62. Figure 1, Panel A, p1652.

4. Physiologic Effects of Glucocorticoids

1. Hemodynamic: Maintains cardiac output Plays a vital supportive role in the maintenance of vascular tone and endothelial integrity Potentiates the vasoconstrictor actions of catecholamines

2. Metabolism: Cortisol is called a glucorticoid because of its glucose regulating properties Increases glycogen synthesis Stimulates gluconeogenesis Activates key hepatic gluconeogenic enzymes Increases substrate availability mobilizes amino acid precursors from bone, skeletal muscle and connective tissue, activates lipolysis acts as an insulin antagonist and suppresses secretion of insulin ocw.tufts.edu/Content/14/lecturenotes/266733 1/8 7/18/12 PPY224 Pathophysiology of Endocrinology, Diabetes and Metabolism, Spring 2005 - Tufts OpenCours… 3. Immune System: glucocorticoids have anti­inflammatory properties and modulate the immune response Stimulates release of neutrophils from bone marrow into blood, but prevents their egress through the capillary membrane (peripheral demargination) Depletes peripheral lymphocytes,monocytes and eosinophils; redistributes them to spleen, lymph nodes, thoracic duct and bone marrow Inhibits production and action of multiple mediators of inflammation including: lymphokines, prostaglandins, interleukins, serotonin, and bradykinins

4. Distribution of total body water Regulates extracellular body water Retards migration of body water into cells Promotes renal free water excretion­ suppresses vasopressin excretion and increases GFR 5. Adrenal Insufficiency

In 1855, Thomas Addison described patients with "general languor and debility.... and a peculiar change of color in the skin..." The patients died and had diseased adrenal glands. Addison thus realized the adrenal glands are essential for life. In 1950, the Nobel Prize was awarded to Kendall, Reichstein, and Hench for the isolation and synthesis of adrenal cortical hormones and their uses in disease.

Adrenal insufficiency is usually divided into 2 categories.

1. Primary adrenal insufficiency (Addison's disease): The defect is in the adrenal gland. In primary adrenal insufficiency there is a lack of both cortisol and aldosterone in most cases, but occasionally there may be a deficiency in cortisol alone. 2. Secondary (central) adrenal insufficiency: The defect is in the hypothalamic­pituitary area and is due to ACTH deficiency. Usually, this is associated with other pituitary hormone deficiencies if due to pituitary disease, but there may be isolated ACTH deficiency.

5.1. Etiology of Adrenal Insufficiency

5.1.1. Primary adrenal insufficiency (Addison's disease) [Elevated ACTH & Low Cortisol ]

Addison's disease may be caused by adrenal dysgenesis/hypoplasia, adrenal destruction or impaired steroidogenesis. Some of the more common causes are listed below.

1. Autoimmune adrenal insufficiency. Autoimmune Addison's disease may occur by itself or as part of an autoimmune polyendocrine syndrome. In autoimmune polyendocrine syndrome type 1 (APS­1), hypoparathyroidism and mucocutaneous candidiasis usually occur along with adrenal insufficiency. Recently, the cytochrome P450 cholesterol side chain cleavage enzyme (P450­SSC) used in the steroid synthetic pathway was found to be the autoantigen. In APS­2, adrenal insufficiency is associated with type 1 diabetes mellitus and autoimmune thyroiditis. The major antigen in this syndrome appears to be 21­hydroxylase (P450c21), an enzyme important in the steroid synthetic pathway (see Congenital Adrenal Hyperplasia lecture). Other autoimmune syndromes may also occur including vitiligo, alopecia and pernicious anemia. Autoimmune Addison's disease is more common in women than men and tends to have an onset in young adulthood. 2. Infections: Tuberculosis of the adrenals is the most common cause of adrenal insufficiency worldwide though relatively less common in the United States. The adrenal glands may appear calcified on CT. Fungal diseases such as histoplasmosis, coccidiomycosis and blastomycoses are uncommon additional causes. Patients with AIDs and HIV as described below may develop AI. 3. HIV and the adrenals. Clinical adrenal insufficiency is rare though subtle adrenal dysfunction is common as HIV disease progresses. As with all infiltrative diseases, about 90% of the gland must be destroyed before clinical adrenal insufficiency occurs. Factors involved include Infections especially CMV but also fungi, mycobacteria and Toxoplasma Medications including ketoconazole which blocks steroidogenesis and rifampin, phenytoin and opiates which increase steroid metabolism Cytokines such as interleukin­1 and tumor necrosis factor may suppress the HPA axis.

