Definition
A.Insufficient production of glucocorticoids and/or mineralocorticoids and adrenal androgens as a result of primary adrenal failure or failure of the pituitary or hypothalamus. Cortisol and mineralocorticoids are essential to life because of their role in energy and fluid homeostasis.
B.Primary adrenal insufficiency (PAI).
1.Also known as Addison’s disease.
2.Deficiency in adrenal hormones as a result of direct injury to the adrenal glands.
C.Secondary adrenal insufficiency (SAI).
1.Insufficient adrenal hormones due to lack of pituitary stimulation.
D.Tertiary adrenal insufficiency (TAI).
1.Insufficient adrenal hormones due to lack of hypothalamic stimulation on the pituitary.
E.Adrenal crisis (AC).
1.Potentially fatal condition that occurs when there is heightened need for cortisol in response to stress in the presence of adrenal insufficiency (AI).
2.May be the initial presentation of AI.
Incidence
A.The prevalence of primary AI is 100 to 140 cases per million.
1.Women more often affected.
2.Peak age 30 to 50 years.
B.The prevalence of secondary AI is 150 to 280 cases per million.
1.Women more often affected.
2.Peak age around 60 years.
C.The risk of AC in patients with existing AI is 6.3% per patient year.
Pathogenesis
A.PAI is caused by destruction of the adrenal cortex, most often by antiadrenal antibodies.
1.Hormone deficiency occurs when 90% of the cortex is lost.
2.All adrenal hormones may be affected, including mineralocorticoids (aldosterone) and adrenal androgens.
B.Central AI includes SAI and TAI.
1.SAI is a result of deficient ACTH from the pituitary gland leading to decreased adrenal stimulation.
2.TAI involves disruption of corticotropin-releasing hormone (CRH), vasopressin, or both, from the hypothalamus, resulting in decreased stimulation of the pituitary gland and reduced ACTH.
3.The hypothalamic–pituitary axis (HPA) is impaired.
4.Production of aldosterone and adrenal androgens is unaffected.
Predisposing Factors
A.Primary AI.
1.Presence of other autoimmune conditions (e.g., autoimmune thyroid disease, type 1 diabetes mellitus, autoimmune polyendocrinopathy syndromes).
2.Disseminated infection (e.g., tuberculosis, HIV, cytomegalovirus, fungal infections).
3.Adrenal hemorrhage, metastases, or infiltration.
4.Various genetic disorders (e.g., congenital adrenal hyperplasia, adrenoleukodystrophy).
5.Use of medications associated with drug-induced AI (e.g., fluconazole, etomidate, phenobarbital, rifampin).
B.Secondary AI.
1.Pituitary tumor or trauma.
2.Infections or infiltrative processes (e.g., tuberculosis, meningitis, sarcoidosis).
3.Pituitary surgery.
C.Tertiary AI.
1.Most common cause: Long-term use of exogenous glucocorticoids.
2.Hypothalamic dysfunction secondary to tumors or infiltrative processes.
D.AC.
1.Abrupt cessation of glucocorticoid use.
2.Acute physiologic stress in the presence of AI.
3.Previous AC.
4.Risk increased if significant comorbidity present.
Subjective Data
A.Common complaints/symptoms.
1.Tends to be nonspecific with an insidious onset, including:
a.Weakness and fatigue.
b.Anorexia and weight loss.
B.Common/typical scenario.
1.History of the present illness.
a.Elicit information about onset, duration, and severity of symptoms.
b.Obtain a detailed medical history.
c.Inquire about recent illness, injury, trauma, surgery, and procedures.
d.Evaluate for history of glucocorticoid use.
2.Other signs and symptoms.
a.AI.
i.Abdominal pain.
ii.Myalgia or arthralgia.
iii.Depression or anxiety.
iv.Dizziness or postural hypotension.
v.Salt craving.
vi.Skin hyperpigmentation.
vii.Decreased libido in women (if androgen deficient).
viii.Loss of pubic and axillary hair in females (if androgen deficient).
ix.Electrolyte imbalances including hyponatremia and hyperkalemia.
x.Hypoglycemia.
b.AC.
i.Severe weakness.
ii.Syncope.
iii.Abdominal pain, nausea, and vomiting.
iv.Back pain.
v.Confusion.
Physical Examination
A.Vital signs.
1.Orthostatic hypotension in AI.
2.Hypotension in AC.
B.Skin.
1.Hyperpigmentation, particularly sun-exposed areas, skin creases, mucous membranes, scars, and breast areolas.
