Monday, September 23, 2013

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. 

25 comments:

Brian Chan said...

My dog, a Chihuahua, weighing 6.4 pounds is diagnosed with Cushing. Ultrasound shows enlarged liver, both adrenal glands are enlarged. According to my vet, the LDDS is positive for cushing too - 130mnol/l at 0hr, 75nmol/l at 3hr, and 110nmol/l at 8hr.

CBC shows ALP at 690u/l, ALT 203u/l. This was done today. Compared to CBC slightly over 2 months ago, ALP was 507u/l and ALT 164 u/l.

As for clinical signs, I don't see my dog is having excessive urination or drinking a lot. I measure her daily water intake for the past one month and it is about 150-160ml per day for a 6.4pound dog. Her appetite is good though but not excessive. The only clinical sign I really see is thining of the skin and slow growth of her hair, and some bruises on her tummy which seems to take some time to heal.

My vet suggested to start with vetoryl at 3mg capsule (to be compounded) twice a day.

I see that you suggested not to immediately start treatment in your response to this particular article.

Do you recommend I start treatment for my dog immediately based on the test results and the elevated ALP/ALT? Or should I wait till a time when the clinical signs are obvious? What would happen to the elevated ALP/ ALT level if I wait? Would waiting be even riskier than taking the risk to put my dog through Vetoryl treatment? I am very concern about the adverse side effects and toxicity of Vetoryl.



Dr. Mark E. Peterson said...

It certainly doesn't appear to me that your dog is asymptomatic. Thinning of the skin, slow growth of her hair, and bruises on her abdomen that take some time to heal are present -- and none of these are early signs. The diagnostic tests all point to pituitary-dependent Cushing's disease. I would recommend following your vet's advice and start the trilostane at the recommended dose.

Based on the information that you have provided, your veterinarian certainly appears to know what he or she is doing!

Brian Chan said...

Thank you for your reply, Dr Peterson.

I have another question. I came across from some sources on the internet that Trilostane may hasten the growth of the pituitary gland tumour because of the reduction in cortisol level, is it true? If true, what is the likelihood of this happening? And if the reduction in cortisol level does hasten the pituitary tumour, then wouldn't treating cushing which solves some of the clinical signs but on the other hand, makes the underlying tumour worse, a worst outcome than trying to solve the clinical signs? I am trying to weigh the benefits and risks of both sides, treating or not treating. My primary goal is for my dog to live a happy and good quality of life for the rest of her life. I do not want to take a decision by treating her with a drug that has the potential to do real damage to her life when her quality of life currently appears good. However, assuming if her quality of life now is very bad such that she urinates frequently, or is drinking so excessively, and is panting, I would not hesitate to put her on Trilostane.

Or maybe I have misunderstood the potential toxicity of Trilostane? What is the likelihood that a dog would reacts adversely (particularly to Addison's disease) at the low starting dosage of 2.2mg per kg per day? What really scares me is the high number of deaths in the clinical trials indicted on the product insert by Dechra although the dosage used in the trials were 3-5x the standard recommended dosage.

I really appreciate your further advice.

Dr. Mark E. Peterson said...

We have no evidence that trilostane would accelerate the growth of a pituitary tumor. It's a possibility, but not ever proven to occur and I wouldn't withhold treatment based on a possibility.

Trilostane has a low rate of serious adverse effects, especially if monitored carefully. We know use dosages that are much lower than Dechra used in the reported clinical trials and that has helped.

Brian Chan said...

Dr Peterson,

This is the third day Kooky has started her treatment on Vetoryl. So far, she is doing well, appetite is still the same, drinking as usual, energy is the same. The only thing I noticed is that her stools are soft, not watery or runny. The first two days, the stools were ok, today, it is soft. I am unsure if it is diarrhea, perhaps very mild diarrhoea. The shape of the stools are well shaped except that it is soft.

Even before her treatment with Vetoryl, she does gets soft stools from time to time and it resolved after a few days.

So I appreciate your advice if this is a cause for concern?

Dr. Mark E. Peterson said...

As long as the appetite is good and no vomiting, I would not be concerned. Make sure you keep in contact with your vet during this initial Vetoryl treatment.

Brian Chan said...

Dr Peterson,

In your opinion, is there any difference between taking Trilostane in the branded form, Vetoryl, or from bulk ingredient compounded generically?

I am using Vetoryl to compound into smaller dosage. But I understand there is a cheaper option of compounding the same dosage from bulk ingredient.

Dr. Mark E. Peterson said...

