Diagnosing Canine Cushing's Disease: Should the ACTH Stimulation Test Ever Be Used?

How does this test work? What are we really evaluating with the ACTH stimulation test?

First of all, the basis for this test is that dogs with pituitary-dependent hyperadrenocorticism (PDH) or functional, cortisol-secreting adrenal tumors (FAT), because of their increased adrenocortical mass or volume, have the capacity to secrete excessive amounts of cortisol.

This is an indirect test that gauges the degree of adrenocortical thickness. Unlike the low-dose dexamethasone suppression test, the ACTH stimulation test doesn’t look at the entire hypothalamic-pituitary-adrenal (HPA) axis or the effect of glucocorticoid-negative feedback on the HPA axis.

In normal dogs, administration of ACTH produces a rise in serum cortisol to values usually >10 μg/dl (>300 nmol/L). In contrast, dogs with Cushing’s syndrome (because of the increased thickness of the adrenal cortex) tend to have an exaggerated cortisol response to ACTH administration, with post-ACTH serum cortisol rising to concentrations >20 μg/dl (>600 nmol/L). Dogs with iatrogenic Cushing's have a blunted cortisol response to ACTH (see figure).

But what’s the percentage of dogs with Cushing’s disease that are actually diagnosed with this test? What’s the test sensitivity?

About half of dogs with cortisol-secreting adrenocortical tumors and about 80% of dogs with pituitary-dependent hyperadrenocorticism (PDH) show an exaggerated cortisol response to the ACTH stimulation test.

In clinical practice and reality, however, the sensitivity is actually worse than those statistics reveal. Although it is clear that over 20% of dogs with Cushing's syndrome have post-ACTH cortisol test results within the reference range (< 20 μg/dl for my laboratory), an additional 20-30% of dogs with Cushing's have test results described as "borderline" (serum cortisol concentrations >16 μg/dl but <24 μg/dl).

In effect, that means that only 50-60% of dogs with Cushing's disease will have serum cortisol responses that are clearly abnormal (> 25 μg/dl). In other word, this test is a poorly sensitive diagnostic test for Cushing’s syndrome. In most dogs, it would be more cost effective to turn to another test, such as the low-dose dexamethasone suppression test, as the first-line screening test.

Other disadvantages to using the ACTH stimulation test:

In addition to the ACTH stimulation test’s mediocre test sensitivity, there are 2 other reasons for choosing one of the other diagnostic tests over the ACTH stimulation test, including the following.

1. First, of all, the cost of the preferred ACTH (cosyntropin; Cortrosyn) is high. I’ll discuss more about why you need to use cosyntropin in my next post (I’ll also offer my suggestions on how to extend the shelf-live of Cortrosyn to make it more cost effective).
2. Secondly, this test cannot determine the underlying cause of Cushing's syndrome. In other words, a positive ACTH stimulation test doesn't tell you whether the dog has PDH or FAT, so additional testing will always be needed to determine that. It is a true screening test, and no features of the ACTH stimulation test result allow discrimination between PDH and FAT.

Are there any clinical situations where we should use the ACTH stimulation test?

Yes, there are definitely 3 situations in which ACTH stimulation testing would be indicated as a diagnostic or monitoring test for adrenal disease in dogs. The major indications for using the ACTH stimulation include the following:

1. Best test to diagnose iatrogenic hyperadrenocorticism in dogs. If the dog has clinical and laboratory features consistent with Cushing’s syndrome (e.g., polyuria, polydipsia, polyphagia, pot-belly, truncal hair loss, high serum alkaline phosphatase) but has a recent history of glucocorticoid use, this is the test of choice. If the cortisol response to ACTH stimulation is low-normal or blunted in this dog, the diagnosis would be iatrogenic Cushing’s, rather than the naturally occurring disease. None of the other pituitary-adrenal function tests can make this differentiation.
2. Best test to use for monitoring and adjusting mitotane or trilostane therapy. Again, this is the only pituitary-adrenal function test that can be used in this situation; none of the other pituitary-adrenal function are useful in monitoring drug treatment.
3. “Gold Standard” test to diagnose spontaneous hypoadrenocorticism (Addison’s disease). This is true whether the dog has primary or secondary hypoadrenocorticism or typical or atypical disease; the ACTH stimulation test is the only test to use for this diagnosis. As you can see in the figure below (an Ad from the company that manufactures Cortrosyn), the main indication for ACTH as a diagnostic test is adrenocortical insufficiency, not Cushing's syndrome.

