Aldosterone is a steroid hormone secreted by the zona glomerulosa of the adrenal cortex. It is responsible for retention of sodium by the distal convoluted tubule of the nephron, along with the excretion of potassium and hydrogen ions. Reclamation of sodium from the filtrate pulls water back into the vascular space, thereby increasing the extracellular fluid volume and systemic blood pressure. Adequate amounts of aldosterone are essential for management of an effective circulating volume, and production is stimulated primarily by angiotensin II. Hyperkalemia also directly triggers the release of aldosterone by the adrenal cortex. Release is inhibited by the natriuretic peptides and is decreased by hypokalemia.
Primary hyperaldosteronism (PHA), or low-renin hyperaldosteronism, is an adrenocortical disorder characterized by excessive, autonomous secretion of aldosterone, leading to systemic hypertension and/or hypokalemia. This disorder, also referred to as Conn's syndrome, was first discovered in people in 1953. For several decades, PHA was considered a rare condition, but with improved screening tests the prevalence is as high as 5% to 13% of all people with arterial hypertension. In cats and people, the inappropriate aldosterone secretion is caused from either unilateral or bilateral neoplasia or bilateral nodular hyperplasia of the adrenal zona glomerulosa. To date, 49 cases of feline PHA have been reported, and it may be the most common adrenocortical disorder in this species.
Depending on the etiology, PHA can be treated surgically or medically, which may cure or alleviate the associated hypertension and/or hypokalemia. Primary hyperaldosteronism is most likely underdiagnosed, which excludes a potentially large number of cats from appropriate therapy and a possible cure for the disease. This may in part be due to the frequent association of arterial hypertension and/or hypokalemia with chronic kidney disease (CKD). Often, CKD is thought to be the causal factor of the hypertension and/or hypokalemia, when in fact the CKD may be a consequence of PHA.
Clinical Findings of Feline Primary Hyperaldosteronism
Most cats with primary hyperaldosteronism are >10 years of age. In a recent report of 10 cats with PHA due to a unilateral adrenal mass, the median age was 12.3 years, with a range of 9–15 years. No breed or gender predispositions have been established in feline patients.
Most cats present with signs related to systemic hypertension, hypokalemia, or both. Signs associated with hypertension include vision loss or acute neurological compromise. Hypokalemia will result in weakness, collapse, and cervical ventroflexion. This may be episodic but is generally associated with serum potassium levels of 2.5 mEq/L or less. Affected cats have poor muscle tone and are often unable to stand unaided. Polyuria and polydipsia are also commonly reported.
Physical examination may suggest a myopathy, with variable weakness and poor muscle tone. A plantigrade stance may be noted in cats with mild hypokalemia. In patients with severe hypertension, ocular lesions are routinely noted, including hyphema, mydriasis, anisocoria, retinal hemorrhage, or detachment.
Hypertension may be an incidental finding during a geriatric wellness examination; if an obvious cause is not apparent, PHA should be considered, even if the serum potassium levels are within the reference range.
Diagnosis of Feline Primary Hyperaldosteronism
Hypokalemia may be noted; this may be marked or borderline. A normal serum potassium concentration does not exclude the possibility of PHA. Serum sodium levels are often normal, because the excess sodium is accompanied by water. A metabolic alkalosis may be noted due to exchange of sodium for hydrogen ions in the distal nephron. Creatinine kinase (CK) may be elevated due to the hypokalemic myopathy. Evidence of renal compromise may be noted, with increases in serum creatinine and urea nitrogen. Interestingly, serum phosphorus concentrations may be borderline low or well within the normal range, despite the accompanying azotemia. This finding is strongly suggestive of PHA and likely reflects excessive secretion of parathyroid hormone.
Urine is often poorly concentrated; this is due to a combination of hypertension, chronic kidney disease, and hypokalemia (low potassium causes a secondary nephrogenic diabetes insipidus). Proteinuria may be noted and should be quantified by measurement of the urine protein:creatinine ratio.
The complete blood count may reveal anemia, reflecting chronic disease +/– impaired erythropoietin secretion in those cats with concurrent CKD.
Imaging
Abdominal ultrasonography should be performed in any cat with a clinical suspicion of PHA. PHA is traditionally associated with a unilateral adrenal mass, although a small number of cats with bilateral tumors have been described. However, bilateral hyperplasia has been reported in some feline patients, which may not be easily detected during abdominal ultrasonography. Simply finding an adrenal mass is not sufficient to establish a diagnosis of PHA, however, because the lesion may be non-functional or secreting catecholamines (a pheochromocytoma), cortisol, or sex hormones. Cats with tumors secreting both progesterone and aldosterone have been reported, with a confusing constellation of clinical signs.
