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.

Q & A: Adjusting The Dose Of Determir Insulin In Dogs

I have an 12-year-old F/S lab who was diagnosed with diabetes 4 months ago. The dog had typical signs of polyuria, polydipdia and weight loss.

She was initially started on NPH insulin at 0.4 U/kg BID (8 U BID). Over the course of 2 months, we increased the NPH dose to 0.7 U/kg BID (14 U BID) but the dog continued to be symptomatic. We did a blood glucose curve and obtained the following results:

• Fed at 7:30 AM
• Glucose at 8:30 AM: 132 mg/dl
• Glucose at 10:30 AM: 103 mg/dl
• Glucose at 12:30 PM: 160 mg/dl
• Glucose at 2:30 PM: 286 mg/dl
• Glucose at 4:00 PM: 381 mg/dl

Based on that curve was concerned that the duration was too short, so we switched to insulin detemir (Levemir). I know that detemir is more potent, so we started at 0.1 U/kg BID (2 units BID). The blood glucose curve 1 week later:

• Fed at 7:30 AM
• Glucose at 8:30 AM: 580 mg/dl
• Glucose at 10:30 AM: 343 mg/dl
• Glucose at 12:30 PM: 364 mg/dl
• Glucose at 2:30 PM: 361 mg/dl
• Glucose at 4:00 PM: 401 mg/dl

We then increased detemir to 3 units BID, and checked again 8 days later:

• Fed at 7:30 AM
• Glucose at 8:30 AM: 422 mg/dl
• Glucose at 10:30 AM: 234 mg/dl
• Glucose at 12:30 PM: 253 mg/dl
• Glucose at 2:30 PM: 309 mg/dl
• Glucose at 4:00 PM: 381 mg/dl

We then increased to 0.2 U/kg BID (4 units BID), and checked again in 2 weeks.

• Fed at 7:30 AM
• Glucose at 8:30 AM: 422 mg/dl
• Glucose at 10:30 AM: 283 mg/dl
• Glucose at 12:30 PM: 321 mg/dl
• Glucose at 2:30 PM: 356 mg/dl
• Glucose at 4:00 PM: 370 mg/dl

We just did a complete urinalysis and urine culture which was negative. Results of a recent CBC and serum chemistry panel were normal, except for the high blood glucose concentration. The dog is doing well clinically at home.

I'm not sure what to make of the persistent hyperglycemia on detemir. Possible Somogyi reaction? Or does the dog just needs more insulin?

When increasing the detemir insulin dosage, should I be going up a certain percentage or unit/half-unit at a time?

My Response:

This certainly doesn't look like an overdose of insulin or Somogyi overswing to me. Most likely, this dog just needs more insulin.

However, you should double check the following points with the owner as the next step:

• That they can accurately measure and then inject the insulin reliably.
• That they are feeding the dog only in morning and evening (no other treats during the day).
• That they are measuring the amount of food being feed, calculated by a veterinarian that it's the correct amount for the dog's ideal body weight.

It doesn't appear clinically that she has any concurrent conditions that would cause insulin resistance, such as infection, inflammation, or Cushing's excess. Some dogs just require more insulin to adequately lower their blood glucose than do other dogs!

In a large dogs, I increase my detemir dose by increments of 1 unit BID. In a small-breed dogs, I increase by less; by increment of 0.5 units BID.

I then wait 1 week or so and then repeat the serial glucose curve to make any additional needed dose adjustments.

Q & A: Can L-Thyroxine Treatment Trigger Excessive Shedding And Exfoliation?

I just rechecked a hypothyroid dog that I put on L-thyroxine (Soloxine) about 1 month ago.  The dog's skin is very, very flaky; she is shedding a great deal and is mildly pruritic.  

I came across something in one of my endocrinology books that indicates this may happen when starting thyroid supplementation, but this is the first time I've seen it in my 16 years of general practice.  The skin scrape is negative, and there are no signs of any other skin pathology: there is no evidence of bacterial, yeast, or immune-mediated skin disease. 

So do you think that this excessive shedding and flaking in this dog is related to initiation of the L-T4 therapy?

How frequently do you see this reaction or side effect?

What can I expect this dog's skin to do from here on? How long for this issue to resolve?

My Response:

Hypothyroid dogs occasionally develop severe shedding and flaking during the first 2 to 3 months of L-thyroxine treatment. During this time, the old telogen hairs are all being shed at the same time. With a bit of time on L-T4 replacement, the old shedded hairs are  replaced with anagen hairs, and the skin cycle is restarted.

So I would expect the excessive shedding to resolve within the next 4 to 8 weeks on the L-T4 supplementation. However, you may want to treat the scaling symptomatically with a mild antiseborrheic shampoo and conditioner therapy such as Sebolux or Humilac. Adding some essential fatty acids (EFAs) to the dog's diet may also be of benefit. 

If scaling persists or worsens beyond 8-weeks time, then skin biopsy for a keratinization disorder such as ichthyosis is recommended.

