Feline hyperthyroidism (Proceedings)

Introduction

A. The most common endocrine disorder in the cat.

B. First cases of functional thyroid tumors reported in 1978.

Etiology

A. Thyroid adenoma or adenomatous hyperplasia.

B. 80 % are bilateral on presentation.

C. 12% due to thyroid carcinoma.

D. Etiology unknown:

Two recent large studies have looked at possible environmental or dietary factors involved in the pathogenesis of hyperthyroidism. One of the studies with a case controlled design looked at 100 cats with hyperthyroidism 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 to include the 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 may 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. 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 2-fold increase in risk of disease. When these 4 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, a persistent protective effect of breed (Siamese or Himalayan) was found. In addition, results suggested a 2- to 3-fold increase in risk of developing hyperthyroidism among cats eating a diet composed mostly of canned cat food and a 3-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 8 hyperthyroid cats and thyroid glands obtained from 4 age-matched euthyroid cats were examined for expression of G inhibitory protein (Gi) and G stimulatory protein (Gs). 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 2 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 immunohistochemically 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 from 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 indicated 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.

Signalment

A. No sex or breed predilection.

B. Average age 13 years.

C. Age range 424 years.

Clinical signs

A. Weight loss

B. Polyphagia

C. Polydipsia

D. Diarrhea

E. Hyperactive

F. Vomiting

G. Bulky, foul smelling stool.

H. In about 10% of cats, apathetic hyperthyroidism is seen with clinical signs dominated by extreme lethargy and weakness, weight loss with anorexia, and cardiac abnormalities.

Many cats are now asymptomatic at the time of diagnosis due to the increased screening of senior cats with TT4 levels.

With time we have seen both an increase in the diagnosis of hyperthyroidism as well as a decrease in the severity of the clinical signs associated with thyrotoxicosis. This is most likely due to an increased awareness on the part of the pet owner and the veterinarian as well as the increased use of T4 concentrations as an integral part of routine feline health screening. We have also seen additional work on some of the less obvious manifestations of hyperthyroidism such as hypertension which may be clinically silent and/or present initially with ocular signs, as well as the effects of hyperthyroidism on the cardiovascular and renal system (to be discussed later).

The presence of ocular abnormalities in cats with hyperthyroidism was evaluated in 10 hyperthyroid cats and 30 clinically normal, geriatric cats. In both groups, ophthalmic examination was performed by use of slit-lamp biomicroscopy and indirect ophthalmoscopy after application of 1% tropicamide to dilate the pupil. Ocular abnormalities were common in both the hyperthyroid and euthyroid cats. Approximately 75% of all eyes were affected with one or more abnormalities, and the range of abnormalities involved all structures of the eye. Significant differences between the euthyroid and hyperthyroid cats were found in the prevalence of prominent suture lines, nonpigmented deposits on the posterior lens capsule, hyperreflective ring around the optic nerve, and hyperpigmentation of the area centralis, but all of these abnormalities were more common in the euthyroid cats than in the cats with hyperthyroidism. Active retinal lesions were only observed in 3 hyperthyroid cats (3%). The results of this study indicated that hyperthyroidism does not seem to be a frequent cause of abnormalities in the eyes of cats. However, none of the cats in this study had blood pressure measurements.

Another paper looked at ocular lesions associated with hypertension in cats and included cats with hyperthyroidism. Sixty-nine cats with hypertensive retinopathy were evaluated. Most cats (68.1 %) were referred because of vision loss; retinal detachment, hemorrhage, edema, and retinal degeneration. Cardiac abnormalities were detected in 37 cats, and neurologic signs were detected in 20 cats. Hypertension was diagnosed concurrently with chronic renal failure (n = 22), hyperthyroidism (5), diabetes mellitus (2), and hyperaldosteronism (1). A clearly identifiable cause for hypertension was not detected in 38 cats; 26 of these cats had mild azotemia, and 12 did not have renal abnormalities. Amlodipine decreased blood pressure in 31 of 32 cats and improved ocular signs in 18 of 26 cats. The authors concluded that blood pressure measurements and funduscopic evaluations should be performed routinely in cats at risk for hypertension (preexisting renal disease, hyperthyroidism, and age > 10 years). Amlodipine was an effective antihypertensive agent in cats although the choice of a beta blocker vs a calcium channel blocker should take into consideration the presence of concurrent disease and concomitant medications.

