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Adrenal Insufficiency

The hypothalamus secretes corticotrophin releasing hormone (CRF), which stimulates the pituitary to secrete ACTH. ACTH then stimulates the adrenal gland to produce cortisol. Cortisol exerts negative feedback effects both at the pituitary and the hypothalamic levels. ACTH also contributes to skin pigmentation. Lipotrophins which are produced with ACTH from pro-opiomelanocortin (POMC) result in the generation of endorphins.

Adrenal insufficiency may be caused by primary adrenal disease or by ACTH deficiency which produces secondary hypoadrenalism. Primary adrenal insufficiency can occur acutely or chronically. Primary acute adrenal insufficiency or adrenal crisis occurs in a variety of clinical settings:

  • Patients with chronic adrenal insufficiency are subjected to any form of stress
  • Patients maintained on exogenous coricosteroids have therapy withdrawn too quickly
  • Patients develop massive adrenal hemorrhage
  • Patients develop DIC and hemorrhagic infarction of adrenals.

Primary chronic adrenal insufficiency is called Addison disease. Clinical manifestations do not occur until >90% of the adrenal cortex has been destroyed. Many diseases can affect the adrenal glands including metastatic cancer, tuberculosis, lymphomas, amyloidosis, sarcoidosis, hemochromatosis, fungal infections and hemorrhage. However, autoimmune adrenalitis accounts 60 to 70% of cases. In about half of these cases, only the adrenal glands are involved, but in the remainder, other autoimmune diseases such as Hashimoto disease, pernicious anemia, type 1 diabetes mellitus, or hypoparathyroidism coexist. Circulating anti-adrenal antibodies are detectable in about half of the cases of Addison disease.

Patients can present with ill defined fatigue, weakness, depression, anorexia, vomiting, unexplained weight loss, hypotension, hyperpigmentation, hypoglycemia, hyponatremia or hyperkalemia.

Any disorder of the hypothalamus or pituitary that reduces ACTH secretion can lead to secondary adrenal insufficiency. It is characterized by deficient cortisol and androgen secretion but normal aldosterone secretion. Hyponatremia and hyperkalemia are not as severe in secondary adrenal insufficiency as in primary disease.

Intitial evaluation of adrenal insufficiency is usually based on measurement of plasma cortisol. Plasma corisol levels <5 ug/dL in the AM or during times of stress are presumptive evidence of glucocorticoid (cortisol) deficiency. A level >20 ug/dL essentially rules out the diagnosis. In most cases, cortisol levels are between these values and further testing is necessary.

The confirmatory tests used most frequently are cosnytropin stimulation and measurement of plasma ACTH level. The standard cosyntopin stimulation test involves obtaining a basal cortisol level and then giving 250 ug of cosyntropin (ACTH 1 - 24) IM or IV. Cosyntropin is a synthetic fragment of ACTH with full potency. This dose is far above the physiologic level. Plasma samples are drawn at 30 and 60 minutes following cosyntopin administration. If the adrenal cortex is functioning normally, the baseline cortisol level will exceed 5 ug/dL, stimulated cortisol level will peak at >18 ug/dl and change over baseline is at least 7 ug/dL.

Once adrenal insufficiency has been diagnosed, an ACTH level should be measured in the morning to distinguish primary from secondary adrenal insufficiency. An elevated ACTH level indicates primary adrenal insufficiency, while a low or low normal result indicates secondary adrenal insufficiency.

A normal consyntropin stimulation test response rules out primary disorders of the adrenal gland, but does not exclude partial ACTH deficiency with impaired reserve. To confirm a diagnosis of impaired ACTH reserve, one should perform the metyrapone test. Metyrapone acts by inhibiting 11-beta hydroxylase which converts 11-deoxycortisol to cortisol. This inhibition causes cortisol deficiency and a subsequent surge of ACTH secretion by the pituitary, that stimulates the adrenal gland to produce 11-deoxycortisol. The overnight test is performed in the following manner. A 30 mg/kg dose of metyrapone is given p.o. at midnight. Blood is drawn the following morning at 08:00 to measure plasma cortisol and 11-deoxycortisol levels. A 08:00 cortisol level below 5 ug/dL confirms that the patient took metyrapone while a 11-deoxycortisol level >7 ug/dL confirms a normal hypothalmo-pituitary-adrenal axis.

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