Resident Editor: Anne Montgomery, MD

Faculty Editor: Anne Schafer, MD

Background

• The adrenal glands are part of the hypothalamic-pituitary-adrenal (HPA) axis, which plays an important role in helping the body deal with stress.
  • The adrenal medulla secretes catecholamines (epi, norepi) and the adrenal cortex secretes glucocorticoids (cortisol) and mineralocorticoids (aldosterone) in response to stimulus from the pituitary 
• Adrenal insufficiency (AI) refers to a state of glucocorticoid deficiency ± mineralocorticoid deficiency caused by disruption of the adrenal cortex.                         

Signs and Symptoms

• Adrenal insufficiency can develop acutely or gradually over time (chronic)
• Acute adrenal crisis can present with hypotension, shock, nausea, vomiting, abdominal pain, hypoglycemia, fever, hyponatremia, and hypokalemia and is often triggered by acute illness, trauma, etc. 
• Clinical manifestations of chronic adrenal insufficiency are often nonspecific and develop gradually, making diagnosis difficult.
  • Symptoms: fatigue, weight loss, weakness, myalgias, dizziness, anorexia, abdominal pain, nausea, vomiting, diarrhea, and depression
    • AI may be [AS1]misdiagnosed as depression or anorexia nervosa
  • Signs: hypotension, hyperpigmentation, vitiligo, hypoglycemia, hypoNa, hyperK

Types of Adrenal Insufficiency

• Primary adrenal insufficiency (Addison’s disease) refers to cortisol (and aldosterone) deficiency from direct destruction of the adrenal cortex with normal hypothalamic-pituitary function.
  • Peak age of diagnosis in fourth decade of life; more common in women.
  • The most common cause is autoimmune adrenalitis (70-90% of cases in developed countries), which can occur in isolation or with autoimmune thyroid disease and other endocrine deficiencies (autoimmune polyglandular syndrome).
    • Other causes: infectious adrenalitis (tuberculosis, HIV, syphilis, disseminated fungal infections), drugs (eg. ketoconazole, fluconazole, etomidate), genetic mutations, infiltrative diseases (metastatic disease, lymphoma, sarcoidosis, amyloidosis), thrombus and infarction (meningococcemia, coagulopathy, APLS; usually acute crisis)
  • Signs and symptoms unique to primary AI:
    • Hyperpigmentation of the skin and mucosal surfaces (due to high plasma ACTH) and salt craving (likely from lack of aldosterone)
    • Association with other autoimmune disorders such as vitiligo, Hashimoto’s thyroiditis, pernicious anemia, and type 1 DM
    • Aldosterone deficiency leading to hyponatremia, hyperkalemia, and metabolic acidosis
• Secondary adrenal insufficiency refers to cortisol deficiency caused by pituitary dysfunction whereas tertiary adrenal insufficiency is caused by hypothalamic dysfunction. 
  • Peak age of diagnoses is sixth decade of life; more common than primary AI and more common in women.
  • Potential causes:
    • Long-term steroid use leading to feedback inhibition of ACTH/CRH (symptoms manifest after discontinuation of steroids), craniopharyngioma, pituitary adenoma, pituitary surgery/radiation, hemochromatosis, autoimmune destruction, infiltrative disease (sarcoidosis, histiocytosis), empty-sella syndrome, Sheehan’s syndrome (pituitary infarction)
  • Signs and symptoms unique to secondary/tertiary AI: 
    • Headache, visual symptoms 
    • Amenorrhea
    • Small testicles, decreased libido
    • Secondary hypothyroidism, diabetes insipidus
    • Hyperpigmentation and salt craving are NOT present, and GI symptoms are less common than in primary disease.

Evaluation

• Diagnosis of adrenal insufficiency is a 3-stage process: 
  • Demonstrating inappropriately low cortisol section
  • Determining whether low cortisol is dependent or independent of ACTH 
  • Identifying the underlying cause of adrenal insufficiency (e.g., adrenalitis, pituitary adenoma)
• Start with short cosyntropin stimulation test (standard high-dose test) when possible: 250mcg ACTH administered either IM or IV, with cortisol level measured before and 30-60 minutes after ACTH administration.
  • A normal response is a rise to ≥18 or 20 mcg/dL
  • A normal response excludes primary AI and most secondary/tertiary AI
  • In patients with recent-onset secondary/tertiary AI (eg. within weeks of pituitary surgery), the adrenal glands have not yet completely atrophied and may still respond to ACTH stimulation 
• If a cosyntropin stimulation test is not feasible, can start with a morning serum cortisol concentration (drawn between 7-9am) ± ACTH concentration 
  • AM cortisol <5mcg/dL is 100% specific, 40% sensitive for AI
  • AM cortisol >18mcg/dL excludes the diagnosis of AI[AS2]
  • AM cortisol in the middle range requires further evaluation
• Interpreting results: 
• Normal ACTH stim test and/or normal AM cortisol = no adrenal insufficiency
• Low cortisol + elevated ACTH + no response to ACTH stim test = primary AI
• Low cortisol + low ACTH + no response to ACTH stim test = severe secondary/tertiary AI
• Low cortisol + low ACTH + appropriate response to ACTH stim test  indeterminate or recent-onset ACTH deficiency
• Note: The majority of cortisol in the blood is bound to cortisol-binding globulin (CBG), so medications or conditions that interfere with CBG will affect serum cortisol measurements
  • Estrogen increases CBG (and total cortisol)
  • Renal disease and cirrhosis decrease CBG (and total cortisol)
• Once a diagnosis of adrenal insufficiency has been made, consider the following additional tests to determine the etiology: 
  • In primary adrenal insufficiency, an adrenal protocol abdominal CT scan should be performed since it can show enlarged adrenal glands or calcification, which can suggest an infectious, hemorrhagic, or metastatic cause. 
    • A serum 21-OH antibody level should also be sent to evaluate for autoimmune adrenalitis
  • In secondary and tertiary adrenal insufficiency, consider brain imaging if suspicious for a pituitary or hypothalamic mass lesion (headache, visual disturbance). 

