Adrenal axis testing: Making the diagnosis (Proceedings)

I. Regulation of Secretion of glucocorticoids - corticosterone and cortisol

     A. hypothalamic-pituitary-adrenal (HPA) axis - classic endocrine feedback loop

          a) CRH (hypothalamus)

          b) ACTH (pituitary)

          c) Cortisol (adrenals)

          d) Cortisol negative feedback on CRH and ACTH release

II. Diseases of the Adrenal Cortex and how to diagnose them

     A. Hypoadrenocorticism

          a) primary disease - destruction of the adrenal cortex

          b) iatrogenic

               i. mitotane (Lysodren)

               ii. trilostane (Vetoryl) – can also cause adrenal necrosis

               iii. abrupt withdrawal of glucocorticoids

               iv. bilateral adrenalectomy

     B. Diagnosis

          a) Decreased Na:K ratio - less than 25-27 consistent with addison's disease

          b) ACTH-stimulation test – definitive test

               i. normal pre 1-4 μg/dl cortisol

               ii. normal post 10-18 μg/dl cortisol

               iii. Addisons: pre and post sample <1 μg/dl of cortisol

               iv. Low dose ACTH (5 mcg/kg cortrosyn) effective

          c) Resting cortisol levels

               i. 2 ug/dl or greater, probably not Addisons

     C. Hyperadrenocorticism

          1. Pathogenesis

               a. primary disease

                    i. adrenal tumor with overproduction of glucocorticoids

                    ii. approximately 15% of animals have this

                    iii. 50% carcinoma

                    iv. secrete cortisol as well as cortisol precursors

                    v. usually unilateral; can be bilateral

               b. secondary disease

                    i. pituitary microadenomas that overproduce ACTH

                    ii. approximately 85% of animals have this

                    iii. pituitary-dependent hyperadrenocorticism (PDH)

                    iv. macroadenomas can cause neurologic signs

               c. iatrogenic - overuse of exogenous glucocorticoids

               d. PDH and adrenal tumors have been found in same animal

          2. Diagnostic screening tests – Cushing's yes/Cushing's no

               a. Urine cortisol:creatinine ratio

                    1. rationale: gives cortisol estimation since last time dog urinated - so usually get an estimate of plasma cortisol over several hours

                    2. procedure: collect urine sample (preferably owners collect at home); urine cortisol measured and compared to creatinine to normalize for urine concentration

                    3. interpretation - if 3 samples on different days less than 10 (or use your lab's reference ranges) then animal probably doesn't have Cushing's. If > 10 then you need to do another screening test. Very sensitive; not specific

               b. ACTH-stimulation test

                    1. rationale: stimulate gland to determine hormonal reserve; if gland is hyperfunctioning you should get an exaggerated response

                    2. interpretation:

                         (1) normal pre 1-4 μg/dl cortisol

                         normal post 10-18 μg/dl cortisol

                         (2) gray area post sample (may/may not be hyperadrenocorticism)18-22 μg/dl (3) post > 22 μg/dl think hyperadrenocorticism

                    3. uses:

                         (1) test of choice for diagnosing iatrogenic hyperadrenocorticism

                         (2) screening test for hyperadrenocorticism – is a more specific test in animals with concurrent disease

                         (3) monitoring lysodren therapy

                         (4) 60-75% sensitive

                         (5) 85-90% specific

               c. Low Dose Dexamethasone Suppression Test (LDDS)

                    1. rationale: take advantage of the normal negative feedback mechanism in the HPA axis. If you can't suppress the system normally, then suspect hyperadrenocorticism

                    2. procedure:

                         (1) get baseline cortisol

                         (2) give 0.01 mg/kg dexamethasone IV

                         (3) get 4 and 8 hour post-injection cortisol samples

                         (4) can use dexamethasone SP or dexamethasone in polyethylene glycol

                    3. interpretation:

                         (1) look at the 8 hour post-injection sample first; in a normal animal it should be below the normal range; the gray area in which you can't make a diagnosis is 1.0-1.4 ug/dl; greater than 1.4 ug/dl is consistent with hyperadrenocorticism

                         (2) the 4 hr post-injection sample is used as a discriminating test (to tell whether there is an adrenal tumor or PDH)

                    4. advantages:

                         (1) more sensitive for diagnosis of hyperadrenocorticism 85-95% sensitive

                         (2) by getting the four hour sample, can also use as a discriminating test for hyperadrenocorticism (i.e. tell whether hyperadrenocorticism is due to a pituitary or adrenal tumor)

                    5. disadvantages:

                          (1) 8 hour test

                         (2) may be less specific in animals with concurrent disease (i.e. get false positives) 70-75% specific

                    6. uses:

                         (1) screening test for hyperadrenocorticism

                          (2) discriminating test for hyperadrencorticism

          3. Discriminating Tests for Adrenal Function

               (tests to differentiate pituitary- versus adrenal-dependent hyperadrenocorticism)

                    a. Low Dose Dexamethasone Suppression test – 4 hour sample

                    b. Endogenous ACTH levels

                         i. measure on a single blood sample

                         ii. if how – adrenal tumor

                         iii. if very high – PDH

                         iv. significant overlap between normal and dogs with PDH

                    c. Ultrasound

                         i. look for adrenal tumors and contralateral adrenal atrophy

                         ii. look for bilateral adrenal enlargement

                         iii. look for potential metastatic disease

                    d. High Dose Dexamethasone Test (HDDST)-no longer recommended

ACTH-Stimulation Test

     1. Synthetic ACTH (cortrosyn)

     2. ACTH gel – compounded by compounding pharmacy (be careful)

     3. Cortrosyn

          a. 5 mcg/kg cortrosyn IV (or IM)

          b. adrenal hormone(s) that you want to measure before and 45-60 min after injection

          c. Can reconstitute and freeze cortorsyn in aliquots. Stable for 6 months.

     4. ACTH gel – trust your pharmacy

          a. 2.2 U/kg IM or check with your pharmacy

          b. Adrenal hormone(s) measured pre and 2 hours post injection

D. Feline Adrenal Axis Testing

     a. LDDST – use 0.1 mg/kg of dexamethasone (instead of 0.01 mg/kg of dex for a dog); use the same criteria for diagnosing hyperadrenocorticism

     b. ACTH-stimulation test

          i. 5 ug/kg synthetic ACTH IV

          ii. Cortisol levels at 60 and 90 minutes

          iii. Cortisol above 16 ug/dl (slightly lower than dogs) consistent with hyperadrenocorticism

     c. Adrenal ultrasonography