I can't give you an incidence for how often excessive flaking and shedding happens after initiation of L-thyroxine supplementation, but it certainly is not rare. I do see increased flaking more frequently in dogs with Cushing's disease during initial treatment with mitotane or trilostane than I do in dogs with hypothyroidism. 

However, the reason I don't see this problem as often in hypothyroidism may simply be that, as a specialist, I only rarely get to treat and manage hypothyroid dogs. Although hypothyroidism can be a problem to accurately diagnose, it's an relatively easy disorder to treat.

Q & A: Hypothyroid Dog Not Responding to L-T4 Replacement

"Molly" is a 7-year-old Laborador Retriever weighing 31 kg, who was diagnosed over a year ago as being hypothyroid based on the finding of a low-normal serum T4 concentration (0.9 μg/dl; reference range, 0.9-3.9 μg/dl). Her clinical signs included non-pruitic alopecia of the pinnae and truncal dermatitis. Based upon her clinical signs and the low serum T4 value, she was started on L-thyroxine (Soloxine) a the dosage of 0.5 mg, BID.

Over the past year, a number of post-pill serum T4 concentrations have been done, but all of her serum T4 values have remained in the low-normal range (between 0.9-1.5 μg/dl). Her dose of Soloxine was increased to 0.6 mg but there still has not been improvement in clinical signs.

This week I repeated an entire thyroid panel while the dog is on the L-T4 and send the serum to the Michigan State University Endocrine Lab (animalhealth.msu.edu). Here are the results of that thyroid panel:

TT4: 59 nmol/L (15-67 nmol)

TT3: 1.5 nmol (1.0-2.5 nmol)

FT4: 20 pmol/L (8-26 pmol)

FT3: 5.2 pmol (4.5-12 pmol)

T4AA: 11% (0-20%)

T3AA: 5% (0-10%)

TSH: 0.01 mU/L (0-37 mU/L)

Thyroglobulin AA: 2% (0-35%)

My questions: Will being on L-thyroxine cause these numbers to all be normal? Is it advisable to stop the thyroid supplementation for a few weeks and run another serum thyroid panel, as clinically it doesn't seem to be doing much? Is she really hypothyroid at all?

Thank you so much for your help!

My Response:

Yes, the goal of thyroid hormone supplementation is to completely normalize the serum thyroid panel (i.e., to raise serum total and free T4 and T3 values and suppress serum TSH concentrations). So these results indicate that the L-T4 supplementation in this dog is being well absorbed and is feeding back on the pituitary gland to lower TSH secretion.

But you are correct: if the dog isn't hypothyroidism, the clinical signs aren't going to improve. I would recommend that you stop the L-T4 supplementation and redo the thyroid panel. Unfortunately, we need the dog off all L-T4 for at least 6 weeks prior to testing to allow the hypothalamic-pituitary-thyroid axis to recover. Once you stop the thyroid medication, this dog may be mildly hypothyroid (due to iatrogenic suppression of pituitary TSH secretion) even if his thyroid gland was normal prior to the thyroid supplementation.

When you do recheck Molly after stopping the thyroid mediation, remember to also run a CBC and serum chemistry panel. This will rule out any nonthyroidal diseases, but will also help in diagnosis of hypothyroidism, especially if mild anemia, or fasting hyperlipidemia/ hypercholesterolemia is present.

PS: I don’t know what the prior post-pill test results showed serum T4 values only in the low-normal range, but the serum T4 on this panel is perfect.  Have the owners been consistently giving the L-T4 without food or at time of meals?

It’s been shown that absorption of L-T4 in dogs can be better when given on an empty stomach. So if the owners were not consistent in when they administer the thyroid medication, that could explain why the previous results were so different that the current results. And it may also explain why the dog hasn’t responded to the thyroid supplementation (if she really is hypothyroid, which still needs to be determined).

References:

1. Le Traon G, Burgaud S, Horspool LJ. Pharmacokinetics of total thyroxine in dogs after administration of an oral solution of levothyroxine sodium. J Vet Pharmacol Ther. 2008;31(2):95-101.

Q & A: Can Basal Cortisol Value Be Used To Diagnose Addison's Disease?

My patient is a 2-year-old MN German short-haired pointer, a 1-day history of lethargy, anorexia, and vomiting once. On physical examination, he was quiet but alert and had good color and a normal heart rate.

Here are an overview of the dog's laboratory results:

• Complete blood count revealed mild lymphocyosis and eosinophilia.
• Serum urea nitrogen and creatinine were both normal.
• Serum sodium was normal at 140 mEq/L.
• Potassium was high at 6.2 mEq/L.
• The Na:K ratio was low at 22.5.
• A basal cortisol concentration was 1.9 μg/dl (reference range, 1-4 μg/dl).

Two questions:

1. Can I make a diagnosis of Addison's disease based upon this dogs' clinical signs, and bloodwork (i.e., lymphocyosis and eosinophilia, hyperkalemia, and low Na:K ratio)? Is the basal cortisol concentration low enough to confirm the diagnosis or do I need to do an ACTH stimulation test? I've heard that you can exclude Addison's disease if the basal cortisol is higher than 2.0 μg/dl, so I'm hoping that the 1.9 μg/dl cortisol value is low enough to confirm the diagnosis.
2. If a single 0.5 mg/kg dose of prednisone was given to this dog, how long would I have wait to do an ACTH stimulation test?

