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Topic #7: Addison’s disease (Adrenal gland insufficiency) The basics of Addison’s – a problem for Westies and people Addison’s disease, also known as hypoadrenocorticism, is an uncommon condition in which the patient’s adrenal glands no longer supply the body with very important hormones, called glucocorticoids and mineralocorticoids. These hormones help regulate metabolism and electrolyte balance in the body. According to the Merck Veterinary Manual (Merck, 2005) this disease develops with non­specific signs of gastroenteritis (vomiting and diarrhea), loss of body condition, lethargy and weakness, and inability to respond to stress in many affected dogs. Addison’s was first reported in a dog in 1953 but is the same condition as human Addison’s disease. It is a difficult condition to diagnose, as the symptoms can indicate many possible diseases. However, when it is properly diagnosed, effective treatment is available and dogs with Addison’s can lead healthy normal lives. How does this disease develop? The adrenal glands are complicated, multifunctional organs. There are two adrenal glands, one on top of each kidney (‘ad renal’ – near the kidney). The outer layer of the gland (the cortex) produces three types of hormones: glucocorticoids, mineralocorticoids and small amounts of sex hormones. The problem in Addison’s disease is a lack of production of the glucocorticoids and mineralocorticoids. Basic physiology of hormone release from the adrenals In the healthy animal, glucocorticoid production is regulated by the brain. The hypothalamus in the brain produces a hormone called corticotrophin releasing hormone (CRH) which stimulates another part of the brain, the pituitary gland, to release a hormone called adrenocorticotrophic hormone (ACTH). ACTH travels to the adrenal glands in the blood and stimulates them to release glucocorticoids in the form of cortisol. When there is a healthy amount of cortisol circulating in the blood, the brain stops sending the CRH and ACTH to stimulate the production of cortisol. This is called a negative feedback system. (The healthy level of cortisol in the blood is a negative influence on the production of more CRH and ACTH.) When there’s not enough cortisol in the blood, the hypothalamus and pituitary glad are stimulated to make more CRH and ACTH, respectively, and that production stimulates the adrenal glands to produce more cortisol until the blood levels reach a healthy value. In contrast, mineralocorticoids are not regulated by the brain, but are instead controlled by a system that starts with special cells in the kidneys, called
juxtaglomerular cells. These special cells can sense when blood pressure is too low, primarily by detecting the amount of sodium and oxygenated blood near them. When these cells detect inadequate flow and changes in blood composition, they will produce a chemical called renin, an enzyme which then reacts with another chemical in the blood, called angiotensinogen, and converts it to angiotensin I. With some help from the lungs, angiotensin I is converted to angiotensin II and it is angiotensin II which stimulates the adrenal glands to produce mineralocorticoids in the form of aldosterone. (Activated forms of angiotensin are very important in regulating blood pressure. They not only stimulate mineralocorticoids from the adrenal glands, but also can cause arteries and arterioles to constrict, raising blood pressure. It is pretty obvious that maintaining the right blood pressure helps dogs and people stay alive!) Addison’s disease can be either a primary or secondary adrenal insufficiency. In secondary adrenal insufficiency cases, the main problem starts in the brain, with insufficient production of either stimulating hormone, CRH or ACTH. Without enough CRH or ACTH to encourage the adrenal glands to produce cortisol, the glands think it’s not needed and they will begin to atrophy (shrink in size and reduce function). However, most cases of Addison’s are primary adrenal insufficiency, meaning that the adrenal glands have been damaged somehow and are no longer able to make cortisol and aldosterone, even when stimulated by CRH/ACTH and angiotensin II, respectively. Most veterinarians and physicians think that an autoimmune process is responsible for destroying the adrenal glands in canine and human patients with Addison’s. That means that the patient has developed