Hypoadrenocorticism is a relatively uncommon disorder of dogs. In secondary hypoadrenocorticism, a deficiency of adrenocorticotropic hormone (ACTH) results in glucocorticoid insufficiency. Possible causes include pituitary neoplasia or abrupt withdrawal from glucocorticoid or progestagen therapy. Primary hypoadrenocorticism (Addison's disease) is more common and can give rise to both mineralocorticoid and glucocorticoid deficiency. It is usually attributed to immune-mediated destruction of the adrenal glands. Most dogs present with evidence of both mineralocorticoid and glucocorticoid deficiency. However, approximately 10 % of cases present with evidence of glucocorticoid deficiency alone (atypical Addison's)^(6,8). These cases may eventually progress to mineralocorticoid deficiency.

Addison's disease tends to affect young to middle-aged dogs. It is reported to predominantly affect females and Standard poodles, West Highland white terriers, great Danes, Rottweilers and bearded collies are predisposed. The condition is known to be inherited in standard poodles and bearded collies, although the exact genetic mechanisms are unclear^(2,7).

Clinical presentation and diagnosis

Dogs typically present with a waxing, waning history of lethargy/depression, weight loss, intermittent gastrointestinal signs, weakness and dehydration that respond, at least initially, to symptomatic therapy. The signs typically progressively worsen and some dogs eventually present in an acute addisonian crisis. These dogs exhibit moderate to severe shock as evidenced by extreme weakness or collapse, hypovolaemia, prolonged capillary refill time, weak pulse and inappropriately low heart rate or obvious bradycardia. Other possible signs include polyuria/polydipsia, shaking, vague abdominal pain, melaena and occasionally haematemesis. The onset of acute clinical signs may be precipitated by a stressful incident.

None of the above clinical signs are pathognomonic for hypoadrenocorticism but the waxing/waning nature of the illness that is exacerbated by stress and that responds to non-specific therapy often alerts clinicians to the possibility of hypoadrenocorticism. In addition, addisonian dogs often have more severe lethargy/depression, weight loss and dehydration than suggested by the other clinical signs and the length of the clinical history.

Survey radiographs, abdominal ultrasonography and electrocardiography are often performed in dogs with hypoadrenocorticism. Most untreated dogs have one or more radiographic abnormalities including small size of heart, cranial lobar pulmonary artery, caudal vena cava or liver, attributed to hypovolaemia. Megaoesophagus has been rarely described. Atrophy of the adrenal glands can lead to ultrasonographic-measurable reduction in the size of the adrenal glands, although this is largely dependent on the use of high quality equipment and operator experience.

Electrocardiographic abnormalities reflect the effect of hyperkalaemia on cardiac function and include spiked T-waves, a shortened Q-T interval, prolongation of the QRS complex, reduction or complete absence of P-waves and bradycardia. In severe cases, ventricular asystole or ventricular fibrillation may be recognised. Although loosely correlated with circulating potassium concentrations, serum measurements are more accurate for assessing severity of hyperkalaemia.

The most common biochemical abnormality (> 90 % of cases) is hyperkalaemia and hyponatraemia resulting in a sodium:potassium ratio of less than 1:23⁽⁸⁾. Hypochloraemia is also common. These electrolyte abnormalities are usually accompanied by azotaemia, which can be severe, acidosis and, less commonly, mild hypercalcaemia. Hypoalbuminaemia is frequently seen, and there may be hypocholesterolaemia and mild hypoglycaemia. Mild non-specific increases in the liver enzymes can also occur probably due to circulatory collapse and hypoxic hepatocellular damage. However, these are of no particular diagnostic value.

Hyperkalaemia is one of the hallmarks of hypoadrenocorticism and can be one of the most clinically significant abnormalities. Circulating potassium concentrations greater than approximately 7.5-8 mmol/L may be associated with cardiac arrhythmias and further increases can become fatal. Hyperkalaemia can occur in other disorders including renal disease, severe, gastrointestinal disease, in dogs with chylothorax and during pregnancy. Extremely low sodium:potassium ratios (< 15) are more commonly associated with hypoadrenocorticism than with other disorders⁽⁹⁾.

