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Adrenal insufficiency Last updated: May 24, 2022

Summary

Etiology

Pathophysiology

Clinical features

Diagnostics

Treatment

Approach

Primary adrenal insufficiency: replacement for hypocortisolism, hypoaldosteronism, and

hypoandrogenism

Glucocorticoids

Mineralocorticoids

Androgens (as needed)

Secondary/tertiary adrenal insufficiency: replacement for hypocortisolism and hypoandrogenism

Glucocorticoids

Androgens (as needed)

Replacement of other hormones if there is concomitant hypopituitarism

Underlying causes: Identify and treat reversible conditions in all patients.

Prevention of adrenal crisis: See “Stress-dose steroids.”

Glucocorticoid replacement therapy with hydrocortisone is required in all forms of adrenal

insufficiency.

Steroid replacement

Glucocorticoids [1]

Agents
[1]
Hydrocortisone
[1]
Cortisone acetate
[1]
Prednisolone

Considerations

The total daily replacement dose should be given in divided doses, with the highest dose given in the
morning to mimic diurnal fluctuations.

Educate patients about increasing their glucocorticoid dose according to outpatient sick day rules.

Side effects may arise due to overtreatment (see “Cushing syndrome”).

Mineralocorticoids [1]

Agent: fludrocortisone; (a synthetic mineralocorticoid with mostly mineralocorticoid and limited

[1][17]
glucocorticoid effects)

Considerations

Advise patients not to restrict their salt intake.

A temporary increase may be advised if increased sweating is anticipated (e.g., in the summer)

Monitor for adequate replacement and consider a dose reduction if hypertension develops. [1]

Side effects are analogous to glucocorticoids (e.g., hyperpigmentation).

Additional side effects include:

Worsening of preexisting heart failure

Edema

Androgens [1]

Consider treatment in anatomically female patients with low libido, depressive symptoms, and low
energy levels.
[1]
Agent: DHEA

Considerations

DHEA is not an FDA-approved drug, but is available as an OTC supplement.

Results of studies investigating the positive effects of DHEA have been mixed and data on long-term
outcomes is lacking. [1]

Discontinue after 6 months if there is no positive effect.

Treatment of the underlying cause and associated conditions

Drug-induced adrenal insufficiency : Consider medication adjustment. [1]

Hypopituitarism: Substitute other pituitary hormones; see “Hypopituitarism.”

Infectious adrenalitis: See “Tuberculosis,” “HIV,” and “Cytomegalovirus infection.”

Adrenal hemorrhage: e.g., Waterhouse-Friderichsen syndrome.

Infiltration of the adrenal glands: Treat malignancy, e.g., via tumor resection.

Autoimmune adrenalitis: Treat other associated autoimmune endocrinopathies.

Stress-dose steroids [29][30]

Steroid doses should be increased to prevent adrenal crisis in at-risk patients, e.g., in acute illness,
surgery, or trauma (see also “Precipitating factors” in “Adrenal crisis”).

Inpatient steroid doses are adjusted according to the level of stress.

Patients who do not require hospitalization can be taught self-treatment plans, known as sick day rules.

If the dose of glucocorticoids is not increased during periods of stress, the patient may
develop an adrenal crisis!

Inpatient stress-dose steroids [1][29]

Adhere to any preexisting protocol/care plan by the patient's endocrinologist. The following
recommendations can apply to all patients on adrenosuppressive doses of glucocorticoids.

Febrile illness: Double the usual oral dose until recovery; consider IV route if the patient is vomiting.
[31]
Critically ill patients: IV hydrocortisone

Perioperative patients

Minor and moderate procedures : usual daily steroid dose PLUS stress-dose hydrocortisone
followed by a return to the usual steroid dose [29]

Major procedure : usual daily steroid dose PLUS stress-dose hydrocortisone followed by
steroid taper as needed [29]

Outpatient sick day rules [1] [19]

The following rules should be taught to patients with primary adrenal insufficiency so that they can self-
administer glucocorticoids in times of illness/physiological stress:

Sick day rule one: circumstances requiring double the routine oral glucocorticoid dose

Illness with any of the following:

Fever

Need for bed rest

Need for antibiotics

Minor outpatient procedures (e.g., dental intervention)

Sick day rule two: circumstances requiring IM/IV glucocorticoids or suppositories

Intractable vomiting or diarrhea

Severe illness

Trauma

Fasting required for a procedure (e.g., colonoscopy)

Perioperative period

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Adrenal crisis (Addisonian crisis)

Adrenal crisis is an acute, severe glucocorticoid deficiency that requires immediate emergency
treatment.
Precipitating factors for adrenal crisis

Stress in patients with underlying adrenal insufficiency e.g.: [19]

Gastrointestinal illness (most common)

Other infections

Perioperative period

Physical stress or pain

Psychological stress

Sudden discontinuation of glucocorticoids after prolonged glucocorticoid therapy

Bilateral adrenal hemorrhage or infarction (e.g., Waterhouse-Friderichsen syndrome)

[32]
Pituitary apoplexy

In order to prevent the development of secondary and tertiary adrenal insufficiency,

prolonged steroid therapy should be tapered slowly rather than stopped abruptly.

