What is adrenal insufficiency?
Adrenal insufficiency means the adrenal glands are not producing enough of some or all of its hormones. Its production is insufficient. Adrenal insufficiency can be primary or secondary. “Addison’s disease, the common term for primary adrenal insufficiency, occurs when the adrenal glands are damaged and cannot produce enough of the adrenal hormone cortisol. The adrenal hormone aldosterone may also be lacking.

“The adrenal glands produce both aldosterone and cortisol while ACTH from the pituitary stimulates cortisol release from the adrenal glands. Based on the underlying reason for insufficiency (primary vs. secondary) there will be deficiencies in either both mineralocorticoids (aldosterone) and glucocorticoids (cortisol) or simply a deficiency in glucocorticoids alone.  Aldosterone aids in sodium retention and potassium secretion and cortisol promotes gluconeogenesis, increases sensitivity to catecholamines, and regulates the immune system. If a patient with primary insufficiency has an adrenal crisis, they may be found to be hyponatremic and hyperkalemic in addition to having hypoglycemia and hypotension due to both aldosterone and cortisol deficiency, respectively. Patients with isolated cortisol deficiency may have only hypoglycemia due to impaired gluconeogenesis and hypotension due to decreased sensitivity to catecholamines. This is why hypotension is often refractory to vasopressors. Stressors that precipitate adrenal crisis also release inflammatory cytokines. Cortisol works to regulate these cytokines. One cytokine, tumor necrosis factor alpha, can promote cortisol resistance. Cortisol will work to suppress this in the acute phase, but when there is a deficiency of cortisol, then tumor necrosis factor (TNF)-alpha release and sensitivity increase leading to further cortisol resistance. This may explain mortality in the setting of adrenal crisis despite appropriate treatment, especially when treatment or recognition is delayed” https://www.ncbi.nlm.nih.gov/books/NBK499968/

Primary, secondary, and tertiary adrenal insufficiency.

Secondary adrenal insufficiency occurs when the pituitary gland fails to produce enough adrenocorticotropin (ACTH) to stimulate the adrenal glands to produce the hormone cortisol. If ACTH output is too low, cortisol production drops. Eventually, the adrenal glands can shrink due to lack of ACTH stimulation. Secondary adrenal insufficiency is much more common than Addison’s disease.” niddk.nih.gov

“Primary adrenal insufficiency (Addison’s disease) is due to adrenocortical disease, while secondary and tertiary adrenal insufficiency are due to disorders of the pituitary gland (corticotropin [ACTH] secretion) or the hypothalamus (corticotropin-releasing hormone secretion), respectively. Primary adrenal insufficiency is associated with both cortisol and mineralocorticoid deficiency. In contrast, secondary and tertiary adrenal insufficiency are associated with cortisol, but not mineralocorticoid deficiency, because aldosterone is regulated primarily by the renin-angiotensin system, which is independent of the hypothalamus and pituitary. This distinction accounts for the different clinical presentation and management of these disorders.” Uptodate.com”

What causes primary adrenal insufficiency?
Addison’s disease is an autoimmune adrenalitis in which the adrenal cortex is destroyed. This results in the loss of mineralocorticoid, glucocorticoid, and adrenal androgen hormone production.

“This patient has signs and symptoms consistent with primary adrenal insufficiency (PAI). In Western countries autoimmunity is responsible for 90% of these cases. Because the corticotropin (ACTH) stimulation test has a higher degree of sensitivity and specificity than morning cortisol and ACTH concentrations, it is the preferred test in all patients with possible primary adrenal insufficiency. Serum aldosterone paired with plasma renin activity is used to screen for adrenal hyperplasia in hypertensive patients and also for establishing the existence of mineralocorticoid insufficiency in patients with PAI. Once the diagnosis is established, 21-hydroxylase antibodies and 17-hydroxylase progesterone levels are used to determine the etiology of PAI.” ABFM Critique

How is the diagnosis made?
The diagnosis is made using characteristic symptoms from history, physical exam findings like hyperpigmentation, lab findings like hyperkalemia and hyponatremia and confirmed with a Cosyntropin (ACTH) stimulation test.

Understanding sodium and potassium abnormalities in adrenal insufficiency.
Normally, aldosterone maintains the total body sodium by absorbing sodium and excreting potassium. In adrenal insufficiency, this mineralocorticoid is absent (or reduced). So you will see sodium being lost (low sodium) and potassium high because it is not being excreted.

“A 22-year-old male presents to your office for evaluation of fatigue, poor appetite, and nausea. He states that when he stands too long he often gets dizzy but this is relieved by sitting. His symptoms have been gradually getting worse over the past year. His vital signs are normal but he is found to be orthostatic. A physical examination is unremarkable except for hyperpigmentation in his palmar creases and around his nipples. A basic metabolic panel is notable for a sodium level of 131 mEq/L (N 135–145) and a potassium level of 5.1 mEq/L (N3.5–5.0).

What is a good diagnosis? Addison’s disease. This patient presents with classic symptoms of Addison’s disease, which is an autoimmune adrenalitis in which the adrenal cortex is destroyed. This results in the loss of mineralocorticoid, glucocorticoid, and adrenal androgen hormone production. Common symptoms of Addison’s disease include anorexia, weakness, fatigue, gastrointestinal symptoms, hypotension, salt cravings, postural dizziness, vitiligo, muscle pain, and joint pain. Hyperpigmentation is the most common physical finding and is generally distributed diffusely over the entire body. It can also be seen in the palmar creases, at the vermillion border of the lips, on the buccal mucosa, around the nipples, and around scars.

Low serum cortisol measured at 8 a.m. suggests adrenal insufficiency

Hyponatremia may also be seen, due to cortisol and mineralocorticoid deficiencies, and hyperkalemia may occur as a result of the lack of mineralocorticoids. If cortisol is low, a cosyntropin stimulation test is the first-line test for diagnosing adrenal insufficiency. People with Addison’s disease require lifelong hormone therapy with glucocorticoids and mineralocorticoids. They also require stress-dose glucocorticoids for illnesses and before surgical procedures because they are unable to mount an adequate response to stress. Generally, the treatment will be prednisone or hydrocortisone along with fludrocortisone. Men with Addison’s disease do not need testosterone replacement because their testes will produce adequate levels. Women may benefit from testosterone replacement because the adrenal glands are their primary source of testosterone.” ABFM Critique. 

 

Reference / Further Reading

Addison disease: Early detection and treatment principles. Am Fam Physician 2014;89(7):563-568.

Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline, The Journal of Clinical Endocrinology & Metabolism, Volume 101, Issue 2, 1 February 2016, Pages 364–389

https://www.niddk.nih.gov/health-information/endocrine-diseases/adrenal-insufficiency-addisons-disease

https://medlineplus.gov/ency/article/000357.

htmhttps://emedicine.medscape.com/article/116716-overview

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