Diagnosing Hypothyroidism in Dogs

I have a 7-year old spayed Golden Retriever who weighs about 110 lbs. No signs of hypothyroidism except for being overweight with a borderline high serum cholesterol concentrations (256 mg/dl). The serum T4 value was slightly low at 0.9 µg/dl (reference interval, 1.0-4.0 µg/dl).

Is this slightly low serum T4 concentration diagnostic for hypothyroidism? Would you start her on levothyroxine (L-T4) and retest T4 levels in a month?

I'd appreciate your thoughts and recommendations.

My Response: 

I would never base the diagnosis on only a resting serum T4 value alone. We commonly find low values that fluctuate in and out of the reference range in dogs that are clinically normal and never develop hypothyroidism. In addition, most non-thyroidal illness will lower the total T4 values in dogs, and these dogs would not benefit from thyroid hormone supplementation (1). It certainly doesn't sound like your dog is sick or acting ill in any way, so this latter explanation probably doesn't apply here.

For your dog, I'd recommend that your veterinarian collect more sera to do a complete thyroid panel, which should include the following tests (2-4):

• Serum T4 concentration
• Serum T3 concentration
• Serum free T4 by dialysis
• Serum TSH concentration
• Serum levels of thyroglobulin autoantibodies

If you have it available in your area, thyroid scintigraphy (nuclear medicine scan) is actually the best and most accurate way to diagnose hypothyroidism in dogs (4.5).

 References: 

1. Kantrowitz LB, Peterson ME, Melian C, et al. Serum total thyroxine, total triiodothyronine, free thyroxine, and thyrotropin concentrations in dogs with nonthyroidal disease. J Am Vet Med Assoc 2001;219:765-769. 
2. Peterson ME, Melian C, Nichols R. Measurement of serum total thyroxine, triiodothyronine, free thyroxine, and thyrotropin concentrations for diagnosis of hypothyroidism in dogs. J Am Vet Med Assoc 1997;211:1396-1402.  
3. Nachreiner RF, Refsal KR, Graham PA, et al. Prevalence of serum thyroid hormone autoantibodies in dogs with clinical signs of hypothyroidism. J Am Vet Med Assoc 2002;220:466-471. 
4. Diaz Espineira MM, Mol JA, Peeters ME, et al. Assessment of thyroid function in dogs with low plasma thyroxine concentration. J Vet Intern Med 2007;21:25-32.  
5. Shiel RE, Pinilla M, McAllister H, et al. Assessment of the value of quantitative thyroid scintigraphy for determination of thyroid function in dogs. J Small Anim Pract 2012;53:278-285. 

World Diabetes Day: November 14 2014

Today, November 14th, is World Diabetes Day

World Diabetes Day is the primary global awareness campaign of the diabetes mellitus world and is held on November 14 of each year (1). It was introduced in 1991 by the International Diabetes Federation and the World Health Organization in response to the alarming rise of human diabetes around the world.

World Diabetes Day is a campaign that features a new theme chosen by the International Diabetes Federation each year to address issues facing the global diabetes community. This year's campaign theme is "Healthy Living and Diabetes"(1).

While the campaigns last the whole year, the day itself marks the birthday of Frederick Banting who, along with Charles Best, first conceived the idea which led to the discovery of insulin in 1922 (2). You can also find out more about Frederick Banting in Wouter de Herder's review Heroes in Endocrinology: Nobel Prizes (3).

Charles H. Best and Frederick G. Banting (on right) with one of the diabetic dogs used in their studies of insulin

In the past few years, diabetes rates among our pets in the U.S. have increased roughly 33% among dogs and 16% among the nation's cat population, per a national analysis of pet health (4). This emphasizes the importance of this disorder in our cats and dogs as well as human patients with diabetes. To successfully manage diabetes in animals, one must understand the disease and monitor and provide daily treatments to the cat or dog with diabetes. Treatment involves a combination of weight loss (if obese), diet, and insulin injections generally twice daily.

References 

1. World Diabetes Day – Official website.
2. Frederick Grant Banting (1891-1941), codiscoverer of insulin. Journal of the American Medical Association 1966;198:660-661. 
3. de Herder WW. Heroes in endocrinology: Nobel Prizes. Endocr Connect. 2014;3:R94-R104. doi: 10.1530/EC-14-0070. 
4. Washburn L. Human health risks on the rise in animals. The Record. April 20, 2011. 

