Diagnosing Feline Hyperthyroidism: Not Always as Simple as One Might Believe

Earlier this year, Dr. Mark Peterson participated in an Endocrinology course organized by the American College of Veterinary Internal Medicine (ACVIM). An overview of his lecture on "Diagnosing feline hyperthyroidism" was summarized by Dr. Jennifer Garcia and published in the July 2015 issue of Veterinary Medicine. To access this article online, click here.

Diagnosing feline hyperthyroidism: It's not always as simple as it seems

Don't rely too heavily on T4 concentrations since cats can have a false elevation.

In his presentation, “Diagnosis of hyperthyroidism: A critical evaluation of our current available tests,” Mark Peterson, DVM, DACVIM, discussed some of the pitfalls in relying too heavily on thyroid (thyroxine, or T4) testing alone. While a total T4 concentration will be enough to make an accurate diagnosis of hyperthyroidism in more than 90% of cases, he warned to always pay attention to the clinical signs and physical examination findings. There are cats that can have a false elevation in their T4 concentration, so supportive clinical signs as well as a palpable thyroid nodule will help rule in or rule out the diagnosis.

When it comes to successfully palpating for evidence of a thyroid nodule, Peterson detailed a few of his favorite techniques:

• Stand behind the cat with the cat facing away from you—the cat feels less stressed if it can’t see you. Peterson also puts the cat in a basket with a towel so the cat feels more secure and is less squirmy. Use your thumb and index finger to gently run the length of the trachea from the larynx to the thoracic inlet.
• Alternatively, with the cat in the same position, turn its head to the left and palpate. Repeat with the cat’s head turned in the other direction.

Examine the cat from behind, with the cat facing the owner.

For patients in which a thyroid nodule can be palpated but there are no clinical signs and there is no elevation in T4 concentration, he recommends monitoring signs at home and rechecking the level in six to 12 months.

Peterson also noted that there are different cut-off values from laboratory to laboratory. This means that a T4 concentration that is normal at one laboratory, may actually be elevated at another. This serves as another reminder of the importance of the physical examination and clinical signs when trying to diagnose hyperthyroidism.

Top Endocrine Publications of 2013: The Feline Thyroid Gland

In my eighth compilation of the canine and feline endocrine publications of 2013, I’m moving on to disorders of the feline thyroid gland.

Listed below are 26 papers published in 2013 that deal with a variety of thyroid gland topics of issues of clinical importance in cats.

These range from from studies of the duration of serum T4 suppression in cats treated with methimazole (1) to the results of a long-term follow-up study of cats treated with transdermal methimazole (2); and from case reports of methimazole or carbimazole-induced toxicity in cats (3,6,19) to the results of an online survey to determine owner experiences and opinions on the management of their hyperthyroid cats using oral anti-thyroid medications (5).

Other studies report the variability in iodine concentrations found in commercial cats foods in the USA (7) to investigation of the radioactivity in the excreta of hyperthyroid cats treated with radioiodine (8); from a comparison of computed tomography and scintigraphy for thyroid imaging in hyperthyroid cats (9) to a review of the clinical usefulness of an assay for measurement of circulating B-type natriuretic peptide (BNP) concentration in hyperthyroid cats (11); and from an overview of the diagnostic tests useful for confirming feline hyperthyroidism (4,12,13,15,17) and hypothyroidism (14) to a study of the effects of an iodine-restricted diet for management of cats with hyperthyroidism (22); from investigations of the pathophysiological mechanism for altered calcium homeostasis in hyperthyroid cats (24) to studies of the renin-angiotensin-aldosterone system activity in hyperthyroid cats with and without hypertension (25).

References:

