Hypoadrenocorticism can be classified as either primary or secondary.​​

The primary form of the condition, otherwise known as Addison’s disease, occurs as a result of destruction of the adrenocortical tissue itself. In most cases, this destruction appears to be immune mediated in origin. Rarer causes of destruction of the adrenal cortex include drug therapy with mitotane or trilostane, creating disease purposefully in order to treat another condition (i.e. by performing a bilateral adrenalectomy) and infectious / infiltrative disease.​​

Secondary hypoadrenocorticism occurs due to suppression of stimulatory hormone. Therefore, there is a deficiency in glucocorticoid due to a lack of production of ACTH. This can occur naturally, after surgery or can occur due to abrupt cessation of pharmaceuticals with glucocorticoid action.  More uncommonly, there can be state of secondary mineralocorticoid deficiency due to a lack of renin.​

The adrenal gland itself is split into a cortex and a medulla. The cortex compromises approximately 75% of the adrenal gland itself and more specifically is split into three regions: the innermost is the zona reticularis; next is the zona fasciculata; and the outer region is termed the zona glomerulosa (Figure 1). It is these three zones that are responsible for producing a range of steroid hormones. 

Figure 1- Diagram showing the architecture of the adrenal gland

Physiology of the Adrenal Glands

Aldosterone is the principle mineralocorticoid hormone and is produced by the zona glomerulosa. Its release is, in part, regulated by the renin-angiotensin system (Figure 2) and its major function is to control blood volumes by the regulation of body electrolytes. Dogs with a deficiency in aldosterone have low sodium and/or increased potassium levels alongside low blood volume. Clinically, this can manifest as dehydration, gastrointestinal signs, bradycardia and muscle weakness. 

Cortisol is the main glucocorticoid hormone secreted by the zona reticularis and fasciculata. Its release is under the control of ACTH secreted from the anterior pituitary, which in turn is controlled by CRH release from the hypothalamus (Figure 2). ​​​

Cortisol can be thought of as the hormone which protects the body against the long term effects of stress. Clinically, a deficiency in cortisol leads to weight loss, lack of appetite, anaemia and low blood sugar levels.

Figure 2 - Diagram depicting the regulation of Aldosterone and Cortisol

Although almost any dog, from a puppy to a geriatric patient, has the potential to be diagnosed with hAC, clues can be gained by assessment of signalment.

Primary hypoadrenocorticism is commonly diagnosed in younger to middle aged dogs and bitches appear more commonly affected than males. Breed is also thought to play a role, specific predispositions include:

• Standard Poodles
• Bearded Collies
• Nova Scotia Duck Tolling Retrievers
• Portuguese Water Spaniels
• Leonbergers
• Great Danes
• West Highland White Terriers
• Rottweilers
• Wheaten Terriers

Analysis into the mode of heritability of hAC appears to point to a genetic predilection in many of these breeds.

Dogs with hAC may present with a non-specific history of vague clinical signs which respond well to non-specific treatment.

Table 1 - Clinical Signs associated with hAC

Observed in almost all cases​	Observed commonly	Observed less commonly
Inappetence	Weakness	Weight loss
Lethargy / depression	Vomiting	Shivering / muscle stiffness ​
	Diarrhoea	Polyuria
		Polydipsia ​
		Regurgitation
		Melena, haematemesis, haematochezia

In particular, a clinician’s index of suspicion should be raised if a patient has responded very positively to intra-venous fluid therapy. However, due to the lack of specificity of clinical signs, hypoadrenocorticism can be easily confused with other, more common, diseases. This has led to hAC being given the colloquial nickname of ‘The Great Pretender’. Diseases which may present in a similar way to hAC include acute renal failure, acute pancreatitis, infectious enteritis and hepatitis to name a few (Table 2). ​ ​

 

