Q & A: Adjusting the Trilostane Dose in Dogs with Cushing's Syndrome: Blunted Cortisol Response to ACTH Stimulation

I am using trilostane (Vetoryl, Dechra Animal Health) to treat a 14-year old, MC Poodle (10 kg) with pituitary-dependent Cushing's disease.  He has also been diabetic for the past year. 

Prior to diagnosis of the Cushing's disease and treatment with Vetoryl (10 mg, BID), his diabetes was difficult to control and he was slightly insulin resistant. Now that he is on treatment for the Cushing's disease, his diabetes is well controlled with NPH insulin (7 U, BID). 

It is now 3 months since we started this dog on Vetoryl.  His 30-day recheck was good, with a basal cortisol of 2.0 μg/dl and a post-ACTH cortisol of 5.2 μg/dl. 

On his 90-day recheck, the dog looks great and the result of his CBC, serum chemistry panel and complete urinalysis look good. Results of the ACTH stimulation test, started 4 hours after the morning dose of Vetoryl, revealed a basal cortisol of 3.8 μg/dl, with a post-ACTH value of 4.0 μg/dl. 

I am concerned about the blunted cortisol response to the ACTH injection, more than the absolute numbers. What do you think? Should I lower the dose of the Vetoryl?

My Response

Do not worry about this dog's blunted serum cortisol response— this is a perfect response for a dog on Vetoryl.

As long as both the basal and ACTH-stimulated cortisol concentrations are above 2 μg/dl and the dog is doing well clinically, you should not be concerned about the lack of cortisol response to ACTH stimulation (1,2). In fact, even if the post-ACTH cortisol concentration was lower than the basal cortisol (but both were greater than 2.0 μg/dl), I would still not be concerned.

If all continues to be well, I'd follow-up with another recheck in 3 months. At each recheck, I would recommend at least a serum chemistry panel, urinalysis, and cortisol determinations (1,2). If no signs of relapse are apparent, you might want to monitor only a basal cortisol concentration (3), but I would recommend that you perform an ACTH stimulation test at every other recheck visit at the minimum.

Remember that dogs with either Cushing's disease or diabetes are predisposed to developing urinary tract infections (1), so I also recommend doing a urine culture every 6 months on these dogs with concurrent diabetes and Cushing's syndrome. These dogs can have asymptomatic urinary tract infections, so the urine culture should be done even if they do not show any overt clinical signs of hematuria or stranguria.

References:

1. 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; pp. 1816-1840.
2. Ramsey IK. Trilostane in dogs. The Veterinary Clinics of North America Small Animal Practice 2010;40:269-283.
3. Cook AK, Bond KG. Evaluation of the use of baseline cortisol concentration as a monitoring tool for dogs receiving trilostane as a treatment for hyperadrenocorticism. Jornal of the American Veterinary Medical Association 2010;237:801-805.

Q & A: Managing Dogs with Cushing's Syndrome: Mitotane vs Trilostane?

I had attended your endocrine lectures at the annual meeting of the Minnesota Veterinary Medical Association last month and heard your great talk on how you workup and treat dogs with Cushing's syndrome.

My patient is a 9-year old, FS, Brittany Spaniel, weighing about 20 kg. She has a 6-month history of increased drinking, urination, hunger, and weight gain. 

On her routine blood tests, she had high serum alanine aminotransferase activity (ALT, 152 U/L; reference range, 12-118 U/L), high serum alkaline phosphatase activity (1998 U/L; reference range, 23-212 U/L). The serum cholesterol was also elevated  at 459 mg/dl (reference range, 110-320 mg/dl). I did a serum bile acids test, which was normal.

After I heard your lecture, I did a low-dose dexamethasone suppression test, with the following cortisol results. 

• Cortisol basal sample: 3.3 μg/dl (reference range, 1-5 μg/dl)
• Cortisol 4 hr: 2.2 μg/dl (reference range, 0.0-1.4 μg/dl)
• Cortisol 8 hr: 3.5 μg/dl (reference range, 0.0-1.4 μg/dl)

I know that the lack of cortisol suppression is diagnostic for Cushing's syndrome but the results do not differentiate between pituitary-dependent hyperadrenocorticism and functional adrenal tumor.

The owner is interested in doing an abdominal ultrasound and wants to pursue treatment eventually. So we are planning to set up an appointment for an ultrasound as the next step, but I did have some questions in terms of longer-term outcome for dogs with Cushing's disease. With some of our other suspected cases, the owners have not pursued pituitary-adrenal function testing or treatment due to cost, so I haven't actually had any that I've gone on to treat (I've also only been practicing since July 2010).  

1. If it is an adrenal tumor, you had recommend treating with trilostane for several weeks prior to surgical adrenalectomy, correct? Does this help to minimize post-operative complications?
2. And if they go on to surgery, and it comes back as benign, do most dogs do pretty well after long-term?
3. If the owner cannot afford/does not want to pursue surgery, can they do relatively well on trilostane (provided it isn't a carcinoma)?
4. If pituitary-dependent and treated with trilostane, do dogs do pretty well long-term? I wasn't sure about their long-term prognosis.

Thanks for you time in advance. I really appreciate any insight you're able to give me since again, we haven't really treated many dogs at my clinic.

My Response:

In answer to your questions:

1. Yes, if this dog has an adrenal tumor, I recommend treating with trilostane (Vetoryl, Dechra Animal Health) for 4-6 weeks prior to surgery (1,2). Controlling the high cortisol values prior to surgery helps to minimize post-operative complications, such as thromboembolism, poor wound healing, and infections.
2. If the dog has a benign adrenal tumor which is removed surgically, the dog would be cured (1). Post-operatively, she will go through a period of adrenal insufficiency (remember that the contralateral adrenal cortex is suppressed and will take a few weeks to start working again). During the immediate post-operative period, glucocorticoid supplementation should be initiated. The doses of the daily glucocorticoids should then be slowly tapered over the next 6-8 weeks, when they can generally be discontinued in most dogs.
3. If the owner cannot afford the cost of adrenalectomy or does not want to pursue surgery, most dogs can be controlled relatively well on trilostane (Vetoryl) but will never be cured (1-3). Overall, the prognosis with medical treatment is not as good as surgical treatment. If the dog has adrenal carcinoma, medical treatment will not prevent tumor growth, invasion into the vena cava, or metastasis (1).
4. If the dog has pituitary-dependent hyperadrenocorticism (PDH) and is treated with trilostane (Vetoryl), most dogs do well when treated with either mitotane (Lysodren) or trilostane. Studies have reported that there is no difference in survival between use of either of these drugs (4,5).

Botton line— We need a differentiating test to help guide our treatment recommendations and determine prognosis. Let me know when you have the results of the abdominal ultrasound on this dog.

Follow-up:

The abdominal ultrasound was just done this morning. Both adrenals were at the upper end of normal size —not nodular— and no masses found on either adrenal gland. 

So these imaging results are consistent with pituitary-dependent Cushing's disease, correct?

My Response:

Yes, your dog has PDH and can be treated with either trilostane or mitotane.

Remember to explain to the owner, however, the dog's problem lies in the pituitary gland, not the adrenal glands. Most of these dogs will have small pituitary tumors that tend to grow slowly over time (1,6,7). Others, however, have large pituitary tumors at time of diagnosis and some of these tumors expand more rapidly and can cause compression of the hypothalamus and lead to neurological signs.

Hopefully, your patient will be well-controlled with the medical treatment and will die of old age before the development of a large, invasive pituitary tumor becomes and issue.

References:

1. 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; pp. 1816-1840.
2. Ramsey IK. Trilostane in dogs. The Veterinary Clinics of North America Small Animal Practice 2010;40:269-283. 
3. Helm JR, McLauchlan G, Boden LA, et al. A comparison of factors that influence survival in dogs with adrenal-dependent hyperadrenocorticism treated with mitotane or trilostane. Journal of Veterinary Internal Medicine 2011; 25:251-260.  
4. Clemente M, De Andrés PJ, Arenas C, et al. Comparison of non-selective adrenocorticolysis with mitotane or trilostane for the treatment of dogs with pituitary-dependent hyperadrenocorticism. Veterinary Record 2007;161:805-809.
5. Kintzer PP, Peterson ME. Mitotane (o,p'-DDD) treatment of 200 dogs with pituitary-dependent hyperadrenocorticism. Journal of Veterinary Internal Medicine  1991;5:182-90. 
6. Ihle SL. Pituitary corticotroph macrotumors. Diagnosis and treatment. The Veterinary Clinics of North America Small Animal Practice 1997;27:287-297. 
7. Kent MS, Bommarito D, Feldman E, et al. Survival, neurologic response, and prognostic factors in dogs with pituitary masses treated with radiation therapy and untreated dogs. Journal of Veterinary Internal Medicine 2007;21:1027-1033. 