1. Boretti FS, Sieber-Ruckstuhl NS, Schafer S, et al. Duration of T4 suppression in hyperthyroid cats treated once and twice daily with transdermal methimazole. J Vet Intern Med 2013;27:377-381. 
2. Boretti FS, Sieber-Ruckstuhl NS, Schafer S, et al. Transdermal application of methimazole in hyperthyroid cats: a long-term follow-up study. J Feline Med Surg 2013;16:453-459. 
3. Bowlt K, Cattin I, Stewart J. Carbimazole-associated hypersensitivity vasculitis in a cat. J Small Anim Pract 2013; doi: 10.1111/jsap.12154. 
4. Bruyette D. Feline hyperthyroidism: Diagnosis and therapeutic modalities. Today's Veterinary Practice 2013;3:25-30.
5. Caney SM. An online survey to determine owner experiences and opinions on the management of their hyperthyroid cats using oral anti-thyroid medications. J Feline Med Surg 2013;15:494-502. 
6. Castro Lopez J, Lloret A, Ravera I, et al. Pyogranulomatous mural folliculitis in a cat treated with methimazole. J Feline Med Surg 2013;16:527-531. 
7. Edinboro CH, Pearce EN, Pino S, et al. Iodine concentration in commercial cat foods from three regions of the USA, 2008-2009. J Feline Med Surg 2013;15:717-724. 
8. Lamb V, Gray J, Parkin T, et al. Measurement of the radioactivity in the excreta of cats treated with iodine-131 for hyperthyroidism. Vet Rec 2013;172:45. 
9. Lautenschlaeger IE, Hartmann A, Sicken J, et al. Comparison between computed tomography and Tc-Pertechnetate scintigraphy characteristics of the thyroid gland in cats with hyperthyroidism. Vet Radiol Ultrasound 2013;54:666-673. 
10. North DL. Uptake of 131-I in households of thyroid cancer patients. Health Phys 2013;104:434-436. 
11. Oyama MA, Boswood A, Connolly DJ, et al. Clinical usefulness of an assay for measurement of circulating N-terminal pro-B-type natriuretic peptide concentration in dogs and cats with heart disease. J Am Vet Med Assoc 2013;243:71-82. 
12. Paepe D, Verjans G, Duchateau L, et al. Routine health screening: findings in apparently healthy middle-aged and old cats. J Feline Med Surg 2013;15:8-19. 
13. Peterson ME. More than just T4: Diagnostic testing for hyperthyroidism in cats. J Feline Med Surg 2013;15:765-777. 
14. Peterson ME. Feline focus: Diagnostic testing for feline thyroid disease: hypothyroidism. Compend Contin Educ Vet 2013;35:E4. 
15. Peterson ME. Feline focus: Diagnostic testing for feline thyroid disease: hyperthyroidism. Compend Contin Educ Vet 2013;35:E3. 
16. Ramoo S, Bradbury L, Anderson G, et al. Sedation of hyperthyroid cats with subcutaneous administration of a combination of alfaxalone and butorphanol. Aust Vet J 2013;91:131-136. 
17. 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 (Letter). Vet Clin Pathol 2014;43:1-3. 
18. Sabatino BR, Rohrbach BW, Armstrong PJ, et al. Amino acid, iodine, selenium, and coat color status among hyperthyroid, Siamese, and age-matched control cats. J Vet Intern Med 2013;27:1049-1055. 
19. Snead E, Kerr M, Macdonald V. Cutaneous lymphoid hyperplasia mimicking cutaneous lymphoma in a hyperthyroid cat. Can Vet J 2013;54:974-978. 
20. Sparkes A. Health screening of cats: some timely justification. J Feline Med Surg 2013;15:5. 
21. Taylor BE, Leibman NF, Luong R, et al. Detection of carcinoma micrometastases in bone marrow of dogs and cats using conventional and cell block cytology. Vet Clin Pathol 2013;42:85-91.
22. van der Kooij M, Becvarova I, Meyer HP, et al. Effects of an iodine-restricted food on client-owned cats with hyperthyroidism. J Feline Med Surg 2013;14:491-498. 
23. Whitehouse-Tedd KM, Cave NJ, Ugarte CE, et al. Isoflavone metabolism in domestic cats (Felis catus): Comparison of plasma metabolites detected after ingestion of two different dietary forms of genistein and daidzein. J Anim Sci 2013;91:1295-1306. 
24. Williams TL, Elliott J, Berry J, et al. Investigation of the pathophysiological mechanism for altered calcium homeostasis in hyperthyroid cats. J Small Anim Pract 2013;54:367-373. 
25. Williams TL, Elliott J, Syme HM. Renin-angiotensin-aldosterone system activity in hyperthyroid cats with and without concurrent hypertension. J Vet Intern Med 2013;27:522-529. 
26. Wongbandue G, Jewgenow K, Chatdarong K. Effects of thyroxin (T4) and activin A on in vitro growth of preantral follicles in domestic cats. Theriogenology 2013;79:824-832. 

