Monday, August 13, 2012

Managing Hypothyroid Dogs with Low T4 Values Despite High Dose L-T4 Replacement



My "problem" patient is an 8-year-old, male hypothyroid Golden Retriever dog (37 kg) that isn't responding as expected to L-T4 supplementation.

The dog was diagnosed as hypothyroid about 3 years ago, based on the findings of low serum concentrations of both T4 and free T4 and a high serum TSH value. He responded well to initial L-T4 replacement therapy (0.5 mg BID) with complete resolution of all clinical signs of hypothyroidism.

We normally monitor and adjust the L-T4 dosage in our hypothyroid dogs by measuring a post-pill T4 value 4 to 6 hours after the morning dose of L-T4 is administered. The last normal post-pill serum T4 value in this dog was now over a year ago. Since that time, all of the serum T4 values have been  low to undetectable, despite a gradual doubling in the dog's L-T4 dose (now on 1.0 mg, BID). We've also sequentially changed our L-T4 preparation from a generic preparation to 3 different brand-name products (i.e., Thyro-tabs, Soloxine, and now Leventa), all to no avail.

The dog is not on any iodine supplements, and is fed a good brand of commercial dry dog food and a few milk bones daily. He has some chronic allergic skin issues (including ears) and has been treated in the past with steroids or antihistamines, but he has not been on any drugs for months.

Clinically, the dog appears happy and healthy and there is no indication of any other systemic disease. Despite the persistently low serum T4 values, the dog is not acting hypothyroid.

What else should I do to help get this dog's thyroid regulated? Can I go higher with his daily L-T4 dosage?

My Response:

There are a number of possible reasons why a hypothyroid dog could have persistently low serum T4 concentrations despite L-T4 supplementation.

Unreliable L-T4 preparation
Although most of the generic L-T4 preparations appear to work reasonably well most of the time, we do occasionally see treatment failures with these generics. In such cases, changing to a brand-name product easily solves the problem. In this dog, you have already ruled out this possibility by trying 3 major name-brand L-T4 products!

Poor bioavailability (poor absorption)
Again, the bioavailabilty (absorption) of brand-name L-T4 products is generally better than the generics, and this is one of the reasons name-brand products are more reliable.

In general, dogs will absorb the L-T4 best if given on an empty stomach. So if an owner has been administering the L-T4 with food, a change of dosing time to when the dog is fasted may help.  However, L-T4 is still absorbed reasonably well when given with food, so this would not explain why this dog has undetectable post-pill T4 values.

Compliance problems
In some cases, an owner may not be giving the L-T4 as directed. I've had owners think that they should not administer the medication on the morning when a recheck exam is scheduled.  We should always confirm that the L-T4 supplementation was administered on the morning of post-pill testing. If the medication wasn't given, a low T4 value should not be unexpected.

Incorrect dosage or underdosage
Obviously, we should always confirm that the dog's dose and L-T4 strength is correct.

Moderate to severe nonthyroidal illness 
In dogs with nonthyroidal illnesses, the serum thyroid hormone values are commonly suppressed, many times into the hypothyroid range (1-4). If a dog has a serious illness, it is possible that the post-pill T4 concentration would remain lower than anticipated. However, we do not generally see illness result in persistently low T4 concentrations, especially on high-dose L-T4 supplementation.

Drugs that suppress serum T4 concentrations
There are a number of drugs that can "falsely" suppress serum T4 (and sometimes free T4) values in dogs. The drugs most commonly associated with low T4 concentrations include the following:
  • Phenobarbital (5-9)
  • Trimethoprim-sulonamides (5, 10,11)
  • Zonisamide (12)
  • Clomipramine (Clomicalm) (13)
  • Aspirin (5,14,15)
  • Glucocorticoids (including topicals on eyes, ears or skin) (16,17)
If a dog is being treated with any of these drugs, it is certainly possible that the post-pill T4 concentration would be lower than anticipated. However, we do not generally see persistently low to undetectable post-pill T4 values, especially in dogs on high-dose L-T4 supplementation.

Laboratory error
Recently, both Antech and IDEXX Laboratories changed their method of T4 analysis from the "gold standard" RIA or chemiluminescence (Immulite) techniques to an automated enzyme immunoassay technique. While most of the T4 results measured by the gold standard methods (RIA or chemiluminescence) versus the new automated immunoassay method show very good agreement, the T4 values are discordant in about 5% of cases.

This problem occurs most commonly in dogs receiving thyroid supplementation. Characteristically, the T4 can be low to undetectable when measured by the automated immunoassay method but the post-pill T4 is normal or even high when measured by RIA or chemiluminescence. The reason for this discrepancy is T4 values between assay techniques is not clear.

In this dog, this could certainly be the problem. How is the lab measuring the T4? If done by automated immunoassay, I'd measure the next post-pill T4 value by either RIA or chemiluminescence to rule out this issue.

Bottom Line—When Is Post-Pill Monitoring Indicated?

From the clinical history, I was stuck by the fact that this dog —despite having persistently low T4 values on a very high dose of L-T4 supplementation— appears happy, healthy, and is not acting hypothyroid.  So my question is: should we even be monitoring post-pill T4 values in hypothyroid dogs which show complete resolution of all signs of disease after L-T4 treatment?

I use post-pill testing when a dog with confirmed hypothyroidism is not improving as well as expected to rule out issues with bioavailabilty, compliance, and unreliable L-T4 products (see my list above). I also use post-pill testing when I suspect iatrogenic hyperthyroidism, and I need to rule out L-T4 overdosage (18).