4. Bilateral adrenal hemorrhage. As with other causes, one should have a high degree of suspicion for this in a patient who is postoperative, on anticoagulants or has a tendency toward thrombosis or coagulopathy. The patient often presents acutely with abdominal, flank or back pain and life­threatening hypotension. The condition has occurred in patients with antiphospholipid syndrome where a lupus anticoagulant is responsible for thrombosis and/or hemorrhage. 5. Metastatic disease to the adrenal. This may occur with any malignancy metastatic to the adrenal that destroyed at least 90% of both adrenals. However, more often adrenal involvement is present without clinical adrenal insufficiency. Common malignancies with metastatic adrenal involvement. 6. Adrenomyeloneuropathy. This occurs in young men associated with neurologic disease. It is an X­linked peroxisomal disorder characterized by progressive demyelination of the CNS along with adrenal insufficiency. The defect is a deficiency of an enzyme which catabolizes very­long­chain fatty acids to ketones. 7. Familial glucocorticoid deficiency. This is a rare autosomal recessive disorder with adrenal unresponsiveness to ACTH. A mutation in the ACTH receptor has not yet been identified.

5.1.2. Secondary (central) adrenal insufficiency [Low ACTH & Low Cortisol]

1. Long­term glucocorticoid therapy This is most common type of secondary AI. It occurs with the use of synthetic glucocorticoids which suppress ACTH secretion as expected; stopping the glucocorticoids may then lead to adrenal insufficiency. ocw.tufts.edu/Content/14/lecturenotes/266733 2/8 7/18/12 PPY224 Pathophysiology of Endocrinology, Diabetes and Metabolism, Spring 2005 - Tufts OpenCours… 2. Other causes listed below will be covered in the section on Hypopituitarism Chronic Acute Pituitary or metastatic tumor Pituitary surgery Histiocytosis X Head trauma Hypothalamic tumors Pituitary apoplexy Craniopharyngioma Postpartum necrosis (Sheehan's) Sarcoidosis Empty sella syndrome Lymphocytic hypophysitis Isolated ACTH deficiency

5.2. Clinical Presentation and Laboratory Evaluation of Adrenal Insufficiency

Addison's original description of a "general languor and debility, feebleness of the heart's action, irritability of the stomach and a peculiar change in the color of the skin" summarize the main clinical features of the disease.

Hydrocortisone, as above, is the principal glucocorticoid produced by the adrenal and is essential in times of stress.

Pathophysiology: The central alteration is cardiovascular: reduced cardiac output and decreased vascular tone with relative hypovolemia. As a result, vasopressin is secreted which leads to water retention and hyponatremia.

Symptoms Frequency (%) weakness and fatigue 100 anorexia 100 nausea and diarrhea 56 Signs Frequency (%) weight loss 100 hyperpigmentation* 97 hypotension 91

vitiligo rare Laboratory Frequency (%) Findings

hyponatremia 90 hyperkalemia* 66 hypoglycemia 40 hypercalcemia 6 hypereosinophilia * Primary Adrenal Insufficiency only

*Hyperpigmentation only occurs in primary adrenal insufficiency due to the increased secretion of βlipotropin which contains melanocyte stimulating MSH and is a component of the ACTH precursor peptide (POMC).

*Hyperkalemia, which is due to a lack of aldosterone, is only present in primary adrenal insufficiency. In secondary insufficiency, only cortisol production is affected while aldosterone production remains intact since it is regulated primarily by the renin­angiotensin system. Therefore, features associated with aldosterone deficiency such as hyperkalemia or profound volume depletion are absent in secondary deficiency.

Hyponatremia is present in both primary and secondary disease. The hyponatremia occurs in both types due to an increase in vasopressin (anti­diuretic hormone, ADH) resulting in impaired free water excretion. In addition, patients with primary adrenal insufficiency lack aldosterone and therefore have urinary sodium loss.