Q & A: Switching a Hyperthyroid Cat From Hill's y/d Back To Methimazole

I have a 7-year old female spayed Siamese cat that has been on Hill's y/d food for the past 2 months. The cat's thyroid levels have not come down (still > 15 μg/dl) and she is miserable on the food. She acts like she's starving (possibly from the uncontrolled thyroid) and is trying to steal food from the owner.

I am discontinuing the food but was wondering if I need to wait a certain amount of time before starting her back on methimazole?

My Response:

I've heard the same story from many cat owners and veterinarians. The y/d just doesn't appear to look and taste very appetizing to many cats (the food certainly looks pretty gross to me, but I must admit — I haven't tasted it!).

If the cat's serum T4 value is still high now, I'd switch the cat to a good diet (higher in protein, lower in carbs) that she wants to eat and start methimazole now.

• A 7-year old Siamese could live a very long time, possibly another 15 years! I'd talk to the owners about the following facts when you discuss how to treat the cat's hyperthyroidism (1-5): 
• This cat, like all hyperthyroid cats, has a thyroid tumor
• The thyroid tumor and hyperthyroidism will never go into spontaneous remission
• The thyroid tumor will continue to grow larger with time
• In some cats treated long term medically, the benign tumor will transform into a malignant thyroid carcinoma. In my studies, the incidence of thyroid carcinoma is above 20% in cats treated medically for longer than 4 years (6).

The bottom line:
If this was my own cat, I'd either do surgery or radioiodine to cure the cat's hyperthyroidism rather than trying to manage it with an iodine deficient diet (Hill's y/d) or methimazole for the rest of her life (1-5,7,8). She is already suffering from a severe case of hyperthyroidism, which will only worsen with time.

In the long run, a definitive treatment would be the wisest (and most cost effective) means of treating this relatively young cat.

References & Suggested Reading:

1. Baral R, Peterson ME. Thyroid gland disorders. In: Little, S.E. (ed), The Cat: Clinical Medicine and Management. Philadelphia, Elsevier Saunders 2012; 571-592. 
2. Peterson ME: Hyperthyroidism, In: Ettinger SJ, Feldman EC (eds): Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat (Fifth Edition). Philadelphia, WB Saunders Co. 2000; pp 1400-1419.
3. Peterson ME: Hyperthyroidism in cats. In: Melian C (ed): Manual de Endocrinología en Pequeños Animales (Manual of Small Animal Endocrinology). Multimedica, Barcelona, Spain, 2008, pp 127-168.
4. Mooney CT, Peterson ME: Feline hyperthyroidism, In: Mooney C.T., Peterson M.E. (eds), Manual of Canine and Feline Endocrinology (Fourth Ed), Quedgeley, Gloucester, British Small Animal Veterinary Association, 2012; in press. 
5. Peterson ME: Hyperthyroidism in cats, In: Rand, J (ed), Clinical Endocrinology of Companion Animals. New York, Wiley-Blackwell, 2012; in press.
6. Peterson ME, Broome MR. Thyroid scintigraphic findings in 917 cats with hyperthyroidism. Journal of Veterinary Internal Medicine 2012;26:754.
7. Peterson ME: Radioiodine treatment for hyperthyroidism. Clinical Techniques in Small Animal Practice 2006;21:34-39.
8. Peterson ME: Radioiodine for hyperthyroidism. In: Bonagura JD, Twedt DC (eds): Current Veterinary Therapy XIV. Philadelphia, Saunders Elsevier, 2008, pp 180-184.

Link to My Other Posts on the Hill's y/d Diet

Q & A: Confirming Hyperthyroidism in a Borderline Cat

Jessie, is a 13-year old female DSH cat that presented to our clinic for annual exam and vaccines. The owner reports that Jessie has been doing fairly well, but that the cat has been drinking more water over the last 4 months. The cat has also been progressively losing weight over the past year, dropping from 4.2 kg to 3.6 kg.

My physical examination was unremarkable, except for evidence of mild muscle wasting. Because of the signs of weight loss and polyuria, we ran a complete blood count and serum chemistry profile, but all of the results (including the serum creatinine, BUN, glucose, and calcium) were within reference range limits.

We also did a serum T4, which showed a high-normal value of 51 nmol/L (reference range, 13-51 nmol/L). Because of the high-normal serum total T4 concentration, I added on a free T4 by dialysis, which came back high at 81 pmol/L (reference range, 10-50 pmol/L).

Based on those thyroid results, I made a diagnosis of hyperthyroidism and started the cat on methimazole (Felimazole, Dechra) at a dosage of 2.5 mg, PO, once daily. After 2 weeks, we rechecked the kidney values (which remained normal) and a free T4 concentration (which was higher than the pretreatment value at 88 pmol/L).

So my main questions include the following:

• Why is the free T4 by ED is still high? 
• Should I only be assessing the free T4 along with a total T4 concentration?  I know that this is important when first trying to diagnose hyperthyroidism, but was wondering if I should be measuring both total and free T4 values on rechecks as well.
• Could the timing of the blood collection make a difference considering she is on SID dosing? She reports that she gives the cat her medication at about midnight and her sample would have been collected at 5:20 PM (so about 17 hours post-pill).

I am going to likely increase the methimazole dose to 2.5 mg BID. I have also gotten the owner to measure the exact water intake over a 24-hour period.

Thanks. Any help would be much appreciated.

My Response:

My first question is: do you think that cat really is hyperthyroid? I know that the cat has lost weight, but you have examined the cat 2 to 3 times and I don't see any mention of a thyroid nodule. Is there tachycardia or any other clinical signs? Is there improvement in the clinical signs after methimazole?

Determination of free T4 concentrations can be helpful in diagnosis of cats with early or mild hyperthyroidism (1), but the test is pretty worthless in monitoring initial methimazole or I-131 treatment. In addition, falsely high free T4 values have been reported in up to 12% of cats with nonthyroidal illness (1,2).

It does bother me that this cat has lost so much weight and is showing signs of polyuria and polydipsia with these mild thyroid values. Could this cat have nonthyroidal illness and not be hyperthyroid at all?

What I do in borderline cats like this is to do one of the following, especially when a thyroid nodule canot be palpated (2-6):

1. Repeat the serum total T4 in a week or two using a different technique (either RIA or Chemiluminescence - ie, Immulite methods). Many labs now use an automatic immunoassay technique, which can sometimes be misleading. But remember, the T4 will fluctuate over time, and some "normal" cats just have higher T4 values than the average normal cat. If you get a high total T4 value, we have the answer. Note that falsely high total T4 values do not occur unless there is lab error. 
2. Repeat the FT4 at the same time as the repeat TT4 test. You have already done this step in this cat, but you didn't repeat the T4 and the cat is on methimazole. Again, a high value with a normal TT4 and no thyroid nodule really doesn't tell you that the cat is hyperthyroid for sure! 
3. If this in not helpful (i.e., the total T4 not high), then I do either a T3 suppression test or thyroid scintigraphy. 
4. Finally, we can just wait and monitor. Over time — generally 3 months — the thyroid tumor (if present) will grow and the T4 will be clearly high. If there is nonthyroidal illness, this will usually become obvious with enough time. 

So in this case, I'd start by asking yourself if the cat is truly hyperthyroid and even needs to be treated. If your answer is yes, the cat is hyperthyroid, then I would increase the dose, and monitor only with a total T4 value. SID dosing is acceptable, but BID dosing is best (7). The timing of the post-pill T4 is not important as long as the medication is given at least once a day (7,9).

Bottom Line: If you are not sure that the cat is hyperthyroid, treating with an antithyroid drug, at least in my opinion, is not a wise choice given that side effects (some serious) can occur. I understand that we all want to look at the "numbers." But when the thyroid numbers are wrong (as they can be), we can never forget that we first must look a the patient.

In other words, we don't treat abnormal lab values — we treat the cat.

