Hypoadrenocorticism

Question 1

In humans, antibodies against 21-hydroxylase have been documented in most patients with hypoadrenocorticism.

What reactions does the 21-hydroxylase enzyme catalyse?

Answer 1

• 21-hydroxylase catalyses the conversion of progesterone to deoxy-corticosterone.
  
  • Deoxycorticosterone is subsequently converted to corticosterone by 11b-hydroxylase and aldosterone (aldosterone synthase)
• 21-hydroxylase also catalyses the conversion of 17-hydroxy progesterone to 11-deoxycortisol, which is subsequently converted to cortisol by 11b-hydroxylase
• Absence of the 21-hydroxylase enxyme therefore leads to reduction in both cortisol and aldosterone and clinical signs consistent with adrenal gland failure

Question 2

Discuss the known or suspected genetic basis to the disease in dogs

Answer 2

• Certain breeds have been shown to have an increased risk
  
  • Great dane, Standard Poodle, Bearded Collie, Portugese water dog
• Various studies have revealed variable answers
• In poodles and the portugese water dog, it is most likely autosomal recessive with a single locus having a major effect
• The MHC II coding for DLA may be involved
• The cytotxic T-lymphocyte associated protein 4 may also be involved
• There is no link as yet between any of the genetic variations / associations and the development of auto-antibodies directed against the adrenal gland or it’s component enzymes

Question 3

What is atypical hypoadrenocorticism?

Note the natural history and link to “typical” hypoadrenocorticism

Answer 3

• Atypical hypoadrenocorticism occurs when there is a marked reduction in cortisol with maintenance of normal sodium and potassium concentrations.
• In some dogs, destruction of the zona glomeurlosa lags behind the loss of the fasiculata and reticularis meanding residual aldosterone production is lost after cortisol. In this scenario, atypical hypoA becomes typical over time.
• The zona glomerulosa contains less 21-hydroxylase that the other 2 layers: The immune destruction may be slower in this layer
• In some dogs with atypical hypoA, aldosterone levels are reduced suggesting Na and K concentrations are not entirely dependent on aldosterone for maintenance.

Question 4

What is secondary hypoadrenocorticism?

What are the potential causes of secondatry hypoadrenocorticism?

Answer 4

• Secondary hypoadrenocorticism results from defective release of ACTH from the pituitary (tertiary if there is CRH failure from the hypothalamus)
• As aldosterone release is largely driven by the RAAS and alterations in potassium concentration, ACTH deficiency generally causes solitary cortisol deficiency
• Causes: Any condition that causes damage to the pituitary could lead to secondary hypoA
  
  • Neoplasia
  • Inflammation
  • Infection
  • Infarction
  • Trauma
  • Idiopathic
• Note: with most of the above, neurological signs and other hormone deficienceis would be likely.

Question 5

Discuss the most commonly identified clinical signs associated with hypoadrenocorticism

Explain the cause for the signs and reason for variability

Answer 5

The signs of dogs with HypoA are often vague initially and can eventually lead to acute or sudden severe decompensation.

• Anorexia
• Vomiting
• Lethargy / weakness / shaking
• Diarrhoea
• Collapse

Most clinical signs are attributable to reduced cortisol

Waxing and waning over time may be due to gradual loss of cortisol production over time.

Eventual collapse and decompensation may or will occur with stressful conditions or if the gland eventually fails completely

With decompensation and collapse, then secondary signs due to electrolyte imbalance and cortisol deficiency become evident (bradycardia, severe dehydration / hypovolaemia,

Question 6

Discuss the physiological abnormalities that occur secondary to mineralocorticoid and glucocorticoid deficiency

Answer 6

Glucocorticoids:

• Gastric mucosal barrier function
  
  • Defective barrier function can lead to inappetance, vomiting, diarrhoea and eventual weight loss
  • Note: ulceration is uncommon, with haematemesis or melena not typically observed with HypoA
• Blood pressure
• Body temperature
• Glucose concentrations
  
  • Reduced gluconeogenesis, reduced lipolysis and protein catabolism
  • May in part be the cause for weakness, lethargy and shaking

Mineralocorticoid:

• lack of sodium resorption - sodium loss in the urine
• Increase sodium loss into the urine causes osmotic diuresis
• Compensatory PD
• Aldosterone triggers the Na+/K+ exchanger, so reduced sodium resoprtion is coupled to reduced potassium excretion and hyperkalaemia

Question 7

Why do we see bradycardia in dogs with acute collapse and severe decompensation due to hypoadrenocorticism

Answer 7

• Aldosterone deficiency leads to increased sodium excretion and reduced potassium excretion with resultant hyperkalaemia
• Elevated potassium in the extracellular fluid reduces the concentration gradietn between intracellular and extracellular potassium in the cardiac pacemaker cells.
• The outward K current is thus reduced or slowed
• The outward K current is necessary for phase 3 of the action potential - rapid repolarisation
• Slowing of rapid repolarisation leads to bradycardia, despite the sympathetic drive due to hypovolaemia and illness.