As stated earlier, the clinical signs associated with hyperthyroidism have been deceasing in severity over the years. A paper examined the electrocardiographic and radiographic changes seen in hyperthyroid cats today versus those seen 10-12 years ago. Two populations (1992 to 1993 and 1979 to 1982) of confirmed hyperthyroid cats were compared to determine whether the incidence of certain cardiovascular specific manifestations of feline thyrotoxicosis had experienced similar changes. Sinus tachycardia, which is the most commonly recognized cardiac manifestation of feline thyrotoxicosis, was not as prevalent in the 1993 group when compared to the 1982 group. This was also true for the finding of an increased R-wave amplitude on lead II electrocardiography. Both groups had a similar low incidence of atrial and ventricular dysrythmias; however, the 1993 group had a significantly higher occurrence of right bundle branch block. Thoracic radiographs were deemed necessary in a larger proportion of the 1982 group when compared to the 1993 group. Although there were no significant differences in radiographically defined cardiac size between the two groups, a larger number of cats in the 1982 group had evidence of congestive heart failure. These findings suggest that feline hyperthyroidism is being diagnosed earlier and with less severe clinical signs than when studied a decade ago.

Physical examination

A. Palpable thyroid gland(s). Normal thyroids can not be felt.

B. An enlarged gland may be found at the thoracic inlet

C. Cardiac examination:

1. Tachycardia > 220 BPM.

2. Murmurs. Be sure to listen over the sternum.

3. Gallop rhythms.

D. Dehydration/emaciation

E. Small kidneys

1. Common in older cats.

2. Renal disease and hyperthyroidism both cause PU / PD.

3. Will need to monitor renal function to differentiate the two.

Over the last ten years with increased awareness of the disease and the ease of diagnosis the clinical signs have become less dramatic as more cats are diagnosed and treated earlier.

Differential Diagnosis

A. Diabetes mellitus

B. Renal disease

C. Liver disease

D. Heart disease

E. Gastrointestinal disease

1. Pancreatic exocrine insufficiency.

2. Inflammatory bowel disease.

3. GI lymphosarcoma

Laboratory Abnormalities

A. PCV and RBC may be increased due to dehydration.

B. Urinalysis

1. Decreased concentrating ability.

2. Presence of concurrent renal disease.

C. Serum biochemistry profile

1. Elevated SAP, SGPT (5075%)

a. Liver function is normal.

b. Will decrease following treatment.

2. Elevated BUN and creatinine (3040%)

a. Most are increased secondary to dehydration.

b. Will need to be reevaluated posttreatment as up to 5% of cats treated for hyperthyroidism (any form of therapy) will develop progressive renal insufficiency.

3. Hyperphosphatemia (20%)

a. Felt to be due to increased bone turnover.