In general, there is a general rule for endocrine disease that is useful to remember when approaching endocrine hyperfunction vs. hypofunction:

In almost all cases, it is better to use stimulation tests to diagnose endocrine hypofunction, whereas suppression tests are best used for endocrine hyperfunction.

So with the ACTH stimulation, the 3 situations (listed above) where this test really has advantages over the other screening tests all include situations where the adrenal glands have been suppressed (iatrogenic steroid use, trilostane, mitotane) or destroyed (Addision’s disease)!

Q & A: Hyperthyroid Cat Not Controlled on High-Dose Methimazole

Tommie is a 14-year old MC DSH cat that presented 6 months ago for vomiting and weight loss. Hyperthyroidism was diagnosed based on a high serum T4 value (11.5 μg/dl; reference range, 0.8-4.0 μg/dl). Results of a CBC, serum chemistry panel, and urinalysis were normal.

I started him on 2.5mg methimazole twice daily. On recheck his serum T4 values was still high at 10.3 μg/dl so I increased the dosage to 5 mg twice daily. After 4 months on this dose, his serum T4 has decreased but remains slightly high at 6.5 μg/dl

I am afraid of increasing his dose any higher than 10 mg per day. All of the other cats I've treated have responded to this or even lower daily doses of methimazole. Any thoughts about the dosage in this cat?

My Response:

The dose of methimazole needed to control hyperthyroid cats is based on what it takes to lower the serum T4 concentration into the reference range, so there is not an upper limit to what methimazole dosage can be used. I've gone as high as 30 mg per day in some cats, although the incidence of side effects tends to be higher as you raise the dose. So in this patient, I would raise the dose to around 7.5 mg twice a day (total dose, 15 mg/day).

A few things that must be considered in this and all hyperthyroid cats that are treated chronically with methimazole is the following:

• Methimazole and other antithyroid drugs work by being taken up by the thyroid tumor where the drugs inhibit thyroid hormone production and secretion. With time, the thyroid tumor will grow larger and larger. Therefore, most hyperthyroid cats will require higher dosages to inhibit thyroid hormone secretion as their goiter becomes larger and the thyroid volume increases.
• In some of these cats, especially those treated for many months to years, the thyroid adenoma can transform into thyroid carcinoma while on these antithyroid drugs.

So, getting back to your cat, are you planning on using the methimazole long-term? At the moment, his daily dose is still quite low, but you are already having trouble regulating him. You might want to discuss the use of surgical thyroidectomy or radioiodine with the owner if you haven't already. Both of these are definitive treatment that are better choices for long-term prognosis, at least in my opinion.

Q & A: How Long Can Glargine and Detemir Insulins Really be Used Once Vial is Started?

Our pharmacist is telling me that determir insulin (Levemir) expires after 30 days. He claims that this is because of the risk of contamination.

At $112 a bottle, this short expiration date would make detemir cost prohibitive for my clients. Is detemir insulin actually stable for longer periods if kept refrigerated, as has been found with glargine insulin (Lantus)?

My Response:

Glargine is marketed for human use with a 28-day shelf-life at room temperature after opening. Similarly, detemir is marketed with a 6-week shelf-life at room temperature after opening of the vial.

The recommended shelf-lives for both detemir and glargine are relatively short, not because of lack of efficacy, but because of the increased risk of bacterial contamination with these multiple-use, injectable medication vials. The FDA believes that the insulin vials may have a high probability of becoming contaminated with microbes by the daily multiple punctures needed to withdraw medication when used past the insulin's expiration date.

For veterinary use, we generally recommend that both insulins be kept refrigerated, although the antimicrobial preservative in these insulins may actually be more effective at room temperature. Owners of diabetic cat or dogs use refrigerated glargine or detemir routinely for up to 3 months without evidence of problems occurring. The insulin should be discarded immediately, however, if any cloudiness or discoloration is noted.

This issue with bacterial contamination seems to be extremely rare. Pet owners are much more likely to accidentally drop and break the vial, than to have to throw it away because it develops discoloration.

Q & A: Does this Dog have Cushing's Syndrome?