Dr. Peterson Interviewed for Dog Fancy Article About Insulin Pen for Dogs

Dr. Peterson was interviewed for the September 2014 issue of Dog Fancy (pictured above). Merck Animal Health has just received approval from the FDA to sell their VetPen product, the first insulin injection pen available for diabetic dogs and cats, and Dr. Peterson weighed in on the benefits of such an easy-to-use device.

Insect Repellent, Antiviral Drug Detected in Jerky Pet Treats for Dogs

Chicken jerky treats consumed by dogs that became sick over the past few month have now been found to be tainted by the insect repellent N,N-diethyl-meta-toluamide, better known as DEET, as well as the antiviral drug amantadine.

This is according to a veterinary pathologist leading an independent probe of the ongoing pet treat mystery.  For more information, click this link to read the article by the Veterinary Information Network News Service.

Insulin Injection Pen (VetPen): More Questions (and Answers) about this New Diabetic Product

Since the FDA approved the use of a new insulin injection pen (VetPen) made by Merck Animal Health last week (1,2), I've received a number of questions from both veterinarians and owners of diabetic pets. Listed below are some of the most common questions with my responses.

Do we buy a single VetPen and use it forever? Or does the VetPen have to be replaced after a month or two?

The VetPen has been tested for at least 3,000 actuations (i.e., how many times the insulin release button is pressed and released). Therefore, a single VetPen is likely to last a lifetime for the majority of dogs and cats treated with diabetes.

How are the pens and cartridges sold? 
The reusable VetPen is supplied in a Starter Kit which contains everything you need to get started (see below). This included everything except the Vetsulin cartridges, which are supplied separately in cartons of ten, 2.7-mL cartridges.

The VetPen itself is available in 2 sizes. For greater accuracy at low doses, the first option (blue cap) has a maximum total dose of 8 units, allowing for dosing increments of 0.5 unit per injection. If higher insulin doses are being administered, the second VetPen option (tan cap) has a maximum total dose of 16 IU per injection, with dosing increments of 1 unit.

What is in each VetPen Starter Kit?
Each Starter Kit contains either an 8-unit or 16-unit VetPen with an instruction leaflet.

The kit also contains a box of 28-g, ultra-thin needles that feature a silicone coating to help minimize injection discomfort, as well as a needle remover that helps to remove used needles, while minimizing the risk of accidental needle stick injury. There is also a travel pouch to hold all of the components.

The kit also contains two adaptors to assist those with dexterity issues. The dose selector adaptor may be used to provide a better grip when selecting a dose. The release button extension may be used to provide a better grip when giving injections.

Are the VetPens an accurate way for insulin dosing?
The VetPen is ideal for cats and small dogs on low doses of insulin, in which dosing accuracy can be a concern (3,4). A recent study comparing the precision and accuracy of the VetPen to U40 syringes demonstrated that even when doses were drawn up by trained laboratory technicians, syringes were found to deliver at least 20% to 25% more insulin than needed for a 1-unit dose (5).

In contrast, VetPen enables doses to be delivered with accuracy and precision down to 0.5 units. In large dogs, dosing accuracy is generally not a problem.

Do the pens and cartridge need to be refrigerated? Other handling precautions?
The VetPen cartridges should be refrigerated (not frozen) and protected from light before opening.

VetPen does not need to be refrigerated after a cartridge has been started (4), although it probably is best to do so. The loaded VetPen can be stored on its side in the refrigerator.

VetPen should always be stored or carried with the needle removed and the cap on. To clean the device, wipe with a damp cloth. Do not immerse in water.

Are the VetPens expensive? How would the costs of the VetPen compare to those associated with the standard insulin vial/syringe method?

The cost of treatment will depend upon the size of the diabetic pet. For smaller dogs and cats, the price of the VetPen with the Vetsulin cartridges and needles will be similar to the cost of the standard 10-mL Vetsulin vial and U-40 insulin syringes.   For larger dogs, the standard way of administering Vetsulin (via an insulin syringe) would generally be a more economical way to provide insulin treatment.

