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Addison’s disease

Ian Ramsey BVSc, PhD, DSAM, DipECVIM-CA, FHEA, MRCVS and Emma Roberts BVetMed (Hons) MRCVS Small Ani - 08/11/2016

Addison’s disease 

What is Addison’s disease (hypoadrenocorticism)?

Addison’s is a disease resulting from loss of production of corticosteroids, principally mineralocorticoids (mainly aldosterone) and glucocorticoids (mainly cortisol).

The most common cause of hypoadrenocorticism is primary hypoadrenocorticism, which is nearly always due to an immune-mediated destruction of the adrenal glands. This condition usually results in deficiencies of both glucocorticoids and mineralocorticoids, however cases of isolated glucocorticoid deficiency have been reported (atypical hypoadrenocorticism).

Secondary hypoadrenocorticism (caused by pituitary dysfunction) results in the deficiency of adrenocorticotropic hormone (ACTH). This is a very rare cause of canine hypoadrenocorticism and tends to result in glucocorticoid deficiency only.


The principal mineralocorticoid released by the zona glomerulosa of the adrenal cortex is aldosterone. The secretion of aldosterone is principally regulated by the renin-angiotensin system (which controls blood pressure in the body) and plasma potassium concentrations. Normally ACTH has only a permissive effect on aldosterone secretion. However pharmacological doses of ACTH, such as that used in an ACTH stimulation test, will induce the secretion of aldosterone. Aldosterone primarily acts on the proximal convoluted tubule in the kidney to increase sodium reabsorption and on the distal convoluted tubule to increase sodium reabsorption in exchange for potassium ions. Osmotic forces ensure that this results in an increase in water retention. Therefore aldosterone maintains blood volume by retaining sodium within the body and it also excretes potassium and hydrogen ions.

Aldosterone deficiency results in low sodium (hyponatraemia), high potassium (hyperkalaemia), increased hydrogen ions (acidosis) and low blood volume (hypovolaemia). Hypovolaemia causes poor renal perfusion and often pre-renal azotaemia. Acidosis, depression and microcardia can also develop. Ultimately ischaemic damage to the gastro-intestinal tract leads to severe vomiting, haemorrhagic diarrhoea and acute pancreatitis. Hyperkalaemia increases the threshold for action potential generation and causes depressed neuromuscular activity resulting in bradycardia and muscle weakness. The failure of sodium reabsorption in the nephron reduces the ability of the loop of Henle to maintain an effective concentration gradient leading to a polyuria and compensatory

polydipsia. Importantly, the urine that is produced may be isosthenuric or only minimally concentrated in such circumstances. This combination of relatively low urine concentration and azotaemia can easily be mistaken for renal disease.



The principal glucocorticoid released by the zona reticularis and zona fasciculate layers of the adrenal cortex is cortisol. Its secretion is regulated by ACTH, which is produced by the pituitary gland. Cortisol acts on virtually every tissue in the body and produces a range of effects, which may be best explained as a group in terms of improving the body’s defences against long term stress (particularly starvation), by mobilising amino acids and fat reserves. This leads to an increase in blood glucose by the breakdown of muscle and by acting against the body’s major anabolic hormone (insulin), as well as increasing fat deposits in the liver and subcutaneous tissues by mobilising fat reserves. It stimulates appetite, red blood cell production and suppresses some aspects of the immune and inflammatory responses, thereby protecting the body from the more deleterious long-term consequences of these responses. Cortisol is the body’s natural anti-pyretic and stimulates the production of scavenger proteins (such as albumin). Cortisol also has some effects on the amino acid metabolism and turnover of enterocytes as well as gastro-intestinal immunity.

Cortisol deficiency therefore results in anorexia, weight loss, anaemia, hypoalbuminaemia and hypoglycaemia. Depression is also associated with hypoadrenocorticism in humans and may be the result of the psychological effects of hypocortisolaemia as well as the metabolic abnormalities that have already been described. It is impossible to know if an animal is depressed but the behaviour of dogs with untreated hypoadrenocorticism would suggest that they suffer from something similar. Deficiency of cortisol may also affect gastro-intestinal motility and contribute to the vomiting, diarrhoea and inappetence seen in many cases of chronic hypoadrenocorticism.


