Endocrine Disorders (Adrenal Insufficiency)

sec_arr Appendix: Adrenal Insufficiency

Appendix: Adrenal Insufficiency


Adrenal insufficiency can be primary or secondary. Primary adrenal insufficiency (Addison’s disease) occurs when at least 90% of the adrenal cortex has been destroyed. As a result, both cortisol and aldosterone may be decreased. Addison’s disease affects 110 to 144 of every 1 million people in developed countries.

Secondary adrenal insufficiency occurs when the pituitary gland fails to produce enough adrenocorticotropin (ACTH), leading to a drop in cortisol levels. Secondary adrenal insufficiency is much more common than Addison’s disease.

Etiologies of Primary Adrenal Insufficiency Addison’s Disease

  • Autoimmune conditions: Up to 80% of Addison’s disease cases are caused by an autoimmune disorder. Sometimes only the adrenal glands are affected, or adrenal insufficiency may be part of polyendocrine deficiency syndrome. Other possible associated autoimmune conditions may include type 1 diabetes, hypothyroidism, vitiligo, and pernicious anemia.
  • Infections such as tuberculosis (TB), Neisseria meningitides, candidiasis, histoplasmosis, syphilis, African trypanosomiasis, paracoccidioidomycosis (e.g., in South America) and cytomegalovirus (CMG). CMG may affect people with immune suppression commonly due to HIV/AIDS.
  • Adrenal metastases due to malignancies such as lung, breast, colon, melanoma, lymphoma.
  • Infiltration due to hemochromatosis, primary amyloidosis.
  • Surgical removal of the adrenal glands usually as treatment for pheochromocytoma or another adrenal tumor.
  • Hemorrhage into the adrenal glands associated with sepsis, anticoagulants, and anti-cardiolipin/lupus anti-coagulant syndrome.
  • Genetic defects such as congenital adrenal hyperplasia (CAH); most forms can cause salt loss.
  • Drug-induced adrenal enzyme inhibitors such as mitotane, ketoconazole, metyrapone, aminoglutethimide, and etomidate.

Etiologies of Secondary Adrenal Insufficiency

  • Abrupt discontinuation of corticosteroid medication in patients on longer term therapy for other conditions such as asthma, rheumatologic conditions, inflammatory bowel disease, etc.
  • Pituitary causes: Surgical removal, tumors, or an infection in the pituitary, loss of blood flow to the pituitary, radiation for the treatment of pituitary or nearby tumors.

Symptoms and Signs

The most common symptoms of adrenal insufficiency are:

  • chronic or long-lasting fatigue
  • muscle weakness
  • loss of appetite
  • weight loss
  • abdominal pain
  • nausea
  • vomiting
  • diarrhea
  • hypotension and orthostatic (postural) hypotension (fall in systolic blood pressure of at least 20 mm Hg or diastolic blood pressure of at least 10 mm Hg when a person assumes a standing position) which may cause dizziness or syncope
  • irritability and depression
  • craving salty foods
  • hypoglycemia (this may occur in people without diabetes; those who already have diabetes [usually type 1] may notice more hypoglycemic episodes and a decrease in the amount of insulin needed)
  • headache
  • sweating
  • irregular or absent menstrual periods
  • hyperpigmentation may occur in primary adrenal insufficiency (Addison’s disease), although not in secondary adrenal insufficiency

The slowly progressing symptoms of adrenal insufficiency are often ignored until a stressful event, such as surgery, a severe injury, an illness, or pregnancy, causes them to worsen, leading to a work-up.

Adrenal Crisis
Each year, approximately 6-8% of patients with adrenal insufficiency have an incident adrenal crisis. Risk factors include prior episodes of an adrenal crisis, co-morbid autoimmune conditions such as type 1 diabetes mellitus and/or thyroid disease (especially hyperthyroidism), and other conditions such asthma, cardiac disease, or congenital adrenal hyperplasia. The most common trigger is infection, especially gastroenteritis since nausea and vomiting may decrease the absorption of medications and contribute to dehydration. Short-term use of certain medications such as immunotherapy or chemotherapy may trigger an adrenal crisis. Non-adherence to the adrenal hormone replacement regimen may also be a cause. Sudden, severe worsening of adrenal insufficiency symptoms may occur in people already diagnosed but sometimes symptoms appear for the first time during an adrenal crisis.