Diagnosing Subclinical Hyperthyroidism in Cats

I have a quick question about a "problem" case, a 9-year old M/C DSH. This cat has lost about 3 pounds over the last year, but weighed 22 pounds last year so the owner has been trying hard to get the cat to lose weight.

The cat came in for his recheck last week. His physical examination was normal and we ran a routine blood panel (CBC, serum chemistry panel, and total T4). His serum T4 was high-normal at 3.7 µg/dl (reference range, 0.8-4.0 µg/dl). I then added on a free T4 by dialysis, which came back as slightly high at 54 pmol/L (10-50 pmol/L). Looking back in his records, his free T4 concentrations were also slightly high when checked a year ago (58 pmol/L).

This cat is not clinical at all otherwise for hyperthyroidism. He has strange seizure-like episodes, about once every 3 months, but these have been happening since he was a young cat. There has been no change in these episodes.

My gut is telling me that because this cat is not clinical and his thyroid values have remained stable over the last year, we probably should not treat hyperthyroidism at this time. However, I wanted to get your opinion and see if you think that this cat is indeed hyperthyroid, and if so, if he may be a candidate for I-131 at this time.

My Response:

In our studies, we have found that up to 30% of cats that present like this (asymptomatic, high-normal T4, slightly high free T4 concentration) will be normal when evaluated by thyroid scintigraphy (1-3). So basically, this cat certainly could be in the preclincal stages of becoming hyperthyroid, but it's also very possible that the free T4 is falsely high and he is euthyroid.

Determination of free T4 is far from being a perfect test, and a diagnosis of hyperthyroidism should NEVER be based on the finding of a high free T4 alone (1,2,4). This is especially true in a cat like this one, that presents without a palpable thyroid nodule or clinical features of thyroid disease.

So you and the owners have 2 options at this time:

1. Do a thyroid scan (scintigraphy) to better define the cat's thyroid function (1-3,5,6). If the thyroid lobes are of normal size and display normal thyroid uptake of the radionuclide, we can definitely rule out hyperthyroidism. If, on the other hand, a small hyperfunctional thyroid adenoma is found, then we know that the cat has early hyperthyroidism and could be treated.
2. The second option is to continue to monitor the cat every 3-6 months (body weight, heart rate, neck palpation, and complete thyroid profile, including serum concentrations of total T4, free T4, and TSH). If hyperthyroid, the serum T4 and free T4 should continue to go higher, where as the TSH should be undetectable (1,2,7,8). If the serum TSH is found to be measurable, that goes against hyperthyroidism since even mild increases in circulating T4 and T3 should feedback to the pituitary to shut off TSH secretion.

Thyroid scintigraphy in a normal cat (on right) and cat with preclinical hyperthyroidism (on left).
Notice that the hyperthyroid cat has a small left thyroid adenoma with complete suppression of the right thyroid lobe. In cats with unilateral hyperthyroid disease, this lack of radionuclide uptake by the normal thyroid lobe is due to the fact that circulating TSH becomes suppressed in almost all hyperthyroid cats, even those with mild disease.

Either option is acceptable - just depends on what the owner wants to do. The cat is not going to be hurt by waiting, as long as he is closely monitored. At 9-years of age, he is still on the young side for being hyperthyroid, but about 5-10% of my cats are less than 10-years, so it's very possible that he is just preclinical at this time and will develop overt signs of hyperthyroidism within the next year.

References:

1. Peterson ME. More than just T4: Diagnostic testing for hyperthyroidism in cats. J Fel Med Surg 2013;15:765-777. 
2. Peterson ME. Feline focus: Diagnostic testing for feline thyroid disease: hyperthyroidism. Compend Contin Educ Vet 2013;35:E3.
3. Peterson ME, Broome MR. Radioiodine for feline hyperthyroidism In: Bonagura JD, Twedt DC, eds. Kirk's Current Veterinary Therapy, Volume XV. Philadelphia: Saunders Elsevier, 2014.
4. 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;218:529-536. 
5. Broome MR. Thyroid scintigraphy in hyperthyroidism. Clin Tech Small Anim Pract 2006;21:10-16. 
6. Peterson ME, Broome MR. Thyroid scintigraphic findings in 917 cats with hyperthyroidism. J Vet Intern Med 2012;26:754.
7. Wakeling J, Elliott J, Syme H. Evaluation of predictors for the diagnosis of hyperthyroidism in cats. J Vet Intern Med 2011;25:1057-1065. 
8. Wakeling J. Use of thyroid stimulating hormone (TSH) in cats. Can Vet J 2010;51:33-34. 