I recently ran a low-dose dexamethasone suppression test on a 11-year-old male neutered Maltese with clinical features of muscle loss, thinning coat, and a pot-bellied appearance.  His serum chemistry panel is completely normal except an alkaline phosphatase activity in the thousands.  Below are the results low-dose dexamethasone suppression test, but I am confused as to what to make of them.

• Basal cortisol:  5.1 μg/dl (reference range = 1-4 μg/dl)
• 5-hr post cortisol:  <0.7 μg/dl (reference range = <1.5 μg/dl)
• 8-hr post cortisol:  1.9 μg/dl (reference range = <1.5 μg/dl)

Thanks in advance.


My Response:

The interpretation would be as follows: Slightly high basal cortisol, with complete suppression of cortisol at 5 hours, followed by escape from cortisol suppression at 8 hours.

The lack of suppression at the 8-hour testing period is diagnostic for hyperadrenocorticism. The fact that the dog suppressed so well at 4 hours tells us that this dog's Cushing's disease cannot be caused by an adrenal tumor (ie, these dogs would not suppress cortisol with either the low- or high-dose dexamethasone suppression test).

The pattern of cortisol suppression at 3-5 hours followed by escape from cortisol suppression at 8 hours, as shown here in this dog, is always diagnostic for pituitary-dependent hyperadrenocorticism.

Q & A: What's the Ideal Prednisone Dose for Dogs with Addison's Disease?

I'm writing to inquire if there is a consensus among the endocrine experts on the dose and frequency of administration of oral prednisone for an Addisonian dog on monthly Percorten injections.

i usually use about 0.1mg/kg SID, but some of my colleagues use 0.2mg/kg SID, whereas others using every other day (EOD) dosing at 0.1 - 0.2mg/kg each dose EOD).

i know each dog is different, and they may require more or less depending on "stressful" situations, but wanted to see if SID or EOD is the preferred frequency. I'd also like to know what dosage you recommend.

My Response:

For dogs with spontaneous hypoadrenocorticism (Addison's disease), it makes the most sense to me to give the glucocorticoid supplementation on a daily basis.

There is no reason to give alternative day steroids to avoid adrenal suppression in these dogs, because the adrenals are already permanently atrophied or destroyed in dogs with Addison's disease. If you give alternate day prednisone, they would have no glucocorticoid reserve on the off day.

I dose prednisone or prednisolone at 0.1-0.2 mg/kg/day. If the dog develops polyuria and polydipsia (PU/PD) or any other signs of iatrogenic Cushing's syndrome, I would lower the dose as needed.  I rarely, if ever, give a higher dose than 5-mg per day to ANY dog. The 5-mg dose is the average human maintenance dose, and we see very few dogs that weigh over 70 kg.

Taking the "Sting" Out of Practice Insulin Injections

In the newly diagnosed diabetic dog or cat, it is common practice for the veterinary staff to instruct the owner how to draw up and administer the insulin injection to their dog or cat. 

In most cases, we have the client practice the subcutaneous injections with sterile water or saline rather than the insulin solution itself. This allows the client to practice giving an injection multiple times if needed. Obviously, we can't give multiple insulin injections within a 15-minute training period!

If this is done, I've found that it is better to use saline, Lactated Ringer's, or another balanced fluid solution rather than sterile water for this purpose.

The subcutaneous administration of sterile water can be quite painful for the pet. If the dog or cat reacts adversely to the practice injection, that can make it more difficult for the owners to administer insulin at home. We all know that administration of any of the commercial insulin solutions, especially with today's small gauge insulin needles, are essentially pain-free!

Remember that many of our pet owners are really afraid of giving injections. Some may even consider euthanasia if their pet has developed diabetes. The last thing we want to do if have them believe that the insulin injections are going to be painful for their pet. 

Q & A: Cushing's in dogs...If it looks like a duck and quacks like a...

I saw a 4-year-old, MC Maltese today for a second opinion consult. The dog has severe polyuria and polydispia (PU/PD), and has also developed progressive lethargy, weight gain, extreme panting, and polyphagia over the last few months. The dog also has a marked pot bellied appearance, and has an large liver on abdominal palpation.

Results of my screening lab work is unremarkable except for a high serum alkaline phosphatase (805 U/L; normal < 100 U/L).  The urine specific gravity is dilute at 1.005.

Results of abdominal ultrasound show an enlarged liver with a diffuse increase in echogenicity. The left adrenal gland is mildly plump at 0.6 cm in diameter and 1.45 cm in length. The right adrenal gland was normal in size.



