Adrenal Insufficiency

Etiology

Primary adrenal insufficiency is characterized by decreased aldosterone and cortisol production due to diminished gland function. It can either present acutely, which may present as an adrenal crisis, or it can be chronic, which is called Addison disease.

The most common cause of primary adrenal insufficiency/Addison disease relates to the autoimmune destruction of the adrenal cortex. Autobodies form against the steroid 21-hydroxylase enzyme in approximately 90% of patients.[6] Other insults to the adrenal gland that lead to primary insufficiency include adrenal hemorrhage, cancer, infections (HIV, syphilis, tuberculosis), and certain drugs such as etomidate, ketoconazole, fluconazole, or metyrapone. Phenytoin and rifampin increase the metabolism of cortisol and can, therefore, precipitate adrenal insufficiency in those predisposed.[7]

Adrenal hemorrhage can occur in patients taking anticoagulants or have 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. Other causes include pituitary tumors, hypophysectomy, and high dose pituitary or whole-brain radiation.[8]

Brain tumors and abrupt withdrawal from long term exogenous steroid use can cause tertiary adrenal insufficiency.

Epidemiology

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.[9][10]

The autoimmune form of adrenal insufficiency has a male-female predisposition based on the type of autoimmune condition. Females are more likely to have a 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.[11]

Pathophysiology

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). Various genetic factors have been identified that play a role in developing primary adrenal insufficiency or autoimmune adrenalitis. These include the major histocompatibility complex (MHC) haplotypes DR3-DQ2 and DR4-DQ8.[12]

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.[13]

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 by metastatic malignant cells. Hemorrhagic infarction occurs due to sepsis with certain organisms (Neisseria species, tuberculosis, fungal infections, Streptococcus species, Staphylococcus species) or adrenal vein thrombosis. Death associated with adrenal insufficiency is usually of septic shock, hypotension, or cardiac arrhythmias.[14][15]

Histopathology

The adrenal cortex is divided into three layers, each responsible for producing a specific hormone. Histopathology varies according to the pathological process involved in adrenal gland dysfunction. In autoimmune adrenalitis, there is atrophy of the adrenal gland with infiltration of lymphocytes along with fibrosis of the adrenal capsule. As adrenal insufficiency is caused by dysfunction of the cortex, the adrenal medulla is not affected and is spared—adrenal insufficiency due to tuberculosis results in enlargement of the adrenal glands with caseating granulomas. The adrenal medulla is usually not spared, and the gland is characterized by diffuse calcification.[16]

In patients with acquired immunodeficiency syndrome (AIDS), there is infarction, hemorrhage, and necrotizing inflammation of the adrenal gland.[17]

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 chronic adrenal insufficiency cases.

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 an investigation for infectious etiology, although it can be present in any form of adrenal insufficiency.[5][18][6]

Evaluation

The diagnosis of primary adrenal insufficiency requires suspicion as it mostly presents with non-specific symptoms. Hyponatremia with hyperkalemia and hypoglycemia may be present. Serum cortisol, ACTH, renin, aldosterone, and chemistry panel should be obtained. Serum cortisol level can help make diagnoses in the presence of elevated ACTH and plasma renin activity. The ACTH stimulation test can be performed to determine if the cause is central or peripheral.[19]

The initial testing in primary adrenal insufficiency should be to measure anti-21-hydroxylase antibodies as these are responsible for the destruction of the adrenal cortex.[20]

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

Adrenal insufficiency presenting later in life is mostly due to a secondary cause. Consider testing for HIV and tuberculosis in patients with unclear etiology. Adrenal insufficiency due to tuberculosis is more common in patients belonging to developing countries.[21][22]

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

Treatment / Management

Treatment of Chronic Primary Adrenal Insufficiency

1. Glucocorticoid replacement (one of the given regimens):

• Hydrocortisone 15 to 25 mg orally in two or three divided doses (the largest dose is taken early in the  morning; typically 10 mg upon awakening in the morning, 5 mg early afternoon, 2.5 mg late afternoon), or
• Prednisone 5 mg (2.5 to 7.5 mg) orally at bedtime, or
• Dexamethasone 0.75 mg (0.25 to 0.75 mg) orally at bedtime
• Monitor clinical symptoms and morning plasma ACTH as needed.