Signs and symptoms [19]

Hypotension, shock

Impaired consciousness, coma

Fever

Vomiting, diarrhea

Severe abdominal pain (which can resemble peritonitis)

Diagnosis [12][19][32]

Based on clinical suspicion: Maintain a low threshold for diagnosis in at-risk patients , especially
those with shock refractory to fluids and/or vasopressors. [33]

Point-of-care testing and routine laboratory studies

Hyponatremia, hyperkalemia, hypercalcemia

Hypoglycemia
[34]
Normal anion gap metabolic acidosis

Endocrine testing: Consider if the diagnosis is uncertain (e.g., first presentation).

[35][36]
Random cortisol level

The sample should be drawn prior to hydrocortisone administration.

ACTH stimulation test: diagnostic confirmation once the patient has been stabilized (see
“Diagnostics”)

Consider adrenal crisis in patients with severe hypotension refractory to

fluid resuscitation and/or vasopressors.

Adrenal crisis can be life-threatening, so treatment with high doses of hydrocortisone

should be started immediately, without waiting for diagnostic confirmation of
hypocortisolism!

Management [1][19]

Empiric glucocorticoid replacement

[1][36]
Hydrocortisone (preferred)

Prednisolone (alternative if hydrocortisone is unavailable)

Dexamethasone (least preferred alternative if hydrocortisone is unavailable)

Consider adding mineralocorticoid replacement, e.g., fludrocortisone (off-label) for the following:
[31]

Patients receiving glucocorticoids other than hydrocortisone

Patients with septic shock [36][37]

Fluid resuscitation

1 L of normal (isotonic) saline in the first hour

Further management should be guided by clinical response (see “Intravenous fluid therapy” and “
Shock”).

Hypoglycemia: IV dextrose, e.g., 50% dextrose

Identify and treat underlying causes (e.g., sepsis).

Consider higher-level monitoring, e.g., intensive care

The 5 S’s of adrenal crisis treatment are Salt (0.9% saline), Sugar (50% dextrose), Steroids
(100 mg hydrocortisone IV once, then 200 mg over 24 hours), Support (normal saline to
correct hypotension and electrolyte abnormalities), and Search (for the underlying
disorder).

Acute management checklist for adrenal crisis

Establish IV access with two large-bore peripheral IV lines.

Administer hydrocortisone IV/IM.

Fluid resuscitation with 1 L of normal (isotonic) saline in the first hour

Treat hypoglycemia with IV dextrose.

Identify and treat the underlying cause (e.g., sepsis).

Consider early endocrinology consult.

Monitor vitals, blood glucose, and urine output every 1–2 hours.

Continue IV fluids to maintain blood pressure and urine output.

Continue substitution of hydrocortisone through boluses or continuous IV infusion.

Consider higher-level monitoring, e.g., ICU, if there is ongoing hemodynamic compromise.

Autoimmune polyglandular syndromes

Definition: a set of conditions characterized by autoimmune disease that causes multiple endocrine
deficiencies, which affect the hormone-producing (endocrine) glands

Types

Type 1: (APS-1, Whitaker syndrome,

autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, or APECED)

Less common than APS-2 (1:100,000)

Autosomal recessive inheritance; no HLA association

Caused by a mutation in the autoimmune regulator gene (AIRE)

Age of onset: usually in childhood

Associated endocrine deficiencies (two or more of the following should be present)

Most commonly

Primary adrenal insufficiency

Hypoparathyroidism

Chronic mucocutaneous candidiasis

Ectodermal dystrophy of skin, nails, and dental enamel

Less commonly: hypogonadism, pernicious anemia, alopecia, vitiligo, hepatitis

Type 2 (APS-2, Schmidt syndrome): defined by the occurrence of primary adrenal insufficiency with
thyroid autoimmune disease and/or type 1 diabetes mellitus [38]

More common than APS-1 (1.4 - 2:100,000)

Associated with HLA-DR3 and/or HLA-DR4 haplotypes

Age of onset: usually in adulthood

Main manifestation: primary adrenal insufficiency

Associated endocrine deficiencies (one or more of the following may be present)

Most commonly

Thyroid autoimmune disease (e.g., Hashimoto thyroiditis)

Type 1 diabetes mellitus

Less commonly: celiac disease, pernicious anemia, alopecia areata, vitiligo

Diagnostics: condition-specific antibody tests (e.g., TPO antibodies in Hashimoto thyroiditis,

antiparietal cell antibodies in pernicious anemia)

Therapy: depends on the endocrine deficiency

Replacement of deficient hormones (e.g., thyroxin, hydrocortisone, insulin)

Antifungal therapy in chronic mucocutaneous candidiasis

Vitamin B12 supplementation in pernicious anemia; vitamin D in hypoparathyroidism

Immunosuppressive therapy for, e.g., hepatitis, nephritis, pneumonitis

References:[39][40]

References

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