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.