i. Fructosamine

Serum fructosamine concentrations in cats are thought to reflect the mean blood glucose concentration of the preceding one to two weeks. However, fructosamine concentrations are affected by the concentration and metabolism of serum proteins. Hyperthyroidism can have a profound effect on protein metabolism and therefore, possibly on serum fructosamine concentrations. In one study, 22 cats, ranging in age from 8 to 20 years, were diagnosed with hyperthyroidism, based on clinical signs of hyperthyroidism, detection of a palpable thyroid gland, and a serum thyroxine (T4) concentration >45 nmol/L. Blood glucose, total protein (TP), and albumin concentrations were within their respective reference ranges. Results for the 22 hyperthyroid cats were compared with those of 42 healthy control cats, 10 newly diagnosed diabetic cats, and nine cats with hypoproteinemia. Serum T4 concentrations ranged from 46-475 nmol/L (median, 86 nmol/L). Serum fructosamine concentrations of hyperthyroid cats were between 154-267 umol/L (median, 198 umol/L), significantly less than those of healthy cats. Serum fructosamine concentrations in cats with hypoproteinemia ranged from 124-254 umol/L (median, 174 umol/L) and were significantly less than those of healthy cats. Serum fructosamine concentrations did not differ between hypoproteinemia and hyperthyroid cats. In hypoproteinemic cats, concentrations of serum TP and albumin were significantly lower than those in hyperthyroid cats, while blood glucose concentrations did not differ between the two groups of cats. Serum fructosamine concentrations of diabetic cats were significantly increased, compared with those of healthy cats, hypoproteinemic cats, and cats with hyperthyroidism. After two weeks of carbimazole treatment in six of the hyperthyroid cats, serum fructosamine concentrations were not significantly different from the initial concentrations. After six weeks of carbimazole treatment, serum fructosamine concentrations were significantly higher than the initial concentrations. Serum T4 concentrations were significantly decreased at both two and six weeks after initiating treatment. The authors concluded that concentrations of serum fructosamine are lower in cats with hyperthyroidism independent of blood glucose concentrations. In the clinical setting this means that serum fructosamine concentration should not be used to initially diagnose or assess the adequacy of diabetic control in cats with concurrent hyperthyroidism in which the hyperthyroidism has not been controlled for at least six weeks.

In another paper fructosamine levels were evaluated in 30 non-diabetic hyperthyroid cats pre and 30 days post treatment with radioiodine and compared to normal control cats. Fructosamine levels were significantly lower in the hyperthyroid cats both pre and post treatment with radiodine. However, treatment was associated with a statistically significant increase in the fructosamine concentration. This paper, like the paper above in cats with diabetes, shows that fructosamine concentrations in hyperthyroid cats will be lower than non-hyperthyroid cats (normal or diabetic) and that this effect is likely due to the effects of hyperthyroidism on protein turnover.

Cardiac Evaluation

Important to assess in animals with clinical signs or abnormalities on physical examination prior to deciding on optimal therapy and to differentiate thyrotoxic heart disease from the two primary feline myocardial diseases, hypertrophic and dilated cardiomyopathy.

A. Radiographs

1. 20 – 30 % have cardiomegaly.

2. < 5 % show signs of failure (pleural effusion, edema).

B. EKG

1. Tachycardia and increased R wave amplitude the most common abnormalities.

C. Ultrasound

1. The best way to differentiate between primary and secondary cardiac disease.

Diagnosis

A. Elevated T4 concentration. Measurement of T3 of little help.

B. May be able to palpate a thyroid nodule before the T4 is elevated. Recheck T4 3 every 3 – 6 months or when signs occur.

C. Occasionally cats with hyperthyroidism may have a T4 in the normal range at the time of sampling. This is especially true in cats with mild hyperthyroidism. A second sample may be needed in those cats with strong clinical evidence of thyrotoxicosis. The second sample should be taken a few days to weeks later, as more pronounced fluctuations in thyroid hormone levels occur over days rather than hours. Nonthyroidal illness may also result in highnormal serum T4 concentrations even in the face of hyperthyroidism. Following correction of the underlying illness or discontinuation of medications, T4 levels will increase into the hyperthyroid range.

In animals in which hyperthyroidism is suspected, but the basal T4 levels are consistently normal, four additional tests can be considered.