Haematological abnormalities include lymphocytosis and eosinophilia. Even without obvious abnormalities, maintenance of reference range eosinophil and lymphocyte numbers should alert the clinician to the possibility of hypoadrenocorticism as they are unusual in a severely ill animal (in which lymphopenia and eosinopenia are both more typical findings). Hypoadrenocorticism is frequently associated with mild normocytic normochromic anaemia, presumably as a consequence of chronic hypocortisolaemia. If gastrointestinal haemorrhage has occurred then a corresponding regenerative anaemia may be present.

Assessment of urine specific gravity is generally unhelpful in distinguishing hypoadrenocorticism from other disorders because of the effect of hypoaldosteronism on urine concentration.

Atypical cases initially have reference range circulating electrolyte concentrations. In these dogs destruction of mineralocorticoid producing cells may not yet have occurred or previous treatment may have masked any abnormalities.

Confirmation of the diagnosis of hypoadrenocorticism requires demonstration of a minimal cortisol response to exogenous ACTH administration. A number of protocols for the ACTH stimulation test have been recommended but intravenous administration of synthetic ACTH (tetracosactrin) appears to be most widely used. Cortisol determinations are usually performed immediately prior to and between 30 minutes and two hours afterwards (usually one hour). The main potential complicating factor in interpretation of test results is iatrogenic adrenal suppression, usually due to prior glucocorticoid/progestagen therapy. This can usually be ruled out based on the patient history, the clinical presentation and additional test results.

Most glucocorticoid preparations cross-react with the widely used commercial cortisol assays and cause artifactually increased cortisol results. The exception to this is dexamethasone, which therefore can be used as emergency treatment in an acute hypoadrenocorticoid crisis whilst the ACTH stimulation test is being performed.

Although ACTH plays only a minor role in regulating aldosterone secretion in the healthy dog, aldosterone measurement before and after administration of a pharmacological dose can be helpful diagnostically^(3,10). Resting circulating aldosterone concentrations are reduced in primary hypoadrenocorticism and typically show little or no increase in concentrations following ACTH administration. There is no real advantage in routinely measuring aldosterone instead of cortisol. However, aldosterone measurement does have the advantage of depicting aldosterone production in atypical cases particularly if a lack of electrolyte abnormalities may have been due to previous treatment. Measurement of aldosterone concentrations may also be valuable if glucocorticoids, other than dexamethasone, have already been used.

Circulating endogenous ACTH concentrations can also be measured and distinguish primary and atypical cases from secondary hypoadrenocorticism providing glucocorticoid therapy has not yet been instituted. Endogenous ACTH is highly labile and strict sample handling precautions must be observed to prevent in vitro degradation following sample collection.

Treatment

Addison's disease is a true medical emergency and rapid identification and treatment is required. Treatment of acute hypoadrenocorticism is primarily directed at

 Restoring circulating blood volume

 Correcting electrolyte and acid-base abnormalities

 Glucocorticoid supplementation.

The emergency treatment is summarised in Table 1. Rapid blood volume replacement with intravenous fluid therapy is the single most important component of treatment. Normal saline is the fluid of choice but any preparation including potassium-containing fluids can be used if availability is limited. Judicious use of fluids is required in severely hyponatraemic animals in order to avoid neurological complications. Fluid therapy is usually required for only 1 to 3 days in most cases and can be withdrawn when the dog is eating well, rehydrated, urine production has returned to normal, and the electrolyte abnormalities and azotemia are corrected.

Considerable improvement of the electrolyte abnormalities usually occurs once fluid therapy has been instituted without the need for specific mineralocorticoid replacement. However, administration of glucocorticoids with mineralocorticoid activity certainly decreases the need for treatment of hyperkalaemia by other methods and, in the authors experience, leads to a more rapid recovery of the animal than when glucocorticoids alone are used. The drug of choice is hydrocortisone sodium succinate/phosphate^(1,5).

If hydrocortisone is not available, another glucocorticoid such as dexamethasone should be started as soon as possible.

The clinical response to emergency therapy in a dog presenting in an acute hypoadrenal crisis is usually dramatic and long-term oral therapy with mineralocorticoid and glucocorticoid supplementation should be started as soon as tolerated. Initially both glucocorticoid and mineralocorticoid therapy is required although in many cases glucocorticoid therapy can eventually be withdrawn.