Acute and chronic hypoadrenocorticism


Dogs with hypoadrenocorticism can present with a gradual onset of clinical signs e.g. intermittent bouts of vomiting and diarrhoea or they may present in an acute life-threatening state (hypoadrenocorticism crisis). Dogs presenting in crisis may also have had chronic clinical signs prior to the acute episode.


Clinical signs


Dogs with hypoadrenocorticism can display an array of clinical signs of varying severity that wax and wane, are non-specific and can be easily mistaken for other diseases e.g. renal disease, gastroenteritis including parvovirus infection, neuromuscular and metabolic diseases. Hypoadrenocorticism has been referred to as ‘the great pretender’. The table below shows the variability of signs that may be reported by owners of dogs with hypoadrenocorticism.


Almost all cases


Less common






Weight loss



Shivering/muscle stiffness












Melena, haematemesis or haematochezia


Physical examination


Due to the variety both in type and severity of clinical signs in cases of hypoadrenocorticism, physical examination findings can range from signs consistent with hypovolaemic shock e.g. prolonged capillary refill times, weak peripheral pulses, weakness or collapse to more subtle changes such as abdominal pain and dehydration. Some cases may not even have any abnormalities noted on clinical examination. It is worth noting that some dogs presenting in hypovolaemic shock may not have the expected tachycardia on examination due to the bradycardic effects of the hyperkalaemia.

The table below shows some of the physical examination findings that may be noted in dogs with hypoadrenocorticism1.


Almost all cases


Less common



Painful abdomen



Prolonged capillary refill time






Weak pulse





Differential diagnoses


As clinical signs/physical examination findings in canine hypoadrenocorticism can be non-specific, it can easily be confused with other diseases. Examples of these are shown in the table below2.


Body system / organ


Similarities in presenting signs

Urinary tract

Acute renal failure


Polyuria / polydipsia



Exocrine pancreas

Acute pancreatitis

Abdominal pain





Gastro-intestinal tract

Infectious enteritis (various)



Haemorrhagic diarrhoea

Hepatobiliary tract

Hepatitis (toxic, inflammatory)



Neuromuscular system

Myasthenia gravis

Episodic weakness


Cardiovascular system

3rd degree heart block


Episodic collapse

Endocrine system




Haematopoietic system


Pale mucous membranes





Haematological changes that are most likely to raise suspicion for hypoadrenocorticism are:


1) Lymphocytosis

2) Eosinophilia

3) Lack of a “stress leukogram” i.e. a normal neutrophil count in an obviously unwell animal


Glucocorticoids inhibit neutrophil departure from the circulation: they cause demarginalisation of neutrophils; promote the movement of lymphocytes out of the circulation and cause lymphocytolysis; and suppress eosinophil numbers by a variety of mechanisms. This results in the typical stress leukogram picture of neutrophilia, eosinopenia and lymphopenia.

In the absence of glucocorticoids in hypoadrenocorticism, dogs can have higher lymphocyte and eosinophil counts than what would be expected for the degree of illness and stress. Therefore, normal or even high eosinophil/lymphocyte counts in a dog that is expected to be stressed due to illness, as well as absence of a neutrophilia should prompt the inclusion of hypoadrenocorticism in the differential diagnosis list. Very occasionally a reverse stress leukogram can be seen.

The haematocrit/PCV in dogs with hypoadrenocorticism is variable. A non-regenerative anaemia is reported to occur in approximately 15% of cases, however dogs presenting in crisis tend to have higher values due to relative erythrocytosis secondary to dehydration/hypovolaemia1.




There are many biochemical changes of varying magnitudes that can occur in hypoadrenocorticism.

One study assessing clinical parameters in 225 dogs with hypoadrenocorticism prior to treatment, found the abnormalities below (with the percentage of dogs with these abnormalities in brackets)3:


1) Increased urea (blood urea nitrogen) (88.4%) and increased creatinine (65.6%)

Azotaemia is common in hypoadrenocorticism due to poor renal perfusion caused by hypovolaemia.

Hypovolaemia occurs as a consequence of the failure to preserve sodium and water due to the lack of aldosterone. Primary renal damage is uncommon in straightforward hypoadrenocorticism cases and the azotaemia is classified as “pre-renal”. In pre-renal azotaemia, urea (BUN) is commonly increased to a greater degree than is creatinine. Another possible explanation for a higher urea than would be predicted from the creatinine concentration is the presence of gastro-intestinal haemorrhage, which can also occur in these cases.


