The Adrenal Part 2

Adrenal Insufficiency

Adrenal insufficiency (Addison disease) is categorized as primary or secondary. Primary adrenal insufficiency results from destruction of the adrenal cortex. There is a long list of causes of primary adrenal insufficiency [see Table 3]; worldwide, tuberculosis is the most common cause, and in the industrialized nations, idio-pathic or autoimmune adrenal destruction is the most common cause. Secondary adrenal insufficiency results from disruption of pituitary secretion of ACTH, which by far is most commonly caused by prolonged treatment with exogenous glucocorticoids.

Figure 4 The severity of the clinical manifestations and the level of urinary free cortisol can be used to define three categories of Cushing syndrome: classic, atypical, and anorexia associated.

With time, doses of exogenous glucocorticoids sufficient to suppress ACTH secretion will lead to dysfunction of CRH-secreting neurons and attendant ACTH deficiency; subsequent withdrawal of glucocorticoids, for whatever reason, will then unmask the deficiency. Recovery of function may require a year or more. A far less common cause of disrupted ACTH secretion is destructive lesions in and around the pituitary gland and hypothalamus [see Table 4].

The symptoms and signs of adrenal insufficiency can be grouped into chronic and acute syndromes. The chronic syndrome is characterized by anorexia, weight loss, fatigue, and or-thostatic hypotension. In patients with primary disease, the predominant signs are weight loss and hyperpigmentation of the skin, especially of the sun-exposed areas and extensor surfaces. The acute syndrome is closely analogous to cardiogenic or septic shock, with reduced cardiac output into a dilated and unresponsive vascular system. Symptoms include prostration and all of the signs and symptoms of the shock syndrome. Shock in this setting tends to be unresponsive to volume replacement and vasoconstrictor therapy.

With both chronic and acute syndromes, the diagnosis should be suspected on clinical grounds, but it requires laboratory confirmation. The critical test for the diagnosis of chronic adrenal insufficiency is the cosyntropin stimulation test. Synthetic ACTH (cosyntropin) is administered in a 250 ^g intravenous bolus, and plasma cortisol levels are then measured after 45 and 60 minutes. Values greater than 20 ^.g/dl exclude adrenal insufficiency as a cause of the clinical findings. Values less than 20 ^g/dl suggest that adrenal compromise could be a contributing factor. In this situation, treatment with glucocorticoids is mandatory until the clinical situation is clarified with more precision.

In acute adrenal insufficiency, the most useful test is measurement of the plasma cortisol level. Cosyntropin stimulation testing is not necessary; the illness, which is sufficiently severe to merit admission to an intensive care unit, represents an endogenous source of maximal physiologic stress. Plasma cortisol levels in acute adrenal insufficiency are greater than 20 ^g/dl, with the only exception being in patients who have a low plasma albumin concentration, which lowers the total cortisol concentration.14 Unfortunately, there are no published data on the interpretation of plasma cortisol values in patients with low albumin concentrations, so most clinicians adhere to the 20 ^g/dl standard. Currently, if the cortisol value is less than 20 ^g/dl, it should be confirmed with a standard cosyntropin stimulation test.

The differential diagnosis of adrenal insufficiency requires the discrimination of primary and secondary causes; the most useful test is measurement of the circulating plasma ACTH level. ACTH levels greater than normal define primary disease; values in the normal range or below define secondary disease.

Patients with primary adrenal disease should have the adrenal glands imaged with CT or MRI. Infectious, malignant, and vascular causes of adrenal insufficiency all result in enlargement of the adrenal glands. In idiopathic or autoimmune adrenal insufficiency, the glands are normal or small in size. Patients with secondary adrenal insufficiency should first be assessed for exogenous glucocorticoid use. If that can be eliminated as a cause, they should undergo CT or MRI scanning of the hypothalamus and pituitary gland to exclude destructive lesions in this area.

Treatment

The goal in treating adrenal insufficiency is to replace the missing hydrocortisone and aldosterone in quantities calibrated to the clinical situation. Hydrocortisone can be replaced with oral or intravenous hydrocortisone. Aldosterone is replaced with oral fludrocortisone. Exogenous hydrocortisone and flu-drocortisone are both equipotent with the endogenously secreted hormone. Unstressed persons secrete hydrocortisone at a rate of 6.5 mg/m2 daily. In the face of stress, such as a surgical procedure or serious trauma, hydrocortisone secretion can rise more than 10-fold. The secretion rate of aldosterone is 100 ^g/day in persons consuming large amounts of sodium (i.e., a typical United States diet).

Primary chronic adrenal insufficiency is treated with oral hy-drocortisone, 12 to 15 mg/m2/day. This is roughly double the amount of hydrocortisone that is normally secreted; the added amount is needed to compensate for first-pass hepatic metabolism. Hydrocortisone is best given as a single daily dose with breakfast. Fludrocortisone is given at a dose of 0.1 mg/day. When moderate stress is anticipated (e.g., a root canal procedure), the dose of hydrocortisone is temporarily doubled, beginning the day before the stress and continuing until 2 days afterward. It is not necessary to alter the fludrocortisone dose. With anticipated major stress (e.g., appendectomy with general anesthesia), the hydrocortisone dosage is increased to 100 mg every 6 hours from the day before the procedure until 2 days afterward. Hydrocorti-sone dosage increases are not required for periods of psychological stress, such as major depression, psychosis, or grief.

