Addison Disease

Article Author:
Sadaf Munir
Article Editor:
Muhammad Waseem
Updated:
11/8/2019 1:35:35 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 androgens. Addison disease's insidious course of action usually presents with glucocorticoid deficiency followed by mineralocorticoid; however, it can present acutely,  often triggered by intercurrent illness. The term Addison disease is used when there is primary adrenal insufficiency.

The most common cause of primary adrenal insufficiency is autoimmune adrenalitis (Addison disease), which is associated with increased levels of 21-hydroxylase antibodies.[1][2]

Etiology

Any disease process which causes direct injury to the adrenal cortex can result in primary adrenal insufficiency (Addison disease). In most of the developed world, autoimmune destruction of the adrenal glands is the most common cause of Addison 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 [3][4]

Other causes include infections (such as sepsis, tuberculosis, and HIV), bilateral adrenal hemorrhages (precipitated by coagulopathy, trauma, meningococcemia, neoplastic processes involving the adrenal glands. Rarer causes include sarcoidosis, amyloidosis, fungal infections, and genetic disorders such as adrenal leukodystrophy and Wolman disease.

Epidemiology

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

Pathophysiology

Adrenal failure in Addison disease results in decreased cortisol production initially followed by that of aldosterone, both of which will eventually cause elevated ACTH and plasma renin levels in the blood through the loss of negative feedback inhibition.[5]

History and Physical

Addison disease usually has an insidious and gradual onset of non-specific symptoms, which often results 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 triggering 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. Symptoms may be quite non-specific and can include fatigue, generalized weakness, weight loss, nausea, vomiting, abdominal pain, dizziness, tachycardia, and/or postural hypotension. Hyperpigmentation of skin and mucous membranes can be diffuse and most prominent in sun-exposed areas, often seen later in the course of the disease. This hyperpigmentation is due to elevated ACTH (as both ACTH and melanocyte-stimulating hormone (MSH) derived from the same precursor POMC) levels. Due to its variable presentation, a high index of suspicion for Addison disease is necessary when evaluating a conglomeration of non-specific symptoms including unexplained fatigue, poor appetite, chronic abdominal pain, or weight loss, Hyponatremia with or without hyperkalemia and/or hypotension can be seen in Addisons disease and Addisonian crisis manifests with severe dehydration, refractory hypotension, and shock.

Addisonian crisis 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 and can be attributed to low cortisol and aldosterone levels. There is hypersecretion of ADH seen in cortisol deficiency triggers hypersecretion of ADH (due to hypovolemia), and there may be enhanced hypothalamic secretion of corticotropin-releasing hormone (CRH) which contributes to ADH hypersecretion. Furthermore, the relative lack of cortisol removes the negative feedback for CRH and ADH production. Loss of aldosterone activity leads to natriuresis and potassium retention, thus further confounding electrolyte abnormalities, including life-threatening hyperkalemia.[6]

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

Typically, low random and stimulated cortisol and aldosterone levels are seen. A cortisol level less than 18 microgram/dL to 20 microgram/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) can be seen, 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 should be checked in cases where adrenal leukodystrophy is suspected based on family history or etiology is unclear after evaluation.

Treatment / Management

As Addison crisis is life-threatening, treatment should be initiated immediately when the diagnosis is suspected. 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.[7][8][9]

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 a 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 micrograms/day to 200 micrograms/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 causes such as sepsis are critical for an 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.

Differential Diagnosis

  • Septic shock
  • Hemorrhage
  • Eosinophilia
  • Miliary tuberculosis

Pearls and Other Issues

Symptoms of Addison disease can be nonspecific and, therefore, can be difficult to recognize. A high index of suspicion is required to make this diagnosis. The acute presentation includes cardiovascular collapse and hemodynamic instability.

In Addisonian crisis, treatment is a priority and should not be delayed for diagnostic confirmation; delayed treatment can be fatal.

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

Enhancing Healthcare Team Outcomes

Addison disease is a serious life-threatening disorder that affects many organs. If the diagnosis is delayed, it carries very high morbidity and mortality. Thus, the condition is best managed by an interprofessional team of healthcare workers that includes an endocrinologist, intensivist, infectious disease expert, gastroenterologist, and pharmacist. The education of patients is mandatory. Physicians, nurses, and pharmacists can do this. Nurses administer treatments, monitor patients, and provide updates to the team. Once the diagnosis is made, the outcomes depend on the primary cause. Any delay in starting corticosteroid treatment can lead to mortality rates in excess of 50%. All patients diagnosed with Addison disease must be urged to wear a medical alert bracelet. Patients should be educated on the signs and symptoms and contact their primary care provider at the slightest change in their vital signs. Finally, in times of stressful situations, even a common cold, the patient should be told to double on the dose of steroids and see the primary care provider.  [10][7] [Level 5]


References

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[10] Milenkovic A,Markovic D,Zdravkovic D,Peric T,Milenkovic T,Vukovic R, Adrenal crisis provoked by dental infection: case report and review of the literature. Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics. 2010 Sep     [PubMed PMID: 20674414]