2. Mineralocorticoid replacement:

• Fludrocortisone 0.1 mg (range: 0.05 to 0.2 mg) orally. Hydrocortisone 20 mg and prednisone 50 mg provide a mineralocorticoid effect that is almost equivalent to 0.1 mg of fludrocortisone. Therefore, fludrocortisone replacement (if needed) must be decreased accordingly. Dexamethasone, however, lacks a mineralocorticoid effect and would require a full dose of fludrocortisone.
• Liberal salt intake.
• Monitor supine and standing blood pressure as well as pulse, edema, serum potassium, and plasma renin activity

3. Androgen replacement:

• Dehydroepiandrosterone (DHEA) initially 25 to 50 mg orally (only in women for psychological well-being, if needed, after optimal glucocorticoid and mineralocorticoid replacement).

4. Patient education:

• Educate the patient about the illness, how to manage stress, and inject dexamethasone or other glucocorticoids intramuscularly or subcutaneously.

5. Emergency precautions:

• Patients should have a medical alert bracelet/necklace, an emergency medical information card on their phone or inside their wallet, and prefilled syringes containing 4 mg of dexamethasone in 1 mL saline.

6. Treatment of minor febrile illness or stress:

• Increase glucocorticoid dose two to three times for the few days of illness. Do not change the mineralocorticoid dose (3x3 rule).
• The patient should contact the clinician if the condition worsens or persists for more than three days.
• No extra dose is required for most uncomplicated, outpatient dental procedures under local anesthesia.
• Glucocorticoid supplement for surgical stress:
• Minor: hydrocortisone 25 mg IV (or equivalent) on the day of the procedure
• Moderate: hydrocortisone 50 to 75 mg IV (or equivalent) on day of surgery and postoperative day 1
• Major: hydrocortisone 100 to 150 mg IV (or equivalent) in two or three divided doses on the day of surgery and postoperative days 1 and 2

7. Emergency treatment of severe stress or trauma:

• Each patient should have an injectable as well as vials of sterile 0.9% normal saline and syringes.

Treatment of Adrenal Crisis

Measures to stabilize the patient:

1. Intravenous access with one or two large-gauge needles
2. Laboratory analysis, including serum electrolytes, glucose, and routine measurement of plasma cortisol and ACTH.
3. Infusion of 2 to 3 liters of isotonic saline or 5% dextrose in isotonic saline as urgently as possible. Periodic hemodynamic monitoring and measurement of serum electrolytes.
4. Give hydrocortisone 100 mg intravenous bolus, followed by 50 mg intravenously every 6 hours (or 200 mg/24 hours as a continuous intravenous infusion for the first 24 hours). If hydrocortisone is unavailable, alternatives include prednisolone, prednisone, and dexamethasone.
5. Correct any ongoing electrolyte abnormalities. Hyponatremia is often corrected by cortisol and volume repletion.

Subacute measures after stabilization of the patient:

1. Intravenous isotonic saline infusion at a slower rate for the next 24 to 48 hours.
2. Diagnosis and treatment of possible infectious precipitating causes of the adrenal crisis.
3. If the patient does not have known adrenal insufficiency, a short ACTH stimulation test should establish the diagnosis and determine its type and cause.
4. Tapering of parenteral glucocorticoid over 1 to 3 days to the oral glucocorticoid maintenance dose, if there are no ongoing contraindications.
5. Initiating mineralocorticoid replacement with fludrocortisone, 0.1 mg by mouth daily after stopping the saline infusion.

Differential Diagnosis

• Adrenal crisis
• Adrenal hemorrhage
• Congenital adrenal hyperplasia
• Eosinophilia
• Histoplasmosis
• Hyperkalemia
• Sarcoidosis
• Tuberculosis

Prognosis

People with adrenal insufficiency can live a normal and active life if they are properly monitored and treated. With proper treatment and regular follow-ups, children grow normally and achieve puberty without difficulty.

Complications

The most dangerous complication of adrenal insufficiency is an adrenal crisis.

If left untreated, adrenal crisis can result in death. Frequent low blood sugar levels can increase the risk of hypoglycemic shock.[23]