Adrenal Insufficiency

Article Author:
Martin Huecker
Article Editor:
Elvita Dominique
8/18/2019 4:33:34 PM
PubMed Link:
Adrenal Insufficiency


Adrenal insufficiency ranges from mild nonspecific symptoms to life-threatening shock condition. Adrenal insufficiency is a diagnosis that will not be made unless the clinician maintains a level of suspicion. The decreasing or suppressed adrenal function may be masked until stress or illness triggers an adrenal crisis.[1][2][3]

An important distinction in these patients is the presence of mineralocorticoid deficiency. Those with secondary or tertiary adrenal insufficiency will typically have preserved mineralocorticoid function due to the separate feedback systems. Mineralocorticoid levels are regulated by the renin-angiotensin system, independent of hypothalamic or pituitary signals.

Another important distinction is acute versus chronic nature of the disease. Acute adrenal insufficiency patients often present in a critically ill state while chronic presentations can be insidious.


Most cases of Addison disease are iatrogenic and caused by long-term administration of glucocorticoids, which suppress the feedback mechanisms. This suppression can be so severe that during a stress period, the brain and adrenal gland may not be able to respond adequately. Alternatively, if the exogenous glucocorticoids are discontinued without a taper, the patient may have an adrenal crisis.[4]

The most common cause of primary adrenal insufficiency relates to autoimmune damage to the adrenal cortex. Other insults to the adrenal gland that lead to primary insufficiency include adrenal hemorrhage, cancer, infections (HIV, syphilis, TB, bacterial), and certain drugs such as etomidate, ketoconazole, fluconazole, metyrapone. Phenytoin and rifampin increase metabolism of cortisol and can, therefore, precipitate adrenal insufficiency in those predisposed.

Adrenal hemorrhage can occur in patients on anticoagulation medications or a bleeding diathesis, or in the postoperative setting. 

Primary adrenal insufficiency can also be congenital. Congenital adrenal hyperplasia has been extensively studied and described in the literature. Panhypopituitarism and many genetic conditions can cause adrenal insufficiency. Pituitary hemorrhage or infarction (Sheehan syndrome) can cause secondary adrenal insufficiency.


As many as 144 million individuals in the developed world may have Addison disease. When treated properly, patients can have a roughly normal lifespan. Untreated patients have a high mortality rate.[5][6]

The autoimmune form of adrenal insufficiency and has male-female predisposition based on the type of autoimmune condition. Females are more likely to have the polyglandular form while isolated adrenal damage is more common in males in the first two decades. By the fourth decade, the isolated form is more common in women.

Due to the diverse causes of adrenal insufficiency, no distinct group of individuals is at increased risk of disease.

The epidemiology of adrenal insufficiency in children is not well-defined. Congenital adrenal hyperplasia (CAH) is the most common etiology of primary adrenal insufficiency in children, occurring once in 14,200 live births.


The pathophysiology of adrenal insufficiency depends on the etiology. With most forms of autoimmune (primary) adrenal insufficiency, the patient has antibodies that attack various enzymes in the adrenal cortex (though cell-mediated mechanisms also contribute).

Secondary adrenal insufficiency refers to decreased adrenocorticotropic hormone (ACTH) stimulation of the adrenal cortex and therefore does not affect aldosterone levels. Traumatic brain injury (TBI) and panhypopituitarism are common causes. 

Tertiary adrenal insufficiency refers to decreased hypothalamic stimulation of the pituitary to secrete ACTH. Exogenous steroid administration is the most common cause of tertiary adrenal insufficiency. Surgery to correct Cushing disease can also lead to tertiary adrenal insufficiency.

The other forms of adrenal insufficiency usually relate to destruction by infectious agents, or infiltration my metastatic malignant cells. Hemorrhagic infarction occurs due to sepsis with certain organisms (Neisseria species, tuberculosis, fungal infections, Streptococcus species, Staphylococcus speciesor due to adrenal vein thrombosis. Death associated with adrenal insufficiency is usually of septic shock, hypotension, or cardiac arrhythmias.

