Hypoadrenocorticism is a complex illness that may present to the veterinary surgeon in a variety of ways. The diagnosis is straightforward and easily made in patients presenting in a typical Addisionian crisis (hypovolaemic shock, bradycardia, hyperkalaemia, hyponatraemia, hypoglycaemia). However, the presenting signs may be quite vague and similar to those seen with renal disease, gastrointestinal disease and/or hepatic disease. Therefore, dysfunction of the adrenal gland should be considered as a potential differential diagnosis in any dog or cat presenting with acute or chronic systemic illness. The diagnosis should never be excluded based on the presence of normal electrolytes. Given that the clinical findings seen in hypoadrenocorticism can be vague, non-specific, intermittent and similar to those seen in a variety of more common diseases, a high index of suspicion is necessary for prompt diagnosis of the disorder.
Pathophysiology
The adrenal glands are responsible for the manufacture of both glucocorticoids and mineralocorticoids. Hypoadrenocorticism typically results in combined glucocorticoid and mineralocorticoid deficiency, although atypical Addison's disease affecting just the glucocorticoid producing adrenal cells has been described. Aldosterone is the primary mineralocorticoid secreted by the adrenal cortex. It promotes sodium, chloride and water reabsorption and potassium excretion. Aldosterone deficiency results in hypovolaemia, hyponatraemia and hyperkalaemia. Glucocorticoids are synthesised by the zona fasciculata and zona reticularis in the adrenal cortex. They stimulate gluconeogenesis and glycogenesis and enhance protein/fat catabolism. Glucocorticoids are important in maintaining normal blood pressure and counteracting the effects of stress. Cortisol deficiency is associated with hypotension, gastrointestinal signs, hypoglycaemia and an impaired response to stress.
Aetiology
Primary hypoadrenocorticism results from destruction or atrophy of the adrenal cortices. In most cases, it is thought to be caused by immune-mediated destruction of the adrenal gland. There is a single report of hypoadrenocorticism caused by adrenocortical lymphoma in cats. Adrenal destruction by granulomatous disease, histoplasmosis and blastomycosis has also been reported. Other causes of adrenal destruction include haemorrhagic infarction, adrenalitis, neoplasia, amyloidosis and necrosis. Primary adrenal failure may be caused by a number of drugs, including mitotane and ketoconazole.
Secondary hypoadrenocorticism results from deficient pituitary adrenocorticotrophic hormone (ACTH) secretion. Destructive lesions in the hypothalamus or pituitary due to neoplasia, inflammation or trauma may cause secondary hypoadrenocorticism. In secondary hypoadrenocorticism, deficient ACTH production results in inadequate glucocorticoid secretion, whereas mineralocorticoid secretion is typically preserved. Administration of glucocorticoid drugs may cause secondary adrenal failure. After corticosteroid administration (topical, oral or injectable) suppression of ACTH production from the pituitary gland occurs within a few days. This results in secondary adrenal atrophy. How long the adrenal axis is suppressed depends on the potency and half-life of the administered glucocorticoid. Long-acting depot drugs are the most potent adrenal suppressants and can cause suppression for 5-6 weeks or longer.
Reversible relative adrenal insufficiency (RAI) has been recognised with increasing frequency in critically ill humans and animals. It is most often associated with sepsis.
Diagnosis
The clinical signs of hypoadrenocorticism are nonspecific and are rarely pathognomonic for the disease. Clinical signs may be either acute or gradual in onset. An important diagnostic clue is a waxing/waning illness that is exacerbated by stress and that responds to non-specific treatment and supportive care. Clinical signs reported in canine hypoadrenocorticism are listed in Figure 1. In cats, the clinical signs are also very non-specific and include anorexia, weight loss, vomiting and depression. Physical examination findings are not helpful unless the animal has bradycardia secondary to hyperkalaemia.
Figure 1. Clinical findings in canine hypoadrenocorticism.
Lethargy/depression
Anorexia
Vomiting
Weakness
Weight loss
Dehydration
Diarrhoea
Waxing/waning course
Collapse
Previous response to therapy
Hypothermia
Slow capillary refill time
Shaking
Polyuria/polydypsia
Melaena
Weak pulse
Bradycardia
Painful abdomen
Hair loss
The diagnosis of hypoadrenocorticism should be considered in patients with hyponatraemia, hyperkalaemia and/or a sodium:potassium ratio <27. Any patient with this combination of serum electrolyte abnormalities should be considered to have hypoadrenocorticism until proven otherwise. Pseudo-Addison's disease (hyperkalaemia, hyponatraemia and/or a sodium:potassium ratio <27) has been reported in animals with trichuriasis, other severe gastrointestinal diseases, pyometra and other causes of body cavity effusions. Other laboratory abnormalities seen in hypoadrenocorticsm are listed in Figure 2. Electrocardiogram (ECG) abnormalities may be seen if the patient is hyperkalaemic. Thoracic radiographs may reveal microcardia and a narrow posterior vena cava. The severity of the changes reflects the degree of hypovolaemia. Occasional dogs may have evidence of mega-oesophagus.
