Q & A: Prolonged Action of Percorten in a Dog with Addison's Disease

My patient is a 2-year old female/spayed Labrador Retriever who was initially examined 2 months ago because of anorexia and vomiting. Routine serum chemistry panel showed prerenal azotemia, hyperkalemia (potassium of 7.4 mEq/L; reference range, 3.5-5.7 mEq/L), hyponatremia (sodium, 127; reference range, 136-148 mEq/L) and a Na/K ratio of 18 (normal <27). An ACTH stimulation test revealed a low basal cortisol (0.2 μg/dl) with no response to ACTH stimulation (0.3 μg/dl). This lack of a cortisol response coupled with the classic serum electrolyte changes was considered diagnostic for primary hypoadrenocorticism (Addison's disease).

I started the dog on oral prednisone (0.15 mg/kg once daily) for glucocorticoid coverage. For mineralocorticoid supplementation, I administered a single dose of desoxycorticosterone pivalate (DOCP; Percorten-V, Novartis) at the recommended dose of 2.2 mg/kg intramuscularly.

The dog has done very well, with a complete clinical response. We have monitored the dog's serum chemistry panel at 15, 25, 35, and 51 days after the initial Percorten-V injection, but the dog's serum potassium value remains within the high-normal range (between 4.5-5.5).

Now on day 53, the dog is acting more lethargic and is not eating well. I just instructed the owner to administer the second Percorten-V injection; the owner is a nurse so they are able to give the injection at home.

I'm confused. Does this dog have Addison's disease or is my diagnosis incorrect? Can Addison's disease ever go into remission? Why is the serum potassium concentration still within the normal range?

My Response:

In answer to your first question, it is clear that this dog does indeed have primary hypoadrenocorticism (Addison's disease) (1-5). That diagnosis is based on the following data:

• Signalment (i.e., young adult female dog)
• History and clinical signs (anorexia, vomiting, lethargy)
• Routine laboratory findings (hyperkalemia, hyponatremia, prerenal azotemia)
• Low basal cortisol concentration
• Lack of a serum cortisol response to ACTH stimulation
• Complete response to glucocorticoid and mineralocorticoid treatment

In answer to your second question: No, dogs with true primary hypoadrenocorticism have destruction of all layers of the adrenal cortex and do not ever go into remission. These dogs require life-long replacement of the missing adrenocortical hormones (3-5).

In answer to your last question, I do not know for certain why an occasional dog will have a prolonged response to the Percorten-V injection, but it certainly does occur. Remember that circulating potassium concentrations are controlled by factors other than just aldosterone. That's one reason we sometimes see dogs with "atypical" Addison's dogs that have persistently normal serum potassium concentrations but no measurable aldosterone concentrations (6-9). Most of those dogs will eventually go on to develop hyperkalemia or hyponatremia, but in some dogs it may take months.

Dogs like this indicate that there are mechanisms which allow normal potassium and sodium balance to be maintained even without the presence of circulating aldosterone. This phenomenon is also recognized in human medicine, where it has been shown that up to 25% of human patients with primary hypoadrenocorticism may have normal serum potassium concentrations. However, all of these Addison's patients will have a high plasma renin to aldosterone ratio, which indicates a failing zona glomerulosa (10,11).

What's the mechanism for this maintenance of normal potassium concentrations in dogs or humans with Addison's disease? Well, that's not clear, but the following physiological mechanisms have been proposed (11-13):

• Hyperkalemia itself will increase potassium excretion; this may help maintain normal serum levels of potassium.
• A high renal tubular flow rate with increased distal delivery of potassium can increase the urinary excretion of potassium and again help maintain normokalemia.
• An increased sensitivity of the distal tubule to aldosterone will enhance the urinary excretion of potassium. Again, this would help maintain the whole body levels of potassium.
• Insulin may also act to compensate for aldosterone deficiency by promoting the transfer of potassium from the extracellular to intracellular space, thus maintaining normokalemia.

