The Physiology of Canine Addison's Disease

Introduction

Addison's disease is quite an uncommon disease in dogs, Its mirror image Cushing's disease is far more common however it is important to examine Addison's in detail as it is so often misdiagnosed. This is due to its wide array of symptoms, and also due to the slow progress of chronic non-specific symptoms such as lethargy or loss of appetite. The failure to diagnose Addison's disease can lead to the death of pets if they encounter high levels of stress, from what is a very easily controlled disease. As it is due to a hormonal imbalance Addison's can be quite easily suppressed and crisis avoided by hormone therapy. Certain breeds are more susceptible to Addison's including; Great Danes, Poodles, West Highland white terriers, Portuguese water dogs, Bearded collies, Rottweilers’, Soft coated Wheaten terriers, Springer Spaniels, Basset hounds and Nova Scotia duck tolling retrievers. (Klein and Peterson 2010)

Mechanism of the Hormone Imbalances in Addison’s Disease

Adrenocorticotropic Hormone (ACTH) is secreted by the pituitary gland upon stimulus of Corticotropin Releasing Factor/Hormone (CRF/CRH) from the hypothalamus. Its Primary function is stimulating production of glucocorticoids and mineralocorticoids in the zona fasiculata and zona reticularis of the Adrenal cortex. To a lesser extent, it stimulates the production of aldosterone in the zona arcuata of dogs. The secretion of ACTH is controlled by negative feedback of glucocorticoids.

The synthesis pathway of ACTH from Pre-Proopiomelanocortin is common to other hormones such as the Melanocyte-Stimulating Hormone (MSH) family and internally produced opiod peptides. Therefore, ACTH cannot be produced without other metabolites of Pre-proopiomelanocortin also being produced.

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• Fig. 1 (Sheridan, 2014)

Hypoadrenocorticism is a term used to describe lowered levels of adrenocorticoids such as cortisol and aldosterone in the blood. When the Adrenal cortex is damaged, the decrease of levels of adrenocorticoids in the blood can no longer inhibit the production of ACTH via negative feedback, causing the pituitary to produce far higher amounts of ACTH. Most commonly the adrenal cortex is damaged by autoimmune diseases (Klein and Peterson 2010). Less common reasons for damage include granulomatous disease, hemorrhagic infarcts, metastases, amyloidosis, trauma and infections such as blastomycosis, coccidioidomycosis, or tuberculosis (Ettinger and Feldman, 2010). The increased synthesis of ACTH from Pre-Proopiomelanocortin causes elevated production of MSH. This hormonal imbalance and its symptoms are known as Primary Addison's disease.

Fig. 2 (Sheridan, 2014)

When hypoadrenocorticism is caused due to an underproduction of ACTH by the Pituitary or lack of CRH secreted from the hypothalamus, it is known as secondary Addison's disease, which is quite rare. This lack of ACTH causes atrophy of the zona reticularis and the zona fasiculata in the adrenal gland. However the zona arcuata continues producing mineralocorticoids. Secondary Addison's can be caused by trauma damaging the hypothalamus or the pituitary.

Fig. 3 (Sheridan, 2014)

Dogs with primary Addison’s with normal electrolyte concentrations were diagnosed with atypical Addison’s disease. This term is redundant. It was originally thought that atypical Addison’s resulted from the lack of damage to the zona glomerulosa and that these dogs had normal levels of aldosterone (Thompson et al. 2005). However, a study recently conducted by Baumstark et all, found the dogs, although they had normal serum electrolytes, they had decreased aldosterone levels, indicating that they had a mineralocorticoid deficiency (Baumstark et al. 2013) Therefore, the pathogenisis of atypical hypoadrenocorticism is no different from primary hypoadrenocorticism. Dogs in both categories have low adrenocorticoid levels. Therefore the term Atypical Addison’s disease cannot be described as a separate disease.

Mineralcorticoids:

Mineralcorticoids are produced in the zona arcuata of the adrenal cortex. The most important mineralcorticoid hormone is aldosterone.

