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.

Q & A: Can Nonthyroidal Illness Suppress Free T4 Concentrations in Cats?

Buster is a 10-year, M/C DSH with asthma. He has been off his asthma medications for the past year but began coughing again recently. I rchecked Buster a week ago, submitted geriatric bloodwork, and started him back on prednisolone and theophylline for his asthma since he waa clinical again.

Buster is overweight at 17 pounds, but he has lost 3 pounds on a weight loss plan. Other than being overweight and increased bronchovesicular sounds on auscultation, his physical examination was unremarkable, with great skin and haircoat.

His overall blood work was totally normal, with the exception of a low serum T4 concentration (0.4 μg/dl; reference range = 0.8-4.0 μg/dl). I added on a free T4 value, expecting it to be normal; however, it was also low at 5 pmol/L (reference range = 10-50 pmol/L).

My question is this: Can the euthyroid sick syndrome can suppress serum T4 and T3 levels in cats, as drugs or disease can do in dogs? I do not feel treatment with levothyroxine (L-T4) is warranted in this cat, but I don't want to ignore low thyroid values either unless I can explain why they might be low.

I'd greatly appreciate your insight on this curious case.

My Response:

I agree with you that Buster would not likely benefit from L-T4 supplementation.

Hypothyroidism is a clinical diagnosis -- if there aren't any clinical signs, the finding of low serum thyroid hormones values alone doesn't justify treatment. This is even more true in cat, where spontaneous hypothyroidism has only been documented in only a couple adults cats. Congenital hypothyroidism in kittens is much more common, but Buster certainly doesn't have congenital hypothyroidism since he is 10 years old!

Figure 1: Notice that the total T4 concentrations are low in about half of the cats with nonthyroidal disease (pink box plot on right).

Figure 2: Notice that the free T4 concentrations tend to stay within normal range in cats with nonthyroidal illness (pink box plot on right), but values are subnormal in about 20% of these cats. Also note the falsely "high" values in other sick cats, illustrating some of the problems with the free T4 assay in cats.

It certainly is possible that his asthma and steroid therapy has suppressed both his total and free T4 concentrations. In 2001, I wrote a research paper (1) where we measured total and free T4 in cat with hyperthyroidism and nonthyroidal illness. As you can see in Figures 1 and 2, both total and free T4 were suppressed to low levels in some of the cats who were ill.

Reference:

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. J Am Vet Med Assoc 2001;218:529-36.

What's the Best Protocol for ACTH Stimulation Testing in Dogs and Cats?

Preparing for the ACTH stimulation test: Does the animal need to be fasted?

The dog or cat does not have to be fasted overnight, and lipemia does not appear to “clinically’ affect serum cortisol values. However, having a nonlipemic sample may be better in some situations, especially if serum cholesterol or triglycerides are being measuring on same sample.

Remember that the ACTH stimulation test is the most useful test for monitoring dogs being treated with trilostane (Vetoryl) or mitotane (Lysodren) see my blog entitled, Diagnosing Cushing's disease: Should the ACTH stimulation test ever be used? Both medications are fat-soluble drugs and must be given at time of meals, or the drugs will not be well absorbed.

With trilostane, it’s extremely important to give the morning medication with food, and then start the ACTH stimulation test 3 to 4 hours later.

Fasting these dogs on the morning in which the ACTH stimulation test is scheduled should be avoided since it invalidates the test results.

When a dog ‘s food is withheld, the absorption of trilostane from the gastrointestinal tract is decreased. This leads to low circulating levels of trilostane, resulting in little to no inhibition of adrenocortical synthesis. Therefore, serum cortisol values will higher when the drug is given in a fasted state than when it is given with food.

The higher basal or ACTH-stimulated cortisol results could prompt one to unnecessarily increase the daily trilostane dose. That misjudgment may lead to drug overdosage, with the sequelae of hypoadrenocorticism and adrenal necrosis in some dogs.

Recommended ACTH stimulation test protocol:

There are many different published protocols for how to perform the ACTH stimulation testing. Both ACTH gel or synthetic ACTH can be used, but over the last 2 decades, the use of cosyntropin (Cortrosyn) has become the “gold standard” preparation for ACTH stimulation testing.