References:

1. Peterson ME, Melian C, Nichols R. Measurement of serum concentrations of free thyroxine, total thyroxine, and total triiodothyronine in cats with hyperthyroidism and cats with nonthyroidal disease. Journal of the American Veterinary Medical Association 2001;218:529-536.
2. Mooney CT, Little CJ, Macrae AW. Effect of illness not associated with the thyroid gland on serum total and free thyroxine concentrations in cats. Journal of the American Veterinary Medical Association 1996;208:2004-2008.
3. Baral R, Peterson ME. Thyroid gland disorders. In: Little, S.E. (ed), The Cat: Clinical Medicine and Management. Philadelphia, Elsevier Saunders 2012;571-592.
4. Mooney CT, Peterson ME: Feline hyperthyroidism, In: Mooney C.T., Peterson M.E. (eds), Manual of Canine and Feline Endocrinology (Fourth Ed), Quedgeley, Gloucester, British Small Animal Veterinary Association, 2012; in press.
5. Peterson ME: Hyperthyroidism in cats, In: Rand, J (ed), Clinical Endocrinology of Companion Animals. New York, Wiley-Blackwell, 2012; in press.
6. Peterson ME. Diagnostic tests for hyperthyroidism in cats. Clinical Techniques in Small Animal Practice 2006;21:2-9.
7. Peterson ME, Kintzer PP, Hurvitz AI. Methimazole treatment of 262 cats with hyperthyroidism. Journal of Veterinary Internal Medicine 1988;2:150–157. 
8. Trepanier LA, Hoffman SB, Knoll M, et al. Efficacy and safety of once versus twice daily administration of methimazole in cats with hyperthyroidism. Journal of the American Veterinary Medical Association 2003;222:954–958. 
9. Rutland BE, Nachreiner RF, Kruger JM. Optimal testing for thyroid hormone concentration after treatment with methimazole in healthy and hyperthyroid cats. Journal of Veterinary Internal Medicine 2009;23:1025-1030.

FDA Approves Release of Vetoryl in Larger Capsule Size

Dechra Veterinary Products LLC announced that their company has received FDA approval to market a larger size (120 mg) of Vetoryl, their trilostane product. This is a welcome addition that will be useful when treating larger dogs with Cushing's syndrome. We now have the same 4 capsule sizes of the drug available in the USA (10-mg, 30-mg, 60-mg, and 120-mg) that veterinarians in Europe have had for some time.

Read the text of the full Press Release below, or visit the News page on the Dechra website to view the original Press Release.

DECHRA RECEIVES SUPPLEMENTAL FDA APPROVAL FOR 

120 MG VETORYL (TRILOSTANE) CAPSULES

OVERLAND PARK, KS, NOVEMBER, 2011 – Dechra Veterinary Products LLC announces the company has received supplemental FDA approval to market 120 mg VETORYL Capsules.

VETORYL, which contains the active ingredient trilostane, is the only FDA approved product indicated for use in pituitary-dependent and adrenal-dependent hyperadrenocorticism (Cushing's syndrome) in dogs. VETORYL is now approved in 10 mg, 30 mg, 60 mg and 120 mg capsules.

“This is great news for the veterinary industry,” said Mike Eldred, President of U.S. Operations. “Having approval for the 10 mg, 30 mg, 60 mg and now 120 mg capsules provides veterinarians with more dosing options and flexibility to treat all sizes of dogs.”

“Now that we have FDA approved trilostane,” said John Angus, DVM, DACVD, “I would recommend against compounding due to variability in the product, not just between compounding pharmacies, but sometimes between batches from the same compounding pharmacy. A study presented at ACVIM 2010 found a tremendous range in the amount of actual active drug compared to what was on the label (1). This can be a problem when trying to regulate a Cushing’s case. Compounding pharmacies provide valuable services and can help in a lot of patients; however, this is not a drug that I would get compounded unless the compounding company is using the FDA approved trilostane (VETORYL Capsules) from Dechra.”

Dechra Veterinary Products LLC, located in Overland Park, Kansas is the U.S. subsidiary of Dechra Pharmaceuticals PLC, a UK listed company focused on international animal healthcare markets. Dechra currently markets a range of specialized veterinary approved products in the U.S. For more information, please visit www.dechra-us.com or call 866-933-2472.

Reference

1. Cook AK, Nieuwoudt CD, Longhofer SL, et al. Evaluation of Content of Compounded Trilostane Products. 2010 ACVIM Forum Abstract #46.

Hyperthyroidism & Renal Disease: Is a "Tapazole Trial" Really Necessary?

Hyperthyroidism and chronic kidney disease (CKD) are both common disorders in older cats. Therefore, it should not be surprising that both disorders frequently develop together in the same cat. The prevalence of concurrent renal disease in cats with hyperthyroidism is estimated to be approximately 30–35% (1,2).

Hyperthyroidism & the Kidney: A Love-Hate Relationship

Hyperthyroidism tends to "artificially" increase the renal blood flow (RBF) as well as the glomerular filtration rate (GFR) (1–4). When the GFR is increased in a hyperthyroid cat with underlying CKD, it can mask renal insufficiency; serum concentrations of urea nitrogen and creatinine may be normal despite mild to moderate kidney disease (1–7). Decreased muscle mass and muscle wasting, a common feature of hyperthyroidism, also contribute to the lowered serum creatinine concentration in these cats (since creatinine is derived from muscle tissue) (1,2).

Treating hyperthyroidism restores the high serum T4 concentration to normal and, in cats without CKD, also returns the high GFR back to normal values. In cats with CKD, however, the GFR will fall to the low-normal or subnormal levels expected with moderate renal dysfunction. Therefore, this decrease in GFR can result in the apparent worsening of the serum kidney function tests or the development of renal disease.

It is important to remember, however, that treating the hyperthyroidism itself does not cause the CKD in these cats. The renal disease was already present before treatment but was masked by the hyperdynamic state of the hyperthyroidism.

Physiological Interactions Between Thyroid Hormones & Renal Function

Hyperthyroidism decreases peripheral vascular resistance by dilating the arterioles of the peripheral circulation. Because of this decrease in systemic vascular resistance, the effective circulating volume decreases, stimulating the renin-angiotensin-aldosterone system. This leads to renal sodium retention with a resultant increase in blood volume. Cardiac output may increase dramatically in cats with hyperthyroidism. In addition to the decrease in systemic vascular resistance, an increase in heart rate, increases in left ventricular contractility and ejection fraction, and increase in blood volume all contribute to this increase in cardiac output (1,2).

These systemic hemodynamic factors (i.e., the increased cardiac output) combined with intrarenal vasodilation lead to increases in renal blood flow (RBF), glomerular hydrostatic pressure, and glomerular filtration rate (GFR). Thyroid hormones also influence renal tubular function including electrolyte handling.

With time, hyperthyroidism can lead to renal changes including glomerular hypertension, glomerulosclerosis, proteinuria, and hyperplasia and hypertrophy of the renal tubules (1,2).

Hyperthyroidism Itself May Contribute to Chronic Kidney Disease

Recent research provides three lines of evidence that untreated hyperthyroidism itself contributes to the development or progression of CKD in cats.

• First of all, a number of recent reports indicate that many untreated hyperthyroid cats develop proteinuria, which resolves within 4 weeks of successful treatment (8,9). This proteinuria, which reverses after treatment, could be a reflection of glomerular hypertension and hyperfiltration, changes in tubular protein handling, or a change in the structure of the glomerular barrier (1). Whatever the cause of the proteinuria, no treatment is generally needed other than treatment of the hyperthyroid state itself.
• Secondly, cats with untreated hyperthyroidism have high levels of retinol binding protein (RBP), a urinary marker for tubular dysfunction or damage (10,11). This high urinary RBP excretion may reflect tubular damage or dysfunction resulting from the thyroid-induced hypertrophy and hyperplasia of the tubular cells. After treatment, these high urinary RBP levels fall in cats without azotemia but may remain slightly high in cats with pre-existing CKD. This too suggests that hyperthyroidism can cause reversible renal dysfunction; however, the renal tubular changes may become irreversible with time as CKD progresses.
• Thirdly, many cats with untreated hyperthyroidism have high values for urinary N-acetyl-ß-D-glucosaminidase (NAG), a lysosomal glycosidase found primarily in epithelial cells of the proximal convoluted tubule (12). Like RBP, NAG is a specific marker of active proximal tubular damage. After treatment, these high urinary NAG levels decrease, again suggesting that these renal changes can be reversed, at least in cats without pre-existing CKD.

Overall, these studies all suggest that that leaving a hyperthyroid cat untreated (or poorly regulated with methimazole) may be detrimental to long-term kidney function. Treating and curing hyperthyroidism may help to both reverse renal damage and preserve remaining kidney function.

Clinical Implications in Hyperthyroid Cats

Decision-making with regard to treating cats with hyperthyroidism and CKD can be difficult. Clinicians can be confronted with two different scenarios concerning hyperthyroid cats with concurrent CKD.

1. First of all, about 10% of hyperthyroid cats have known pre-existing CKD at time of diagnosis. These cats have obvious clinical and biochemical evidence of mild to moderate kidney disease, and do not present a diagnostic dilemma. However, hyperthyroid cats with pre-existing azotemia are more difficult to treat successfully, at least on a long-term basis. They have a worse prognosis than do cats that are not azotemic prior to treatment for hyperthyroidism.
2. In the second scenario, cats are initially not azotemic but develop high serum concentrations of urea nitrogen or creatinine only after they have been treated for hyperthyroidism. These cats, which represent 20% to 25% of all hyperthyroid cats, are much more of a diagnostic dilemma because one may not even suspect that they have concurrent renal disease.