My Response:

You definitely need to do an ACTH stimulation test to confirm Addison's disease in this dog.

First of all, although the routine blood work is certainly suspicious, there are a number of canine conditions other than Addison's disease that can lead to lymphocyosis or eosinophilia, as well as a low sodium to potassium ratio (1).

A 2007 study reported that almost all dogs with Addison's will have serum or plasma cortisol values less than 2 μg/dl and proposed that the use of a basal cortisol determination can be used as a screening test to rule out hypoadrenocorticism (2). Basically, Addison's disease can be excluded in any dog that has a baseline cortisol >2 μg/dl.  However, if the baseline cortisol concentrations <2.0 μg/dl, little to no information regarding adrenal gland function can be obtained and an ACTH stimulation test MUST be done to make a definitive diagnosis.

The bottom line: dogs with Addison's will generally have very low to undetectable serum cortisol concentrations (<1.0 μg/dl). A few dogs with maintain low-normal serum cortisol concentrations, between 1.0-2.0 μg/dl (2,3).  Although sick dogs without Addison's disease rarely have low cortisol concentrations, low-normal cortisol values (between 1.0-2.0 μg/dl) are common in sick dogs without adrenal gland disease.

In answer to your second question, waiting 48 hours after administration of a single dose of prednisone will be long enough to do the stimulation test.

If the dog is symptomatic and you are worried about adrenal crisis, it would be fine to give a small dose of dexamethasone (1-2 mg) or give a routine monthly dose of Percorten (2.2 mg/dl). Neither will cross-react in the cortisol assay to falsely elevate the measured values.

However, all of forms of glucocorticoid therapy and well as fludrocortisone acetate (Florinef) will cross-react in the cortisol assay and should not be given before the ACTH stimulation test is completed.

References:

1. Nielsen L, Bell R, Zoia A, et al. Low ratios of sodium to potassium in the serum of 238 dogs. Vet Rec 2008;162:431-435.
2. Lennon EM, Boyle TE, Hutchins RG, et al. Use of basal serum or plasma cortisol concentrations to rule out a diagnosis of hypoadrenocorticism in dogs: 123 cases (2000-2005). J Am Vet Med Assoc 2007;231:413-416.
3. Peterson ME, Kintzer PP, Kass PH. Pretreatment clinical and laboratory findings in dogs with hypoadrenocorticism: 225 cases (1979-1993). J Am Vet Med Assoc. 1996; 208:85-91

Q & A: Atypical Addison's Disease In Dogs With Gastrointestinal Signs

I read your recent post regarding Addison's disease and I'm writing to see if you could clear up (or add to the debate) a discussion that we are having at our hospital. I am a second-year medicine resident and our medical staff is having a debate about what is considered a normal vs. an abnormal cortisol response to ACTH stimulation and what exactly is "atypical" Addison's disease.

For example, what about dogs that have chronic gastrointestinal (GI) signs that have not yet been been diagnosed but a flat cortisol response to ACTH stimulation is found? If we perform an ACTH stimulation test on these dogs, many will have a basal cortisol level well within reference range limits (e.g., 2 to 4 μg/dl) but the post-ACTH stimulated cortisol concentration will not rise to levels 3-5 times higher than the basal cortisol concentration. Some of these dogs will have ACTH-stimulated cortisol concentrations that are below the post-ACTH reference range (e.g., in the range of only 3-6 μg/dl). Is this atypical Addison's disease?

What do you do in these cases? Look for other causes of the GI signs? And if no other cause found supplement with steroids? Should we just repeat the ACTH stimulation test down the line?

Thank you for your time!

My Response:

First of all, you must remember that the blog post on Addison's disease you are referring to was written primarily for dog owners, not veterinarians. I was trying to be clear, which is difficult when we are discussing a topic that could include typical, atypical, or secondary adrenal insufficiency.

Almost all dogs with primary hypoadrenocorticism (typical Addison's disease) and near complete destruction of the adrenal cortex will have subnormal basal and ACTH-stimulated serum cortisol concentrations (<1 μg/dl).

Dogs with secondary hypoadrenocorticism (pituitary ACTH deficiency) have low to low-normal basal cortisol values that may rise very slightly to ACTH stimulation, but the cortisol response is very blunted (post-ACTH values generally < 3 μg/dl). This has all been published (1-3), and I don't think anyone would strongly disagree with those guidelines.

The problem with "atypical" Addison's disease is that, at least most of the time, the dogs have never been worked up properly to differentiate primary from secondary hypoadrenocorticism. Most would define "atypical" Addison's simply as glucocorticoid-deficient hypoadrenocorticism, but that is really being quite simplistic and does not help guide what replacement therapy may be needed or predict prognosis.

