Hypoadrenocorticism - Is This an Under-Recognised Problem and What Can I Do to Optimise My Management of These Patients?
Naturally occurring hypoadrenocorticism is characterized by clinically significant loss of adrenocortical secretory capacity. In the overwhelming proportion of cases, hypoadrenocorticism is a direct result of inadequate adrenocortical function (primary hypoadrenocorticism) rather than a result of subnormal production of adrenocorticotrophic hormone (secondary hypoadrenocorticism).
In most cases the underlying reason for adrenal destruction appears to be idiopathic or immune-mediated. Interestingly a marked genetic predisposition for hypoadrenocorticism has been demonstrated in Standard Poodles, Bearded Collies and Nova Scotia Duck Tolling Retrievers. Additionally there are a number of other breeds where hypoadrenocorticism is encountered more commonly than would be expected. In those breeds in which a marked breed predilection has not been reported, female dogs are more commonly affected with a ratio of approximately 2.3:1.
Most affected dogs with hypoadrenocorticism present in young to middle age. The clinical features vary from acute collapse with generalized under perfusion to a variably present group of more nonspecific signs that suggest the animal is unwell but do not focus the clinician's attention on any particular body system.
Patients presenting with acute collapse usually have evidence of generalized, marked hypovolaemia and dehydration, together with vomiting, diarrhoea, abdominal pain and hypothermia. Some may have severe gastrointestinal haemorrhage with melaena. These patients are unstable and represent a true medical emergency.
It is not uncommon for dogs with primary hypoadrenocorticism to have a waxing and waning illness characterized by vague illness with variable gastrointestinal signs and depression/weakness interspersed with periods of apparent normality before they present in a collapsed state.
Routine Clinical Pathology
In the presence of appropriate clinical signs, suspicion for hypoadrenocorticism is dramatically increased by the presence of lymphocytosis and/or eosinophilia or simply the absence of a stress leukogram (i.e., lymphopenia and eosinopenia) in a clearly "unwell" patient.
Acute hypoadrenocorticism commonly results in a nonregenerative or variably regenerative anaemia. If severe enough, gastrointestinal haemorrhage may result in a regenerative anaemia.
The most consistent biochemical abnormalities include azotaemia, hyponatraemia, hyperkalaemia, hypochloraemia and less commonly hypoglycaemia and hypercalcaemia.
In a proportion but certainly not all patients with hypoadrenocorticism, circulating sodium concentrations are less than 135 mmol/L and potassium concentrations are greater than 5.5 mmol/L. Circulating chloride concentration is also reduced in patients with hypoadrenocorticism and concentrations of less than 100 mmol/L are frequently encountered.
Although the presence of these electrolyte changes support a diagnosis of hypoadrenocorticism, they can occur in a variety of other conditions as well as being artefactual.
Additionally, approximately 35% of dogs with primary hypoadrenocorticism have normal electrolyte concentrations. Consequently the diagnosis of hypoadrenocorticism cannot be precluded in animals with normal or mild electrolyte changes.
As with all hypovolaemic conditions, animals with primary hypoadrenocorticism develop azotaemia as a consequence of renal under perfusion. However unlike other hypovolaemic conditions where renal concentrating ability is maintained, dogs with primary hypoadrenocorticism are generally unable to concentrate their urine effectively. As a consequence, azotaemia is usually accompanied by inappropriately dilute urine increasing the potential for affected animals to be mistakenly diagnosed with severe primary renal disease.
Other biochemical abnormalities commonly encountered in dogs and cats with hypoadrenocorticism include hypercalcaemia, hypoglycaemia and varying levels of hypoalbuminaemia or hypoproteinaemia. As with anaemia, the severity of the hypoproteinaemia may be masked by the hypovolaemia/dehydration. Hypoproteinaemia is presumably a consequence of gastrointestinal haemorrhage.
Supplementary Diagnostic Aids
Other diagnostic aids that may provide supporting evidence for hypoadrenocorticism include electrocardiography, thoracic radiography and abdominal ultrasonography.
Confirmation of Diagnosis
The definitive diagnostic test for hypoadrenocorticism is an ACTH stimulation test. As both the clinical signs and the various routine diagnostic aids can be so nonspecific and untreated hypoadrenocorticism is both a critical and potentially fatal disease, it is reasonable to expect that clinicians with even a low index of suspicion for clinically significant impaired adrenocortical function will perform an adrenal function test, especially if the test is safe, easy to perform and relatively inexpensive.
ACTH Stimulation Test
A definitive diagnosis of spontaneous hypoadrenocorticism requires the demonstration of subnormal basal and post-ACTH plasma cortisol concentrations in an animal that has not recently received exogenous glucocorticoid therapy.
In dogs the ACTH stimulation test can be performed by sampling before and one hour after the administration of the ACTH analogue tetracosactrin (cosyntropin) either given intravenously at a dose of 5 µg/kg, or intramuscularly at a dose of 250 µg per animal.
