Key Points
- Primary adrenal insufficiency (PAI) was first described in 1855 by Thomas Addison and is therefore commonly termed Addison’s disease.
- PAI is defined by the inability of the adrenal cortex to produce sufficient amounts of glucocorticoids and/or mineralocorticoids.
- PAI is a severe and potentially life-threatening condition due to the central role of these hormones in energy, salt, and fluid homeostasis.
- Cortisol deficiency results in a decrease in feedback to the hypothalamic-pituitary axis and subsequent enhanced stimulation of the adrenal cortex by elevated levels of plasma ACTH. Consequent to disruption of adrenal mineralocorticoid synthesis, renin release by the juxtaglomerular cells of the kidneys increases. This is of clinical, diagnostic, and therapeutic relevance because PAI needs to be distinguished from secondary adrenocortical insufficiency due to insufficient production of ACTH and without impact on the renin-angiotensin-aldosterone system.
Diagnosis
Who Should Be Tested and How
- The Endocrine Society (ES) recommends diagnostic testing to exclude PAI in acutely ill patients with otherwise unexplained symptoms or signs suggestive of PAI (volume depletion, hypotension, hyponatremia, hyperkalemia, fever, abdominal pain, hyperpigmentation or, especially in children, hypoglycemia). (1|⊕⊕⊕o)
- ES recommends confirmatory testing with the corticotropin stimulation test in patients with clinical symptoms or signs suggesting PAI when the patient’s condition and circumstance allow. (1|⊕⊕⊕⊕)
Optimal Diagnostic Tests
- ES suggests the standard dose (250 μg for adults and children ≥2 y of age, 15 μg/kg for infants, and 125 μg for children <2 y of age) IV corticotropin stimulation (30 or 60 min) test over other existing diagnostics tests to establish the diagnosis of adrenal insufficiency. Peak cortisol levels below 500 nmol/L (18 μg/dL) (assay dependent) at 30 or 60 minutes indicate adrenal insufficiency. (2|⊕⊕oo)
- ES suggests the low-dose (1 μg) corticotropin test for diagnosis of PAI only when the substance itself is in short supply. (2|⊕⊕oo)
- If a corticotropin stimulation test is not feasible, ES suggests using a morning cortisol <140 nmol/L (5 μg/dL) in combination with ACTH as a preliminary test suggestive of adrenal insufficiency (until confirmatory testing with corticotropin stimulation is available). (2|⊕ooo)
- ES recommends measurement of plasma ACTH to establish PAI. The sample can be obtained at the same time as the baseline sample in the corticotropin test or paired with the morning cortisol sample. In patients with confirmed cortisol deficiency, a plasma ACTH >2x the upper limit of the reference range is consistent with PAI. (1|⊕⊕⊕o)
- ES recommends the simultaneous measurement of plasma renin and aldosterone in PAI to determine the presence of mineralocorticoid deficiency. (1|⊕⊕⊕o)
- ES suggests that the etiology of PAI should be determined in all patients with confirmed disease. (For diagnostic workup, see Table 2 and Figure 1.) (U)
Table 1. Clinical Features of Adrenal Insufficiency and Adrenal Crisis
Adrenal Insufficiency
| Symptom | Signs | Routine Laboratory Tests |
|---|---|---|
| Fatigue | Hyperpigmentation (primary only), particularly of sun-exposed areas, skin creases, mucosal membranes, scars, areola of breast | Hyponatremia |
| Weight loss | Low blood pressure with increased postural drop | Hyperkalemia |
| Postural dizziness | Failure to thrive in children | Uncommon: hypoglycemia, hypercalcemia |
| Anorexia, abdominal discomfort |
Adrenal crisis
| Symptom | Signs | Routine Laboratory Tests |
|---|---|---|
| Severe weakness | Hyponatremia | |
| Syncope | Hypotension | Hyperkalemia |
| Abdominal pain, nausea, vomiting; may mimic acute abdomen | Abdominal tenderness/guarding | Hypoglycemia |
| Back pain | Reduced consciousness, delirium | Hypercalcemia |
| Confusion |
Most symptoms are nonspecific and present chronically, often leading to delayed diagnosis. Hyponatremia and, later, hyperkalemia are often triggers to diagnosis, requiring biochemical confirmation of adrenal insufficiency. Hyperpigmentation is a specific sign, but it is variably present in individuals and must be compared with the patient’s background pigmentation, such as that in siblings. Adrenal crisis is a medical emergency with hypotension, marked acute abdominal symptoms, and marked laboratory abnormalities, requiring immediate treatment. Continuing effort to prevent adrenal crisis is integral to patient management. Additional symptoms and signs may arise from the underlying cause of adrenal insufficiency—eg, associated autoimmune disorders, neurological features of adrenoleukodystrophy, or disorders that may lead to adrenal infiltration.
