Treating Small-Breed Addison's Dogs with Low Doses of Prednisone or Prednisolone

My 4-year old Toy Poodle was diagnosed with atypical Addison's disease about 6 weeks ago. She weighs 11.8 lbs and is taking 1.25 mg of prednisolone per day. She is not receiving any mineralocorticoid supplementation (i.e., Florinef or Percortin-V) for now since her serum sodium and potassium levels are in the normal range. We will continue to monitor that because we know that that might change and mineralocorticoids will have to be added to her treatment.

For her glucocorticoid needs, we are using a 5-mg tablet of prednisolone that we cut into quarters to administer a 1.25-mg dose each day. This is extremely tricky, and there is probably never a day that she gets an exact dose because the tablets do not cut without some crumbling.

So I have two main questions:

1. First, my dog has developed a ravenous appetite and finishes her meals very quickly. Normally, she has a picky appetite. I know that you generally recommend giving these dogs a much lower dosage, and that a lower dosage would be better for her overall health since she will be on this daily dosage for the rest of her life. Should her prednisolone dosage be lowered to help with the appetite issue? 
2. Second, is there any other tablet or form of prednisolone that would be easier for us to administer to her so that she gets the proper amount each day? The 5-mg tablet just isn't working very well for us. 

Thank you for your help.

My Response:

The glucocorticoid replacement dose I use for prednisone or prednisolone in dogs with Addison's disease is 0.1-0.2 mg/kg/day. So at 11.8 pounds (5.4 kg), that calculates out to be only 0.5 mg/day, up to a maximum dose of 1.0 mg/day. So if you are giving your small dog 1.25 mg/day, that means you are giving too much of the drug. That would certainly be enough to induce iatrogenic Cushing's disease, as reflected by the increased appetite.

In dogs, prednisone is converted to prednisolone within the body. So basically, these two glucocorticoids can be used interchangeably.

I would try to lower the daily prednisone/prednisolone dose down to 0.5 mg each day. Administrating too much glucocorticoid will cause increased hunger (as you see in your dog).  Overdosage of prednisone, prednisolone or any other glucocorticoid can also lead to lethargy, weight gain, enlargement of the abdomen, muscle atrophy, and muscle weakness. Decreasing the dose of the prednisone or prednisolone should help prevent any of these problems.

Fig. 1: Prednisone is available as a 1-mg tablet

Fig 2: PrediapredOral prednisolone
liquid (1 mg/mL) 

Prednisone tablets are available as 1-mg and 2.5-mg sizes, which can be helpful in dosing small to medium-sized dogs (Figure 1).

In addition, both prednisone and prednisolone are available as a syrup/oral liquid or solution, available as a 1 mg/mL concentration (Figure 2).  Examples of liquid prednisolone products include Pediapred® (Celltech Pharm); Millipred® (Laser); Orapred® (Sciele); Veripred® 20 Hawthorn); and Flo-Pred® (Taro). For prednisone, Intensol® Concentrate (Roxane) oral solution is available.

All of these formulations are human-labeled products so your veterinarian may not be familiar with them. Your local pharmacy will know about them, however.

Either way, I'd get either the 1-mg tablets and give half a tablet a day. Or use a liquid formulation (1 mg/mL) and give 0.5 mg (1/2 mL per day).

References:

1. Plumb, DC. Plumb's Veterinary Drug Handbook. Seventh Edition, Wiley-Blackwell. 2011.

Tapering the Glucocorticoid Dose in Dogs with Addison's Disease

My dog is a 2-year old, male Saint Bernard., weighing almost 145 pounds (75 kg). He was just diagnosed with Addison's disease and was treated with an intramuscular injection of Percorten-V (65 mg) and started on oral prednisone (30 mg per day —15 mg in AM and 15 mg in PM). 

As my veterinarian and I are learning more about treating Addison's disease in dogs, we realize that he is now suffering from cortisol overload. His current signs include lethargy, frequent urinations and incontinence, and excessive hunger and thirst. 

After reading your work, we know that we should lower his daily prednisone dose, probably down to 5 mg per day. Considering that he hasn't been on it for even a week, I've started to taper the dose fairly rapidly. His appetite remains fine but he now has some diarrhea. 

Here is how we've begun lowering the daily prednisone dosage: 

• Day 1-4: 15 mg twice a day (AM and PM)
• Day 5-6: 15 mg in AM, none at night 
• Day 7: 10 mg in AM, none at night  

Can I just give him 10 mg today and begin just 5 mg tomorrow? Or is that too much danger without tapering? 

My Response: 

You should be fine to lower the dose to 5 mg per day now. Remember that a 5-mg dose is the human replacement dose, so we are still giving the amount that you or I would need to survive. So even for your large breed dog, that will still be plenty!

As far as how fast to taper, you can base that on his appetite. As long as he is eating well without vomiting, you should be fine to taper the dose down, especially since he has also received the mineralocorticoid supplementation (i..e, Percoten-V).

You might want to check his serum chemistry panel and electrolytes soon, just to ensure that the serum sodium and potassium are back within the reference range limits.

Follow-up Question: 

I have lowered the prednisone dose to 5 mg once daily in the AM, which he has been on for the last week. He seemed fine for the first few days on this new dose (good appetite, no vomiting or diarrhea), but more recently he has been pretty lethargic.  

Could this be because he only gets prednisone once a day? Can I experiment and give a divided dosage, with 2.5 mg in the AM and another 2.5 mg in the PM? 