antibodies (like those that are normally used to fight diseases like the flu, etc.) which attack and destroy their own adrenal cells. The triggers for the development of this autoimmune attack on the adrenals are not known, but are the subject of active research (see below). While auto­immune disease is uncommon, it is more likely in females; females are twice as likely to develop Addison’s as males. Unfortunately, Westies seem to be at a higher risk than other breeds for developing Addison’s, so there is likely to be some genetic component to the disease, as has been shown in other breeds. Very rarely, other events, such as granulomatous diseases (a special type of chronic inflammation), hemorrhagic infarctions (blood clots forming and lodging in the adrenals and other tissues), cancer of the adrenals or nearly tissues, and trauma can induce enough damage to the adrenal glands to cause Addison’s. What are common clinical signs of Addison’s disease in Westies and other dogs? The typical canine Addison’s patient is young to middle­aged (average age is 4­5 years old) and female. The most common sign that dogs show is lethargy. Affected dogs may seem listless, reluctant to exercise or even do normal activities, and may seem more tired and sleepy than they previously did. Many
of the signs of Addison’s are not specific to the disease and all relate to the deficiencies of glucocorticoids (cortisol) and mineralocorticoids (aldosterone). Because cortisol is important to the body’s metabolism, cortisol deficiency often manifests in a loss of appetite, vomiting, stomach pain, weight loss and lethargy. Aldosterone (the primary mineralocorticoid) enables the kidneys to retain sodium and excrete potassium, balancing the body’s electrolytes and maintaining proper blood pressure. With too little aldosterone, due to Addison’s disease, there is too little sodium in the blood and blood pressure drops due to insufficient circulating blood volume. Low blood pressure means all the patient’s organs won’t receive enough nutrients and will suffer. This effect is especially a problem for the kidneys. Patients with low blood sodium may lose weight, feel weak, have smaller than normal hearts and produce dilute­looking urine even though they may be dehydrated. High levels of potassium in the blood can cause heart rhythm problems (called ‘arrhythmias’), which can be life­threatening. Addison’s disease is usually a slowly worsening problem that may appear to wax and wane. Early cases may only become evident when the patient is stressed, such as from undergoing surgery, being sick or even boarding or showing. Other cases may manifest suddenly as an “Addisonian crisis” due to severe dehydration (signs of kidney problems) or heart problems. How is Addison’s disease diagnosed? Addison’s disease is a difficult disease to diagnose because of the myriad of signs dogs can have, and these signs are non­specific and can occur in many other diseases besides Addison’s disease. Blood tests can easily indicate whether a dog has low sodium and high potassium, which would raise the suspicion of Addison’s. When a veterinarian suspects Addison’s disease, he or she can run other fairly simple blood tests to confirm it. First, a base line cortisol level is measured in the blood. Then, the veterinarian will give the dog the hormone ACTH to mimic the pituitary gland’s secretion of ACTH. Healthy adrenal glands should respond to the ACTH like they would to naturally occurring ACTH from the pituitary and produce cortisol, raising the level of cortisol in the blood. The cortisol level in the blood is measured again one hour after administration of the ACTH. If the adrenal glands have not responded to the ACTH by raising the blood cortisol level, a diagnosis of Addison’s is made. While the ACTH stimulation test only tests cortisol levels, it is considered to indirectly assess aldosterone levels, since damage to the adrenal cortex should effect production of both hormones simultaneously. Unfortunately, the ACTH stimulation test does not distinguish between primary and secondary adrenal insufficiency. Patients with secondary adrenal insufficiency may eventually respond to enough ACTH given by the veterinarian, while those with primary adrenal insufficiency will not. Veterinarians may also use radiographs and electrocardiograms (measurements of the heart’s electrical output) to help make a definitive diagnosis of Addison’s disease.