1. T3 Suppression Test:

a. Basis of the Test: The normal pituitarythyroid axis will be suppressed following supplementation with T3. A decrease in TSH concentration will lead to a decrease in T4 levels.

b. Performing the Test

i. Determine basal T4 level.

ii. Administer T3 (25 µg) every 8 hours for two days, giving the last dose on the morning of day 3.

iii. Determine T3 and T4 concentrations 4 hours following the last dose of T3.

iv. Normal cats:

1. T4 levels suppress greater than 50% from pretreatment value.

2. TRH Stimulation Test:

a. Basis of the Test: TRH is the hypothalamic peptide that regulates TSH release from the pituitary. TSH response to TRH is blunted in patients with hyperthyroidism.

b. Performing the Test:

i. Obtain basal T4 level.

ii. Administer 0.1 mg/kg TRH IV.

iii. Obtain 4 hour post TRH T4.

iv. Normal cats:

1. Twofold rise in T4 post TRH

2. Hyperthyroid cats have minimal to no increase in T4.

c. Free T4

i. In cats where the TT4 is in the upper 50% of the basal resting range, an elevated fT4ED in the face of clinical signs is highly predictive of hyperthyroidism. Use of fT4ED should not be used as the initial screening test as some euthyroid senior cats have have elevated fT4ED. Due to the simplicity of the test, fT4ED should be the first line test in diagnosing cats with hormonally occult (normal TT4) hyperthyroidism.

d. Imaging

i. Technetium scans may be helpful in hormonally borderline cases where bilateral uptake is clearly increased or unilateral disease is present.

Summary

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 assesses 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. In a recent very large study TT4, ft4ED and T3 concentrations were measured in 917 cats with hyperthyroidism, 221 cats with non-thyroidal illness, and 172 clinically normal cats. Ft4ED was significantly more sensitive (0.985) then TT4 (0.913) as a diagnostic test for hyperthyroidism, however of the 221 cats with non-thyroidal illness, 12 cats had a high fT4ED (false postive). Therefore the calculated specificity of fT4ED as a diagnostic test for hyperthyroidism was significantly lower (0.937) than the specificity of TT4 (1.0). This study indicates 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. 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.

We have known for a long time that many cats with hyperthyroidism have elevated ALP and/or ALT concentrations. Bile acids and liver biopsies in these cats are generally clinically insignificant and the abnormalities resolve after treatment of the hyperthyroidism in the majority of cats. We have also seen cats with hypercalcemia and hyperthyroidism. The Ca abnormalities appear to correct following successful treatment and no other cause for the hypercalcemia has been found. Several recent papers have examined the effects of hyperthyroidism on bone and calcium metabolism in hyperthyroid cats.

One paper investigated the tissue sources of ALP in cats with hyperthyroidism. Alkaline phosphatase as measured in the serum is made up of enzymes that arise from the liver, bone, and intestine as well as other tissues. The source of elevated ALP in hyperthyroid cats has been suggested to be from liver and bone. In this paper isoenzymes of ALP were measured by serum electrophoresis in five normal cats and in 34 cats with hyperthyroidism. Homogenates of kidney, intestine, bone, and liver were subjected to electrophoresis to identify and quantify isoenzymes of alkaline phosphatase. The highest concentration of alkaline phosphatase was found in kidney, followed by intestine, liver, and bone in descending order of concentration. The liver isoenzyme was the only type identified in the serum of normal cats. Serum total ALP activity was elevated in 53% of hyperthyroid cats. Thirty of the 34 hyperthyroid cats had two main isoenzyme bands on electrophoresis corresponding to liver and bone isoenzymes. There was significant correlation between total T4 and total serum ALP concentration and T4 and liver isoenzyme concentration, but not T4 and bone isoenzyme concentrations in hyperthyroid cats. The proportion of bone and liver isoenzyme in sera of hyperthyroid cats varied considerably, with the liver isoenzyme making up 17 to 100% of the ALP and bone 0 to 74% of ALP. The authors concluded that abnormalities in bone and liver account for the elevations in serum ALP found in hyperthyroid cats. This paper is relevant as it points out that clinicians should evaluate thyroid function in an older cats with a high ALP. Although bone disease has not been reported in cats with hyperthyroidism it is likely that the high bone ALP activity is related to increased bone turnover. This was reinforced in 2 papers looking at bone turn over and Ca metabolism in hyperthyroid cats.