As hydrocortisone, prednisolone and prednisone all cross-react in cortisol assays it is essential that the ACTH stimulation test be performed before these agents are administered to the dog. In contrast, dexamethasone does not cross-react in cortisol assays. It is worth noting dexamethasone does directly inhibit endogenous cortisol production, however this usually takes at least 4–6 hours to take effect.
Endogenous Plasma ACTH Concentration
Estimating the plasma ACTH concentration is the most reliable means of differentiating primary from secondary hypoadrenocorticism and can also alert the clinician to the likelihood of a prior undisclosed glucocorticoid injection.
Because of the combination of a potentially critical patient and the inability to confirm a diagnosis by cortisol estimation within hours of hospitalization, there are frequently times when suspected hypoadrenocorticism requires treatment before a diagnosis has been reliably confirmed. Initially most affected animals require concurrent intravenous fluid and parenteral glucocorticoid/mineralocorticoid replacement therapy.
Initial Stabilising Therapy
Fluid therapy should be started as soon as possible in the acutely sick patient. Patients with hypoadrenocorticism are susceptible to fluid overload and additionally rapid correction of the hyponatraemia may result in structural neurological disease and myelinolysis characterized by a variety of variably reversible neurological signs (Brady et al. 1999; MacMillan 2003). There is thus a conflict between the need to rapidly correct the severe hypovolaemia while insuring the serum sodium concentration does not increase rapidly. Consequently the fluid of choice is normal saline (0.9%) and most endocrinologists and criticalists recommend an initial rate of 10–30 ml/kg/h with a subsequent reduction to no more than twice maintenance levels (120 ml/kg/24 hours) after 2–3 hours.
Although fluid therapy alone generally results in a marked reduction in plasma potassium, restoration of renal perfusion and correction of acidosis; it should be complemented by treatment with a parenteral agent possessing both glucocorticoid and mineralocorticoid activity such as hydrocortisone sodium succinate (HSS). Although soluble dexamethasone or prednisolone preparations can be used, their lack of mineralocorticoid activity make them less attractive.
Hydrocortisone sodium succinate is administered as an intravenous infusion at a dose of 0.5 mg/kg/h until normal gastrointestinal function has returned. It is best to administer it in its own fluid bag made up to a concentration of 1 mg/ml.
Once the patient is stabilised, glucocorticoid and mineralocorticoid replacement therapy is almost always needs to be maintained for the remainder of the animal's life. Traditionally, a semi-selective mineralocorticoid, fludrocortisone and a semi-selective glucocorticoid (cortisone acetate or prednisolone) are initially used together. The former is discontinued in a proportion of patients after one to two months.
Some of the pertinent features of the most effective drugs used to maintain hypoadrenocorticism patients are given below.
The dose of fludrocortisone is 10 to 30 µg/kg administered orally once daily. Dose adjustments are usually made after weekly electrolyte evaluations. Once these are stable and within the normal range adjustments can be made every 3 to 4 months.
Desoxycorticosterone pivalate: is a potent mineralocorticoid analogue with little if any glucocorticoid activity. The recommended dose of DOCP is 2.2 mg/kg by subcutaneous injection every 25 days. Plasma electrolyte, urea and creatinine concentrations are monitored every two weeks to determine the duration of action and help individualize the dose. Once stabilised it is prudent to check electrolytes every 3 to 6 months. Most dogs are well controlled on 1.1 to 2.2 mg/kg every 3 to 4 weeks although it has been suggested that occasional individuals will require more frequent dosing. As DOCP has no glucocorticoid activity it is essential that patients receive concurrent glucocorticoid supplementation with either cortisone acetate or prednisolone.
Cortisone is rapidly activated to biologically active hydrocortisone. As it has equipotent glucocorticoid and mineralocorticoid activity it will also provide more mineralocorticoid activity than other synthetic glucocorticoids such as prednisolone.
In patients with hypoadrenocorticism the dose of cortisone acetate must be individualized according to the severity of the condition, the response obtained and what other glucocorticoid or mineralocorticoid is being concurrently administered. In the changeover period as animals recover from an acute crisis, start eating and drinking and are changed from parenteral to oral medication most hypoadrenocorticoid dogs are started on a dose of 0.5–1.0 mg/kg/12–24 h. However once they are stable, generally a dose of 0.5 mg/kg/12–24 h provides adequate additional glucocorticoid supplementation.
Prednisolone is a synthetic adrenal steroid with moderately potentiated glucocorticoid activity (approximately 5 times that of hydrocortisone) and less than 10% of hydrocortisone's mineralocorticoid activity. Some clinicians advocate its use as a glucocorticoid supplement in the long-term management of hypoadrenocorticism at a dose rate of between 0.2–0.5 mg/kg/24 h. In the author's opinion cortisone acetate is a more effective alternative, especially in dogs under 20 kg in bodyweight.