When To Start Thyroid Hormone Replacement in Cats Treated with Radioiodine (I-131)

I have a question about thyroid hormone supplementation for iatrogenic hypothyroidism, especially in cats treated with radioiodine (I-131). More specifically, how long after radioactive iodine therapy do you wait before recommending supplementing hypothyroid cats with thyroxine?

I work as a small animal internist at a referral hospital where we treat hyperthyroid cats with radioiodine. After treatment, we routinely run serum T4 and free T4 concentrations and full blood work 30 and 90 days after the cat is discharged. I have found that about 20% of these cats are biochemically hypothyroid (low total or free T4 values) at the 30-day recheck, but many of these cats will revert to normal by the 90-day recheck. The other internist at my practice supplements these cats with L-thyroxine at the first recheck if the serum T4 and free T4 values are low. She does this even if they are not azotemic, with the rationale being that the studies show that hypothyroid cats develop worsening azotemia, which can affect their survival (1).

I am not sure if this is the best approach since I have heard that the residual thyroid follicles may take a few months to regain full function after being suppressed by the over-active thyroid tissue for so long. However, I just want to do what's best (don't we all!)

Thank you so much. I enjoy reading your website and attending your lectures at conferences.

My Response:

First of all, I don't find that free T4 determinations are all that helpful in the diagnosis of feline hypothyroidism (2-4). Many cats treated with radioiodine with maintain low-normal values for both total and free T4 but develop high serum TSH concentrations, a situation commonly referred to as subclinical hypothyroidism in human patients. The problem with our cats, however, is that although most of these cats do remain nonclinical for hypothyroidism, many will develop azotemia that will progressively worsen without treatment with thyroid hormone replacement.

So what I do is as follows: at 30-days post-treatment, I monitor serum concentrations of T4, free T4, and TSH, along with a serum chemistry panel to follow kidney values. If T4 or free T4 values fall into the lower third of the reference range (below 1.5-2.0 µg/dl; reference interval ≈1-4 µg/dl) and TSH rises (above 0.5-0.6 ng/dl; reference range, 0.03-0.03 ng/ml), then the cat is mildly hypothyroid. Some of these cats will recover enough thyroid function to end up as euthyroid, but most remain mildly hypothyroid at both 3 and 6 months, at least based on the finding of high TSH concentrations.

In these cats with mild or subclinical hypothyroidism, I don't like to treat with levothyroxine (LT4) at this time unless evidence of chronic kidney disease (CKD) has developed, with serum creatinine values rising from normal to greater than 2.0 mg/dl. However, this definitely indicates the need for LT4 replacement in order to help maintain renal perfusion and stabilize the serum creatinine concentrations (3-5).

If we decide not to treat (which is generally the case unless new azotemia has developed), then we monitor again with the same thyroid and renal profiles at 3- and 6 months. Again, if T4 falls into the low-normal range (less than 1.5-2.0 µg/dl) and TSH is clearly high (above 0.5-0.6 ng/dl), I would definitely supplement if new or worsening azotemia is detected. If no azotemia is present, I generally continue to monitor and don't supplement with LT4 unless azotemia does develop.

Now, if the serum T4 is below normal and the TSH is clearly high at 3 or 6 months (or later), then the cat has overt hypothyroidism (no longer subclinical) and I would definitely supplement with L-T4 (2-4). Many of these cats are still not very symptomatic, but that may simply be a matter of time. If left untreated for 1 to 2 years, most of those cats will develop classical signs of hypothyroidism (eg, lethargy, hair loss, etc).

So in your case, I would add-in serum TSH to your monitoring protocol. If your owners find that too expensive, then I would replace the free T4 measurement with TSH determination, which is more more helpful in monitoring for cats treated with radioiodine.

References:

1. Williams TL, Peak KJ, Brodbelt D, et al. Survival and the development of azotemia after treatment of hyperthyroid cats. J Vet Intern Med 2010;24:863-869. 
2. Peterson ME. Feline focus: Diagnostic testing for feline thyroid disease: hypothyroidism. Compend Contin Educ Vet 2013;35:E4.  
3. Peterson ME. Diagnosis and management of iatrogenic hypothyroidism In: Little SE, ed. August's Consultations in Feline Internal Medicine: Elsevier, 2014;in press.
4. Peterson ME, Guterl JN.Subclinical iatrogenic hypothyroidism in the cat: Clinical, laboratory, and thyroid scintigraphic findings in 35 cases. J Vet Intern Med 2015;29:448-449.
5. Williams TL, Elliott J, Syme HM. Effect on renal function of restoration of euthyroidism in hyperthyroid cats with iatrogenic hypothyroidism. J Vet Intern Med 2014;28:1251-1255.

Top Endocrine Publications of 2014: The Canine Thyroid Gland

Large goiter due to thyroid carcinoma

In my third compilation of the canine and feline endocrine publications of 2014, I’m moving on to disorders of the canine thyroid gland. Listed below are 21 research papers written in 2014 that deal with a variety of thyroid gland topics and issues of clinical importance.

A number of these publications deal with clinical, pathologic, diagnostic, or therapeutic aspects of thyroid carcinoma (1-6,10,13,14,17,18).  Of these, two papers (1,14) deal specifically with ectopic thyroid tumors arising in the sublingual location, which may indicate that such ectopic tumors are not as uncommon as once thought.