In the USA, Cortrosyn is available through Henry Schein (800-872-4346; www.henryschein.com) where it can be purchased as an individual vial ($68/vial) or a box of 10 ($720 per box or 68/vial). 

This is the protocol for the Cosyntropin (Cortrosyn) ACTH stimulation test that I recommend:

1. Collect baseline serum or plasma sample for cortisol determination.

Use of a serum separator tube should be acceptable for serum cortisol measurements, but check with your laboratory to ensure proper sample collection.

2. Prepare the ACTH preparation for administration (see below).

Cortrosyn is supplied by the manufacturer as a lyophilized cosyntropin powder in vials containing 0.25 mg (250 µg) of ACTH to be reconstituted with sterile saline solution.

In order to make this test more cost effective when using Cortrosyn and to make it easier to administer this dose to smaller dogs, I recommend diluting the Cortrosyn and dividing the solution into 25-μg to 50-μg aliquots in a tuberculin or insulin syringe, and then refrigerating or freezing the capped syringe.

For specific guideline on how to dilute the Cortrosyn and store it to extend it’s shelf-life, look for may next post entitled: How to extend your supply of Cortrosyn and lower the cost of ACTH stimulation testing.

3. Administer the cosyntropin at a dosage of a 5.0 μg/kg, up to a maximum dose of 250 μg; 1 entire vial).

This 5.0 μg/kg dosage will result in maximum stimulation of the adrenocortical reserve, the most important criteria for any ACTH stimulation protocol.

4. In dogs, the Cortrosyn can be administered either IV or IM, with equivalent cortisol results. Obviously, if the dog is dehydrated or in shock, the Cortrosyn must be administered intravenously.

In cats, its best to administer the Cortrosyn IV, because the adrenocortical response is more consistent and the peak is higher. Given subcutaneously, the Cortrosyn is not well absorbed in cats. In addition, giving Cortrosyn by the IM route is painful for cats and should be avoided.

5. Collect post-ACTH serum sample for cortisol determination 1 hour later.

6. After the clot has retracted, centrifuge both samples. 

If using plasma or a serum tube without a separator, aspirate the plasma or serum and transfer into a plastic or glass vial.

Test protocol for tetracosactide (Synacthen):

If you live in a part of the World other than the USA, it’s likely that you will be using tetracosactide (Synacthen) rather than Cortrosyn as the synthetic ACTH preparation. The chemical structure of tetracosactide and cosyntropin are identical, and the test protocol outlined above will work. However, because the cost of Synacthen is much less than Cortrosyn, it is common practice to administer Synacthen at the dose of a half vial (125 μg) to a cat or small dog and an entire vial (250 μg) to a larger dog, rather use the 5-ug/kg dosage.

Q & A: Unexplained Weight Loss in Hyperthyroid Cat on 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 July and has developed polyphagia, polyuria and polydipsia over the last month. On exam yesterday, my main physical exam finding was that he 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 I131 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 cat.

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!

Large goiter in hyperthyroid cat

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. 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 would 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.

That all said, why is your cat loosing weight despite a normal serum T4? With the polyphagia, the cat should be taking in enough calories. If there vomiting or diarrhea? (I am guessing no diarrhea 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 GI tract. 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 serum concentrations of free T4 or T3 are still high and that could explain some of the cat's weight loss.

References:

1) Harvey AM, Hibbert A, Barrett EL, Day MJ, Quiggin AV, Brannan RM, Caney SM. Scintigraphic findings in 120 hyperthyroid cats. J Feline Med Surg. 2009 11:96-106.

Q & A: Vetsulin Insulin Discontinued, Now What Insulin?

I have a 10-year-old male neutered diabetic chihuahua that was diagnosed after Vetsulin went off the market.  We tried for several months to regulate him on Humulin N, but we never could get him controlled.  

We finally got him enrolled in the Vetsulin Critical Need Program.  He is doing great on Vetsulin given twice daily, but now we're unable to get any more of the Vetsulin.  As you know, the Vetsulin Critical Need's Program has been discontinued!

Now that that honeymoon is over, what insulin can I try on this problem diabetic?

