1. Pathogenesis
Hyperthyroidism remains the most common endocrine disorder in the cat. However, after 25 years, we still do not understand its causation. In the last few years, additional work has been done to elucidate the pathogenesis of feline hyperthyroidism. These studies have included work on genetic, environmental, and dietary risk factors.
Two recent large studies have looked at possible environmental or dietary factors involved in the patho-genesis of hyperthyroidism. One of the studies with a case controlled design looked at 100 cats with hyper-thyroidism and 163 control cats. The cats medical records were reviewed and the owners were asked to complete a mailed questionnaire. Data included demographic variables, environmental exposures, and diet (including preferred flavors of canned cat food). In this study, housing, exposure to fertilizers, herbicides, regular use of flea products, and the presence of a smoker in the house were not associated with an increased risk, but cats that preferred fish or liver and giblets flavors of canned cat food had an increased risk. The results suggested that cats that prefer to eat certain flavors of canned cat food might have a significantly increased risk of hyperthyroidism.
In the second case controlled study owners of 379 hyperthyroid and 351 control cats were questioned about their cats' exposure to potential risk factors including breed, demographic factors, medical history, indoor environment, chemicals applied to the cat and environment, and diet. The association between these hypothesized risk factors and outcome of disease was evaluated by conditional logistic regression. Two genetically related cat breeds (Siamese and Himalayan) were found to have diminished risk of developing hyperthyroidism. Cats that used litter had higher risk of developing hyperthyroidism than those that did not. Use of topical ectoparasite preparations was associated with increased risk of developing hyperthyroidism. Compared with cats that did not eat canned food, those that ate commercially prepared canned food had an approximate two-fold increase in risk of disease. When these four variables (breed, use of cat litter, consumption of canned cat food, and use of topical ectoparasite preparations) from the univariate analysis were selected for further study as candidate risk factors and analyzed by multivariate conditional logistic regression, a persistent protective effect of breed (Siamese or Himalayan) was found. In addition, results suggested a two- to three-fold increase in risk of developing hyperthyroidism among cats eating a diet composed mostly of canned cat food and a three-fold increase in risk among those using cat litter. In contrast, the use of commercial flea products did not retain a strong association. The results of this study indicate that further research into dietary and other potentially important environmental factors (cat litter) is warranted.
Altered G protein expression was found in thyroid gland tissue from hyperthyroid cats compared to normal control cats. Adenomatous thyroid glands obtained from eight hyperthyroid cats and thyroid glands obtained from four age-matched euthyroid cats were examined for expression of G(i) and G(s). Expression of G(i) was significantly reduced in thyroid gland adenomas from hyperthyroid cats, compared with normal thyroid gland tissue from euthyroid cats. Expression of G(s) was similar between the two groups. A decrease in expression of G(i) in adenomatous thyroid glands of cats may reduce the negative inhibition of the cAMP cascade in thyroid cells, leading to autonomous growth and hypersecretion of thyroxine. What we don’t know is why or what causes the reduction in G(i) in hyperthyroid cats. The factors mentioned above in the studies of environmental and dietary risk factors may play in role in altering the G protein expression found in this study.
Oncogenes and the tumor suppressor gene p53 were examined in cats with hyperthyroidism. Formalin-fixed, paraffin-embedded thyroid glands from 18 cats diagnosed with hyperthyroidism were evaluated immuno-histochemically for overexpression of the products of oncogenes c-ras (a mitogenic oncogene) and bcl2 (an apoptosis inhibitor) and the tumor suppressor gene p53. Fourteen thyroid glands from euthyroid cats without histologically detectable thyroid lesions were examined similarly as controls. Results of these investigations showed that all cases of nodular follicular hyperplasia/adenomas stained positively for overexpression of c-ras protein using a mouse monoclonal anti-human pan-ras antibody. The most intensely positively staining regions were in luminal cells surrounding abortive follicles. Subjacent thyroid and parathyroid glands from euthyroid cats did not stain immunohistochemically for pan-ras. There was no detectable staining for either Bc12 or p53 in any of the cats. These results indicate that overexpression of c-ras was highly associated with areas of nodular follicular hyperplasia/adenomas of feline thyroid glands, and mutations in this oncogene may play a role in the etiopathogenesis of hyperthyroidism in cats. As with the study on G protein abnormalities, c-ras mutations could either be an initiating cause of hyperthyroidism or simply mediate the effects of a yet unidentified dietary or environmental initiator.