1. Pre-existing Azotemia in a Newly Diagnosed Hyperthyroid Cat
In hyperthyroid cats with overt CKD, we can predict that the GFR will fall once the euthyroidism is restored. Therefore, it is generally advised to try medical management prior to a more definitive treatment in cats with concurrent hyperthyroidism and pre-existing CKD. A low starting dose (i.e., 1.25 mg orally once daily) of methimazole with gradual dose escalation is prudent when starting a cat with CKD and hyperthyroidism on medical therapy. Cats should be monitored every 2 weeks with a CBC, biochemical profile, urinalysis, and serum T4 concentration.

Because the initial decline in GFR stabilizes after a month of successful resolution of the hyperthyroidism, one can decide at that time whether or not the cat's renal function is stable or worsening.

Hyperthyroid cat with overt CKD
and hypokalemia

Concurrent management of CKD is also extremely important these cats. If the renal function remains stable after a euthyroid state is established, a more definitive treatment, such as 131-I, should be strongly considered. If, on the other hand, renal function declines dramatically after antithyroid drug treatment, especially if accompanied by marked clinical deterioration of the cat's renal failure (to IRIS Stage 3 or 4), it may be best to maintain the cat on a reversible anti-thyroid therapy, decrease the dose, or stop it all together if need be.

In some of these cats with severe CKD, maintenance of a mild hyperthyroid state may give the best short-term clinical result. However, this course of action is far from ideal, and these cats have a very guarded to poor prognosis. Except in these extreme circumstances, the validity of maintaining a cat in a mildly hyperthyroid state is questionable given that uncontrolled hyperthyroidism, in itself, appears to be damaging to renal function (1,8,10–12)

2. Non-Azotemic Before Treatment of Hyperthyroidism; Development of Post-Treatment Azotemia
Hyperthyroidism is known to increase GFR, decrease circulating creatinine concentrations, and mask underlying renal disease. About 20% to 25% of hyperthyroid cats without known CKD develop azotemia after successful treatment of hyperthyroidism, irrespective of therapeutic modality (methimazole/carbimazole, surgical thyroidectomy, or radioiodine) (1).

Predicting which hyperthyroid cats will develop overt azotemia after treatment of hyperthyroidism can be difficult to impossible. The determination of GFR is clearly the best predictor of post-treatment CKD, with a low to low-normal GFR indicating that a hyperthyroid cat is at increased risk for post-treatment azotemia. However, techniques for assessment of GFR are not widely used in practice, and even GFR determinations are not a 100% perfect predictor of CKD. Routine pre-treatment parameters such as serum urea or creatinine concentrations, and urine specific gravity are certainly useful, but they cannot consistently predict impending azotemia (13).

Should Methimazole Trials be Performed in all Hyperthyroid Cats?

For years, it has been accepted practice to perform a methimazole trial in cats in which hyperthyroidism has been newly diagnosed to evaluate the impact of a euthyroid state on renal function.  Again, determining which untreated hyperthyroid cats have clinically significant underlying CKD can sometimes be difficult. Use of methimazole or carbimazole can provide a "preview" of how the cat will be after curing hyperthyroidism. Thus, many veterinarians attempt trial therapy with methimazole or carbimazole to help test what renal function might remain after treating the hyperthyroidism. If no marked deterioration occurs, then a more permanent therapeutic option for hyperthyroidism may be recommended.

Except for advanced (IRIS Stage 3–4) CKD, the necessity of this approach in cats without pretreatment azotemia is questionable, given that treatment for the hyperthyroidism is strongly recommended whatever the outcome. In support of this reasoning, the survival of cats that do develop azotemia is not shorter than those that do not develop azotemia after treatment of hyperthyroidism. In one study, the median survival time of cats that developed azotemia (595 days) was similar to that in cats that remained non-azotemic (584 days) after treatment (14).

Preventing Hypothyroidism after Treatment for Hyperthyroidism

Whatever treatment option for hyperthyroidism is considered, it is important to avoid hypothyroidism as it may have its own detrimental effects on GFR. Hypothyroidism in both humans and dogs has been showed to reduce GFR (15,16), and it is likely that similar changes occur in cats that develop iatrogenic hypothyroidism.

In a recent study by Williams et al (17), cats with iatrogenic hypothyroidism were more likely to develop azotemia in the 6 months after treatment than cats that remained euthyroid. Hypothyroid cats with azotemia also had shorter survival times than nonazotemic cats, whereas no difference in survival between euthyroid cats with or without azotemia could be detected. This suggests that the development iatrogenic hypothyroidism contributes to the development of azotemia, at least in cats with mild underlying CKD (IRIS Stage I or II) (17,18). More importantly, the hypothyroidism may shorten survival after treatment of hyperthyroidism.

If a cat with post-treatment azotemia develops a low T4 concentration, a serum TSH level should be measured to help exclude hypothyroidism (19). The finding of a high serum TSH concentration confirms hypothyroidism. A specific assay for feline TSH is not yet available. However, the commercially available canine TSH assay cross-reacts with feline TSH enough to enable its use as a diagnostic test for hypothyroid cats (19,20).

If iatrogenic hypothyroidism is diagnosed, treatment with L-thyroxine (0.1 mg once to twice daily) is indicated (20,21). The dosage should be adjusted based on post-pill serum T4 and cTSH determinations. Most cats treated will show improvement in their azotemia as the hypothyroidism resolves and euthyroidism is restored (18).

Long-Term Renal Function in Cats that Develop Azotemia after Treatment

In most cats that develop post-treatment azotemia, the CKD is not that severe or life threatening. It is also unusual to see a jump of more than one IRIS stage after treatment (22). In other words, hyperthyroid cats with IRIS Stage I–II CKD may develop overt azotemia after treatment, but one would not expect those cats' CKD to advance to more than IRIS Stage II–III after treatment (Figure 1).

Figure 1. Box plots of serum creatine concentrations in 45 hyperthyroid cats
before and after treatment. Prior to treatment 34 of the 45 cats were not azotemic, whereas 11 cats (Green Box) had IRIS stage 2 CKD.
After treatment, 12 of the 34 nonazotemic cats progressed to stage 2 CKD (Red Box).  All 11 cats with prior azotemia remained azotemic, but the the median value was not significantly different (Green Box).
Click image above to enlarge figure.

In addition, the decline in GFR after successful treatment of a cat's hyperthyroidism is not very progressive. Rather, the fall in GFR is detectable within 1 month but then remains stable at this level for months thereafter (1,6). The rise in serum urea nitrogen and creatinine values in cats with CKD follow the decrease in GFR, so that azotemia, when it does occur, would be expect to develop within 1 month of treatment but remain relatively stable over many months (6,22).

The Bottom Line

For years, conventional wisdom has been to perform a methimazole trial in cats in which hyperthyroidism has been newly diagnosed to evaluate the impact of a euthyroid state on renal function. In most cats without overt CKD, use of a methimazole trial prior to definitive therapy is not needed.

Remember that hyperthyroidism itself has long-term deleterious effects on renal function, and survival of cats that do develop azotemia after treatment for hyperthyroidism is no shorter than for those whose renal function remains stable. For those cats that do develop azotemia after their hyperthyroid state is corrected, the renal disease is not generally severe or life-threatening and usually stabilizes within the first month of therapy.