My Response:

Vetsulin (Lente insulin) is actually a mixture of rapid-acting and long-acting insulins (Semi-lente and Ultralente). So knowing that your patient responded better to the Vetsulin, you have 3 'general' choices for selecting the next insulin preparations in this dog. I do not believe that Vetsulin will be returning to the market anytime soon. You also know from past experience that human NPH isn't a good choice for this diabetic patient.

Humulin 70/30 (Eli Lilly) may be a good choice in this dog. This is a 100 U/ml pre-mixed combination of 30% short-acting and 70% intermediate-acting insulin. Because it has a similar duration/action curve to Vetsulin, Humulin 70/30 insulin is well suited to a twice-daily dosing regimen in diabetic dogs where meals are fed at the same time as the insulin injections.

Another insulin choice similar to Humulin 70/30, is a pre-mixed combination of a short-acting synthetic insulin analogue (ie, Lispro or Aspart insulin) with a longer-acting insulin analogue (ie. Lispro or Aspart Protamine Insulin). Examples of these synthetic insulin combinations include Humalog Mix 75/25 (Eli Lilly) or NovoLog 70/30 (Novo Nordisk).  Both of these insulin analogue mixtures are given twice daily with meals.

Finally, my third choice is detemir insulin (Levemir, Novo Nordisk). This is another insulin analogue with a long duration of action with a similar action profile to glargine (Lantus), but detemir appears to be more potent and work better in dogs than than glargine does.   Detemir is the most potent of these insulin choices and is dosed initially at  0.1 U/kg BID, again generally administered at time of feeding.

Q & A: Does Feeding Decrease Absorption of L-Thyroxine?

I recently read one of your posts on your Animal Endocrine blog site regarding 'How Do We Treat Dogs with Hypothyroidism.' In that post, you indicated that thyroid replacement medication should be given on an empty stomach. And you indicated that this was quite important.

My question about this is: I have a number of dogs that are on L-thyroxine but the owners have always given the medication at the time of feeding. If we are doing post-pill serum T4 testing at 4 to 6 hours after administration of the morning dose and adjusting the daily dose according to those thyroid results, does it matter that the owners give the pills with food?

Thank you.

My Response:

Good question. Yes, the absorption of L-thyroxine (L-T4) in dogs has indeed been shown to be much higher when given on an empty stomach.

To my knowledge, this difference in the absorption has only been reported for Leventa, a liquid L-T4 medication (1). In one study, food intake concomitant with L-T4 oral administration delayed L-T4 absorption and decreased its rate and extent by about 45% (2).

I know of no other reports of the effects of feeding on absorption of L-T4 tablets in dogs, but I assume that the differences in absorption might also be true for other brands and formulations of L-T4.

The bottom line: In your patients, giving the L-T4 with food is not wrong. If the post-pill serum T4 is within the therapeutic range and the dog has responded with resolution of the clinical signs of hypothyroidism, I certainly wouldn't change the dose or feeding regime.

My point in that my L-T4 blog post is that if the owners did administer the L-T4 pill on an empty stomach, the daily required dose of L-T4 could likely be lowered. In some dogs, that could be a huge issue in the success of therapy, but in most dogs it probably doesn't make that much difference clinically.

References

1. Leventa (levothyroxine sodium) oral solution. Intervet/Schering-Plough Animal Health. Package insert available at: http://www.leventa.com/default.asp

2. 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.

What ACTH Preparations Should Be Used For Stimulation Testing?

The pituitary hormone corticotropin (adrenocorticotropic hormone or ACTH) is a single-chain 39-amino-acid peptide hormone synthesized in the corticotrophs of the anterior lobe (pars distalis) of the pituitary gland). Although the amino acid sequence of ACTH varies among species, the first 24 amino acids are identical among all species studied to date. Canine ACTH differs from human ACTH by only one amino acid residue, at position 37, although the amino terminal end of the ACTH molecule (amino acids 1 to 18) is responsible for its biologic activity.

ACTH is available in two general forms as a diagnostic testing agent. Both of these forms or preparations of ACTH work by stimulating the adrenal cortex to secrete cortisol, corticosterone, aldosterone, and a few other weakly androgenic substances.