I did a low-dose dexamethasone suppression test with these results:  Pre 8.6 μg/dl;  4-hr Post 0.4 μg/dl; and 8-hr Post 1.4 μg/dl. The owner was told by other veterinarians that these results were not diagnostic for Cushing's syndrome, I guess, because of the 8 hr Post of 1.4 μg/dl.



This dog definitely looks Cushingoid. Clients refused to do a University of Tennessee adrenal panel or a urine creatinine ratio because of finances.  I am very inclined to treat with trilostane.   What do you think?

My Response:

This dog certainly sounds like he has Cushing's syndrome to me, too.  The results of the low-dose dexamethasone suppression test are very suggestive of pituitary-dependent Cushing's disease, with complete suppression at 4 hours and some escape at the 8-hour test period. I understand that the laboratory may have a diagnostic "cut off" value that is slightly higher than 1.4 μg/dl, but this test is very suggestive given the dog's signalment and clinical features.



I do agree with the owner that the University of Tennessee panel is expensive and is probably a waste of money for this dog. Everything so far is pointing to "typical" Cushing's disease so we need to use the time-honored tests for Cushing's first. In many dogs, we have to do more than one of the screening tests (sometimes more than once over to time) to confirm this disease, and you have only done one screening test on one occasion. So which should you do next, the ACTH stimulation test or measure urinary cortisol:creatine ratios (UCCRs)?



I would not bother with an ACTH stimulation test because it has the lowest test sensitivity (only 60-80%). This is another reason not to do the University of Tennessee adrenal panel. In addition, the ACTH that must be injected is expensive.



I would have the owner collect 3 urine samples at home and bring them to your hospital for submission for UCCRs. If money is an issue, you can take a small aliquot (1.0 ml) from each of the 3-day's urine samples the owner collected, and submit the pooled urine for a single UCCR result. This will then give you a 3-day average of urine cortisol secretion. If this is positive, then I'd treat with either trilostane or mitotane.



What if the owner refuses to do more tests? Then I certainly wouldn't start treatment at all. If the owner does not have the money to do a single UCCR, then how can they afford the medication or monitoring costs??  Cushing's is a very serious disease and, unfortunately, we do not have an inexpensive means of treating this disease.

 

It's time to have a heart to heart talk with the owner about this disease and what they really can afford.

Q & A: Hypercalcemia in an Older Lab - Is This Primary Hyperparathyroidism?

My patient is an 11-year-old spayed female Lab who has polyuria, polydipsia, and weight loss but is otherwise normal. Diagnostic testing has been relatively normal except that she has isosthenuria, hypercalcemia, and hypophosphatemia. These abnormalities are repeatable. 

Her serum parathyroid hormone (PTH) concentration is high (32.3, normal 3.0-17.0), ionized calcium is high (1.92, normal 1.25-1.45), and the parathyroid hormone-related polypeptide (PTHrp) is negative (0.0, normal 0.0-1.0). No gross evidence of perianal masses are seen including on rectal exam, and no lymph node enlargement can be palpated.

Will this be enough evidence to say that this dog definitely has primary hyperparathyroidism? Or should we do more to rule out other malignancy as the cause of hypercalcemia in this dog?

My Response:

Yes, it certainly does appear that your dog has primary hyperparathyroidism. I'd recommend chest radiographs and abdominal ultrasound to complete the workup, but they will likely be normal.

If you can do a parathyroid ultrasound, that would be recommended especially if surgical parathyroidectomy is planned.

Next Question:

Sorry to be a bother, but no chance that this dog couldn't have hypercalcemia of malignancy?

How about renal renal secondary hyperparathyroidism or nutritional secondary hyperparathyroidism?

My Response:

Hypercalcemia of malignancy is possible but extremely unlikely in this dog. While hypercalcemia of malignancy does not always produce high levels of PTH-rp, the PTH concentration should be low in that situation, not high as is the case in your dog.

Unless the dog is eating some bizarre diet, we can rule out nutritional disease in a dog of this age, and I assume the dog is not in renal failure at this time, which largely eliminates that consideration. So primary hyperparathyroid disease remains the most likely by far.

Follow-up and Final Diagnosis:

A single, parathyroid mass was identified and removed at time of exploratory surgery. Results of histopathology confirmed parathyroid adenoma.