References

1. Syme HM. Cardiovascular and renal manifestations of hyperthyroidism. Veterinary Clinics of North America: Small Animal Practice 2007;37:723-743. 
2. Langston CE, Reine NJ. Hyperthyroidism and the kidney. Clinical Techniques in Small Animal Practice 2006;21:17-21. 
3. Graves TK, Olivier NB, Nachreiner RF, et al. Changes in renal function associated with treatment of hyperthyroidism in cats. American Journal of Veterinary Research 1994;55;1745-1749. 
4. Adams WH, Daniel GB, Legendre AM. Investigation of the effects of hyperthyroidism on renal function in the cat. Canadian Journal of Veterinary Research 1997;61:53-56. 
5. Becker TJ, Graves TK, Kruger JM, et al. Effects of methimazole on renal function in cats with hyperthyroidism. Journal of the American Animal Hospital Association 2000;36:215-223. 
6. Boag AK, Neiger R, Slater L, et al. Changes in the glomerular filtration rate of 27 cats with hyperthyroidism after treatment with radioactive iodine. Veterinary Record 2007;161:711-715. 
7. DiBartola SP, Broome MR, Stein BS, et al. Effect of treatment of hyperthyroidism on renal function in cats. Journal of the American Veterinary Medical Association 1996;208:875-878. 
8. van Hoek I, Lefebvre HP, Peremans K, et al. Short- and long-term follow-up of glomerular and tubular renal markers of kidney function in hyperthyroid cats after treatment with radioiodine. Domestic Animal Endocrinology 2009;36:45-56. 
9. Williams TL, Peak KJ, Brodbelt D, et al. Survival and the development of azotemia after treatment of hyperthyroid cats. Journal of Veterinary Internal Medicine 2010;24:863-869. 
10. van Hoek I, Daminet S, Notebaert S, et al. Immunoassay of urinary retinol binding protein as a putative renal marker in cats. Journal of Immunological Methods 2008;329:208-213. 
11. van Hoek I, Meyer E, Duchateau L, et al. Retinol-binding protein in serum and urine of hyperthyroid cats before and after treatment with radioiodine. Journal of Veterinary Internal Medicine 2009;23:1031-1037. 
12. Lapointe C, Bélanger MC, Dunn M, et al. N-acetyl-beta-D-glucosaminidase index as an early biomarker for chronic kidney disease in cats with hyperthyroidism. Journal of Veterinary Internal Medicine 2008;22:1103-1110. 
13. Riensche MR, Graves TK, Schaeffer DJ. An investigation of predictors of renal insufficiency following treatment of hyperthyroidism in cats. Journal of Feline Medicine and Surgery 2008;12:160-166. 
14. Wakeling J, Rob C, Elliott J, et al. Survival of hyperthyroid cats is not affected by post-treatment azotemia. Journal of Veterinary Internal Medicine 2006;20:1523.
15. Iglesias P, Diez JJ. Thyroid dysfunction and kidney disease. European Journal of Endocrinology 2009;160:503-515. 
16. Gommeren K, van Hoek I, Lefebvre HP, et al. Effect of thyroxine supplementation on glomerular filtration rate in hypothyroid dogs. Journal of Veterinary Internal Medicine 2009;23:844-849. 
17. Williams T, Elliott J, Syme H. Association of iatrogenic hypothyroidism with azotemia and reduced survival time in cats treated for hyperthyroidism. Journal of Veterinary Internal Medicine 2010;24:1086-1092. 
18. Wakeling J. Use of thyroid stimulating hormone (TSH) in cats. Canadian Veterinary Journal 2010;51:33-34. 
19. Greco DS. Diagnosis of congenital and adult-onset hypothyroidism in cats. Clinical Techniques in Small Animal Practice 2006;21:40-44. 
20. Peterson ME: Feline hypothyroidism, In: Kirk RW (ed): Current Veterinary Therapy X. Philadelphia, WB Saunders Co., pp 1000-1001, 1989
21. Harley LS, Peterson ME, Langston CE, Nichols RL: IRIS stages of chronic kidney disease before and after treatment with radioiodine in cats with hyperthyroidism. Journal of Veterinary Internal Medicine 25: 678-679, 2011.

Top Endocrine Publications of 2010: The Feline Adrenal Gland

In my seventh compilation of the canine and feline endocrine publications of 2010, I’m moving on to disorders of the feline adrenal gland.

Listed below are 8 research papers written in 2010 that deal with a variety of adrenal gland topics of issues of clinical importance in cats.

These range from a report of a cat with concurrent adrenal pheochromocytoma and contralateral adrenocortical tumor (1) to investigation of plasma catecholamines in diagnoses of feline pheochromocytoma (8); from a review of primary hyperaldosteronism (Conn's syndrome) to a overview of endocrine hypertension in cats (3,4); from a report of Cushing's syndrome in a cat with generalized toxoplasmosis (6) to reports on the risks of human estrogen sprays to cats through contact with treated skin (7).

References:

1. Calsyn JD, Green RA, Davis GJ, et al. Adrenal pheochromocytoma with contralateral adrenocortical adenoma in a cat. Journal of the American Animal Hospital Association 2010;46:36-42.
2. Cohn LA, DeClue AE, Cohen RL, et al. Effects of fluticasone propionate dosage in an experimental model of feline asthma. Journal of feline medicine and surgery 2010;12:91-96.
3. Reusch CE, Schellenberg S, Wenger M. Endocrine hypertension in small animals. The Veterinary clinics of North America Small animal practice 2010;40:335-352.
4. Schulman RL. Feline primary hyperaldosteronism. The Veterinary clinics of North America Small animal practice 2010;40:353-359.
5. Sieber-Ruckstuhl NS, Zini E, Osto M, et al. Effect of hyperlipidemia on 11-beta-hydroxysteroid-dehydrogenase, glucocorticoid receptor, and leptin expression in insulin-sensitive tissues of cats. Domestic Animal Endocrinology 2010;39:222-230.
6. Spada E, Proverbio D, Giudice C, et al. Pituitary-dependent hyperadrenocorticism and generalised toxoplasmosis in a cat with neurological signs. Journal of feline medicine and surgery 2010;12:654-658.
7. Voelker R. Estrogen spray poses risks to children, pets through contact with treated skin. Journal of the American Medical Association 2010;304:953.
8. Wimpole JA, Adagra CF, Billson MF, et al. Plasma free metanephrines in healthy cats, cats with non-adrenal disease and a cat with suspected phaeochromocytoma. Journal of feline medicine and surgery 2010;12:435-440.

Top Endocrine Publications of 2010: The Canine Adrenal Gland

In my sixth compilation of the canine and feline endocrine publications of 2010, I’m moving on to disorders of the canine adrenal gland.

Listed below are 31 research papers written in 2010 that deal with a variety of adrenal gland issues of clinical importance in dogs.

These range from the investigations of hypoadrenocorticism (1, 14-16, 19, 29) to typical (3, 5, 8-10, 13, 17, 20, 24, 26, 30) and atypical (4, 6) hyperadrenocorticism; from diagnostic tests for Cushing's syndrome (17, 30) to studies of ultrasonography for evaluation  and differentiation of adrenal disease (5, 28);  and from trilostane (3,8, 9, 24) to studies of the efficacy of transsphenoidal surgery as treatment for Cushing's disease (13.

In addition, other studies include the investigation of urine and plasma catecholamines in diagnoses of canine pheochromocytoma (7, 11, 18,  23) to a review of canine chemodectoma (22); and from  studies of the endocrine hypertension (19, 25) to reports on the risks of human estrogen sprays to pets through contact with treated skin (28).

References:

1. Adissu HA, Hamel-Jolette A, Foster RA. Lymphocytic adenohypophysitis and adrenalitis in a dog with adrenal and thyroid atrophy. Veterinary Pathology 2010;47:1082-1085.
2. Adissu HA, Hayes G, Wood GA, et al. Cardiac myxosarcoma with adrenal adenoma and pituitary hyperplasia resembling Carney complex in a dog. Veterinary Pathology 2010;47:354-357.
3. Arteaga A, Dhand NK, McCann T, et al. Monitoring the response of canine hyperadrenocorticism to trilostane treatment by assessment of acute phase protein concentrations. The Journal of Small Animal Practice 2010;51:204-209.
4. Behrend EN, Kennis R. Atypical Cushing's syndrome in dogs: arguments for and against. The Veterinary Clinics of North America: Small Animal Practice 2010;40:285-296.
5. Benchekroun G, de Fornel-Thibaud P, Rodriguez Pineiro MI, et al. Ultrasonography criteria for differentiating ACTH dependency from ACTH independency in 47 dogs with hyperadrenocorticism and equivocal adrenal asymmetry. Journal of Veterinary Internal Medicine 2010;24:1077-1085.
6. Bromel C, Feldman EC, Davidson AP, et al. Serum 17-alpha-hydroxyprogesterone concentrations during the reproductive cycle in healthy dogs and dogs with hyperadrenocorticism. Journal of the American Veterinary Medical Association 2010;236:1208-1214.
7. Cameron KN, Monroe WE, Panciera DL, et al. The effects of illness on urinary catecholamines and their metabolites in dogs. Journal of Veterinary Internal Medicine 2010;24:1329-1336.
8. Cook AK, Bond KG. Evaluation of the use of baseline cortisol concentration as a monitoring tool for dogs receiving trilostane as a treatment for hyperadrenocorticism. Journal of the American Veterinary Medical Association 2010;237:801-805.
9. Galac S, Buijtels JJ, Mol JA, et al. Effects of trilostane on the pituitary-adrenocortical and renin-aldosterone axis in dogs with pituitary-dependent hypercortisolism. Veterinary Journal 2010;183:75-80.
10. Galac S, Kool MM, Naan EC, et al. Expression of the ACTH receptor, steroidogenic acute regulatory protein, and steroidogenic enzymes in canine cortisol-secreting adrenocortical tumors. Domestic Animal Endocrinology 2010;39:259-267.
11. Gostelow R, Syme H. Plasma metadrenalines in canine phaeochromocytoma. The Veterinary Record 2010;166:538.
12. Hanson JM, Mol JA, Meij BP. Expression of leukemia inhibitory factor and leukemia inhibitory factor receptor in the canine pituitary gland and corticotrope adenomas. Domestic Animal Endocrinology 2010;38:260-271.
13. Hara Y, Teshima T, Taoda T, et al. Efficacy of transsphenoidal surgery on endocrinological status and serum chemistry parameters in dogs with Cushing's disease. The Journal of Veterinary Medical Science 2010;72:397-404.
14. Hughes AM, Jokinen P, Bannasch DL, et al. Association of a dog leukocyte antigen class II haplotype with hypoadrenocorticism in Nova Scotia Duck Tolling Retrievers. Tissue Antigens 2010;75:684-690.
15. Klein SC, Peterson ME. Canine hypoadrenocorticism: part I. The Canadian Veterinary Journal 2010;51:63-69.
16. Klein SC, Peterson ME. Canine hypoadrenocorticism: part II. The Canadian Veterinary Journal 2010;51:179-184.
17. Kooistra HS, Galac S. Recent advances in the diagnosis of Cushing's syndrome in dogs. The Veterinary Clinics of North America: Small Animal Practice 2010;40:259-267.
18. Kook PH, Grest P, Quante S, et al. Urinary catecholamine and metadrenaline to creatinine ratios in dogs with a phaeochromocytoma. The Veterinary Record 2010;166:169-174.
19. Kook PH, Grest P, Raute-Kreinsen U, et al. Addison's disease due to bilateral adrenal malignancy in a dog. The Journal of Small Animal Practice 2010;51:333-336.
20. Lien YH, Hsiang TY, Huang HP. Associations among systemic blood pressure, microalbuminuria and albuminuria in dogs affected with pituitary- and adrenal-dependent hyperadrenocorticism. Acta Veterinaria Scandinavica 2010;52:61.
21. Mori N, Lee P, Muranaka S, et al. Predisposition for primary hyperlipidemia in Miniature Schnauzers and Shetland sheepdogs as compared to other canine breeds. Research in Veterinary Science 2010;88:394-399.
22. Noszczyk-Nowak A, Nowak M, Paslawska U, et al. Cases with manifestation of chemodectoma diagnosed in dogs in Department of Internal Diseases with Horses, Dogs and Cats Clinic, Veterinary Medicine Faculty, University of Environmental and Life Sciences, Wroclaw, Poland. Acta Veterinaria Scandinavica 2010;52:35.
23. Quante S, Boretti FS, Kook PH, et al. Urinary catecholamine and metanephrine to creatinine ratios in dogs with hyperadrenocorticism or pheochromocytoma, and in healthy dogs. Journal of Veterinary Internal Medicine 2010;24:1093-1097.
24. Ramsey IK. Trilostane in dogs. The Veterinary clinics of North America Small Animal Practice 2010;40:269-283.
25. Reusch CE, Schellenberg S, Wenger M. Endocrine hypertension in small animals. The Veterinary Clinics of North America: Small Animal Practice 2010;40:335-352.
26. Trapani F, Del Basso De Caro ML, Insabato L, et al. Type II muscle fibers atrophy associated with silent corticotroph adenoma in a dog. Folia histochemica et Cytobiologica 2010;48:403-406.
27. van Rijn SJ, Grinwis GC, Penning LC, et al. Expression of Ki-67, PCNA, and p27kip1 in canine pituitary corticotroph adenomas. Domestic Animal Endocrinology 2010;38:244-252.
28. Voelker R. Estrogen spray poses risks to children, pets through contact with treated skin. Journal of the American Medical Association 2010;304:953.
29. Wenger M, Mueller C, Kook PH, et al. Ultrasonographic evaluation of adrenal glands in dogs with primary hypoadrenocorticism or mimicking diseases. The Veterinary Record 2010;167:207-210.
30. Zeugswetter F, Bydzovsky N, Kampner D, et al. Tailored reference limits for urine corticoid:creatinine ratio in dogs to answer distinct clinical questions. The Veterinary Record 2010;167:997-1001.
31. Zimmerman KL, Panciera DL, Panciera RJ, et al. Hyperphosphatasemia and concurrent adrenal gland dysfunction in apparently healthy Scottish Terriers. Journal of the American Veterinary Medical Association 2010;237:178-186.

Top Endocrine Publications of 2010: Canine and Feline Diabetes Mellitus

I know that many of you are very busy and may have trouble keeping up with the latest research studies and publications on issues concerning companion animal endocrinology. Therefore, I’ve compiled a fairly extensive list of some of the best clinical endocrine papers written last year (in 2010), and I’ll be sharing these with you over the next few weeks.

We are going to start off with papers that deal with the theme of Diabetes mellitus and its diagnosis and treatment in dogs and cats.

Listed below are 29 research papers written in 2010 that deal with a variety of diabetic topics and issues.

These range from the use of continuous glucose monitoring systems (1, 15, 22) to home glucose monitoring (5, 28); from insulin autoantibodies (4, 18) to insulin resistance (11, 25, 26);  from new insulin analogues (8, 10, 24) to diabetic cataracts (12, 21); and from the causes of secondary diabetes (2, 6, 13, 14, 16) to diabetic remission (29).

2010 Papers on Canine and Feline Diabetes Mellitus:

1. Affenzeller N, Benesch T, Thalhammer JG, et al. A pilot study to evaluate a novel subcutaneous continuous glucose monitoring system in healthy Beagle dogs. Veterinary Journal 2010;184:105-110.
2. Blois SL, Dickie EL, Kruth SA, et al. Multiple endocrine diseases in cats: 15 cases (1997-2008). Journal of Feline Medicine and Surgery 2010;12:637-642.
3. Claus MA, Silverstein DC, Shofer FS, et al. Comparison of regular insulin infusion doses in critically ill diabetic cats: 29 cases (1999-2007). Journal of Veterinary Emergency and Critical Care 2010;20:509-517.
4. Davison LJ, Herrtage ME, Catchpole B. Autoantibodies to recombinant canine proinsulin in canine diabetic patients. Research in Veterinary Science 2010.
5. Dobromylskyj MJ, Sparkes AH. Assessing portable blood glucose meters for clinical use in cats in the United Kingdom. The Veterinary Record 2010;167:438-442.
6. Fall T, Hedhammar A, Wallberg A, et al. Diabetes mellitus in elkhounds is associated with diestrus and pregnancy. Journal of Veterinary Internal Medicine 2010;24:1322-1328.
7. Furrer D, Kaufmann K, Reusch CE, et al. Amylin reduces plasma glucagon concentration in cats. Veterinary Journal 2010;184:236-240.
8. Gilor C, Graves TK. Synthetic insulin analogs and their use in dogs and cats. The Veterinary Clinics of North America Small Animal Practice 2010;40:297-307.
9. Gilor C, Graves TK, Lascelles BD, et al. The effects of body weight, body condition score, sex, and age on serum fructosamine concentrations in clinically healthy cats. Veterinary Clinical Pathology 2010;39:322-328.
10. Gilor C, Ridge TK, Attermeier KJ, et al. Pharmacodynamics of insulin detemir and insulin glargine assessed by an isoglycemic clamp method in healthy cats. Journal of Veterinary Internal Medicine 2010;24:870-874.
11. Hess RS. Insulin resistance in dogs. The Veterinary Clinics of North America Small Animal Practice 2010;40:309-316.
12. Kador PF, Webb TR, Bras D, et al. Topical KINOSTAT ameliorates the clinical development and progression of cataracts in dogs with diabetes mellitus. Veterinary Ophthalmology 2010;13:363-368.
13. McLauchlan G, Knottenbelt C, Augusto M, et al. Retrospective evaluation of the effect of trilostane on insulin requirement and fructosamine concentration in eight diabetic dogs with hyperadrenocorticism. The Journal of Small Animal Practice 2010;51:642-648.
14. Meij BP, Auriemma E, Grinwis G, et al. Successful treatment of acromegaly in a diabetic cat with transsphenoidal hypophysectomy. Journal of Feline Medicine and Surgery 2010;12:406-410.
15. Moretti S, Tschuor F, Osto M, et al. Evaluation of a novel real-time continuous glucose-monitoring system for use in cats. Journal of Veterinary Internal Medicine 2010;24:120-126.
16. Niessen SJ. Feline acromegaly: an essential differential diagnosis for the difficult diabetic. Journal of feline medicine and surgery 2010;12:15-23.
17. Niessen SJ, Powney S, Guitian J, et al. Evaluation of a quality-of-life tool for cats with diabetes mellitus. Journal of Veterinary Internal Medicine 2010;24:1098-1105.
18. Nishii N, Takasu M, Kojima M, et al. Presence of anti-insulin natural autoantibodies in healthy cats and its interference with immunoassay for serum insulin concentrations. Domestic Animal Endocrinology 2010;38:138-145.
19. Nishii N, Yamasaki M, Takasu M, et al. Plasma leptin concentration in dogs with diabetes mellitus. The Journal of Veterinary Medical Science 2010;72:809-811.
20. O'Brien MA. Diabetic emergencies in small animals. The Veterinary Clinics of North America Small Animal Practice 2010;40:317-333.
21. Oliver JA, Clark L, Corletto F, et al. A comparison of anesthetic complications between diabetic and nondiabetic dogs undergoing phacoemulsification cataract surgery: a retrospective study. Veterinary Ophthalmology 2010;13:244-250.
22. Reineke EL, Fletcher DJ, King LG, et al. Accuracy of a continuous glucose monitoring system in dogs and cats with diabetic ketoacidosis. Journal of Veterinary Emergency and Critical Care 2010;20:303-312.
23. Rucinsky R, Cook A, Haley S, et al. AAHA diabetes management guidelines. Journal of the American Animal Hospital Association 2010;46:215-224.
24. Sako T, Mori A, Lee P, et al. Time-action profiles of insulin detemir in normal and diabetic dogs
25. Scott-Moncrieff JC. Insulin resistance in cats. The Veterinary Clinics of North America Small Animal Practice 2010;40:241-257.
26. Verkest KR, Fleeman LM, Rand JS, et al. Basal measures of insulin sensitivity and insulin secretion and simplified glucose tolerance tests in dogs. Domestic Animal Endocrinology 2010;39:194-204.
27. Zeugswetter F, Handl S, Iben C, et al. Efficacy of plasma beta-hydroxybutyrate concentration as a marker for diabetes mellitus in acutely sick cats. Journal of Feline Medicine and Surgery 2010;12:300-305.
28. Zeugswetter FK, Rebuzzi L, Karlovits S. Alternative sampling site for blood glucose testing in cats: giving the ears a rest. Journal of Feline Medicine and Surgery 2010;12:710-713.
29. Zini E, Hafner M, Osto M, et al. Predictors of clinical remission in cats with diabetes mellitus. Journal of Veterinary Internal Medicine 2010;24:1314-1321.