Follow-up Response: 

Yes, dividing the dose of the prednisone may help and certainly can't hurt.

Remember, however, that dogs with Addison's disease have both glucocorticoid and mineralocorticoid deficiencies. Some of his lethargy could be related to the fact that his mineralocorticoid dosage might need to be adjusted.

Therefore, it's important to have his serum chemistry panel and electrolytes rechecked. After the first injection of the Percorten-V, I recommend rechecking the serum electrolytes at 10-14 days and then again at 25-30 days, just before the second injection.

References:

1. Kintzer PP, Peterson ME. Treatment and long-term follow-up of 205 dogs with hypoadrenocorticism. J Vet Intern Med 1997;11:43-49. 
2. Church DB. Canine hypoadrenocorticism In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;156-166.

Interpreting the ACTH Stimulation Test in Dogs with Suspected Addison's Disease

I am hoping you may be able to offer me some insight/information about testing for hypoadrenocorticism (Addison's disease) in dogs.

I have a 3-year old male neutered German Shorthaired Pointer. Since April, Luke has been steadily losing weight despite no changes in his diet. He has also seemed "off" (slightly lethargic, just not himself) and had slight changes in gait from time to time. He then would seem better and back to his normal self.

In November, he began having chronic diarrhea and losing weight at a much more rapid pace. He has now last 20 pounds, going down from 85 to 65 lbs. He has had an ultrasound, exocrine pancreatic insufficiency test, full tick panel, fecal tests, serum thyroid tests, and complete blood count and serum chemistry panel. No clinically significant abnormalities have been detected in any these tests.

He had no response to treatment with Panacur, Proviable, or Flagyl. He responded to high-dose prednisone, but then when we tapered the dose, his clinical signs returned. He was off prednisone for 3 days before doing the first ACTH stimulation test, which came back out of range:

• Basal cortisol: 1.2 μg/dl (Reference range, 1.0-6.5 μg/dl)
• ACTH-stimulated cortisol:  3.6 μg/dl (Reference range, 6.5-18.0 μg/dl)

We waited 3 weeks to do the second ACTH stimulation test which came in within the normal range. These results were as follows:

• Basal cortisol: 1.3 μg/dl  
• ACTH-stimulated cortisol:  9.5 μg/dl  

Based on this information, is it possible he has Addison's disease? Or is the fact that his stimulated cortisol value came back within the normal range on the second test just an indication that the prednisone was affecting the results in the first ACTH stimulation test?

I have been doing a lot of research on this because he seems to have many symptoms that match up with Addison's disease. Some things I've read have said that it is possible in atypical Addison's disease to have varying test results. Other things have disagreed. This is why I am trying to contact someone who specializes in this field. In your experience, is this something you have encountered?

I really appreciate any insight you may be able to give me. Thank you for your time.

My Response:

Causes of Hypoadrenocorticism in Dogs
In dogs, as in man, hypoadrenocorticism can be classified into primary and secondary subtypes (1-6). With primary hypoadrenocorticism, the primary disease process is in the adrenal glands themselves. In secondary hypoadrenocorticism, the problem lies in the pituitary gland where ACTH is secreted; with secondary forms of the disease, the cortisol secretion goes down because of too little ACTH secretion from the pituitary gland.

The most common cause of secondary hypoadrenocorticism is iatrogenic (induced inadvertently by the veterinarian) resulting from overly rapid discontinuation of long-term and/or high-dose glucocorticoid therapy. Very rare spontaneous or natural causes in the dog include pituitary or hypothalamic lesions (e.g., large destructive pituitary tumors) or idiopathic isolated ACTH deficiency.

In addition to primary Addison's disease or hypoadrenocorticism  (the failure of the adrenal glands to produce both glucocorticoid and mineralocorticoid hormones), and secondary (which is the failure of the pituitary gland to secrete ACTH, a hormone which stimulates the adrenal glands), a third type of hypoadrenocorticism has been described — "atypical" Addison's disease (7-9). This is a confusing term, which I believe can and should not be avoided because it really does not describe a definitive diagnosis.

Almost all of these dogs diagnosed with atypical Addison's can be classified into primary or secondary forms of the disease with proper diagnostic testing (10-11). In addition to ACTH stimulation testing, this may include  determination of circulating ACTH concentrations (the pituitary hormone). In some dogs, repeating the ACTH stimulation test and measuring the basal and ACTH-stimulated concentrations of aldosterone, a mineralocorticoid hormone is helpful.  Properly classifying the dogs into primary and secondary subtypes helps us better predict the needs for long-term treatment.

In  this dog, there is no reason to go any further because the last ACTH stimulation test completely rules out all forms of Addison's disease — primary, secondary, and atypical hypoadrenocorticism (see below).

ACTH Stimulation Testing
In normal dogs, administration of a dose of ACTH generally produces a rise in serum cortisol to values greater than 6 μg/dl. In contrast, dogs with hypoadrenocorticism (typical or atypical Addison's disease) have an absent or blunted response to ACTH administration. Basal and post-ACTH serum cortisol concentrations are less than 1 μg/dl in over 75% of dogs and less than 2 μg/dl in virtually all dogs with primary hypoadrenocorticism (1-6).

Although the post-ACTH serum cortisol concentration may be as high as 2 to 3 μg/dl in a few dogs with naturally occurring secondary hypoadrenocorticism (due to pituitary ACTH deficiency), the great majority of these dogs also have ACTH-stimulated cortisol concentrations of less than 2 μg/dl.

