Adrenal Insufficiency

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ADDISON:

A: Autoimmune (most) D: Deposition D: Drugs I: Infections S: Sarcoidosis O: Overload of Iron (HC) N: Neoplasia

Do not confuse acute adrenal crisis with Addison disease.

Addison disease is a syndrome of long-term adrenal insufficiency that develops over months to years, with weakness, fatigue, anorexia, weight loss, and hyperpigmentation as the primary symptoms.

Primary Adrenal Insufficiency is also known as

Addison's Disease in honor of Dr. Thomas Addison

uggest secondary hyperaldosteronism.

High levels of both plasma renin activity and aldosterone s

Secondary Adrenal Insufficiency

Caused by pituitary failure of ACTH secretion which causes a drop in the adrenal glands production of cortisol but not aldosterone.

• Basal ACTH levels:

In primary adrenal insufficiency, 8 am plasma ACTH level is elevated, whereas in secondary adrenal insufficiency, plasma ACTH values are low or inappropriately normal.

Catecholamine Excess:

Phaeochromocytoma

however, in secondary adrenocortical insufficiency

(ie, secondary to disease or suppression of the hypothalamic-pituitary axis), mineralocorticoid function is preserved.

Adrenal Insufficiency

*Arises when cortisol levels are not sufficient to meet the needs of the body

The cosyntropin stimulation test

, on the other hand, uses a synthetic analogue of ACTH to stimulate cortisol production in the adrenal gland.

However, because aldosterone secretion is variable

, the negative and positive predictive value of a single random aldosterone level is limited.

In secondary and tertiary adrenal insufficiency, cortisol levels continue to rise for ≥ 24 h.

The simple short test is usually done initially, because a normal response obviates the need for further investigation.

confirms the diagnosis of primary aldosteronism.

When serum aldosterone is elevated above 22 ng/dL and renin is suppressed, the serum aldosterone test virtually

Acute adrenal insufficiency (Adrenal Crisis) should be expected in any patient

acute, unexplained volume depletion and shock • Hyperkalemia, acidosis, and hypoglycemia may also be accompanying

• A level of > 500 nmol/L rules out

adrenal Insufficiency except in the setting of a critically ill patient

In contrast,

an acute adrenal crisis can manifest with hypovolemic shock and electrolyte disturbances.

Results for the first hour are similar for both the short and prolonged tests,

but in Addison disease there is no further rise beyond 60 min.

• Primary and secondary deficiency may be distinguished

by measurement of aldosterone from the same blood samples. • In secondary, but not primary, adrenal insufficiency, the aldosterone increase from baseline will be normal (≥5 ng/dL)

• Secondary Adrenal Insufficiency may present with

evidence of adrenal insufficiency as well as other evidence of hypopituitarism

In primary adrenocortical insufficiency,

glucocorticoid and mineralocorticoid properties are lost;

healthy individuals

have aldosterone levels of less than 15 ng/dL

• Intermediate (82-500)cortisol concentrations require

investigation with an ACTH stimulation test.

Phaeochromocytoma

is a rare neuroendocrine tumor of the medulla of the adrenal glands (originating in the chromaffin cells), or extra-adrenal chromaffin tissue that secretes excessive amounts of catecholamines (epinephrine and norepinephrine) • 10% are malignant and 10% occur outside the adrenal gland (paraganglia)

The insulin tolerance test (ITT)

is considered the gold standard for assessing adrenal function, and consists of provoking insulin-induced hypoglycemia that should result in HPA activation and consequently, cortisol release. This is a labor-intensive test that requires very close monitoring and carries many inherent risks due to hypoglycemia.

• In most patients with primary aldosteronism, the 24-hour Urinary Aldosterone

is greater than 14 mcg/day (after 3 days of salt loading). Only about 7% of patients with primary aldosteronism have values of less than 14 mcg/day

Patients with primary hyperaldosteronism typically have

plasma aldosterone > 15 ng/dL (> 0.42 nmol/L) and low levels of Plasma Renin Activity, with a ratio of plasma aldosterone (in ng/dL) to plasma renin activity (in ng/mL/h) > 20.

thus it is a useful test to distinguish between high levels of plasm catecholamines caused by

release from the sympathetic nerves and those from phaeochromocytoma

• Mineralocorticoid deficiency typically leads to

renal wasting of sodium, retention of potassium, and reduced intravascular volume

Clonidine acts via

the alpha pre-ganglionic receptors to reduce catecholamine secretion (decrease efferent sympathetic flow)

• Cortisol aids in maintaining

vascular tone, hepatic gluconeogenesis

Primary Adrenal Insufficiency

• Adrenal insufficiency occurs when at least 90 percent of the adrenal cortex has been destroyed. As a result, often both glucocorticoid and mineralocorticoid hormones are lacking

Serum aldosterone level

• After 3 days of an unrestricted sodium diet and 1 hour of full recumbency, .