2) Metabolic acidosis (40.5%)

Mild metabolic acidosis is likely to be the consequence of reduced aldosterone mediated hydrogen excretion, hypovolaemia, hypotension and hypoperfusion.


3) Increased “liver” enzymes (ALKP, ALT, AST; 28.7-31.1%)

There are often mild increases in “liver” enzymes in dogs with hypoadrenocorticism. This may reflect the hepatic impact of reduced tissue perfusion perhaps in addition to portal challenges from compromised gastrointestinal mucosa. Primary hepatic pathology is unlikely to be a feature.


4) Hypoalbuminaemia (6.3%)

The mechanism by which some dogs with hypoadrenocorticism have low albumin is not understood.

Interestingly, it is more often observed in dogs that have normal electrolyte concentrations (that are not in crisis when they present), suggesting that it could be a finding that is masked by dehydration and hypovolaemia in the classic cases.


5) Hypoglycaemia (16.7%)

Glucocorticoids promote hepatic gluconeogenesis and reduce insulin sensitivity. Consequently, in the absence of glucocorticoids, reduced gluconeogenesis and increased insulin mediated uptake result in lower circulating glucose concentrations. The hypoglycaemia is not caused by increased insulin concentrations4.


6) Hypocholesterolaemia (7%)

The mechanisms by which a proportion of hypoadrenocorticoid dogs are hypocholesterolaemic are not clear. Glucocorticoids promote lipolysis and their absence may reduce the baseline level lipolysis and serum lipids. There may be reduced intestinal fat absorption. It has been noted that hypocholesterolaemia is more common in dogs with “glucocorticoid deficient” hypoadrenocorticism than typical hypoadrenocorticism5.


7) Urine Specific gravity < 1.030 (57.6%)

In the classic description of pre-renal azotaemia due to reduced renal perfusion, concentrated urine with a high urine specific gravity (USG >1.030) would be expected. However, dogs with hypoadrenocorticism commonly have a USG < 1.030. It is believed that the mechanism for this is due to chronic loss of sodium caused by the lack of aldosterone mediated sodium resorption, resulting in reduced renal medullary sodium, a reduced medullary concentrating gradient and compromised concentrating ability of renal collecting ducts.

The combination of azotaemia and poorly concentrated urine can make the differentiation between renal disease and hypoadrenocorticism challenging and endocrine testing to assess for the presence of hypoadrenocorticism should be considered in these cases.




The electrolyte changes that can be documented in hypoadrenocorticism (with the percentage of dogs with these abnormalities from one study on canine hypoadrenocorticism):3


1) Decreased sodium to potassium ratio (95.6%)

2) Hyperkalaemia (95.6%)

3) Hyponatraemia (81.3%)

4) Hyperphosphataemia (68.3%)

5) Hypochloraemia (41.7%)

6) Hypercalcaemia (30.7%)


A very high proportion of dogs with primary hypoadrenocorticism will have hyperkalaemia, hyponatraemia and/or reduced sodium to potassium ratio (< 27). The presence of a low sodium to potassium ratio raises suspicion for hypoadrenocorticism, however, there are other non-adrenal causes of low sodium to potassium ratios, so this finding is not diagnostically specific6,7.

Diagnostic specificity does increase progressively with lower sodium to potassium ratios, with a specificity of 96% reported at < 24 and 100% reported with a ratio < 238,9. It should be remembered however that dogs with atypical primary hypoadrenocorticism or secondary hypoadrenocorticism will not have electrolyte abnormalities, as their aldosterone production is unaffected. Electrolyte abnormalities are also not present in all cases of primary hypoadrenocorticism.

Hypercalcaemia is observed in a significant proportion of cases of hypoadrenocorticism, particularly in those that present in crisis. The mechanism is not clearly understood and different authors have recorded different findings concerning total and ionized calcium results. The hypercalcaemia documented can be due to total hypercalcaemia with or without concomittant ionized hypercalcaemia but ionized hypocalcaemia can also occur3,8,10. Decreased glomerular filtration rate and decreased urinary excretion of calcium have been suggested to occur but there are rarely derangements of PTH, PTHrP or vitamin D11.