In other words, if that "atypical" dog has primary Addison's disease with normal electrolytes, it is very possible or even likely that mineralocorticoid replacement will be needed. On the other hand, it a dog has secondary hypoadrenocorticism, mineralocorticoid replacement will never be needed, but pituitary imaging (CT or MRI scan) might be indicated to exclude a pituitary mass.

The easiest way to differentiate primary from secondary hypoadrenocorticism, of course, would be to measure plasma ACTH concentration, but that must be done before any glucocorticoids have been administered (or after 1-2 weeks off all steroids).

If the plasma ACTH value is low (generally < 20 pg/ml) in a dog with a severely blunted serum cortisol response to ACTH stimulation, that would be diagnostic for secondary hypoadrenocorticism (1-4). As you know, ACTH deficiency is rare and is most commonly associated with a pituitary tumor (3). By far the most common cause is iatrogenic secondary hypoadrenocorticism resulting from glucocorticoid administration. So it's extremely important in dogs with "atypical" Addison's disease to go back in the history and make sure that they haven't received any steroid in the last few weeks to even months.

If the plasma ACTH value is high (generally >250 pg/ml) with a severely blunted serum cortisol response to ACTH stimulation, that would be diagnostic for primary hypoadrenocorticism (1-4). If the serum electrolytes are normal, that could be called "atypical" Addison's disease. Some of these dogs will certainly go on to develop serum electrolyte changes, whereas others never seem to do so. I suspect that these latter dogs do not actually have adrenal destruction, but may have an ACTH receptor defect where circulating ACTH values are high but the adrenal gland doesn't bind the ACTH so it cannot act to stimulate cortisol secretion. Again, the best way to distinguish secondary from primary hypoadrenocorticism in these dogs is to measure plasma ACTH before any glucocorticoids are administered (or off all glucocorticoids for at least 1-2 weeks).

But let me get back to your original question about the dogs that have chronic GI signs and whose ACTH stimulation test results reveal a normal (or low) basal cortisol with a post-ACTH cortisol values that is blunted, rising to only 3-6 μg/dl. This is certainly not a "normal" response, abut it's very difficult for me to explain why these dogs would have any signs when these circulating cortisol values are within or slightly above the normal basal range. If this was a dog on mitotane or trilotane, for example, we would be very pleased with those serum cortisol results and would not be worried about hypoadrenocorticism (5-7).

In my experience, most of these dogs have a history of being treated with glucocorticoids, which could lead to secondary (iatrogenic) hypoadrenocorticism. Again, if you would measure a plasma ACTH concentration in these dogs, the values should be low-normal if they do indeed have secondary ACTH deficiency. If there is now history of glucocorticoid use, I would certainly repeat basal or ACTH-stimulated cortisol values in 2-4 weeks, but most of these dogs do not end up having primary adrenal disease.

Now that's not to say that they don't need steroid supplementation, but not for "atypical" adrenal disease.

References:

1. Peterson ME, Kintzer PP, Kass PH. Pretreatment clinical and laboratory findings in dogs with hypoadrenocorticism: 225 cases (1979-1993). J Am Vet Med Assoc 1996;208:85-91.
2. Kintzer PP, Peterson ME. Primary and secondary canine hypoadrenocorticism. Vet Clin North Am Small Anim Pract 1997;27:349-357.
3. Feldman EC, Nelson RW. Canine and Feline Endocrinology and Reproduction.Third Edition. Saunders, 2003.
4. Peterson ME, Orth DN, Halmi NS, et al. Plasma immunoreactive proopiomelanocortin peptides and cortisol in normal dogs and dogs with Addison's disease and Cushing's syndrome: basal concentrations. Endocrinology 1986; 119: 720-730.
5. Kintzer PP, Peterson ME. Mitotane (o,p'-DDD) treatment of 200 dogs with pituitary-dependent hyperadrenocorticism. J Vet Intern Med 1991;5:182-190.
6. Peterson ME, Kintzer PP. Medical treatment of pituitary-dependent hyperadrenocorticism. Mitotane. Vet Clin North Am Small Anim Pract 1997;27:255-272.
7. Ramsey IK. Trilostane in dogs. Vet Clin North Am Small Anim Pract 2010;40:269-283.

Radiation Safety Recommendations After Treatment Of Human Patients With Thyroid Diseases By Radioiodine

Radiation safety is an essential component in the treatment of human patients with thyroid diseases by radioiodine (I-131). This is true of human patients, as well as the cats and dogs that we treat with radioiodine.

The American Thyroid Association (ATA) created a task force to develop recommendations that would inform medical professionals about attainment of radiation safety for patients, family members, and the public. The task force was constituted so as to obtain advice, experience, and methods from relevant medical specialties and disciplines.

This publications from the ATA Taskforce on Radiation Safety details a summary of their conclusions and recommendations, depending on the dose of radioiodine administered to the patients.

As you can see, the guidelines recommended for human patients are much less stringent that we have to follow for our feline and canine patients treated with radioiodine!

Reference:

Sisson TA, Freitas J, McDougall IR, Dauer LT, Hurley JR, Brierley JD, Edinboro CH, Rosenthal D, Thomas MJ, Wexler JA, Asamoah E, Avram AM, Milas M, Greenlee C. Radiation safety in the treatment of patients with thyroid diseases by radioiodine 131-I: practice recommendations of the American Thyroid Association.Thyroid 2011; 21(4):335-346.