Alterations in the thyrotropin (TSH) receptor were also examined in cats with hyperthyroidism. The authors used the polymerase chain reaction (PCR) to amplify codons 480–640 of the previously uncharacterized feline thyrotropin receptor (TSHR) gene, and determined the DNA sequence in this transmembrane domain region. They then analyzed single stranded conformational polymorphisms in thyroid DNA from 11 sporadic cases of feline thyrotoxicosis and leukocyte DNA from two cases of familial feline thyrotoxicosis. They also determined the DNA sequence of this region of the TSHR in five of the cases of sporadic feline thyrotoxicosis and the two familial thyrotoxic cats. The normal feline TSHR sequence between codons 480–640 is highly homologous to that of other mammalian TSHRs, with 95%, 92%, and 90% amino acid identity between the feline receptor and canine, human, and bovine TSHRs, respectively. Thyroid gland DNA from 11 cats with sporadic thyrotoxicosis did not have mutations in this region of the TSHR gene. Leukocyte DNA from two littermates with familial feline thyrotoxicosis did not harbor mutations of this region of the TSHR gene. These studies suggested that TSHR gene mutations are likely not involved in feline hyperthyroiodism.
More work is obviously needed to further elucidate the pathogenesis of this common disorder in order to start meaningful work on newer therapies and, most importantly, prevention
2. Laboratory Diagnosis and Laboratory Changes Associated With Hyperthyroidism
In the last few years, it is still apparent that the best test to use in the initial approach to the patient with hyperthyroidism is measurement of total T4 (TT4) concentrations. TT4 testing is simple and inexpensive and will provide the correct diagnosis in the majority of feline patients presented for evaluation. However, we are now faced with attempting to diagnose or confirm hyperthyroidism in cats that are asymptomatic, have only mild clinical signs, and/or have concurrent illness that may affect accurate laboratory assessment of thyroid function. These cases can be very challenging though recent work seems to indicate that measurement of free T4 by equilibrium dialysis (fT4ED) represents the logical next step (though it should be emphasized, not the first step) in the approach to these patients. This approach will likely eliminate the need for additional expensive or problematic tests such as TRH stimulation and T3 suppression testing. We also have seen recent work on the effects of thyrotoxicosis on bone and calcium metabolism and how hyperthyroidism can affect our laboratory assessment of concurrent diseases such as diabetes.
Two excellent papers have assessed the value of fT4ED in the diagnosis of hyperthyroidism in cats and/or the effects of non-thyroidal illness on thyroid function. As is the case in dogs, euthyroid cats with non-thyroidal illness may have a decrease in TT4 levels that is most likely the result of protein binding abnormalities. In a study looking at 98 cats with non-thyroidal illness and 50 normal control pet cats, thyroid function was assessed by measurement of TT4 and fT4ED. T4 concentrations were measured by radioimmunoassay, and serum free T4 concentrations were measured by direct equilibrium dialysis. Serum total T4 concentrations were significantly (P < 0.001) lower in sick cats (mean +/- SD, 17.18 +/- 8.14 nmol/L), compared with healthy cats (mean +/- SD, 26.00 +/- 7.62 nmol/L). Serum total T4 concentrations were inversely correlated with mortality. Differences in serum free T4 concentrations in sick cats (mean +/- SD, 27.70 +/- 13.53 pmol/L) compared with healthy cats (mean +/- SD, 24.79 +/- 8.33 pmol/L), were not significant. A few sick cats had serum free T4 concentrations greater than the reference range. This study showed that as is the case in dogs and man, euthyroidism is maintained in sick cats, despite low serum total T4 concentrations. In addition, measurement of serum total T4 concentrations was a valuable prognostic indicator, as it appeared to be an excellent predictor of mortality. Lastly and perhaps more importantly, with respect to diagnosing hyperthyroidism, some euthyroid older cats have elevated fT4ED concentrations. This would indicate that initial use of fT4ED as a screening test for hyperthyroidism in older cats can lead to false positive results.
One of the challenges in diagnosing hyperthyroidism is the effect of non-thyroidal illness on thyroid function tests in cats with concurrent hyperthyroidism. This was illustrated in a separate study that showed that measurement of fT4ED is only indicated in those cats with clinical signs and a TT4 in the upper 50% of the normal resting range. In cats with TT4 levels in the lower 50% of the resting range hyperthyroidism was not diagnosed in any cat evaluated with fT4ED. It appears that concurrent non-thyroidal illness in some cats with hyperthyroidism may be sufficient to drop TT4 values into the upper half of the normal resting range. In these animals, the fT4ED will be elevated. In our experience, we see this most commonly in cats with moderate to severe GI disease (IBD, lymphoma) or in cats on concurrent glucocorticoids. The biggest challenge to the clinician is on deciding on how to treat such cats appropriately. In general, one must decide what role both diseases are playing with respect to the clinical signs and address each disease separately.
