Managing Addison's Dogs with Concurrent, Uncontrolled Diabetes

I have a 10-year old male Terrier dog named Scooter who now weighs in at 11 pounds (5 kg). He was originally diagnosed diabetes mellitus that we could not get regulated with Vetsulin, even at doses as high as 8 units twice daily. 

Scooter was subsequently diagnosed with with pituitary-dependent Cushing's disease and was treated with mitotane (Lysodren). Once we got the Cushing's disease under control, his daily insulin requirements fell to 3 units twice a day, and the diabetes was well regulated based on glucose curves done at my vet's hospital. However, after a few months of treatment with mitotane, it was apparent that Scooter had been severely overdosed with the medicine, which resulted in complete adrenal insufficiency and threw him into a severe Addison's crisis. It was a near death experience for him, but he has pulled threw and is now doing much better off of the mitotane and on treatment for his iatrogenic Addison's disease. 

Now we have spent the last 3 months trying to stabilize his iatrogenic Addison's disease and concurrent diabetes. Currently, he is on 2.5 mg of fludrocortisone (Florinef) twice day along with 1.25 mg of prednisone twice daily. The Florinef dose has had to be gradually increased to keep his serum electrolytes (sodium and potassium) within their proper ratio and ranges. Based on his last blood test, we may have to increase it yet again, since his serum potassium remains slightly high. 

To make matters even worse, his diabetes is now completely out of control, as evidenced by his intense thirst and excessive urinations with heavy amount of glucose in the urine. Serial blood glucose monitored done at my veterinarian's clinic confirms that the blood glucose readings remain very high throughout the day. We have gradually increased the insulin dose back up to 7 units twice daily, but it just doesn't seem to be working at all at this point. 

What do you recommend that I do? We need to get the Addison's disease controlled but as we have raised the doses of the Florinef and prednisone, Scooter's diabetes is getting worse! My vet has suggested that I transition Scooter from the Florinef tablets to Percorten injections in order to stabilize his serum electrolytes. He also told me that the Florinef contains some steroid activity which may be contributing to his high insulin doses.  Is the steroid in Florinef any less hard on him than the prednisone?   

Any advice would be greatly appreciated. 

My Response: 

With Scooter, we need to address both his poorly-regulated Addison's disease and his uncontrolled diabetes, as well as the increased thirst (polydipsia) and urination (polyuria). There is a lot going on with Scooter, so let's take one problem at a time.

Mineralocorticoid replacement: Florinef vs. Percorten-V? 
For mineralocorticoid replacement for dogs with Addison's disease, either oral fludrocortisone acetate (Florinef) or injectable desoxycorticosterone pivalate (DOCP; Percorten-V) can be used successfully (1-3).

In your dog, however, I would definitely make the switch to Percorten-V. Some dog's just don't respond very well to treatment with Florinef, and it's not uncommon for dogs to require increasing doses of daily Florinef over time to control the serum electrolyte concentrations (1-3). With high doses of Florinef, this can lead to signs of increased thirst and urination, and may also lead to problems with management of diabetes, as you are seeing in Scooter.

Since you are having problems controlling the serum electrolytes, I'd recommend starting with the label dose of 2.2 mg/kg, injected every 25-30 days (4). If this drug works to stabilize the serum sodium and potassium levels (and I expect that it will), then we can try to gradually lower the Percorten dosage after a few weeks to months (e.g., I generally try reducing the dose by 10% or so each month). Many dogs will maintain normal serum electrolyte levels on doses between 1-1.5 mg/kg per month, and a few will even need less (1,5).

Glucocorticoid supplementation in Addison's disease
Now let's next turn to your dog's glucocorticoid needs. Dogs with Addison's disease, either spontaneous or iatrogenic (that is, drug-induced, as it was in Scooter), will require replacement glucocorticoids (e.g., prednisone or prednisolone) in addition to the mineralocorticoid supplementation (1-3). Some dogs will do fine without any glucocorticoid supplementation, but the vast majority of dogs will feel better with a small daily dose of glucocorticoid administered daily. Since we know that these dogs cannot secrete normal amounts of cortisol, it certainly makes a great deal of sense to use low-dose glucocorticoid replacement.

