Whether to Think of It?

Feline primary hyperaldosteronism (PHA, also referred to as primary aldosteronism or Conn's syndrome) has been incidentally reported in veterinary literature for many years now. However, recent case series have alluded to the fact that it might be occurring at increased frequency in cats. In fact, it has been suggested that it is the most common adrenocortical disorder in cats and it may also be an important cause of arterial hypertension in this species. Knowledge of its characteristics is therefore of use to anyone dealing with a high feline case load. The condition may be the result of one of two conditions: adrenocortical neoplasia or, the increasingly recognised syndrome of bilateral adrenocortical hyperplasia (idiopathic hyperaldosteronism).

When and What to Think of It?

We should think of this endocrinopathy as soon as we detect signs compatible with hypokalaemia and/or hypertension; this therefore includes patients presented with renal azotaemia, since this could be explained both through chronic renal disease (CRD) induced hypertension and hypokalaemia associated with CRD induced inappetence, but also through hyperaldosteronism-induced hypokalaemia, hypertension and azotaemia. In the latter case scenario, the excessive secretion of aldosterone causes increased renal tubular reabsorption of sodium and water and increased renal excretion of potassium. The physiological effects may include systemic arterial hypertension, hypernatraemia (though not always present) and, often severe and clinically significant, potassium depletion. Signs may include hypokalaemic episodes of muscle weakness, plantigrade stance of hind limbs, problems jumping, paroxysmal flaccid paresis, hyporeflexia, respiratory problems, acute blindness due to retinal detachment, intraocular haemorrhage, increased tortuosity of the retinal vessels, retinal oedema and other hypertensive-induced end-organ damage (kidney, heart or brain). These signs are not consistently present in all cats with some presenting with only one or two of the above.

In primary mineralocorticoid excess, the plasma concentration of aldosterone is characteristically high and plasma renin activity (PRA) is immeasurably low. In hyperaldosteronism due to an adrenocortical tumour plasma aldosterone concentration (PAC) is usually obviously and highly elevated. In idiopathic hyperaldosteronism/bilateral adrenocortical hyperplasia, PAC is usually only slightly elevated or within the upper limit of the reference range. Nevertheless, the latter more subtle form should still be relatively easily diagnosed if we adhere to sound physiological principles: as hypokalaemia is a predominant factor in lowering PAC, in the presence of hypokalaemia moderately elevated aldosterone values can still be regarded as inappropriately high.

The PRA is ideally also taken into account, although its measurement is unfortunately rarely available to clinicians. Additionally PRA measurement often requires a large blood volume (up to 4 ml) and immediate separation and freezing of the sample as well as frozen transport. Finally, PRA reference intervals vary according to laboratories and species emphasising the necessity of sending control samples if a human laboratory is used.

The combination of a high-normal or elevated PAC and low PRA indicates persistent aldosterone synthesis in the presence of little or no stimulation by the renin-angiotensin system. The combination of a high-normal or elevated PAC and high PRA suggests physiological mechanisms are at play induced by decreased renal blood flow, with cardiovascular, renal and hepatic disease particularly in need of consideration, instead of PHA (in other words secondary hyperaldosteronism is at play). In human medicine the PAC:PRA ratio (ARR) is considered to be a very useful tool in diagnosing PHA. This also seems to be true for cats with idiopathic hyperaldosteronism.

An alternative diagnostic approach has been investigated recently. This suggested method involves the measurement of the urinary aldosterone:creatinine ratio (UACR). Cats excrete smaller quantities of aldosterone and its 18-glucuronidated metabolite in urine than humans or dogs, but nevertheless the UACR can be determined. This has allowed the development of a dynamic test. In 42 healthy cats the upper limit for the UACR was 46.5 x 10^-9. The administration of fludrocortisone, like aldosterone a mineralocorticoid (0.05 mg/kg body weight) reduced the UACR by 44–97% (median 78%). A subsequent prospective study in 9 PHA cases and 10 controls revealed a basal UACR above 46.5 x 10^-9 in 3 cats with PHA. All PHA cats had basal UACRs > 7.5 x 10^-9. In all non-PHA cats with a basal UACR > 7.5 x 10^-9, fludrocortisone administration induced > 50% suppression. In contrast, fludrocortisone administration resulted in < 50% suppression in 6 of the 9 PHA cats. Neither basal UACR, nor UACR after suppression testing, correlated with the etiology of PHA (adenoma, adenocarcinoma, or suspected bilateral hyperplasia of the zona glomerulosa). Fludrocortisone induced hypokalaemia in 7 cats, but did not induce worsening of arterial hypertension. The use of this test is relatively new and its performance dependent of the accuracy of the assays used by the used laboratory. It is therefore possible, or in fact quite likely, that the by the authors suggested cut-offs, need to be adjusted by the laboratory used by an individual practice. Additionally, veterinary medicine is still getting to know its benefits and flaws, as well as its ability to diagnose idiopathic hyperaldosteronism. Nevertheless, if we combine a suggestive clinical image, which includes hypokalaemia, with abdominal ultrasound (showing adrenal enlargement), elevated plasma aldosterone, clinicians usually have a decent evidence base to work with. A UACR assessment in combination with the fludrocortisone suppression test could add an additional level of confidence, especially when basal aldosterone concentrations are only mildly elevated.