Q & A: Pacing and Circling in a Cushing's Dog Treated with Trilostane

I'm having a problem with Rigby, a 12-year-old male Lab mix diagnosed with pituitary-dependent Cushing's disease 3 years ago. We started him on trilostane (Vetoryl, Dechra Veterinary Products) at that time and the dog has done well, with complete resolution of clinical signs of polyuria and hair loss.

The owner called today and said that Rigby has been having urinary and defecation accidents in the house for 3 weeks. He has also been pacing, and possibly circling much of the night.

It sounds to me like the dog could be suffering from canine cognitive dysfunction. Can I use selegiline for canine cognitive dysfunction when the dog is already on treatment with trilostane? I was wondering, of course, because at one point in time selegilene was commonly used to treat Cushing's disease.

My plan is to first work the dog up to rule out an urinary tract infection, but do you have any other thoughts about the pacing and circling?

My Response:

First of all, your idea to do a workup for urinary tract infection (complete urinalysis with culture) is a good one and that should be the first step in your diagnostic testing. Urinary tract infections are common in dogs with Cushing's disease, even on treatment. If you haven't recently monitored the effects of trilostane treatment with an ACTH stimulation test, that should also be done at this time.

If you believe that Rigby has canine cognitive dysfunction, you can certainly use the drug selegiline hydrochloride, also known as L-deprenyl (veterinary trade name, Anipryl) along with the trilostane that the dog's already getting.

As you know, Anipryl is approved by the FDA for use in dogs for treatment of pituitary-dependent hyperadrenocorticism, as well as canine cognitive dysfunction. This drug has fallen out of favor for treating dog's with Cushing's syndrome because it only partially controlled the disease in most dogs.

For cognitive dysfunction, some owners have reported marked improvement changes in their geriatric dog's behavior after starting Anipryl, while other dogs may not respond at all. Because of the drug's low incidence of side effects, however, it's certainly worth a try in dogs with suspected cognitive dysfunction.

I'd also recommend a good neurological exam. Remember that this dog has pituitary-dependent Cushing's disease. In most of these dogs, the cause have a pituitary ACTH-secreting tumor. With time, these pituitary tumors can grow and become large macrotumors, expanding and compressing the hypothalamus. That of course could be the cause of the dog's pacing as well. If that is suspected, a CT or MRI is recommended to confirm the presence of a large pituitary mass.

Adrenal Tumors in Cats

Click here to view the slides as you read through this lecture.

Adrenal tumors are an uncommon finding in cats. Based on available data, it is estimated that approximately 0.03% of the feline population (representing 0.2% of all cat tumors) develop a primary adrenal gland tumour. Metastasis to the adrenal glands from other organs is uncommon but when it does occur, lymphoma seems to be the most common (1).

An adrenal tumour may be functional (i.e., producing and secreting a hormone) or nonfunctional. In cats, adrenocortical tumors can secrete excessive amounts of cortisol, progesterone and other sex steroid hormones, or aldosterone. Feline adrenal medullary tumors (pheochromocytoma), although extremely rare, secrete excessive amounts of catecholamines.

Cortisol-Secreting Adrenal Tumors
A cortisol-secreting adrenal mass causing hyperadrenocorticism is the most common functional adrenal tumour identified in cats. Naturally occurring hyperadrenocorticism (Cushing’s syndrome) is rare in cats (2-4). Pituitary-dependent hyperadrenocorticism accounts for the majority of cases, but cortisol-secreting adrenocortical neoplasia is responsible in approximately 20% of cats. About one-third of theses adrenal tumors in cats are malignant.

Historical and clinical findings in cats with cortisol-secreting adrenal tumors may include lethargy, weakness, pendulous abdomen, thin fragile skin, bilaterally symmetric alopecia, dull haircoat, seborrhea sicca, muscle atrophy, polyuria, polydipsia, and polyphagia (2-4). In contrast to dogs with hyperadrenocorticism, polyuria and polydipsia in affected cats appear to be secondary to concurrent diabetes mellitus in the vast majority of cases. Hyperglycemia and glycosuria are seen in up to 90% of cats and hypercholesterolemia and elevated serum ALT activity are common. However, a high serum alkaline phosphatase activity is not a consistent finding in cats with hyperadrenocorticism.

In addition to the typical clinical signs and clinicopathologic findings associated with hyperadrenocorticism, diagnosis of hyperadrenocorticism due to a functional adrenal tumour is confirmed using tests of pituitary-adrenocortical axis (ie, high dose dexamethasone suppression test and endogenous ACTH concentrations). Finally, imaging studies (ie, abdominal ultrasound, CT, MR) should be used to confirm the presence of an adrenal tumour in these cats (2-4). In cats with adrenal-dependent hyperadrenocorticism, the contralateral adrenal gland is expected to be small or atrophied as a result of suppressed pituitary ACTH secretion.

Unilateral adrenalectomy is most successful method of treating cats with cortisol-secreting adrenocortical tumour (2-5). In cats with adrenal adenoma or adrenal carcinoma that has not yet metastasized, adrenalectomy may be curative. If tumour resection is successful, circulating cortisol fall to low concentrations and these cats generally require glucocorticoid supplementation for approximately two months postoperatively until the glucocorticoid secretory function of the atrophied contralateral gland recovers.

Because of the deleterious effects of chronic cortisol excess on skin fragility as well as on immune and cardiovascular function, many cats with untreated hyperadrenocorticism are poor surgical candidates. Surgery has been difficult to perform owing to the debilitated condition of these cats. Although further investigation needs to be done, trilostane (5-15 mg/kg) appears to be useful in the preoperative preparation of these cats prior to adrenalectomy (3,6). In those cats that are not surgical candidate or have adrenal tumour metastasis, trilostane (Vetoryl. Dechra Veterinary Products) may also be useful in their long-term management, at least for a few weeks to months.