Q & A: Does T3 Hyperthyroidism Occur in Cats?

Prior to veterinary school, I worked as for a few years at a major medical center as a nurse in their endocrine clinic. In older human patients with hyperthyroidism, was not that uncommon for these folks to present with perfectly normal serum T4 values but have very high serum T3 concentrations.

Do cats also develop a similar syndrome of T3 hyperthyroidism? That is, can some hyperthyroid cats maintain normal serum concentrations of T4 and free T4, but have clinical signs resulting from high circulating T3 values alone?

I've reviewed the literature, but I don't see that T3 thyrotoxicosis has ever been reported in cats. Is that because we just aren't checking serum T3 levels in hyperthyroid cats? Do you think that we are missing these cases?

My Response:
This syndrome is commonly referred to as triiodothyronine (T3) thyrotoxicosis or just T3 toxicosis. This disorder is found almost exclusively in the elderly and may be the cause of hyperthyroidism in up to 10% of older patients. T3 thyrotoxicosis is characterized by the finding of high serum T3 with normal or even low T4 levels, which can sometimes even lead to an erroneous diagnosis of hypothyroidism.

In the late 1970s and throughout most of the 1980s, we routinely measured serum T3 on all hyperthyroid cats. Although serum T3 concentrations were very high in many of these cats, we never documented a cat with isolated T3 thyrotoxicosis (1).

So over the last 35 years, I have certainly looked for this syndrome of T3 thyrotoxicosis. I have always expected to find some cats with normal T4 but high T3 levels, but to date the syndrome of T3 hyperthyroidism has yet to be documented in cats.

Today, we rarely use serum T3 concentrations as a diagnostic test for hyperthyroidism. Use of total T4 alone is diagnostic in over 90% of cats, whereas serum T3 values are high in only about two-thirds of cats (2).

That said, however, it still is possible that hyperthyroid cats could develop T3 hyperthyroidism. Certainly in circumstances where a low iodine diet is fed, you might see a situation where T3 is being secreted preferentially over T4 (3).

In states of iodine deficiency, it’s easier for the thyroid gland to make T3 compared to T4. The reason for that is simple — it takes one less iodide atom to make T3 than T4, since T3 only has 3 iodine atoms whereas T4 contains 4 iodine atoms.

T4 has 1 more iodine atom than T3

Therefore, you have a cat in which hyperthyroidism is suspected, especially if a palpable goiter was present, but total and free T4 values are normal, I would certainly recommend that you run a serum T3 concentration to rule out T3 thyrotoxicosis.

References:

1. Peterson ME, Kintzer PP, Cavanagh PG, et al. Feline hyperthyroidism: pretreatment clinical and laboratory evaluation of 131 cases. J Am Vet Med Assoc 1983;183:103-110.
2. 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. J Am Vet Med Assoc 2001;218:529-536.
3. Laurberg P. Mechanisms governing the relative proportions of thyroxine and 3,5,3'-triiodothyronine in thyroid secretion. Metabolism: clinical and experimental 1984;33:379-392.

Q & A: Prednisone and Cushing's Syndrome: Which Screening Test Is Best?

I'm treating a 10-year old, F/S Bichon Frise who has been on 2.5 mg of prednisone daily for months. Her appetite has always been good, but recently she has become extremely ravenous on the same dose of prednisone. In addition, lately she has become noticeably more polyuric and polydipsic (PU/PD). 

So, I suspect that naturally-occurring Cushing's syndrome may be developing — oddly, while taking predisone. We found not abnormalities on her routine lab work except an very high serum alkaline phosphatase activity of 1100 U/L (reference range < 100 U/L).

My thought is that stopping the predisone for a few days should be enough to allow for us to perform an ACTH stimulation test or a low-dose dexamethasone suppression test (LDDST). That amount of time will allow the predisone to leave the system so there won't be any interference with the testing. It would seem to me that an interval longer than a few days shouldn't be needed.

That being said, everyone keeps telling me it will take a few months for the adrenals to regenerate once I stop the prednisone. Presuming this dog has truly developed PDH or an FAT, does it make any sense to you that I should have to wait any longer than just a few day to let the prednisone out of the body?

My Response:

Good question. If this dog's pituitary and adrenal glands are "normal" (ie, she does not have naturally occurring Cushing's disease - either pituitary-dependent hyperadrenocorticism or a functional adrenal tumor), then the prednisone could feedback on the dog's normal pituitary gland to inhibit ACTH secretion. With time, the resulting low circulating ACTH concentrations would lead to atrophy of the inner 2 zones of the adrenal gland that secrete cortisol.

If you stop the prednisone for 24-48 hours and do an ACTH stimulation test in that dog, the results would likely show a low to low-normal basal cortisol with a "blunted" cortisol response to ACTH stimulation (generally > 2.0 ug/dl but < 6 ug//dl). Despite the suppression basal and ACTH-stimulated cortisol values, that same dog with iatrogenic hypoadrenocorticism could show clinical signs of iatrogenic hyperadrenocorticism (due to the direct glucocorticoid effects of the prednisone).

