Addison Disease

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Introduction to Addison Disease

Adrenal insufficiency describes a related group of disorders that are generally divided into two broad categories. Disorders that are due to a primary inability of the adrenal glands to synthesize and secrete hormone constitute the primary adrenal insufficiency syndromes. Disorders of adrenal function that result from inadequate adrenocortiocotropic hormone (ACTH) synthesis or release from the anterior pituitary constitute the secondary adrenal insufficiency syndromes. The major primary adrenal insufficiency syndrome is Addison disease.

Addison disease was first described by Thomas Addison in 1855. Dr. Addison's original description of the disorder listed the characteristic features as....."general languor and debility, remarkable feebleness of the heart’s action, irritability of the stomach, and a peculiar change of color in the skin, occurring in connection with a diseased condition of the suprarenal capsules". In this early description, the diseased condition of the suprarenal capsules was primarily (70-90%) the result of tuberculosis. Addison’s description of the clinical features associated with this form of primary adrenal insufficiency was extremely elegant given that at the time the function of the adrenal glands was unknown.

Following Addison's initial description, much work has been done to understand the underlying biochemistry and physiology behind the symptoms associated with adrenal insufficiency. It is now known that Addison disease results from the inability of the adrenal cortex to synthesize and secrete glucocorticoid (primarily cortisol) and mineralocorticoid (primarily aldosterone) hormones. Although most of the early cases were the result of infection with Mycobacterium tuberculosis, today the most frequent cause of Addison disease is idiopathic atrophy, most often the result of autoimmune destruction of the cortical tissue of the adrenal glands. Rare instances of Addison disease are associated with adrenoleukodystrophy, tumor metastases, HIV infection, cytomegalovirus (CMV) infection, bilateral hemorrhage, amyloidosis, and sarcoidosis. The consequence of adrenal cortical hormone synthesis failure is increased secretion of ACTH, from anterior pituitary corticotropes, in an effort to stimulate the adrenal glands. In addition, the loss of adrenal cortisol production results in loss of the normal feed-back inhibitory loop that cortisol exerts upon the pituitary corticotrophic cells that secrete ACTH.

Primary and secondary adrenal insufficiency share many clinical features, yet have easily distinguishable differences. The associated increase in ACTH secretion in Addison disease contrasts with secondary adrenal insufficiency which is due to ACTH deficiency. In addition, Addison disease is associated with hyperpigmentation. The hyperpigmentation in Addison disease is related to melanocyte stimulation by ACTH and α-melanocyte-stimulating hormone (α-MSH), where ACTH is the more potent stimulator of melanogenesis. Indeed, as discussed in detail in the Gut-Brain Interrelationship page, α-MSH function is more related to control of feeding behaviors than to any role in pigmentation. In secondary adrenal insufficiency syndromes, mineralocorticoid synthesis is essentially normal, whereas, glucocorticoid synthesis is insufficient. The normal mineralocorticoid synthesis in secondary adrenal insufficiency is due to the fact that it is primarily regulated by salt and water metabolism rather than ACTH.

Without treatment, adrenal insufficiency can be fatal, hence, early recognition is extremely important.

Clinical Features of Addison Disease

Physical Findings

The characteristic clinical presentation of acute primary adrenal insufficiency includes an insidious onset of asthenia (fatigability and weakness), cutaneous and mucosal pigmentation, agitation, nausea, vomiting, anorexia, weight loss, orthostatic (postural) hypotension (drop in blood pressure upon standing), confusion, circulatory collapse, abdominal pain, and fever. Indeed, one can consider the hallmark features of Addison disease to be asthenia, weight loss, and pigmentation (particularly on sun-exposed skin), as these three symptoms are present in >97% of patients. Addison disease is also associated with a characteristic sequelae of biochemical presentations. These include hyponatremia, hypoglycemia, hyperkalemia, unexplained eosinophilia, and mild prerenal azotemia (accumulation of urea and creatinine in the body). The typical history and clinical findings of chronic primary adrenal insufficiency include a protracted history of malaise, fatigue, anorexia, weight loss, joint and back pain, and darkening of the skin. In addition, patients may crave salt and may develop preferences for salty foods and fluids.

As pointed out above, darkening of the skin is one of the hallmark signs of primary adrenal insufficiency. The hyperpigmentation associated with Addison disease may be homogeneous or blotchy and occurs in all racial and ethnic groups. In addition, isolated darker areas occur at the palmar creases, flexural areas, sites of friction, recent scars, vermilion border of the lips, and genital skin. Mucosal membranes, in particular the buccal, periodontal, and vaginal mucosa may also show patchy macular areas of increased pigmentation. The cutaneous and mucosal pigmentation increases with age and advancement of the symptoms of Addison disease.

Autoimmune destruction is the most common cause of primary adrenal insufficiency in industrialized countries and may be the sole cause or, in rare instances, be associated with inherited autoimmune polyglandular syndromes. These latter syndromes tend to present either in childhood (type 1), in association with hypoparathyroidism and mucocutaneous candidiasis, or in adulthood (type 2), in association with insulin-dependent diabetes mellitus, autoimmune thyroid disease, and vitiligo (autoimmune destruction of melanocytes). Suspicion of Addison disease should be high in individuals with AIDS as well as other viral disorders such as CMV necrotizing adrenalitis.