But if a dog has responded clinically to L-T4 as if this was a miracle drug, why even bother measuring the post-pill value? Why rock the boat and make dose adjustments when the owner and dog are happy? And if you do T4 monitoring in this situation, please don't get too excited if the post-pill T4 is slightly lower than anticipated. Remember that T4 doesn't act in the serum; it gets taken up by cells where it is converted to T3 and does all of its actions at an intracellular level. So it is very likely that thyroid hormone is still working fine in the tissues, even when measured values are not "high enough" in serum.

What are we treating here—the dog or the abnormal lab result?  At least for me, I treat my patient, not the post-pill T4 result. So when you recheck these patients, remember to take an overall look at the whole picture. That is, does the dog still look hypothyroid or are the clinical signs resolving? Has the mild anemia, hypercholesterolemia, or hypertriglyceridemia — all characteristic of this disease— persisted or have these abnormalities resolved on the L-T4 replacement therapy?  Is the owner happy or still not satisfied?

Again, if the dog has shown an excellent response to the current dose of L-T4, what do we really have to gain by monitoring a serum T4 concentration? In most cases, I'd say not as much as we might think.

References:
  1. Peterson ME, Ferguson DC: Thyroid diseases, In: Ettinger SJ (ed): Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat (Third Edition). Philadelphia, WB Saunders Co. 1989;1632-1675.
  2. Peterson ME, Ferguson DC, Kintzer PP, et al. Effects of spontaneous hyper­adrenocorticism on serum thyroid hormone concentrations in the dog. American Journal of Veterinary Research 1984;45:2034-2038.  
  3. Ferguson DC, Peterson ME. Serum free and total iodothyronine concentrations in dogs with spontaneous hyperadrenocorticism. American Journal of Veterinary Research 1992;53: 1636-1640. 
  4. Kantrowitz LB, Peterson ME, Melián C, et al. Serum total thyroxine, total triiodothyronine, free thyroxine, and thyrotropin concentrations in dogs with nonthyroidal disease. Journal of the American Veterinary Medical Association 2001;219:765-769.  
  5. Daminet S, Ferguson DC. Influence of drugs on thyroid function in dogs. Journal of Veterinary Internal Medicine 2003;17:463-472.  
  6. Gaskill CL, Burton SA, Gelens HC, et al. Effects of phenobarbital treatment on serum thyroxine and thyroid-stimulating hormone concentrations in epileptic dogs. Journal of the American Veterinary Medical Association 1999;215:489-496.  
  7. Kantrowitz LB, Peterson ME, Trepanier LA, et al. Serum total thyroxine, total triiodothyronine, free thyroxine, and thyrotropin concentrations in epileptic dogs treated with anticonvulsants. Journal of the American Veterinary Medical Association 1999;214:1804-1808. 
  8. Müller PB, Wolfsheimer KJ, Taboada J, et al. Effects of long-term phenobarbital treatment on the thyroid and adrenal axis and adrenal function tests in dogs. Journal of Veterinary Internal Medicine 2000; 14:157-164.
  9. Gieger TL, Hosgood G, Taboada J, et al. Thyroid function and serum hepatic enzyme activity in dogs after phenobarbital administration. Journal of Veterinary Internal Medicine 2000;14:277-281. 
  10. Williamson NL, Frank LA, Hnilica KA. Effects of short-term trimethoprim-sulfamethoxazole administration on thyroid function in dogs. Journal of the American Veterinary Medical Association 2002;221:802-806.  
  11. Frank LA, Hnilica KA, May ER, et al. Effects of sulfamethoxazole-trimethoprim on thyroid function in dogs. American Journal of Veterinary Research 2005;66:256-259. 
  12. Boothe DM, Perkins J. Disposition and safety of zonisamide after intravenous and oral single dose and oral multiple dosing in normal hound dogs. Journal of Veterinary Pharmacology and Therapeutics 2008;31:544-553. 
  13. Gulikers KP, Panciera DL. Evaluation of the effects of clomipramine on canine thyroid function tests. Journal of Veterinary Internal Medicine 2003;17:44-49. 
  14. Daminet S, Croubels S, Duchateau L,  et al. Influence of acetylsalicylic acid and ketoprofen on canine thyroid function tests. Veterinary Journal 2003;166:224-232.   
  15. Panciera DL, Refsal KR, Sennello KA, et al. Effects of deracoxib and aspirin on serum concentrations of thyroxine, 3, 5, 3’-triiodothyronine, free thyroxine, and thyroid-stimulating hormone in healthy dogs. American Journal of Veterinary Research 2006; 67:599-603.
  16. Torres SM, McKeever PJ, Johnston SD. Effect of oral administration of prednisolone on thyroid function in dogs. American Journal of Veterinary Research 1991; 52:416-421.  
  17. Gottschalk J, Einspanier A, Ungemach FR, et al. Influence of topical dexamethasone applications on insulin, glucose, thyroid hormone and cortisol levels in dogs. Research in Veterinary Science 2011;90:491-497. 
  18. Dixon RM, Reid SW, Mooney CT. Treatment and therapeutic monitoring of canine hypothyroidism. Journal of Small Animal Practice 2002;43:334-340. 

2 comments:

John Hess, DVM said...

Several years ago a lecturer, at a meeting probably sponsored by whoever was manufacturing Soloxine at the time, advised avoiding generic l-thyroxine products and trusting only Soloxine or Thyrotabs. (Pre-Leventa era).He stated that l-thyroxine has a relatively short shelf life and is relative heat-labile and should almost require refrigeration. Do you agree with these statements? With Thyrotabs on back order and Soloxine relatively expensive, as I believe is Leventa, is there a good reason to avoid generics?

Dr. Mark E. Peterson said...

I'd always recommend starting a dog on a brand-name product for the first month or two. Once the dog has a good response to replacement therapy, a generic can certainly be tried.

Most dogs will do fine on these generic preparations but I have seen dogs show a relapse of signs and again do better on a brand-name product.