History and Physical

Patients with adrenal insufficiency often present with hypotension, altered mental status, anorexia, vomiting, weight loss, fatigue, and recurrent abdominal pain. Reproductive complaints typically occur in women (amenorrhea, loss of libido, decreased axillary, and pubic hair). Salt craving and orthostatic hypotension are common in patients with primary adrenal insufficiency, due to the volume depletion from the reduced mineralocorticoid function. Obtaining a history of exogenous corticosteroid use is crucial in making the diagnosis, especially in cases of chronic adrenal insufficiency.

Patients may have poor skin turgor and increased skin pigmentation. Patients may also manifest neuropsychiatric signs and symptoms. One might notice signs of Cushing syndrome, such as skin atrophy, striae, edema, obesity, muscle wasting, and neuropsychiatric disturbance.

As many as half of the patients will develop shock with no preceding hypotension. Hypotension can be present in any form of adrenal insufficiency. Fever should lead to investigation for infectious etiology, although it can be present in any form of adrenal insufficiency.


Diagnosis of primary adrenal insufficiency requires suspicion. Hyponatremia with hyperkalemia and hypoglycemia may be present. Serum cortisol, ACTH, renin, aldosterone, and chemistry panel should be obtained early. Serum cortisol levels can help make diagnoses in the presence of elevated ACTH and plasma renin activity. The ACTH test can be performed to determine if the cause is central or peripheral.[7]

Patients with secondary adrenal insufficiency are more likely to have hypoglycemia, but will not have dehydration, hyperkalemia or skin hyperpigmentation.

Consider testing for HIV and tuberculosis in patients with unclear etiology.

The most common laboratory findings in chronic primary adrenal insufficiency are anemia, hyponatremia, and hyperkalemia.

Treatment / Management

The treatment of Addison disease is glucocorticoid replacement. If the infection is the inciting event of a crisis or the cause of primary adrenal failure, it must be treated aggressively. Patients in shock will require intravenous hydration and often, dextrose.[8][9][10]

In patients with established adrenal insufficiency, hydrocortisone is the treatment of choice, with 100 mg IV every 8 hours being the standard dose. Hydrocortisone has some mineralocorticoid effect in case the patient has deficient aldosterone. In an undiagnosed patient, dexamethasone (4 mg initial bolus) should be used, as this does not interfere with cortisol assays. Mineralocorticoid replacement with fludrocortisone may be required but is not usually necessary in an acute adrenal crisis. 

If patients with adrenal insufficiency require surgery, a stress dose of glucocorticoids must be given and continued for 24 hours after the procedure.

Differential Diagnosis

  • Sepsis
  • Shock
  • Hemorrhage
  • Miliary tuberculosis
  • Fungal infection

Pearls and Other Issues

As mentioned above, patients in adrenal crisis manifest nonspecific symptoms and therefore can be difficult to diagnose. Those physicians who prescribe the glucocorticoids such as prednisone must also be aware of the need to limit the length of time the patient is on the medication and taper when discontinuing.

Enhancing Healthcare Team Outcomes

Adrenal insufficiency is a life-threatening disorder which if not recognized can lead to very high morbidity and mortality. Because of the varied presentation, it is best managed by an interprofessional team that consists of an endocrinologist, radiologist, an infectious disease specialist, intensivist, critical care nurse, and a pharmacist. While the cause of adrenal insufficiency is being investigated, the patient should immediately be managed with corticosteroids and mineralocorticoids because even with treatment, mortality rates remain high. The pharmacist should assist with medication reconciliation and appropriate dosing. Once treatment is initiated patients need close monitoring by a specialty trained critical care nurse with open and rapid communication to the clinicians. Any type of infection or stress can precipitate adrenal crises leading to death, hence patients and families should be educated by the nurses about the symptoms and when to return immediately to the emergency department. Finally, all patients with a diagnosis of adrenal insufficiency should be urged to wear a medical ID bracelet. [11][12](Level V)


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