Diagnosis and Management of Addison's Disease in a Swiss Mountain Dog
Dana A. Hardisky
Clinical Advisor: Dr. Pedro Bento
Pre-Clinical Advisor: Dr. John Randolph
Senior Seminar Paper
Cornell University College of Veterinary Medicine
May 7, 2014
Abstract
A 6-year-old female spayed Swiss Mountain dog was referred to the Small Animal Internal
Medicine Service of the Cornell University Hospital for Animals by the Community Practice
Service for a one-year history of waxing and waning gastrointestinal signs and a several month
course of lethargy. Routine hemogram and serum biochemistry profile revealed findings
suggestive of primary hypoadrenocorticism (Addison's disease). Baseline cortisol concentration
was subsequently discovered to be subnormal.
On presentation to the Small Animal Internal Medicine Service, the dog was bright, alert, and
responsive with no abnormalities detected on physical examination. Serum electrolyte panel
confirmed the previously detected hyperkalemia. Cortisol concentration following administration
of exogenous ACTH was subnormal. Endogenous ACTH concentration was increased.
These collective findings were indicative of primary hypoadrenocorticism (Addison's disease).
Mineralocorticoid (desoxycorticosterone pivalate [DOCP]) and glucocorticoid (prednisone)
replacement therapy was initiated. The dog has been well controlled on these medications for the
past three months.
Introduction
Primary hypoadrenocorticism or Addison's disease is an uncommon, but well described,
endocrinopathy in dogs. It results from presumed immune-mediated destruction of the adrenal
cortices, leading to body wide deficiencies in mineralocorticoids (aldosterone) and
glucocorticoids (cortisol).1 Destruction of the adrenal cortices must be significant with 85% to
90% of the adrenocortical tissue destroyed before clinical signs ensue.4 Addison's disease can be
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suspected on finding a subnormal baseline cortisol in an ill dog. However, definitive diagnosis is
based on finding subnormal cortisol concentrations before and after administration of exogenous
ACTH in conjunction with abnormal electrolyte concentrations (hyponatremia, hyperkalemia,
hypochloremia, sodium to potassium ratio <24:1) accompanying aldosterone deficiency.2 Low
aldosterone concentration can also be used to diagnosis hypoadrenocorticism in conjunction with
the above mention diagnostic tests, however this method is seldom used. Measuring aldosterone
concentrations can be particularly helpful in cases of atypical hypoadrenocorticism where normal
concentrations of potassium, sodium, and chloride are observed.3
Familial tendency for Addison's disease has been described in some dog breeds including the
Standard Poodles, Portuguese Water Dogs, and Nova Scotia Duck Tolling Retrievers.4,5 These
dog breeds have been used as research models in human medicine studies to determine if specific
mutated genes can be linked to primary hypoadrenocorticism. However, the most commonly
diagnosed dogs with Addison's disease are young to middle age females of a mixed breed
origin.4 Dogs with Addison’s disease can be effectively managed long term on mineralocorticoid
and glucocorticoid replacement therapy with an excellent quality of life.
Signalment, Chief Compliant, Case History, Clinical Findings
A 6 year old spayed Swiss Mountain dog presented to the Emergency Service of the Cornell
University Hospital for Animals for vomiting, diarrhea, and hyporexia. Quick assessment tests
revealed mildly elevated total protein (8.2 g/dL, reference range 5.9 -7.8 g/dL). Fecal wet mount
disclosed roundworm infection. The dog was administrated 1000 mL of sodium chloride fluids
subcutaneously and sent home on a course of fenbendazole and metronidazole.
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Thirty-five days later, the dog presented to the Community Practice Service of the Cornell
University Hospital for Animals for 3 days of anorexia, hematochezia, and lethargy. Blood was
drawn for complete blood count, serum biochemistry profile, thyroxine concentration, and 4Dx
SNAP test. Fecal floatation and gram stain of fecal smear were also performed. The 4Dx
SNAP test was negative for heartworm, anaplasma, borrelia, and ehrlichia. Fecal gram stain and
floatation did not show any evidence of bacterial overgrowth or intestinal parasites. Complete
blood count disclosed mature neutrophilia (9.6 thou/µL, reference range 2.7 – 9.4 thou/µL).
Serum biochemistry profile revealed mildly elevated total protein (7.3 g/dL, reference range 5.3
– 7.0 g/dL), mildly elevated aspartate aminotransferase activity (66 U/L, reference range 14 -51
U/L), hypercholesterolemia (675 mg/dL, reference range 138-332 mg/dL), and mildly elevated
creatine kinase (486 U/L, reference range 48-261 U/L). Thyroxine concentration was decreased
(< 0.05 µg/dL, reference range 1.5-3 µg/dL). The dog was diagnosed with hypothyroidism and
enteritis, and was discharged on metronidazole, fenbendazole, and famotidine for the enteritis
and levothyroxine for the hypothyroidism. Within the next several days, resolution of the
gastrointestinal signs was noted. The dog continued to be monitor by the Community Practice
Service during the next year where dose adjustments were occasionally made in the dose of
levothyroxine.
