Non-Cortisol Secreting Adrenal Tumours

Question 1

Discuss the diagnostic approach and consideration of differential diagnoses after identifying an incidental adrenal mass

Answer 1

• An incidental adrenal mass may be identified by either US or CT and may or may not be the reason for the initial imaging investigation
  
  • Benign or malignant non-functional tumours are unlikely to cause clinical signs unless they invade or compress adjacent vasculature, rupture or become necrotic
  • Functional tumours may or may not cause clinical signs or be high on the differential diagnosis list and be the reason for imaging investigation
• The differentials for an adrenal mass include both cortical (carcinoma, adenoma, aldosteronoma) and medullary (phaeochromocytoma) tumoours. These may be functional or non-functional
• Further investigations may include blood and urine testing to assess electrolytes and renal function for possible aldosterone producing tumours or plasma or urine catecholamines for phaeochromocytoma
• Fine needle aspiration could be considered pending size
• Thoracic imaging may be recommended
• Repeat US monitoring in 1-3 months if the mass was truly incidental and non-clinical
• All investigations would need to consider the liklihood that the adrenal mass is the reason for initial investigation. ie. consideration of and the importance of concurrent conditions must be taken into account.

Question 2

Discuss the role and regulation of aldosterone

Answer 2

• Aldosterone is produced by the zona glomerulosa in the outer most layer of the adrenal cortex.
  
  • Also produced in the heart, brain and vascular tissues where it likely acts in a paracrine manner
• Aldosterone primarily acts to balance sodium and potassium concentrations and preserve ECV

​Regulation:

• Aldosterone is released directly in response to an increase in potassium - most potent stimulator
• Activation of the RAAS via reduced ECV or BP will trigger aldosterone production (increase Angiotensin II)
• Reduced atrial stretch can trigger aldosterone release

Specific Actions:

• Aldosterone blocks potassium resorption and triggers sodium reabsorption in the distal convoluted tubule and collecting duct - acts via the Na+/K+ pump on the basolateral surface.
  
  • creates a potassium concentration gradient for diffusion into the luminal space
• Increases ATP dependent H+ secretion in the collecting duct
• Sodium preservation in the gut, sweat, saliva
  
  • Increases in sodium indirectly cause increased free water preservation and expansion of the ECV

Question 3

What are the potential causes of hyperaldosteronism in cats and dogs?

How might primary and secondary hyperaldosteronism be differentiated?

Answer 3

• Hyperaldosteronism can be primary or secondary

Primary:

• Aldosterone producing tumour - autonomous secretion
  
  • High aldosterone, low renin

Secondary:

• Congestive heart failure - reduced ECV, systemic hypotension
• Chronic kidney disease
  
  • High aldosterone, high renin

Question 4

Describe the history and clinical signs in cats with primary hyperaldosteronism

Answer 4

• Most cats are older with a median age of 13 y.
• Clinical signs relate to the presence of low potassium and or high blood pressure

Low potassium:

• ​Muscle weakness, especially cervical ventroflexion
• Episodic or acute signs
• Difficulty jumping
• Listlessness and ataxia
• Limb rigidity - uncommon
• Dysphagia - uncommon

High blood pressure:

• Acute blindness or ocular colour change (due to hyphema) is the most common sign
• Neruological signs - ataxia, seizure, mentation changes may be seen with intracerebral vascular accident (haemorrhage or ischaemia)

Question 5

Describe the typical clinicopathological findings in cats with primary or secondary hyperaldosteronism

Answer 5

Primary:

• Primary hyperaldosteronism is characterised by a low potassium
• Increased CK is common due to hypokalaemic myopathy
• Metabolic alkalosis is common due to aldosterone mediated increased H+ excretion (via ATP dependent excretion in the distal convoluted tubule)
• Elevated BUN and creatinine can be seen secondary to primary hyperaldosteronism
• Increased serum aldosterone on specific testing

Secondary:

• Elevated BUN and creatinine (and SDMA) in cats with primary renal disease
  
  • Hyperaldosteronism will result with potassium retention or mineralocorticoid receptor bloackade
  • Hyperaldosteronism can also increase due to dehydration and reduction in the ECV

Question 6

Describe the interpretation of the urinary aldosterone to creatinine ratio.

Answer 6

• This test theoretically assesses urinary excretion of aldosterone over time (compared with creatinine) and may be a more accurate reflection of aldosterone levels than a single serum sample
• However, aldosterone is primarily metabolised within the liver and urinary excretion is minimal.
  
  • only 3 of 9 cats with primary hyperaldosteronism had elevated UACR in one study (JVIM 2013)

Question 7

Discuss the merit of the fludrocortisone suppression test in cats suspected of having primary hyperaldosteronism.

What are the risks and limitations of the test?

Answer 7

• As primary hyperaldosteronism is a condition of autonomous aldosterone secretion, confimation via a suppression test is ideal
• Fludrocortisone promotes retention of sodium and water, increasing ECV
  
  • This effect would normally suppress release of aldosterone in the absence of hyperkalaemia (which would be a contraindication for the test in the first place)
• The suppression test requires oral administration of fludrocortisone orally q 12 hours for 4 days
• In normal cats, this should reduce UACR by > 50%.
• With primary hyperaldosteronism, the UACR should be unchanged, though 4/9 were suppressed in one study

Risks/limitations:

• Plasma basal aldosterone was more definitive in one small study
• Fludrocortisone can enhance hypokalaemia in cats with the disease or induce hypokalaemia in normal cats
• Minimal studies have been performed, so the most appropriate protocol has not been established

Question 8

Surgery is the treatment of choice for most cats with primary hyperaldosteronism.