Regulation:

• Aldosterone (predominant mineralocorticoid) is secreted by cells in the zona glomerulosa in response to angiotensin (mainly); and by ACTH (not significant)

Prolonged Cosyntropin Stimulation Test

• Another option that may be used to diagnose secondary (or tertiary, ie, hypothalamic) adrenal insufficiency. • In secondary or tertiary adrenal insufficiency, the adrenal glands display cortisol secretory capacity following prolonged stimulation with ACTH, whereas in primary adrenal insufficiency, the adrenal glands are partially or completely destroyed and do not respond to ACTH.

Etiologies include:

• Any cause of primary or secondary hypopituitarism • Exogenous Glucocorticoid Therapy: A temporary form of secondary adrenal insufficiency may occur when a person who has been receiving a glucocorticoid hormone such as prednisone for a long time abruptly stops or interrupts taking the medication.

diagnosis

• Baseline Cortisol levels should be obtained in the early morning • A morning cortisol level of < 82 nmol/L is virtually diagnostic

Several Other Mechanisms Exist:

• Bilateral adrenal hemorrhage • Infection: Tuberculosis, CMV, Histoplasmosis • Metastatic Disease • Deposition Diseases: Hemochromatosis, Amyloidosis, Sarcoidosis • Drug Induced: Ketoconazole, Etomidate, Rifampin, Anticonvulsants • Congenital Adrenal Hyperplasias enlarged Adrenal glands present from birth - due to a defect in Enzyme involved in Steroid production

4. Clonidine Suppression test:

• Clonidine (α2 -adrenergic agonist), a centrally-acting hypotensive agent. It crosses the blood-brain barrier and acts in the hypothalamus to induce a decrease in blood pressure.

Short (low dose) Cosyntropin Stimulation Test

• Cosyntropin (synthetic part of ACTH) retains the full stimulating effect of ACTH on adrenal glands in healthy individuals • less time consuming; can be done on OPD basis • Measure morning cortisol level (pre-test level) • Administer 1 mg dose Cosyntropin • Measure a second cortisol level 1 hour after Cosyntropin administration • Normal response: cortisol > 550 nmol/L

Prolonged Cosyntropin Stimulation Test

• Cosyntropin 1 mg IM is given, and cortisol is measured at intervals for 24 h, typically at 1, 6, 12, and 24 h.

3. Saline Suppression test

• IV isotonic saline infusion should normally suppress aldosterone release by decreasing renin levels • In patients with primary hyperaldosteronism, the level of aldosterone in the blood is still high and the level of renin is low even after this salt loading

1. Plasma catecholamine levels

• In patients with pheochromocytoma, plasma catecholamine levels may not be continuously elevated, but only secreted during a "spell." By contrast, production of metanephrines (catecholamine metabolites) appears to be increased continuously. • Thus, the recommended first-line laboratory tests for pheochromocytoma are the tests that look for the Metanephrines either in the plasma or urine

MINERALOCORTICOID EXCESS

• Is the hypersecretion of the adrenal mineralocorticoid, aldosterone.

(eg, due to licorice ingestion (renal 11bHSD2 inhibitor) or Cushing syndrome)

• Low levels of both plasma renin activity and aldosterone suggest non-aldosterone mineralocorticoid excess.

2. Fractionated Free Plasma Metanephrines

• Metanephrine and normetanephrine (collectively referred to as metanephrines) are the 3-methoxy metabolites of epinephrine and norepinephrine, respectively. The metanephrines are stable metabolites and are co-secreted directly with catecholamines by pheochromocytomas and other neural crest tumors. This results in sustained elevations in plasma free metanephrine levels, making them more sensitive and specific than plasma catecholamines in the identification of pheochromocytoma patients.

Primary Adrenal Insufficiency

• Most commonly is of an autoimmune etiology, resulting from chronic destruction of the adrenal cortex • Typical histologic feature is lymphocytic infiltration • Antibodies to adrenal cortical antigens are present early in the disease process

Primary hyperaldosteronism Clinical Features

• Most patients with primary hyperaldosteronism have headaches and diastolic hypertension. • Edema is characteristically absent, unless congestive heart failure or renal disease is present. • Hypokalemia, caused by urinary potassium losses, may cause muscle weakness and fatigue, though potassium levels may be normal in mild primary aldosteronism. • Hypernatremia and metabolic alkalosis may also occur.