2.In females, pubic and/or axillary hair loss.
C.Signs of dehydration.
D.Cardiovascular examination.
E.Mental status examination.
1.Altered consciousness and delirium in AC.
Diagnostic Tests
A.Diagnostic testing for AI should be performed in any hospitalized patient with symptoms suggestive of AI that are otherwise unexplained.
B.AI is usually diagnosed by a low morning (8 a.m.) serum cortisol level and a low stimulated cortisol level.
1.Cortisol levels are usually at their highest levels in the morning; low levels should raise suspicion of AI.
2.The diagnosis of AI is likely if the morning cortisol level is less than 5 mcg/dL, and less than 3 mcg/dL is highly suggestive.
3.A low serum cortisol level (<5 mcg/dL) in addition to a high ACTH level (>66 pmol/L) is highly predictive of AI.
a.ACTH twice the upper limit of normal of the reference range is consistent with PAI.
4.A high ACTH with a normal cortisol level may be an early indicator of AI.
C.The most common stimulation test is the corticotropin stimulation test (cort-stim
), also known as the ACTH test or cosyntropin test.
1.This test is the gold standard for diagnosing primary (not secondary) AI.
2.Cosyntropin is synthetic ACTH given to patients intramuscularly (IM) to stimulate the adrenal glands to produce cortisol.
3.Cosyntropin testing can be done at any time of day.
a.Testing is often done early morning (8 a.m.) so morning cortisol levels can be drawn simultaneously.
4.Steps for performing the cort-stim test include:
a.Draw baseline lab tests, including serum cortisol and ACTH.
b.Administer 250 mcg of cosyntropin IM or intravenous (IV).
c.After 30 or 60 minutes, draw peak serum cortisol level.
5.Peak serum cortisol levels less than 18 mcg/dL indicate AI.
a.Certain conditions can alter cortisol measurements (alter cortisol-binding globulin [CBG]).
i.Estrogen-containing contraceptives can falsely increase cortisol.
ii.Patients with nephrotic syndrome, liver disease, or those with critical illness may have low CBG values and falsely low cortisol levels.
6.High ACTH levels (often >300 ng/L) are characteristic of PAI.
7.Renin and aldosterone should be measured to assess mineralocorticoid deficiency if there is a concern for PAI.
a.PAI is associated with loss of the part of the adrenal gland that produces mineralocorticoid hormones.
i.Elevated plasma renin and low or inappropriately normal aldosterone is typical.
8.If SAI or TAI is suspected (pituitary or hypothalamus dysfunction), it is recommended that an endocrinologist be consulted to assist with biochemical testing and confirmatory testing.
Differential Diagnosis
A.Malnutrition.
B.Gastrointestinal (GI) dysfunction.
C.Malignancy.
D.Failure to thrive.
E.Hyperthyroidism.
Evaluation and Management Plan
A.General plan: Replacement of glucocorticoid with physiologic dosing; hemodynamic stability.
B.Pharmacotherapy.
1.If AI is diagnosed in the hospital and the patient is acutely ill/decompensating, stress-dose steroids should be used immediately and continued until the patient show signs of recovery.
2.If AI or adrenal crisis is suspected in a hospitalized patient who is acutely ill, start stress-dose steroids prior to receiving results of diagnostic testing.
a.Example: Hydrocortisone 50 mg IV q6h.
b.Alternative: Hydrocortisone 100 mg IV given immediately, followed by 200 mg hydrocortisone given over 24 hours (continuous IV or intermittent injections).
3.Stress dosing of steroids should be used for patients with previously diagnosed AI who present to the hospital with acute illness or injury.
4.Patients should also be given a bolus of IV fluids for acute adrenal crisis.
a.1,000 mL saline or 5% dextrose in saline given within the first hour.
5.If AI is diagnosed in the hospital and the patient is not acutely ill or demonstrating signs of AC, physiologic dosing may be started with careful consideration to other comorbid conditions and patient acuity.
6.All patients with confirmed PAI require lifelong glucocorticoid therapy.
a.Options—may be dosed based on body mass index or weight.
i.Hydrocortisone 15 to 20 mg in the morning and 5 to 10 mg in the afternoon (12–4 p.m.).
ii.Prednisolone 3 to 5 mg/d total in 1 to 2 daily doses.
b.Patients may occasionally be given glucocorticoid divided into three daily doses.
c.Dexamethasone should generally be avoided due to potential for Cushing-like features and overreplacement.