The dog developed iatrogenic hypoparathyroidism and hypocalcemia during the immediate post-operative period. But now, 2 months after surgery, the serum calcium concentration is normal without any calcium or vitamin D supplementation.

Q & A: Pseudomyotonia in Dogs with Cushing's Syndrome?

One of my canine patients is a much-loved Collie-cross dog that has Cushing’s syndrome and pseudomyotonia. I really would like to learn more about the connection between these diseases but have not had much luck!

Could you update me on the latest on pseudomyotonia in dogs with Cushing’s disease?

My Response:

Pseudomyotonia is a very rare disorder affecting less than 1% of all dogs with Cushing’s syndrome. This disorder is characterized by continued muscle contraction after cessation of a stimulus or voluntary effort. The relaxation of the involved muscle(s) are delayed and associated with persistent, repetitive electrical activity.

Muscle changes associated with pseudomyotonia include weakness, stiff and stilted gait, distal muscle wasting, and sometimes muscle enlargement. Muscle spasms may be elicited when a muscle belly is tapped gently with a percussion hammer.


There are two forms of myotonia: acquired and congenital subtypes. Congenital myotonia is likely inherited in most breeds, and clinical signs appear at a young age. I personally have not seen such a case, since these dogs do not have any underlying endocrine disease.

Acquired myotonia is secondary to some underlying disease, usually hyperadrenocorticism (Cushing’s syndrome), and that’s the form of the disease that I’ve seen. That said, it is an extremely rare clinical feature of Cushing’s syndrome, and the cause is not at all clear.

Diagnosis of pseudomyotonia is based on characteristic clinical signs, characteristic electromyographic (EMC) findings, and muscle biopsy. Myotonic, bizarre, high-frequency discharges are noted on the EMG, Histologic findings in the musculature are characterized by a noninflammatory degenerative myopathy.

Most of the Cushing’s dogs that develop pseudomyotonia also have the more common clinical features seen in dogs with hyperadrenocorticism including polyuria, polydipsia, pot belly, hepatomegaly, and hair loss. In general, these dogs with pseudomyotonia have severe and advanced Cushing's syndrome.

With spontaneous (endogenous) hyperadrenocorticism, myotonic signs generally partially improve with effective mitotane or trilostane therapy. However, in my experience, the signs of myotonia never completely resolve. However, others have suggested that this disease is not a simple consequence of Cushing’s syndrome but is a full-fledged disease in itself (see paper by Siliart et al in reference list).

I’ve listed some references that I could find below. When available, I’ve put a link to the abstract of the article so that you can get additional information.

References:

1. Vite CH: Myotonia and disorders of altered muscle cell membrane excitability. Vet Clin North Am Small Anim Pract 2002 Vol 32 (1) pp. 169-187.
   
2. Blot S: Disorders of the skeletal muscles. Textbook of Veterinary Internal Medicine, Diseases of the Dog and Cat, 5th ed. Philadelphia, WB Saunders 2000 Vol 1 pp. 684-690.
   
3. Braund KG, Dillon AR, Mikeal RL: Subclinical myopathy associated with hyperadrenocorticism in the dog. Vet Pathol 1980 Vol 17 (2) pp. 134-148.
   
4. Duncan ID, Griffiths IR, Nash AS: Myotonia in canine Cushing's disease. Vet Rec 1977 Vol 100 pp. 30-31.
   
5. Kortz G: Canine myotonia. Semin Vet Med Surg (Small Anim) 1989 Vol 4 (2) pp. 141-145.
   
6. Swinney GR, Foster SF, Church DB, Malik R: Myotonia associated with hyperadrenocorticism in two dogs. Aust Vet J 1998 Vol 76 (11) pp. 722-724.
   
7. Siliart B, Marouze C, Martin L, Gayet C: Pseudomyotonia Associated with Hyperadrenocorticism in the French Poodle: 151 clinical cases (1993-2000). 12th EVCIM-CA/ESVIM Congress 2002. (see abstract below)