Autoimmune Addison's disease develops over several years. Autoantibodies appear first to the antigens described above. As functional adrenal mass starts to decline, plasma renin activity increases at rest followed by a low plasma aldosterone. Zona fasciculata dysfunction then becomes evident (months to years later) by an elevation in the afternoon ACTH level. This is followed by a depressed cortisol response to ACTH stimulation (see Cortrosyn stimulation test below) and finally by decreased basal cortisol levels and the appearance of clinical symptoms.

5.2.1. Tests for Diagnosis of Adrenal Insufficiency

Cortrosyn Stimulation Test

Cortrosyn is a synthetic analogue of ACTH and is used as the initial diagnostic test to test the adrenal glands. 250 mcg of IV or IM Cortrosyn is given and cortisol levels are drawn at time 0, 30 and 60 minutes. Normal response is a stimulated cortisol level above 18­20 mcg/dl . In primary adrenal insufficiency, the cortisol level starts out low and does not rise or rises minimally. In secondary adrenal insufficiency, the cortisol level starts out low and rise but does not get above 18 mcg/dl. Lack of an aldosterone response is also consistent with primary adrenal insufficiency. An abnormal test requires either adrenal destruction or chronic pituitary insufficiency (lack of ACTH results in adrenal atrophy). If acute pituitary insufficiency should occur, this test may still be "normal" because the adrenals have not yet atrophied and can respond to the cortrosyn stimulation. In this clinical situation either a insulin tolerance or a metyrapone test (described below) is recommended to test the pituitary function. A low dose (1 mcg) ACTH test has been studied, however it is not accepted uniformly by endocrinologists and is not currently commercially available. ocw.tufts.edu/Content/14/lecturenotes/266733 3/8 7/18/12 PPY224 Pathophysiology of Endocrinology, Diabetes and Metabolism, Spring 2005 - Tufts OpenCours… ACTH Level In the setting of a low cortisol level, a high ACTH level suggests primary adrenal insufficiency while a normal (inappropriately normal) or low level is consistent with secondary adrenal insufficiency.

Insulin Tolerance Test The insulin tolerance test is the "gold standard" used to test the hypothalamic and pituitary response to a hypoglycemic stress and thus indirectly tests the adrenal. IV insulin is given at 0.1­0.15 U/kg with the aim of achieving a plasma glucose level of less than 40 mg/dl. With this stimulus, a normal response would be a rise in ACTH (as well as growth hormone) which would then stimulate cortisol to greater than 18 mcg/dl. If pituitary reserve is impaired, a suboptimal response will be seen. This test should not be done in patients with a seizure disorder, known coronary artery disease and older patients. The test is not necessary if the cortrosyn stimulation test is abnormal. It is primarily used to test pituitary reserve which may be abnormal even when the Cortrosyn test is normal (as described above).

Overnight Metyrapone Test The overnight metyrapone test is also a test of pituitary reserve which can be done in all patients. Metyrapone is a compound which blocks the last step in cortisol synthesis from 11­deoxycortisol (compound S) to cortisol. It is given at 11 pm and blood is drawn the following morning at 8 am for cortisol, ACTH and 11­deoxycortisol. In a normal individual, cortisol production is diminished by the Metyrapone resulting instimulation of ACTH secretion. ACTH, in turn, stimulates the adrenals to increase synthesis of the precursors of cortisol, including the hormone of interest, 11­deoxycortisol (normal values after Metarypone testing: cortisol< 5 mcg/dl, ACTH >100 pg/ml, 11­ deoxycortisol > 7 mcg/dl). In someone with an impaired pituitary, the cortisol level would be low (assuming enough metyrapone was given) but ACTH and 11­deoxycortisol will not rise to the expected levels. As above, the test is not necessary if the cortrosyn stimulation test is abnormal. This test requires an inpatient stay because of the risk of precipitating an adrenal crisis and is therefore not routinely performed.

5.3. Treatment of Adrenal Insufficiency

Both primary and secondary adrenal insufficiency require glucocorticoid replacement. Primary adrenal insufficiency also requires mineralocorticoid replacement due to aldosterone deficiency.