Unfortunately, many dogs with Addison's disease are treated with too much glucocorticoid. Remember that our goal with glucocorticoid supplementation is to provide the same amount of steroid that the dogs would normally produce if their adrenals had not failed.

For dogs, the daily glucocorticoid maintenance dose for prednisone is only 0.1-0.2 mg/kg/day (3), so that calculates out to only 0.5-1.0 mg per day for Scooter, quite a bit lower that what you are currently giving (2.5 mg per day). That would certainly be enough to cause an increased thirst by itself, but would also contribute to glucocorticoid-induced insulin resistance, making the diabetes uncontrollable despite the higher insulin doses.

Therefore, we should try to lower the prednisone dosage first down to 1.0 mg once daily (or divided). If he is doing well clinically (i.e., normal appetite and no vomiting), then the dose can be lowered even further, down to 0.5 mg per day. Prednisone or prednisolone are available in 1-mg tablets, as well as an oral solution, making it possible to administer these smaller dosages (6,7).

Florinef also contains significant glucocorticoid activity
In addition to the fact that Addison's dogs are commonly overdosed with prednisone, it's very important to realize that fludrocortisone acetate also possesses moderate glucocorticoid activity, as well as having marked mineralocorticoid potency (2,3). By comparison, fludrocortisone has 10-times the glucocorticoid activity and 125-times the mineralocorticoid activity of cortisol, the glucocorticoid hormone secreted by the adrenal gland. In this regard, fludrocortisone is very different than Percorten-V, which possess no glucocorticoid activity (2,3).

For the dog with Addison's disease, a glucocorticoid is a glucocorticoid —it makes no difference to Scooter if this glucocorticoid activity comes from prednisone or from the Florinef.  This potent glucocorticoid activity of fludrocortisone explains why some dogs will develop polydipsia and polyuria, common side effects associated with higher-dose glucocorticoid treatment in dogs (8). This is another reason why we need to get Scooter off of the Florinef and switch to the Percorten-V.

Glucocorticoid-induced insulin resistance
In all likelihood, the reason for Scooter's poorly controlled diabetes is related to insulin resistance associated with glucocorticoid excess (9,10). By stopping the Florinef and providing mineralocorticoid replacement with Percorten-V instead, we will remove one source of excess glucocorticoid. Lowering his daily prednisone dose will also help.

As we remove the cause of the insulin resistance, the dose of insulin will again fall. You should monitor Scooter closely during this period to ensure that insulin overdosage and hypoglycemia do not occur, and lower the insulin dose as needed.

Don't forget to rule out urinary tract infections
Finally, don't forget that diabetic dogs, no matter what the cause, will commonly develop urinary tract infections. Think about it: a bladder full of sugar-laden urine is a perfect breeding ground for bacteria to thrive! Such urinary tract infections will also commonly contribute to insulin resistance (9,10) but can also lead to kidney failure, if the infection ascends from the bladder up to the kidneys.

For this reason, I always recommend checking a complete urinalysis and urine culture in all dogs (and cats) with insulin resistance. However, even if the diabetes is well-controlled, I still recommend doing a urinalysis with culture twice yearly in all of my diabetic patients.

