Hans S. Kooistra, DECVIM-CA
Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
The terms hypoadrenocorticism and adrenocortical insufficiency comprise all conditions in which the secretion of adrenal steroid hormones falls below the requirement of the animal. Two forms can be distinguished:
1. Primary adrenocortical insufficiency, which results from disease processes located in the adrenal cortices.
2. Secondary adrenocortical insufficiency, which is due to insufficient adrenocorticotrophic hormone (ACTH) release by the pituitary.
Primary Adrenocortical Insufficiency
Primary hypoadrenocorticism or Addison's disease results from progressive destruction of the adrenal cortices, which must involve 90% or more before it causes signs and symptoms. In dogs the often-found atrophy is probably the end-result of an immune-mediated destruction. In the end there is an absolute deficiency of usually both glucocorticoids and mineralocorticoids together with high plasma levels of ACTH as a result of the loss of negative feedback effect on the pituitary by the absence of cortisol. Rarely the destruction is confined to the two inner zones of the adrenal cortices, although it may occur more often and remain unnoticed for quite some time as there is (initially or permanently) no mineralocorticoid deficiency. The reverse, that is selective destruction of the zona glomerulosa with intact glucocorticoid production, has also been described. Primary hypoadrenocorticism may be part of a polyglandular deficiency syndrome.
Other possible causes of primary adrenocortical insufficiency include infections, haemorrhage and metastatic disease, but they seem to be very rare. Finally an iatrogenic cause of the disease should be mentioned; chemotherapy with o,p'-DDD for hyperadrenocorticism may deliberately or non-deliberately destruct the adrenal cortices to such an extent that hypoadrenocorticism ensues.
Hypoadrenocorticism is an uncommon disease of primarily young to middle-aged dogs (mean 4 years) with a predilection for the female. Familial occurrence of hypoadrenocorticism has been described for several breeds and heritability has been investigated in Nova Scotia Duck Tolling retrievers, bearded collies and standard poodles.
Although glucocorticoid deficiency may cause some lethargy and weakness and this certainly will contribute to the clinical manifestations, Addison's disease is primarily a syndrome caused by mineralocorticoid deficiency. Many of the signs and symptoms can be related to hypotonic dehydration due to the sodium losses. The hyperkalemia contributes to the problems by affecting neuromuscular function, particularly leading to conduction disturbances in the heart.
As the disease usually is caused by a gradual autoimmune destruction of the adrenal cortices one might expect an insidious onset of slowly progressive weakness, fatigue, anorexia and vomiting. Although this may be the case, more often the animals are presented as an emergency in a state of rather severe depression and hypotonic dehydration. There may not have been a start with mild signs or the signs may have remained unnoticed by the owner and are only remembered in retrospect. Apparently the animals can cope with the hormone deficiencies for a long time until a critical threshold in the maintenance of fluid and electrolyte homeostasis is passed.
Thus commonly the cases are brought in as rather young, suddenly very sick animals with a history of anorexia, vomiting and weight loss. On physical examination there is usually severe lethargy in combination with signs of (10-12%) dehydration: hypotonic veins and weak pulse. Radiographically the hypovolemia becomes manifest by the small sizes of the heart, pulmonary vessels and caudal vena cava. The hyperkalemia causes bradycardia with ECG changes such as low R wave, spiked high T wave and wide or absent P wave.
Results of routine laboratory examination usually include hypoplastic anemia (often masked by hemoconcentration due to dehydration), (prerenal) azotemia, hyponatremia and hyperkalemia. In about 30% of cases there may also be hypercalcemia, which in part may be due to hemoconcentration.
For the cardinal features of the disease, i.e., rapidly worsening depression, weakness, anorexia and vomiting, there is only a limited number of syndromes that may have a similar picture. These are ileus, (acute) renal insufficiency, acute gastroenteritis and acute pancreatitis. Initially the differentiation may pose problems as the other conditions occasionally are associated with electrolyte disturbances as well. However, further diagnostic work-up and especially the favourable result of treatment in Addison's disease usually brings the clinician quickly in the right track.