Form of corticosteroid Physiologic amount (mg) Cortisone acetate 25 Hydrocortisone 20 Prednisone 5 Methylprednisolone 4 Dexamethasone 0.75

Most commonly, either hydrocortisone or prednisone are used for replacement with the majority of the dose given in the morning and the rest of the dose given in the late afternoon. Prednisone may often be given once per day in the morning since it is longer acting than hydrocortisone. Fludrocortisone is the synthetic mineralocorticoid that is used and is generally given once daily in the morning.

The adequacy of glucocorticoid replacement is generally assessed with clinical parameters such as symptoms and orthostatic blood pressures. Measurement of ACTH, plasma renin activity and serum potassium help to assess the adequacy of glucocorticoid and mineralocorticoid therapy.

When a patient with adrenal insufficiency is ill, the dose of glucocorticoid must be adjusted to deal with the stress. This is meant to simulate what the adrenals would normally do under a similar situation. For minor stresses, the dose of steroid may be doubled or tripled. For major stresses or around surgery, a "stress" dose is usually given which is equivalent to 150 mg or more of hydrocortisone per day. This is generally given either IV or IM. (A frequently mentioned dose in many texts for "stress" steroids is hydrocortisone 100 mg IV every 8 hours which is probably more than is actually needed). As the stress resolves, the steroid dose is tapered down to baseline as indicated by the clinical status. A bracelet, necklace, or wallet card is mandatory as is patient education in order to avoid catastrophe during emergencies. In some cases, the patient may keep an injectable form of glucocorticoid (often dexamethasone) at home for emergency use. 6. Adrenal Hypersecretion and Neoplasia

Most adrenal tumors are benign adrenal adenomas. Formerly rare in the living (they were detected only at autopsy or when they produced excess hormones), adrenal tumors now are detected fairly often as a serendipitous result of CT or MRI studies of the abdomen done for other reasons. Up to 4% of abdominal CT scans may show an adrenal "incidentaloma".

The potential mechanisms of adrenocortical tumorigenesis are being uncovered. These include:

Activation of protooncogenes ­ ras, G proteins Inactivation of tumor suppressor genes ­ p53, retinoblastoma Inhibition of senescence or apoptosis ­ telomerase, bcl­2 Changes in adrenocortical tissue specific transcription factors ­ DAX­1, SF­1 Benign adrenocortical tumors may be either polyclonal or monoclonal. Adrenal carcinomas are all monoclonal.

6.1. Primary Hyperaldosteronism

6.1.1. Review: Control of aldosterone secretion

Aldosterone is primarily under the control of the renin­angiotensin system. When effective blood volume drops, the juxta­glomerular cells in the kidney are stimulated to secrete renin which acts on angiotensinogen to convert to angiotensin I. This is converted to angiotensin II by angiotensin converting enzyme (ACE) which can either directly increase blood pressure or act on the adrenal cortex to stimulate aldosterone secretion. Aldosterone raises blood pressure by increasing renal distal tubular sodium reabsorption which leads to an increase in effective blood ocw.tufts.edu/Content/14/lecturenotes/266733 4/8 7/18/12 PPY224 Pathophysiology of Endocrinology, Diabetes and Metabolism, Spring 2005 - Tufts OpenCours… volume. When sodium is reabsorbed, potassium is secreted and lost in the urine. Aldosterone is also stimulated by hyperkalemia, hyponatremia and pharmacological amounts of ACTH (it should normally rise with a cortrosyn stimulation test).

6.1.2. Etiology

Primary hyperaldosteronism is characterized by over production of aldosterone that is independent of renin. The classical clinical syndrome, first described by Conn in 1954, includes hypertension, hypokalemia, elevated aldosterone levels and low plasma renin activity. However, most patients do not exhibit hypokalemia. The prevalence of primary aldosteronism is high in hypertensive patients (up to 20% in patients with resistant hypertension). Causes of primary hyperaldosteronism are shown below.

