Wednesday, June 4, 2014

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.