The brand name product is recommended. Who knows what's really in the bulk product? Sometimes it works and other times it doesn't.

judymag said...

Dr. Peterson: I am a long time member of the k9cushings.com forum. The administrators suggested I post here with questions regarding my 12 year old beagle, Abbie, who is my second Cushing's pup (first was also a beagle). I adopted Abbie in 2003 when she was 7 years old. She was diagnosed in 10/2015 with Cushing’s (PDH) via ultrasound, symptoms (significant PU/PD, lethargy, potbelly), blood test results and ACTH. Treatment with Lysodren was started (my vet did not use Vetoryl at all). Cortisol was lowered after loading but it was not possible to maintain control during maintenance, including after a mini-load when pre and post dropped to below 1. After 7 months it was decided to switch to Vetoryl. Last ACTH on 6/10/15 was pre of 5.4 and post of 15.6. Thirty days after stopping Lysodren Abbie is asymptomatic for Cushing’s.

Consistently high urinary protein levels led to UPC test on 4/21/15; result was 5.0. BP average was 168 systolic. Treatment was immediately started with 5 mg. enalapril once a day. Two weeks later UPC result was 4.7. Enalapril increased to twice a day. Two weeks later UPC result was 4.9. BP average lowered to 124 systolic. Amlodipine added (one week on 2.5 mg. once a day, one week on 5 mg. once a day). Latest UPC result on 6/17/15 was 4.8. My vet has been consulting with an IMS regarding proteinuria treatment but not Abbie's IMS.

Abbie has hx of frequent soft stools with periods of diarrhea since adopting her 5 years ago. One reason may be that she eats as many crispy dead worms as she can grab! She has been on and off metronidazole, 125 mg. 2x/day; she is currently on it. Food is Purina DCO dry mixed with small amount of Royal Canin LF canned. After trying many different foods with varying fiber levels, this combination helped more than others to control soft stools. I give Abbie S-Adenosyl 225 daily and Forti-Flora on her evening meal. Superchem on 6/17/15 showed continued elevated ALP, cholesterol and triglycerides as well as slightly elevated potassium. Current treatment plan is to continue current meds and re-test BP with renal panel in 2.5 weeks. Follow-up ultrasound to be done in October. FYI, at my urging, my vet has consulted with Dechra re Vetoryl.

Questions: in light of high, uncontrolled proteinuria, would you recommend starting Vetoryl even though Abbie is not showing any symptoms? If/when we do start Vetoryl, would you recommend doing an ACTH prior to treatment to get a more accurate measure of cortisol since last one was 30+ days ago?

Thank you!

Judy H.

Dr. Mark E. Peterson said...

Yes, I would start trilostane now (1 mg/kg twice daily). I see no reason to recheck the ACTH stimulation test. The values are already too high.

judymag said...

Dr. Peterson: Thank you so much for your quick reply. Can you explain why twice daily dosing would be preferable for Abbie? I now feed her first meal at 7:30 and her second meal at 3:45 with same portion at each meal. I know trilostane needs to be administered with food. If twice daily dosing is best, is a small snack with the evening dose, i.e., few pieces of kibble plus a teaspoon of canned, be sufficient? Abbie currently weighs 24 lbs. so I would expect that 20 mg. of trilostane daily (once or split into two doses) would be the best starting dose.

Because Abbie is on enalapril, I know that extra caution needs to be taken when on trilostane. Should a full renal panel be run with every ACTH or are serum electrolytes by themselves sufficient?

Judy H.

Dr. Mark E. Peterson said...

Twice daily administration is needed for the best control, and that's why you need here. Yes, monitor a complete biochem panel every time you retest.

judymag said...

Dr. Peterson: Thanks for your reply. Just want to clarify Abbie's dosing/feeding schedule when we start twice daily trilostane --

I now feed her first meal at 7:30 and her second meal at 3:45 with same portion at each meal. I would give her 10 mg. with the morning meal. I really don't want to change the timing of her 3:45 meal but could reduce it. Since the trilostane does need to be given with food, is a small snack (a few pieces of kibble with a teaspoon of canned food) before the 10 mg. evening dose at 7:30-8:00 sufficient?

Judy H.

Dr. Mark E. Peterson said...

As long as the treat contains some fat (Trilostane is a fat-soluble drug), that would be fine.

Dr. Mark E. Peterson said...

As long as the treat contains some fat (Trilostane is a fat-soluble drug), that would be fine.

judymag said...