Prevalence Estimates from Melby, JC. JCEM 1989 Unilateral aldosterone producing adenoma (APA) 65% Idiopathic Hyperaldosteronism (IHA, bilateral hyperplasia) 30% Unilateral Primary Adrenal Hyperplasia (PAH) < 2% Glucocorticoid Remediable Aldosteronism (GRA) < 2% Aldosterone­producing adrenocortical carcinoma 1%

GRA is an autosomal dominant disorder caused by a mutation creating a chimeric gene with the regulatory region of the 11 beta­hydroxylase gene and the coding sequences of the aldosterone synthase gene. Different hybrid steroids such as 18­OH cortisol are produced. Thus, aldosterone production in this condition is stimulated by ACTH. This is a very rare cause of hyperaldosteronism.

6.1.3. Evaluation

In a patient with resistant hypertension and hypokalemia, a plasma aldosterone concentration to plasma renin activity ratio (PAC/PRA) is a useful screening test for primary aldoseronism. A ratio > 20 is suggestive of the disorder. It is important to recognize that up to 1/3 of patients with hyperaldosteronism may not have hypokalemia. Very high ratios (>100) with elevated aldosterone levels are usually diagnostic for aldosterone producing adenomas.

The diagnosis should be confirmed by demonstrating that a high volume status will not suppress plasma aldosterone levels (with a low PRA). This is generally done by placing the patient on a high sodium diet for 3 days and measuring 24­hour urine for aldosterone, sodium and potassium. Normally, this would lead to suppression of aldosterone secretion. In a patient with hyperaldosteronism, aldosterone remains elevated. The potassium level must be aggressively replaced prior to performing this test as it could rapidly decline with the large amounts of sodium being given (high sodium intake leads to increase renal potassium wasting).

Following biochemical confirmation of hyperaldosteronism, imaging is performed to identify the cause. Imaging tests include CT or MRI of the adrenals, nuclear imaging (iodocholesterol scan), and the "gold standard", adrenal venous sampling (AVS). Often aldosteronomas are very small and will not been seen on CT or MRI imaging scans. Adrenal venous sampling is felt to have nearly 100% accuracy. It is done by catheterizing the adrenal veins via the inferior vena cava to assess the relative aldosterone production from each adrenal gland. In APA, the adrenal with the adenoma generally produces at least 4 times that of the normal adrenal (usually much higher).

6.1.4. Treatment

Unilateral causes (APA, primary hyperplasia) should be treated with laparoscopic adrenalectomy while IHA should be treated medically. Of note, surgery may not cure hypertension (as most patients will also have essential hypertension). Spironolactone is a weak potassium sparing diuretic and is a competitive antagonist at the aldosterone receptor. It can cause gynecomastia due to antagonism at the testosterone receptor and thus should be used with caution in men. Eplerenone, a selective aldosterone­receptor antagonist with very weak affinity for androgen receptors, is an excellent alternative to spironolactone. Amiloride is also a weak potassium sparing diuretic which blocks sodium channels in the kidney and may be used as an alternative medical treatment. Nifedipine has also been shown to decrease aldosterone levels. Finally, inhibitors of the angiotensin converting enzyme (ACE inhibitors) have been shown to be effective in IHA.

6.2. Pheochromocytoma

Pheochromocytoma (phios [dusky], chroma [color], cytoma [tumor]) is a rare catecholamine producing tumor which arises from the chromaffin cells of the adrenal medulla and occasionally the sympathetic ganglia (paraganglioma). They can arise anywhere from the base of the brain to bladder. Only 0.01­.1% of hypertensive patients have a pheochromocytoma as a cause. The rule of 10's is often quoted as 10% are extra­adrenal, 10% occur in children, 10% are multiple or bilateral, 10% are malignant, and 10% will recur after resection.

Catecholamines are synthesized starting with the amino acid tyrosine. The rate limiting step is the first step which involves tyrosine hydroxylase converting tyrosine to dopamine. Dopamine is the first catecholamine produced which can then be converted to norepinephrine (NE) and subsequently epinephrine (E).

There are certain syndromes that are associated with pheo, shown below. These will be discussed in more detail in the pathology section.