Aldosterone has an important role in the regulation of sodium/potassium levels in the blood. It causes the reabsorption of sodium (Na⁺) ions and water into the blood and secretion of potassium (K⁺) ions in the distal tubules and collecting ducts of the kidney. Aldosterone also stimulates the sodium and potassium transporters, and the sodium/potassium ATPases (pumping proteins). Chlorine (Cl⁻) ions are also reabsorbed with sodium ions to maintain an electrolyte balance. Aldosterone also causes secretion of hydrogen (H⁺) ions in the distal tubules of the kidney. As well as aldosterone’s effect in the kidney, it also has similar effects on the intestines, salivary gland and sweat glands.

With a mineralcorticoid deficiency there will be an upset in the regulation of the dog’s electrolyte and water balance. Hyperkalemia, hyponatremia, and hypochloremia are the most common abnormalities among dogs with hypoadrenocorticism, particularly primary hypoadrenocorticism (Klein and Peterson, 2010). Hyperkalemia is a condition in which blood levels of K⁺ are high, hyponatremia is described as low Na⁺ levels, and hypochloremia is a condition with low Cl⁻ levels in the body. These abnormalities are due to the lack of aldosterone being produced. Due to inadequate amounts water being reabsorbed in the kidneys and the intestines, this results in diarrhoea and dehydration in the dog. It can also account for polydipsia (excessive thirst) and polyuria (excessive passage/production of urine). Renal sodium loss is accompanied by renal water loss, although water loss can be exacerbated by gastrointestinal losses (Klein and Peterson, 2010). In addition, low levels of aldosterone cause metabolic acidosis (increased acidity of the blood) due to lack of secretion of H⁺ ions in the kidney.

Glucocorticoids:

The main glucocorticoids produced in the adrenal cortex are cortisol and corticosterone. They play a vital role in accessing the body’s energy reserves, especially under conditions of stress. Glucocorticoids stimulate the breakdown of carbohydrates, proteins and fats. They have an anti-insulin effect and they stimulate glyconeogenesis, causing hyperglycaemia. “The aetiology of hypoglycamemia associated with hypoadrenocorticismis poorly understood” (Gow et al). They increase the rate of protein catabolism in every tissue and slow the rate of protein synthesis in order to have enough free amino acids for glyconeogenesis. The rate of lipid metabolism is increased in the peripheries causing an increase in the level of FFA's in the blood, an increase in the catabolism of fat and a redistribution of fat from the extremities of the body to the liver.

Insufficiency of Glucocorticoids can lead to; Hyponatremia and potentially water poisoning, hypovolemia, hyperkalemia and cardiac weakness, muscular weakness and lethargy, and oedema due to an increased permeability of the capillaries. Lack of glucocorticoids can also attribute to depression of the dog. It also lowers the dogs’ ability to cope with stress and can lead to an Addisonian crisis.

Symptoms of Addison’s disease

The symptoms of Addison's disease are due to the hormone deficiencies or overproduction and can be quite varied. Symptoms are often described as “waxing and waning”, meaning that they come and go. Addison’s disease can also be referred to as “The Great Pretender” as its symptoms are so vague and can be common to several other conditions, such as renal failure or intestinal diseases. Drawing from a number of sources, which are listed in the bibliography, the preceding table outlines the symptoms associated with Addison’s Disease:

Most Common Symptoms:

• Poor appetite/Anorexia
• Depression/Lethargy
• Vomitting
• Weakness
• Weight loss
• Diarrhoea
• Dehydration (Polyuria and Polydipsia)

Symptoms that may occur:

• Melana (Black faeces, blood in the faeces)
• Hematemesis (Blood in the vomit)
• Bradycardia (Slow heart rate)
• Weak pulse
• Slow capillary refill
• Hair loss
• Hypothermia
• Shaking/Tremors
• Collapse
• Painful/Sensitive abdomen

According to Klein and Peterson; “among dogs with hypoadrenocorticism, the most common clinical signs reported by caregivers include poor appetite/anorexia (88% to 95%), lethargy/depression (85% to 95%), and vomiting/regurgitation (68% to 75%). Other clinical signs include weakness (51% to 75%), weight loss (40% to 50%), diarrhea (35%), polyuria/polydipsia (17% to 25%), shaking/shivering/tremors (17% to 27%), collapse (10%), or a painful abdomen (8%). Hematemesis, hematochezia, melena, ataxia, seizures, and difficult breathing have also been reported (11), as has prior response to nonspecific fluid or corticosteroid therapy (35%) (28). Hair loss has been rarely reported (5%) (28). Episodic muscle cramps in both the thoracic and pelvic limbs were reported” (Klein and Peterson, 2010)

Clinical features that should heighten the index of suspicion of hypoadrenocorticism include a normal or slow heart rate in the face of circulatory shock, a previous response to corticosteroid or fluid therapy, and a “waxing and waning” course of disease before collapse (Greco, 2007). Symptoms of Addisons may not show up for a long period of time, or they may appear suddenly.