Bottom Line:

These insulin pen devices are an alternative to the traditional insulin vial-and-syringe method and offer many advantages. In human diabetic patients, insulin pens have also been found to be less painful than the vial-and-syringe method and are often associated with greater patient preference and social acceptability (6-11).  Similar preliminary findings have been documented in dogs and cats (12,13). As a result, this method of insulin delivery may ultimately help to improve glycemic control and should be considered as an alternative insulin delivery method.

Insulin pens are designed to deliver a fixed insulin dose while insulin syringes rely on the ability of the user to accurately draw up the required insulin dose. One recent study reported that for low doses (below 8 units), the VetPens were more precise and accurate than the insulin syringes (5). In particular, insulin syringes tend to over-deliver, compared to the insulin pen, for very low doses (1 unit). For higher doses (16 units), both devices were comparable (5).

Similar findings have been reported in human pediatric patients, in which very low doses of insulin must be administered. One older study looked at the reliability of using U100 syringes for accurately administering low doses of insulin in the hospital by pediatric nurses. In that study, attempts to administer doses of 0.5 U or 1.0 U of U-100 insulin resulted in overdosage of 95% and 66%, respectively (14). Based on this study, it's no wonder that small diabetic dogs or cats are often a challenge to regulate when small insulin doses are needed.

References: 

1. FDA website. FDA Approves First Insulin Product for Use with Automatic Injection Pen in Cats and Dogs.
2. Press release. Merck Animal Health Receives FDA Approval of VetPen  
3. Merck Caninsulin website. Caninsulin® VetPen® helps make pet diabetes management easier 
4. Pet Diabetes website. What you need to know about the Caninsulin VetPen. 
5. Burgaud S, Riant S, Piau N. Comparative laboratory evaluation of dose delivery using a veterinary insulin pen. Proceedings World Congress ASAVA/FECAVA/BSAVA 2012;567.
6. Molife C, Lee LJ, Shi L, et al. Assessment of patient-reported outcomes of insulin pen devices versus conventional vial and syringe. Diabetes Technol Ther 2009;11:529-538. 
7. Pearson TL. Practical aspects of insulin pen devices. J Diabetes Sci Technol 2010;4:522-531. 
8. Wright BM, Bellone JM, McCoy EK. A review of insulin pen devices and use in the elderly diabetic population. Clin Med Insights Endocrinol Diabetes 2010;3:53-63. 
9. Cuddihy RM, Borgman SK. Considerations for diabetes: treatment with insulin pen devices. Am J Ther 2013;20:694-702. 
10. Davis EM, Foral PA, Dull RB, et al. Review of insulin therapy and pen use in hospitalized patients. Hosp Pharm 2013;48:396-405. 
11. McCoy EK, Wright BM. A review of insulin pen devices. Postgrad Med 2010;122:81-88. 
12. Burgaud S, Guillot R, Harnois-Milon G. Clinical evaluation of a veterinary insulin pen in diabetic cats. Proceedings World Congress ASAVA/FECAVA/BSAVA 2012;499.
13. Burgaud S, Guillot R, Harnois-Milon G. Clinical evaluation of a veterinary insulin pen in diabetic dogs. Proceedings World Congress ASAVA/FECAVA/BSAVA 2012;568.
14. Casella SJ, Mongilio MK, Plotnick LP, et al. Accuracy and precision of low-dose insulin administration. Pediatrics 1993;91:1155-1157. 

FDA Approves First Insulin Automatic Injection Pen for Diabetic Dogs and Cats

VetPen, for use with Vetsulin (in USA) and Caninsulin (outside USA)

The U.S. Food and Drug Administration (FDA) has approved the first insulin injection pen (VetPen, Merck Animal Health) for diabetic cats and dogs, the agency announced today, March 19, 2014 (1).

2 Sizes of VetPens

The VetPen may now be used to administer Vetsulin insulin cartridges, also made by Merck Animal Health. The refillable VetPen automatically measures the prescribed insulin dose and provides the owners of diabetic dogs and cats with an additional option for insulin delivery.

There are two sizes of refillable VetPens. One (tan cap) dispenses insulin doses from 1-16 units per dose in full unit increments. The other (blue cap) dispenses 0.5-8 unit doses in full or half unit increments. Both pens use 2.7 ml insulin cartridges which hold a total of 108 units (IU) of U-40 Vetsulin (or Caninsulin).