Now, if this dog really does have natural Cushing's syndrome (either pituitary-dependent hyperadrenocorticism or adrenal tumor), the doses of prednisone you are giving will NOT be high enough to shut off pituitary ACTH secretion or suppress adrenal cortisol section. (This "resistance" to glucocorticoid negative feedback in Cushing's disease is the whole physiologic basis for use of the low-dose dexamethasone suppression test.).

So in this dog with Cushing's syndrome, performing an ACTH stimulation test after being off the prednisone for 24-48 hours would show a normal to high basal cortisol with a high-normal to exaggerated serum cortisol response. In other words, the prednisone would not affect the ACTH stimulation test because the adrenal cortex would still be hypertrophied.

Another important point: in this scenario, you want to use and ACTH stimulation test, not the low-dose suppression test. If another long discussion for me to explain the reason why that's the case, but you can get false-positive results in dogs with iatrogenic Cushing's disease so you do NOT want to use a low-dose dexamethasone suppression test in this dog, at least as your initial test.

Q & A: Huge Thyroid Mass In Cat Treated With Long-Term Methimazole

Bailey is a 14-year-old male neutered domestic short hair who was diagnosed with hyperthyroidism by another veterinarian about 3 years ago and has been on methimazole since then. He also has a history of chronic constipation that has been well controlled in the last year on enulose (Lactulose) only.

I last saw Bailey a year ago, at which point he was doing well clinically but had lost about 1 lb. since his last check. At that time, he was on 5 mg of methimazole BID. A geriatric profile at that time showed a total T4 of 3.3 μg/dl, a normal CBC and serum chemistry profile (creatinine = 1.5 mg/dl, BUN = 23 mg/dl), and a urine specific gravity of 1.065. I recommended increasing his dose of methimazole to 7.5 mg in the morning and 5 mg in the evening and rechecking in 4-6 weeks.

The owner did increase the daily methimazole dose but did not follow up with us until now. Bailey has lost an additional 3 lbs. since his last exam and has developed polyphagia, polyuria, and polydipsia over the last month.

On exam yesterday, the cat now has a fairly large mass in his left ventral neck area (about 3-4 cm, slightly firm and irregular), which I had not noted on the last exam. His blood work from yesterday showed a T4 of 1.9 μg/dl, and very normal renal function (serum creatinine = 1.1 mg/dl; BUN = 22 mg/dl, USG =1.030).

So, I'm suspicious that the thyroid mass is or has become a carcinoma at this point. But would you expect the cat to lose weight secondary to a thyroid carcinoma even if the T4 is within normal range? Could it be secreting another hormone to cause the weight loss?

I thought I should recommend full-body radiographs to try to rule out any metastasis or other obvious neoplasia, and then consider surgical removal and biopsy of the mass. I've read that it can be helpful to follow-up with I-131 treatment after excision of a thyroid carcinoma, so I would speak to the owner about referral for that.

Does that sound like a reasonable course of action to you or are there other things you would recommend doing first? Thank you very much for any help or advice you can give me on this perplexing case.

My Response:

There are many ways you could go in your workup of this cat. Most cats that I see who are loosing weight while on treatment with methimazole have high serum T4 concentrations, which can explain the weight loss. Obviously, that's not the case here, which makes this cat more interesting!

Many cats (in fact, probably nearly all hyperthyroid cats) will have an increase in goiter size with time — that makes sense since we aren't inhibiting thyroid tumor growth with the methimazole. We are only blocking thyroid hormone secretion with the drug.

Recently, a paper was published showing that on thyroid biopsy, some cats with long-standing hyperthyroidism had evidence of transformation of thyroid adenoma to carcinoma (1). I do believe that this happens more than we realize, and I now see almost a cat a month with thyroid carcinoma. Almost all cats with thyroid carcinoma that I see have been on methimazole for longer than 2 years.

So in your cat, the enlargement of the thyroid mass could indicate that the tumor has simply grown larger with time, or it could indicate malignant transformation. As you indicated, thyroid biopsy would be helpful in making that diagnosis. Many of these cats have extension or metastasis into the thoracic cavity so you might not be able to cure that cat with surgical thyroidectomy if that is the case. What I like to do in that situation is to perform a thyroid scan (thyroid scintigraphy) prior to surgery, which we certainly could do in this cat. This will tell us where the thyroid tumor tissue is located and help direct what needs to be removed or biopsied, if the cat does go to surgery.

Thyroid Scan of cat with large thyroid carcinoma (left) compared to normal cat (right)
Notice the extension & invasion of the thyroid tumor into the thoracic cavity
(horizontal line indicates the region of the thoracic inlet)

That all said, why is your cat loosing weight despite a normal serum T4? With the polyphagia, the cat should bee taking in enough calories. If there vomiting or diarrhea? (I assume that diarrhea isn't present because of the constipation.)