3. Treatment Options
Treatment options involve the use of surgery, medical management, or radioiodine. The choice between these various options is based on the clinical needs of the animal, costs, and the experience of the clinician and/or the availability of radiation. We will review some of the more recent papers on treatment options.
Surgery is a commonly used treatment for hyperthyroidism especially where radioiodine is not available or an option or the cat experiences side effects with long-term oral medical management. Since the first description of feline hyperthyroidism in 1978, numerous treatment options for hyperthyroidism have been reported. Surgical removal of enlarged, autonomously functioning thyroid glands is one of the most commonly used treatment options. Affected cats must have a careful pre-operative evaluation to detect concurrent medical conditions such as renal disease or cardiomyopathy. Since more than 80% of hyperthyroid cats have neoplastic changes in both thyroid glands, bilateral thyroidectomy is necessary for treatment of the majority of hyperthyroid cats. Several different thyroidectomy techniques have been developed in an attempt to minimize potential post-operative complications associated with bilateral thyroidectomy such as hypocalcemia or recurrence of hyperthyroidism. Damage to or removal of all four parathyroid glands during bilateral thyroidectomy causes hypocalcemia, the most common post-operative complication.
This complication was recently addressed by looking at the efficacy of autotransplantation of parathyroid tissue in normal cats. Eight, healthy, adult, random-source cats underwent bilateral thyroidectomy and parathyroidectomy with parathyroid autotransplantation to mimic a clinical situation. Serum calcium concentrations normalized much more quickly than they did in previously reported cats undergoing bilateral thyroidectomy and parathyroidectomy. Parathyroid autotransplantation greatly reduced morbidity in the parathyroidectomized cat. Transplanted normal thyroid tissue was present in at least three of eight cats with thyroparathyroidectomy with auto-transplantation. This would indicate that when performing this procedure in hyperthyroid cats, it would be important to remove all associated thyroid tissue to prevent the possible recurrence of hyperthyroidism.
Due to the incidence of GI side effects in cats treated with methimazole (10-20%) and the problems with carbimazole availability in the United States, preliminary studies have been done on alternative medications. One study involved the use of ipodate. Ipodate is an iodine-containing contrast agent that has the ability of inhibiting the peripheral conversion of T4 -> T3. This is similar to the effects of propranolol on thyroid function. In the study from AMC, 12 cats with hyperthyroidism initially received 100 mg of ipodate q24h PO. The drug's effects on clinical signs, body weight, heart rate, and serum triiodothyronine (T3) and thyroxine concentrations were evaluated 2, 4, 6, 10, and 14 weeks after initiation of treatment. A CBC and serum biochemical analyses were performed at each evaluation to monitor potential adverse effects of the drug. Dosage of ipodate was increased to 150 mg/d and then to 200 mg/d at 2-week intervals if a good clinical response was not observed. In this study, eight cats responded to treatment and four did not.
Among cats that responded, mean body weight increased and mean heart rate and serum T3 concentration decreased during the study period. Among cats that did not respond, mean body weight decreased and mean heart rate and serum T3 concentration were not significantly changed. Serum thyroxine concentration remained high in all cats. Adverse clinical signs or hematologic abnormalities attributable to ipodate treatment were not reported in any of the cats. Ipodate may be a feasible alternative to methimazole for medical treatment of hyperthyroidism in cats, particularly those that cannot tolerate methimazole and are not candidates for surgery or radiotherapy.
Cats with severe hyperthyroidism are less likely to respond to ipodate than are cats with mild or moderate disease; cats in which serum T3 concentration does not return to the reference range are unlikely to have an adequate improvement in clinical signs. Since the publication of the study, ipodate is no longer available in the US. However, a similar product iopanoic acid (Telepaque) is available through compounding pharmacies. Like ipodate, iopanoic acid is an inhibitor of the peripheral conversion of T4 -> T3.
No published studies currently exist on the efficacy of iopanoic acid though in the author’s experience the dose, efficacy and side effects appear to be similar to those reported with ipodate. As was the case with ipodate, animals that have been treated with iopanoic acid will likely need to have the medication discontinued prior to the administration of radioiodine therapy as both medications do have an effect on thyroid iodine uptake.