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.
3. Kintzer PP, Peterson ME. Canine hypoadrenocorticism In: Bonagura JD, Twedt DC, eds. Kirk's Current Veterinary Therapy, Volume XV. Philadelphia: Saunders Elsevier, 2014; pp 233-237.  
4. Lynn RC, Feldman EC, Nelson RW. Efficacy of microcrystalline desoxycorticosterone pivalate for treatment of hypoadrenocorticism in dogs. DOCP Clinical Study Group. J Am Vet Med Assoc 1993;202:392-396. 
5. Bates JA, Shott S, Schall WD. Lower initial dose desoxycorticosterone pivalate for treatment of canine primary hypoadrenocorticism. Aust Vet J 2013;91:77-82. 
6. Peterson ME: Treating small-breed Addison's dogs with low doses of prednisone or prednisolone. Animal Endocrine Clinic blog, December 14, 2013. 
7. Plumb, DC. Plumb's Veterinary Drug Handbook. Seventh Edition, Wiley-Blackwell. 2011.
8. Melián C, M. Pérez-Alenza, D, Peterson ME. Hyperadrenocorticism in dogs, In: Ettinger SJ (ed): Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat (Seventh Edition). Philadelphia, Saunders Elsevier, 2010;1816-1840.
9. Hess RS. Insulin resistance in dogs. Vet Clin North Am Small Anim Pract 2010;40:309-316. 
10. Peterson ME. Diagnosis and management of insulin resistance in dogs and cats with diabetes mellitus. Vet Clin North Am Small Anim Pract 1995;25:691-713.  

Working Up the Asymptomatic Dog for Cushing's Disease

I have an 11-year old small (20 pounds) male dog of mixed breeding. In preparation for a routine dental procedure, he had a blood panel done, which showed that two of his liver enzymes are high. The serum alkaline phosphatase was 617 U/L (normal < 100 U/L), and the serum alanine aminotransferase (ALT) was 172 U/L (normal < 100 U/L).

He was placed on Denosyl (SAMe) at the daily dosage of 90 mg for 6 weeks. Repeat serum chemistry testing at that time revealed that his liver enzyme levels were slightly decreased, with an alkaline phosphatase value of 426 U/L and an ALT of 115 U/L.

My vet then changed his medication to Denamarin (a supplement containing both SAMe and milk thistle) and suggested retesting in 4 weeks.  When I brought my dog in for that recheck, however, the vet did an ACTH stimulation test instead of running the liver enzymes! The results of the ACTH stimulation test were normal, with a baseline cortisol value of  2.1 µg/dL and a post-ACTH cortisol value of 14.1 µg/dL. Despite the fact that both of those cortisol levels are within the normal range, the vet is now telling us he thinks our dog has Cushing's disease and wants to do an ultrasound at a cost of $300!

My dog is COMPLETELY asymptomatic, and he has no signs of Cushing's disease (normal thirst, appetite, and hair coat). I would have never known he had high liver enzymes without the dental blood panel. Now I feel like I'm being taken for a ride. He has not been rechecked for liver enzymes so I have no idea if the medication he's been on has been working, and we're chasing this test result that by the vet's own admission can be greatly skewed by stress. Finally, he still needs the dental!

Am I wrong for declining the ultrasound and seeking a second opinion or am I missing something here? What would your recommend?

My Response:

What you're describing in your dog is a common scenario that we see frequently in every day practice. The increases in the liver function tests that are present in your dog could indeed be due to Cushing's syndrome, which is a common disease in older dogs (1). Dogs with Cushing's disease tend to develop a characteristic type of hepatopathy, which frequently helps lead us to the diagnosis (1-3). However, the liver enzymes may be high because of primary liver disease too (2).

The Denosyl and Denamarin can't hurt your dog and may help some types of liver disease, but they probably aren't going to change the clinical course if he does have Cushing's disease.

Testing for Cushing's disease
The finding of normal results on an ACTH stimulation test certainly goes against the diagnosis of Cushing's disease. However, the finding of normal results would not be all that unusual in a dog with early or mild Cushing's disease. For that reason, the ACTH stimulation test is not my test of choice for screening dogs with possible Cushing's syndrome. I'd rather do a low-dose dexamethasone suppression test, which is a more specific test since it evaluates the entire pituitary-adrenal axis (1,4-6).  But that's an 8-hour test and more money, so you might want to either just continue to monitor the liver tests or go straight to an abdominal ultrasound at this point.