Addisonian Crisis

Due to the fact symptoms of Addison’s disease may not show any clinical signs for a long period of time, a dog suffering from it may not be diagnosed and treated on time. Under conditions of stress for the dog, such as fighting, boarding an aeroplane, being put into kennels etc., can lead to a severe case of acute adrenocorticoid insufficiency called Addisonian crisis.

This is a medical emergency due to severe hypovolemia, dehydration, hypotension, electrolyte derangements, and acid-base abnormalities (Klein and Peterson). Physical examination of animals with acute Addisonian crisis reveals weak pulses, bradycardia, prolonged capillary refill time, severe mental depression and profound muscle weakness (Greco, 2007). Treatment should be sought immediately in the case of Addisonian crisis. Treatment includes repairing the body’s electrolyte imbalance and the hypotension, hypovolemia and acid-base balance of the body. Addisonian crisis can cause death by hypovolemia and shock (Klein and Peterson, 2010).

The first priority is therefore to rapidly correct hypovolemia and perfusion with large volumes of intravenous fluids (Greco, 2007). The dog should be given appropriate amounts corticosteroid supplementation (Klein and Peterson, 2010). Continuous monitoring of the dog is essential to ensure the dog recovers fully. It is ideal to make sure that the patient remains stable for 24 hours off fluids and parenteral medications prior to discharge (Klein and Peterson, 2010).

Testing for Addison’s Disease

A series of tests must be carried out to confidently diagnose a patient with Addison’s disease. Firstly, a basal serum/plasma cortisol level test is performed. A canine has a set basal level of cortisol in its blood plasma, if the results show a level of cortisol below 1-2mcg/dl, hypoadrenocorticism may be the cause (Klein and Peterson, 2010). However, this is simply a screening test; there are non-adrenocortical illnesses which can also lower the resting cortisol level. As Addison’s disease is a lifelong ailment a positive result for this test must be ensued by the ACTH stimulation test. (Klein and Peterson, 2010)

ACTH stimulation

Blood samples are taken before administration of the ACTH and one hour after. If there no significant changes to the cortisol levels pre- and post- ACTH stimulation, hypoadrenicorticism l can be deduced. (Klein and Peterson, 2010)

Primary Hypoadrenocorticism or Secondary Hypoadrenocorticism?

Even though ACTH stimulation confirms canine hypoadrenocorticism, it does not determine which type; primary or secondary hypoadrenocorticism. It is very important, in respect to the follow on treatment that the differentiation is made in all dogs diagnosed with Addison’s disease (Klein and Peterson, 2010). To do this the endogenous plasma ACTH concentration is measured. If the results show a high concentration this indicates the absence or lack of inhibition of cortisol on the ACTH secretion, and therefore represents primary hypoadrenocorticism. In contrast, secondary hypoadrenocorticism will show a low endogenous ACTH concentration as there has been a decreased release of ACTH from the pituitary gland. (Klein and Peterson, 2010)

Cortisol-to-ACTH Ratio (CAR)

The measurement of Cortisol-to-ACTH Ratio (CAR) is a new method that can determine primary hypoadrenocorticism. A single blood sample is tested, where a low CAR equates to the disease. This is a major step towards making this disease more easily diagnosed. (Lathan and Montcrieff, 2014) The process of CAR testing is much simpler than ACTH stimulation, and does not require Cosyntropin, making it less of a fiscal hindrance for both clinician and owner. (Lathan and Montcrieff, 2014) However, as of yet, this method is not as widely used as ACTH stimulation.

Treatment for Addison’s Disease

Treatment is varied depending on the severity of the hypoadrenocorticism

Acute Adrenocortical Insufficiency Treatment

In an Acute Addisonian Crisis emergency action must be taken. First and foremost, the dog is stabilised with an infusion of sodium chloride or lactated Ringers solution. This addresses hypovolemia and hypotension. The sodium chloride solution also dilutes the blood aiding with the hyperkalaemia, while increasing the sodium levels. However, caution must be taken to administer the solution slowly, as fast perfusion leads to a risk of neurological damage developing. Fluid therapy is continued after blood pressure, volume and electrolytes have normalised, until the dog is eating again (Klein and Peterson, 2010).