Question 8

What are the major findings in acutely unwell dogs with hypoadrenocorticism that may help differentiate from acutely unwell dogs with normal adrenal gland function

Answer 8

• A lack of cortisol, leads to a lack of the normal or expected stress/inflammatory response in a sick dog.
• Dogs with hypoadrenocorticism have
  
  • significantly elevated lymphocyte and eosinophil counts (often within the normal range though)
  • Significantly lower neutrophil counts, again often within the normal range

Question 9

Whatis the utility of sodium, potassium and the sodium:potassium ratio in the diagnosis of hypoadrenocorticism

Answer 9

• Hyponatremia and Hyperkalaemia have been identified in > 80% of dogs with hypoA
  
  • HyperK - 98%
  • Hyponatraemia - 83%
• The ratio of Na to K has been shown to be of both high sensitivity and specificity
  
  • Care to avoid over-interpretation in the face of significant haemolysis
• Adler et al 2007 reported the sodium potassium ratio of 27 or 28 as a cut off with good sensitivity and specificity
  
  • 27: sensitivity 89%, specificity 97%
  • 28: sensitivity 93%, specificity 96%
• Levels below 27 have reduced sensitivity whereas values of 29 or above have specificity < 90%
• The median ratio of 73 dogs with hypoA, was 22.9.
  
  • While a ratio of 23 had a specificity ~ 100%, the sensitivity was only 74%

Question 10

List the potential biochemistry changes seen with hypoadrenocorticism.

Note the incidence of each and likely cause

Answer 10

• Azotemia - increased BUN and creatinine are common
  
  • Particularly common in dogs with acute or decompensated illness, consistent with an AKI
  • Generally 100% reversible with rapid treatment
• Acidemia
  
  • ~60%
  • Due to reduced H⁺ excretion, normally mediated by aldosterone (Na⁺ / H⁺ exchanger in the distal convoluted tubule)
• Hypochloraemia
  
  • Reduced resorption with sodium in the kidney
  • Vomiting
• Hypercalcaemia
  
  • Reduced calciuresis, normally mediated by cortisol
  • Increased liberation of Ca⁺⁺ from albumin due to acidosis (H⁺ binding to albumin)
• Hypoglycaemia
  
  • ~ 20% of dogs
  • Likely due to cortisol deficiency, reduced gluconeogenesis and glycogenolysis
  • Increased insulin release does not appear to contribute
  • Reduced caloric intake and GIT disturbances mnay contribute
• Hypoalbuminemia and hypocholesterolemia (uncommon)
  
  • Reduced GIT intake or increased GIT loss

Question 11

List the testing options for assessment of adrenal function in dogs

Note the utility of each test

Answer 11

• ACTH stimulation tests
  
  • Can assess cortisol and other hormones
• Endogenous ACTH assay
  
  • Typically elevated in dogs with hypoA
  • More often used to differentiate PDH and AT in dogs with hyperadrenocorticism
• Endogenous cortisol assay
  
  • Cortisol levels display random fluctuation and some dogs without hypoA can have low baseline cortisol with normal adrenal function
  • Can be used to screen for hypoA - normal result excludes the diagnosis
• Cortisol:endogenous ACTH ratio
  
  • Has been shown to be significantly reduced in dogs with hypoA with no overlap in the ratio with normal dogs

Question 12

Note the treatment priorities in dogs during an acute Addisonian crisis

Answer 12

• IV fluid therapy
  
  • To correct dehydration
  • Correction of electolyes and acid base status
    
    • Sodium chloride is generally recommended despite the low pH
    • Acidosis generally resolves after ~12-24 hours of diuresis
  • Care must be taken not to increase hyponatremia too quickly when the abnormality is severe - hypertonic saline is absolutely contraindicated
• Glucose / dextrose
  
  • Indicated if hypoglycaemia is present at initiation of treatment
  • Can be administered if hyperkalaemia persists after 6-8 hours of fluid therapy
• Insulin can be utilised if hyperkalaemia persists after glucose/dextrose and blood glucose is > 11 mmol/L
• Glucocorticoids
  
  • Typically reserved until an ACTH stimulation test has been performed
  • While hydrocortisone is sufficient to manage cortisol deficiency, a low dose of dexamethasone is often used

Question 13

What is DOCP and how is it used in the management of hypoadrenocorticism

Answer 13

• Desoxycorticosterone pivalate is an analogue of deoxycorticosterone
  
  • Deoxycorticosterone is converted to corticosterone and finally aldosterone within the zonal glomerulosa of the adrenal gland
• DOCP is available as a long-acting injection
• Administered initially at 2.2 mg/kg SC each 25 days.
• Electrolytes should be monitored at 14 days, with a 10% dose reduction if the Na:K is > 32
• If the Na:K is > 32 on day 25, then the next injection can be delayed 5 days
• The target Na:K is 29-32 and the dose can be reduced or interval extended when >32. The opposite occurs if the Na:K is < 28