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Addison’s Disease in the Dog

Catharine Scott-Moncrieff MA, Vet MB, MS, DACVIM, DSAM, DECVIM - 31/08/2014

Addison’s Disease in the Dog

Catharine Scott-Moncrieff MA, Vet MB, MS, DACVIM, DSAM, DECVIM

Introduction

Addison’s disease, or hypoadrenocorticism, is a deficiency of corticosteroid secretion by the adrenal glands. In dogs the most common cause is primary adrenal failure, which usually causes deficiency of both glucocorticoids (primarily cortisol) and mineralocorticoids (primarily aldosterone). A rarer cause of hypoadrenocorticism is pituitary dysfunction resulting in decreased or absent ACTH secretion and secondary adrenal failure.

What do I need to know about adrenal physiology?

It is important to understand basic adrenal physiology to appropriately diagnose and treat patients with Addison’s disease (Figure 1). The hypothalamic pituitary adrenal axis regulates the synthesis and secretion of cortisol by the adrenal glands. Synthesis and secretion of aldosterone is regulated by the renin-angiotensin axis, the plasma potassium concentration and (to a minor extent) the plasma sodium and ACTH concentration. Corticosteroids have a variety of effects that make them critical for survival. figure 1: hypothalamic pituitary adrenal axisGlucocorticoids stimulate hepatic gluconeogenesis and glycogenesis, enhance protein and fat catabolism, and are important in maintaining normal blood pressure and counteracting the effects of stress. Mineralocorticoids increase absorption of sodium and secretion of potassium in the kidney, sweat glands, salivary glands and intestinal epithelial cells, and are critical for conserving sodium.

What are the most common causes of Addison’s disease?

Most cases of canine Addison’s disease are believed to be due to immune-mediated destruction. This is important because it means that with appropriate diagnosis and treatment, dogs with Addison’s disease can have a good quality of life and a normal life span. Other more unusual causes of adrenal gland destruction include fungal infection, haemorrhagic infarction, amyloidosis, necrosis and neoplasia. Rapid withdrawal of exogenous glucocorticoid drugs is the most common cause of secondary hypoadrenocorticism. Spontaneous secondary hypoadrenocorticism is rare and is caused either by idiopathic ACTH deficiency or destructive lesions in the hypothalamus or pituitary gland.

What are the most common breeds of dogs affected?

Addison’s disease is inherited as an autosomal recessive trait in the standard poodle, Portuguese water dog, and Nova Scotia duck-tolling retriever, and is also an inherited disease in the bearded collie (1-4) although other breeds are predisposed (5). In the general dog population approximately 70% of affected dogs are female; however in the Portuguese water dog, standard poodle, and bearded collie, males and females are equally affected. Addison’s disease is most commonly diagnosed in young to middle-aged dogs (median age 4) but may be diagnosed in dogs as young as 4 months and as old as 14 years (6).

What are the most common clinical signs?

It is important to recognize that clinical signs in dogs with Addison’s disease are extremely vague and non-specific (6-8). Clinicians should have a high index of suspicion in any dog presented with vague signs of illness. table 1: pointers of canine addison's diseaseClinical signs may be acute or gradual in onset, may wax and wane in severity, and are sometimes triggered by a stressful event. Owners of affected dogs may not recognize how long their dog has been ill until treatment results in dramatic improvement in activity level. A history of episodic illness or gastrointestinal upset that improves with supportive care should alert the clinician to the possibility of Addison’s disease. The spectrum of clinical signs observed is shown in Table 1. It is important to remember that the majority of the clinical signs can be caused by glucocorticoid deficiency alone, although hypovolemic shock and collapse are usually only observed in dogs deficient in both glucocorticoids and mineralocorticoids.

What changes on the minimum database should alert me?

Abnormalities that may be present on the CBC, biochemical panel, and urinalysis in dogs with hypoadrenocorticism are shown in Table 2. table 2: clinico-pathological changes observed in dogs with addison's diseaseIt is important to recognize that the constellation of abnormalities observed may mimic other diseases such as: hepatic failure, renal failure, insulinoma, or protein-losing enteropathy (9,10).

Haematology: the most common haematologic abnormality found in dogs is the absence of a stress leukogram (an increase in neutrophils without a left shift and a decrease in lymphocytes and eosinophils as a result of systemic stress) which is an abnormal finding in the presence of systemic illness.