Approximately one year following the diagnosis of hypothyroidism, the dog represented to the
Community Practice Service with vague signs of lethargy and hyporexia. Again, a variety of
diagnostic tests including complete blood count, serum biochemistry profile, and baseline
cortisol concentration were conducted. Complete blood count revealed normocytic,
normochromic non – regenerative anemia (Hct 38%, reference range 41-58%; MCV 71 fL,
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reference range 64-76 fL; MCHC 26 pg, 21-26 pg; absolute reticulocyte count 77.2 thou/µL,
reference range 11-92 thou/µL). Serum biochemistry profile disclosed hyperkalemia (6.1
mEq/L, 142-150 mEq/L), low sodium potassium ratio (24:1, reference range 27:1 – 40:1), mild
azotemia (creatinine 1.6 mg/dL, reference range 0.6 – 1.4 mg/dL; BUN 30 mg/dL, reference
range 10-32 mg/dL), and hypocholesterolemia (99 mg/dL, reference range 138-332 mg/dL).
These collective findings prompted investigation of baseline cortisol concentration which was
subnormal (< 0.2 µg/dL, reference range 1.8-4.0 µg/dL).
At this point, hypoadrenocorticism was suspected and the dog was referred to the Small Animal
Internal Medicine Service of the Cornell University Hospital for Animals for further evaluation
of laboratory findings and diagnostic work –up. Recheck electrolyte panel confirmed
hyperkalemia (5.6 mEq/L, reference range 3.8 – 5.4 mEq/L). To confirm a definitive diagnosis
of hypoadrenocorticism, an ACTH stimulation test was performed. The pre ACTH cortisol level
was again subnormal (< 0.2 µg/dL, reference range 1.8-4.0 µg/dL). The post ACTH cortisol
level was also subnormal (< 0.2 µg/dL; reference range 7.0-16.0 µg/dL), confirming a definitive
diagnosis of Addison’s disease. An endogenous ACTH concentration was elevated (322 pg/mL,
reference range 0-25 pg/mL) further supporting primary hypoadrenocorticism.
Problem List & Differential Diagnosis
The problem list in this case includes hyperkalemia, hypocholesterolemia, waxing and waning
gastrointestinal signs, lethargy, low baseline cortisol concentration, prerenal azotemia, and
normocytic, normochromic, non – regenerative anemia.
Hyperkalemia can be a hallmark finding in Addison’s disease. When aldosterone is no longer
produced, potassium secretion decreases leading to hyperkalemia. Addison’s disease is
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frequently characterized by sodium to potassium ratio of <24:1.6 Other common causes of
hyperkalemia include gastrointestinal disease (such as Salmonella and Trichuris infections),
acidosis, urinary obstruction, and renal disease.7
Hypocholesterolemia is related to the body’s function to facilitate intestinal fat absorption via
cortisol.4 Without cortisol, this cannot be accomplished. Other causes for hypocholesterolemia
include liver disease, intestinal malabsorption, exocrine pancreatic insufficiency, and certain
neoplastic diseases (eg, histiocytic sarcoma).
Waxing and waning gastrointestinal signs in Addisonian dogs result from a lack of cortisol.
Cortisol plays a key role in stabilizing membranes and endothelium, thus diarrhea (sometimes
hemorrhagic) may develop. Other considerations for intermittent gastrointestinal signs included
dietary indiscretion, primary gastrointestinal disease, pancreatitis, and liver disease.
Lethargy was part of the problem list for this dog. However, the vagueness of this clinical sign
results in innumerable possible different diagnoses.
Low baseline cortisol concentration was found during diagnostic work - up of this case. The
subnormal baseline cortisol was the result of hypoadrenocorticism based on further investigation
with the ACTH stimulation test. Normal variation of cortisol was also considered for the
subnormal baseline value. However, very low values such as (˂ 0.2 µg/dL), are unlikely to
represent a normal variation of baseline cortisol.
Prerenal azotemia, seen in the dog of this report, is a common finding with Addison’s disease.
Azotemia in dogs with hypoadrenocorticism results from deficiencies of both aldosterone and
cortisol. When sodium is lost in excessive volumes due to lack of aldosterone, water will follow.
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Body wide water lost leads to hypovolemia and decrease renal perfusion causing the buildup
creatinine and urea nitrogen.4 Lack of cortisol causes decreased peripheral vascular tone leading
to hypotension and poor renal perfusion. Additional differential diagnoses for azotemia included
renal disease and dehydration.