MEN 2A ­ pheochromocytoma, medullary thyroid carcinoma and hyperparathyroidis MEN 2B ­ pheochromocytoma, medullary thyroid carcinoma, mucosal neuromas, marfanoid body habitus, other findings Neurofibromatosis ­ pheochromocytoma and neurofibromas Von Hippel Lindau syndrome ­ pheochromocytoma retinal angiomatosis cerebellar hemangioblastoma, renal and pancreatic cysts and renal cell carcinoma

6.2.1. Clinical Presentation

Pheochromocytoma is one of the many possible causes for a "spell" that some people describe. Symptoms may occur in paroxysms with any number of the 5 P's: ocw.tufts.edu/Content/14/lecturenotes/266733 5/8 7/18/12 PPY224 Pathophysiology of Endocrinology, Diabetes and Metabolism, Spring 2005 - Tufts OpenCours… Pressure ­ sudden major increase in blood pressure Pain ­ abrupt throbbing headache, chest, abdominal pain Perspiration ­ generalized diffuse diaphoresis Palpitations usually with true tachycardia often with feelings of panic or anxiety Pallor of the skin from vasoconstriction

Symptoms are characteristic for each patient and they can be precipitated by stressful situations. Clinical signs include hypertension, postural hypotension, retinopathy, weight loss, hyperglycemia, hypercalcemia, fever and tremor. There is a very large differential diagnosis of the symptom complex that goes along with a pheochromocytoma including a variety of endocrine, cardiovascular, psychological, neurologic and pharmacologic syndromes. Since pheochromocytoma is uncommon, the majority of people with "spell" symptoms will not have one but if there is some clinical suspicion, biochemical screening should be done since it can be fatal if it is missed.

6.2.2. Evaluation

6.2.2.1. Urinary catecholamines and metabolites

A 24­hour urine collection for catecholamines (total and individual levels of dopamine, NE and E), metanephrines, and VMA is the preferred initial screening test. This test has a sensitivity of 85% and specificity of 99.7% to detect a pheochromocytoma. Metanephrines and VMA are catecholamine metabolites. One should be aware that a variety of medications may cause false elevation of these levels. However, most pheochromocytomas will have catecholamine levels that are several times above the normal range rather than the small elevations that may occur with interfering factors including stress, anxiety or pain. Generally, before a diagnosis of pheochromocytoma is made several 24­hour urine measurements are completed.. Optimally, urine collections should be obtained during spells.

6.2.2.2. Plasma catecholamines andmetanephrines

Plasma catecholamines (E and NE) may also be done. This is a more difficult test to perform, as the patient must be supine for at least 30 minutes, in a quiet environment, with the needle for blood drawing in place prior to the sampling. Plasma levels are also increased by many factors including medications, smoking, renal insufficiency and fear of having blood drawn. Plasma metanephrines have recently been demonstrated to have a higher sensitivity (almost 100%) than urinary catecholamines but a lower specificity (~85%). Thus, this test is associated with more false positives. Therefore, it is recommended that high risk patients (such as those with MEN and other familial syndromes or a prior pheochromocytoma) be screened with plasma metanephrines. In the more common clinical scenario, when a sporadic pheochromocytoma is sought, a 24­hour urine for catecholamines, VMA and metanephrines should be obtained. Plasma metanephrines have less variability than plasma catecholamines and can be drawn without the preparation mentioned above.

6.2.2.3. Other Tests

Clonidine, glucagon and histamine testing are additional tests that are rarely used.

6.2.2.4. Diagnostic Imaging

Imaging studies should be done only after a biochemical diagnosis is made. Over 90% of pheochromocytomas are located in the adrenal and 98% are in the abdomen. Magnetic resonance imaging (MRI) is the preferred imaging test ahead of computer assisted tomography (CT) scanning. MRI has a sensitivity of up to 100% in detecting adrenal pheochromocytomas, does not necessitate contrast and does not expose the patient to ionizing radiation. Classically, pheochromocytomas appear very bright on the T2 weighted image. Nuclear imaging with MIBG (I131­metaiodobenzylguanidine) or occasionally octreotide (somatostatin analogue) is reserved for cases when a pheochromocytoma is confirmed biochemically but CT or MRI fail to visualize the tumor. MIBG uses radiolabeled iodine­123 attached to a compound which incorporates into tissues making large amounts of catecholamines. Positron emission tomography (PET) is another modality using specifically labeled radiopharmaceuticals which may sometimes be helpful in detecting pheochromocytomas.

