Monday, December 19, 2016

Approach to Adrenal Insufficiency

We recently discussed a case of adrenal insufficiency. Here is an overview and some key points about the presentation and work-up for adrenal insufficiency (AI):

Signs and symptoms:  * they are non-specific

History: Nausea, vomiting, anorexia, abdominal pain, presyncope, salt craving (only in primary AI)
Physical Exam: Evidence of volume depletion including tachycardia and hypotension, hyperpigmentation (only in primary AI)
Labs: Normocytic anemia, hyponatremia, hyperkalemia (only in primary AI), hypercalcemia, hypoglycemia

How to diagnose AI:

·         In patients who are unstable, with suspected severe adrenal insufficiency symptoms or adrenal crisis, the JCEM guidelines recommend immediate therapy with IV hydrocortisone at an appropriate stress dose prior to the availability of the results of diagnostic tests
o   There is some practice variation and no universally accepted or evidence-based “stress dose of steroids”
o   Some reasonable doses can include hydrocortisone 100mg IV x1 then hydrocortisone for a total of approximately 200mg IV/day (for example hydrocortisone 50mg IV q6h or hydrocortisone 100 mg IV q8h) x 24 hours then reduce the doses based on clinical picture)
o   If there is a need to give a stress dose of steroids immediately due to clinical instability but there is a plan to still test for AI after by measuring serum cortisol, giving dexamethasone may be a good choice of steroid, as it is not measured in the assays for serum cortisol (hydrocortisone will interfere with the test and is measured in the cortisol radioimmunoassay).  
·         Based on the most recent JCEM guidelines, the recommended test to diagnose adrenal insufficiency is a corticotropin stimulation test (ACTH stim test).
·         If a corticotropin stimulation test cannot be performed, measure morning (8am) serum cortisol
o   If 8 am cortisol <140 140="" nbsp="" nmol="" span="">à adrenal insufficiency
o   If 8 am cortisol 140-500 nmol/L à indeterminate à need further testing (ACTH stim test)
o   If 8 am cortisol >500 nmol/L à essentially rules out AI à in most cases no further testing necessary

Corticotropin stimulation test (ACTH stim test):

How to do it: There are 2 protocols of ACTH Stimulation tests. Both use synthetic ACTH (cosyntropin) to assess the adrenal’s response to ACTH.
Standard high-dose ACTH stimulation test: Give cosyntropin 250 mcg IV and measure serum cortisol at time 0, 30, 60 mins post-injection.
Low-dose ACTH stimulation test: Give cosyntropin 1 mcg IV and measure serum cortisol at time 0 and 30 mins post-injection.

Notes:
* Can also measure ACTH before giving the cosyntropin to help determine if it is primary or secondary AI
* Do the stimulation test in the morning as cortisol responses are greatest in the morning. If you do it in the evening, you could get a False Positive test in a normal individual.
* Theoretically the low-dose ACTH stim test is a more sensitive test, especially for secondary AI, as it is a more physiological dose of ACTH, but typically high-dose ACTH stim test in the standard test that is done first (it is what is recommended in JCEM guidelines)
*Hold oral contraceptives before ACTH Stim tests, as the increased cortisol-binding globulins with oral contraceptive can affect the results of the test (can lead to underestimation of hypocorticolism)
* If you suspect an adrenal crisis, do not delay glucocorticoid replacement therapy while awaiting the results of ACTH stim test to confirm the diagnosis. You can consider using dexamethasone as the initial steroid of choice as it does not interfere with serum cortisol assays.

How to interpret ACTH Stim test:
Peak serum cortisol >500 nmol/L at any point during ACTH stim test (before or after cosyntropin injection at 30 or 60 mins) à no AI à no further testing necessary
Peak serum cortisol <500 500="" acth="" during="" nbsp="" span="" stim="" test="">à indicates adrenal insufficiency à further testing to determine etiology

Determine etiology:

ACTH Stim test confirms adrenal insufficiency (cortisol remains <500 span="">à measure serum ACTH
ACTH >2-fold the upper limit of the reference range à consistent with Primary AI (including Addison’s disease) à further work up which may include CT adrenal, adrenal antibodies, 17-OH proesterone
ACTH in low/low-normal range à Secondary or tertiary AI à Pituitary MRI, measure other pituitary hormones to rule out panhypopituitarism

Management

Acute management (adrenal crisis): 
ABCs, IV normal saline, electrolyte management, stress-dose steroids (no universally accepted or evidence-based dose, one example is hydrocortisone 100mg IV x1 then hydrocortisone for a total of approximately 200mg IV/day (for example hydrocortisone 50mg IV q6h or hydrocortisone 100 mg IV q8h) x 24 hours then reduce the doses based on clinical picture)

Chronic management:
·         Glucocorticoid replacement: guidelines suggest hydrocortisone (15-25mg) or cortisone acetate (20-35mg) daily in two or three divided oral doses/day, with the highest dose given in the morning
·         Mineralocorticoid replacement: Fludrocortisone (starting dose 50-100 mcg) and no salt intake restriction. Monitor mineralocorticoid replacement based on clinical assessment (salt craving, postural hypotension, electrolytes).
·         Other: medical alert identification, patient education, patient education regarding stress dosing when sick (basics: double or triple dose of oral steroid when sick until recovery (usually 2-3 days); if not tolerating PO intake, need to come to hospital for IV steroids), education and consultation regarding peri-operative management.

References:
1.       Bornstein S et al. Diagnosis and treatment of primary adrenal insufficiency: an endocrine society clinical practice guildeline. J Clin Endocrinol Metab. 2016;101(2):364-89
2.     Klose M et al. Factors influencing the adrenocorticotropin test: role of contemporary cortisol assays, body composition, and oral contraceptive agents.  J Clin Endocrinol Metab. 2007;92(4):1326. 


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