Why do an abdominal ultrasound in this dog?
In my opinion, performing an abdominal ultrasound this time is not a bad idea. Doing an ultrasound examine would allow us to take a good look at the liver to determine if the liver is small or large in size, as well as to look for any obvious pathology (e.g., liver nodules or tumors). Dogs with Cushing's disease tend to develop liver changes that have a characteristic appearance on ultrasound, so that can also help us in the diagnosis (1,7).

In addition to just examining the liver, performing an ultrasound examination will also allow us to look at the entire abdomen, including the adrenal glands. If both adrenal glands are large, that can be consistent with pituitary-dependent Cushing's disease, the most common type of this disease in dogs. On the other hand, if one adrenal gland is very large and the other is very small, that would be consistent with unilateral adrenal tumor (1,3,8). Since half of adrenal tumors are malignant (1), it's always a good idea to locate the adrenal tumor and remove it as soon as possible.

Now most likely, your dog does not have an adrenal tumor, and he may not have Cushing's disease at all. If both adrenals are enlarged (consistent with pituitary-dependent Cushing's disease),  I certainly wouldn't start treatment immediately since your dog is not showing any clinical signs.  None of the medical treatments we use for Cushing's disease, including trilostane (Vetoryl) or mitotane (Lysodren) actually cure the dog — these drugs only act to lower the cortisol values and control the clinical signs (1).  Again, if you dog has an adrenal tumor, I'd recommend removing it because of the risk of malignancy.

If your dog does have mild Cushing's disease, it is likely that clinical signs will develop at some time in the future. This could be in a week or a year or more, and may never happen.

What about the dental procedure?
If the abdominal ultrasound rules out significant liver pathology (i.e., no hepatic tumors or cancer) and both adrenal gland are similar in size (i.e., no adrenal tumor), then I would definitely recommend having the dental procedure done. Some dogs with severe dental disease can develop high liver enzymes secondary to the oral inflammation, so a good dental procedure may actually help to lower the liver function tests.

References:

1. Pérez-Alenza D, Peterson ME. Hyperadrenocorticism in dogs In: Ettinger SJ,Feldman EC, eds. Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat (Seventh Edition) Philadelphia, Saunders Elsevier, pp 1816-1840, 2010. 
2. Sepesy LM, Center SA, Randolph JF, et al. Vacuolar hepatopathy in dogs: 336 cases (1993-2005). J Am Vet Med Assoc 2006;229:246-252. http://www.ncbi.nlm.nih.gov/pubmed/16842046 
3. Graves TK. When normal is abnormal: keys to laboratory diagnosis of hidden endocrine disease. Top Companion Anim Med 2011;26:45-51. 
4. Peterson ME. Diagnosis of hyperadrenocorticism in dogs. Clin Tech Small Anim Pract 2007;22:2-11.
5. Gilor C, Graves TK. Interpretation of laboratory tests for canine Cushing's syndrome. Top Companion Anim Med 2011;26:98-108 
6. Kooistra HS, Galac S. Recent advances in the diagnosis of Cushing's syndrome in dogs. Vet Clin North Am Small Anim Pract 2010;40:259-267. Melián CM, 
7. Hoffmann KL. Ultrasonographical examination in canine hyperadrenocorticism. Aust Vet J 2003;81:27-30. 

FDA Video: Safe Handling of Pet Food in the Home

This week the U.S. Food and Drug Administration’s Center’s for Veterinary Medicine released a new video that cautions consumers about the health dangers — in the form of food-borne illness and disease—associated with feeding pet foods.

Based upon the unsettling assumption that pet food or treats might be contaminated, the video brings to light how your pet (and you) might avoid becoming ill if you follow some basic, commonsense food safety guidelines. And what steps to take should you suspect a pet food has adversely affected you or your pet.