Other publications include a case report of a hypothyroid dog suffering from insulin-resistant diabetes mellitus and acromegaly (8); interestingly, after treatment with L-thyroxine, the insulin resistance and diabetes resolved.

Other papers report on various studies on hypothyroidism in dogs including the effect of age of lipid metabolism (9) to the association between gall bladder mucoceles and hyperlipidemia (12);  and from exercise-induced hypercoagulability, von Willebrand factor, and thyroid hormone concentrations in sled dogs (11) to evaluation of serum thyroid hormones in dogs with systemic inflammation or sepsis (16).

Finally, other papers include a case report of a hypothyroid dog with polyneuropathy that resolved following thyroid supplementation (20), to a study of the pharmacokinetics of total T4 after repeated oral administration of L-T4 solution in hypothyroid dogs (21). 

References:

1. Broome MR, Peterson ME, Walker JR. Clinical features and treatment outcomes of 41 dogs with sublingual ectopic thyroid neoplasia. J Vet Intern Med 2014;28:1560-1568. 
2. Campos M, Ducatelle R, Kooistra HS, et al. Immunohistochemical expression of potential therapeutic targets in canine thyroid carcinoma. J Vet Intern Med 2014;28:564-570. 
3. Campos M, Ducatelle R, Rutteman G, et al. Clinical, pathologic, and immunohistochemical prognostic factors in dogs with thyroid carcinoma. J Vet Intern Med 2014;28:1805-1813. 
4. Campos M, Kool MM, Daminet S, et al. Upregulation of the PI3K/Akt pathway in the tumorigenesis of canine thyroid carcinoma. J Vet Intern Med 2014;28:1814-1823. 
5. Ciaputa R, Nowak M, Kandefer-Gola M, et al. Morphological and immunohistological characteristics of follicular-compact thyroid carcinoma in dog. Folia Histochem Cytobiol 2014;52:157-161. 
6. Deitz K, Gilmour L, Wilke V, et al. Computed tomographic appearance of canine thyroid tumours. J Small Anim Pract 2014;55:323-329. 
7. Higgs P, Costa M, Freke A, et al. Measurement of thyroxine and cortisol in canine and feline blood samples using two immunoassay analysers. J Small Anim Pract 2014;55:153–159. 
8. Johnstone T, Terzo E, Mooney CT. Hypothyroidism associated with acromegaly and insulin-resistant diabetes mellitus in a Samoyed. Aust Vet J 2014;92:437-442. 
9. Kawasumi K, Kashiwado N, Okada Y, et al. Age effects on plasma cholesterol and triglyceride profiles and metabolite concentrations in dogs. BMC Vet Res 2014;10:57. 
10. Kobayashi R, Yamada N, Kitamori T, et al. Follicular thyroid carcinoma characterized by abundant stromal components with chondroid and osseous metaplasia in a dog. J Vet Med Sci 2014;76:1161-1164. 
11. Krogh AK, Legind P, Kjelgaard-Hansen M, et al. Exercise induced hypercoagulability, increased von Willebrand factor and decreased thyroid hormone concentrations in sled dogs. Acta Vet Scand 2014;56:11. 
12. Kutsunai M, Kanemoto H, Fukushima K, et al. The association between gall bladder mucoceles and hyperlipidaemia in dogs: A retrospective case control study. Vet J 2014;199:76-79. 
13. Metivier KS, Deitz K, Xu WW, et al. Gene expression profiling demonstrates differential expression of osteopontin in follicular thyroid carcinomas compared to normal thyroid tissue in dogs. Vet Comp Oncol 2014;12:181-197. 
14. Milovancev M, Wilson DM, Monnet E, et al. Partial resection of the hyoid apparatus during surgical treatment of ectopic thyroid carcinomas in dogs: 5 cases (2011-2013). J Am Vet Med Assoc 2014;244:1319-1324. 
15. Muller TR, Assis MM, Doiche DP, et al. Do thyroid ultrasonographic features change according to age in euthyroid dogs? Anat Histol Embryol 2014;43:468-473. 
16. Pashmakova MB, Bishop MA, Steiner JM, et al. Evaluation of serum thyroid hormones in dogs with systemic inflammatory response syndrome or sepsis. J Vet Emerg Crit Care (San Antonio) 2014;24:264-271. 
17. Pessina P, Castillo V, Sartore I, et al. Semiquantitative immunohistochemical marker staining and localization in canine thyroid carcinoma and normal thyroid gland. Vet Comp Oncol 2014. 
18. Pineyro P, Vieson MD, Ramos-Vara JA, et al. Histopathological and immunohistochemical findings of primary and metastatic medullary thyroid carcinoma in a young dog. J Vet Sci 2014;15:449-453. 
19. Rasmussen SH, Andersen HH, Kjelgaard-Hansen M. Combined assessment of serum free and total T4 in a general clinical setting seemingly has limited potential in improving diagnostic accuracy of thyroid dysfunction in dogs and cats. Vet Clin Pathol 2014;43:1-3. 
20. Utsugi S, Saito M, Shelton GD. Resolution of polyneuropathy in a hypothyroid dog following thyroid supplementation. J Am Anim Hosp Assoc 2014;50:345-349. 
21. van Dijl IC, Le Traon G, van de Meulengraaf BD, et al. Pharmacokinetics of total thyroxine after repeated oral administration of levothyroxine solution and its clinical efficacy in hypothyroid dogs. J Vet Intern Med 2014;28:1229-1234. 