Fluctuation in Serum Thyroid Hormone Concentrations: An Issue in Diagnosis of Feline Hyperthyroidism?

Examining a cat with hyperthyroidism

I am writing this email to you because of your recent article published in the Journal of Feline Medicine and Surgery about diagnostic testing for hyperthyroidism (1). In that paper, you mentioned that hyperthyroid cats can show fluctuation of serum T4 and T3 concentrations (2), leading to difficulty in diagnosis in some cats.

My question is this: When, in your opinion or experience, is the best moment of the day (or the best conditions), to get the blood samples for thyroid hormone analysis to avoid this fluctuation problem?

Thanks! Looking forward to hearing from you.

My Response:

Unfortunately, there is no way to predict if and when this fluctuation in T4 and T3 will occur. So collecting blood samples at a particular time of day would not be helpful.

Remember, however, that this fluctuation is only of clinical importance in cats with very mild hyperthyroidism; in these cats, the serum T4 value may vary from the upper third of the reference range limits to just slightly above normal. In cats with more advanced stages of hyperthyroidism, fluctuation in circulating T4 concentration will occur throughout the day and over a period of a few days, but all T4 values will be high (1-3). Thus, in most hyperthyroid cats, the fluctuation in circulating thyroid hormone levels will not contribute to problems in the diagnosis.

References:

1. Peterson ME. Diagnostic testing for hyperthyroidism in cats: more than just T4. J Fel Med Surg 2013;15:765-777.  
2. Peterson ME, Graves TK, Cavanagh I. Serum thyroid hormone concentrations fluctuate in cats with hyperthyroidism. J Vet Intern Med 1987;1:142-146. 
3. Peterson ME. Feline focus: Diagnostic testing for feline thyroid disease: Hyperthyroidism. Compend Contin Educ Vet 2013;35:E1-E6.

Q & A: Hypothyroidism in a 17-year-old Chihuahua

My patient is an older 17-year old male Chihuahua. His weight is normal at 6.8 pounds. He is having episodes of pain at time of defecation and appears painful in his back.

We ran routine blood work which was all completely normal. However, a screening serum total T4 concentration was low at 0.4 μg/dl (reference range, 0.38-4.0 μg/dl). I added on a free T4 concentration and that was also low at  0.3 ng/ml (0.6 to 3.7 ng/ml). 

Would you recommend starting a thyroid supplementation in this dog?

My Response:

I doubt if this dog is truely hypothyroid for a number of reasons (1-3).

• First of all, the clinical signs the dog is showing are not at all characteristic of hypothyroidism.
• Secondly, the dog has neither anemia or hypercholesterolemia, which would make a diagnosis of hypothyroidism more likely.
• Finally, would be very unusual for a 17-year old dog to develop hypothyroidism; most dogs with hypothyroidism are young to middle age adult dogs, not geriatric animals.

In this dog, it's more likely that the serum thyroid concentrations are low either because of 1) a non-thyroidal illness, or 2) administration of a drug that is causing "suppression" of the circulating thyroid values. Such thyroid-lowering drugs include the following (3-5):

• Phenobarbital
• Sulfur antibiotics
• Clomipramine (Clomicalm) 
• Aspirin and other anti-inflammatory drugs
• Glucocorticoids

The steroids involved can be oral, parenteral, or topical, applied to the eyes, ears or skin. We need to get a good drug history in these dogs not only by reviewing the record to see what has been dispensed, but also by asking the owner what they're actually doing, as they may have bags of medications at home that we know nothing about.

Of course, if you do believe that the dog has hypothyroidism, then the next step would be to verify the low serum T4 concentration, repeat the serum free T4 using an equilibrium dialysis technique if possible, and to measure a serum cTSH concentration (2,3). If the total and free T4 remain low and the cTSH value is high, then treatment would be indicated.

The most accurate way to make a diagnosis (or rule out) a diagnosis of hypothyroidism is by use of thyroid scintigraphy (6,7). Although not widely used or available as a diagnostic test for dogs with suspected hypothyroidism, the diagnosis of hypothyroidism is easily made by the lack of finding any visible cervial thyroid tissue with thyroid imaging (see Figure below).