Vetsulin is an FDA-approved insulin for use in dogs and cats (2). This insulin is identical to Caninsulin, the brand name of the insulin sold in Europe (3).

Merck said the VetPen is easier to dose and administer and is more accurate than traditional delivery systems, such as syringes and vials (4). “For years, insulin pens have made managing diabetes more convenient for human diabetics,” the company said. “Merck Animal Health has now brought the same technology to veterinary medicine.”

An informational website (2) provides tools for both veterinarians and pet owners to make managing pet diabetes easier. More online information about the VetPen can also be found on the Caninsulin website (5); the Pet Diabetes website has an informational brochure that can be downloaded (6).

Administering insulin to a cat with the VetPen

For questions on how to obtain Vetsulin or the VetPen, please contact Merck Animal Health Customer Service at 800-521-5767.

References: 

1. FDA website. FDA Approves First Insulin Product for Use with Automatic Injection Pen in Cats and Dogs.
2. Merck Vetsulin website. www.vetsulin.com
3. Merck Caninsulin website. www.caninsulin.com
4. Press release. Merck Animal Health Receives FDA Approval of VetPen  
5. Merck Caninsulin website. Caninsulin® VetPen® helps make pet diabetes management easier 
6. Pet Diabetes website. What you need to know about the Caninsulin VetPen. 

What's the Best Insulin for Treating Dogs with Diabetes Mellitus?

I am writing you regarding my 11-year old male Weimaraner, Duke. He has always been in good health but over this past week he has had 2 ”accidents” where he has urinated in the bed. He has also been drinking a lot more water than usual and urinating more too.

I  took him to the vet because I had a feeling he might be diabetic. My veterinarian confirmed that it was indeed diabetes mellitus and started him on 10 units of NPH, once after breakfast and once after dinner.  He has improved since starting the insulin, but remains quite thirsty and continues to urinate excessively.

Now I know that this will not give very good control alone because NPH is only a long-acting insulin. I am a Type 1 diabetic, diagnosed when I was 12 years old, so I have quite a bit of experience dealing with this disease. I want my poor puppy to be as controlled as possible so he does not feel like I do when my sugars are out of control— lethargic, nausea, headaches, unquenchable thirst, urinating all the time, and just plain crappy! Not to mention the stress this puts on the on the rest of the body.

If dogs are anything like people, I believe that Duke needs an insulin mixture that will bring his blood glucose down to normal and keep it leveled out. I have been giving him the rapid-acting insulin analog Humalog (insulin lispro) along with the NPH and that seems to be working really well, with marked improvement in his thirst and urination.  The only problem is that he needs 4-6 injections of Humalog each day. I was hoping you have had experience with something that would give him the same control as Humalog but with less injections daily.

In the past, I have used short-acting Regular insulin (before Humalog was invented) but I do not remember how the dosing went. I do have much better control with the Humalog but I am also on an insulin pump, so NPH insulin is no longer necessary.

Any help you can give to allow my dog Duke better control long term without so many injections would be greatly appreciated.

My Response:

In dogs, veterinarians commonly start with an intermediate-acting insulin (NPH or Vetsulin) twice a day (1,2). In some dogs, I find it necessary to add a short-acting insulin to the longer-acting insulin preparation, but many dogs can achieve adequate glucose control without giving more than 2 injections per day.

Insulin of choice for canine diabetics
In my opinion, the insulin of choice for most dogs is Vetsulin (porcine insulin zinc suspension; Merck Animal Health) (3). The main advantage of Vetsulin (known as Caninsulin outside the USA (4), is that it is actually composed of both short- and long-acting insulin components (see Figure below, showing the duel peaks of activity) (5,6). So giving Vetsulin is like administrating NPH together with a second, short-acting insulin preparation, like you are doing now.  However, Vetsulin works better than NPH for most dogs because it has a longer duration of action than NPH.