6.2.3. Treatment

Surgical resection is the treatment of choice and usually results in the cure of hypertension. Careful preoperative preparation with alpha and then beta­adrenergic antagonists is required to prevent intraoperative hypertensive crises.

Start alpha blockade with phenoxybenzamine (a nonselective alpha blocker) or prazosin (selective alpha­1 antagonist which is associated with less tachycardia) 7­10 days preoperatively to allow for expansion of blood volume. The patient should be volume expanded with isotonic sodium chloride. Encourage liberal salt intake. Initiate a beta­blocker (eg. propanolol) only after adequate alpha blockade. If beta blockade is started prematurely, unopposed alpha stimulation will WORSEN the hypertension and could precipitate a hypertensive crisis. Phentolamine is an IV non­selective alpha antagonist that should be ready in the OR if the blood pressure rapidly rises during surgical manipulation of these tumors. Both an experienced anesthesiologist and an experienced surgeon are crucial to the success of the operation. Antiarrhythmics should also be available if necessary in the OR. Patients must be followed carefully postoperatively as hypotension and hypoglycemia may occur. Long­term follow­up involves yearly surveillance with plasma metanephrines for recurrence.

6.3. Cushing's Syndrome

Cushing's syndrome is defined as symptoms and signs of cortisol excess. The most common cause is exogenous glucocorticoids given for other medical conditions. Other causes of Cushing's syndrome are shown in the table below.

6.3.1. Clinical Presentation ocw.tufts.edu/Content/14/lecturenotes/266733 6/8 7/18/12 PPY224 Pathophysiology of Endocrinology, Diabetes and Metabolism, Spring 2005 - Tufts OpenCours… Clinically, the result of excessive glucocorticoid includes any of the following symptoms and signs:

Centripetal obesity Osteoporosis Proximal Myopathy Hyperpimentation Facial plethora Spontaneous ecchymoses Amenorrhea (moon facies) Poor wound healing Acne Peptic ulcers Hypertension Hirsutism Glucose intolerance, diabetes mellitus Suppression of immune response Hypokalemia Dark purple striae Psychiatric disease:depression, psychosis Alkalosis (>1 cm) (usually with ectopic disease)

(See lecture on Pituitary Neoplasia and Hypersecretion for Diagnostic Testing for Cushing's)

6.3.2. Etiology of Endogenous Cushing's Syndrome

ACTH –dependent PITUITARY Cushing's disease 60% (High ACTH, high cortisol) ECTOPIC 15% ACTH syndrome <1% CRH syndrome ACTH­independent ADRENAL 25% (Low ACTH, high cortisol) Unilateral 10% Adrenal Adenoma 8% Adrenal carcinoma 1% Bilateral Micronodular hyperplasia Macronodular hyperplasia Pseudo­Cushing's syndrome Major depression 1% Alcoholism <1%

6.3.3. Physiology

The following concepts are important to understanding the dynamic tests used to evaluate patients with Cushing’s syndrome:

1. The normal hypothalamic­pituitary­adrenal axis has a precisely controlled system of feedback inhibition. 2. Pituitary tumors are partially autonomous­they retain feedback inhibition but at a higher set point than the normal pituitary gland. 3. Adrenal and ectopic tumors have autonomous hormone secretion and do not usually exhibit feedback inhibition.

6.3.4. Treatment of Adrenal Cushing's Syndrome

If an adrenal tumor is found, it should be surgically removed. The remaining adrenal will be suppressed after surgery due to persistent pituitary suppression that may last for months and thus the patient should be put onto glucocorticoid coverage. Bilateral adrenalectomy is occasionally done either for primary macronodular/micronodular hyperplasia or for ACTH dependent causes not cured otherwise. Such patients require lifelong glucocorticoid and mineralocorticoid therapy. Medical adrenalectomy with mitotane which is toxic to the adrenals or a combination of other adrenolytics including ketoconazole, metyrapone and aminoglutethimide which all block steroid synthesis may be needed for patients who are not surgical candidates. Treatment of Cushings's syndrome will be covered more extensively in the lecture of pituitary hyperplasia. 7. Incidental Adrenal Mass