Dog on Long-Term Thyroid Hormone Supplementation: Hypothyroid, Hyperthyroid, or Cushing's Syndrome?

My patient is an 11-year old, spayed female Spaniel-Mix, named Molly. She weighs 31 pounds (14.1 kg) and is slightly overweight, with a body condition score of 7/9. About 5 years ago, she was initially diagnosed as having hypothyroidism based upon clinical signs of hair loss, together with low serum concentrations of total thyroxine (T4) and free T4. Molly responded well to thyroid hormone replacement with brand-name levothyroxine (L-T4) at the dose of 0.2 mg, twice daily.

Over the following 3 years, the dog did well (complete hair regrowth), but the daily L-T4 dose was increased (to 0.3 mg, twice daily) based on post-pill serum T4 testing, done about 5 hours after administration of the morning dose.

About 2 years ago, Molly was seen for new hair loss, increased appetite, and polyuria and polydipsia (PU/PD). Results of a CBC and serum chemistry panel were considered to be normal, and a post-pill serum T4 concentration was low-normal at 1.5 µg/dl (40 nmol/L). A complete urinalysis was unremarkable, other than a urine specific gravity of 1.013. Based on Molly's relapse of her hair loss and low-normal post-pill T4, the L-T4 dose was increased to 0.4 mg, BID.

Follow-up thyroid testing 6 months later revealed a post-pill serum T4 value in the high-normal range (3.9 µg/dL; 50 nmol/L) so the L-T4 was maintained at 0.4 mg BID. At that time, the PU/PD had lessened, and the increased appetite had normalized so no further workup was recommended.

On followup 1 year later (now 5 months ago), Molly again presented with increased appetite and more severe PU/PD. Her post-pill total T4 concentration was quite high at was 10.1 µg/dl (130 nmol/L), so the dosage of LT4 was decreased to 0.2 mg, BID. Repeat testing 2 months later revealed that the serum T4 value remained high (5.5 µg/dL; 70 nmol/L) so administration of L-T4 was discontinued. Other than truncal hair thinning, Molly's physical examination at that time was normal, with a normal heart rate (85 bpm); no thyroid masses could be palpated.

Now 3 months later, the owner reports progressive truncal hair loss, PU/PD, increased appetite, panting, and weight gain. Molly's physical exam was again unremarkable. Results of routine testing revealed a normal CBC (no stress leukogram), with severe hypercholesterolemia (660 mg/dL; 17.0 mmol/L). The serum alkaline phosphatase activity was also moderately high at 311 U/L (reference interval less than 100 U/L).

We next ran a complete thyroid profile, with the following results:

• Total T4: 16 nmol/L (reference interval, 11-60 nmol)
• Total T3: 0.4 nmol/L (reference interval, 0.8-2.1 nmol)
• Free T4 by dialylsis: 12 pmol/L (reference interval, 10-50 pmol/L)
• TSH: 1.0 ng/ml (reference interval, 0-0.6 ng/ml)
• Thyroglobulin autoantibodies: 10% (reference interval, 0-35%)

I'm at a loss. I thought that the dog's signs might indicate hyperthyroidism but these results appear to be most consistent with hypothyroidism. Should L-T4 be restarted? We have only used a single brand-name L-T4 preparation in this dog — should we switch to another product?

Should I be testing Molly's pituitary-adrenal axis to rule out Cushing's syndrome?

My Response:

This dog is indeed a rather complicated case. Looking back at the history, Molly has displayed clinical signs of hair loss, PU/PD, and increased appetite for the past 2 years. All of these signs have waxed and waned in severity over this time, which explains her long duration of illness.

During that entire time, she was being treated with adequate replacement doses of thyroid hormone and never had post-pill T4 values that were low. In fact, many of her serum T4 concentrations checked during monitoring were too high— clearly in the hyperthyroid range (1). Overall, this strongly suggests that hypothyroidism alone cannot explain all the dog's problems, a conclusion that also is consistent with the fact that neither PU/PD nor increased appetite are signs of thyroid hormone deficiency (2,3).

Hypothyroid or hyperthyroid?
Given the fact that 2 of the post-pill serum T4 values were high, could this dog have iatrogenic hyperthyroidism secondary to an overdosage of L-T4? That certainly is possible, and thyrotoxicosis could account for the increased appetite and PU/PD (4-6). In fact, almost all hyperthyroid dogs will develop moderate to marked PU/PD, which is a much more prominent sign in dogs than in most cats with hyperthyroidism (7).

However, these signs persisted for 3 months after we stopped all thyroid hormone supplementation. In addition, the last thyroid hormone panel showed low to low-normal serum concentrations of total T4, T3, and free T4, in conjunction with high serum concentration of TSH; this combination of results is most consistent with primary hypothyroidism (the original diagnosis) (2,3). Overall, these findings completely rule out either natural hyperthyroidism associated with a hyperfunctional thyroid tumor or iatrogenic thyrotoxicosis from overdosage of L-T4 (5-7).

