Atypical Addison’s disease

The adrenals are paired endocrine glands that are positioned immediately cranial to the kidneys, in the retroperitoneum, flanking the caudal vena cava and abdominal aorta.

During periods of stress, adrenocorticotropic hormone (ACTH) is released from the anterior pituitary gland, inducing the production and release of cortisol from the zona fasciculata and zona reticularis of the adrenal gland cortex.

Among its activities, cortisol increases the plasma glucose concentration through gluconeogenesis and insulin resistance, and primes vascular smooth muscle to the effects of catecholamines epinephrine and norepinephrine.

During periods of hypovolaemia, the renin-angiotensin-aldosterone system is activated. Renin is released from the kidneys in response to reduced renal blood flow. Renin, via the production of angiotensin II, results in increased production and release of aldosterone from the zona glomerulosa of the adrenal glands. Aldosterone promotes sodium and water retention in the distal convoluted tubules, and cortical collecting ducts of the kidneys.

What is so atypical?

In canine Addison’s disease – that is, hypoadrenocorticism – a failure of adequate corticosteroid production in response to stimulation exists. In “classical” cases, a combined loss of functional capacity to secrete glucocorticoids (predominantly cortisol) and mineralocorticoids (predominantly aldosterone) occurs. The severe clinical signs and complications of hypoadrenocorticism (for example, polyuria [PU]/polydipsia [PD], hypovolaemia, dehydration, collapse, hyponatraemia and severe hyperkalaemia) can often be attributed to the mineralocorticoid deficiency.

Dogs with “atypical” hypoadrenocorticism have a failure to produce glucocorticoids alone, and do not have the classical electrolyte disturbance of combined hyponatraemia and severe hyperkalaemia, although some dogs can have isolated hyponatraemia. Some have questioned the appropriateness of the term “atypical Addison’s disease” for both humans and dogs, as evidence exists of dysfunction of the zona glomerulosa in these “atypical” cases.

In human patients with atypical hypoadrenocorticism, all had increases in renin levels, suggestive of inadequate aldosterone secretion. In dogs, the situation is less clear. In one study, all four cases diagnosed with atypical hypoadrenocorticism had undetectable levels of aldosterone pre-ACTH stimulation and one hour post-ACTH stimulation¹; however, others have shown this is not the case in all dogs with atypical hypoadrenocorticism².

Hypoadrenocorticism, in general, is uncommon, although some breeds – such as the Nova Scotia duck tolling retriever, standard poodle, Portugese water dog and bearded collie³ – have a hereditary form resulting in a higher incidence. The most common form of hypoadrenocorticism occurs due to bilateral adrenal gland failure (greater than 95% of cases) resulting from immune-mediated destruction, although cases of hypoadrenocorticism have been reported with infiltrative (for example, fungal and neoplastic), traumatic or vascular disease^3,4.

Infrequently, hypoadrenocorticism may be accompanied by hypothyroidism (Schmidt-like syndrome) or other endocrinopathies, such as diabetes mellitus or hypoparathyroidism⁵. Secondary adrenal gland failure, where pituitary gland dysfunction results in a lack of ACTH secretion, may also lead to a lack of secretion of glucocorticoids.

The true prevalence of atypical hypoadrenocorticism is difficult to determine. In the literature, frequencies of 24% and 45% have been reported^6,7. However, these studies comprise those from referral populations that may be skewed towards atypical cases, as the more classical cases of hypoadrenocorticism – that is, with electrolyte disturbances – may more readily be identified in first opinion practice and subsequently not referred.

‘Not quite right’

Although the severe clinical signs and complications of hypoadrenocorticism (PU/PD, hypovolaemia, dehydration, collapse and severe hyperkalaemia) can often be attributed to the mineralocorticoid deficiency, glucocorticoid deficiency alone can result in significant morbidity. Despite being uncommon, the consequences of missing a diagnosis of atypical hypoadrenocorticism are still potentially life-threatening. Clinical signs (Panel 1) are often waxing and waning – particularly in hindsight – and none are specific to hypoadrenocorticism.

An index of suspicion

In some cases, physical examination may reveal poor body condition, the consequences of gastrointestinal disease (for example, dehydration, ptyalism and harsh lung sounds with aspiration pneumonia) or blood loss (for example, pallor) or even ascites (for example, abdominal distention with fluid thrill); however, physical examination may be unremarkable.

The biggest challenge with this disease is having hypoadrenocorticism on the differential list for a dog with a vague history of non-specific signs and potentially unremarkable physical examination (or unusual presentation), where other differentials are more likely (for example, dietary indiscretion for dogs with vomiting or diarrhoea).

