Life without ACTH hypoadrenocorticism

ClINICAl uPDAte

life without ACtH – hypoadrenocorticism

Simon Clark is an associate at the Hamilton Small Animal Veterinary Centre (HSAVC) and a member of the CAV executive Committee. Here he describes how adrenal diseases in companion animals have been diagnosed and managed in his clinic since Synacthen became unavailable, reducing the use of the ACtH stimulation test. This second of two articles discusses the options for diagnosis and monitoring of hypoadrenocorticism in dogs and cats without Synacthen.

SImON ClARk, BVSc, mVm

the ACtH stimulation test measures the adrenal gland’s response to an I/V injection of ACtH (Adrenocorticotropic hormone). ACtH is no longer extracted from cadavers, and a synthetic ACtH product is commercially available for human use, called Synacthen (SynACtH-en). Synacthen (tetracosactide hexaacetate) is not a brand, but more akin to a nickname for an active ingredient. there are many different products containing Synacthen as the active ingredient. Some of these are licensed for human use in New Zealand, some are not. None are licensed for veterinary use in New Zealand. Synacthen became unavailable for purchase a few years ago because the only brands stocked by New Zealand distributors were listed under Section 29 of the medicines Act (see Box 1). When this occurred, veterinarians at HSAVC divided up what they had into small aliquots and froze them. Even though some Synacthen products are licensed for human use, and so available for discretionary veterinary use, this availability is intermittent and unpredictable. I discussed how to diagnose hyperadrenocorticism and hypoadrenocorticism and how to monitor my patients with Sandra

Contact: Simonthevet@gmail.com Box 1: Section 29

Section 29 medicines are human medicines that are non-consented. these medicines don't have a current product registration with medSafe (similar to a veterinary medicine being registered with ACVm), so according to Section 29 of the medicines Act 1981 they can still be sold to and used by registered medical practitioners, but they cannot be sold to or used by anyone who isn't a registered medical practitioner (i.e. veterinarians). the medicines Act is overseen by the ministry of Health (moH), and is therefore outside of the jurisdiction of mPI’s ACVm group. the Act went under review in 2019, and NZVA/VCNZ made a combined submission that addressed the animal welfare impacts of veterinarians not having access to Section 29 medicines. the moH is still in the review process. medications that fall under Section 29 may be imported by veterinarians through a Special Circumstances Approval process via mPI. the information can be found at: https://www.mpi.govt.nz/processing/agricultural-compounds-and-vet-medicines/veterinarymedicines/getting-a-veterinary-medicine-authorised/authorisation-of-veterinary-medicines-underspecial-circumstances/. mPI only issues the approval, they do not help facilitate the importation process. Some veterinary wholesalers may be able to assist with importation of products, on a case-by-case basis.

Forsyth, a clinical pathologist at SVS Laboratories and reviewed the 4th Edition of Canine and Feline Endocrinology (Feldman et al. 2015). Based on these sources I have been adopting new tests, and have found the options for diagnosing hyperadrenocorticism faster, easier and cheaper, and therefore much more convenient for the client than the tests using Synacthen. The ACTH stimulation test remains the gold standard for diagnosing hypoadrenocorticism. As hypoadrenocorticism is less common than hyperadrenocorticism, avoiding the use of Synachten on patients suspected of hyperadrenocorticism, as discussed in the first of these two articles, will save our reserves for diagnosing hypoadrenocorticism.

Summary of hypoadrenocorticism

the cortex of the adrenal gland produces three classes of hormones. Glucocorticoids (cortisol), mineralocorticoids (aldosterone) and androgens. Naturally occurring adrenocortical insufficiency in the dog has been recognised since the 1950s. the disease was first recognised in cats in the 1980s and has been much less researched leading to limited understanding of the disease in this species. therefore, the following discussion will focus on diagnosis and monitoring in dogs. there are a variety of causes of hypoadrenocorticism including tumours, infections, autoimmune disease, and

genetic disorders. Interested readers are encouraged to learn more (see Feldman et al. 2015). Disease originating in the adrenal gland is referred to as primary hypoadrenocorticism, and disease originating in the pituitary gland is referred to as secondary hypoadrenocorticism.

Addisonian crisis

Addisonian crisis is where a patient is severely hyperkalaemic, and coma and death are direly imminent. Rapid recognition and treatment of this syndrome are necessary to save the patient. A classic component of presentation is signs of hypotension and poor perfusion (weak pulses, slow capillary refill time, low blood pressure) but with normal or reduced heart rate instead of the expected tachycardia that is usually seen with shock.