Timing of meals and insulin injection
The short-acting amorphous fraction of the Vetsulin, which composes 35% of the insulin activity, acts like regular insulin or Humulog, mainly to control the rise in blood glucose after each meal (6).  To help prevent severe rises in glucose after meals, however, it is also important to give the insulin before meals, instead of after the food is ingested, as you are doing now. This protocol will allow the short-acting insulin to be absorbed into the blood stream and ready to act to lower the blood sugar as soon as the food is absorbed from the gastrointestinal tract (7).

The only time I don't do this insulin-feeding protocol is in dogs that don't always eat their meal well; but even in those dogs, I never wait long after the meal is finished to give the insulin. Instead, I always give the insulin injection as soon as possible, once the dog has eaten a sufficient amount of food.

Vetsulin (porcine insulin zinc suspension), with it's 2 peaks of insulin activity

References:

1. Nelson RW. Canine diabetes mellitus In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat. Seventh Edition ed. St. Louis: Saunders Elsevier, 2010;1449-1474.
2. Davison LJ. Canine diabetes mellitus In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;116-132.
3. Vetsulin website. www.vetsulin.com 
4. Caninsulin website. www.caninsulin.com
5. Monroe WE, Laxton D, Fallin EA, et al. Efficacy and safety of a purified porcine insulin zinc suspension for managing diabetes mellitus in dogs. J Vet Intern Med 2005;19:675-682.
6. Fleeman LM, Rand JS, Morton JM. Pharmacokinetics and pharmacodynamics of porcine insulin zinc suspension in eight diabetic dogs. Vet Rec 2009;164:232-237.
7. Cobry E, McFann K, Messer L, et al. Timing of meal insulin boluses to achieve optimal postprandial glycemic control in patients with type 1 diabetes. Diabetes Technol Ther 2010;12:173-177. 

U-40 Insulin Syringes Recalled

Med-Vet International Issues Recall of 1/2-cc U-40 Insulin Syringes Due to Mismarked Syringe Barrels (1).  

On February 14, 2014 , Med-Vet International initiated a voluntary nationwide recall of 140 boxes of 1/2-cc U-40 insulin syringes (1). The syringes are incorrectly labeled as 40 units per 1/2-cc syringe, whereas they should be marked with only 20 units per 1/2 cc. Obviously, this could potentially result in a lower-than-prescribed dose of insulin being administered, and lead to relapse of signs of diabetes, as well as development of ketoacidosis.

Consumers who have these insulin syringes should quarantine all products subject to recall. In addition, if you, as the veterinarian, may have sold these syringes, please inform the clients at once about this product recall so they can change to another insulin syringe.

The following 1/2-cc U-40 insulin syringes have been recalled:

• 140 boxes of 1/2-cc insulin syringe U-40 with 29g x 1/2” needle. Lot Number: 20120610
• The product can be identified by Item number: MV1/2CCINS-40 or 1/2CCINS-40 by Oasis.

Med-Vet International is arranging for return of all recalled 1/2-cc U-40 insulin syringes. Consumers with questions may contact the company via telephone at (800) 544-7521 or via e-mail at customerservice@shopmedvet.com.

References:

1. FDA website (www.fda.gov). Med-Vet International Issues Nationwide Recall of Veterinary 1/2cc U-40 Insulin Syringes Due to Mismarked Syringe Barrels

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.  

Combining Rapid and Long-Acting Insulin Analogs for Dogs with Diabetes

I am the owner of Coco, a 6-year old male Poodle who has been diagnosed with diabetes mellitus. I noticed the symptoms myself, as I too am a Type 1 diabetic (I was diagnosed 42 years ago at the age of 7 years). 

My dog's blood sugar was slightly more than 400 mg/dl when I brought him in for testing. That’s terribly high. I am a man with deep concern about this disease, and I personally keep myself in very good control (my A1-C tests are always in the 6’s). And thus, I am interested in having excellent control of my dogs health too. 

I’ve been directed by my veterinarian to give ”Coco” 2 daily injections of long-acting type insulin (I give him glargine (Lantus) since that’s what I use for my diabetes). So I started him 5 units of Lantus twice a day but still found him to be drinking far too much water and still having high sugar levels. So, I then added in small amounts of insulin lispro (Humalog) to better control his sugar. I’ve not yet taken him back in for spot checking of his blood, but I do notice the Humalog is helping decrease his water drinking and urinating at normal levels. So now, I give him 2 shots at breakfast and 2 at dinner—5 units of Humalog and 10 units of Lantus twice per day. And I watch him closely but find he is doing well. I see no signs of low blood sugar. 