ACTH Gel Preparations

In the past, the main ACTH preparation used for adrenal function testing was ACTH gel, which is extracted from bovine and porcine pituitary glands. The ACTH in these gel preparations is composed of the entire 39-amino-acid sequence of the ACTH peptide.

Brand name ACTH gel preparations

In the USA, the only FDA-approved, brand-name ACTH gel preparation is H.P. Acthar gel Repository Injection (80 U/ml; Questcor Pharmaceuticals). The FDA has specifically labeled H.P. Acthar Gel for use in diagnostic testing of adrenal function. However, the package insert lists a variety of other diseases and disorders for which it may be used including acute multiple sclerosis, infantile spasm, rheumatoid arthritis, hemolytic anemia, allergic conjunctivitis, and ulcerative colitis (1).

In late 2007, Questcor announced a new strategy and business model for H.P. Acthar Gel Repository Injection (2). The cost of the product was increased from an average wholesale price of $2,063 per 5-ml vial to an estimated $23,000 per vial! The company explained that its price increase was crucial in order to continue manufacturing and distributing this agent to patients who needed it, as well as to fund projects that could contribute to the company’s growth.

This increase in price has led physicians to totally abandon its use for adrenal function testing, since synthetic ACTH is so much cheaper. H.P Acthar Gel is almost 29 times more expensive than either formulation of cosyntropin available in the USA (see below). Many have also questioned the therapeutic value of H.P. Acthar Gel, especially as it compares with lower-priced and potentially therapeutically equivalent alternatives, such corticosteroids.

During the late 1970’s and early 80’s, I used this H.P. Acthar gel product routinely for ACTH stimulation testing because it was very cost effective. As the price of Acthar gel started to increase and synthetic ACTH preparations became more available, however, I had completely switched to use of only synthetic ACTH preparations by the late 1980s for adrenal gland testing in dogs and cats.

Today, performing an ACTH stimulation test with H.P. Acthar gel would cost the veterinarian over $1000 per dog just for the product alone, not including the serum cortisol determinations! Obviously, it is highly unlikely that you will be using this ACTH gel preparation for use in testing dogs and cats anytime in the future.

Generic ACTH gel preparations
Generic preparations of ACTH gels (usually 40 U/ml) can be purchased from several veterinary-compounding pharmacies. The following is a partial list of compounding pharmacies that sell such generic ACTH gels: Wedgewood Pharmacy, Pet Health Pharmacy, Red Oak Drug, Meds for Vets, and Diamond Back Drugs. Many practicing veterinarians favor these compounded ACTH products because they are slightly cheaper than Cortrosyn (and certainly much less expensive than H.P. Acthar gel!)

But as someone smart once said, ”you generally get what you pay for.”

There are 4 reasons why I do NOT recommend these compounded ACTH products:

1. Compounding pharmacies are not governed or regulated by the FDA. Therefore, we have no guarantee that the potency of these compounded formulations are what the pharmacy claims them to be. Some batches of compounded ACTH gel may be very potent and maximally stimulate cortisol secretion, whereas others batches or preparations fail to stimulate maximal cortisol secretion or may not stimulate it at all!
2. Because of the potential for lot-to-lot variability in compounded ACTH formulations, one should consider assessing the activity of each new vial by performing an ACTH stimulation test on a normal dog to ensure that the preparation is bioactive (i.e., it will work to stimulate cortisol secretion from the adrenal cortex). Of course, that suggestion is totally impractical for the practicing veterinarians.
3. Because of the differences in potency and absorption of these compounded products, peak ACTH-stimulated cortisol values may occur from 30 minutes to 2 hours after gel administration (3). In contrast to H.P. Acthar gel, where peak cortisol secretion occurred 2 hours after administration, the compounded ACTH preparations are not consistent.   Because of this variability in the duration of cortisol response, most authorities recommend collecting post-ACTH at both 1 and 2 hours when using a compounded gel preparation (3).
4. The added time and need to collect and measure a third cortisol concentration offsets any cost savings gained from using a compounded ACTH product. (And remember my second point — we should validate the test with every new vial by testing a clinically normal dog!).

The bottom line: while these compounded ACTH preparations may be less expensive than other available products, they are not recommended because the potency can vary from bottle to bottle.

Stick with synthetic ACTH preparations, as described below!