Diagnosis of hypoadrenocorticism

Clinical presentation

Glucocorticoid deficiency leads to hypotension, hypoglycaemia, anorexia, vomiting, diarrhoea, muscle weakness, and inability to maintain vascular tone and endothelial integrity. mineralocorticoid deficiency, which was discovered in humans in the 1930s and is the most life-threatening part of hypoadrenocorticism, leads to hyponatraemia, hyperkalaemia, hypochloraemia and metabolic acidosis. Naturesis and consequent loss of the renal medullary concentration gradient leads to polyuria and compensatory polydipsia. Some patients present in Addisonian crisis before they are diagnosed with hypoadrenocorticism.

Basal cortisol assay

Low cortisol concentration in the serum of a stressed dog is highly suspicious of glucocorticoid deficiency. Low aldosterone concentration is assumed to also be present if matching electrolyte abnormalities are also present (i.e., hyponatraemia and hyperkalaemia). If the disease originates in the pituitary gland (i.e. secondary hypoadrenocorticism), only glucocorticoid function will be affected. mineralocorticoid secretion is usually preserved. In about 30% of patients with primary hypoadrenocorticism electrolyte concentrations are normal – this is referred to as “atypical” hypoadrenocorticism. A study of 123 dogs with clinical signs suspicious of hypoadrenocorticism (110 with non-adrenal disease and 13 with hypoadrenocorticism) showed that a cut-off for basal cortisol concentration (i.e. unstimulated by Synacthen) of 55 nmol/L was 100% sensitive for hypoadrenocorticism (Lennon et al. 2007). It is important to understand that while basal cortisol is helpful in ruling out hypoadrenocorticism, it is not adequate to confirm the diagnosis since some healthy dogs with a normal pituitary-adrenal axis have low basal cortisol concentrations.

urinary cortisol:creatinine ratio

Recent conference proceedings have discussed how uCCR can be used to diagnose hypoadrenocorticism. one article (Rowland et al. 2018) claimed that a cut-off ratio of <3 was 100% sensitive and 100% specific. Further study will verify this claim, but this finding makes uCCR a much better option for investigating hypoadrenocorticism than basal cortisol.

ACtH stimulation test

this test remains the gold standard for diagnosing hypoadrenocorticism, and if stocks of Synachthen are low or intermittently available to veterinary practitioners, this product should be frozen and saved for investigating suspected hypoadrenocorticism patients and not wasted on suspected hyperadrenocorticism patients. It should certainly not be wasted on monitoring hyperadrenocorticism patients where a pre-trilostane cortisol assay is just as effective, faster and less expensive.

monitoring

As it is the mineralocorticoid deficiency that makes most hypoadrenocorticism patients unwell, and most are maintained only mineralocorticoid supplementation (e.g. fludrocortisone acetate), monitoring usually consists only of measuring the electrolytes sodium and potassium. there is no value in repeating ACtH stimulation tests.

Summary

Hypoadrenocorticism is much less common than hyperadrenocorticism, but it is often on our differential list for a wide variety of presentations. Starting with a uCCR for patients suspected of hypoadrenocorticism is a good early, inexpensive way to rule hypoadrenocorticism in or out, the same as it is for our patients suspected of hyperadrenocorticism. If the uCCR is low, then proceeding to an ACtH stimulation test is the gold standard diagnostic test. monitoring of patients under treatment is by biannual electrolyte assay. Saving the Synacthen that we can store frozen, divided into aliquots of one diagnostic dose, for diagnosing hyperadrenocorticism is the best option to care for our patients.

References

Feldman EC, Nelson RW, Reusch CE,

Scott-Moncrieff JC, Behrend EN

(eds.) Canine and Feline Endocrinology (4th edtn.). elsevier, St. louis, mO, uSA, 2015

Lennon EM, Boyle TE, Hutchins RG,

Friedenthal A, Correa MT, Bissett SA,

... & Birkenheuer AJ. (2007). use of basal serum or plasma cortisol concentrations to rule out a diagnosis of hypoadrenocorticism in dogs: 123 cases (2000–2005). Journal of the American

Veterinary Medical Association, 231(3), 413–416.

Rowland A, Birkenheuer AJ, Mamo

L, Lunn KF. (2018). Comparison of

Urine Cortisol:Creatinine Ratio and

Basal Cortisol for the Diagnosis of Canine

Hypoadrenocorticism. ACVIm 2018 l

As at the time of printing CAV have become aware that Synacthen is now available from Provet.