Q & A: Hypothyroid Dog on T4 Treatment with Persistent High TSH Value

This patient is a 6-year-old, female spayed dachshound, first diagnosed as being hypothyroid almost a year ago At that time, the main owner complains included obesity (body weight, 10.1 kg) and lethargy. My physical examination findings included moderate alopecia of the ventral chest and abdomen, with some hyperpigmentation. The body condition score was 4 out of 5.

Result of my complete blood count and serum chemistry panel were normal except for mild hypercholesterolemia (302 mg/dl; reference range < 250 mg/dl). My thyroid panel result were as follows:

• Total T4: 0.5 μg/dl (reference range, 1.0-4.0 μg/dl)
• Free T4: 5 pmol/L  (reference range, 10-40 pmol/L)
• cTSH: 3.2 mg/ml  (reference range, 0.01-0.6 ng/mll)

Based upon these results, the dog was diagnosed with primary hypothyroidism. She was initially treated with levothyroxine (L-T4) at the dose of 100 μg twice daily.  Two months later, her recheck thyroid and cTSH values were the following:

• Total T4 (before treatment): 2.5 μgdl 
• Total T4 (4 hrs after treatment): 4.9 μg/dl
• cTSH: 2.5 ng/ml

Based on these results, I continued the same dosage of L-T4 and rechecked 3 months later:

• Total T4 (before treatment): 2.0 μgdl 
• Total T4 (4 hrs after treatment): 4.1 μg/dl
• cTSH: 2.8 ng/ml

Because the cTSH value remained high, I raised the dosage up to 150 μg twice daily, and rechecked again 4 months later:

• Total T4 (before treatment): 2.6 μgdl 
• Total T4 (4 hrs after treatment): 5.5 μg/dl
• cTSH: 1.9 ng/ml

During the treatment the dog clinically seems to be doing well. The hair coat has regrown and the dog has lost a pound — still  a bit overweight but better.   So, I have a dog on a daily dose of L-T4 that may be  slightly too high dose based on my post-pill T4 values, but the dose still it seems to be deficient based on the high cTSH values.

Do you have an explanation? How I should proceed with this dog's treatment?

My Response:

All of the reasons why L-T4 supplementation would not lower serum TSH concentration generally all  come down to a single issue — we have failed to adequately raise circulating T4 (and T3) values. If circulating thyroid hormone levels stay too low, we will not see the negative-feedback, suppressive effect on pituitary TSH secretion, and serum TSH values may remain high.

So what could lead to subnormal post-pill T4 levels? These are the most common reasons:

• failure of the owner to actually administer the L-T4 supplementation
• failure of a thyroxine preparation to be potent (some generic L-T4 preparations)
• presence of a non-thyroidal illness suppressing the serum T4 to low values
• presence of thyroid-lowering drugs (e.g., steroids, phenobarbatol, sulfa drugs) suppressing circulating T4 and T3 concentrations

But the idea that the serum TSH concentration remains high despite a post-pill T4 that is too high doesn't fit with any of my above explanations.

The first thing I would recommend is to verify the high canine TSH concentrations by submitting a sample to another laboratory. I would expect the result to be similar, especially since we have multiple cTSH values that are all very high.

When I see dogs with persistently high cTSH values on LT4 supplementation, another explanation that we should consider (based on studies in human patients) is the phenomenon termed the "reset thyrostat" (1,2).

• In human patients, this condition of "reset thyrostat" reflects an initial transient unresponsiveness of the hypothalamic-pituitary axis (hypertrophied thyrotrophs) to thyroid hormone replacement). 
• The higher the initial serum TSH concentrations, the more likely one is to observe persistent elevations in TSH concentrations despite adequate L-T4 replacement. 
• Once appropriate thyroid hormone replacement therapy is given, however, the thyrostat typically (but not always) resets to normal within a few months.
• Most of the human patients in which the "reset thyrostat" phenomenon has been reported were either clinically normal, obese, or had a long history of hypothyroidism.
• Some researchers have even reported that euthyroid but obese individuals maintain normal serum T4 values but have higher levels of TSH, again suggesting that they may have reset their "central thyrostat."

As all of you know, there have been no reports of reset thyrostat in dogs or cats (at least to my knowledge) but I think we must consider it in a dog like this. Maybe his obesity is playing a role in the increased TSH secretion, like that reported in the obese human patients (2). If that's the problem, the solution would be not to worry about it!   

Unfortunately, it's clear we still have much to learn about both the canine and feline thyroid gland physiology and regulation of their pituitary-thyroid axis, especially in states of hyper- and hypothyroidism.  

References:

1. Kabadi UM, Cech R. Normal thyroxine and elevated thyrotropin concentrations: evolving hypothyroidism or persistent euthyroidism with reset thyrostat. Journal of Endocrinological Investigation 1997;20:319-326.
2. Michalaki MA, Vagenakis AG, Leonardou AS, et al. Thyroid function in humans with morbid obesity. Thyroid 2006;16:73-78.