Cats with weight loss that are eating normally must have either increased loss of glucose in the urine or impaired absorption of nutrients from the GIT. To that end, I would recommend that you perform an abdominal ultrasound, in addition to your full-body x-rays, prior to either thyroid biopsy or thyroid scintigraphy. Urine culture should also be considered to exclude pyelonephritis.

As far as other hormones being secreted, I'd suggest that you also measure a serum free T4 and T3 concentration on this cat. It's possible that the free T4 or T3 concentrations are still high and that could explain some of weight loss in this cat.

Reference:
1. Hibbert A, Gruffydd-Jones T, Barrett EL, Day MJ, Harvey AM. Feline thyroid carcinoma: diagnosis and response to high-dose radioactive iodine treatment. J Feline Med Surg. 2009 11:116-24. 

Q & A: What To Do With Cortrosyn That's About to Expire

Due to an inventory error, we have found ourselves with 3 bottles of synthetic ACTH (Cortrosyn) that have an expiration date of a month from now. Would you recommend reconstituting all 3 vials and freezing into aliquots at this point? Before I throw out several hundred dollars worth of Cortrosyn, I wanted to ask you opinion.

Additionally, for future use, what is the current dosing recommendation when using previously reconstituted Cortrosyn? Are there special considerations for freezing it?

Thanks so much for your help.

My Response:

Officially, I cannot condone the use of drugs past their expiration date, but it makes some sense to me that if you reconstitute it and freeze it now, that you could keep the aliquots for 6 months. The problem is if you get results that you weren't expecting (ie, lower than expected ACTH-stimulated cortisol values), then you have to question whether the Cortrosyn is still potent, but I'd suspect it will be okay.

If it was still in date, you could try selling some to neighboring clinics, but I'm not so sure you can or should do that with expired drug.

Click here to see my previous post about how I recommend reconstituting and freezing Cortosyn for future use. And click here to see my post on the best dose to use for ACTH stimulation testing.

Assay for Parathyroid Hormone Related Protein (PTHrp) Is Back

About a month ago, I posted that the Diagnostic Center for Population and Animal Health (DCPAH) at Michigan State University had announced that the reagents for their parathyroid hormone related protein assay (PTHrP) were not longer available.

This week Michigan State University's DCPAH announced that they are back in business and can again run serum samples for both parathyroid hormone (PTH) as well as PTHrp.

This is the only laboratory that offers the PTHrp test used in the workup for dogs and cats with hypercalcemia. So this is great news that this important assay is up and running again soon.

See the Announcement page on the DCPAH website for more information.

Q & A: What's the Best Screening Test for Feline Hyperthyroidism?

We are trying to concur on choice of the single best test to screen cats for hyperthyroidism. Is determination of total T4 still the gold standard for screening the majority of cats?

My Response:

TT4 is diagnostic in 90% of cats
with hyperthyroidism

Use of a serum total T4 concentration is absolutely the best single screening test. But remember, the diagnosis of hyperthyroidism can never be based on a single total T4 alone. It has to be based on the presence of clinical features (eg. weight loss despite a good appetite) together with the presence of a thyroid nodule. If many clinical signs of hyperthyroid are present in a cat with a high total T4 but a thyroid nodule is not palpable, it's always a good idea to confirm the diagnosis by repeating the T4 and/or measuring a free T4 concentration.

Falsely high FT4 values common
in cats with other illness

In some cats with mild hyperthyroidism, the total T4 can be high-normal or only borderline high. In these cats, a free T4 measurement is commonly used to help verify the diagnosis. The free T4 value should NEVER be run without a total T4; the specificity of the T4 is quite poor, and many cats without hyperthyroidism will have a high free T4 concentration. Therefore, the presence of a high free T4 with a normal T4 is not really diagnostic for hyperthyroidism unless the cat is showing clinical signs of the disease and has a palpable thyroid nodule. 

Thyroid scan of a cat with
mild hyperthyroidism

Again, without clinical features and physical exam findings consistent with hyperthyroidism, it's always best to wait and retest at 1-3 month intervals. Thyroid scintigraphy (see Figure on left) can also be a very helpful diagnostic aid in these cats. Cats with mild hyperthyroidism have an increased uptake of the radionuclide by their thyroid nodules. The percent uptake (or thyroid:salivary ratio) can be calculated and used as a sensitive diagnostic test for hyperthyroid cats.

Sound difficult? Unfortunately, it is not always so easy to correctly diagnose hyperthyroidism in cats. But remember that treatment of hyperthyroidism is never an emergency, especially if the hyperthyroidism is very mild. If a 'borderline' cat does have hyperthyroidism, the thyroid nodule will grow and the total T4 will become high with time.

How to Extend Your Supply of Cortrosyn and Lower the Cost of ACTH Stimulation Testing

Cortrosyn is expensive. And once reconstituted, it has a limited shelf-life.

However, by following the protocol outlined below, you can easily dilute, aliquot and store Cortrosyn after reconstitution for up to 6 months. This makes each ACTH stimulation test much less expensive, because each vial of Cortrosyn can be used to perform as many as five ACTH stimulation tests.