Figure 1. Diagnostic approach to the patient with PAI
Table 2. Major Etiologies of PAI and Associated Features
Etiology and Associated Features
- Autoimmune
- Isolated
- Not associated with other autoimmune disorders
- Isolated
- APS type 1 (APECED)
- Chronic cutaneous candidiasis, hypoparathyroidism
- APS type 1 (APECED)
- APS type 2
- Autoimmune thyroid disease, type 1 diabetes
- APS type 2
- Adrenal—infiltration/injury
- Adrenal hemorrhage
- Associated with sepsis, anticoagulants, anti-cardiolipin/lupus anti-coagulant syndrome
- Adrenal hemorrhage
- Adrenal metastases
- Malignancies: lung, breast, colon, melanoma, lymphoma
- Adrenal metastases
- Infections: adrenalitis
- Tuberculosis, HIV/AIDS, CMV, candidiasis, histoplasmosis, syphilis, African trypanosomiasis, paracoccidioidomycosis
(eg, in South America)
- Tuberculosis, HIV/AIDS, CMV, candidiasis, histoplasmosis, syphilis, African trypanosomiasis, paracoccidioidomycosis
- Infections: adrenalitis
- Infiltration
- Hemochromatosis, primary amyloidosis
- Infiltration
- Bilateral adrenalectomy
- Procedure for intractable Cushing’s syndrome or bilateral pheochromocytoma
- Bilateral adrenalectomy
- CAH: most forms can cause salt loss
- Commonest cause of PAI in children (80%) May be diagnosed in older individuals
- 21-Hydroxylase deficiency
- Commonest type of CAH is 21-hydroxylase deficiency,
with associated hyperandrogenism
- Commonest type of CAH is 21-hydroxylase deficiency,
- 21-Hydroxylase deficiency
- 11β-hydroxylase deficiency
- Hyperandrogenism, hypertension (in older children and adults)
- 11β-hydroxylase deficiency
- 3β-hydroxysteroid dehydrogenase II deficiency
- Ambiguous genitalia in boys, hyperandrogenism in girls
- 3β-hydroxysteroid dehydrogenase II deficiency
- P450 side-chain cleavage deficiency
(CYP11A1 mutations)- XY sex reversal
- P450 side-chain cleavage deficiency
- P450 oxidoreductase deficiency
- Skeletal malformations, abnormal genitalia
- P450 oxidoreductase deficiency
- Congenital lipoid adrenal hyperplasia
(StAR mutations)- XY sex reversal
- Congenital lipoid adrenal hyperplasia
- Adrenal hypoplasia congenita
- X-linked NROB1, Xp21 deletion (with Duchenne’s muscular deficiency), SF-1 mutations, (XY sex reversal), IMAGe syndrome
- ACTH insensitivity syndromes
- Type 1: ACTH receptor, melanocortin 2 receptor gene MC2R
- Type 2: MRAP
- Familial glucocorticoid deficiency (MCM4, NNT, TXNRD2)
- TripleA (Allgrove’s) syndrome, achalasia, Addison’s disease, alacrima, AAAS gene mutation
- Drug-induced
- Adrenal enzyme inhibitors: mitotane, ketoconazole, metyrapone, etomidate, aminoglutethimide, drugs that may accelerate cortisol metabolism and induce adrenal insufficiency
- T4 also accelerates cortisol metabolism (at least in part through stimulation of 11β-HSD2)
- CTLA-4 inhibitors may enhance autoimmunity and cause PAI
- Other metabolic disorders
- Mitochondrial disease (rare)
- Adrenoleukodystrophy in males
- Wolman’s disease
Derived from E. Charmandari E, et al: Adrenal insufficiency. Lancet. 2014;383:2152–2167, with permission. © Elsevier.