Sex hormone Secreting Adrenal Tumors
A functional tumour arising from the adrenal cortex could secrete excessive amounts of adrenal progestagens, androgens, or estrogens. Progesterone-secreting adrenal tumors have been the most common sex hormone secreting adrenal tumour reported in cats (6-10). Clinical signs are similar to those in cats with cortisol-secreting tumors. Excessive progesterone secretion in affected cats causes diabetes mellitus and feline fragile skin syndrome, which is characterized by progressively worsening dermal and epidermal atrophy, endocrine alopecia, and easily torn skin. In most of these cats with progesterone-secreting adrenal tumors, results of tests of the pituitary-adrenocortical axis are normal to suppressed and the contralateral adrenal gland is normal in size and shape on abdominal ultrasound. Diagnosis requires documenting an increased concentration of one or more adrenal sex steroids, ideally measured before and after ACTH stimulation.
Recently, a male cat that had developed strong urine order and aggressive behaviour was documented to have a functional adrenal adenoma associated with high circulating concentration of androstenedione and testosterone (11). After adrenalectomy, serum concentrations of the androgens decreased and urine spraying urine aggression resolved.

Aldosterone Secreting Adrenal Tumors
Primary hyperaldosteronism (Conn's syndrome) appears to be a relatively rare but greatly underdiagnosed disease of older cats. This syndrome is characterized by excessive autonomous secretion of aldosterone from one or both adrenal glands, resulting in clinical signs relating to hypertension and/or hypokalemia (13-16).

About half of cases have been due to unilateral aldosterone-secreting adrenal adenomas, whereas most of the remaining cats have unilateral adrenal carcinomas. Less commonly, bilateral adrenal adenomas or bilateral adrenal hyperplasia (17) have been reported. Occasionally, an aldosterone-secreting adrenal tumour is also found to be hypersecreting another adrenocortical hormone, most commonly progesterone (9,11); these cats also had diabetes mellitus and dermatologic changes, both attributed to progesterone excess rather than hyperaldosteronism.
Aldosterone is the major mineralocorticoid secreted by the adrenal cortex and is responsible for regulation of sodium and potassium balance. Therefore, the hormone helps maintain intravascular fluid volume and acid-base balance. Historical findings are generally nonspecific can include generalized weakness (sometimes episodic), lethargy, stiffness, muscle pain, polyuria/polydipsia, and blindness (13-17). Physical examination findings might include ventroflexion of the neck, hypertension, blindness, and retinal vessel tortuosity.

Cats with hyperaldosteronism commonly have moderate to severe hypokalemia and metabolic alkalosis. The sodium concentration is normal to mildly elevated. Demonstration of an inappropriately elevated serum aldosterone concentration along with a low plasma renin concentration provides a definitive diagnosis of hyperaldosteronism. Ideally a diagnosis is made on the basis of marked hyperaldosteronemia in conjunction with hypertension, hypokalemia, inappropriate kaliuresis (high urinary fractional excretion of potassium), and low plasma renin activity (14-17). The presence of renal failure presents a particular diagnostic dilemma, as renal failure itself can lead to a similar constellation of abnormalities. The magnitude of aldosterone elevation may be the key (ie, aldosterone is only about 2-3 times normal with renal failure).

A recent report assessed changes of the urinary aldosterone-to-creatinine ratio in normal cats in response to increased dietary salt or administration of fludrocortisone acetate (18). In that study, normal cats showed the most consistent decrease of the urinary aldosterone-to-creatinine ratio with administration of fludrocortisone acetate as compared with dietary salt supplementation. One cat with an aldosterone-secreting adrenal carcinoma had an elevated ratio and no suppression in response to fludrocortisone acetate. Such mineralocorticoids function tests may prove useful as more cats are diagnosed with this syndrome.

Initial treatment of cats with hyperaldosteronism should be directed toward provision of parenteral or oral potassium supplementation and correction of any fluid deficits and acid-base imbalances. For this purpose, potassium gluconate is generally given at the dosage of 2-6 mEq/day, with the dose adjusted as necessary to maintain normokalemia. If necessary, the diuretic spironolactone, which acts as an aldosterone receptor antagonist, can also be administered at the dosage of 2-4 mg/kg/day.

Surgical adrenalectomy is the treatment of choice in most cats with hyperaldosteronism that do not have evidence of metastatic disease. For those cats that have bilateral adrenal hyperplasia, metastatic disease, or whose owners have declined surgery, medical management with oral spironolactone and potassium can be continued indefinitely.


Catecholamine Secreting Adrenal Tumors
Pheochromocytoma is a catecholamine-producing tumour derived from the chromaffin cells of the adrenal medulla that is extremely rare in cats (1, 2). Clinical signs and physical examination findings develop as a result of the space-occupying nature of the tumour and its metastases, or as a result of excessive secretion of catecholamines and their impact on blood pressure and cardiac function. A diagnosis of pheochromocytoma prior to surgery is usually one of exclusion. Unlike a cortisol-secreting adrenal tumour, the contralateral adrenal gland should be normal in size and shape with a catecholamine-producing adrenal tumour. Catecholamine secretion by the tumour, and thus systemic hypertension, tends to be episodic; failure to document systemic hypertension does not rule out pheochromocytoma. Measurement of urinary catecholamine concentrations or their metabolites can strengthen the tentative diagnosis of pheochromocytoma but is not commonly performed in cats. Because many of the clinical signs and blood pressure alterations are similar for pheochromocytoma and adrenal-dependent hyperadrenocorticism, it is important to rule out adrenal-dependent hyperadrenocorticism before focusing on pheochromocytoma.

References
1. Withrow Stephen J, and David M. Vail. Small Animal Clinical Oncology. St Louis: Saunders Elsevier, 2007.

2. Peterson ME, Randolph JF, Mooney CT. Endocrine diseases. In: Sherding RG eds. The Cat: Siagnosis and Clinical Management (2nd ed). New York: Churchill Livingstone, 1984; 1404-1506.
3. Duesberg C. Peterson ME. Adrenal disorders in cats. Vet Clin North Am Small Anim Pract 1997;27:321-347.

4. Peterson ME. Feline hyperadrenocorticism. In: Mooney CT, Peterson ME (eds). BSAVA Manual of Endocrinology (Third Ed), Quedgeley, Gloucester, British Small Animal Veterinary Association, pp 205-212, 2004.

5. Duesberg CA, Nelson RW, Feldman EC, et al. Adrenalectomy for treatment of hyperadrenocorticism in cats: 10 cases (1988-1992). J Am Vet Med Assoc 1995;207:1066-1070.

6. Boag AK, Neiger R, Church DB. Trilostane treatment of bilateral adrenal enlargement and excessive sex steroid hormone production in a cat. J Small Anim Pract 2004;45: 263-266.

7. Boord M, Griffin C. Progesterone-secreting adrenal mass in a cat with clinical signs of hyperadrenocorticism. J Am Vet Med Assoc 1999; 214: 666-669.

8. Rossmeisl JH, Scott-Moncrieff JC, Siems J, et al. Hyperadrenocorticism and hyper-progesteronemia in a cat with an adrenocortical adenocarcinoma. J Am Anim Hosp Assoc 2000; 36: 512-517.

9. Declue AE, Breshears LA, Pardo ID, et al: Hyperaldosteronism and hyperprogesteronism in a cat with an adrenal cortical carcinoma. J Am Vet Med Assoc 2005:19: 355-358.

10. Quante S, Sieber-Ruckstuhl N, Wilhelm S, et al. Hyperprogesteronism due to bilateral adrenal carcinomas in a cat with diabetes mellitus. Schweizer Archiv fur Tierheilkunde 2009; 151: 437-442.

11. Millard RP, Pickens EH, Wells KL. Excessive production of sex hormones in a cat with an adrenocortical tumour. J Am Vet Med Assoc. 2009;234:505-508.

12. Briscoe K, Barrs VR, Foster DF, et al. Hyperaldosteronism and hyperprogesteronism in a cat. J Fel Med Surg 2009; 11: 758-762.

13. Rose SA, Kyles AE, Labelle P. Adrenalectomy and caval thrombectomy in a cat with primary hyperaldosteronism. J Am Anim Hosp Assoc. 2007; 43: 209-214.

14. Ash RA, Harvey Am, Tasker S. Primary hyperaldosteronism in the cat: a series of 13 cases. J Feline Med Surg 2005; 7: 173-82.

15. Gunn-Moore D. Feline endocrinopathies. Vet Clin North Am Small Anim Pract 2005; 35: 171-210.

16. Rijnberk A, Voorhout G, Kooistra HS, et al: Hyperaldosteronism in a cat with metastasised adrenocortical tumour. Vet Q 2001; 23: 38-43.

17. Javadi S, Djajadiningrat-Laanen SC, Kooistra HS et al. Primary hyperaldosteronism, a mediator of progressive renal disease in cats. Domestic Animal Endocrinol 2005; 28: 85-104.

18. Djajadiningrat-Laanen SC, Galac S, Cammelbeeck SE, et al. Urinary aldosterone to creatinine ratio in cats before and after suppression with salt or fludrocortisone acetate. J Vet Intern Med 2008;22:1283-2388.