Distinguishing between neoplastic and non-neoplastic mineralocorticoid excess requires diagnostic imaging and if possible histopathological assessment. Ultrasonography and/or computed tomography could prove useful through visualisation of possible local and distant tumorous invasions (e.g., caudal vena cava).

How to Deal with It?

Primary Surgical Treatment

Unilateral adrenalectomy is the treatment of choice for confirmed unilateral PHA. Although the procedure has in the past been associated with a high mortality rate (some report approximately one third of cats dying due to severe acute haemorrhage), the advent of specialist referral hospital with multidisciplinary teams (including endocrinologists, criticalists, anaesthetists and soft tissue surgeons) have improved the situation considerably. In the author's hospital the mortality rate is currently < 10%. Preoperatively and perioperatively hypokalemia should be controlled as well as possible, by oral or intravenous supplementation. Analogous to the postoperative management of hypercortisolaemia due to adrenocortical tumours, temporary fludrocortisone therapy should probably be considered. However, in the reported cases such postsurgical measures have not been necessary and their omission does not seem to have had deleterious effects. Concurrent hypercortisolism can occur and if the clinical picture suggests its presence to be possible, testing is advised, since it would indicate the peri- and postoperative supplementation of glucocorticoids is also required. The author uses a hydrocortisone infusion, since it provides both mineralocorticoid and glucocorticoids supplementation and a continuous rate infusion (CRI) of 0.5 mg/kg/h will usually yield a plasma cortisol level of 1000 nmol/l, sufficient to prevent a hypoadrenocorticism crisis. Oral fludrocortisone can be started as soon as the cat starts eating again postoperatively, at which stage the CRI can be stopped. Oral hydrocortisone 0.5 mg/kg/day can be added to provide additional glucocorticoids supplementation if concurrent hypercortisolism is suspected, or, alternatively, prednisolone (0.2 mg/kg/day). The oral medication can be slowly, and safely, tapered over 4–6 weeks, whilst monitoring clinical image and electrolytes (hyperaldosteronism) and ACTH-stimulated cortisol concentration (combined hyperaldosteronism and hypercortisolism). For the latter a basal cortisol can also prove useful, especially when tested 24 hours after the last glucocorticoid administration. If this proves > 55 nmol/l or 2 µg/dl remaining hypocortisolism post adrenalectomy is unlikely and medication can be stopped.

Primary Medical Treatment

If surgery is not possible or if the adrenocortical disease is bilateral, medical treatment is possible with the mineralocorticoid-receptor antagonist spironolactone and oral supplementation with potassium gluconate. The initial doses could be 2 mg spironolactone/kg and 0.5 mmol potassium gluconate/kg, twice daily. Persistent arterial hypertension could be treated with the calcium blocker amlodipine (1–2 mg/kg). In cases of adrenocortical tumour medical treatment may lead to resolution of symptoms and signs such as the myopathy in cats, but complete normalisation may not be achieved. Particularly plasma potassium tends to remain below the reference range, despite increasing doses of both spironolactone and potassium. Doses of spironolactone > 4 mg/kg may cause anorexia, diarrhoea, and vomiting. These side effects may be due to interference by spironolactone with aldosterone action on transepithelial electrolyte transport in the distal colon.

Medical treatment appears to be preferable in cats with hyperaldosteronism due to bilateral adrenocortical hyperplasia. However, experience is currently still limited. The hyperaldosteronism is usually somewhat milder than in cases due to a tumour and normokalaemia may be maintained for a long period with spironolactone alone or together with low doses of potassium. However, bilateral adrenalectomy could be considered in refractory cases rendering the cat Addisonian, which is a very manageable, and less dynamic, disease in itself.

What Is the Prognosis?

After complete removal of a unilateral non-metastasised mineralocorticoid-producing tumour, the prognosis is generally excellent, without the need for any long-term medication. The prognosis is more guarded for cats with idiopathic (bilateral) hyperaldosteronism treated with spironolactone, since this treatment will not abolish the mineralocorticoid excess as definitively as surgery would do, providing an argument for bilateral adrenalectomy in cases where we have a convincing diagnosis and poor response to medical treatment.

Hyperaldosteronism as Cause for Chronic Kidney Disease (CKD)?

Renewed interest has arisen in PHA, because of its possible role in the progression of kidney disease. Indeed, the exact cause of CKD in the cat remains unknown. Javadi and colleagues (2005) report the findings in 11 geriatric cats presented with hypokalaemic paroxysmal flaccid paresis and loss of vision due to haemorrhagic retinal detachment. PAC, PRA and PAC:PRA ratios indicated PHA with all PACs in the upper end of or higher than the reference interval, whilst all PRAs were at the lower end of the reference interval. Interestingly, imaging revealed only minor adrenal changes and nodular hyperplasia was confirmed with histopathology. All cats presented with, or ended up with elevations in urea and creatinine concentrations. The histopathological changes in the kidneys mimicked those of humans with hyperaldosteronism: hyaline arteriolar sclerosis, glomerular sclerosis, tubular atrophy and interstitial fibrosis. In light of these findings the authors suggested that at least in some cats diagnosed with renal disease, hyperaldosteronism could be the mediator and clinicians should therefore consider also testing this group of patients. This remains an area of research, though it seems prudent to consider PHA in CRD cases, especially when the encountered hypokalaemia and/or hypertension are resistant to treatment.

References

References are available upon request.