Radiography may be indicated as part of the investigation of many of the presenting signs associated with hypoadrenocorticism. Radiographic findings in primary hypoadrenocorticism can include a small cardiac silhouette (microcardia) due to volume depletion, reduced diameter of the caudal vena cava and cranial lobar pulmonary artery and a small liver12. On very rare occasions a megaoesophagus may be seen.




Abdominal ultrasonography may also be indicated as part of the investigation of many of the presenting signs associated with hypoadrenocorticism e.g. to assess the pancreas with cases presenting with abdominal pain. It can be used to demonstrate a reduction in adrenal size, however such changes are not consistent13,14. Identification of adrenal glands can be technically challenging and therefore this can be operator dependent. The main modality of ultrasonography in these cases is mainly to assess for other disease processes that could be confused with hypoadrenocorticism e.g. pancreatitis and gastro-intestinal disease.




Electrocardiographic (ECG) changes are apparent in some cases of hypoadrenocorticism and develop because of the reduced conduction caused by the hyperkalaemia. ECG changes correlate poorly with the absolute potassium concentration because of the effects of hypercalcaemia (which protects the heart to some extent) and acidosis (which increases the extra-cellular potassium concentration). ECG changes include sinus bradycardia, a reduction (and eventual loss) of the P wave, an increase in T wave amplitude and a widening of the QRS interval. The absence of a bradycardia does not exclude hypoadrenocorticism.


Basal cortisol


Basal cortisol has been shown to be an effective screening test for hypoadrenocorticism in cases where this condition is considered as a differential. The use of a cortisol value ≤ 55 nmol/L resulted in a 100% sensitivity for diagnosing hypoadrenocorticism, however due to the poor specificity at this value (63.3%), an ACTH stimulation test should then be performed to confirm the presence of the disease15. Cases with a basal cortisol > 55 nmol/L are unlikely to have the disease and so other disease processes should be considered in these cases.


ACTH stimulation test


The ACTH stimulation test is the gold standard for diagnosing hypoadrenocorticism in dogs.


Interpretation of ACTH stimulation

• Post-ACTH cortisol results < 55 nmol/L (< 2 μg/dL) are positive.

• Most cases have pre- and post-ACTH cortisol < 27 nmol/L (< 1 μg/dL)


Subnormal responses

In some cases of naturally occurring hypoadrenocorticism, adrenal function can deteriorate more gradually and so, as the disease progresses, there may be varied stages of subnormal cortisol responses to ACTH. These subnormal responses may not be sufficiently abnormal to result in clinical signs. If there is sufficient dysfunction to result in clinical signs, it is expected that post-ACTH cortisol will be less than 55 nmol/L (< 2 μg/dL).


False positives

It should be remembered that individual dogs have differing degrees of hypothalamic-pituitary adrenal axis sensitivity to the suppressive effects of glucocorticoids (and glucocorticoid acting substances such as progestogens). Some dogs are very sensitive and reduce their production of cortisol in response to very low doses of exogenous glucocorticoids. All history relating to recent glucocorticoid exposure must be considered in the interpretation of a positive ACTH response test result including “minor” exposure such as topical, eye, ear and skin treatments including over the counter owner-sourced products. False positive results are seen commonly in these circumstances.


Exaggerated responses

When the cortisol response to ACTH is exaggerated, e.g. post-ACTH cortisol > 600 nmol/L, hypoadrenocorticism is excluded. However this exaggerated response should not be used as the basis for considering a diagnosis of hyperadrenocorticism. Dogs that are sufficiently ill to be suspected of hypoadrenocorticism will be sufficiently ill to generate abnormally high cortisol as part of the stress response to their illness, i.e. generate a false positive result for hyperadrenocorticism.




The traditional analyte of interest in ACTH stimulation is cortisol. However, this only assesses glucocorticoid production and not mineralocorticoid production. The inclusion of aldosterone measurement assists with:


1) determining the need for mineralocorticoid supplement and

2) the differentiation of primary from atypical primary or secondary hypoadrenocorticism.