Thoracic radiography should also be considered. This may identify metastatic lesions or evidence of cardiomegaly.
Aldosterone Concentrations
The first step in establishing a diagnosis of PHA is measurement of circulating aldosterone concentrations. These can be determined by many veterinary reference laboratories. In people, confounding factors such as salt intake, concurrent anti-hypertensive medications, and body position are carefully controlled. It is unclear whether these factors also impact aldosterone measurements in cats, but it seems likely they would. Aldosterone levels should be interpreted in light of the concurrent potassium status, because hypokalemia should suppress aldosterone release by the zona glomerulosa. In one report, aldosterone levels in some affected cats were in the high normal range despite hypokalemia; these patients were still thought to have PHA.
Plasma Renin Activity and Aldosterone:Renin Ratio
Concurrent determination of plasma renin activity is ideal, because this helps to differentiate PHA (low renin) from secondary hyperaldosteronism (increased renin). Unfortunately, this assay is not consistently available for feline patients. In people, the aldosterone:renin ratio (ARR) is a primary screening test for PHA, with a high value strongly supportive of the diagnosis. The ARR is usually very high in cats with an adrenocortical tumor, because renin release is totally inhibited, but may be less dramatic in cats with nodular hyperplasia, in which some renin activity may be present. If available, this test is widely regarded as the gold standard for establishing a diagnosis of PHA.
Urine Aldosterone:Creatinine Ratio (UACR)
This test has recently been proposed as a suitable screening test for PHA in cats. It is superior to simply measuring aldosterone in serum or plasma, because it reflects events over several hours and not just one time point. However, the reference range is quite wide, and the test may lack sensitivity when used alone.
Fludrocortisone Suppression Test
The idea behind this test is similar to that behind the dexamethasone suppression test, namely that administration of an exogenous aldosterone analogue will suppress aldosterone release in a healthy individual. Failure to suppress suggests autonomous/inappropriate secretion and would support a diagnosis of PHA. There is limited information on this test in cats with PHA, but it is certainly promising. The protocol is as follows:
Determine baseline UACR
Administer fludrocortisone for 4 days (0.05 mg/kg twice daily PO)
Determine UACR
Treatment of Feline Primary Hyperaldosteronism
Hypokalemia
Hypokalemia is a medical emergency and should be treated immediately. Cats can become acutely compromised with cardiac arrhythmias and compromised ventilation when serum potassium levels are low. Even if the patient is substantially dehydrated, it is more important initially to manage the hypokalemia than replace fluid losses. Bear in mind that even modest amounts of unsupplemented fluid therapy may markedly exacerbate hypokalemia and result in death.
The best way to provide potassium supplementation is by an infusion of KCl; this can be caustic to the vein if given undiluted, but is well tolerated if diluted with > 4 parts D5W. The maximum rate of administration of parenteral potassium ('K-max") is 0.5 mEq/kg/hour; exceeding this rate is not recommended. For example, if the cat weighs 3.5 kg, the maximum rate for infusion of KCl is 0.5 x 3.5 = 1.75 mEq/hour. Oral potassium supplementation can be started concurrently and repeated every 4–6 hours until serum levels are back in the reference range. Fluid losses can be cautiously replaced throughout 24 hours using an appropriate replacement fluid such as Ringer’s lactate solution.
Chronic medical management includes oral potassium supplementation, along with the administration of spironolactone (starting at 2 mg/kg twice daily). This agent is an aldosterone receptor antagonist, so it directly inhibits the action of the hormone on the distal convoluted tubules.
Hypertension
Prompt control of systemic hypertension is essential to protect the retina, central nervous system, and kidney from further damage. Amlodipine is often a good first choice, with minimal risk of side effects and a rapid onset of action. Angiotensin-converting enzyme inhibitors (eg, enalapril) are unlikely to be helpful, because renin is suppressed.
Surgical
In cats with a nonmetastatic unilateral adrenal mass, adrenalectomy is the treatment of choice. The reported outcomes are fairly positive, although a high level of surgical expertise and careful postoperative management is needed.
Key Points
Primary hyperaldosteronism is likely underdiagnosed, especially in senior cats with azotemia.
Although hypertension and hypokalemia are the most common abnormalities, the absence of one of these abnormalities does not rule out the diagnosis.
Early diagnosis and intervention to lower or block the effects of aldosterone may result in decreased morbidity and mortality from cardiovascular and renal disease.
