Addison Disease

Article Author:
Sadaf Munir
Article Editor:
Muhammad Waseem
Updated:
6/24/2017 7:18:50 PM
PubMed Link:
Addison Disease

Introduction

Addison disease is an acquired primary adrenal insufficiency, which is a rare but potentially life-threatening endocrine disorder that results from bilateral adrenal cortex destruction leading to decreased production of adrenocortical hormones including cortisol, aldosterone, and/or adrenal. Addison disease's insidious course of action usually presents with glucocorticoid deficiency followed by mineralocorticoid; however, it can present acutely, especially with inter-current illness, with adrenal crisis.

The most common cause of primary adrenal insufficiency is autoimmune adrenalitis (Addison disease) which is associated with increased levels of 21-hydroxylase antibodies.

Etiology

Any disease process which causes direct injury to the adrenal cortex can result in primary adrenal insufficiency (Addison disease). In the developing world, autoimmune destruction of the adrenal glands is the most common cause of Addison disease; while, worldwide, other possible causes include infection such as sepsis, tuberculosis, and HIV, bilateral adrenal hemorrhages (secondary to sepsis, coagulopathy, or trauma), and neoplastic processes affect adrenal glands. Rare causes include sarcoidosis, amyloidosis, fungal infection, and certain genetic conditions (e.g., adrenal leukodystrophy, Wolman disease). Autoimmune destruction can be an isolated finding or part of autoimmune polyglandular endocrinopathies (type 1 and 2). Patients with autoimmune adrenal disease are more likely to have polyglandular autoimmune syndromes

Epidemiology

The incidence is 0.6/100,000 of population per year. The total number of people affected with this condition at a given time 4 to 11/100,000 of the population.

Pathophysiology

Addison disease is initially due to adrenal failure resulting in decreased production of cortisol, and subsequently, aldosterone which leads to loss of negative feedback on adrenocorticotropic hormone (ACTH) and plasma renin activity, respectively, both of which are elevated with complete adrenal failure.

History and Physical

Addison disease usually has an insidious course with gradual onset of symptoms which are non-specific and attributed to other conditions often resulting in delayed diagnosis. In many cases the diagnosis is made only after the patient is presented with an acute adrenal crisis (hypotension, hyponatremia, hyperkalemia, and hypoglycemia) precipitated by a stressful illness or factors such as infection, trauma, surgery, vomiting, and diarrhea.

Addison disease can occur at any age but most often presents during the second to third decade of life. As mentioned above, the presentation is usually insidious in onset, and symptoms may be non-specific and include fatigue, generalized weakness, weight loss, nausea, vomiting or abdominal pain, dizziness, tachycardia and/or postural hypotension. Hyperpigmentation of skin and mucous membranes can be seen later in the course of disease resulting from elevated ACTH (as both ACTH and melanocyte stimulating hormone (MSH) derived from the same precursor POMC). The presentation can be variable therefore a high index of suspicion is necessary for the presence of multiple non-specific symptoms including unexplained fatigue, poor appetite, chronic abdominal pain, weight loss, hyponatremia with or without hyperkalemia and/or hypotension. The manifestations of Addisonian crisis may include dehydration, refractory hypotension, and shock.

It should be suspected in

  • Patients receiving steroids
  • Hemodynamically unstable patients despite aggressive fluid therapy
  • Septic shock.

Evaluation

Hyponatremia is the most common initial laboratory finding which is not unexpected because cortisol has weak mineralocorticoid activity and it is also needed for free water excretion. Loss of aldosterone activity leads to natriuresis and potassium retention, thus further confounding electrolyte abnormalities (including life-threatening hyperkalemia).

Hypoglycemia is multifactorial including decreased oral intake and lack of glucocorticoids, which is needed for gluconeogenesis.

Low random and stimulated cortisol and aldosterone level. A cortisol level less than 18 µg/dL to 20 µg/dL is considered diagnostic.

High ACTH level is diagnostic of primary adrenal destruction in the absence of ACTH resistance.

  •  Primary adrenal insufficiency: Elevated ACTH
  •  Central adrenal insufficiency: Abnormally normal or low ACTH

Increased Plasma Renin Activity (PRA) often late in the course of the disease (due to mineralocorticoid deficiency).

Anti-adrenal antibodies (such as 21-hydroxylase antibodies) serves as the markers of autoimmune destruction of the adrenal gland.

In suspected cases of adrenal hemorrhages, abdominal CT scan may provide useful information.

A chest x-ray may reveal a small heart.

PPD should be performed to evaluate for tuberculosis.

Plasma very long chain fatty acid profile in cases where adrenal leukodystrophy is suspected (based on family history or etiology is unclear after evaluation).

Treatment / Management

Treatment should be immediately initiated if the diagnosis of acute adrenal crisis is suspected as it is a potentially life-threatening condition. However, blood samples should be saved for subsequent measurement of ACTH and cortisol levels. It is important to remember that a random measurement of plasma cortisol cannot confirm or exclude the diagnosis unless cortisol is unequivocally elevated. Elevation of ACTH with low cortisol is diagnostic of a primary adrenal problem. Measurement of cortisol in the ACTH stimulation test may be performed in equivocal cases where baseline lab evaluation cannot confirm the diagnosis. PRA is often elevated and is indicative of mineralocorticoid deficiency along with low aldosterone level.

Patients with adrenal crisis require the following

  • Fluid resuscitation with intravenous (IV) normal saline (to correct volume depletion)
  • Dextrose (to correct hypoglycemia)
  • Hormone replacement to correct a lack of circulating glucocorticoid.

The first-line hormonal treatment is hydrocortisone. As stress dose hydrocortisone has significant mineralocorticoid activity, fludrocortisone (synthetic mineralocorticoid) is usually not required in the acute phase. Stress dose hydrocortisone for acute adrenal crisis is 50 mg/m2 to -100 mg/m2, which can be given as a continuous infusion. Typical replacement fluid after normal saline bolus is D5 Normal saline. Beware that if left untreated, adrenal crisis can be fatal.

 In adults, the typical replacement oral dose of hydrocortisone is 10-15 mg/m2/day divided into two to three doses. If compliance with frequent dosing is an issue, more potent glucocorticoids can be given less frequently, for example, prednisone qd-bid and dexamethasone qd; however, prednisone and dexamethasone do not have mineralocorticoid activity.

Also, mineralocorticoids should be replaced in the form of fludrocortisone at 50 µg/day to 200 µg/day (0.05-0.2 mg/day). In the presence of fever, infection, or other illnesses, the dose of hydrocortisone should be doubled to account for stress response. This should be tailored according to the degree to stress. Identification and treatment of underlying cause such as sepsis are critical for optimal outcome.

During replacement treatment, the following should be monitored to assess the adequacy of replacement therapy:

  • Signs and symptoms suggestive of adrenal insufficiency
  • Measurement of serum electrolytes, cortisol, and ACTH
  • Measurement of plasma renin activity.

Patients who are non-stressed can be treated with either hydrocortisone or prednisone with or without fludrocortisone.

Pearls and Other Issues

Symptoms of Addison disease can be nonspecific and therefore may be difficult to recognize. A high index of suspicion is required to make this diagnosis.

In Addison crisis, treatment is a priority and should not be delayed for diagnostic confirmation.

Glucocorticoid doses should be doubled in the presence of fever, infection, or other stresses.