Table 2 - Differential Diagnoses for Hypoadrenocorticism​

Body System / Organ	Examples​	Similarities in presenting signs ​
Urinary tract ​	Acute renal failure	Dehydration​
		Polyuria/Polydipsia​
		Vomiting ​
		Anorexia​
Exocrine pancreas	Acute pancreatitis ​	Abdominal pain
		Dehydration
		Vomiting
		Anorexia
		Diarrhoea
Gastrointestinal tract	Infectious enteritis​	Vomiting
		Anorexia
		Haemorrhagic Diarrhoea​
Hepatobiliary tract	Hepatitis	Vomiting
		Diarrhoea
Neuromuscular system ​	Myasthenia gravis ​	Episodic weakness​
		Regurgitation / vomiting​
Cardiovascular system​	3rd degree heart block ​	Bradycardia​
		Dullness
Endocrine system ​	Hypothyroidism ​	Bradycardia
		Dullness
Haematopoietic system ​	Anaemia	Pale mucous membranes​

 

The alternative presentation for dogs with adrenal insufficiency is in an acute adrenal crisis. This was previously known as an ‘Addisonian crisis’, however recent specialist recommendation discourages the use of this terminology (European Society of Veterinary Endocrinology ALIVE Committee, 2021) Many patients which present in an adrenal crisis will have a history of chronic non-specific disease, however, for some, this will be the initial presentation.​

Dogs suffering with an adrenal crisis often display:​

• Collapse​
• Generalised dehydration​
• Vomiting​
• Diarrhoea​​​

Some cases will display a lack of associated compensatory tachycardia, which again should increase suspicion for a clinician. However,it is important not to rule hypoadrenocorticism out on the basis of an increased heart rate. ​​

Without rapid appropriate treatment, hypoadrenocorticism can be fatal to these patients.​​

 

Routine haematology, biochemistry and urinalysis are recommended as the starting point for diagnosis of most endocrine conditions. This will rule out other causes of illness and often shows non-specific changes which will increase the index of suspicion.

Haematologically, a lack of a ‘stress leukogram’ in an unwell patient, and in particular the presence of a lymphocytosis or eosinophilia, should move hAC up the list of differentials. It is worth noting that results may still be within normal reference range, and this highlights the importance of looking at all parameters – even if deemed to be ‘normal’. Packed Cell Volume (PCV) can be variable in dogs with hypoadrenocorticism, some may show a non-regenerative anaemia, but this may be masked due to the presence of dehydration (Scott-Moncrieff, 2015)​.

As previously highlighted, the main biochemical abnormalities seen are electrolyte disturbances. Most cases will have a decreased sodium to potassium ratio (<27) due to a hyperkalaemia and a hyponatraemia. However, there are other disease processes which can lower this ratio – making it a non-specific finding. Equally, many routine biochemical blood profiles do not include electrolytes as standard, and where they do, the Na:K ratio is not automatically generated. Therefore a biochemical report may appear normal even if the patient truly has hAC.

An example is shown in Table 3. The absolute values for sodium and potassium sit within the reference range for this patient, therefore are not highlighted as abnormal on the biochemistry report. However, when the ratio is calculated it reveals a low value and therefore hypoadrenocorticism should still be included as a differential.

Table 3 - Sample electrolyte values

It is therefore sensible to consider both the individual electrolyte values with respect to their individual reference ranges and the sodium: potassium ratio when evaluating suspect cases.

Other changes in biochemistry which may be seen include azotaemia, decreases in albumin, glucose, cholesterol and chloride levels, alongside increases in ‘liver’ enzymes (ALKP, ALT and AST), phosphate and calcium (Peterson et al, 1996)​.

Typically, dogs with hypoadrenocorticism have a urine specific gravity (USG) of <1.030. This can complicate matters even further for the clinician. The presence of azotaemia, increased phosphate and low USG in an ill patient may point towards acute renal failure. This highlights the requirement for specific endocrine testing in these cases, without which it may be difficult to decide upon a definite diagnosis.