Symptoms of adrenal crisis include:

  • sudden, severe pain in the lower back, abdomen, or legs
  • severe vomiting and diarrhea
  • dehydration
  • low blood pressure
  • loss of consciousness


The police physician should obtain all medical records from the treating physician (preferably an endocrinologist), to include date of initial diagnosis, etiology, current medications, current laboratory values (should be performed within past 12 months) such as electrolytes, thyroid function tests, documentation of any episodes of an adrenal crisis and precipitating event (if known), and full history and physical exam focusing on symptoms and signs above.

Optimal Diagnostic Tests

Intravenous corticotropin (ACTH) stimulation (30 or 60 minutes) test using standard dose (250 µg for adults) is preferable over other existing diagnostics tests to establish the diagnosis of adrenal insufficiency.

  • Peak cortisol levels below 500 nmol/L (18 mcg/dL) (assay dependent) at 30 or 60 minutes indicates adrenal insufficiency.
  • Diagnostic testing to exclude primary adrenal insufficiency (PAI) should be done in acutely ill patients with otherwise unexplained symptoms or signs suggestive of PAI (volume depletion, hypotension, hyponatremia, hyperkalemia, fever, abdominal pain, hyperpigmentation.
  • Corticotropin releasing hormone (CRH) stimulation test. When the response to the ACTH test is abnormal, a CRH stimulation test can help determine the cause of adrenal insufficiency. In this test, the patient is given an IV injection of synthetic CRH, and blood is taken before the injection and 30, 60, 90, and 120 minutes after the injection. The cortisol levels in the blood samples are measured in a lab. People with Addison’s disease respond by producing high levels of ACTH, yet no cortisol. Those with secondary adrenal insufficiency do not produce ACTH or have a delayed response. CRH will not stimulate ACTH secretion if the pituitary is damaged, so no ACTH response points to the pituitary as the cause. A delayed ACTH response points to the hypothalamus as the cause.

Other labs:

  • Na looking for hyponatremia
  • K looking for hyperkalemia
  • Ca looking for hypercalcemia


  • Glucocorticoid and mineralocorticoid replacement are necessary in primary adrenal insufficiency.
  • Once-daily fludrocortisone (50-100 µg/d) and hydrocortisone (15-25 mg/d) or cortisone acetate replacement (20-35 mg/d) given in 2 to 3 daily doses in adults. The highest dose should be given in the morning at awakening, the next either in the early afternoon (2 hours after lunch; 2-dose regimen) or at lunch and afternoon (3-dose regimen). Shift work may alter this regimen.
  • Higher frequency regimens and size-based dosing may be beneficial in individual cases.
  • Prednisolone (3-5 mg/d), administered orally once or twice daily, may be used as an alternative to hydrocortisone especially in patients with reduced compliance.
  • Dexamethasone should not be first line therapy because for the treatment of PAI because of risk of Cushingoid side effects due to difficulties in dose titration.
  • Monitor glucocorticoid replacement by using clinical assessment including body weight, postural blood pressure, energy levels, signs of glucocorticoid excess.
  • Monitoring mineralocorticoid replacement based on clinical assessment (salt craving, postural hypotension, or edema), and blood electrolyte measurements.
  • In patients who develop hypertension while receiving fludrocortisone, reduce the dose of fludrocortisone.
  • Patients should be educated about stress dosing and equipped with a steroid card (MedAlert) and glucocorticoid preparation for parenteral emergency administration. Follow-up should aim at monitoring appropriate dosing of corticosteroids and associated autoimmune diseases, particularly autoimmune thyroid disease.