Hypothyroid or Cushing's syndrome?
Since Molly's clinical signs are also classical for hyperadrenocorticism, we should consider testing for that common canine disorder. While the high cholesterol concentration could be due to hypothyroidism or Cushing's syndrome, the finding of a high serum alkaline phosphatase activity certainly is consistent with chronic cortisol excess (8,9).

Before embarking on a workup for spontaneous Cushing's syndrome, remember to first make sure that Molly is not on any exogenous steroids, including a topical preparation for her eyes, ears, or skin, which can result in iatrogenic hyperadrenocorticism. You determine that not only by reviewing the record to see what your hospital has dispensed, but also by asking the owner what they're using to treat their dog, as they may have bags of steroid medications at home that weren't dispensed by you.

If Molly is suffering from Cushing's syndrome, it is possible that chronic cortisol excess is contributing to the low serum thyroid hormone concentrations.  Canine Cushing's syndrome can actually produce a secondary form of hypothyroidism, one that is reversible upon correction of the hyperadrenocorticism (10,11). However, it is very unlikely that Molly has had undiagnosed Cushing's disease for the past 5 years, given that she appears to be doing so well clinically. In addition, chronic cortisol excess suppresses serum TSH values (9,11), so Molly's high TSH value goes along more with primary hypothyroidism than a secondary form of hypothyroidism resulting from Cushing's syndrome.

As you continue to work up this dog, I would restart your thyroid hormone supplementation at a low dose (0.2-0.3 mg per day, divided). The dog certainly appears to be hypothyroid, based on the last serum thyroid profile, as well as worsened hair loss.

Causes of marked variation in L-T4 absorption
The marked variation in serum post-pill T4 concentrations are both interesting, as well as somewhat perplexing.

I'd start by questioning the owners about the timing of L-T4 administration, since the absorption of the medication is known to be increased when given on an empty stomach, as compared to when administered with meals (12,13). Could some of the marked variation in her past serum post-pill T4 levels have been due to administration of the drug with meals on some occasions and on an empty stomach on others? 

Other drugs and medications can also have an effect on L-T4 absorption (14). In this dog, we must carefully record all dietary changes as well as any administered drugs or supplements, all of which could potentially alter the absorption of the L-T4 preparation. 

References:

1. Dixon RM, Reid SW, Mooney CT. Treatment and therapeutic monitoring of canine hypothyroidism. J Small Anim Pract 2002;43:334-340. 
2. Mooney CT, Shiel RE. Canine hypothyroidism In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;63-85.
3. Mooney CT. Canine hypothyroidism: a review of aetiology and diagnosis. N Z Vet J 2011;59:105-114. 
4. Bosje T, den Hertog E, Dijksta M. Does the T4 measurement belong in the standard blood analysis in polyuria/polydipsia? Tijdschr Diergeneeskd 2013;138:230-231. 
5. Peterson ME. Hyperthyroidism and thyroid tumors in dogs In: Melian C, Perez Alenza MD, Peterson ME, et al., eds. Manual de Endocrinología en Pequeños Animales (Manual of Small Animal Endocrinology). Barcelona, Spain: Multimedica, 2008;113-125.
6. Mooney CT. Canine hyperthyroidism In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;86-91.
7. Nichols, R., Peterson ME. Investigation of polyuria and polydipsia In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Gloucester: British Small Animal Veterinary Association, 2012;215-220.
8. Herrtage ME, Ramsey IK. Canine hyperadrenocorticism In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;167-189.
9. Melián CM, Pérez-Alenza D, Peterson ME. Hyperadrenocorticism in dogs In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat (Seventh Edition) Philadelphia, Saunders Elsevier, pp 1816-1840, 2010. Seventh ed. Philadelphia: Saunders Elsevier, 2010;1816-1840.
10. Peterson ME, Ferguson DC, Kintzer PP, et al. Effects of spontaneous hyperadrenocorticism on serum thyroid hormone concentrations in the dog. Am J Vet Res 1984;45:2034-2038. 
11. Ferguson DC, Peterson ME. Serum free and total iodothyronine concentrations in dogs with hyperadrenocorticism. Am J Vet Res 1992;53:1636-1640. 
12. Lamson MJ, Pamplin CL, Rolleri RL, et al. Quantitation of a substantial reduction in levothyroxine (T4) absorption by food. Thyroid 2004;14:876.
13. 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.
14. Liwanpo L, Hershman JM. Conditions and drugs interfering with thyroxine absorption. Best Pract Res Clin Endocrinol Metab 2009;23:781-792.

Treatment and Monitoring of Hypothyroid Dogs with Thyroid Hormone Autoantibodies

I'm a veterinarian from Finland, and I'd like your opinion and advice on a 2-year old, male neutered Doberman Pincher (body weight, 42 kg). This dog had been diagnosed with hypothyroidism together with serum T3 antibodies by another veterinarian.