Do you find my plan a good one? Am I overreacting by giving him Humalog in addition to the Lantus? I’m not a doctor, but I think a blood sugar curve should be between 70-150 mg/dl to keep him healthy, just like in human diabetic patients. Is this correct? Is there something better I can do? 

Finally, is there a simpler way to give the injections? I use a small needled Pen for his injections between his shoulders in a pinch of skin. Is there a needle-free ”Jet” type injection system that would be better than the needles? 

Thank you very much for any help advice you can share. 

My Response: 

Although insulin glargine (Lantus) can be used to treat diabetic dogs (1-3), it doesn't always work well as the sole insulin preparation, as you have discovered in your dog. Therefore, I don't usually start with glargine in dogs, but I use either NPH (Humulin) or lente (Vetsulin) insulins, which give us a higher success rate (4,5).

Your approach to combining a long-acting insulin analog (glargine; Lantus) with a rapid-acting analog (lispro; Humalog) is certainly an acceptable one. Insulin lispro has been proven to be effective in dogs (6) and combing Lantus with Humalog  has been recommended as an option by some investigators (1). If you use Lantus and Humalog yourself, this may be a good option for you. The rapid-acting Hunalog insulin will lower the blood sugar rise that occurs after meals, whereas the longer-acting Lantus will act as a background insulin to maintain glucose levels between meals.

You mention that you would like keep your dog's blood sugar well-controlled. That is a good idea, especially if you want to prevent the formation of diabetic cataracts, which are common in dogs with diabetes (7,8). However, to do that, the use of "spot checks" of his blood glucose concentration will not be enough. You are going to have to do periodic blood glucose curves, either done at home or in the hospital (9-11). 

Finally, our current options for insulin injections are either use of an insulin needle and syringe or an insulin pen, such as the Lantus SoloStar pen (12).Use of needle-free, jet injector for insulin delivery has been reported (13,14). However, to my knowledge, such jet injectors are not yet available commercially, and they certainly have not been tested in diabetic dogs.

References:

1. Mori A, Sako T, Lee P, et al. Comparison of time-action profiles of insulin glargine and NPH insulin in normal and diabetic dogs. Vet Res Commun 2008; 32:563-573. 
2. Fracassi F, Boretti FS, Sieber-Ruckstuhl NS, et al. Use of insulin glargine in dogs with diabetes mellitus. Vet Rec 2012;170(2):52.
3. Peterson ME. Treating diabetic dogs with insulin glargine. Blog post. May 3, 2012.
4. Palm CA, Boston RC, Refsal KR, et al. An investigation of the action of neutral protamine Hagedorn human analogue insulin in dogs with naturally occurring diabetes mellitus. J Vet Intern Med 2009;23:50–55. 
5. Monroe WE, Laxton D, Fallin EA, et al. Efficacy and safety of a purified porcine insulin zinc suspension for managing diabetes mellitus in dogs. J Vet Intern Med 2005;19:675-82.
6. Sears KW, Drobatz KJ, Hess RS. Use of lispro insulin for treatment of diabetic ketoacidosis in dogs. J Vet Emerg Crit Care (San Antonio) 2012;22:211-218. 
7. Beam S, Correa MT, Davidson MG. A retrospective-cohort study on the development of cataracts in dogs with diabetes mellitus: 200 cases. Vet Ophthalmol 1999;2:169-172. 
8. Wilkie DA, Gemensky-Metzler AJ, Colitz CM, et al. Canine cataracts, diabetes mellitus and spontaneous lens capsule rupture: a retrospective study of 18 dogs. Vet Ophthalmol 2006;9:328-334. 
9. Wiedmeyer CE, DeClue AE. Glucose monitoring in diabetic dogs and cats: adapting new technology for home and hospital care. Clin Lab Med 2011;31:41-50. 
10. Cook AK. Monitoring methods for dogs and cats with diabetes mellitus. J Diabetes Sci Technol 2012;6:491-495.
11. Davison LJ. Canine diabetes mellitus In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;116-132.
12. Association AD. Insulin administration. Diabetes Care 2001;24:1984-1987. 
13. Engwerda EE, Abbink EJ, Tack CJ, et al. Improved pharmacokinetic and pharmacodynamic profile of rapid-acting insulin using needle-free jet injection technology. Diabetes Care 2011;34:1804-1808. 
14. Engwerda EE, Tack CJ, de Galan BE. Needle-free jet injection of rapid-acting insulin improves early postprandial glucose control in patients with diabetes. Diabetes Care 2013;36:3436-3441. 