Synthetic ACTH Preparations

Cosyntropin is a synthetic form of ACTH, created by isolating the first 24 amino acids from the 39-amino-acid ACTH peptide. The only indication for use of cosyntropin is in diagnostic testing of adrenal function. A dose of cosyntropin 0.25 mg, which is biologically similar to a dose of 25 units of ACTH gel, maximally stimulates the adrenal cortex.

Cosyntropin has many advantages over the use of the ACTH gels for ACTH stimulation testing. First of all, the cosyntropin test takes half the time of the ACTH gel test (1 hour vs. 2 hours). Secondly, the ACTH-stimulated cortisol response to cosyntropin is more consistent and variations in potency are not an issue. Finally, cosyntropin is less immunogenic than ACTH gel. The amino acids 22 to 39 in ACTH produce most of the molecule’s antigenicity; thus, cleaving of most of these amino acids from cosyntropin molecule renders it less likely to elicit an allergic response.

In the USA, cosyntropin is either as the brand-name product Cortrosyn (Amphastar Pharmaceuticals) or a generic cosyntropin preparation (Sandoz).

In most countries outside the USA, cosyntropin is called tetracosactide (Synacthen). Despite these differences in name, the chemical structure of tetracosactide is identical to cosyntropin (both 1-24 ACTH).

Cortrosyn

The brand-name product Cortrosyn is supplied by the manufacturer as a lyophilized powder in vials containing 0.25 mg (250 µg) of ACTH. The cosyntropin powder must be reconstituted with sterile saline solution at time of injection (4).

Unlike ACTH gels, which can be given intramuscularly (IM) or subcutaneously (SQ). Cortrosyn should NOT be administered via the SQ route. However, Cortrosyn be safely given either IM or IV (4).

In dogs, it has been shown that that either IM or IV routes of administration provide equivalent serum cortisol responses. In cats, however, a more consistent and greater adrenocortical response is elicited after IV administration of cosyntropin, so IM administration is not recommended in this species.

The current cost of Cortrosyn is $72 per vial ($62 per vial if purchased in boxes of 10-vials). Nowadays, it is common practice to dilute Cortrosyn and freeze the diluted aliquots for up to 6 months. This not only extends its shelf life, but makes the use of Cortrosyn much more cost effective.

Generic cosyntropin

Sandoz’s generic cosyntropin, in contrast, is supplied as a solution for injection (0.25 mg per vial).

According to the product insert (5), the synthetic ACTH preparation should be given only intravenously. The product insert also states that cosyntropin injection is intended as a single dose injection and contains no antimicrobial preservative; any unused portion should be discarded.

To my knowledge, no research studies of this cosyntropin generic preparation have been reported in either the dog or cat. It’s safe to assume that this product would be as effective as Cortrosyn in stimulating adrenocortical secretion. However, it is not know if the IM route would be reliable.

Even more importantly, we do not know if this preparation can be diluted and stored in the refrigerator or freezer without loss of potency.

Finally, for reasons that are unclear to me, the current cost of this generic preparation ($99 per vial) is about 30% more than the cost of an identical amount of Cortosyn.

My bottom line: for all of the reasons listed above (including the cost of
product),I would stick with Cortrosyn.

Synacthen

Outside of the U.S., the synthetic ACTH preparation tetracosactide (Synacthen, Novartis) is supplied as a solution for injection (0.25 mg per vial). This preparation appears to be very similar to the generic cosyntropin solution made by Sandoz.

According to my expert sources in the UK and Europe, Synacthen is ‘dirt-cheap.’ So no one has studied if this synthetic ACTH preparation is stable when diluted or how long it’s potency is maintained when stored long-term.

Generally, either one-half or the entire contents of the Synacthen vial are administered per test, depending on the size of the animal.