Treatment – current thinking and successes Fortunately, Addison’s disease in can be effectively treated simply by giving patients the hormones they can’t produce themselves. Glucocorticoids can be replaced with prednisone (a manufactured form of the hormone) tablets given orally every other day. Mineralocorticoids can be replaced either with an injectable drug called desoxycorticosterone pivalate (DOCP) or fludrocortisone pills given twice daily. DOCP requires a trip to the vet’s office about once a month, while fludrocortisone may be given at home, like prednisone. While fludrocortisone is more convenient for owners, it does carry some side effects, such as increased urination, drinking, and possible incontinence. It is very important that owners of Westies with this disease provide an adequate supply of drinking water to meet the needs of the dog. This may require frequent refilling of water bowls or providing additional water bowls. Likewise, you and your veterinarian will have a discussion of the right diet, and especially the right amount of minerals like salt, that your dog will need. Working out the right treatment for each dog and owner is a process that may involve a few months of tweaking doses and making sure the dog’s blood work looks healthy. Fludrocortisone, while mainly a mineralocorticoid also has some glucocorticoid effects and some patients may not need additional glucocorticoid replacement while on fludrocortisone. Medications will need to be increased during times of stress for patients, such as boarding and travel. Treating Addison’s disease in your dog is a life­long commitment. Patients with this disease are dependant on their owners and veterinarians to provide the hormones their bodies need to sustain their metabolism and electrolyte balance, which are essential to life. The good news is that once patients with Addison’s are stabilized and properly diagnosed, they can lead healthy and normal lives. The average life span after diagnosis with Addison’s disease is approximately seven years (there is some individual variation) – about a typical life expectancy. Current research on Addison’s disease Recent research on Addison’s disease has focused on four areas: neurologic complications of treatment of Addisonian crisis, the genetic contribution to the disease, new tools for diagnosis and maintenance, and reviewing treatment options. Neurologic complications of Addison’s disease Treating hyponatremia (low serum sodium) is one of the major goals of addressing a hypoadrenocorticism emergency, or an Addisonian crisis. When dogs experience a ‘crisis’, they have very abnormal blood electrolyte levels and this can be life­threatening, especially in terms of cardiac and renal failure. Several recent case studies have illustrated the dangers of over­aggressive
treatment of dogs in crisis and rapid blood sodium level correction. One recent paper described a case of a 3­year­old mixed­breed dog in Addisonian crisis which was treated to restore cardiovascular stability and serum electrolyte balance. During treatment, this dog developed severe neurologic signs from rapid increases in serum sodium (Brady, et al, 1999). The dog eventually recovered fully, but brain lesions were demonstrated even at 23 weeks after the initial presentation. Another case study followed the treatment of an 18­month­ old Westie which was diagnosed with myelinolysis (breakdown of the material that covers nerves in the brain and spinal cord) caused by rapid administration of IV fluids (MacMillan, 2003). This study noted that existing literature varied on recommendations for electrolyte restoration and provides calculations for determining a safer restoration rate. A review article published in 2007 recommends correcting serum sodium at a rate no faster than12 mEq/L (milliequivalents/liter) per day (Meeking, 2007). The author recommended withholding mineralocorticoid administration until serum electrolyte balance has been restored, so as not to increase the rate of correction. New research into the genetics of canine Addison’s disease One of the main areas of interest in canine Addison’s disease is the suspected genetic inheritability of the disease. Recent research has indicated that the disease is “highly heritable” in Bearded Collies (Oberbauer, et al, 2002) and in Standard Poodles (Famula, et al, 2003). Another study proposed a “genetic comparison of Addison’s disease in the Portuguese Water Dog to the analogous disease in humans” (Chase, et al, 2006). These authors describe the genetic aspect as complex and similar in humans and dogs. When we speak about “inheritability” we need to mention that among the potential factors that might be inherited (passed in the genome) are:
· One or more mutations of genes controlling basic physiologic function of the brain (hypothalamus and pituitary) and adrenal glands
· One or more mutations controlling hormone secretion from these endocrine glands
· One or more mutations controlling tissue sensitivity to hormone effects
· One or more mutations controlling the structure of glands and tissues they effect
· One or more mutations that predispose individual dogs to developing automimmune disease
· And other effects not listed here! Genetic research for canine disease is a rapidly emerging field, now that the entire canine genome has been mapped. At the time of publication of this Topic, The Westie Foundation of America is seeking genetic samples from Westies to contribute to research on the genetic heritability of Addison’s (and other diseases) in the breed. See the Foundation’s website for more information on this and other studies. Understanding the role of the gene(s) that may contribute
to the development and progression of Addison’s disease in Westies and other dog breeds will help breeders and veterinarians prevent the disease. Advances in diagnosing Addison’s disease – responding to the challenge As we have mentioned, making the diagnosis of Addison’s disease can be a challenge for veterinarians. The signs are not pathognemonic (absolutely indicative of a particular disease) and vary from individual to individual. New tools for diagnosis have been a major interest in current research on Addison’s and will hopefully contribute to easier recognition of the disease. A recent paper reported on the ultrasonographic evaluation of adrenal glands in healthy and Addison’s patients (Hoerauf, et al, 1999). The authors found that Addison’s patients had shorter and thinner adrenal glands than healthy dogs, when examined with ultrasonography, and that these differences were statistically significant in the left adrenal glands. In the same year, a separate study examined imaging of other organs in Addison’s patients (Melian, et al, 1999). Melian and co­authors quantified the presence of radiographic abnormalities in dogs with Addison’s disease, using a variety of measurement and computational methods. According to there report, 81.8% of untreated dogs with primary hypoadrenocorticism had one or more radiographic abnormalities. These included small heart, small cranial lobar pulmonary artery, small vena cava and small liver. Renal blood flow may also be another tool for both diagnosis of Addison’s and management of the disease, since the kidneys are ultimately responsible for balancing serum electrolytes like sodium and potassium and also insuring the state of body hydration. Koch and co­authors measured intrarenal blood flow in a Tibetan terrier with Addison’s using duplex Doppler (Koch, et al, 1997), an imaging method that allows visualization and measurement of blood flow. They report that, using a “resistive index” system, blood flow can be used to evaluate proper control of Addison’s disease patients with pharmaceuticals. Once the disease was properly controlled with treatment, the patient’s resistive index fell within a normal range. Traditionally, the definitive diagnosis of Addison’s is made by measuring blood cortisol levels before and after administration of ACTH. Aldosterone is not typically measured but is assumed to be indirectly accounted for as most patients with hypoadrenocorticism have uniform damage to the adrenal cortex which affects the production of both hormones simultaneously. However, Thompson and co­workers, in a study on 46 dogs with hypoadrenocorticism, determined that 35 (76%) were deficient in both glucocorticoids and mineralocorticoids and that 11 (24%) were only glucocorticoid deficient. These results indicate a higher than expected presence of patients with only glucocorticoid deficiency. Two Westies were among the 11 patients with primary glucocorticoid deficiency (Thompson, et al, 2007).
Similarly, a paper by Javadi, et al, offered a new set of parameters for assessing Addison’s in dogs (Javadi, et al, 2006) This study measured the traditional plasma concentration of cortisol and of ACTH but also measured the concentration of aldosterone and renin. The authors found that while these values “overlapped” with those of healthy dogs, the cortisol­to­ACTH ratio and the aldosterone­to­renin ratio did not. These ratios definitively separated the two groups of dogs, allowing “the specific diagnoses of primary hypocortisolism and primary hypoaldosteronism.” Making progress in the treatment of Addison’s disease in dogs Research to develop new treatments for affected dogs has been very active for over a decade. Kintzer and Peterson published data on the long­term treatment of 205 dogs with Addison’s (Kintzer, et al, 1994). According to these authors, 190 dogs were initially treated with fludrocortisone acetate and treatment lasted a median of 2.6 years. Twenty seven (27) of these dogs were switched to DOCP due to “adverse effects, poor response or financial considerations.” Median treatment with DOCP was 3.5 years. 