Clinically, the dog has shown a partial response to treatment with L-thyroxine (L-T4), but serum T4 concentrations remain very low and serum TSH remains high on post-pill testing. These are results of my thyroid testing (always at 4 hours post-pill), together with the L-T4 dose and physical examination:

Initial exam:

• Dose: Levothyroxine 400 µg BID
• Exam findings: Clinically quite normal but slightly overweight
• Total T4:  <9.0 nmol/L (reference interval =  13 - 52 nmol/L)
• Free T4 (CLIA): >77 pmol/L (reference interval =  8 - 48 pmol/L )
• TSH: 3.24 ng/ml (reference interval = less than 0.5 ng/ml)

4-week recheck:

• Dose: Levothyroxine 500 µg BID
• Exam findings: Clinically normal; but still overweight
• Total T4: < 9.0 nmol/L  
• TSH: 3.59 ng/ml  

8-week recheck:

• Dose: Levothyroxine 600 µg BID
• Exam findings: Mild weight loss, heart rate 82/bpm, very active and perky
• Total T4: <9.0 nmol/L  
• Free T4 (CLIA): 62 pmol/L
• TSH: 2.2 ng/ml  

I reviewed the L-T4 supplementation with the owner and made sure the dog is ingesting the pills and made certain that they administered the thyroid medication the morning of each recheck—  no problem there. I next recommended repeat testing, again looking at the autoantibody levels and free T4 measured by equilibrium dialysis (ED).

11-week recheck:

• Dose: Levothyroxine 800 µg BID
• Exam findings: Normal
• Total T4: < 9.0 nmol/L 
• Free T4 (ED): 8 pmol/L (reference interval = 6-40 pmol/L) 
• TSH: 1.5 ng/ml  
• T4 antibodies: 13% (1-20%)
• T3 antibodies: 43% (1-10%)
• Thyroglobulin autoantibodies: positive

Overall, I'm confused about this dog's thyroid status. Biochemically, this dog appears to have persistent hypothyroidism (low T4, high TSH) but may also have iatrogenic hyperthyroidism (high free T4 values). How do I know?

I also need advice about how to determine the correct L-T4 replacement dose for this dog. Do I just keep on increasing the medication until the serum T4 concentration normalizes?

My Response:

Obviously, your testing confirms that this dog has thyroiditis, with positive thyroglobulin autoantibodies and high levels of T3 autoantibodies (1-4). Based on the low serum concentrations of free T4 by dialysis and high TSH levels, the dog certainly is hypothyroid (5), but it does not appear that the dog is responding well to the L-T4 supplementation.

Method for T4 assay
What method is being used to measure total T4 concentrations? These days, most commercial veterinary labs don't use radioimmunoassay (RIA) to measure serum T4, even though that method is still considered the gold standard (5,6). Most laboratories use either a chemiluminescent immunoassay method (CLIA; Immulite) or an automated enzyme immunoassay (EIA) method (7,8).

For some reason not well understood, the EIA method will fail to accurately detect circulating post-pill T4 values, at least in some T4-treated dogs. In other words, the serum T4 values remain falsely low, even when the actual T4 values are within the mid- to high-normal range and the dogs are clinically improved. This issue needs more research and has not been published, but there is no doubt that the problem exists. If suspected, one can verify the problem very easily, simply by repeating the post-pill serum T4 concentration by either RIA or chemiluminescence.

Method for Free T4 assay
In this dog, the finding of a high free T4, measured by CLIA (Immulite) can not be easily explained. The fact that the serum TSH is persistently high in your dog suggests persistent hypothyroidism, not hyperthyroidism (5,9).  The low-normal value for the free T4 concentration, when remeasured by equilibrium dialysis (ED), also points to hypothyroidism. Thyroid autoantibodies can not interfere with the free T4 value when determined by the dialysis method, since all protein molecules (including the thyroid autoantibodies) are removed (dialyzed) prior to assay.

Given that we know your dog has thyroid hormone autoantibodies, it's tempting to postulate that the high free T4 value measured by CLIA are falsely high due to the autoantibodies. The bottom line is that we just don't know. However, what is clear is that these free T4 values are not helping us to determine the best treatment for this dog — only confusing the situation.

Brand of L-thyroxine
What brand of LT4 is being administered? In any dog that is not responding well to thyroid hormone supplementation, a brand name product is always recommended.  In addition, sometimes it can help to switch to another size or brand, suggesting that the absorption rate may vary slightly between products. In some studies, use of a liquid L-T4 solution has been found to be be better absorbed, at least in select patients (10,11).

Timing of L-T4 and meals
Are the owners giving the LT4 with meals or on an empty stomach?  The standard of care for human patients requiring L-T4 is to administer the drug on an empty stomach, generally an hour before meals.

Simultaneous administration of L-T4 with food can markedly delay and inhibit the absorption of the drug in both humans and dogs (11-13). In one study of dogs, giving the L-T4 with food decreased its absorption by about 45% (11).

Follow-up Information:

The serum T4 is being measured by EIA. We are giving a brand-name L-T4 product (14). The owner is consistently giving the L-T4 at 12-hour intervals at the time of meals. No other medication is being given.

My Response:

Again, with the EIA method, the total T4 result may not be accurate when measuring a post-pill T4 concentration. We need to do the post-pill T4 by either chemiluminescence (CLIA; Immulite) or RIA on the next followup.

However, the fact that the free T4 concentration is low-normal and the TSH is still high means that the absorbed dose of L-T4 is not high enough. None of your problems appear to have anything to do with T4 or T3 autoantibodies.

I'd first change the timing between the L-T4 dose and feeding to ensure "empty stomach dosing." If that fails to adequately increase the total T4 concentration (RIA or CLIA) and normalize the high serum TSH concentrations, I'd next consider switching to a liquid L-T4 preparation to see if that helps. Finally, if all else fails, you may have to continue to increase the L-T4 dose, but at 0.8 mg twice daily, your dog is already on a more-than-adequate dose for most dogs (5).