Thyroid Image (Scintigraphy) in a Boston Terrier with Hypothyroidism.
Notice the uptake of the radioactive tracer by the salivary glands, but the complete lack of uptake by the thyroid gland.  The normal location for the 2 thyroid lobes is indicated by yellow ovals.

Thyroid imaging typically reveals decreased or even absent radionuclide uptake in dogs with hypothyroidism (thyroid gland is not visible on the scan). In contrast, dogs that have falsely low serum thyroid hormone concentrations secondary to illness or drug therapy have a normal thyroid image. In one study of comparing thyroid imaging to other diagnostic tests for hypothyroidism in dogs, there was no overlap between dogs with primary hypothyroidism and dogs with nonthyroidal illness when thyroid scintigraphy was employed (6).   Of all of the current thyroid imaging techniques (CT, ultrasound), nuclear imaging is considered to be the best test for dogs with suspected hypothyroidism.

References:

1. Chastain CB. Canine pseudohypothyroidism and covert hypothyroidism. Problems in Veterinary Medicine 1990;2:693-716.  
2. Mooney, CT. Canine hypothyroidism: A review of aetiology and diagnosis. New Zealand Veterinary Journal 2011;59:105-114.
3. Peterson ME, Melián C, Nichols R. Measurement of serum total thyroxine, triiodothyronine, free thyroxine, and thyrotropin concentrations for diagnosis of hypothyroidism in dogs. Journal of the American Veterinary Medical Association 1997;211:1396-1402. 
4. 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. 
5. 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. 
6. Diaz Espineira MM, Mol JA, Peeters ME, et al. Assessment of thyroid function in dogs with low plasma thyroxine concentration. J Vet Intern Med 2007;21:25-32. http://www.ncbi.nlm.nih.gov/pubmed/17338146
7. Taeymans O, Peremans K, Saunders JH. Thyroid imaging in the dog: current status and future directions.J Vet Intern Med 2007;21:673-684. http://www.ncbi.nlm.nih.gov/pubmed/17708386

Q & A: Diabetes Insipidus in a Hypothyroid Golden Retriever

I have an interesting situation with a dog with polyuria and polydipsia (PU/PD) that I have not seen before, and wonder if you can offer any insight.

My patient is a 7-year old, male neutered Golden Retriever-mix weighing 69 pounds who was diagnosed as being hypothyroid and has been on L-thyroxine replacement (Soloxine) for at least 5 years. He was recently diagnosed with diabetes insipidus (DI) because of signs of severe PU/PD and low urine specific gravity. The dog was examined by a neurologist, who found no neurological deficits. On MRI examination, the dog had no abnormal findings to explain the onset of DI (i.e, no hypothalamic or pituitary lesions or masses). 

He is now on Soloxine at a dosage of 0.7 mg twice daily (there has been no change in L-T4 dose for last year). For the DI, we have him on 0.01% desmopressin, with drops administered twice daily into the conjunctival sac (1 drop in morning and 2 drops in evening).

His owner reports he has been doing great in the last 3 to 4 months since he added the desmopressin. Recently, however, we rechecked a 6-hour post-pill serum T4 concentration and found that the value was high at 5.5 μg/dl (reference range, 1-4 μg/dl).

My questions are:

1. Can this be due to an interaction of desmopressin and L-thyroxine?
2. Is this a result of correcting/properly treating his diabetes insipidus and is this common?
3. Do we need to take any special factors into consideration with dosing either drug, or just lower his Soloxine as we would in other hypothyroid dogs getting routine T4 rechecks for proper dosing?
4. Is this just a coincidence and no known correlation?

My Response:

The main sign of hyperthyroidism in dogs is PU/PD so I'm be a bit worried that the thyroid hormone supplementation is causing the signs (1-4). You could drop the dose down a bit to see if that helps the PU/PD. After a week or so on the reduced dose of L-T4, you could try stopping the desmopressin for a couple of days and see if the PU/PD returns.

I don't know of any problems with concurrent use of desmopressin and thyroid hormone. But it is somewhat unlikely that a 7-year old dog would develop DI without the presence of any obvious pituitary or CNS pathology (1,2,4).

Many dogs with undefined PU/PD will respond to desmopressin but most of those dogs do not have DI. I'm not saying that we shouldn't use the desmopressin to control the signs, but DI is very unlikely.

Follow-up Question:

Thank you for your ideas, Dr. Peterson.

