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Clinical chemistry

Adrenal insufficiency


Author: Renu Virk, M.D., University of Massachusetts Memorial Hospital (see Reviewers page)

Revised: 13 April 2010, last major update July 2009

Copyright: (c) 2009, PathologyOutlines.com, Inc.




● Clinical condition which occurs when there is more than 90% destruction of the adrenal gland


Clinical Features


● Often insidious in onset, patients may present in shock due to increased stress

● Malaise, lassitude, fatigue, weakness, anorexia, weight loss, nausea, vomiting, hypotension, hypoglycemia, hyponatremia, hyperkalemia and hyperpigmentation (with primary adrenal insufficiency)

● Morning serum cortisol level >13 mcg/dL reliably rules out adrenal insufficiency (J Fam Pract 2009;58:281a)

● Relative adrenal insufficiency: if patient's cortisol response is inadequate for the degree of illness or stress (J Perinatol 2009;29 Suppl 2:S44)


Acute Adrenal Crisis


● Infection or major stress may transform chronic adrenal insufficiency into acute crisis

● Patient usually presents in shock


Primary Adrenal Insufficiency


● See also Adrenal Gland chapter

● Chronic cases are also known as Addison’s disease

● Characterized by low morning serum cortisol, low morning salivary cortisol levels, high ACTH levels, low serum aldosterone levels, high plasma renin activity

● Note: late night (11 pm to midnight) salivary cortisol level testing is also useful (J Clin Endocrinol Metab 2009 Jul 14 [Epub ahead of print])

Causes: amyloidosis, autoimmune adrenalitis, drugs, hemorrhagic infarction, infections (tuberculosis, histoplasmosis, HIV) that destroy substantial adrenal cortical tissue, metastases to adrenal gland, polyglandular autoimmune syndrome, radiation


Secondary and Tertiary Adrenal Insufficiency


● See also Adrenal Gland chapter

● Due to pituitary (secondary) or hypothalamic (tertiary) disease

● Characterized by low ACTH levels, low morning serum cortisol, low morning salivary cortisol levels (Horm Metab Res 2009 Jul 7 [Epub ahead of print])

● Note: androgens and cortisol levels are low because their production is influenced by ACTH, but androgens are less affected in males since they are also produced by testis; hypoglycemia is more common than with primary adrenal insufficiency

● Serum aldosterone, sodium and potassium and plasma renin activity levels are usually normal, since they are controlled by renin-angiotensin axis, which is not under the control of ACTH

Causes (secondary): panhypopituitarism, isolated ACTH deficiency (very rare); traumatic brain injury

Causes (tertiary): chronic high dose glucocorticoid therapy, tumor, sarcoidosis, cranial irradiation




● Low early morning serum cortisol levels (less than 3 mcg/dl)

● Low basal urinary cortisol and 17-hydroxycorticosteroid levels
● Salivary cortisol value at 8 am < 1.8ng/ml or an early morning serum cortisol level < 10 mcg/dl is suggestive of adrenal insufficiency

● Normal levels of morning salivary cortisol exclude adrenal insufficiency

● ACTH, aldosterone and plasma renin levels vary by cause (primary versus secondary / tertiary)


ACTH stimulation tests


● Patients with primary adrenal insufficiency show subnormal rise in cortisol after ACTH stimulation test

● This test may not detect partial secondary adrenal insufficiency

● 48-hour ACTH stimulation test reliably separates primary from secondary or tertiary adrenal insufficiency

● ACTH test is the single best test for confirming the diagnosis of chronic adrenal insufficiency (Lancet 1999;354:179)


CRH stimulation test


● Differentiates secondary from tertiary adrenal insufficiency

● Seldom used due to expense and a requirement for multiple blood samples

● Secondary - have subnormal results; Tertiary - normal response

● See also CRH stimulation test under Adrenal hypercortisolism


Insulin induced hypoglycemia and Metyrapone stimulation tests


● More helpful if partial secondary/tertiary adrenal insufficiency is suspected

● Metyrapone test is less expensive


Additional references


Wikipedia, eMedicine #1#2


End of Clinical Chemistry - Adrenal insufficiency




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