Haematology and serum biochemistry (Panel 2) may provide valuable markers that should raise the suspicion of hypoadrenocorticism – particularly as other more likely differentials are excluded. However, it should be noted none are pathognomonic for hypoadrenocorticism – nor does their absence exclude hypoadrenocorticism as a diagnosis. Hyponatraemia may occur with atypical hypoadrenocorticism, albeit in the absence of hyperkalaemia³.

Proof is in….

…the ACTH stimulation test. Most dogs with both classical and atypical hypoadrenocorticism will have pre-ACTH and one hour post-ACTH cortisol measurements below the lower limit of detection for the assay used.

Where it is safe to delay treatment to pend results, basal cortisol measurement can be considered as a screen for hypoadrenocorticism – saving owner finances, as well as preserving ACTH for use in cases in which it is definitively indicated. This is particularly applicable to dogs with non-specific clinical signs and unremarkable electrolyte measurements.

Analyses of data from two veterinary laboratories found basal cortisol measurement less than or equal to 55nmol/L to be very sensitive (99.4% to 100%) for the detection of hypoadrenocorticism^8,9 (Panel 3). However, the same studies also showed around one in three dogs with non-adrenal disease also have basal cortisol measurements less than 55nmol/L (that is, specificity of 63.3% to 67%).

Authors concluded that where basal cortisol is less than or equal to 55nmol/L, an ACTH stimulation test should be performed. A one hour post-ACTH cortisol measurement of less than or equal to 55nmol/L confirms a diagnosis of hypoadrenocorticism in dogs with compatible clinical signs, while a measurement of greater than 55nmol/L, but less than 138nmol/L, is considered equivocal, and a measurement of greater than 138nmol/L rules out hypoadrenocorticism.

On a personal note, the author has seen a couple of cases of hypoadrenocorticism with basal cortisol values of approximately 60nmol/L, above the cut-off for the “screen”, while in one of the aforementioned studies⁹, one dog with hypoadrenocorticism appeared to have a basal cortisol of approximately 80nmol/L to 90nmol/L; therefore, where an alternate diagnosis is not apparent and finances allow, she will often perform an ACTH stimulation test in dogs with a basal cortisol greater than 55nmol/L, but less than 90nmol/L where hypoadrenocorticism remains a differential.

Note, concurrent or recent administration of corticosteroids (including topical preparations), trilostane, mitotane or ketoconazole can result in a suppressed adrenal response to ACTH. Repeat measurement following a suitable washout period (this is dependent on steroid administered, duration of administration and route of administration – and can take a number of weeks) is required. Errors in performing the ACTH stimulation test, or in samples analysis if performed in-house, may also result in a lack of apparent response.

In dogs with a failure of cortisol response to ACTH, but without electrolyte disturbances – which could be consistent with atypical hypoadrenocorticism – measurement of endogenous ACTH could be considered to confirm a diagnosis. However, measurement of canine endogenous ACTH is a specialist test that is often not performed due to sampling requirements (Panel 3) and cost.

Measurement of aldosterone concentrations pre-ACTH stimulation and one hour post-ACTH stimulation¹ is not a useful marker in predicting whether a dog is likely to require mineralocorticoid supplementation. Similarly, the absolute measurements of aldosterone and renin in dogs with hypoadrenocorticism have significant overlap with healthy dogs¹⁰. However, the ratio of aldosterone to renin is likely to be markedly reduced in dogs with hypoadrenocorticism.

Determination of the aldosterone to renin ratio could be considered in dogs with atypical hypoadrenocorticism to assess mineralocortoid activity; however, few reports describe its measurement in this subset of dogs. Measurement of plasma renin activity is also a specialist test that is often not performed due to sampling requirements (Panel 3) and cost.

How to manage

Not unexpectedly, glucocorticoid deficiency requires glucocorticoid replacement at physiological doses (prednisolone 0.1mg/kg to 0.25mg/kg) once daily. Once clinical signs are controlled, the dose can be titrated down to the lowest effective dose to minimise the risk of steroid excess (for example, thin skin, alopecia and PU/PD). Due to the nature of the disease, a reduction in dose frequency is not indicated, physiological or recommended.

Dogs with atypical hypoadrenocorticism do not require replacement mineralocorticoids at time of diagnosis, although some may go on to require these at a future date^1,7,11. Periodic monitoring of serum electrolytes (it is important to look at the actual values rather than the sodium to potassium ratio); counselling owners to the significance and clinical signs of mineralocorticoid deficiency; and immediate measurement, if concern exists, are advisable.

Conclusion

Atypical hypoadrenocorticism is easy to diagnose and treat – as long as you remember to look for it.

• Some drugs are used under the cascade.