In morning report we discussed two cases from the past that highlight an important diagnosis: adrenal insufficiency.
Both case examples were that of patients presenting with fatigue, lethargy, one patient had recurrent gastrointestinal infections and both were subsequently noted to have hyperpigmentation on exam and hyponatremia, and hyperkalemia.
Subsequent testing revealed primary adrenal insufficiency...aka Addison's disease.
First described by Thomas Addison in 1855, adrenal insufficiency is an important, life threatening, but treatable condition.
(Bornstein, SR, NEJM 2009)
The disease is best thought of by always referring back to the hypothalamic-pituitary-adrenal axis.
Recall that CRH is released from the hypothalamus that stimulates the anterior pituitary to release ACTH, that then stimulates the production of cortisol from the adrenal glands.
Differentiate Primary (ie adrenal disease) vs Secondary/Tertiary (ie pituitary/hypothalamic disease)
Primary adrenal insufficiency is due to destruction of the gland itself, DDx includes:
- infectious (TB, Fungal, HIV)
- hemorrhage (coaguloapthy, Waterhouse-Friderichson post meningococcal disease, now recognized in other infections such as Staph)
- iatrogenic (medications that inhibit the axis, surgical removal of glands)
- genetic (CAH, Adrenoleukodystorphty, Adrenomyeloneuropathy)
- ischemia (ie Sheehan's syndrome)
- infiltrative disease
Non specific symptoms of fatigue, weakness, lethargy, abdominal pain, nausea.
Classically described as hyperpigmentation including but not limited to the buccal mucosa and teeth, elbows, creases, nipples.
Hypotension (especially treatment refractory hypotension)
Electrolyte abnormalities (ie hyponatremia for both primary and secondary, hyperkalemia for primary). May also see acidosis, anemia, hypoglycemia, rarely hypercalcemia, as well as eosinophilia.
AM cortisol if < 80 sensitive to rule out, if > ~500-550 can rule in
If AM cortisol nondiagnostic, then next step would be an ACTH aka Cosyntropin stim test.
If normal you would expect to see an appropriate rise in cortisol in response to the administered Cosyntropin.
In primary you can measure ACTH levels and would expect them to be high due to the lack of cortisol and the continued stimulation due to lack of negative feedback.
High levels of ACTH, and inappropriate response to ACTH stim test = primary AI
In secondary, ACTH levels should be low. IF prolonged secondary AI, the adrenals will have atrophied due to lack of stimulation and so above test would be abnormal. IF it is early in the course of disease, or mild, then there still may be a normal response to the standard ACTH stim test.
Further testing to diagnose secondary AI
- low dose ACTH stim test. The thinking here is that if a tiny dose of ACTH stimulates a normal response, then it is very unlikely that the patient has AI, thus it is a sensitive test
- Insulin induced hypoglycemia (should NOT be done in patients with contraindications e.g. CAD, seizures). This test induces hypoglycemia and should activate the HPA axis.
- Similarly, a metyrapone test blocks 11-deoxycortisol conversion to cortisol. This again should activate the HPA axis and 11-deoxycortisol levels should go up if there is no disease.
- Lastly one can do a CRH stim test, essentially acting as the hypothalamus to try and stimulate the pituitary. This test can help to distinguish between hypothalamic disease and pituitary disease.
Once determined if primary vs secondary, next step is imaging (adrenals for primary, head for secondary).
Other clues to secondary that may lead to earlier imaging is neurologic symptoms such as headache, visual problems.
Principles of management
- treat underlying cause
- replace cortisol, and mineralocorticoids if primary
- stress in the right situations
Remember that in primary both cortisol AND aldosterone are low because the adrenal gland itself is damaged.
In secondary, cortisol is low because of low ACTH stimulating cortisol production, but aldosterone should be normal because the renin-angiotensin system is still intact. Thus more likely to see hyperkalemia in primary.
Both primary and secondary will have hyponatremia because of low ECFV, ADH release, water retention, and in the case of primary low aldo and salt wasting.
See this 1996 NEJM review article on adrenal insufficiency
And this more recent 2009 NEJM article that touches on predisposing factors, genetics, and has more info regarding culprit meds. The above image is from this 2009 NEJM article by Bornstein, "Predisposing Factors fro Adrenal Insufficiency".