The Physiology of Canine Addison's Disease

Contents

  1. The Physiology of Canine Addison's Disease
    1. Introduction
    2. Mechanism of the Hormone Imbalances in Addison’s Disease
      1. Mineralcorticoids:
      2. Glucocorticoids:
    3. Symptoms of Addison’s disease
      1. Most Common Symptoms:
      2. Symptoms that may occur:
      3. Addisonian Crisis
    4. Diagnosis
      1. Testing and Screening
      2. ACTH Stimulation
      3. Primary Hypoadrenocorticism or Secondary Hypoadrenocorticism?
    5. Treatment
      1. Maintenance
      2. Prognosis
    6. Bibliography
      1. Other Source Material
      2. Pictures

Introduction

Hypoadrenocorticism, also known as Adisson's disease, involves the deficiency of adrenocortiocid hormones. Addison's disease is an uncommon disease in dogs, it's mirror image Cushing's disease is far more common, which involves an overproduction of adrenocortiocid hormones. 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.

https://fbcdn-sphotos-f-a.akamaihd.net/hphotos-ak-xpf1/v/t1.0-9/10341495_10203972007593137_7909433475281359624_n.jpg?oh=2e356ad5b97cb592b50151fd5d028e00&oe=550F1CF6&__gda__=1428037513_2030f4e93b4d21ed62326bccdc48d286
Fig 1.
Healthy Dog.

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.

https://scontent-a-fra.xx.fbcdn.net/hphotos-xpa1/v/t1.0-9/10509767_10203972007633138_2196840489485609664_n.jpg?oh=c0df544cd0e2a288983ed94462e06a6b&oe=552055EE
Fig 2.
Primary Addison's.

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.

https://fbcdn-sphotos-d-a.akamaihd.net/hphotos-ak-xap1/v/t1.0-9/10352140_10203972007513135_4032215110361305063_n.jpg?oh=c6026d108a4bc41b946bb1eb029c2f50&oe=550AE74D&__gda__=1425943320_7c2ab9dd32602af96de2798db1953ba7
Fig 3.
Secondary Addison's.

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 al. (2013), 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. 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. Hypoglycaemia can be related to hypoadrenocorticism, but "the aetiology of hypoglycaemia associated with hypoadrenocorticism is poorly understood" (Gow et al., 2007). 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 imbalance and they can be quite varied. Symptoms are often described as “waxing and waning”, meaning that they come and go. Drawing from a number of sources, which are listed in the bibliography, the symptoms associated with Addison’s Disease are as follows:

Most Common Symptoms:

Symptoms that may occur:

According to Klein and Peterson (2010); “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, 2010). 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).

Diagnosis

The diagnosis of Addison’s disease is a task many veterinarians tend to fail, as the symptoms of the disease are so vague. “The Great Pretender” can mimic renal failure, gastro-intestinal failure as well as many neurological diseases (Klein and Peterson, 2010). In many cases, the disease is overlooked on account of its rarity; it appears to be most common in middle aged female dogs, but is generally an uncommon illness in canines (Klein and Peterson, 2010). However, this trend should not negate testing for the disease if suspicious.

Testing and Screening

The veterinary surgeon will undergo two main tests to eliminate or confirm Addison’s as a cause of the dogs ailments, of which have been previously mentioned. The first test is a screening to detect cortisol levels in the blood. A dog will naturally have a certain amount of physiological cortisol; this is referred to as the ‘basal level’. This basal level measures at approx. 1-2mcg/dl in healthy dogs (Klein and Peterson, 2010). If the test reveals a measurement below this, it signifies that not enough cortisol is being produced by the adrenal gland in the body.

Even though this outcome indicates Addison’s disease, it is important to be mindful that other non-adrenocortical diseases can cause this hypoadrenocorticism.

ACTH Stimulation

As Addison’s disease is a lifelong ailment that requires diligent daily care by the owners, it is important that it is confidently diagnosed. Therefore, the clinician proceeds with a second test called ‘ACTH stimulation’. This test is specific to Addison’s disease. Recalling the result of the previous test, it is known that cortisol is in low amounts. The following test is concerned with the functionality of the adrenal gland. ACTH is a pituitary hormone that transmits signals to the adrenal gland to make cortisol. If the result of the ACTH stimulation is negative i.e. a treated blood sample has unchanged cortisol levels both pre- and post- ACTH stimulation, it can be deduced that the patient has Addison’s disease (Klein and Peterson, 2010). In other words, the adrenal gland has been damaged, usually due to autoimmune disease and therefore has an inability to secrete the adrenocorticoids (mineralocorticoids and glucocorticoids).

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). In this case 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).

Treatment

Treatment is varied depending on the severity of the hypoadrenocorticism. In dealing with an Acute Addison’s 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).

Maintenance

The day to day treatment of Addison’s disease has two aims; to replace the missing steroid hormones and shield the dog from situations which require their use. The treatment entails refuelling the body with two very important classes of cortisol steroid hormones, mineralocorticoids (aldosterone) and glucocorticoids. Drugs such as Prednisone, DOCP (Deoxycortisosterone Pivalate) and Fludrocortisone are mineralocorticoid and glucocorticoid replacement supplements (Klein and Peterson, 2010). Glucocorticoids have a major effect on the electrolyte balance and therefore have a primary need for replacement in secondary hypoadrenocorticism (Klein and Peterson, 2010). Prednisone is used as a glucocorticoid replacement, and is injected into dogs both with secondary and primary hypoadrenocorticism.

The dosage varies from dog to dog and is tapered to the minimum amount that is effective without any side effects. The side effects include; weight gain, increased urination and increased thirst. Mineralocorticoids are only required in dogs suffering from primary hypoadrenocorticism i.e. they require both glucocorticoid and mineralocorticoid replacement (Klein and Peterson, 2010). The replacement drugs are DOCP and Fludrocortisone, which are administering into the body orally. Each supplement is equally as effective, and the longevity of the dog is not altered by either medication. DOCP is also less expensive and therefore may be the preference of some owners (Klein and Peterson, 2010).Owners must be made aware that the condition is heightened by their pet’s exposure to stressful situations. Dogs with Addison’s disease are not equipped with the hormones (cortisol) to cope with stress; hence it is imperative that the owner prevents a situation that may cause there dog stress. If it is not avoidable, the dose level of Prednisone can be increased by up to 10 fold.

Prognosis

The prognosis of Addison’s disease is excellent. With the accurate medication and well informed, vigilant owners there is no reason why a dog suffering from this condition cannot live a very long and happy life.

Bibliography

Other Source Material

Pictures

CanineAddisonsDisease (last edited 2014-12-04 10:00:39 by 2721E)