200 dogs were treated with prednisone but treatment was stopped in 22 dogs due to adverse effects. The good news is that 80% of cases were found to have a good to excellent response to therapy and the median survival time was 4.7 years, with choice of treatment making no difference. Unfortunately, 31% of cases had one or more signs of iatrogenic (caused by medical therapy) hyperadrenocorticism but these were generally resolved by decreasing or stopping prednisone or by switching to DOCP. Researchers in New Zealand may be offering a new treatment for Addison’s: licorice. Licorice contains glycyrrhizinic acid and its metabolite, glycyrrhetinic acid, can increase mineralocorticoid activity, as has been shown in humans. At the time of publication, the researchers had had success with a 4­year­old male with Addison’s but were seeking participants for a larger study (Jarrett, et al, 2005) In summary… Addison’s disease (hypoadrenocorticism) may be difficult to diagnose in early stages of disease, due to relatively non­specific clinical signs. However, once detected, it can be effectively managed through a combination of hormone replacement therapy, diet, good husbandry, and regular veterinary care. We need to find out why Westies, as a breed, seem to be more prone to develop this disease than many other dog breeds, but we are now using powerful diagnostic and genomic tools to do this. References and Resources
Brady CA, Vite CH, Drobatz KJ, “Severe neurologic sequelae in a dog after treatment of hypoadrenal crisis” J Am Vet Med Assoc. 215(2):222­5, 210, 1999 Chase K, Sargan D, Miller K, Ostrander EA, Lark KG, “Understanding the genetics of autoimmune disease: two loci that regulate late onset Addison's disease in Portuguese Water Dogs” International Journal of Immunogenetics 33(3):179­84, 2006 Famula TR, Belanger JM, Oberbauer AM, “Heritability and complex segregation analysis of hypoadrenocorticism in the standard poodle” Journal of Small Animal Practice 44:8, 2003 Feldman EC, Nelson RW, “Hypoadrenocorticism (Addison’s disease)” in Canine and Feline endocrinology and reproduction. 3 rd ed. Philadelphia. WB Saunders Co., 2004; 394­439 Greco DS, “Hypoadrenocorticism in small animals” Clinical Techniques in Small Animal Practice 22(1):32­5, 2007 Hoerauf A, Reusch C, “Ultrasonographic evaluation of the adrenal glands in six dogs with hypoadrenocorticism” Journal of the American Animal Hospital Association 35(3):214­8, 1999 Javadi S, Galac S, Boer P, Robben JH, Teske E, Kooistra HS, “Aldosterone­to­ renin and cortisol­to­adrenocorticotropic hormone ratios in healthy dogs and dogs with primary hypoadrenocorticism” Journal of Veterinary Internal Medicine 20(3):556­61, 2006 Jarrett RH, Norman EJ, Squires RA, “Licorice and canine Addison's disease” New Zealand Veterinary Journal 53(3):214, 2005 Kintzer PP, Peterson ME, “Diagnosis and management of primary spontaneous hypoadrenocorticism (Addison's disease) in dogs” Seminars in Veterinary Medicine and Surgery (Small Animal) 9(3):148­52, 1994 Kintzer PP, Peterson ME, “Treatment and long­term follow­up of 205 dogs with hypoadrenocorticism” Journal of Veterinary Internal Medicine 11(2):43­9, 1997 Koch J, Jensen AL, Wenck A, Iversen L, Lykkegaard K, “Duplex Doppler measurements of renal blood flow in a dog with Addison's disease” The Journal of Small Animal Practice 38(3):124­6, 1997 MacMillan KL, “Neurologic complications following treatment of canine hypoadrenocorticism” The Canadian Veterinary Journal 44(6):490­2, 2003
Meeking S, “Treatment of acute adrenal insufficiency” Clinical Techniques in Small Animal Practice 22(1):36­9, 2007 Melian C, Stefanacci J, Peterson ME, Kintzer PP, “Radiographic findings in dogs with naturally­occurring primary hypoadrenocorticism” Journal of the American Animal Hospital Association 35(3):208­12, 1999 Merck Veterinary Manual, 9 th edition, Kahn, CM, Line, S, (eds.), Merck & CO, Whitehouse Station, NJ, 2005, p.436­437 Oberbauer AM, Benemann KS, Belanger JM, Wagner DR, Ward JH, Famula TR, “Inheritance of hypoadrenocorticism in bearded collies” American Journal of Veterinary Research 63(5):643­7, 2002 Riesen SC, Lombard CW, “ECG of the Month. Atrial fibrillation secondary to hypoadrenocorticism” Journal of the American Veterinary Medical Association 229(12):1890­2, 2006 Thompson AL, Scott­Moncrieff JC, Anderson JD, “Comparison of classic hypoadrenocorticism with glucocorticoid­deficient hypoadrenocorticism in dogs: 46 cases (1985­2005)” Journal of the American Veterinary Medical Association 230(8):1190­4, 2007