Chronic Treatment: Maintenance

Patients suffering from Primary Hypoadrenocorticism require mineralocorticoids and glucocorticoid supplementation, to regulate electrolyte levels. Secondary hypoadrenocorticism only requires glucocorticoids (Klein and Peterson, 2010) However secondary hypoadrenocorticism patients usually develop electrolyte abnormalities later in life and therefore require routine check-ups (Klein and Peterson, 2010). Prednisone is used as a glucocorticoid replacement. It is used for both primary and secondary Hypoadrenocorticism. The dosage varies from dog to dog and is tapered to the minimum amount that is effective without any side effects; this dose is approx. 0.2 -0.25 mg/kg/d (Klein and Peterson, 2010). The side effects include; weight gain, increased urination and increased thirst. During times of stress, cortisol is released, as there is a lack of this steroid hormone in Dogs with Addison’s disease, the animal cannot cope well with stress. Stress inducing situations should be avoided at all costs. If this is impossible, Prednisone dosage should be increased by 10 -20 fold (Klein and Peterson, 2010).

In the case of primary hypoadrenocorticism, DOCP and Fludrocortisone acetate are used as a supplement of mineralocorticoids. Each supplement is equally as effective, and longevity of the dog is not altered by either medication. In some dogs, Fludrocortisone acetate has been known to cause hypocholesterolemia in patients when initially taken, therefore a change to DOCP is undertaken. DOCP is also less expensive and therefore may be the preference of some owners (Klein and Peterson, 2010)

Prognosis

The prognosis of Addison’s disease is excellent, of course only in accordance with great vigilance and dedication of the caregivers. Therefore, the education of the owner about their pet’s inability to cope with stress, along with correct and routine administration of their medication is the key for the dog to have a long and happy life.

Bibliography

• Ettinger, SJ. and Feldman, EC. (2010) Textbook of veterinary internal medicine. Philadelphia: WB Saunders

• Klein, SC. and Peterson, ME. (2010) Canine hypoadrenocorticism',The Canadian veterinary journal, 51 (1), pp.64. available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2797351/?tool=pmcentrez [Accessed 20/11/2014]

• Greco, D. (2007) ‘Hypoadrenocorticism in Small Animals’, Clinical Techniques in Small Animal Practice, 22, pp. 32-35. Available at: http://www.2ndchance.info/addison's-Greco2007.pdf [Accessed on 20/11/2014]

• Gow, AG et al (2011) ‘Insulin concentrationin dogs with hypoadrenocorticism’, Research in Veterinary Science, (93) pp. 97-99. Available at: http://ac.els-cdn.com.ucd.idm.oclc.org/S0034528811001731/1-s2.0-S0034528811001731-main.pdf?_tid=7c47f20a-7345-11e4-8a85-00000aab0f01&acdnat=1416770480_2607d8ff1657c660707fbda59eda7fd6 [Accessed on the 20/11/2014]

• Thompson, AL et al (2007) ‘ Comparison of classic hypoadrenocorticism with glucocorticoid-deficient hypoadrenocorticism in dogs: 46 cases (1985–2005).’ Journal of the American Veterinary Medical Association 2007;230:1190–1194.

• P.Lathan, J.C. et al (2014). ‘Use of Cortisol-to-ACTH Ratio for Diagnosis of Primary Hypoadrenocorticism in Dogs’, Journal of Veterinary Internal Medicine, vol.28, no.5, pp. 1546-1550.

• The Physiology and Biochemistry Department. (2014) Endocrinology [Lecture to 3rd Semester Veterinary Students], SAOEB04EN: Physiology II. Szent István Faculty of Veterinary Medicine, Budapest. Available at: http://www.vetphysiol.hu/eng/lecturenotes.php [Accessed on 21/11/2014]

Other Source Material

• Feldman, EC. and Nelson, RW. (1996). Canine and Feline Endocrinology and Reproduction (ed 2). Philadelphia: WB Saunders

• Peterson, ME. and Kintzer, P. (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

Pictures

• Sheridan, JH. (2014) Diagrams: Normal Function, Primary Addison's, Secondary Addison's.