When borderline results occur (post ACTH cortisol concentrations between 2 and 6 μg/dl), the first thing that one must consider is the recent use of glucocorticoids, which would act through the negative-feedback effect to suppress circulating ACTH and cause temporary and mild atrophy of the adrenal cortical cells that secrete cortisol. That is likely what happened in your dog.

My Bottom Line

So in your dog, the first ACTH stimulation test is borderline for Addison's, but the cortisol response is high enough to make it unlikely. Remember that the dose given for Addison's disease would only be between 2.5-5 mg per day (around 0.1 mg/kg/day), so anything higher than that dose would suppress pituitary ACTH secretion and could lead to blunting of the cortisol response.

In accord with that, his second ACTH stimulation test done 3 weeks later is completely normal, totally excluding Addison's disease.

It's time to look for another disease. Consider an abdominal ultrasound or endoscopy next to better define your dog's gastrointestinal disease.

References:

1. Church DB. Canine hypoadrenocorticism. In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. 3rd ed. Quedgeley, Gloucester: British Small Animal Veterinary Assoc, 2004; 172-180.
2. Feldman EC, Nelson RW. Hypoadrenocorticism (Addison’s disease). In: Canine and Feline Endocrinology and Reproduction, 3rd ed. Philadelphia: Saunders, 2004; 394-439.  
3. Kintzer PP, Peterson ME. Primary and secondary canine hypoadrenocorticism. Veterinary Clinics of North American Small Animal Practice 1997;27:349-357. 
4. 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.
5. Klein SC, Peterson ME. Canine hypoadrenocorticism: part I. Canadian Veterinary Journal 2010;51:63-69.
6. Klein SC, Peterson ME. Canine hypoadrenocorticism: part II. Canadian Veterinary Journal 2010;5:179-184.
7. 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.
8. Lifton SJ, King LG, Zerbe CA. Glucocorticoid deficient hypoadrenocorticism in dogs: 18 cases (1986-1995).  Journal of the American Veterinary Medical Association1996;209:2076-2081. 
9. Sadek D, Schaer M. Atypical Addison’s disease in the dog: A retrospective survey of 14 cases. J Am Anim Hosp Assoc 1996;32:159-163. 
10. 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.
11. Insights into Veterinary Endocrinology Blog. Atypical Addison's Disease in Dogs with Gastrointestinal Signs. April 14, 2011.

Watch Out for Canine Addison's Disease

Dr. Peterson's expertise in veterinary endocrinology was tapped by Dog Fancy Magazine to provide professional insight into the diagnosis and treatment of Addison's disease.

This article was a part of the monthly "Watch Out For" feature which gives an overview of common diseases and medical conditions, with Dr. Peterson's Addison's disease article appearing in the October issue.

Updated Book on Canine and Feline Endocrinology Now Available

BSAVA Manual of Canine and Feline Endocrinology

Edited by:

Carmel T. Mooney

Mark E. Peterson

Building on the success of previous editions, the editors have sought to combine the best of the old with the new in this updated Fourth Edition of the BSAVA Manual of Canine and Feline Endocrinology.

Since publication of the last edition in 2004, there have been many significant advances in clinical endocrinology of companion animals. Several endocrine disorders, such as feline acromegaly and hyperaldosteronism, have risen in importance. The use of novel insulins in diabetic cats and dogs, as well as a wide range of new therapies, have emerged for routine use and are discussed in detail in this Manual. In addition, the genetic risks associated with many endocrine disorders have not been elucidated.

This new edition has been comprehensively updated, while retaining the emphasis on the common problems encountered in investigating and treating endocrine diseases. The Manual is divided into sections covering each endocrine gland and the major and minor endocrine disorders of each species. A separate section deals with relevant presenting complaints in a problem oriented manner.

The fourth edition of this manual provides a ready source of practical information for the practicing veterinarian and will also be useful for students, technicians, and graduates embarking on further specialization.

Click on the link to read a sample chapter from this book, on "Investigation of unstable feline diabetes mellitus."


Table of Contents:

Part 1: Introduction

• Hormone assays and collection of samples
• Principles of interpreting endocrine test results  

Part 2: The Pituitary Gland

• Disorders of vasopressin production
• Pituitary dwarfism
• Acromegaly

Part 3: The Parathyroid Gland

• Hyperparathyroidism
• Hypoparathyroidism

Part 4: The Thyroid Gland

• Canine hypothyroidism
• Canine hyperthyroidism
• Feline hyperthyroidism
• Feline hypothyroidism

Part 5: The Pancreas 

• Canine diabetes mellitus
• Feline diabetes mellitus
• Insulinoma and other gastrointestinal tract tumours 

Part 6: The Adrenal Gland

• Canine hypoadrenocorticism
• Canine hyperadrenocorticism 
• Feline hyperadrenocorticism 
• Feline hypoadrenocorticism 
• Feline hyperaldosteronism

Part 7: Presenting Complaints and Their Investigation

• Investigation of polyuria and polydipsia
• Investigation of hypercalcaemia and hypocalcaemia
• Investigation of unstable canine diabetes mellitus
• Investigation of unstable feline diabetes mellitus
• Ketoacidosis
• Investigation of hypoglycaemia
• Investigation of symmetrical alopecia in dogs
• Investigation of adrenal masses
• Investigation of hyperlipidaemia
• Index

International Contributors:

Amanda K. Boag, UK; Rosario Cerundolo, UK; Dennis J. Chew, USA; David B. Church, UK; Sylvie Daminet, Belgium; Lucy J. Davison, UK; Steve Dodkin, UK; Peter A. Graham, UK; Danièlle Gunn-Moore, UK; Andrea M. Harvey, UK; Michael E. Herrtage, UK; Peter P. Kintzer, USA; Hans S. Kooistra, The Netherlands; Carlos Melian, Spain; Carmel T. Mooney, Republic of Ireland; Raymond F. Nachreiner, USA; Rhett Nichols, USA; Stijn J.M. Niessen, UK; Kostas Papasouliotis, UK; Mark E. Peterson, USA; Ian K. Ramsey, UK; Jacquie Rand, Australia; Nicki Reed, UK; Kent R. Refsal, USA; Patricia A. Schenck, USA; Johan P. Schoeman, South Africa; Robert E. Shiel, Australia; Barbara J. Skelly, UK; Annemarie M.W.Y. Voorbij, The Netherlands.

Purchase the Fourth Edition of the BSAVA Manual of Canine and Feline Endocrinology:

• Amazon
• BSAVA website

Dr. Peterson Lectures at the VetCo International Congress in Poland

Dr Peterson was invited to lecture at the 2011 Vetco International Congress in Warsaw, Poland, on May 21st and 22nd along with Dr. Richard W. Nelson. The theme of this year's VetCo Congress was "Endocrinology of Small Animals in Practice." Dr. Peterson delivered four lectures during the Congress:

• Diagnosis and treatment of hyperthyroidism in cats
  
• Diagnostic testing for canine hyperadrenocorticism
  
• Treatment of hyperadrenocorticism in dogs
  
• Addison’s disease in dogs: an overview

Dr. Peterson and Dr. Nelson both graduated from the University of Minnesota College of Veterinary Medicine in the late 1970s, when they first met and became friends. Like Dr. Peterson, Dr. Nelson has authored numerous manuscripts, book chapters and textbooks and has lectured nationally and internationally. 

Dr. Peterson (left) and Dr. Nelson (right) at the 2011 VetCo Congress in Poland.

Hypoadrenocorticism (Addison’s Disease) in Cats

Hypoadrenocorticism, also called adrenal insufficiency or Addison’s disease, is a disorder in which the adrenal gland does not produce sufficient adrenal hormones that are essential for life.  When the adrenal glands fail, the consequences are very severe. Untreated, hypoadrenocorticism may lead to death.

Fortunately, naturally occurring hypoadrenocorticism is extremely rare in cats, with less than 25 cases reported. However, the disease is generally missed because veterinarians rarely consider this problem as a differential diagnosis in cats.

A much more common reason that cats develop hypoadrenocorticism is long-term treatment with steroids for a variety of dermatologic or behavioral reasons. These cats do not show signs of adrenal insufficiency unless the mediation is stopped too abruptly. This is also known as iatrogenic hypoadrenocorticism (see, "What causes this disease in cats," below).

What are the missing hormones in cats with hypoadrenocorticism?

Like dogs or people with Addison’s disease, cats with hypoadrenocorticism are unable to produce one or two steroid hormones, both secreted from the adrenal cortex (outer layer of the adrenal gland).

1. The first hormone that's missing is cortisol, which is very important in maintaining a normal metabolism, as well as a general sense of well-being.
2. The second hormone that's missing is aldosterone, which manages the water balance and serum electrolytes in the body.

What are the different forms of hypoadrenocorticism in cats?

Hypoadrenocorticism can be divided into primary and secondary subtypes:

• With primary hypoadrenocorticism (Addison's disease), the problem lies in the adrenal gland itself, with atrophy or destruction of the gland.
• With secondary hypoadrenocorticism, the adrenal glands are normal, and the problem lies in the pituitary gland. The pituitary gland normally secretes a hormone called ACTH (adrenocorticotropic hormone) that stimulates the adrenal gland to secrete its hormones. In secondary hypoadrenocorticism, ACTH is not secreted in needed amounts, leading to the secondary adrenal insufficiency.

What causes this disease in cats?

In most cats with naturally occurring hypoadrenocorticism, the exact cause for the adrenal failure is never known for certain.  

Many cats, however, develop the problem because of iatrogenic causes. The term iatrogenic means that the disease is caused by, or results from, a medical or surgical treatment for another problem (i.e., the disease did not develop spontaneously).  

In cats with primary hypoadrenocorticism, the following causes must be considered.

• Most cats that develop Addison’s disease spontaneously appear to have an autoimmune condition in which the body destroys part of the adrenal cortex.
• Infiltrative conditions such as lymphoma (a form of cancer) can destroy the adrenal gland to cause Addison’s disease.
• Surgical removal of both adrenal glands for treatment of feline Cushing’s disease will result in iatrogenic Addison’s disease, but this is a rarely used operation for cats.  
• Rarely, primary adrenal failure can occur secondary to trauma. This may be temporary or permanent.

In cats with secondary hypoadrenocorticism, the following underlying causes should be excluded. Again, all of these conditions are associated with deficient secretion of the pituitary hormone, ACTH.

• Congenital deficiency of ACTH secretion (not yet reported in cats).
• Pituitary tumors, inflammation, or trauma that have destroyed most of the ACTH-secreting cells in the pituitary gland, leading to deficient ACTH secretion.
• Iatrogenic hypoadrenocorticism that results from administration of large doses of cortisone-like hormones (glucocorticoids or progesterone-like drugs), which are then withdrawn too rapidly. In this case, the term iatrogenic means that the hypoadrenocorticism is caused by the high-dose glucocorticoid or progestin (megestrol acetate; trade names, Ovaban or Megace) treatment.   

