Hypoadrenocorticism

Hypoadrenocorticism is the umbrella term for a range of naturally-occurring or iatrogenic disorders that cause reduced function of the adrenal cortex and results in a state of glucocorticoid deficiency, mineralocorticoid deficiency or both.

Comments:
• Addison’s disease is a term synonymous with “primary hypoadrenocorticism” and does not include other forms of hypoadrenocorticism.

Primary hypoadrenocorticism is due to adrenocortical injury. It can be naturally-occurring (most commonly immune-mediated) or iatrogenic due to surgery (bilateral adrenalectomy) or drugs (e.g. trilostane, mitotane).

Comments:
• There are acute and chronic presentations, and, in chronic presentations, animals sometimes have periods without overt clinical signs
• Addison’s disease is a term synonymous with “primary hypoadrenocorticism”; ALIVE encourages the use of the latter term since it is more descriptive and, thus, less open to confusion.
• Less common causes of naturally-occurring adrenal injury include neoplasia, infarction, infection, haemorrhage and necrosis.

A state of glucocorticoid or, less likely, mineralocorticoid deficiency due to lack of ACTH or renin, respectively. Secondary glucocorticoid-deficient hypoadrenocorticism can be naturally-occurring or iatrogenic due to surgery (e.g. hypophysectomy, post-adrenalectomy of a cortisol-producing adrenal tumour) or abrupt discontinuation of drugs with glucocorticoid activity, including progestins.

This is defined as hypoadrenocorticism with hyperkalemia and/or hyponatremia. This is due to primary hypoadrenocorticism.

Comments:
• This form has previously been referred to as typical hypoadrenocorticism.
• ALIVE recognizes a current inability to accurately measure aldosterone concentrations. Therefore, clinical status is currently classified by sodium and potassium abnormalities and not by measurement of aldosterone concentration.
• Depending on the magnitude of hyponatremia and/or hyperkalemia, measurement of endogenous ACTH to differentiate primary and secondary hypoadrenocorticism may be considered.
• Rare cases of isolated aldosterone deficiency exist for which cortisol concentrations are within the reference interval. Diagnosis is made by documentation of hyponatremia and hyperkalemia and exclusion of all other causes. For these cases the measurement of aldosterone concentrations would be ideal; however, ALIVE recognizes a current inability to accurately measure aldosterone concentrations.
• Dogs with confirmed isolated mineralocorticoid-deficiency may progress to become also glucocorticoid-deficient.

This is defined as hypoadrenocorticism with normal serum concentrations of potassium and sodium. This could be due to primary or secondary hypoadrenocorticism. In order to prove that primary hypoadrenocorticism is present, endogenous ACTH concentration must be measured and be normal or above the reference interval.

Comments:
• This form has previously been referred to as atypical hypoadrenocorticism.
• ALIVE recognizes a current inability to accurately measure aldosterone concentrations. Therefore, clinical status is currently classified by sodium and potassium abnormalities and not by measurement of aldosterone concentration.

• Pre- and post-ACTH cortisol concentrations are within or less than the bottom quartile of the reference interval for basal cortisol; e.g. if the reference interval for basal cortisol concentration is 30-120 nmol/L (1.1-4.4 ug/dL), a post-ACTH cortisol concentration of 53 nmol/L (1.9 ug/dL) or less is diagnostic for hypoadrenocorticism.
• For diagnosis of naturally-occurring hypoadrenocorticism, it is essential to confirm that no prior exogenous glucocorticoids or progestogens are being or have been administered by any route, including topical.

Comments:
• ALIVE emphasizes that topical routes of glucocorticoid therapy include ophthalmic and otic, among others.
• ALIVE recommends employed cortisol assays should be validated and subjected to quality control; usually this means tests should be run by reference laboratories and not performed in-house to be reliably accurate.