Pseudomyotonia Associated With Hyperadrenocorticism in the French Poodle: 151 Clinical Cases (1993-2000)
Objectives: To understand why pseudomyotonia affects only 1% of dogs with hyperadrenocorticism (HAC); why the breed affected is usually the French poodle; and why damage is generally limited to hind leg extensors.
Materials: 151 French poodles with pseudomyotonia referred on suspicion of Cushing's syndrome and 498 dogs of varied breeds affected by typical Cushing's syndrome. (HAC was confirmed based on stimulation by ACTH, when post-ACTH cortisol value was higher than 450 nmol/l after 90 minutes).
Results: Most myotonic French poodles were toy (75%), apricot coat (69%), female (66.2%), and old (11 ± 5 years) poodles. A genealogical study of the pedigrees suggested recessive autosomal transmission. Myotonia developed before typical signs of HAC appeared (6 months to 4 years before) and it developed first on the hind legs (hyperextension). The typical signs (cutaneous signs, polyuria-polydipsia, abdominal distension, and obesity) were less intense than in dogs with simple HAC, but cardiac disorders were more frequent. Biological signs: 13% of the dogs did not exhibit HAC and mean AKLP and cortisol values were lower than in simple HAC. Treatment of HAC had no effect on pseudomyotonia, even though cortisolemia decreased.
Conclusion: This disease is not a simple consequence of HAC, but a full-fledged disease and it is strongly suspected to be of genetic origin.

Test for Parathyroid Hormone Related Protein (PTHrP) No Longer Available

The Diagnostic Center for Population and Animal Health (DCPAH) at Michigan State University recently announced that the reagent for their parathyroid hormone related protein assay (PTHrP) is no longer available.

Currently, Michigan State University's DCPAH is the only laboratory that offers this particular test used in the workup for dogs and cats with hypercalcemia. They are looking in other assay reagents and will hopefully will be have this important assay up and running again soon.

See the DCPAH website at www.animalhealth.msu.edu for more information.

Q & A: PTH Assay Not Currently Available: Alternatives for Workup of Hypercalcemia?

I have a 12 year, F/S, Shih Tzu with hypercalcemia. A tumor search (lymph node aspirates, rectal exam, chest and abdominal radiographs) have revealed nothing so far. I sent a PTH, iCa, to the Michigan State Endocrine Laboratory (part of the Diagnostic Center for Population and Animal Health). After two weeks of waiting, I just received notification that the lab can't run the PTH due to unavailability of the reagents and may not be able to run the test for several weeks.

Are there any alternatives to confirming the diagnosis of primary hyperparathyroidism? Are there other veterinary laboratories that run PTH?

My Response:

The only other thing to consider diagnostically while waiting for the PTH result would be cervical ultrasound by an experienced sonographer armed with the proper transducer. If a large parathyroid mass mass is identified, that would be pretty decent presumptive evidence of primary hyperparathyroidism

If you haven't already done so, I'd repeat the total calcium and confirm the hypercalcemia by also measuring an ionized calcium. It is possible to have a high total calcium with a normal ionized calcium value. If that's the case, it's probably nothing to worry about. If the dog ill or showing any renal compromise? If the dog is stable, I'd just be patient. There's usually no need to rush to treatment if the underlying cause of the hypercalcemia is a parathyroid tumor.

Update: 
We just got notification from the Michigan State Endocrine Laboratory that they received the PTH reagents and that all back ordered test results would be available soon. So the good news is the the PTH assay is back up and running. See the link below for more information.
www.animalhealth.msu.edu/News/Announcements.php#85

It turns out that all of the commercial laboratories (Antech and Idexx), as well as most (if not all of the veterinary labs (e.g., Cornell, CSU, UC-Davis, Minnesota, Auburn, and Tennessee) all send their PTH samples to the Michigan State Endocrine Laboratory.

More Information on the Discontinuation of the Vetsulin® Critical-Need Program (CNP)

Intervet/Schering-Plough Animal Health has announced it is discontinuing the VETSULIN® Critical-Need Program (CNP) effective immediately and will no longer provide VETSULIN® after the current supply is exhausted, which is expected to be the end of this month (February 2011).

Quality tests showed that the sterility of the most recent batch of VETSULIN® manufactured for the Critical-Need Program may be compromised by bacterial contamination.  This batch of VETSULIN® has not been released.  We therefore cannot supply the program and it is being discontinued.