References

1. H.P. Acthar Gel, Repository Corticotropin Injection, package insert. Union City, CA: Questcor. Available at: http://www.acthar.com/Pdf/Acthar_PI_pdf
2. Questcor Board approves new strategy and business model for H.P. Acthar Gel. Union City, CA: Questcor; August 2007. Available at: http://phx.corporate-ir.net/phoenix.zhtml?c=89528&p=irol-newsArticle&ID=1044912&highlight
3. Kemppainen RJ, Behrend EN, Busch KA. Use of compounded adrenocorticotropic hormone (ACTH) for adrenal function testing in dogs. J Am Anim Hosp Assoc 2005;41:368-372. Abstract available at: http://www.ncbi.nlm.nih.gov/pubmed/16267060
4. Cortrosyn Injection, package insert. Rancho Cucamonga, CA: Amphastar. Available at: http://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?id=3164&type=display  
5. Cosyntropin Injection (Generic), package insert. Princeton, NJ: Sandoz. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/022028lbl.pdf

Q & A: Desmopressin No Longer Controlling Diabetes Insipidus?

I have a female-spayed 14-year-old, mixed-breed dog in which I diagnosed diabetes insipidus (DI) 4 years ago. The diagnosis of DI was based on signs of intense polyuria and polydipsia (PU/PD) and her response to desmopressin (DDAVP). She has been on desmopressin drops (0.1mg/ml), a the dosage of 3 drops in each eye twice daily. She had been doing very well on the drops, but the owners have noticed, especially in the evenings, frequent urination and increased water drinking once again. 

A repeat complete blood count, serum chemistry panel, and complete urinalysis with culture are all normal. I am planning to have the owners increase the dose to 4 drops in each eye twice daily.

Can dogs with DI become resistance to the desmopressin drops? Any other suggestions?

My Response:

Are you using brand name, generic, or compounded desmopressin product? Any recent change in desmopressin formulation or brand?

Other than reevaluating for other problems such a Cushing's disease (much more common in a 14-year-old dog than DI), I don't see why the signs would worsen on the same desmopressin product.

I've found that desmopressin administered by subcutaneous injection to be most effective route of administration. You might want to try that, starting at a dose of 2 to 4 ug BID, and evaluate the effect. If no improvement, then I'd definitely work up the dog for another cause of polyuria and polydipsia.

For more information, see my previous blog posts that discuss workup of polyuria and polydipsia and treatment of DI with desmopressin.

Q & A: Free T4 vs. Thyroid Scintigraphy for Diagnosis of Occult Hyperthyroidism in Cats?

One of my patients is a 10-year-old, FS, DSH cat with a history of vomiting and recent weight loss.  I'm at a loss about where to go next with this cat and I would deeply appreciate any help you can provide.  

Routine CBC, serum chemistry panel, and complete urinalysis have been either completely normal or  unremarkable. Results of both chest radiographs and an abdominal ultrasound were unremarkable. 

Serum T4 values have been normal but appear to be slowly creeping up into the high-normal range (normal < 4.0 μg/dl).  In addition, on my last examination, I palpated a small cervical nodule that might be thyroid tumor.  Here's some cats' serial T4 values and body weight:

Date:                   T4 (ug/dl)             Weight (pounds)              

12/14/08                  2.0                           12.3         

11/20/09                  1.8                           11.7      

11/19/10                  2.3                           10.9      

02/13/11                  2.8                           10.2

I believed that this cat was probably early hyperthyroid and placed her on methimazole 2.5 mg once daily.  My intention was to recheck the T4 after a couple of weeks.  However, the cat developed SEVERE gastroenteritis within 2 days of starting the medication. It took about 5 days of supportive care to get her back to normal.   

Where should I go from here? Would running a free T4 on the cat be helpful? My inclination is to try the cat on transdermal methimazole to see if the cat would regain some of the lost weight, but I'm worried that the cat might severe another severe reaction to the medication.  

Would a thyroid scan be a helpful diagnostic aid in this cat?

My Response:

Cats like this can be problematic and sometimes difficult to diagnose, even if truly hyperthyroid. Running a free T4 may be helpful, since the sensitivity of that test is higher than a total T4 concentration. In other words, this cat may have a mid- to high-normal total T4 but the free T4 could be clearly high. That would be consistent with hyperthyroidism.

The problem is that a high free T4 is not 100% diagnostic for hyperthyroidism since the specificity of the assay is rather poor. In other words, it's quite common to see 'falsely' high free T4 concentrations in cats that have nonthyroidal illness and are not  hyperthyroid at all (see figure on left). 


So the finding of a high free T4 by itself can never be considered diagnostic for feline hyperthyroidism.