• Pre- and post-ACTH cortisol concentrations are within or less than the bottom quartile of the reference interval for basal cortisol; e.g. if the reference interval for basal cortisol concentration is 30-120 nmol/L (1.1-4.4 ug/dL), a post-ACTH cortisol concentration of 53 nmol/L (1.9 ug/dL) or less is diagnostic for hypoadrenocorticism.
• Documentation of a normal or above normal endogenous ACTH. Measurement of endogenous ACTH should ideally be performed. ALIVE finds it reasonable to abstain from measurement of endogenous ACTH given the more common nature of primary versus secondary hypoadrenocorticism. However, secondary hypoadrenocorticism cannot be diagnosed without an endogenous ACTH measurement.
• It is essential to confirm that no exogenous glucocorticoids or progestogens are being or have been administered by any route, including topical.
• Rare cases of isolated aldosterone deficiency exist for which cortisol concentrations are within the reference interval. Diagnosis is made by documentation of hyponatremia and hyperkalemia and exclusion of all other causes. For these cases the measurement of aldosterone concentrations would be ideal; however, ALIVE recognizes a current inability to accurately assess aldosterone concentrations.
• Dogs with confirmed isolated mineralocorticoid deficiency may also progress to become glucocorticoid-deficient.

Comments:
• ALIVE emphasizes that topical routes of glucocorticoid administration include ophthalmic and otic, among others.
• ALIVE recommends employed cortisol assays should be validated and subjected to quality control; usually this means tests should be run by reference laboratories and not performed in-house to be reliably accurate.

• Pre- and post-ACTH cortisol concentrations are within or less than the bottom quartile of the reference interval for basal cortisol; e.g. if the reference interval for basal cortisol concentration is 30-120 nmol/L (1.1-4.4 ug/dL), a post-ACTH cortisol concentration of 53 nmol/L (1.9 ug/dL) or less is diagnostic for hypoadrenocorticism.
• Endogenous ACTH concentration is below the reference interval.

Comments:
• If cortisol deficiency is known to be due to hypophysectomy, removal of a cortisol-producing adrenal tumour or abrupt discontinuation of a drug with glucocorticoid activity, measurement of endogenous ACTH to confirm the diagnosis of secondary hypoadrenocorticism is not necessary.
• ALIVE recommends employed cortisol assays should be validated and subjected to quality control; usually this means tests should be run by reference laboratories and not performed in-house to be reliably accurate.

A syndrome referred to as CIRCI (previously called relative adrenal insufficiency or RAI) is reported in the literature.  Definitive evidence for the existence of CIRCI is lacking.  Some critically ill patients, especially those that are volume-depleted, hypotensive and vasopressor-resistant, may benefit from administration of drugs with glucocorticoid activity.  However, if CIRCI exists, criteria for diagnosis and guidelines for treatment of the syndrome are currently unknown.

A severe, acute presentation of hypoadrenocorticism which usually includes weakness, hypovolaemia and hypotension in addition to anorexia and vomiting; abdominal pain may be present. If untreated, an adrenal crisis can progress to shock and death.

Comments:
• Since Addison’s disease is a term synonymous with “primary hypoadrenocorticism” and an adrenal crisis can also occur with other forms of hypoadrenocorticism (i.e. secondary hypoadrenocorticism), ALIVE encourages the use of “Adrenal crisis” instead of “Addisonian crisis”.

• Clinical signs
• Hypotension
• Hypovolaemia
• Electrolyte imbalances, most importantly hyperkalaemia
• Hypoglycaemia (if present)
• Anaemia (if severe and life threathening)

Comment:
•  ALIVE emphasises the need to avoid rapid correction of hyponatraemia in order to minimise the risk of osmotic myelinolysis.

• Lack of clinical signs
• Normal or near normal electrolyte concentrations
• Specifically avoiding excessive, chronic glucocorticoid supplementation (resulting in iatrogenic Cushing’s syndrome, weight gain, and/or any biomarkers of excess glucocorticoid activity such as increased blood alkaline phosphatase activity [ALP], marked lymphopaenia, etc.) and mineralocorticoid supplementation (resulting in hypertension, hypokalaemia and/or hypernatraemia).