See attached letters for more information (click on each letter to enlarge):

No Resolution to Problems in Shortage of Vetsulin

A new development in the ongoing Vetsulin recall situation. From the FDA website: http://www.fda.gov/AnimalVeterinary/NewsEvents/CVMUpdates/ucm242368.htm

FDA Announces Upcoming Shortage of Vetsulin for Dogs and Cats in the Critical Need Program

February 4, 2011

The Food and Drug Administration (FDA) announced today an anticipated shortage of Vetsulin (porcine insulin zinc suspension), a product used to treat diabetes mellitus in dogs and cats. Vetsulin is manufactured by Intervet/Schering-Plough Animal Health and is only available to animals currently enrolled in the Vetsulin Critical Need Program.

In November 2009, FDA announced its concerns about the stability of Vetsulin, which may cause the product to have unpredictable onset and duration of action in dogs and cats treated with Vetsulin. At that time, FDA recommended that diabetic dogs and cats currently receiving Vetsulin be switched to other insulin products. In May 2010, Intervet/Schering-Plough Animal Health initiated the Vetsulin Critical Need Program, intended for a critical need dog or cat that, in the medical judgment of the pet’s veterinarian, could not be effectively managed on another insulin product.

In November 2010, Vetsulin intended for use in the Critical Need Program, failed critical manufacturing tests which are routinely conducted to assure consistency and quality of the drug. The tests showed that the sterility of the most recently manufactured batches of Vetsulin may be compromised by bacterial contamination. This batch of Vetsulin has not been released.

FDA has no evidence that Vetsulin currently on the market and being used under the Critical Need Program is affected. No adverse events consistent with bacterial infection in cats and dogs receiving Vetsulin have been reported to CVM under the current program.

Intervet/Schering-Plough Animal Health has indicated that it will be sending letters to owners of the pets enrolled in the Vetsulin Critical Need Program and their veterinarians. In those letters, the firm will be notifying veterinarians and pet owners of the upcoming shortage of Vetsulin and consequent discontinuation of the Vetsulin Critical Need Program. Owners of diabetic cats and dogs are encouraged to consult their veterinarian as soon as possible about transitioning their pets to other insulin products. Intervet/Schering-Plough Animal Health is planning to provide detailed instructions to veterinarians on how to manage the transition.

Q & A: Hypercalcemia in a Dog with Addison's Disease?

"Molly" is a 5-year-old Westie who was diagnosed with hypoadrenocorticism 3 years ago.  She has been getting DOCP (Percorten) injections every 3 to 4 weeks since that time.  She has been remarkably easy to regulate and very stable. She only takes prednisone as needed for stressful times (eg, boarding or grooming).  

The owners have been complaining of polyuria and polydispia (PU/PD) almost since the start of her treatment for Addison's disease, but lately they feel it is worse.  There has been no vomiting or diarrhea, and the dog appears normal in all other respects. 

We did a serum chemistry profile and, although the serum sodium and potassium concentrations were normal, her calcium was mildly high. The pertinent results are listed below:


     Potassium = 4.1  mEq/L (reference range, 3.7-5.8 mEq/L)

     Sodium = 143  mEq/L (reference range, 138-160 mEq/L)

     Calcium = 12.3 mg/dl (reference range, 8.6-11.8 mg/dl)

     Albumin= 4.1  mg/dl (reference range, 2.5-4.4 mg/dl)
     Urine specific gravity = 1.012
     Urine culture - negative


My questions: Molly has not had an high serum calcium level in the past. Is the mild hypercalcemia a concern at this point?  Should we consider changing her dose?  Right now she is taking 2 mg/kg of the Percorten IM every 3 - 4 weeks.  Would it be better to consider changing her to oral Florinef? Should I pursue running an ionized calcium or a PTH level?  

The owners are stretched financially just paying for the DOCP injections.  I am not sure how much more they will pay if I can't give them a really good reason for more tests.  



Thank you for your advice.

My Response:

The Addison's disease is NOT causing the hypercalcemia at this point. We only see that in unregulated patients (who generally are in adrenal crisis). In contrast, this dog appears to be very stable. The dog's PU/PD could be related to the hypercalcemia since she isn't on daily glucocorticoids. However, I'd also seen PU/PD develop secondary to the Percorten treatment.



I'd repeat the serum calcium at some point in the relatively near future (2-3 weeks). If the total calcium remains high at that point, I'd verify the hypercalcemia with a ionized calcium and get a PTH value. If the ionized calcium is normal, then the hypercalcemia may not be anything to worry about.

Diagnosing Cushing's Syndrome in Dogs: When Should I Test? What's the Best Test to Use?