Chain of events leading to severe hypoadrenocorticism in cats

With primary hypoadrenocorticism (Addison's disease), cats develop complete adrenocortical destruction with both cortisol and aldosterone deficiencies.

Aldosterone is the main mineralocorticoid hormone, and it affects the levels of potassium, sodium, and chloride in the blood. Low levels of aldosterone cause potassium to gradually build up in the blood and, in severe cases, cause the heart to slow down or beat irregularly. Some cats have such a slow heart rate (50 beats per minute or lower) that they can become weak or go into shock.

More commonly, cats will develop iatrogenic, secondary hypoadrenocorticism (see above, What causes this disease in cats) to treatment with steroid-like drugs used for anti-inflammatory purposes. This subgroup of hypoadrenal cats is only deficient in cortisol and maintains a normal aldosterone level. These cats are more difficult to diagnose because their signs are milder and the serum potassium, sodium, and chloride values all remain normal.

What are the clinical signs and symptoms of feline hypoadrenocorticism?

Signs of hypoadrenocorticism may include repeated episodes of vomiting and diarrhea, loss of appetite, dehydration, and gradual, but severe, weight loss.

Because the clinical signs of hypoadrenocorticism are vague and nonspecific, it can be difficult to diagnose in the earlier stages of disease. Therefore, severe consequences, such as shock and evidence of kidney failure, can develop suddenly in some cats with complete adrenocortical destruction.

In cats with secondary hypoadrenocorticism, the clinical signs generally are not as severe and are usually not life threatening.

How is feline hypoadrenocorticism diagnosed? 

A veterinarian may suspect hypoadrenocorticism based on the cat’s history (including past treatment with steroids or progestins), clinical signs, and certain laboratory abnormalities, such as low serum sodium and high potassium concentrations. However, one must specifically evaluate adrenal function to document low cortisol levels to definitively diagnose hypoadrenocorticism.

The diagnosis of hypoadrenocorticism is confirmed by lack of cortisol response to ACTH administration. It is important to recognize that the reference range for the post ACTH cortisol is lower in cats than in dogs. To confirm a diagnosis of hypoadrenocorticism, however, the serum concentrations of both the basal cortisol level and ACTH-stimulated cortisol levels are low (generally less than 2 μg/dl).   

How is primary hypoadrenocorticism (Addison’s disease) treated?

Untreated, primary hypoadrenocorticism (Addison’s disease) can lead to an adrenal crisis.  An adrenal crisis is a medical emergency that requires intravenous fluids to restore the body’s levels of fluids, salts, and sugar to normal.  Once stabilized, the cat can then be treated with hormone replacement therapy (either orally or by injection).  With proper treatment, the long-term prognosis is excellent.

Long-tem treatment of primary hypoadrenocorticism (Addison’s disease) includes treatment with either both missing adrenal hormones.  For mineralocorticoid replacement, either oral fludrocortisone (trade name, Florinef) or injectable desoxycortisone privalate (DOCP, trade name, Percorten) are given. In cats, glucocorticoid replacement is best given as oral or injectable prednisolone.   

Response to treatment is similar although clinical signs such as anorexia, lethargy, and weakness may sometimes take longer to resolve than in dogs. Prognosis for long-term survival is good with the exception of cats in which the underlying cause is adrenal neoplasia.

How is iatrogenic hypoadrenocorticism (secondary to overtreatment with steroids or progestins) treated?

In cats with iatrogenic hypoadrenocorticism due to overtreatment with steroids for nonendocrine problems, treatment simply involves reinstituting glucocorticoid replacement at a gradual tapering dosage over weeks to months. This allows the pituitary ACTH-secreting cells to recover and stimulate normal cortisol secretion once again.

Treating Dogs with Hypoadrenocorticism (Addison's Disease)

Addison's disease, the common name for hypoadrenocorticism or adrenal insufficiency, as I have discussed in my last two blog posts, is a disease with vague clinical features that are common in many other ailments, making diagnosis difficult in many cases. But once Addison's disease is correctly diagnosed, a properly treated dog can live a normal and happy active life.

The missing adrenal hormones

The adrenal, one on each kidney, is made up of two layers, the cortex and the medulla. The inner medulla secretes epinephrine (adrenaline) and is not affected by Addison's disease. The outer cortex layer secretes two corticosteroid hormones, cortisol and aldosterone, both of which are deficient in Addison's disease.

Aldosterone is a corticosteroid hormone (more specifically, a mineralocorticoid — think minerals: salt, sodium, potassium) responsible for maintaining normal circulating electrolyte levels. Once secreted, aldosterone acts on the kidney to conserve sodium, excrete potassium, and retain needed water.

Cortisol is also a corticosteroid hormone (in this case, a glucocorticoid — think glucose, sugar, energy) that is essential for life. It supports a variety of important cardiovascular, metabolic, immunologic, and stress functions.

Not all forms of hypoadrenocorticism are treated the same
There are three forms of hypoadrenocorticism: primary, secondary and atypical Addison's disease.

1. Primary Addison's disease is most commonly is the result of immune-mediated damage to the glands.
2. Atypical Addison's disease is a poorly understood disorder, thought to generally be an early stage of primary Addison's disease.
3. Secondary hypoadrenocorticism results from a deficiency of the pituitary hormone, adrenocorticotropic hormone (ACTH). Without circulating ACTH, cortisol cannot be secreted by the adrenal glands.