Serum electrolyte abnormalities: the most common findings on a serum chemistry panel are hyperkalaemia and hyponatraemia; however as many as 30% of dogs with Addison’s disease lack these classic electrolyte abnormalities (3,11,12). This presentation is called “atypical” or “glucocorticoid deficient” Addison’s disease, and may be due to secondary hypoadrenocorticism (ACTH deficiency), concurrent illnesses such as hypothyroidism or gastrointestinal disease, and selective destruction of the cortisol secreting zones (zona fasciculata and reticularis) of the adrenal cortex. Some Addisonian cases initially present with glucocorticoid deficiency alone, losing the ability to secrete mineralocorticoids some months later; however not all cases of glucocorticoid-deficient Addison’s progress to complete adrenocortical failure.

The Na:K ratio is usually low (<24) in dogs with hypoadrenocorticism, and a low ratio may increase the index of suspicion for Addison’s disease while waiting for definitive test results (13): however reliance on measurement of electrolytes alone for diagnosis of hypoadrenocorticism can be misleading, since there are many other causes of hyperkalaemia and hyponatraemia, and diagnosis should always be confirmed by an ACTH stimulation test. Conversely it is important to remember that electrolyte concentrations (and therefore the Na:K ratio) can be completely normal in dogs with Addison’s disease (3,11,12). Failure to consider hypoadrenocorticism as a differential diagnosis in patients with vague systemic signs of illness will result in a missed or incorrect diagnosis, leading to owner frustration or even patient death.figure 2: thoracic radiograph (ventrodorsal view) demonstrating microcardia in a five-year-old great dane with hypoadrenocorticism

Diagnostic imaging results in dogs with Addison’s disease may demonstrate microcardia (Figure 2), small cranial lobar pulmonary artery and posterior vena cava, and microhepatia (14). Reversible megaesophagus has also been observed. Ultrasonography may indicate small or undetectable adrenal glands (15) but since there is overlap with the size of normal adrenal glands, detection of normal sized glands does not rule out Addison’s disease, and the presence of small adrenal glands on ultrasound, although supportive of a diagnosis of hypoadrenocorticism, is not adequate for confirmation of the disease.

Electrocardiography: In Addisonian dogs that are hyperkalaemic, electrocardiographic changes may be present. In mild hyperkalaemia (>5.5 mmol/L) there is peaking of the T wave; with further increases (>6.5 mmol/L) there is widening of the QRS complex, decreased QRS amplitude, increased duration of the P wave, and increased P-R interval, and when the potassium increases above 8.5 mmol/L, there may be complete loss of P waves and ventricular fibrillation or asystole (Figure 3).

figure 3: ECG demonstrating changes expected before and after treatment if hyperkalaemia

Which endocrine testing should be performed to confirm the diagnosis?

Normal basal cortisol is a useful test to exclude a diagnosis of hypoadrenocorticism; however a low result is not adequate to confirm the diagnosis because some normal dogs have a low basal cortisol level yet have a normal response to ACTH administration (16).

The ACTH stimulation test (Figure 4) should always be performed in patients with suspected Addison’s disease prior to initiating long-term treatment. Once treatment has been initiated it is impossible to confirm the diagnosis retrospectively without withdrawing treatment for several weeks. figure 4: ACTH stimulation test. Lines depict a normal response, a response consistent with Addison's disease, and a response that is most consistent with exposure to exogenous corticosteroidsThe product of choice for performing the test is synthetic ACTH, administered at a dose of 5 μg/kg (maximum dose of 250 μg/dog) IV or IM (17). Blood samples for measurement of serum cortisol are collected prior to and one hour after administration of ACTH. If it is clinically necessary to administer corticosteroids prior to performing the ACTH stimulation test, dexamethasone should be used; one dose will cause some blunting of, but will not abolish, the response to ACTH. In dogs with spontaneous Addison’s disease, both the pre- and post-ACTH cortisol concentrations should be less than the reference range for basal cortisol (28-56 nmol/L) and in fact most cases show both the pre- and post-cortisol concentration to be < 28 nmol/L. Other causes of an inadequate or blunted response to ACTH stimulation include prior glucocorticoid administration, treatment with drugs such as mitotane, trilostane, or ketoconazole, loss of potency of the ACTH product, and errors in administration of ACTH.

Endogenous ACTH concentration is useful in dogs with confirmed glucocorticoid-deficient Addison’s disease. Measurement of an ACTH concentration above the reference range confirms a diagnosis of primary hypoadrenocorticism, while a level within or below the reference range is consistent with secondary hypoadrenocorticism. Dogs with primary atypical Addison’s disease are at risk for progression to complete adrenal failure, usually within 12 months of diagnosis; long-term monitoring of electrolyte concentrations after initial diagnosis is recommended.

Measurement of cortisol: ACTH ratio (CAR) has been proposed as an alternative diagnostic test for primary hypoadrenocorticism (18). In these cases ACTH concentrations are increased in the face of an inappropriately low cortisol concentration resulting in a very low cortisol:ACTH ratio. Further studies are necessary to evaluate the CAR in dogs with other illnesses that might undergo testing for hypoadrenocorticism.