Mineralocorticoid therapy using oral fludrocortisone acetate should be started at 0.015 mg/kg/day. Monitoring of electrolytes should be performed weekly initially and the dosage adjusted accordingly. Most dogs can be successfully treated on once daily therapy but some will require twice daily treatment to maintain electrolyte concentrations within the reference ranges. Fludrocortisone possesses a small degree of glucocorticoid activity and therefore also assists in weaning affected dogs off prednisolone therapy. The dosage of fludrocortisone increases with time for reasons that are yet unclear⁽⁴⁾.

An alternative method of providing mineralocorticoid replacement is the use of desoxycorticosterone pivalate (DOCP). This preparation is administered at a dose of approximately 2 mg/kg by intramuscular injection and provides mineralocorticoid activity for an average of 25 days. As with oral supplementation, monitoring is based on blood electrolyte measurements. This preparation is not commercially available worldwide.

Salt supplementation can be used to help maintain circulating sodium concentrations. The dose required is variable but approximately 0.1 mg/kg/day may be appropriate. It is rarely used initially but may help reduce the dose of mineralocorticoid required and therefore reduce the cost of long term therapy.

Oral glucocorticoid therapy should also start as soon as the patient has been stabilised and is not vomiting. Prednisolone is the most appropriate drug to use, being widely available and inexpensive. Initial therapy at 0.5 mg/kg once daily should be used, but this can usually be reduced fairly quickly. Adjustments in the dose should be based on clinical response and the presence of side effects to the drug. In many dogs the prednisolone therapy can eventually be stopped altogether except at times of stress such as the development of other illness, kenneling, etc. However, in others a low maintenance dose, often approximately 0.2 mg/kg/day will be permanently required. Oral glucocorticoid therapy is the sole drug used to treat secondary and atypical cases. However, care should be taken with atypical cases as mineralocorticoid supplementation may be required with time.

The prognosis for treated dogs is excellent but it is possible that affected dogs are at increased risk of developing other immune-mediated endocrine disorders such as diabetes mellitus, hypoparathyroidism and hypothyroidism (polyglandular disorders).

Table 1. Initial emergency therapy for the dog with acute hypoadrenocortical crisis.

References

1.  Church DB, Nicholson AI, Ilkiw JE & Emslie, DR (1994) Effect of non-adrenal illness, anaesthesia and surgery on plasma cortisol concentrations in dogs. Research in Veterinary Science 56, 129-131.

2.  Famula TR, Belanger JM & Oberbauer AM (2003) Heritability and complex segregation analysis of hypoadrenocorticism in the standard poodle. Journal of Small Animal Practice 44, 8-12.

3.  Golden DL & Lothrop CD (1988) A retrospective study of aldosterone secretion in normal and adrenopathic dogs. Journal of Veterinary Internal Medicine 2, 121-125.

4.  Kintzer PP & Peterson ME (1997) Treatment and longterm follow-up of 205 dogs with hypoadrenocorticism. Journal of Veterinary Internal Medicine 11, 43-49.

5.  Lamb WA, Church DB, Emslie, DR (1994) Effect of chronic hypocortisolaemia on plasma cortisol concentrations during intravenous infusions of hydrocortisone sodium succinate in dogs. Research in Veterinary Science 57, 349-352.

6.  Lifton SJ, King LG & Zerbe CA (1996) Glucocorticoid deficient hypoadrenocorticism in dogs: 18 cases (1986-1995) Journal of the American Veterinary Medical Association 209, 2076-2081

7.  Oberbauer AM, Benemann KS, Belanger JM, Wagner DR, Ward JH & Famula TR (2002) Inheritance of hypoadrenocorticism in bearded collies. American Journal of Veterinary Research 63, 643-647.

8.  Peterson ME, Kintzer PP & Kass PH (1996) Pretreatment clinical and laboratory findings in dogs with hypoadrenocorticism: 225 cases (1979-1993). Journal of the American Veterinary Medical Association 208, 85-91.

9.  Roth L & Tyler RD (1999) Evaluation of low sodium:potassium ratios in dogs Journal of Veterinary Diagnostic Investigation 1, 60-64.

10. Willard MD, Refsal K & Thacker E (1987) Evaluation of plasma aldosterone concentrations before and after ACTH administration in clinically normal dogs and in dogs with various diseases. American Journal of Veterinary Research 12, 17131718.