Biochemical Findings

Upon suspicion of Addison disease, biochemical testing is needed to confirm the diagnosis of adrenal insufficiency. As the disease advances, serum sodium, chloride, and bicarbonate levels will be reduced while serum potassium levels will be elevated all of which results from insufficient mineralocorticoid (aldosterone). Aldosterone exerts its primary effects through actions on the kidneys but also functions in the colon and sweat glands. The principle effect of aldosterone is to enhance sodium (Na+) reabsorption in the connecting tubule (CNT) and cortical collecting duct of the nephrons in the kidneys. Within these regions of the nephron aldosterone induces the expression of the Na+,K+-ATPase subunit genes (ATP1A1 and ATP1B1), the genes encoding the subunits (SCNN1A, SCNN1B, and SCNN1C) of the epithelial sodium channel (ENaC), and the SLC12A3 gene (encoding the Na+-Cl cotransporter, NCC). The net effect of the induction of these transporter genes, by aldosterone, is enhanced Na+ reabsorption as a function of the apical membrane localized ENaC and NCC transporters and delivery to the blood via the action of the basolateral membrane localized Na+,K+-ATPase. Secondary to the Na+ uptake is efflux of potassium (K+) to the tubular lumen. In addition to K+ excretion, aldosterone enhances the excretion of hydrogen (H+) ions from the collecting duct which is a compensating action to counter the accumulation of the positive charge imparted by increased Na+ reabsorption. Therefore, the hyponatremia of Addison disease results from both the loss of sodium to the urine and to the movement of sodium into the intracellular compartment. As sodium moves into the cell, fluid depletion in the vasculature ensues which exacerbates the hypotension of Addison disease. The hyperkalemia, primarily due to loss of aldosterone, is also a result of acidosis and impaired glomerular filtration.

Plasma levels of cortisol and aldosterone are reduced below normal levels. In addition, neither hormone levels rise in response to administration of ACTH as would be expected in a normal individual. Normal cortisol levels in the hypotensive state, due to the absence of adrenal insufficiency, are expected to be in the range of 18μg/dL (495nmol/L) following administration of cosyntropin (250μg administered IM or IV). In individuals in whom the cosyntropin administration test results in cortisol values greater than 19μg/dL (524nmol/L), Addison disease can be excluded as the cause of associated symptomology. Alternatively, if the cortisol level is less than 3μg/dL (83nmol/L) it is virtually assured that the patient's symptoms are due to Addison disease. Measurement of free cortisol in the urine is not at all useful in the correct diagnosis of Addison disease.

Measurement of plasma ACTH helps to determine if the observed symptoms and biochemical results are due to primary or secondary adrenal insufficiency. With primary insufficiency the values of plasma ACTH will be above the normal range, whereas, in secondary insufficiency the plasma levels will be lower than normal. Identification of hypokalemia in the presence of elevated plasma renin levels signifies a mineralocorticoid deficiency and, therefore, allows for discrimination of primary adrenal insufficiency.


All patients with primary adrenal insufficiency should be treated via physiologic replacement of the deficient glucocorticoid and mineralocorticoid hormones. Patients with acute adrenal insufficiency should also receive fluid resuscitation. Administration of hydrocortisone (cortisol) IV (100mg every 8hr) is the standard treatment protocol for acute treatment of Addison disease. For chronic therapy, oral hydrocortisone (12–15 mg/day) provides adequate glucocorticoid replacement. Administration can be in divided doses during the day to grossly recapitulate the normal diurnal pattern of cortisol secretion. In obese individuals or in patients being treated with anticonvulsants, the dosage of hydrocortisone needs to be increased. Conversely, in patients with type 2 diabetes or who are hypertensive, the hydrocortisone dosage needs to be reduced. Administration of hydrocortisone does not replace the mineralocorticod component missing in Addison disease. For this deficiency patients take oral fludrocortisone (0.05–0.1 mg/day). In order to prevent excessive sodium loss during this therapy, patients need to take 3–4gm/day of sodium. Also, when patients are experiencing an additional illness, especially accompanied with fever, the dose hydrocortisone should be doubled. Due to the increased risk for excessive sodium loss, patients are advised to take this increased dosage with a salty broth such as beef or chicken boullion.

Due to the fact that there is no simple way to assess whether the replacement dose of glucocorticoid is correct, clinical evaluation is necessary to identify signs and symptoms of over-or under-replacement. A recurrence of symptoms of adrenal insufficiency clearly suggest that the dose of hydrocortisone is insufficient. These symptoms may be vague, such as malaise, and may be difficult to ascribe solely to glucocorticoid deficiency. Development of Cushing syndrome-like features such as weight gain, hyperglycemia, hypertension, or osteopenia, is indicative of excessive hydrocortisone administration.  The dosage of fludrocortisone should be adjusted so that plasma renin activity is normal. Measurement of plasma renin levels should be considered first in patients with continued salt craving or hypotension. If abnormal then adjustment of fludrocortisone dosage, and addition of salt should be considered before the glucocorticoid dose is increased in order to avoid excessive glucocorticoid treatment.












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Michael W King, PhD | © 1996–2017, LLC | info @

Last modified: November 22, 2017