It is important which form of hypoadrenocorticism is present in order to provide the correct treatment. In primary hypoadrenocorticism, both cortisol and aldosterone are deficiency and must be replaced for life. In atypical and secondary hypoadrenocorticism, on the other hand, only the glucocorticoids need to be replaced, at least initially.

Treating the acute adrenal crisis: A true medical emergency
Untreated, hypoadrenocorticism (especially primary Addison's disease) can lead to an adrenal crisis. An adrenal crisis is a medical emergency that requires intravenous fluids and glucocorticoids to restore the body’s levels of fluids, salt, and sugar to normal.

Once stabilized, the dog can then be treated with glucocorticoid and mineralocorticoid replacement therapy at home.

Treating chronic hypoadrenocorticism: A lifelong disease
Depending of the subtype of hypoadrenocorticism, synthetic corticosteroid drugs that act like mineralocorticoid or glucocorticoids used for hormone replacement therapy.

Mineralocorticoid treatment

For mineralocorticoid (aldosterone) replacement, either an oral medication called fludrocortisone acetate (Florinef™) or the injectable desoxycorticosterone pivalate (DOCP; Percorten-V™) is used.

We typically institute treatment with DOCP (Percorten-V) at a dosage of 2.2 mg/kg, subcutaneously or intramuscularly, every 25 to 30 days. Side effects associated with DOCP therapy are rare. This dosage interval is effective in almost all dogs, and most are well controlled with a DOCP injection every 4 weeks.

Initially, serum kidney and electrolyte concentrations should be monitored at approximately 2-weeks intervals in order to determine the drug’s peak effect and to help make necessary dosage adjustments. Once stabilized, serum electrolyte and creatinine concentrations are checked every 3 to 6 months. Because DOCP is a pure mineralocorticoid and has no glucocorticoid activity, it is essential that dogs receive concurrent glucocorticoid supplementation (see below).

Fludrocortisone is a synthetic corticosteroid that possesses moderate glucocorticoid activity as well as having marked mineralocorticoid potency. By comparison, fludrocortisone has 10 times the glucocorticoid activity and 125 times the mineralocorticoid activity of cortisol. In this regard, fludrocortisone is very different than DOCP, which possess no glucocorticoid activity.

If fludrocortisone acetate is employed as mineralocorticoid supplementation, we recommend an initial oral dosage of approximately 0.02 mg/kg/day.

After initiation of fludrocortisone therapy, serum electrolyte and creatinine concentration should be monitored weekly, with the dosage adjusted by 0.05-0.1 mg/day increments until values have stabilized within the reference range. Once this is achieved, the dogs should be reevaluated monthly for the first 3 to 6 months of therapy, then every 3 to 6 months thereafter.

For dogs that have atypical or secondary Addison’s, mineralocorticoid replacement therapy with DOCP or fludrocortisone aren't needed because the production of aldosterone isn’t effected and the serum electrolytes remain in balance.

Glucocorticoid treatment

In addition to replacing deficient mineralocorticoids in dogs with Addison's disease, the missing glucocorticoids must also be replaced. This is typically done with an oral form of the synthetic glucocorticoids prednisone, prednisolone, or hydrocortisone. With atypical Addison's and secondary forms of hypoadrenocorticism, glucocorticoid replacement is all that is needed, at least initially, since these dogs do not have serum electrolyte abnormalities.

 The correct dose of the supplemented glucocorticoids, such as prednisone, cannot be measured with a blood test. Rather it's determined by your observations: the lowest dose that keeps your dog symptom free, happy and eating! The most common side effect of overdosage is an increase in thirst and urination, which can be intense in some dogs.

Prognosis of Addison's disease

With proper treatment, the long-term prognosis is excellent. While your dog with Addison’s disease will need medications and monitoring for the rest of his life, most dogs with Addison’s can return to their favorite activities. You will help your dog lead a normal, active and fun-filled life.

How Is Canine Addison’s Disease Best Diagnosed?

Addison’s disease (also referred to as hypoadrenocorticism or adrenal insufficiency) is an uncommon disorder in which the adrenal cortex fails to secrete sufficient amounts of its steroid hormones. These include cortisol, aldosterone, or both hormones (see my last post on Addison's disease for more information). Because these adrenal hormones are essential for life, the consequences can be life threatening when they are not secreted in normal amounts.

Natural course of hypoadrenocorticism

Two adrenal glands are located
cranial (in front of)
to each kidney

During the initial stages of this Addison’s disease, the clinical signs are generally vague and nonspecific, making diagnosis very difficult. As time goes on, more and more of the adrenal cortex is destroyed in these dogs.

Approximately 90% of the adrenal cortex must be destroyed before

overt clinical signs of Addison’s disease are generally observed.

Without early diagnosis and treatment, the disease can result in a phenomenon known as an Addisonian crisis. The dog collapses in shock due to its inability to adapt to their circulatory requirements in time stress. Blood sugar may drop dangerously low. Potassium levels soar and disrupt the heart rhythm because there is not enough conserved sodium to exchange for potassium. Heart rate slows, and arrhythmias may result. The dog may not survive this episode.

Approximately 30% of dogs with Addison's disease are NOT diagnosed

until they develop a life-threatening adrenal crisis.

Making the diagnosis
Because of the nonspecific and vague clinical signs that are seen in dogs with Addison's disease, this disorder has earned a distinct medical nickname —The Great Imitator.