Taking these precautions are very important in animals with endocrine disease, especially since many hormonal problems (e.g., diabetes, hyperadrenocorticism, hyperthyroidism) lead to a suppressed immune system and a decreased ability to ward off infections or other toxicities.

To see the video, click here to to directly to the FDA website or see the link below.

Link:

• FDA Website: Safe Handling of Pet Food in the Home (Video) http://www.fda.gov/AnimalVeterinary/ResourcesforYou/AnimalHealthLiteracy/ucm296800.htm?source=govdelivery

3 Things You Can Do To Help Your Dog Lose Weight

We are an overweight society and our pets are no different. Over half of American dogs are overweight, and up to 25% are obese.

Dogs with obesity are more prone to a variety of health problems, just like people. These include an increased incidence of diabetes, asthma, and hip and joint problems.

Losing weight can help overweight dogs become healthier and happier. It can also help them to live longer.

Here are some things you can do tomorrow that can help your dog start losing weight.

1. Cut the treats in half. If you must feed treats, cut them in half or give half as many in a day. This can help cut calories. Switching to carrots may help.
2. Exercise your dog more. Ask your vet if your pet is healthy enough to tolerate more exercise. If you play with your dog every day, play a few minutes longer. If you go on a walk, go a little farther. This helps burn calories.
3. Lower the amount of calories your dog consumes each day by changing your dog's food. I like to use diets lower in carbohydrates and higher in protein.

There are several diets formulated for weight loss. Discuss it with your veterinarian to learn more. But remember, whatever diet is chosen, portion control is a big issue.

Although the most common explanation for an overweight pet is simply a lack of exercise and too much to eat. But what if you feed your dog sensibly, exercise adequately, and your dog still has a weight problem?

There could be a number of underlying diseases may be causing your dog to become overweight or obese. Hormonal diseases such as hypothyroidism and Cushing’s syndrome commonly cause weight gain. Steroid pills or tablets with cortisone-like drugs could also be contributing to the obesity.

If these 3 simple hints don't help, ask your veterinarian if an underlying disease could be part of the problem.

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.

Obesity in Dogs: Is your Dog Just Eating Too Much, or Is Something Else Wrong?

We are an overweight society and our pets are no different. By far, the most common explanation for an overweight pet is simple: lack of exercise and too much to eat. But what if you feed your dog sensibly, exercise adequately, and your dog still has a weight problem?

There could be a number of reasons your dog is still overweight, including heredity, temperament, and overall activity level. However, a disease may be causing your dog to become overweight or obese.  Hormonal diseases such as hypothyroidism and Cushing’s syndrome commonly cause weight gain. Hormone pills or tablets with cortisone-like drugs could also be contributing to the obesity.

Hypothyroidism is deficient thyroid hormone, and it causes alterations in cellular metabolism that affect the entire body. The dog may not feel like exercising and may gain weight because calories consumed are not matching calories expended. The weight gain then makes the dog feel like exercising even less. Hypothyroidism is usually inherited and a common genetic illness in dogs. Untreated hypothyroidism means a lower quality of life for your dog, but with the proper thyroid supplementation, this condition can be easily controlled, allowing your dog to enjoy a good quality of life.

Cushing’s syndrome (hyperadrenocorticism) is chronic excess of a glucocorticoid hormone, cortisol. This hormone is essential for functions such as maintaining blood glucose levels, metabolizing fats, keeping major organs functioning properly. There are different types of Cushing’s with many symptoms and causes, so it can sometimes be difficult to diagnose. Furthermore, its onset is slow, so its symptoms are often mistaken for signs of age. Cushing’s syndrome can cause reduced activity, change in appetite, and hair loss. Other symptoms include an increased thirst and urination, muscle weakness, and obesity. The cause of the Cushing’s syndrome determines the treatment, which is also influenced by the overall health of the dog.  

Adequate exercise and proper diet are essential for all animals, but if your dog is overweight and you suspect an underlying disease, see a veterinarian for a thorough physical exam including laboratory tests.

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.