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.

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. 

How to Adjust the Glucocorticoid Dose in Dogs Treated for Addison's Disease

Zoe, a female Rat Terrior with Addison's disease

Zoe is a 4-year-old 17.5 lb (8.0 kg) female Rat Terrier who was diagnosed with Addison’s disease 7 months ago. She receives Percorten injections every 28 days, along with 5 mg of prednisone daily.

She is active and playful but is always famished. Her water intake has also increased on the medication, but she isn't showing any incontinence.

My major concern is that she has lost her hair on all four legs and belly, and now it is progressing up her shoulders, hind quarters, and to her head!

Her lab tests are within normal range according to her vet, who wants to take a wait and see approach. I thought she may be getting too much prednisone, but my vet is afraid to cut back for fear of her ”crashing” and developing an adrenal crisis.

Any thoughts on this? Zoe could sure use the help before all the other dogs start teasing her!

My Response:

Based on the clinical features of increased appetite, increased thirst, and hair loss, it is most likely that Zoe is being overdosed with the prednisone and has developed iatrogenic Cushing's syndrome (glucocorticoid excess).

In support of that, the daily maintenance dose of prednisone or prednisolone in dogs with Addison's disease is only 0.1-0.2 mg per kg per day. So at 8 kg (Zoe's body weight), that calculates out to 0.8 mg to 1.6 mg per day. This is only 15-30% of the dose that she is now receiving every day. When you think about that, it's no wonder that she is showing signs of glucocorticoid (prednisone) excess!

Remember that the adrenal glands in dogs with Addison's disease have failed so we must replace the missing hormones. These dogs will require lifelong replacement with both a mineralocorticoid (e.g., Percoten-V) and glucocorticoid (e.g., prednisone) hormone.  Both the mineralocorticoids and glucocorticoid dosages must be individualized for that particular dog.

The dosage of the mineralocorticoids can best be determined by monitoring the serum electrolyte concentrations (sodium, chloride, and potassium); the dosage is increased to decreased, as needed to normalize the circulating electrolyte concentrations.

Prednisone (or prednisolone), a common glucocorticoid used to treat dogs with Addison's disease, is ideally started at physiological dosages (0.1-0.2 mg/kg/day). This dosage should be adjusted up or down as needed, as some dogs show exquisite sensitivity to the adverse prednisone’s effects. The amount of prednisone that enhances the dog’s well-being (normal activity level and appetite) but prevents side effects (increased thirst, panting, polyphagia, hair loss) may be very small.

If a dog's serum electrolytes are normal on Percorten replacement therapy, dogs with Addison's disease aren't going to develop serious adrenal crisis, even if the prednisone dosage is lowered too much for a day or two.

My Bottom Line: 

Your dog is receiving too much glucocorticoid supplementation. With time, even a mild overdose will lead to signs of iatrogenic Cushing's syndrome, which may include hair loss, increased thirst and urination, and increased appetite. I'd taper the dose down to 1 mg per day over the next couple of weeks. The prednisone is available as a 1-mg tablet, which would make dosing much more convenient.

If the hair loss doesn't resolve after two to three months, I'd recommend that your veterinarian check a serum thyroid panel. Some dog's with Addison's disease will also develop concurrent hypothyroidism, which commonly leads to hair loss in dogs.

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 Association, 2004; 172-180.
2. Kintzer PP, Peterson ME. Treatment and long-term follow-up of 205 dogs with hypoadrenocorticism. J Vet Intern Med 1997;11:43-49.
3. Klein SC, Peterson ME. Canine hypoadrenocorticism: part I. Can Vet J 2010;51:63-69.
4. Klein SC, Peterson ME. Canine hypoadrenocorticism: part II. Can Vet J 2010;51:179-184.