COME BACK NEXT WEEK FOR THE SECOND HALF OF THIS ARTICLE... TREATMENT!

This article was kindly provided by Royal Canin, makers of a range of veterinary diets for dogs and cats.  For the full range please visit www.RoyalCanin.co.uk or speak to your Veterinary Business Manager:

References

1. Famula TR, Belanger JM, Oberbauer AM. Heritability and complex segregation analysis of hypoadrenocorticism in the standard poodle. J Small Anim Pract 2003; 44: 8-12.

2. Oberbauer A, Bell JS, Belanger JM, et al. Genetic evaluation of Addison’s disease in the Portuguese water dog, BMC Vet Res 2006; 2: 15-21.

3. Hughes AM, Nelson RW, Famula TR, et al. Clinical features and heritability of hypoadrenocorticism in Nova Scotia duck tolling retrievers: 25 cases (1994-2006). J Am Vet Med Assoc 2007; 231: 407-412.

4. Oberbauer A, Benemann KS, Belanger JM, et al. Inheritance of hypoadrenocorticism in bearded collies. Am J Vet Res 2002; 63: 643-647.

5. Kelch WJ, Smith CA, Lynn RC, et al. Canine hypoadrenocorticism (Addison’s disease). Comp Contin Educ 1998; 20: 921-935.

6. Peterson ME, Kintzer PP, Kass PH. Pretreatment clinical and laboratory findings in dogs with hypoadrenocorticism: 225 cases. J Am Vet Med Assoc 1996; 208: 85-91.

7. Medinger TL, Williams DA, Bruyette DS. Severe gastrointestinal tract hemorrhage in three dogs with hypoadrenocorticism. J Am Vet Med Assoc 1993; 202: 1869-1872.

8. Saito M, Olby NJ, Obledo L, et al. Muscle cramps in two standard poodles with hypoadrenocorticism. J Am Anim Hosp Assoc 2002; 38: 437-443.

9. Langlais-Burgess L, Lumsden JH, Mackin A. Concurrent hypoadrenocorticism and hypoalbuminemia in dogs: A retrospective study. J Am Anim Hosp Assoc 1995; 31: 307-311.

10. Adamantos S, Boag A. Total and ionized calcium concentrations in dogs with hypoadrenocorticism. Vet Rec 2008; 163: 25-26.

11. Thompson AL, Scott-Moncrieff JC, Anderson JD, et al. Comparison of classic hypoadrenocorticism with glucocorticoid-deficient hypoadrenocorticism in dogs: 46 cases (1985-2005). J Am Vet Med Assoc 2007; 230: 1190-1194.

12. Lifton SJ, King LG, Zerbe CA: Glucocorticoid Deficient Hypoadrenocorticism in Dogs: 18 Cases (1986-1995). J Am Vet Med Assoc 1996; 209: 2076-2081.

13. Adler JA, Drobatz KJ, Hess RS, et al. Abnormalities of serum electrolyte concentrations in dogs with hypoadrencorticism. J Vet Intern Med 2007; 21: 1168-1173.

14. Melián C, Stefanacci J, Peterson ME, et al. Radiographic findings in dogs with naturally-occurring primary hypoadrenocorticism. J Am Anim Hosp Assoc 1999; 35: 208-212.

15. Hoerauf A, Reusch C. Ultrasonographic evaluation of the adrenal glands in six dogs with hypoadrenocorticism. J Am Anim Hosp Assoc 1999; 35: 214-218.

16. Lennon EM, Boyle TE, Hutchins RG, et al. Use of basal serum or plasma cortisol concentrations to rule out a diagnosis of hypoadrenocorticism in dogs: 123 cases (2000-2005). J Am Vet Med Assoc 2007; 231: 413-416.

17. Lathan P, Moore GE, Zambon S, et al. Use of a low dose ACTH stimulation test for diagnosis of hypoadrenocorticism in dogs. J Vet Intern Med 2008; 22: 1070-1073.

18. Javardi S, Galac S, Boer P, et al. Aldosterone-to-renin and cortisol-toadrenocorticotrophic hormone ratios in healthy dogs and dogs with primary hypoadrenocorticism. J Vet Intern Med 2006; 20: 556-561.

19. Kintzer PP, Peterson ME. Treatment and long-term follow up of 205 dogs with hypoadrenocorticism. J Vet Intern Med 1997; 11: 43-49.

20. Melian C, Peterson ME. Diagnosis and treatment of naturally occurring hypoadrenocorticism in 42 dogs. J Small Anim Pract 1996; 37: 268-275.

 

This article was previously published on VetGrad.co.uk in 2011.

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