These replacement regimens roughly reproduce the patterns of cortisol and aldosterone secretion in persons with normal adrenal function. The need for these temporary dosage increases has not been clearly established, on either clinical or biologic grounds, but this has become the standard of practice and is not likely to change. Chronic secondary adrenal insufficiency is treated in the same way as chronic primary disease but with replacement of hydrocortisone only, not aldosterone.

Patients with acute adrenal insufficiency are treated in the same fashion as those with chronic adrenal insufficiency who are experiencing major stress. Treatment is monitored clinically. Signs of Cushing syndrome indicate overtreatment; hypona-tremia, orthostasis, and anorexia indicate undertreatment. There is no good clinical evidence to suggest that the dosage regimens ever need to be exceeded. If a patient on recommended replacement doses of hydrocortisone and fludrocortisone fails to do as well as expected, the reason is something other than the adrenal replacement regimen.

All patients with adrenal insufficiency should wear a medical-alert bracelet imprinted with the words "adrenal insufficiency" and carry a similar wallet card at all times.

Pheochromocytoma

The adrenal medulla accounts for about 10% of the weight of the adrenal gland. It is composed primarily of chromaffin cells, which are named for the yellow-brown color they take on when stained with chromatic salts. The cells of the medulla are directly innervated by preganglionic sympathetic nerve cells. Hence, these epinephrine-secreting cells are analogous to the postgan-glionic neurons in the other areas of the sympathetic nervous system. These cells are not neurons, however, and have no dendrites or axons. In addition, the primary secretory product of the adrenal medulla is epinephrine, whereas the remainder of the sympathetic nervous system employs norepinephrine as the neurotransmitter. The reason for this difference is that the blood supply to the adrenal medulla is derived from the capillary plexus draining the adrenal cortex. This capillary blood is extremely rich in cortisol—perhaps the highest concentration of cortisol in the human body is in the adrenal medulla—and corti-sol induces catechol-O-methyl transferase, the enzyme that converts norepinephrine to epinephrine. The primary disease of the adrenal medulla is pheochromocytoma; 90% of pheochromocy-tomas occur in the adrenal medulla. Extra-adrenal tumors of the chromaffin cell are known as paraganglions or chemodectomas, depending on the location. All have similar clinical presentations, and all are treated in the same way (see below).

The main clinical manifestation of pheochromocytomas is hypertension. The hypertension can be sustained or episodic; the two forms occur with equal frequency. Paroxysmal hypertension is associated with tachycardia, diaphoresis, anxiety, and a sense of foreboding. Patients also complain of nausea and abdominal pain. The association of headache, palpitations, and sweating with hypertension has a high (> 90%) sensitivity and specificity for pheochromocytoma. The differential diagnosis for pheochromocytoma is extensive and includes anxiety and panic attacks, thyrotoxicosis, amphetamine and cocaine use, and use of over-the-counter cold medicines that depend upon cate-cholamines for effect, such as atomizers for nasal congestion [see Table 5]. Pheochromocytomas are usually benign (90%) and usually unilateral (90%). The incidence of pheochromocytoma is markedly increased in several genetic syndromes: multiple endocrine neoplasia types 2a and 2b and the phakomatoses, including neurofibromatosis, cerebelloretinal hemangioblastosis, tuberous sclerosis, and Sturge-Weber syndrome.

Diagnosis

The traditional tests for diagnosing pheochromocytoma are measurements of the urinary fractionated catecholamines and urinary metanephrine excretion in 24-hour urine samples. Total catecholamine excretion is normally less than 100 ^g/day, with no more than 25% being epinephrine. Urinary metanephrine excretion is normally less than 1.3 mg/day. The urine for these tests must be collected in an acid medium (laboratories typically provide appropriate containers) and need not be refrigerated. Creati-nine should also be measured, as an indicator of completeness of collection. The patient should be taken off all medications when possible. If the hypertension must be treated, diuretics, vasodilators, calcium channel blockers, and angiotensin-converting enzyme (ACE) inhibitors interfere minimally with the assays. When there is concordance between the clinical picture and the biochemical tests, CT or MRI scans should be employed to localize the tumor. MRI is particularly useful because these tumors almost always "brighten" with T2-weighted images. If CT and MRI fail to reveal an adrenal tumor, radiolabeled meta-iodobenzyl-guanidine (MIBG) can be a useful scanning technique for locating tumors outside of the adrenal gland, such as those in the carotid body, heart, urinary bladder, and the organ of Zuckerkandl.

Figure 5 Congenital adrenal hyperplasia may result from mutations that inactivate any of the six enzymatic steps in the biosynthesis of cortisol from cholesterol. The clinical manifestations of the disorder vary with the enzyme deficiency.