Do you mean that perhaps he was being overtreated for his hypothyroidism thus making him hyperthyroid leading to the PU/PD that initially caused us to diagnose the diabetes insipidus? I'm pretty sure that his T4 was in the normal range at that time. And now when we just tested him and discovered the T4 high, he is no longer PU/PD (since being on the desmopressin).

That is interesting that even dogs who do not truly have DI will respond to desmopressin. Will desmopressin eventually stop helping though? Or would you just keep him on it as long as it controls the severe PU/PD?

My Response:

Remember that when we are doing a post-pill T4, we are only doing a single spot check. That doesn't really indicate that is happening throughout the day.

In addition, the finding of a serum T4 value within the lab's reference range does not indicate what that particular dog's individual T4 normal range actually is — in other words, some dogs may be perfectly euthyroid having a serum T4 value of 4.5 μg/dl, whereas others may be clinically hyperthyroid with a serum T4 of 3.5 μg/dl.

And yes, most dogs that respond to desmopressin do not really have DI. As long as you and the client realize that, this is a pretty safe drug and it can be used to control PU/PD for long periods (and maybe forever).

Again, I'd still try cutting back on the L-T4 dose first -- why give desmopressin if we can figure out the real cause of the PU/PD?

References:

1. Peterson ME, Nichols R: Investigation of polyuria and polydipsia, In: Mooney C.T., Peterson M.E. (eds), Manual of Canine and Feline Endocrinology (Third Ed), Quedgeley, Gloucester, British Small Animal Veterinary Association, pp 16-25, 2004.
2. Randolph JF, Nichols R, Peterson ME: Diseases of the hypothalamus and pituitary. In: Birchard SJ, Sherding RG (eds): Manual of Small Animal Practice (Third Edition), Philadelphia, Saunders Elsevier, pp 398-408, 2006.
3. Peterson ME: Hyperthyroidism and thyroid tumor in dogs. In: Melian C, Perez Alenza MD, Peterson ME, Diaz M, Kooistra H (eds): Manual de Endocrinología en Pequeños Animales (Manual of Small Animal Endocrinology). Multimedica, Barcelona, Spain, 2008, pp 113-125.
4. Nichols R, Peterson ME: Investigation of polyuria and polydipsia, In: Mooney C.T., Peterson M.E. (eds), Manual of Canine and Feline Endocrinology (Fourth Ed), Quedgeley, Gloucester, British Small Animal Veterinary Association, 2012; 215-220.

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.

Q & A: Hypothyroid Dog Not Responding to L-T4 Replacement

"Molly" is a 7-year-old Laborador Retriever weighing 31 kg, who was diagnosed over a year ago as being hypothyroid based on the finding of a low-normal serum T4 concentration (0.9 μg/dl; reference range, 0.9-3.9 μg/dl). Her clinical signs included non-pruitic alopecia of the pinnae and truncal dermatitis. Based upon her clinical signs and the low serum T4 value, she was started on L-thyroxine (Soloxine) a the dosage of 0.5 mg, BID.

Over the past year, a number of post-pill serum T4 concentrations have been done, but all of her serum T4 values have remained in the low-normal range (between 0.9-1.5 μg/dl). Her dose of Soloxine was increased to 0.6 mg but there still has not been improvement in clinical signs.

This week I repeated an entire thyroid panel while the dog is on the L-T4 and send the serum to the Michigan State University Endocrine Lab (animalhealth.msu.edu). Here are the results of that thyroid panel:

TT4: 59 nmol/L (15-67 nmol)

TT3: 1.5 nmol (1.0-2.5 nmol)

FT4: 20 pmol/L (8-26 pmol)

FT3: 5.2 pmol (4.5-12 pmol)

T4AA: 11% (0-20%)

T3AA: 5% (0-10%)

TSH: 0.01 mU/L (0-37 mU/L)

Thyroglobulin AA: 2% (0-35%)

My questions: Will being on L-thyroxine cause these numbers to all be normal? Is it advisable to stop the thyroid supplementation for a few weeks and run another serum thyroid panel, as clinically it doesn't seem to be doing much? Is she really hypothyroid at all?

Thank you so much for your help!

My Response:

Yes, the goal of thyroid hormone supplementation is to completely normalize the serum thyroid panel (i.e., to raise serum total and free T4 and T3 values and suppress serum TSH concentrations). So these results indicate that the L-T4 supplementation in this dog is being well absorbed and is feeding back on the pituitary gland to lower TSH secretion.