References:

1. 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 Practice 1997;22:16-17.
2. Young DW. Antibodies to thyroid hormone and thyroglobulin in canine autoimmune lymphocytic thyroiditis. Canine Practice 1997;22:14-15. 
3. 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. 
4. Patzl M, Mostl E. Determination of autoantibodies to thyroglobulin, thyroxine and triiodothyronine in canine serum. J Vet Med A Physiol Pathol Clin Med 2003;50:72-78. 
5. Mooney CT, Shiel RE. Canine hypothyroidism In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;63-85.
6. Kemppainen RJ, Birchfield JR. Measurement of total thyroxine concentration in serum from dogs and cats by use of various methods. Am J Vet Res 2006;67:259-265.
7. Singh AK, Jiang Y, White T, et al. Validation of nonradioactive chemiluminescent immunoassay methods for the analysis of thyroxine and cortisol in blood samples obtained from dogs, cats, and horses. J Vet Diagn Invest 1997;9:261-268. 
8. Horney BS, MacKenzie AL, Burton SA, et al. Evaluation of an automated, homogeneous enzyme immunoassay for serum thyroxine measurement in dog and cat serum. Vet Clin Pathol 1999;28:20-28. 
9. Dixon RM, Reid SW, Mooney CT. Treatment and therapeutic monitoring of canine hypothyroidism. J Small Anim Pract 2002;43:334-340. 
10. Pirola I, Formenti AM, Gandossi E, et al. Oral liquid L-thyroxine (L-T4) may be better absorbed compared to L-T4 tablets following bariatric surgery. Obes Surg 2013;23:1493-1496. 
11. 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. 
12. Liwanpo L, Hershman JM. Conditions and drugs interfering with thyroxine absorption. Best Pract Res Clin Endocrinol Metab 2009;23:781-792.
13. Lamson MJ, Pamplin CL, Rolleri RL, et al. Quantitation of a substantial reduction in levothyroxine (T4) absorption by food. Thyroid 2004;14:876. 
14. Forthyron LT4 product insert: http://www.forthyron.com/data/acms/docs/treatment/1_forthyron_pi_200_400_en.pdf

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. 

Hypercalcemia in Canine Hypothyroidism

Hypercalcemia in a Dog with Primary Hypothyroidism

R. G. Lobettia

Journal of the South African Veterinary Association 2011;82: 242–243

Hypercalcemia is a relatively common problem in dogs, with the most common cause being malignancy-associated hypercalcemia (i.e., resulting from lymphoma, anal gland adenocarcinoma, multiple myeloma, or various other carcinomas). Other common causes include primary hyperparathyroidism, hypoadrenocorticism (Addison’s disease) chronic renal failure, and vitamin D toxicosis (1-3).

Hypothyroidism is not generally considered in the differential diagnosis or hypercalcemia in dogs. However, hypercalcemia has been reported in puppies with congenital hypothyroidism (4,5), and, if left untreated, these hypothyroid dogs may continue to show slightly high serum calcium concentrations during adulthood (4).

In this case report (6), Lobetti describes a middle-aged dog with primary hypothyroidism that also developed symptomatic hypercalcemia. After instituting thyroid replacement therapy, both the hypercalcemia and associated clinical signs of polyuria resolved. This is the first report of this association between adult-onset hypothyroidism and symptomatic hypercalcemia in dogs.

Case Report
A 7-year old female beagle was examined because of polyuria and polydipsia, poor appetite, and weight gain. Physical examination revealed that the dog was slightly obese, with bradycardia (80 bpm). Routine blood work revealed marked hypercalcemia (3.27 mmol/L [13.1 mg/dl]; reference range, 2–3 mmol/L). A tentative diagnosis of hypothyroidism was made on the basis of a low serum T4 concentration (<6 nmol/L; reference range, 18–45 nmol/l) together with a high serum TSH value (1.05 ng/ml; reference range, 0.02–0.8 ng/ml).  

The dog was referred for further workup. On repeat serum biochemistry analysis, abnormalities included hypercholesterolemia (13.5 mmol/L [521 mg/dl]; reference range, 3–6 mmol/L) and hypercalcemia (3.44 mmol/ L [13.8 mg/dl]). Results of a complete blood count and urinalysis revealed no abnormalities.

An abdominal ultrasound examination, survey thoracic radiographs, and fine needle aspirate cytology of the spleen, liver and peripheral lymph nodes were all normal. Therefore, hypercalcemia of malignancy was considered unlikely.

A plasma parathyroid hormone (PTH) was low (7 pg/ml; reference range, 15–25 pg/ml). In addition, ultrasonography of the parathyroid glands was normal, making primary hyperparathyroidism unlikely.

The dog was treated with L-thyroxine (300 μg, twice a day). On follow up assessment 2 weeks later, the dog was more active and the bradycardia had resolved, but the polyuria and polydipsia were still present. A repeat serum calcium concentration remained high at 3.46 mmol/L (13.8 mg/dl). Supplementation with L-T4 was continued at 300 μg twice a day.

On recheck 9 weeks later, the dog was active and had lost weight, but now the polyuria and polydipsia had resolved. The serum concentrations of both calcium (2.97 mmol/ L [11.88 mg/dl]), and total T4 (25.5 nmol/L) has normalized.