How do we best diagnose hyperadrenocorticism in dogs? Which is the best diagnostic test?  A presumptive diagnosis of should be made from clinical signs, physical examination, routine laboratory tests, and diagnostic imaging findings, but the diagnosis must be confirmed by use of cortisol hormone assays and pituitary-adrenal function tests. For screening tests designed to diagnose Cushing's syndrome, we have three choices:

• ACTH stimulation test
  
• Low-dose dexamethasone suppression test (LDDST)
  
• Urinary cortisol:creatinine ratio (UCCR)

Which screening test is best?

Unfortunately, none of the diagnostic tests used in dogs with suspected Cushing's syndrome are totally reliable, and both false-positive and false-negative results are common. Because there are inherent problems with these diagnostic tests, the veterinarian is frequently challenged when attempting to properly interpret the dog’s tests results.

It is important to remember, however, that the predictive value of a positive screening test result for Cushing's increases in direct proportion to the number and severity of clinical signs and biochemical changes that develop in this disease. Therefore, one must always remember the importance of the dog’s signalment, history, and physical examination findings when interpreting the diagnostic test results of all pituitary-adrenal function tests.

Who should be tested for hyperadrenocorticism?

Testing for hyperadrenocorticism in a dog should be done because they have one or more clinical signs of the disease. Typically the disease is insidious and slowly-progressive, so most dogs have had clinical signs, such as abdominal enlargement, panting, muscle weakness, thin skin, lethargy, polyphagia, polyuria and polydipsia (PU/PD) for months to even years before the owners recognize a problem and seek veterinary help.

Who should NOT be tested for hyperadrenocorticism?

Testing for Cushing's syndrome is not recommended if the only abnormality is an increased serum alkaline phosphatase (SAP) activity on a serum chemistry panel, and the dog is otherwise apparently healthy. It is difficult enough to interpret endocrine tests in dogs with clinical signs of the disease; if they have no clinical signs, all of the endocrine tests may be difficult to interpret because of false-positive and false-negative results. The first step in workup in these dogs may include an abdominal ultrasound or bile acid testing.

One should not screen dogs for hyperadrenocorticism when the dog is sick with clinical signs that would not be related to Cushing's syndrome (e.g., vomiting, anorexia, weight loss). Many non-specific illnesses and other systemic diseases will produce false-positive results with the endocrine tests. Remember, hyperadrenocorticism is only slowly progressive, so hyperadrenocorticism is never an emergency diagnosis.

Before diagnostic testing is performed, it is therefore always good to ask oneself: if the test results would indicate hyperadrenocorticism, would I then feel confident to start treating with mitotane (Lysodren®) or trilostane (Vetoryl®) given the clinical picture of the patient? Would treatment help the dog's clinically signs? If either answer is "no," then it is probably best not to screen for hyperadrenocorticism in the first place.

My dog has clinical signs of hyperadrenocorticism and now other nonrelated illness − now can I test?

If the dog has any or all of the clinical signs of hyperadrenocorticism, yes, you should proceed with testing of the pituitary-adrenal axis. However, it is necessary first to ensure that the dog is not being exposed to exogenous glucocorticoids, including topical glucocorticoids on the eyes, ears or skin. First check with the owner to ensure that they are not applying topical glucocorticoids to their own skin − sometimes, dogs may ingest glucocorticoids by licking steroid-containing cream off of the owner's skin. If there is any doubt, ask the owner to bring in all and any medications that dog is receiving (including over the counter preparations) and anything that the owner or owner's family might be using in order to verify that no glucocorticoids are in any of these medications.

Next, obtain a routine database (CBC, serum chemistry analysis, and complete urinalysis) before any endocrine testing is undertaken. Finding the expected clinical pathology changes in a dog with suspected Cushing's syndrome helps confirm what the initial history and physical exam suggested. Typical abnormalities in dogs with hyperadrenocorticism include high values for serum alkaline phosphatase, alanine aminotransferase, low to low-normal serum urea nitrogen, and dilute urine specific gravity.  On the CBC, we may see a  'stress' leukogram (elevated mature neutrophils and monocytes, decreased lymphocytes and eosinophils), and a hematocrit and RBC count at the high end of normal.

What about now? Now should I use one of the screening tests?

If all the analyses point to hyperadrenocorticism at this stage, test away! In an upcoming blog, I'll be discussing the pros and cons of the ACTH stimulation test for Cushing's syndrome.