But you are correct: if the dog isn't hypothyroidism, the clinical signs aren't going to improve. I would recommend that you stop the L-T4 supplementation and redo the thyroid panel. Unfortunately, we need the dog off all L-T4 for at least 6 weeks prior to testing to allow the hypothalamic-pituitary-thyroid axis to recover. Once you stop the thyroid medication, this dog may be mildly hypothyroid (due to iatrogenic suppression of pituitary TSH secretion) even if his thyroid gland was normal prior to the thyroid supplementation.

When you do recheck Molly after stopping the thyroid mediation, remember to also run a CBC and serum chemistry panel. This will rule out any nonthyroidal diseases, but will also help in diagnosis of hypothyroidism, especially if mild anemia, or fasting hyperlipidemia/ hypercholesterolemia is present.

PS: I don’t know what the prior post-pill test results showed serum T4 values only in the low-normal range, but the serum T4 on this panel is perfect.  Have the owners been consistently giving the L-T4 without food or at time of meals?

It’s been shown that absorption of L-T4 in dogs can be better when given on an empty stomach. So if the owners were not consistent in when they administer the thyroid medication, that could explain why the previous results were so different that the current results. And it may also explain why the dog hasn’t responded to the thyroid supplementation (if she really is hypothyroid, which still needs to be determined).

References:

1. 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.

Q & A: Does T3 Hyperthyroidism Occur in Cats?

Prior to veterinary school, I worked as for a few years at a major medical center as a nurse in their endocrine clinic. In older human patients with hyperthyroidism, was not that uncommon for these folks to present with perfectly normal serum T4 values but have very high serum T3 concentrations.

Do cats also develop a similar syndrome of T3 hyperthyroidism? That is, can some hyperthyroid cats maintain normal serum concentrations of T4 and free T4, but have clinical signs resulting from high circulating T3 values alone?

I've reviewed the literature, but I don't see that T3 thyrotoxicosis has ever been reported in cats. Is that because we just aren't checking serum T3 levels in hyperthyroid cats? Do you think that we are missing these cases?

My Response:
This syndrome is commonly referred to as triiodothyronine (T3) thyrotoxicosis or just T3 toxicosis. This disorder is found almost exclusively in the elderly and may be the cause of hyperthyroidism in up to 10% of older patients. T3 thyrotoxicosis is characterized by the finding of high serum T3 with normal or even low T4 levels, which can sometimes even lead to an erroneous diagnosis of hypothyroidism.

In the late 1970s and throughout most of the 1980s, we routinely measured serum T3 on all hyperthyroid cats. Although serum T3 concentrations were very high in many of these cats, we never documented a cat with isolated T3 thyrotoxicosis (1).

So over the last 35 years, I have certainly looked for this syndrome of T3 thyrotoxicosis. I have always expected to find some cats with normal T4 but high T3 levels, but to date the syndrome of T3 hyperthyroidism has yet to be documented in cats.

Today, we rarely use serum T3 concentrations as a diagnostic test for hyperthyroidism. Use of total T4 alone is diagnostic in over 90% of cats, whereas serum T3 values are high in only about two-thirds of cats (2).

That said, however, it still is possible that hyperthyroid cats could develop T3 hyperthyroidism. Certainly in circumstances where a low iodine diet is fed, you might see a situation where T3 is being secreted preferentially over T4 (3).

In states of iodine deficiency, it’s easier for the thyroid gland to make T3 compared to T4. The reason for that is simple — it takes one less iodide atom to make T3 than T4, since T3 only has 3 iodine atoms whereas T4 contains 4 iodine atoms.

T4 has 1 more iodine atom than T3

Therefore, you have a cat in which hyperthyroidism is suspected, especially if a palpable goiter was present, but total and free T4 values are normal, I would certainly recommend that you run a serum T3 concentration to rule out T3 thyrotoxicosis.

References:

1. Peterson ME, Kintzer PP, Cavanagh PG, et al. Feline hyperthyroidism: pretreatment clinical and laboratory evaluation of 131 cases. J Am Vet Med Assoc 1983;183:103-110.
2. 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;218:529-536.
3. Laurberg P. Mechanisms governing the relative proportions of thyroxine and 3,5,3'-triiodothyronine in thyroid secretion. Metabolism: clinical and experimental 1984;33:379-392.

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.

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.