The final problem noted in our patient was normocytic, normochromic, non – regenerative
anemia. Cortisol stimulates hematopoietic cells in the bone marrow and without that stimulating
effect decreased red blood cell production ensues.4 Other differential diagnoses for normocytic,
normochromic, non – regenerative anemia include anemia of chronic disease, hypothyroidism,
and renal disease. In this case, the dog's hypothyroidism had been well controlled on
levothyroxine, making hypothyroidism an unlikely cause of the anemia.
Prognosis, Treatment, and Outcome
Primary hypoadrenocorticism can be managed successfully with lifelong replacement therapy of
mineralocorticoids and glucocorticoids. Two options exist for replacing mineralocorticoids,
desoxycorticosterone pivalate (DOCP) or fludrocortisone acetate.
A trimethylacetate ester of naturally occurring desoxycorticosterone, DOCP is a
mineralocorticoid replacement therapy given subcutaneously or intramuscularly on average of
every 25 days.2,8 When starting DOCP, the dog's electrolyte concentrations must be monitored
closely at days 12 and 25 after initiating therapy to adjust dose volume and frequency.2 Starting
doses of DOCP vary from 1.0 - 2.2 mg/kg, and monthly doses are expensive.8 Many dogs can be
adequately maintained on doses of DOCP which are much lower than the suggested upper limit
of the starting dose range. Mark Peterson’s study which followed 205 dogs diagnosed with
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hypoadrenocorticism long term determine that the mean requirement among the group for DOCP
was 1.7 mg/kg.8
Fludrocortisone acetate is a potent synthetic daily oral mineralocorticoid replacement therapy
with some glucocorticoid activity.8 Starting dose of fludrocortisone is 0.02 mg/kg/day.
Interestingly, the dose of fludrocortisone is substantially higher in dogs than humans. Most
humans take 0.1 mg of fludrocortisone daily, whereas dogs take the same dose for every 10
pounds of body weight. Unfortunately, the higher dose needed in dogs to restore electrolyte
concentrations associated with mineralocorticoid deficiency can lead to glucocorticoid excess.8
Excessive glucocorticoids result in side effects such as polyuria, polydipsia, polyphagia, and
muscle wasting. Fludrocortisone is expensive with each 0.1mg pill costing over one dollar.
Maintaining our 44.7 kg Addisonian on this replacement therapy would have cost over ten
dollars per day.
Glucocorticoid replacement therapy is easily accomplished with prednisone. Prednisone is given
daily by mouth at a physiologic dose of 0.1 to 0.2 mg/kg. Addisonian dogs during times of stress
or illness may require increased doses of prednisone (2 to 5 times the physiologic dose) in order
to have more cortisol available to cope with these events. Prednisone is a relatively inexpensive
replacement therapy that makes it amendable to many owners’ budgets.
The current therapy protocol for the dog of this case report is subcutaneous injections of DOCP
given at 25-day intervals and daily 5 mg prednisone PO. The dog has been well controlled for
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the last three months. The owner no longer reports gastrointestinal signs, lethargy, or poor
appetite.
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References
1. Mitchell AL, Pearce SH. Autoimmune Addison disease: pathophysiology and genetic
complexity. Nat Rev Endocrinol 2012;8:306-316.
2. Klein SC, Peterson ME. Canine hypoadrenocorticism: Part II. Can Vet J 2010;51:179-184
3. Baumstark ME, Sieber-Ruckstuhl NS, Muller M, et al. Evaluation of aldosterone
concentrations in dogs with hypoadrenocorticism. J Vet Intern Med 2014;28:154-159.
4. Klein SC, Peterson ME. Canine hypoadrenocorticism: Part I. Can Vet J 2010;51:63-69.
5. Oberbauer AM, Bell JS, Belanger JM, et al. Genetic evaluation of Addison's disease in the
Portuguese Water dog. BMC Vet Res 2006;2:15-22.
6. McGonigle KM, Randolph JF, Center SA, et al. Mineralocorticoid before glucocorticoid
deficiency in a dog with primary hypoadrenocorticism and hypothyroidism. J Am Anim Hosp
Assoc 2013;49:54-57.
7. Venco L, Valenti V, Genchi M, et al. A dog with pseudo-addison disease associated with
Trichuris vulpis infection. Journal of Parasitology Research 2011,vol. 2011, Article ID
682039, 3 pages, 2011. doi:10.1155/2011/682039
8. Kintzer PP, Peterson ME. Treatment and long-term follow up of 205 dogs with
hypoadrenocorticism. J Vet Intern Med 1997;11:43-49.
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