Figure 2. Laboratory findings in canine hypoadrenocorticism.
Hyperkalaemia
Hyponatraemia
Sodium:potassium ratio <27
Hypochloraemia
Hypercalcaemia
Azotaemia
Decreased TCO2
Elevated alanine aminotransferase/aspartate aminotransferase
Hyperbilirubinaemia
Hypoglycaemia
Anaemia
Eosinophilia
Lymphocytosis
Urine specific gravity <1.030
Relative adrenal insufficiency should be suspected in septic patients that remain hypotensive despite volume resuscitation and catecholamine therapy.
Definitive diagnosis of hypoadrenocorticism requires the demonstration of inadequate adrenal reserve with an ACTH response test. Dexamethasone sodium phosphate does not cross-react with the cortisol assay and should be used in the initial treatment of acute adrenocortical insufficiency. In dogs that have received prednisone, prednisolone or hydrocortisone, glucocorticoid therapy is changed to dexamethasone for at least 24 hours before an ACTH stimulation test is done.
Treatment
Treatment of hypoadrenocorticism requires administration of the appropriate mineralocorticoid and/or glucocorticoid replacement. Initial dosage, route of administration and urgency of treatment depend on the clinical presentation.
Acute adrenocortical insufficiency (Addisonian crisis) is a medical emergency requiring immediate therapy. Given appropriate signalment, history and clinical signs, therapy should begin immediately. Immediate therapy revolves around correction of electrolyte and volume disturbances. 0.9% saline is administered until resolution of hyperkalaemia and hypovolaemia. If hypoglycaemia is present, the patient should receive a bolus of dextrose and the fluids should be supplemented with dextrose. Fluid administration helps quickly lower the serum potassium concentration, as a result of a dilutional effect as well as improved renal perfusion with concomitant increased potassium excretion. If severe hyperkalaemia persists despite such fluid administration, or if death from hyperkalaemic myocardial toxicity is imminent, intravenous insulin and glucose are indicated. Regular insulin is given at a dosage of 0.5 IU/kg and 2-3 g of glucose per unit of insulin is administered, half as an intravenous bolus and half in the intravenous fluids over the next 6-8 hours. Such patients must be closely monitored for signs of hypoglycaemia, as dogs with adrenocortical insufficiency are sensitive to the hypoglycaemic action of insulin. Continuous electrocardiographic monitoring is indicated until the ECG has returned to normal.
The second important item in the treatment of the Addisonian crisis is the intravenous administration of a rapid-acting glucocorticoid, such as dexamethasone sodium phosphate (0.25-1.0 mg/kg) or prednisolone sodium succinate (4-6 mg/kg), repeated in 2-6 hours if necessary. Dexamethasone sodium phosphate must be used if an ACTH response test is in progress in order to avoid cross-reaction with the cortisol assay. Glucocorticoid is gradually tapered to a maintenance dosage of prednisone (0.2 mg/kg daily), administered parenterally until vomiting has ceased. Replacement mineralocorticoids are usually withheld until confirmation of disease. They are unnecessary when coupled with saline in the short term.
Many dogs with hypoadrenocorticism may not require the aggressive therapeutic intervention described above. Nonetheless, fluid therapy and parenteral glucocorticoid administration may be needed if azotaemia, dehydration or vomiting is present and should be continued until these problems have resolved and oral therapy can be started. Maintenance therapy of hypoadrenocorticism consists of lifelong mineralocorticoid and/or glucocorticoid replacement therapy. Patients with atypical hypoadrenocorticism require only glucocorticoid replacement but some dogs may eventually develop mineralocorticoid dependency.
Conclusion
Hypoadrenocorticism is a complex illness that has been rightly labeled the 'great pretender'. You should always suspect hypoadrenocorticism when:
There is unexplained weight loss, depression, or anorexia
There is chronic and unexplained gastrointestinal disease including haemorrhagic gastroenteritis
Dogs or cats are ADR and you cannot find any other explanation
Signs develop following sudden withdrawal from chronic steroid administration
Hypoglycaemia is identified
A patient with septic shock is non-responsive to catecholamine therapy