What is eunatraemic, eukalaemic hypoadrenocorticism?

The European Society of Veterinary Endocrinology ALIVE committee, define eunatraemic, eukalaemic hypoadrenocorticism as hAC with normal serum concentrations of potassium and sodium (European Society of Veterinary Endocrinology ALIVE Committee, 2021). Previously this type of hAC has been referred to as ‘atypical Addison’s disease’.

These dogs present with the same, often chronic, clinical signs of primary hAC, but do not have the characteristic changes in electrolytes. Other non-specific biochemical findings, such as hypocholesterolaemia and hypalbuminaemia may point towards disease, but diagnosis is challenging.

It is recommended to measure both aldosterone and endogenous ACTH in these cases in order to truly define the condition (see further detail below) and therefore such cases may benefit from the advice of an internal medicine specialist.

 

The combination of history, clinical signs and routine laboratory findings will often lead to increased suspicion of hypoadrenocorticism. However, specific endocrine testing is then required to confirm diagnosis.

The FAQs below answer common questions posed on the topic:

1. What is the best test to use to diagnose hypoadrenocorticism?

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

2. How do I undertake an ACTHST?

The ACTH stimulation test is a measure of adrenocortical reserve. The following protocol has been prepared by Dechra in combination with specialist laboratories. However, if you have any queries, we would recommend checking this protocol with your regular laboratory before carrying out the test.

1. Collect a basal blood sample (1-2 ml) and label this tube as ‘pre-ACTH’
2. Immediately inject 5 µg/kg synthetic ACTH (tetracosactide) IV / IM
3. Collect a second blood sample (1-2 ml) one-hour post injection of synthetic ACTH. Label tube as ‘post-ACTH’
4. Submit tubes and request form to the laboratory

3. How do I interpret an ACTHST?

A deficiency in post ACTH cortisol indicates the presence of hypoadrenocorticism. This usually equates to a value of   < 55 nmol/L (< 2 μg/dL) However, it is recommended that you consult your specific laboratory for reference ranges specific to your results.

Practically, however, most dogs with hAC will have a pre- and post-ACTH cortisol of < 27 nmol/L (< 1 μg/dL)

4. When might I get a false positive result for hypoadrenocorticism using the ACTHST?

Unfortunately, the administration of exogenous glucocorticoids before undertaking an ACTHST can lead to false positive results. It is therefore essential to gain a thorough history when undertaking a work-up for a suspected case of hAC, given that even small exposure to glucocorticoids can lead to suppression of the hypothalamic-pituitary adrenal axis which could be interpreted as a positive result for hAC.

Exogenous glucocorticoids are not limited to oral or injectable preparations, consideration should also be given to topical therapies (most often for the skin, ear or eye) and owner administered preparations.

5. When is measurement of aldosterone recommended?

By measuring cortisol after stimulation by ACTH, there is an assumption that this reflects all hormone production by the adrenal gland. However, isolated hormone deficiencies can occur. The only true way of knowing if a dog is able to produce mineralocorticoid is by measuring aldosterone itself.

This is done in the same way as the ACTHST, and can allow you to determine if aldosterone supplementation is truly required (this becomes most clinically relevant when deciding on a treatment plan for eunatraemic, eukalaemic hypoadrenocorticism – see below).

6. When is measurement of endogenous ACTH recommended?

As stated above, there are two main types of hypoadrenocorticism. Clinical signs can arise due to a deficiency in the adrenal gland itself (primary disease) or due to a deficiency of stimulation by the pituitary (secondary disease).

It is possible to differentiate between primary and secondary disease by the measurement of endogenous ACTH (eACTH).

In primary disease, (including eunatraemic, eukalaemic hypoadrenocorticism), eACTH should be elevated, as the pituitary detects the low circulating levels of cortisol and releases ACTH compensate.

In secondary disease, eACTH will be low, as it is a failure of ACTH production which is the cause of disease.