• In primary hypoadrenocorticism, there will be no aldosterone response

• In secondary (pituitary) hypoadrenocorticism or atypical primary hypoadrenocorticism, there   

  will be an aldosterone response


Endogenous ACTH


In primary hypoadrenocorticism, the adrenal cortex has failed and both mineralocorticoid and glucocorticoid production are affected. However in atypical primary hypoadrenocorticism and secondary (pituitary dependent) hypoadrenocorticism, only the adrenal production of glucocorticoids but not mineralocorticoids is affected.

Endogenous ACTH (eACTH) can therefore be used to differentiate between atypical primary hypoadrenocorticism and secondary hypoadrenocorticism cases.

• In primary atypical hypoadrenocorticism (adrenocortical failure) eACTH will be high

• In secondary hypoadrenocorticism (pituitary failure) as well as iatrogenic hypoadrencorticism,  

  eACTH will be low

• Beware of possible false low results due to sample handling and shipping

Endogenous ACTH should be interpreted with the results of the ACTH stimulation test and not used in isolation to diagnose hypoadrenocorticism. Animals that are sick/stressed because of non-adrenal illness will have high values (but will not have a failure to stimulate cortisol by ACTH).


This article was kindly provided on behalf of Dechra Veterinary Products.








1. Melian, C & Peterson, M. E (1996) Diagnosis and treatment of naturally occurring hypoadrenocorticism in 42 dogs. The Journal of Small Animal Practice, 37(6), 268–275

2. Ramsey, I.K & Herrtage, M,E (2015) Adrenal gland diseases, BSAVA Manual of Small Animal Clinical Pathology (3rd Edition) Ed Villers E.J. & Ristic J.A. BSAVA publications, Gloucester

3. Peterson, M. E, Kintzer, P. P & Kass, P. H (1996) Pretreatment clinical and laboratory findings in dogs with hypoadrenocorticism: 225 cases (1979-1993). Journal of the American Veterinary Medical Association, 208(1), 85–91

4. Gow, A. G et al (2012) Insulin concentrations in dogs with hypoadrenocorticism. Research in Veterinary Science, 93(1), 97–99

5. Lifton, S. J, King, L. G & Zerbe, C. A (1996) Glucocorticoid deficient hypoadrenocorticism in dogs: 18 cases (1986-1995). Journal of the American Veterinary Medical Association, 209(12), 2076–2081

6. Nielsen, L et al (2008) Low ratios of sodium to potassium in the serum of 238 dogs. The Veterinary Record, 162(14), 431–435

7. Roth, L & Tyler, R. D (1999) Evaluation of low sodium:potassium ratios in dogs. Journal of Veterinary Diagnostic Investigation: Official Publication of the American Association of Veterinary Laboratory Diagnosticians, Inc, 11(1), 60–64

8. Adler, J. A, Drobatz, K. J & Hess, R. S (2007) Abnormalities of serum electrolyte concentrations in dogs with hypoadrenocorticism. Journal of Veterinary Internal Medicine / American College of Veterinary Internal Medicine, 21(6), 1168–1173

9. Seth, M et al (2011) White blood cell count and the sodium to potassium ratio to screen for hypoadrenocorticism in dogs. Journal of Veterinary Internal Medicine/ American College of Veterinary Internal Medicine, 25(6), 1351–1356

10. Adamantos, S & Boag, A (2008) Total and ionised calcium concentrations in dogs with hypoadrenocorticism. The Veterinary Record, 163(1), 25–26

11. Gow, A. G et al (2009) Calcium metabolism in eight dogs with hypoadrenocorticism. The Journal of Small Animal Practice, 50(8), 426–430

12. Melian, C et al (1999) Radiographic findings in dogs with naturally-occurring primary hypoadrenocorticism. Journal of the American Animal Hospital Association, 35(3), 208–212

13. Hoerauf, A & Reusch, C (1999) Ultrasonographic evaluation of the adrenal glands in six dogs with hypoadrenocorticism. Journal of the American Animal Hospital Association, 35(3), 214–218

14. Wenger, M et al (2010) Ultrasonographic evaluation of adrenal glands in dogs with primary hypoadrenocorticism or mimicking diseases. The Veterinary Record, 167(6), 207–210

15. Bovens, C et al (2014) Basal Serum Cortisol Concentration as a Screening Test for Hypoadrenocorticism in Dogs. Journal of Veterinary Internal Medicine / American College of Veterinary Internal Medicine, 1541–1545

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