The incidental adrenal mass should be evaluated initially for function with screening tests as outlined elsewhere for pheochromocytoma, hyperaldosteronism, hypercortisolism and elevated sex hormones. Therapy depends on functional status. If the mass is found to be non­ functional and is under 3­4 cm in diameter, it may be followed by serial imaging (initially at 3 months and then 12 months). Some would suggest that the non­functional mass undergo fine needle aspirate (FNA) under CT guidance at this point. It is important never to biopsy an adrenal mass that you suspect is a pheochromocytoma because a hypertensive crisis can be induced by the biopsy. If the mass is functional or greater than 4­5 cm in diameter, it should be surgically resected. The risk of adrenal cancer increases in adrenal masses greater than 4­5 cm in diameter. 8. Adrenal Carcinoma

Adrenal cortical carcinoma (ACC) is a rare aggressive malignancy. The clinical presentation of patients with ACC is dependent on whether the tumor is hyperfunctioning. ACC is hyperfunctioning in 50­70% of patients and nonfunctioning in the remainder.

Hyperfunctioning syndromes in ACC may involve any of the hormones of the adrenal cortex including isolated Cushing’s (40%), isolated virilization (22%), Cushing’s and virilization (22%), feminization (2%), and hypertension (10%). Large carcinomas are only sometimes associated with adrenal cortical hyperfunction as they are often highly inefficient at synthesizing hormones. If hyperfunction occurs, pursuing the source of the hyperfunction will turn up the tumor.

In patients with nonfunctioning tumors, the three most common presenting features are pain, a palpable abdominal mass and metastases. Fatigue, weight loss, and fever may also be present. In patients with hyperfunctioning tumors the manifestations vary but may include those associated with virilization, feminization (in males), Cushing's syndrome or hyperaldosteronism. Adrenal sex hormones, primarily ocw.tufts.edu/Content/14/lecturenotes/266733 7/8 7/18/12 PPY224 Pathophysiology of Endocrinology, Diabetes and Metabolism, Spring 2005 - Tufts OpenCours… androgens, are produced mostly in the reticulosa layer of the adrenal cortex and when overproduced in adrenal carcinoma (also in major forms of congenital adrenal hyperplasia) may lead to virilization syndromes in women. The major symptoms and signs of this include hirsutism, cystic acne, oligomenorrhea, temporal balding, increased libido and clitoromegaly. Rarely, a feminization syndrome may occur in a male. The hormonal presentation of patients varies but most commonly includes elevated adrenal sex steroids such as serum testosterone, dehydroepiandrosterone sulfate (DHEAS), androstenedione, estrone levels as well as urinary free cortisol and 17­ketosteroids (metabolites of androgens).

ACC are usually irregularly shaped, heterogeneous, large (>4­5 cm in diameter) and easily seen on CT. There is often unilateral evidence of invasion or local metastases.

Complete surgical resection is the only effective and potentially curative treatment for adrenocortical carcinoma. Frequently the tumor is large and unresectable. Mean survival time in unresectable patients 3­9 months. Mean survival for patients undergoing complete resection was 28 months and a five­year survival of 48%. 9. References

Bornstein SR, moderator. Adrenocortical tumors: recent advances in basic concepts and clinical management. Ann Intern Med 130: 759­771, 1999. Cook DM, Loriaux L, The incidental adrenal mass, Am J Med 101: 88­94, 1996. Oelkers W, Current Concepts: Adrenal insufficiency, N Engl J Med 335: 1206­1212, 1996. Orth D, Medical Progress: Cushing's syndrome, N Engl J Med 332: 791­803, 1995. Ten S, New M, Maclaren N, Addison's Disease 2001, J Clin Endocrinol Metab 86: 2909­2922, 2001. Ganguly A. Primary aldosteronism. N Engl J Med 339(25):1828­34, 1998. Young WF Jr. Management approaches to adrenal incidentalomas. A view from Rochester, Minnesota. Endocrinol Metab Clin North Am. 29 (1):159­85, 2000.

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