Short (low dose) Cosyntropin Stimulation Test interpretation

• Patients with both primary and secondary adrenal insufficiency will not demonstrate appropriate response • "if the adrenal glands lack ACTH for enough time (due to pituitary failure), cortisol production can be low because of adrenal atrophy"

Plasma aldosterone/plasma renin activity ratio

• Plasma renin activity is usually measured in the morning with the patient recumbent.

• Clinical effects

• Retains Na and H2O accompanied by K depletion leads to excess intravascular volume Hypertension

Testing for primary hyperaldosteronism

• Screening for primary aldosteronism may be indicated in patients with hypertension who have spontaneous or thiazide-induced hypokalaemia. (see slide 51 of this presentation for approach) • Initial laboratory testing consists of plasma aldosterone levels and plasma renin activity. Ideally, the patient should not take any drugs that affect the renin-angiotensin system (eg, thiazide diuretics, ACE inhibitors, angiotensin II receptor blockers, beta-blockers) for 4 to 6 wk before tests are done.

Clinical features:

• Symptoms may be episodic and include headache, palpitations, sweating, anxiety, nausea and weight loss • The signs which may also be intermittent and include hypertension, tachycardia and pallor. • There may be impaired glucose tolerance.

Chronic insufficiency typically develops more insidiously

• Symptoms may include weakness, weight loss, nausea, vomiting, anorexia, and postural hypotension • Hyponatremia and Hyperkalemia may develop secondary to a lack of aldosterone

24-Hour urinary aldosterone excretion test

• The 24-hour urinary aldosterone excretion test is one of the most useful confirmatory diagnostic tools because it is an index for total daily aldosterone secretion (in a fashion similar to the 24-h urinary free cortisol, which is typically elevated in patients with Cushing syndrome).

3. Fractionated Free 24 hr urine Metanephrines

• The 24-hour urinary fractionated metanephrines (a more specific assay) may be used as the first test for low suspicion cases and also as a confirmatory study in patients with a less than 2-fold elevation in plasma free fractionated metanephrines. Reference Values • Age and sex dependent reference intervals for each metabolite • Increased metanephrine and normetanephrine levels are found in patients with pheochromocytoma and tumors derived from neural crest cells

2. Fractionated Free Plasma Metanephrines (continued)

• The best test for excluding pheochromocytoma. The test's sensitivity approaches 100%, making it extremely unlikely that individuals with normal plasma metanephrine and normetanephrine levels suffer from pheochromocytoma Reference Values •Free metanephrine < 0.50 nmol/L •Free normetanephrine < 0.90 nmol/L • It is recommended to confirm elevated plasma free metanephrines with a second, different testing strategy in order to avoid large numbers of false-positive test results.

Primary aldosteronism

• The most common cause of mineralocorticoid excess • refers to an adrenal cause and can be due to either * an adrenal adenoma (conn's syndrome) * or bilateral adrenal hyperplasia.

Serum potassium and bicarbonate levels:

• Typically, it is associated with mild metabolic alkalosis (serum bicarbonate level >31 mEq/L) and inappropriate kaliuresis (urinary potassium excretion >30 mmol/day).

2. Captopril Suppression Test

• decrease the renin-stimulated aldosterone production in secondary aldosteronism; • no response in primary aldosteronism.

Secondary aldosteronism

• increased adrenal production of aldosterone in response to extra-adrenal stimuli such as renal hypoperfusion (e.g. Cardiac Failure, Nephrotic syndrome..)

Inadequate cortisol in times of stress can lead to

•hypotension, shock, and hypoglycemia

In normal individuals, even if they are anxious,

•the plasma catecholamines will suppress into the normal range 3 hours after 0.3 mg clonidine orally (noradrenaline 0.2-0.8 ng/ml, adrenaline 0.04-2 ng/ml). Phaeochromocytoma patients do not.

• Autoantibody screen:

Adrenocortical antibodies or antibodies against 21-hydroxylase can be detected in more than 90% of patients with recent onset autoimmune adrenalitis. Furthermore, antibodies that react against other enzymes involved in the steroidogenesis (P450scc, P450c17) and anti-steroidproducing cell antibodies are present in some patients


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