Based on my studies done 2 decades ago, it's clear that most dogs with Addison's disease can be maintained quite well with DOCP when given at much lower monthly doses than 2.2 mg/kg/injection (4,5).  In one study (4), the final median dose of DOCP needed in 33 dogs was 1.69 mg/kg/month, with a range of 0.75-3.4 mg/kg/month (Figure 1, below). 

Figure 1: Initial and final maintenance doses of DOCP (Percorten-V) administered to 33 dogs with Addison's disease. 
Data is displayed as "box plots," in the the whiskers represent the main body of data (i.e., the range). The box represents the interquartile range for the 25th to75th percentile (the middle half of the data). The horizontal bar through the box is the median value. Outlying data points are represented by open circles.

If this was my case, I would not waste any more time or money trying to determine the longest interval you can go between Percorten-V injections. Remember, it's not necessary for hyperkalemia to redevelop before the next injection; in fact, you don't want that to ever happen!  Rather, I recommend that you treat with low dose of Percorten-V once monthly. It's very difficult to "overdose" Percorten-V, so we don't have to worry about giving the injections too frequently, especially when we are giving a smaller monthly dose.

How low can you go with the monthly Percorten-V injections? I'd start by lowering the dose by about 10-20% and then check the serum electrolytes again in a month. If they remain normal, then I'd continue to decrease the dose by another 10-20%. Again, in my studies, over half the dogs did very well on a monthly dose of Percorten-V <1.6 mg/kg. Almost all dogs need a monthly dose of at least 1.0 mg/kg/month to maintain normal serum electrolytes on a long-term basis (Figure 1).

References

1. Peterson ME, Kintzer PP, Kass PH. Pretreatment clinical and laboratory findings in dogs with hypoadrenocorticism: 225 cases (1979-1993). Journal of the American Veterinary Medical Association 1996;208:85-91.
2. Klein SC, Peterson ME. Canine hypoadrenocorticism: part I. Canadian Veterinary Journal 2010;51:63-69.
3. Klein SC, Peterson ME. Canine hypoadrenocorticism: part II. Canadian Veterinary Journal 2010;5:179-184.
4. Kintzer PP, Peterson ME. Treatment and long-term follow-up of 205 dogs with hypoadrenocorticism. Journal of Veterinary Internal Medicine 1997; 11:43-49.
5. Melián C, Peterson ME. Diagnosis and treatment of naturally occurring hypoadrenocorticism in 42 dogs. Journal of Small Animal Practice 1996;37:268-275.
6. Bartges JW, Nielson DL. Reversible megaesophagus associated with atypical primary hypoadrenocorticism in a dog. Journal of the American Veterinary Medical Association 1992; 201: 889-891.
7. Feldman EC, Nelson RW. Hypoadrenocorticism (Addison's disease). In: Feldman EC, Nelson RW (Eds). Canine and Feline Endocrinology and Reproduction, 3rd Edition. WB Saunders. St. Louis, Missouri, 2004, pp 394-439.
8. Mueller C, Boretti FS, Wenger M, et al. Investigation on the aldosterone concentration before and after ACTH application in 44 dogs with hypoadrenocorticism. Kleintierpraxis 2007;52:216-224.
9. Baumstark ME, Mueller C, Boretti FS, et al.  Evaluation of aldosterone concentrations in dogs with Addison's disease (abstract). Proceeding of the 2011 ACVIM Forum.
10. Oelkers W, Diederich S, Baehr V. Diagnosis and therapy surveillance in Addison's disease: rapid adrenocorticotropin (ACTH) test and measurement of plasma ACTH, renin activity, and aldosterone. Journal of Clinical Endocrinology and Metabolism 1992;75:259-264.
11. Shiah CJ, Wu KD, Tsai DM, et al. Diagnostic value of plasma aldosterone/potassium ratio in hypoaldosteronism. Journal of the Formosan Medical Association 1995;94:248-524. 
12. Harvey TC. Addison's disease and the regulation of potassium: the role of insulin and aldosterone. Medical Hypotheses. 2007;69:1120-1126. 
13. Gagnon RF, Halperin ML. Possible mechanisms to explain the absence of hyperkalaemia in Addison's disease. Nephrology, Dialysis, Transplantation 2001;16:1280-1284.