The first step in making a diagnosis of Addison’s disease is to perform basic blood tests, which commonly show abnormalities that point to hypoadrenocorticism as the potential problem. For example, a complete blood count (CBC) may reveal the following changes that could indicate Addison’s disease:

• Anemia (low red blood cell count)
• High numbers of lymphocytes, a type of white blood cell
• High numbers of eosinophils, another type of white blood cell

A serum chemistry profile generally reveals one or more of the following abnormalities in dogs with Addison’s disease:

• High potassium concentration
• Low sodium concentration
• Low sodium/potassium ratio (Na:K less than 27:1)
• High urea nitrogen concentration
• High creatinine concentration
• High phosphorus concentration
• High calcium concentration
• Low glucose concentration

Chest and abdominal x-rays may reveal a smaller than normal heart and liver. These radiology changes are the result of the Addisonian dog’s shock-like state, which reduces the circulating fluid volume in the body.

Confirming the diagnosis
When screening laboratory tests are consistent with Addison’s disease, the next step is to directly evaluate the dog’s adrenal function. To do this, the veterinarian will perform an adrenocorticotropic hormone (ACTH) stimulation test. This the only definitive test for Addison's disease and allows us to confirm the diagnosis.

To perform an ACTH stimulation test in a dog with suspected Addison’s disease, we collect a blood sample to measure the level of cortisol. We then administer a dose of ACTH, the pituitary hormone responsible for the release of corticosteroids in times of stress. After an hour, we collect a second blood sample to measure the dog’s serum cortisol concentration once again. (For more information on the protocol for ACTH stimulation testing, see my blog post written for vets and vet technicians).

In healthy dogs, the baseline cortisol concentration is normal, and ACTH will stimulate the adrenal gland to secrete cortisol. Generally, a 3 to 5 fold increase in cortisol occurs after ACTH injection (see Figure below).

In contrast, dogs with Addison’s disease (hypoadrenocorticism) have a low baseline cortisol concentration (before we administer the ACTH) and show little or no rise in the cortisol value after the ACTH injection (see Figure above). The subnormal levels of cortisol combined with the lack of cortisol response after ACTH stimulation is diagnostic for Addison's disease.

Differentiating primary hypoadrenocorticism from secondary and atypical  hypoadrenocorticism

The finding of severe serum electrolyte disturbances (i.e, high potassium, low sodium,  low sodium/potassium ratio), together with subnormal cortisol values that fails to rise after ACTH injection (see Figure above) is diagnostic for primary Addison's disease.

However, in dogs with secondary and atypical hypoadrenocorticism, the serum electrolytes are generally normal, making diagnosis more difficult. In these dogs, further diagnostic testing is recommended, including determination of the pituitary hormone, ACTH, or measuring serum concentrations of aldosterone - the adrenal hormone responsible for maintaining normal serum electrolytes. For more information, see this blog post on atypical Addison's disease I wrote for veterinarians.

In my next post, I'll discuss our treatment options for this life-threatening disease.

Addison’s Disease in Dogs: A Life-Threatening Disorder

Addison’s disease, also called hypoadrenocorticism, is a disorder in which the adrenal gland does not produce sufficient hormones. The adrenal glands are essential for life. When the adrenal gland fail, the consequences are very severe.

What are the missing hormones in Addison's disease?
Dogs with hypoadrenocorticism (Addison's disease) are unable to produce one or two steroid hormones, both secreted from the adrenal cortex (outer layer of the adrenal gland).

1. The first hormone that's missing is cortisol, which is very important in maintaining a normal metabolism, as well as a general sense of well being.
2. The second hormone that's missing is aldosterone, which manages the water balance and serum electrolytes in the body.

What are the different forms of hypoadrenocorticism?
Hypoadrenocorticism can be divided into primary and secondary subtypes. A third form, called "atypical" Addison's disease appears to be an early stage of primary hypoadrenocorticism in most dogs.

• With primary hypoadrenocorticism (Addison's disease), the problem lies in the adrenal gland itself, with atrophy or destruction of the gland.
• With secondary hypoadrenocorticism, the adrenal gland are normal, and the problem lies in the pituitary gland. The pituitary gland normally secretes a hormone called ACTH (adrenocorticotropic hormone) that stimulates the adrenal gland to secrete its hormones; in secondary hypoadrenocorticism, ACTH is not secreted in needed amounts, leading to the secondary adrenal insufficiency.
• The third subtype, atypical Addison's disease appears to be an early stage of primary hypoadrenocorticism in which only part of the adrenal gland has been completely destroyed.

What causes Addison's disease in dogs?
In most dogs, we cannot determine what caused their adrenal disease. With primary hypoadrenocorticism, the following causes must be considered.

• Most dogs with the primary form appear to have an autoimmune condition in which the body destroys part of the adrenal cortex
• Very rarely, infiltrative conditions such as cancer can metastasis to and destroy the adrenal gland to cause Addison’s disease
• Occasionally, treatment of Cushing’s disease with the drugs mitotane and trilostane will result in complete adrenal destruction and Addison’s disease

With secondary hypoadrenocorticism, we must rule out the following underlying causes.

• Congenital deficiency of ACTH secretion
• Pituitary tumors, inflammation or trauma that have destroyed most of the ACTH-secreting cells in the pituitary gland, leading to deficient ACTH secretion

With atypical hypoadrenocorticism:

• The mechanism by which atypical Addison's disease develops in not well-understood
• Most of these dogs appear to have an early stage of primary hypoadrenocorticism
• In these dogs, destruction of the adrenal cortex is not complete, making diagnosis more difficult

Are some dogs predisposed to developing this disease?
Although hypoadrenocorticism can develop in any age, breed, or sex of dogs, the following points should be taken into consideration when making a diagnosis.