Cortrosyn is supplied in vials each containing 0.25 mg (250 μg) of synthetic ACTH (cosyntropin) in powder form. Because the dose of Cortrosyn used to perform an ACTH stimulation test is only 5 μg/kg, small to medium sized dogs require only a fraction of the ACTH contained in each vial.  

For more information on how to perform an ACTH stimulation test, see my post entitled, What's the best protocol for ACTH stimulation testing in dogs and cats?

How to aliquot and store each vial of Cortrosyn for subsequent use? It's simple — just follow the directions outlined here:

1. Reconstitute the Cortrosyn power by adding exactly 2.5-ml of sterile saline solution to the vial. With this dilution, the resulting concentration of the Cortrosyn solution in the vial would be 100 μg /ml.

2. Once Cortrosyn is reconstituted, aspirate 50-μg doses (0.5 ml) into 5 plastic syringes.  Or, if smaller ACTH doses are desired, aspirate 25-μg doses (0.25 ml) into 10 syringes.  (For more accurate dosing, I use insulin or tuberculin syringes).

    DO NOT store reconstituted Cortrosyn in glass containers or vials. The reason that the Cortrosyn needs to be stored in plastic is that ACTH will stick to glass, thereby lowering the available amount of Cortrosyn that would be injected at time of testing.

3. The syringes containing the reconstituted, diluted Cortrosyn should be labeled with the product, dose in each syringe, and the date the Cortrosyn was reconstituted.  

4. Freeze each of the syringes at -20^oC.  Avoid storing these syringes in a frost-free freezer, which must periodically warm up to de-frost. Repeated freezing and thawing cycles would compromise the integrity of the Cortrosyn.

    When frozen properly, aliquots can be stored for up to 6 months without loss of efficacy.

5.  Alternatively, the Cortrosyn solution can be stored refrigerated (4^oC) where it has been shown to be bioactive and stable for at least 4 weeks.

 

Diluting the Cortrosyn and using a low-dose ACTH stimulation test protocol is very cost-effective. In this way, 1 vial of Cortrosyn can be used to test multiple patients without compromising the quality of the test results.

As an example, at the 5-µg/kg dose, 5 dogs weighing 10 kg (22 lbs) can be tested using a single vial, reducing the cost of the drug by 80%. By looking at the cost benefit, it is clear that the savings could be significant by using this testing protocol.

Radiation Risks to Health: A Joint Statement from Leading Scientific Experts

The growing concern surrounding the release of radiation from an earthquake and tsunami-stricken nuclear complex in Japan has raised fears of radiation exposure to populations in North America from the potential plume of radioactivity crossing the Pacific Ocean.

Because I use radioactive materials both to treat cats with hyperthyroidism (radioiodine; I-131) and to perform nuclear imaging procedures (ie, thyroid, bone, renal, liver scans— see my website for more information), many veterinarians have contacted me with questions and concerns.

Over the weekend, the American Association of Clinical Endocrinologists, the American Thyroid Association, The Endocrine Society and the Society of Nuclear Medicine issued a joint statement written to help Americans understand their radiation-related health risks. I thought that many of you might find this helpful in understanding the situation and what you and your family should know.

RADIATION RISKS TO HEALTH:

A Joint Statement from the American Association of Clinical Endocrinologists, the American Thyroid Association, The Endocrine Society and the Society of Nuclear Medicine

March 18, 2011

Chevy Chase, MD (March 18, 2011)--The growing concern surrounding the release of radiation from an earthquake and tsunami-stricken nuclear complex in Japan has raised fears of radiation exposure to populations in North America from the potential plume of radioactivity crossing the Pacific Ocean. To help Americans understand their radiation-related health risks, the American Association of Clinical Endocrinologists (AACE), the American Thyroid Association (ATA), The Endocrine Society and the Society of Nuclear Medicine (SNM) issued a joint statement.

The statement suggests that the principal radiation source of concern, in regard to impact on health, is radioactive iodine including iodine-131.This presents a special risk to health because exposure of the thyroid to high levels may lead to development of thyroid nodules and thyroid cancer years later.

Radioactive iodine uptake to the thyroid can be blocked by taking potassium iodide (KI) pills. However the statement cautions KI should not be taken unless there is a clear risk of exposure to high levels of radioactive iodine. While some radiation may be detected in the United States as a result of the nuclear reactor accident in Japan, current estimates indicate radiation levels will not be harmful to the thyroid gland or general health. If radiation levels did warrant the use of KI, the statement recommends it should be taken as directed by physicians or public health authorities until the risk for significant exposure dissipates.

The statement discourages individuals needlessly purchasing or hoarding of KI in the United States. Since there is not a radiation emergency in the United States or its territories, the statement does not support the ingestion of KI prophylaxis at this time. KI can cause allergic reactions, skin rashes, salivary gland inflammation, hyperthyroidism or hypothyroidism in a small percentage of people.

The American Association of Clinical Endocrinologists, American Thyroid Association, The Endocrine Society and the Society of Nuclear Medicine will continue to monitor potential risks to health from this accident and will issue amended advisories as warranted.