In cases with a characteristic routine biochemical pattern (prerenal azotemia, hyponatremia and hyperkalemia) and with a good response to treatment, there may be little doubt about the diagnosis. However, it is a diagnosis with as a consequence life-long treatment and therefore also in these cases it should be secured by an endocrine test. Basal levels of cortisol, either in urine or plasma, are low in cases of complete primary hypoadrenocorticism, but they may also be low for other reasons, such as previous administration of (long-acting) corticosteroids. Therefore a test of adrenocortical reserve capacity is necessary to establish the diagnosis, i.e., the ACTH-stimulation test. In this test plasma for cortisol measurements is collected immediately before and 60-90 min after intravenous administration of 0.25 mg synthetic ACTH. Most commonly there are low to low-normal baseline cortisol concentrations that fail to increase after ACTH administration. Plasma ACTH concentrations are high in dogs with primary hypoadrenocorticism as a result of the loss of negative feedback on pituitary ACTH secretion. Determination of a low cortisol/ACTH ratio and a low aldosterone/renine ratio may be an alternative for the ACTH stimulation test in the diagnosis of primary hypoadrenocorticism. Ultrasonographic measurements may reveal small sized adrenal glands, which may contribute to the diagnosis.
Secondary Adrenocortical Insufficiency
In secondary adrenocortical insufficiency there is hyposecretion by the two inner zones of the adrenal cortices as a result of ACTH deficiency. In its spontaneous and complete form the condition is rare and most commonly caused by large pituitary tumours, which usually give rise to multiple pituitary-hormone deficiencies. Isolated ACTH deficiency due to autoimmune hypophysitis, as described in humans, has not been documented for dogs, although isolated ACTH deficiency has been reported to occur in dogs.
The iatrogenic form due to long-term corticosteroid therapy is much more common than the spontaneous disease. Via negative feedback this therapy causes chronic suppression of ACTH production and as a consequence atrophy of the zona fasciculata and reticularis. Thus like in the spontaneous cases these animals have two deficits, a loss of adrenocortical responsiveness to ACTH and a failure of pituitary ACTH release. Upon corticosteroid withdrawal these insufficiencies may continue to exist for several months before full recovery ensues.
Another iatrogenic form of the disease and a more permanent one is of course ACTH deficiency due to hypophysectomy.
In secondary adrenocortical insufficiency the mineralocorticoid production is virtually unaffected as it is primarily regulated via extra-pituitary mechanisms. Therefore there is not that tendency to hypotension and shock that gives primary adrenocortical insufficiency its dramatic features. On the contrary, although glucocorticoid deficiency may give rise to slight depression and anorexia, the abnormality may remain unnoticed for a long time. Nevertheless the condition has to be regarded as potentially dangerous because of the animals' inability to cope with stress by activating their pituitary-adrenocortical system. Major (surgical) trauma might cause a crisis and/or non-recovery from anaesthesia, when no extra glucocorticoids are given.
Suspicion of secondary adrenocortical insufficiency may be strengthened when the urinary corticoid/creatinine ratios are low in the absence of hyponatremia and hyperkalemia. In an ACTH-stimulation test low initial cortisol levels will be found, whereas after stimulation there may be (1) a normal or somewhat impaired cortisol response, or (2) no cortisol response. The first mentioned outcome almost excludes primary hypoadrenocorticism but not secondary hypoadrenocorticism as the response might be seen following recent onset. In the case of absent cortisol response there is the possibility of long-standing ACTH deficiency. However, there is also the exceptional possibility that there is still primary adrenocortical insufficiency with selective atrophy of the two inner zones and minimal or no involvement of the zona glomerulosa (see above).
For differentiation between these possibilities further studies are required, which should include measurements of plasma concentrations of ACTH, eventually together with a CRH-stimulation test. In dogs with primary adrenocortical insufficiency basal ACTH concentrations are high. In dogs with secondary adrenocortical insufficiency ACTH levels are low and non-responsive to stimulation with CRH.
Once there is biochemical certainty about the presence of secondary hypoadrenocorticism, visualization of the pituitary should follow in order to obtain some information on the morphology of the lesion that is causing the ACTH deficiency.
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