Treatment

• Patients with adrenal insufficiency of any type should be referred to endocrinology for management.
  • Patients should be treated with hydrocortisone[AS4] (15-25mg) in 2-3 divided doses per day with the highest dose given in the early morning. 
  • Dose adjustments are based on clinical response with the goal of using the smallest possible dose to reduce the risk for weight gain and osteoporosis.
  • Patients with confirmed aldosterone deficiency should also receive fludrocortisone in a singly daily dose of 50-100 mcg (sometimes then titrated up to 200 mcg)
• All patients with adrenal insufficiency should wear a medical ID bracelet and should carry a card containing information on current medications and recommendations for treatment in emergency situations.
• Patients should be advised to double or triple doses of hydrocortisone during febrile illnesses and should be referred to the hospital for IV steroids if necessary.
• Note that for patients suspected of having acute adrenal crisis, empiric treatment with stress-dose hydrocortisone should be started before test results return.
  • Draw blood for baseline cortisol and ACTH before administering hydrocortisone; a confirmatory cosyntropin stim test can be performed after treatment when the patient’s condition is stable. 

Perioperative Management of Glucocorticoids and Adrenal Insufficiency

• Patients who receive replacement doses of glucocorticoids (ie. prednisone doses of less than 5mg/day in the morning) are generally not at risk of HPA axis suppression.
• In contrast, patient taking glucocorticoids in doses equivalent to 20mg daily of prednisone for more than 3 weeks or with clinical Cushing’s syndrome should be assumed to have functional HPA axis suppression.
• Other patients with intermediate risk should have evaluation of their HPA axis prior to surgery:
  • Patients on doses of prednisone 5-20mg taken for more than 3 weeks, even if discontinued prior to surgery; recovery of the HPA axis depends on both the dose and duration of steroids and can take up to a year to fully recover. 
  • Patients taking glucocorticoids at night. 
• If perioperative glucocorticoid therapy is indicated, how much should be administered?  
  • Minor surgical stress (ie. procedures under local anesthesia and <1 hour): 
    • The patient should take usual morning steroid dose if still taking or administer hydrocortisone 25mg or equivalent.
  • Moderate surgical stress (i.e. vascular surgery of a lower extremity or total joint replacement): 
    • The patient should take the usual morning steroid dose and be administered hydrocortisone 50mg IV just before procedure and 25mg of hydrocortisone Q8H for 24H after. 
  • Major surgical stress (ie. esophagogastrectomy, total proctocolectomy, open heart surgery):
    • The patient should take morning steroid dose and be administered hydrocortisone 100mg IV before induction of anesthesia, and 50mg Q8H for 24H (if there are no complications). Taper does by half per day to maintenance level.
  • Recommendations are based on hydrocortisone, which at high doses (>100mg QD) has mineralocorticoid activity and can lead to fluid retention, edema, and hypokalemia. Methylprednisolone (methylprednisolone 4mg = hydrocortisone 20mg) can be used in patients who have disorders with fluid retention (i.e. CHF, cirrhosis).

References

Axelrod L. Perioperative management of patients treated with glucocorticoids. Endocrinol Metab Clin North Am. 2003; 32:367-383.

Bornstein SR, B Allolio, W Arlt, et al. Diagnosis and treatment of primary adrenal insufficiency: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab Feb 2016;101(2):364-89.

Hamrahian A, Roman S, and Milan S. The management of the surgical patient taking glucocorticoids. UpToDate Online. Updated Feb 2017. Accessed April 21, 2018.

Nieman L. Diagnosis of adrenal insufficiency in adults. Uptodate Online. Updated May 2017. Accessed April 21, 2018..

Oelkers W. Adrenal Insufficiency. NEJM. Oct 1996;335:1206-12.