Dr. Peterson -- thanks for all your input! I received the Vetoryl yesterday and Abbie will get her first dose on 7/29 with an ACTH (along with superchem panel and UPC) scheduled for 8/11 assuming all goes well until then.

Question: Abbie is prone to yeast flare-ups in both ears. To keep this under control, I flush her ears with Vet Solutions Ear Cleansing Solution followed by Mometamax every couple of weeks. If the yeast is widespread, there have been periods when Mometamax is applied daily for a week to ten days with flushing every few days. Is the amount of mometasone in the Mometamax significant enough to affect cortisol levels?

Judy H.

Dr. Mark E. Peterson said...

Possible, but unlikely to make a difference for a dog on Vetoryl.

Brian Chan said...

Dr Peterson,

I would appreciate your advice. My dog, a chihuahua, weighs 2.7kg, is on 3mg of vetoryl twice daily. She started vetoryl about a month ago. On the 10th day of vetoryl, an acth test was done and the base cortisol shows 96 nmol/l and post acth 349 nmol/l.

Then on the 30th day, the second acth test was done. This time, the cortisol level worsened, the base is 118 nmol/l and post 566 nmol/l.

My vet suggests to continue current dosage and see if her cortisol will trend down in 1.5 months time.

My question is 1) is this usual that cortisol on the 30th day is worse than on the 10th day of medication, 2) if the cortisol level remains uncontrolled and does not trend down, and if my vet is to recommend an increase, what is the safe level to increase? is it by half of current dosage or 10% or 20%?

Thank you

Dr. Mark E. Peterson said...

Given these values, I'd consider raising the dose now. Now "safe" amount to go up.. every dog is different. Once any dose adjustment is made, I'd recheck another ACTH stim test in 2-3 weeks. That all said, if your dog is stable, it's not wrong just to wait either. Talk to your vet again about your concerns and what to do.

judymag said...

Dr. Peterson: Back with a question about Abbie's treatment -- she has been on twice-daily Vetoryl for three weeks. Fourteen-day post-ACTH did show a drop in cortisol to 11.3 so at least we are going in the right direction. Unfortunately, her UPC jumped back up to 5.6 and we are now gradually lowering enalapril and starting telmisartan. A super-chem was done right after ACTH. Cholesterol was doubled and triglycerides tripled and I am thinking the lack of fasting may have contributed to these increases.

Question: With Vetoryl being given at 7:30 am after morning meal, how do we schedule a fasting blood test? Should a morning dose be skipped the day after the ACTH so that she is fasting? Or is the lack of fasting not a significant factor in test results?

Due to adding telmisartan, my vet wants to do a super chem 7 days after she has been on a twice daily dosing without the enalapril. This will be a week after her 30 day ACTH but would still have same issue of fasting.

Thanks in advance for your guidance!

Judy H.

Dr. Mark E. Peterson said...

The fasting sample should be collected on a separate day from when you are doing an ACTH stimulation test.

Joanne Gunner said...

Dr Peterson, may I just ask a very quick question regarding the use of Telmisartan in a dog also taking Vetoryl? My JRT (weight 8.7kg) is on 20 mg vetoryl and has just been prescribed a half dose of Telmisartan in an effort to gain control of her high proteinuria levels. She also takes 5mg Fortekor/Benazepril. Are there any contraindications between these drugs?

Dr. Mark E. Peterson said...

I would check with your veterinarian and the drug company. I an not familiar with Telmisartan.

Unknown said...

Hi Dr. Peterson.

Much like the other people who have posted, our 10 year old lab mix was first discovered to have elevated ALP levels last year. We just started some additional testing a month ago, and discovered she has dilute urine as well.

We just got an abdominal ultrasound done today. Everything looked fine. From what I remember the vet saying, there were some minor blemishes on the liver and spleen. She aspirated the spleen, but was unable to get to the liver due to it's location, fat between the entry point and the liver and a lack of desire to anesthetize our dog. She also took a urine sample for a culture to test for a hidden UTI. The only symptom we really have is that over the last 7 months she's gained 5 pounds (from 45 in May to 50 now, despite food being cut in half). She did have surgery last February for a sarcoma as well.

Otherwise our dog is asymptomatic. She does develop hot spots, and recently she has lost hair from the back of her legs, but that seems to be related to itchiness.

The vet seemed to be of the opinion that if everything comes back negative from today's tests, it's best to leave our dog alone. I'm inclined to agree, as it is starting to feel like we're chasing an abstract number for the sake of the number itself.

What do you think?

Dr. Mark E. Peterson said...

I agree. Monitoring is the best "treatment" in dogs like yours.