Fifteen months after the initial diagnosis, the dog’s body weight was stable and her activity normal; no polyuria and polydipsia were reported. Serum concentrations of calcium (2.93 mmol/L [11.7 mg/dl]), T4 (32 nmol/L), TSH (0.11 ng/ml), and PTH (20 pg/ml) were all within the respective reference ranges.

Bottom Line
Little is known about the effects of hypothyroidism on calcium metabolism in adult dogs (1-3), but the effects appear to be mild and clinically insignificant. In agreement with that, humans with adult-onset hypothyroidism serum concentrations of calcium and phosphorus are typically within normal limits (7-9). However, up to 25% of children with congenital hypothyroidism can exhibit mild degrees of hypercalcemia (10), and mild hypercalcemia has been reported in puppies with congenital hypothyroidism (4,5). The proposed mechanism for the hypercalcemia in hypothyroidism is decreased renal clearance and/or increased gastrointestinal absorption of calcium (11).

In the closing paragraph of this paper, Dr. Lobettia concludes that “the only logical explanation for the cause of the hypercalcemia in this dog would be hypothyroidism, as no other etiology was discovered, the hypercalcemia resolved with thyroxine therapy, and the PTH normalized.”

Unfortunately, another cause for this dog’s hypercalcemia must be considered — spurious total hypercalcemia, rather than true ionized hypercalcemia (12-14). In this dog, only the total calcium concentrations were measured, despite the well-documented fact that it is the ionized calcium fraction that has biologic activity.

Why ionized calcium was never measured in this dog is unclear, but it is possible that the serum ionized calcium value would have been normal, and the dog’s signs of polyuria may not have been caused by hypercalcemia after all.

In one study, it was documented that measuring total calcium concentrations tended to overestimate the perceived calcium value in dogs that were truly normocalcemic based on ionized calcium measurements. (13)  Use of total calcium or adjusted total calcium concentrations to predict the ionized calcium status in dogs could cause serious mistakes in diagnosis and case management, and that may have been the situation in the dog of this case report.

So before we add another differential to the differential list for hypercalcemia in dogs, just remember — always measure an ionized calcium to confirm true hypercalcemia (12-14)!

References:

1. Messinger JS, Windham WR, Ward CR. Ionized hypercalcemia in dogs: a retrospective study of 109 cases (1998-2003). Journal of Veterinary Internal Medicine 2009;23:514-519.
2. Feldman EC. Disorders of the parathyroid glands. In Ettinger S J, Feldman E C (eds), Textbook of Veterinary Internal Medicine (7th ed). Saunders Elsevier, St Louis. 2010;1722–1750.
3. Schenck PA, Chew DJ. Investigation of hypercalcaemia and hypocalcaemia In: Mooney CT,Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;221-233.
4. Greco D S, Peterson M E, Cho D Y, et al. Juvenile-onset hypothyroidism in a dog. Journal of the American Medical Veterinary Association 1985;187: 948–950. 
5. Greco D S, Feldman E C, Peterson M E, et al. Congenital hypothyroid dwarfism in a family of giant schnauzers. Journal of Veterinary Internal Medicine 1991;5: 57–65.
6. Lobetti RG. Hypercalcaemia in a dog with primary hypothyroidism. Journal of the South African Veterinary Association 2011;82:242-243. 
7. Auwerx J, Bouillon R. Mineral and bone metabolism in thyroid disease: a review. Quarterly Journal of Medicine 1986;60: 737–752. 
8. Begic-Karup S, Wagner B, Raber W, et al. Serum calcium in thyroid disease. Wiener Klinische Wochenschrift 2001; 113: 65–68. 
9. Shivaleela MB, Poornima RT, Jayaprakash Murthy DS. Serum calcium and phosphorous levels in thyroid dysfunction. Indian Journal of Fundamental and Applied Life Sciences 2012;2:179 -183.
10. Verrotti A, Greco R, Altobelli E, et al. Bone metabolism in children with congenital hypothyroidism – a longitudinal study. Journal of Pediatric Endocrinology and Metabolism 1998;11: 699–705. 
11. Pérez A V, Picotto G, Carpentieri A R et al. Mini-review on regulation of intestinal calcium absorption. Emphasis on molecular mechanisms of transcellular pathway. Digestion 2008;77: 22–34. 
12. Schenck PA. Calcium homeostasis in thyroid disease in dogs and cats. Veterinary Clinics of North America: Small Animal Practice 2007;37:693–708. 
13. Schenck PA, Chew DJ. Prediction of serum ionized calcium concentration by use of serum total calcium concentration in dogs. American Journal of Veterinary Research 2005;66:1330-1336.
14. Schenck PA, Chew DJ. Calcium: total or ionized? Veterinary Clinics of North America: Small Animal Practice 2008;38:497-502.

Megaesophagus and Hypothyroidism in Dogs

Reversible Megaesophagus Associated with

Primary Hypothyroidism in a Dog

By F. Fracassi and A. Tamborini

Veterinary Record 2011; 168: 329b.

Hypothyroidism is frequently cited as a possible cause of megaesophagus in dogs (1-4). However, a definitive association between hypothyroidism and megaesophagus has not been proven. Based on the limited response to the appropriate thyroid hormone supplementation in most dogs, there has been little proof of a true causal relationship between hypothyroidism and megaesophagus (1-4).