• Hypoadrenocorticism is most common in young to middle-aged dogs.
• Most dogs with Addison's disease are females.
• Bearded Collies, Standard Poodles (see photo on left, below) , Great Danes, Portuguese Water Dogs, West Highland White Terriers (see photo on right, below), and Leonbergers are all predisposed to developing this disease.

Chain of events leading to severe hypoadrenocorticism in dogs
With primary hypoadrenocorticism (Addison's disease), the dog generally develops complete adrenocortical destruction with both cortisol and aldosterone deficiencies.

Aldosterone is the main mineralocorticoid hormone, and it affects the levels of potassium, sodium, and chloride in the blood. Low levels of aldosterone cause potassium to gradually build up in the blood and, in severe cases, cause the heart to slow down or beat irregularly. Some dogs have such a slow heart rate (50 beats per minute or lower) that they can become weak or go into shock.

Less commonly, dogs will develop secondary or "atypical” primary hypoadrenocorticism. This subgroup of dogs are only deficient in cortisol and appear to maintain a normal aldosterone level, at least early in the course of their disease. These dogs are more difficult to diagnose because their signs are milder and the serum potassium, sodium, and chloride values all remain normal.

Clinical features of hypoadrenocorticism in dogs
Historically, hypoadrenocorticism generally has a waxing and waning course and may be confused with other diseases because the clinical signs are not specific. The most common clinical signs and physical exam finding include the following:

• Depression or lethargy
• Weakness or collapse
• Anorexia (poor appetite)
• Weight loss
• Vomiting or diarrhea
• Excessive thirst and urination
• Hypothermia (low body temperature)
• Dehydration and shock

Signs of Addison’s disease include repeated episodes of vomiting and diarrhea, loss of appetite, dehydration, and gradual, but severe, weight loss. Because the clinical signs of Addison’s disease are vague and nonspecific, it can be difficult to diagnose in the earlier stages of disease. Therefore, severe consequences, such as shock and evidence of kidney failure, can develop suddenly in some dogs.

In my next post, I'll discuss how we can diagnose hypoadrenocorticism, can will be fatal if not properly managed.

An Overview of Endocrine Disease in Dogs and Cats

Either “Too Much” or “Not Enough” of a Hormone

Endocrine diseases stem from imbalances in hormone levels. Hormone imbalances can affect your pet’s health in many ways.  Although some endocrine disorders are not life threatening, many are fatal if not diagnosed and treated.

Diseases can develop because an endocrine gland itself is faulty or because the control of that gland is faulty (i.e., a problem in the pituitary can harm the adrenal glands).  Endocrine diseases develop when the body produces too much hormone (hyper- diseases) or too little hormone (hypo- diseases).

A tumor or other abnormal tissue in an endocrine gland often causes it to produce too much hormone. Hormone excess disorders often begin with the prefix “hyper.” For example, in hyperthyroidism, the thyroid gland produces too much thyroid hormone.

Hormone excess (“Hyper”) disorders in dogs and cats

• Pituitary tumors (most commonly, secrete too much growth hormone or ACTH)
  
• Hyperthyroidism (secrete too much thyroid hormone)
  
• Hypercalcemia (circulating calcium too high)
  
• Hyperparathyroidism (secrete too much parathyroid hormone)
  
• Pancreatic insulin-secreting tumor, usually called insulinoma (secrete too much insulin)
  
• Hyperadrenocorticism, usually called Cushing’s syndrome (secrete too much cortisol)
  
• Hyperaldosteronism, usually called Conn’s syndrome (secrete too much aldosterone)
  
• Pheochromocytoma (secrete too much adrenaline)
  
• Hypertension (blood pressure too high)

When an endocrine gland is destroyed, removed, or just stops working, not enough hormone is produced. Hormone deficiency disorders often begin with the prefix “hypo.” For example, in hypothyroidism, the thyroid gland does not produce enough thyroid hormone.

Hormone deficiency (“Hypo”) disorders in dogs and cats

• Pituitary dwarfism (secrete too little growth hormone in young animals)
  
• Diabetes insipidus (secrete too little antidiuretic hormone or vasspressin)
  
• Hypothyroidism (secrete too little thyroid hormone)
  
• Hypocalcemia (circulating calcium too low)
  
• Hypoparathyroidism (secrete too little parathyroid hormone)
  
• Diabetes mellitus (secrete too little insulin)
  
• Hypoadrenocorticism, usually called Addison’s disease (too little cortisol and aldosterone secreted)
  
• Hypotension (blood pressure too low)

Treating Endocrine Disease Again, Based on Either “Too Much” or “Not Enough” of a Hormone

Endocrine diseases caused by too much of a hormone can be treated surgically (tumor removal), with radiotherapy (such as the use of radioactive iodine to destroy an overactive thyroid gland), or with medications used to block the tumor from over-secreting the hormone.

One can normally treat hormone deficiency syndromes simply by supplementing the missing hormone.  For example, one can treat diabetes mellitus by giving insulin injections. Steroid and thyroid hormone replacements can usually be given orally.  Dogs and cats taking hormone replacement therapy must be monitored for side effects and periodically retested to make sure the drug dosage is correct. In some cases, such as after an endocrine tumor is surgically removed, the remaining gland will recover and hormone replacement will no longer be needed.
Unfortunately, most of these treatments are life-long.