Discuss the role of medical management in cats with primary hyperaldosteronism

Answer 8

• Medical management can be utilised as sole treatment or to help stabilise a cat with PHA prior to surgery
• Treatment is aimed at minimising the effects of increased aldosterone, high blood pressure and low potassium

Treatment:

• Potassium supplementation
  
  • 2-6 mEq PO q 12 hours
• Spironolactone (aldosterone receptor blockade)
  
  • 2-4 mg/kg PO q 24 hours
• Amlodipine (calcium channel blocker)
  
  • 0.625-2.5 mg mg PO q 24 hours
  • To help lower blood pressure with dose titrated to effect starting at the low end
• Monitoring involves measurements of potassium, blood pressure and intermittent ultrasound to evaluate the adrenal mass. As renal function can be affected by high aldosterone levels, renal function should also be monitored and management with a renal diet commenced initially.

Question 9

Describe the eitiology of phaeochromocytoma

Answer 9

• Phaeochromocytoma is a tumour of the chromaffin cells within the adrenal medulla
• The tumour is of neuroendocrine cells
• Aetiology in dogs is largely unknown
• In humans, phaeochromocytoma has been associated with a missense mutation in the succinate dehydrogenase subunit D
  
  • There is high homology between SDHD in humans and dogs

Question 10

Describe the pathway of catecholamine production within the adrenal medulla.

Answer 10

• Tyrosine enters the chromaffin cells
• Tyrosine converted to L-dihydroxyphenylalanine (L-DOPA)
  
  • Tyrosine hydroxylase
  • This is the rate limiting step and norepinephrine exerts negative feedback on tyrosine hydroxylase
• L-DOPA is converted to dopamine
  
  • DOPA debarboxylase
• Dopamine is converted to noradrenaline
  
  • Dopamine beta-hydroxylase
• In the adrenal medulla, PNMT converts noradrenaline to adrenaline
  
  • Note that PNMT is only present in the adrenal medulla and gene expression is influenced by cortisol

Question 11

Describe the process of catecholamine release from the adrenal gland

Answer 11

• Catecholamines are stored within vesicles within the medullary chromaffin cells
• They are in an active equilibrium with catecholamines in the surrounding cytoplasm
• Catecholamines “leak” from their storage granules and a methylated within the cytoplasm and small amounts can leak into the circulation as free metanephrine and free normetanephrine
  
  • The methylated catecholamines are produced within the adrenal gland
• Norepinephrine and epinephrine are released into the circulation via exocytosis from storage vesicles after stimulation by the sympathetic nervous system - via acetylcholine

Question 12

How can catecholamine levels be measured?

Which test is most reliable in the diagnosis of a phaeochromocytoma

Answer 12

• Catecholamines can be measured either within plasma or urine
  
  • The catecholamine metabolites NMN and MN are primarily excreted within the urine
  • NMN and MN are more reliable and consistent measures of catecholamine production than the parent compounds
• Plasma metaneprhine and normetanephine levels more accurately reflect tumour mass
  
  • epinephrine and norepinephrine are secreted in an episodic manner and are rapidly metabolised
• Urinary metanephrine and normetanephrine should be compared with creatinine within the same sample
• In both urinary and plasma measurements, normetaneprhine is a more reliable indicator than metanephine,
  
  • This suggests that most produce and secrete norepinephine preferentially or in excess of epinephrine

Question 13

What are the potential clinical manifestations of a phaeochromocytoma

Answer 13

• The clinical signs either relate to the space occupying mass or the physiological action of increased catecholamines
• Hormone secretion is sporadic and inconsistent, therefore the presenting signs also vary
• Despite this, the majority of dogs have an unremarkable physical examination

Catecholamine effects:

• Cardiovascular
  
  • Hypertension, tachycardia, panting, tachpnoea, arrhythmia, collapse, pallor
  • Secondary to hypertension - retinal detachment, hyphaemia, vascular accident
• Neuromuscular
  
  • Weakness, tremors, anxiety, pacing, seizures
• Non-specific
  
  • PU/PD, vomiting, inappetance, weigh loss, vomiting, diarrhoea, abdominal pain

Abdominal mass

• Invasion of the CVC - ascites, hind limb oedema
• Invasion of the aorta - cold hind limbs, claudication/pain
• Spontaneous rupture - haemabdomen

Question 14

Describe the mechanism of action of phenoxybenzamine.

How and why is the drug used in the management of phaeochromocytoma?

Answer 14

• Phenoxybenzamine is a long-acting alpha-adrenergic antagonist.
• This blocks the actions of norepinephrine and epinephrine at the alpha receptors
  
  • Alpha 1 adrenergic receptors mediate:
    
    • Vasoconstriction - increased peripheral resistance
    • Increased caridac output
    • Increased blood pressure
    • Stimulates gluconeogenesis
  • Alpha-2 adrenergic receptors:
    
    • Inhibit release of norepinephrine, acetycholine and insulin
• Pheochromocytoma is a tumour that increases release of epinephine and norepinephrine, the effects of which are mediated via both alpha and beta receptors
• The alpha effects are potentially deliterious and significantly increase anaesthetic risk