Iatrogenic Hyperthyroidism in a Boxer Treated with Massive Doses of L-T4

My problem case is a 9-year-old F/S Boxer (weighing 30 kg) that was diagnosed as hypothyroid by another veterinarian about a year ago. She has been on 1.2 mg of levothyroxine (L-T4) every 12 hours. Clinically, the dog is doing very well, but she has mild polyuria and polydipsia. I have never had a dog on this high of a L-T4 dose, so I'm worried about thyroid hormone overdose and cardiac complications.

I did a complete thyroid profile at Michigan State University's Endocrine Laboratory (see results of the panel, below). The sample was collected about 6 hours after the morning L-T4 was administered. As you can see, the free T3 is extremely high, but the total T3 is undetectable.

I'm really confused. My questions include the following:

1. Why the discordant results between the total and free T3 levels in this dog?
2. Do I need to worry about the high FT3?
3. Is the high T3 autoantibody value significant?
4. Is this dog now hyper- or hypothyroid?
5. Does this dog have a T4 to T3 conversion defect?
6. Should I lower the L-T4 dose or add L-T3 to this dog's treatment regimen?

My Response:

Your dog has very high serum levels of T3 autoantibodies, together with lower, but detectable, levels of both T3 and thyroglobulin autoantibodies.  When thyroid hormone autoantibodies are present, they can interfere with immunoassays used to measure the serum concentrations of either T4 or T3 (or both) (1-4). In the radioimmunoassays used at the Michigan State Endocrine Laboratory, the presence of high T3 autoantibodies will cause a false elevation of the serum FT3 concentration and a false lowering of the total T3 (the value of "0" in this dog). These thyroid hormone values are spurious —they represent a laboratory artifact because it is difficult to accurately measure the true hormone concentration when these autoantibodies are present (1-4).

Thyroid autoantibodies in dogs with hypothyroidism
Lymphocytic thyroiditis is a frequent cause of hypothyroidism in dogs and is generally accepted to have an autoimmune pathogenesis. Part of the immune response is reflected by production of thyroid autoantibodies (1-4).

The most common thyroid autoantibody detected in dogs are thyroglobulin autoantibodies (2-5). These autoantibodies do not interfere with the standard measurement of serum total or free thyroid hormone concentrations. Thyroid hormone autoantibodies that bind to T3 or T4 are seen less frequently (2-6); however, when high T4 or T3 autoantibody titers are reached, the antibodies may interfere with the hormone immunoassay measurements to produce erroneous thyroid test results.

Does this dog have a T4 to T3 conversion defect?
The short answer is no —a dog with an undetectable serum T3 concentration despite a normal T4 concentration (before or after L-T4 treatment) is not a dog with a T4 to T3 conversion defect. Again, in this dog, the presence of T3 autoantibodies has resulted in an artefactual low T3 result (5,6). The true serum T3 concentration may actually be normal, and we certainly do not have to supplement with L-T3 in this dog.

Such a T4 to T3 conversion defect has not ever been recognized in either normal dogs or dogs with hypothyroidism (2-4).

How common are thyroid hormone autoantibodies in dogs suffering from hypothyroidism?
Investigators have reported that 35% of dogs with hypothyroidism will have T3 autoantibodies whereas 14% have T4 autoantibodies (5-7). Almost all dogs with T3 or T4 autoantibodies will also have positive titers for thyroglobulin autoantibodies; thus, positive results are evidence of thyroid autoimmunity. The relatively high incidence of positive T3 autoantibodies may explain why the diagnostic accuracy of T3 measurements is poor in dogs suffering from hypothyroidism.

The 10 breeds with the highest prevalence of thyroid hormone antibodies, many of those with a propensity for autoimmune thyroiditis, were the Pointer, English Setter, English Pointer, Skye Terrier, German Wirehaired Pointer, Old English Sheepdog, Boxer, Maltese, Kuvasz, and Petit Basset Griffon Vendeen (3).

My Bottom Line: Adjusting the thyroid hormone dose in this dog
It is important to recognize that these antibodies have no influence on the choice or dosage of thyroid medication, because the capacity of the antibodies to bind thyroid hormone is relatively small and can be saturated with administered thyroid hormone (5,6).

In this dog, you are going to have to regulate the L-T4 dose based upon the dog's clinical signs and serum concentrations of total T4, free T4, and TSH. Serum total or free T3 should not be measured because the T3 autoantibodies will only produce spurious test results that will confuse diagnostic interpretation.

At this time, this dog is showing clinical signs consistent with mild hyperthyroidism (i.e., polyuria and polydipsia). This finding, together with the borderline high serum T4 and completely suppressed TSH concentrations, suggests that the dog's current L-T4 dose is too high.

Dogs are quite resistant to developing iatrogenic hyperthyroidism, but this dog's current dose of 2.4 mg per day is extremely high. Almost all dogs respond quite nicely to doses of 20 µg/kg, administered either once or twice daily, which calculates into a dose of only 25-50% of the current L-T4 dose given to this dog.

For this dog, I'd try cutting the L-T4 dosage in half and monitoring again in another 4 weeks. Remember that thyroid hormone supplementation is best give on an empty stomach to enhance absorption (8).

References:

1. Kemppainen RJ, Young DW. Canine triiodothyronine autoantibodies. In: Kirk RW, Bonagura JD, editors. Current Veterinary Therapy XI: Small Animal Practice. Philadelphia: W.B. Saunders Co; 1992. p. 327-330.
2. Graham PA, Refsal KR, Nachreiner RF. Etiopathologic findings of canine hypothyroidism. Vet Clin North Am Small Anim Pract 2007;37:617-631. 
3. Ferguson DC. Testing for hypothyroidism in dogs. Vet Clin North Am Small Anim Pract 2007;37:647-669.   
4. Mooney CT. Canine hypothyroidism: a review of aetiology and diagnosis. N Z Vet J 2011;59:105-114.
5. Nachreiner RF, Refsal KR, Graham PA, et al. Prevalence of serum thyroid hormone autoantibodies in dogs with clinical signs of hypothyroidism. J Am Vet Med Assoc 2002;220:466-471. 
6. Nachreiner RF, Refsal KR, Thacker EL, et al. Incidence of T3 and T4 autoantibodies in dogs using a sensitive binding assay (abstract). J Vet Intern Med 1990;4:114.
7. Refsal KR, Nachreiner RF. Thyroid hormone autoantibodies in the dog: their association with serum concentrations of iodothyronines and thyrotropin and distribution by age, sex, and breed of dog. Canine Pract 1997;22:16–17.
8. 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;31:95-101.