A diagnostic imaging procedure called thyroid scintigraphy or thyroid scanning has long been considered the 'gold standard' for diagnosing feline hyperthyroidism. After administrating a short-acting radionuclide that concentrates in thyroid tissue, thyroid imaging directly visualizes the  normal thyroid gland, as well as the small tumor(s) responsible for hyperthyroidism in cats.

Thyroid scintigraphy of a normal cat. Notice the similar uptake of the radionuclide in the 2 normal thyroid lobes and salivary glands

Thyroid scintigraphy of a mildly hyperthyroid cat with small bilateral thyroid adenomas. Notice the increased uptake (brightness) of the radionuclide in both thyroid lobes.

The advantage of thyroid imaging is that it's the most sensitive test we have to diagnose early hyperthyroidism in cats. With the scan, we can calculate the size and the brightness of the thyroid gland. Because this procedure uses the physiology of the thyroid gland to create an image, thyroid imaging is so sensitive that it can actually demonstrate the presence of a hyperfunctioning thyroid tumor long before they cause the serum T4 to rise to above normal.

Q & A: How is Radioiodine (I-131) Administered and Dosed in Hyperthyroid Cats?

I have a general question regarding how veterinarians administer and dose the radioiodine ( I-131) as treatment for hyperthyroid cats. Although I have had a number of my hyperthyroid patients treated successfully with radioiodine, I do not know how one administers and doses it.

A little explanation would be appreciated.

My Response:

We've been giving the radioiodine subcutaneously since 1986. Prior to that, we initially tried the oral route, but that meant handling radioactive capsules (and hoping the cat's wouldn't chew them) or stomach tubing the cats (and hoping the cats wouldn't vomit). In human patients, they generally put the radioiodine solution into a juice drink to cover up the 'iodine" taste and the people just drink the solution. Obviously, that wouldn't work in cats.

From around 1980 to 1986 we gave all of the doses IV, which worked fine. However, that meant that two people always needed to be exposed when the dose is administered and the cat needed to have a catheter placed for the injection. The IV administration worked well, but occasionally, I saw anaphylactoid reactions (rather terrifying!) upon treatment. Obviously, there is something in the solution that that cats don't like when the drug is given more than once intravenously.

Today I still administered the radioiodine to all of my hyperthyroid cats by the subcutaneous route. In many of these cats, I can perform the treatment by myself, thereby not exposing another member of my staff to the full dose of radiation that is contained in the syringe. I have NEVER seen an anaphylactoid reaction when the radioiodine solution is given subcutaneously.

As far as dosing goes, I really do believe that facilities that use a 'fixed dose' are overdosing most of the cats, and under-dosing others.

I give a range of doses from 2-10 mCi to cats with benign adenoma (adenomatous hyperplasia). This method of dose determination is somewhat more complicated, and is based on the following factors:

• Clinical severity of hyperthyroidism
• Magnitude of the serum T4 level
• Size of thyroid tumor(s) on palpation
• Result of thyroid scintigraphy (thyroid scanning)
• Age of the cat
• Known concurrent diseases

Cats with thyroid carcinoma generally require much larger radioiodine doses, generally in amounts of around 30 mCi but sometimes even more. These cats generally have larger thyroid masses, generally invading soft tissue and extending into the thoracic cavity.

Hyperthyroid cat with thyroid carcinoma (on left) demonstrating the massive, multinodular tumor, invading and extending into the thoracic cavity. The horizontal line is the region of the thoracic inlet. 

My goal of therapy is to 'cure' the hyperthyroid state without causing hypothyroidism. Many treatment facilities boast about the fact that they can cure 98% of hyperthyroid cats. Well, that's easy; anyone can order a big dose for all hyperthyroid cats and cure them, but many will become hypothyroid. I agree it's more difficult to titrate the doses because one has to think about the whole cat and what we are doing, but I do believe it's so very important. That's where this whole treatment issue become more tricky.

It's becoming increasing clear that both hyperthyroidism and hypothyroidism are bad for the kidneys, so that last thing we want to do is cure the hyperthyroidism but create iatrogenic hypothyroidism. And that is especially true if the owners cannot give oral medication or if the cat already has mild renal disease.