In this case report by Fracassi and Tamborini (5), they describe a dog with well-documented hypothyroidism and concurrent megaesophagus. This dog responded very well to L-thyroxine replacement therapy, with complete resolution of all clinical signs of hypothyroidism, as well as the associated megaesophagus.

Case Report
A 7-year old female German shepherd dog presented for regurgitation shortly after feeding. On physical examination, the dog had a body condition score of 6/9 and a diffusely poor, dull and dry hair coat. There were areas of alopecia and hyperpigmentation in areas of friction, as well as on the tail.

Routine blood test results showed a moderate, non-regenerative normochromic and normocytic anemia, with mild hypercholesterolemia. Survey radiography of the thorax, before and after oral administration of barium, revealed that megaesophagus was present (Figure 1).

Chest x-ray of dog with hypothyroidism, showing megaesophagus

Serology for acetylcholinereceptor antibodies was negative; therefore, myasthenia gravis was considered unlikely.

Results of thyroid function testing showed a high concentration of serum cTSH (0.84 μg/L; reference range, 0.03-0.38 μg/L) together with low basal value for total T4 (6.4 nmol/L; reference range, 14-45 nmol/L). This combination of low T4 and high TSH values was consistent with primary hypothyroidism.

A recombinant human TSH stimulation test was also performed, by measuring the serum T4 concentration before and 6 hours after IV injection of 75 μg of rhTSH (6). Results of the TSH stimulation test showed low serum concentrations of both basal T4 and post-TSH T4, diagnostic for hypothyroidism. The final diagnosis was hypothyroidism associated with probable secondary megaesophagus.

Treatment was initiated with levothyroxine (20 μg/kg , BID). One week later, the owner reported that the dog was much more active, with no more regurgitation. At recheck 25 days later, the dog was found to be in a good condition; its hair coat was less dull and areas of new hair growth were apparent. Repeat chest radiographs showed resolution of the megaesophagus. The serum T4 value collected 4-hours post-pill was in the high-normal range (47.6 nmol/L) and considered adequate for replacement.

Two years after the diagnosis, the dog was clinically well on L-T4 replacement. No further dermatological signs or regurgitation have been reported.

My Bottom Line

The clinical signs of canine hypothyroidism can be vague and are frequently nonspecific (1-4). The most common presenting signs include lethargy, obesity or weight gain, and dermatologic signs (Figure 2). The metabolic features are often considered subtle, whereas dermatological changes more frequently prompt investigation of thyroid function.

Prevalence of clinical features of canine hypothyroidism

Is there really a true association between hypothyroidism and megaesophagus? This issue is quite controversial (3,4,7). In a case-controlled study of 136 dogs with acquired megaesophagus, 272 control dogs from the general hospital population and 151 control dogs that underwent a TSH response test, no association between hypothyroidism and megaesophagus was found (7).

Similarly, in another retrospective study of 29 hypothyroid dogs, 4 dogs had megaesophagus—although one dog showed an improvement of the clinical signs of regurgitation after L-T4 treatment, radiological evidence of megaesophagus persisted in all 4 the dogs (8). This suggests that there may not be any relationship between thyroid dysfunction and megaesophagus in these dogs.

However, there also have been a few well-documented cases of dogs with concurrent hypothyroidism and megaesophagus in which complete resolution of the clinical and radiographic signs were seen after L-T4 treatment (9). This suggests, as does this present case report, that at least some hypothyroid dogs with secondary megaesophagus will respond well to thyroid hormone replacement therapy with resolution of all esophageal signs.

Overall, megaesophagus, although a very rare signs of hypothyroidism, does appear to be associated with hypothyroidism in at least some dogs.

References:

1. Panciera DL. Hypothyroidism in dogs: 66 cases (1987-1992). J Am Vet Med Assoc 1994;204:761-767. 
2. Dixon RM, Reid SW, Mooney CT. Epidemiological, clinical, haematological and biochemical characteristics of canine hypothyroidism. Vet Rec 1999;145:481-487. 
3. Mooney CT. Canine hypothyroidism: a review of aetiology and diagnosis. N Z Vet J 2011;59:105-114. 
4. Mooney CT, Shiel RE. Canine hypothyroidism In: Mooney CT,Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;63-85.
5. Fracassi F, Tamborini A. Reversible megaoesophagus associated with primary hypothyroidism in a dog. Vet Rec 2011;168:329b. 
6. Boretti FS, Sieber-Ruckstuhl NS, Wenger-Riggenbach B, et al. Comparison of 2 doses of recombinant human thyrotropin for thyroid function testing in healthy and suspected hypothyroid dogs. J Vet Intern Med 2009;23:856-861. 
7. Gaynor AR, Shofer FS, Washabau RJ. Risk factors for acquired megaesophagus in dogs. J Am Vet Med Assoc 1997;211:1406-1412.  
8. Jaggy A, Oliver JE, Ferguson DC, et al. Neurological manifestations of hypothyroidism: a retrospective study of 29 dogs. J Vet Intern Med 1994;8:328-336. 
9. Huber E, Armbrust W, Forster JL, et al. Resolution of megaesophagus after treatment of concurrent hypothyroidism in a dog. Schweiz Arch Tierheilkd 2001;143:512-514.

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.