The effect of hyperthyroidism on serum markers for increased bone metabolism and turnover was evaluated in 36 cats with elevated serum levels of thyroxine and alkaline phosphatase. Serum was analyzed for total and iCa and phosphorous. Alkaline phosphatase isoenzymes were separated by agarose gel electrophoresis and osteocalcin was measured by radioimmunoassay. Values for hyperthyroid cats were compared with those for healthy cats. Alkaline phosphatase bone isoenzyme was markedly increased in all 36 hyperthyroid cats. Osteocalcin was increased in 44% of the cats. There was no correlation among the magnitude of increase in alkaline phosphatase bone isoenzyme, osteocalcin, and serum thyroxine concentrations. Increased serum phosphorus was found in 35% of the cats. Total calcium was within the reference range in all cats, while 50% of the cats had reduced levels of serum iCa. While clinically insignificant the study provided evidence that bone turnover is increased (as assessed by osteocalcin levels) in hyperthyroid cats. The finding of low iCa in 50% of the cats is interesting and should be repeated in other studies looking at PTH levels in thyrotoxicosis.

One recent paper did just that by looking at parathyroid (PTH) and iCa concentrations in hyperthyroid vs normal cats.They looked at 30 cats with untreated hyperthyroidism and 38 age-matched control cats. The hyperthyroid group of cats were found to have significantly lower blood iCa and plasma creatinine concentrations and significantly higher plasma phosphate and parathyroid hormone concentrations. Hyperparathyroidism occurred in 77 per cent of hyperthyroid cats, with parathyroid hormone concentrations reaching up to 19 times the upper limit of the normal range. The etiology, significance and reversibility of hyperparathyroidism in feline hyperthyroidism remains to be established but could have important implications for both bone strength and renal function. The decreased creatinine concentrations found in the hyperthyroid cats may be due to either increased GFR or decreased muscle mass though this was not evaluated in this study. We will examine the effects of thyrotoxicosis on renal function at the end of this section.

We will continue to learn more about the importance of hyperthyroidism on both clinical and laboratory findings. As many of our hyperthyroid patients are senior and are likely to have concurrent disease it will be very important to look at these interrelations in more detail.

Treatment

A. Surgery

i. A number of articles have been written on the technique.

ii. Thyroid scans, if available can be very helpful to the surgeon:

1. Identify unilateral vs bilateral disease.

2. Identify ectopic or metastatic thyroid tissue.

iii. A number of important points to be remembered are:

1. Treat the hyperthyroidism medically for 46 weeks prior to surgery. These cats are anesthetic risks until euthyroid.

2. All abnormal thyroid tissue should be removed. If thyroid scanning is not available and at the time of surgery you can see both thyroid glands, remove both of them. Normal thyroid tissue would have atrophied due to the increased level of T4.

3. Some clinicians have advocated staged thyroidectomies though no studies have been published. Staged procedures should decrease the risk of hypoparathyroidism but they may also result in the need for a second surgical procedure to correct recurrent hyperthyroidism.

iv. Disadvantages of surgery

1. Poor surgical risk due to concurrent illnesses.

2. Potential for iatrogenic hypoparathyroidism, Horner's syndrome, laryngeal paralysis.

v. Advantages of surgery

1. Relatively inexpensive.

2. Surgical procedure is not difficult.

vi. Postsurgery

1. Do not get overzealous with fluid therapy.

2. If bilateral thyroidectomy, measure serum calcium once daily for 7 days.

3. Signs of hypocalcemia include facial muscle twitching, ear twitching, rubbing of the face, generalized muscle fasiculations, and seizures.

4. Therapy for hypocalcemia (also see Hypoparathyroidism)

a. DHT (Dihydrotachysterol) 0.03 mg/kg daily

b. Ca gluconate tablets (13/day)

c. For acute hypocalcemic tetany:

i. 1 cc/kg of calcium gluconate (10%) IV slowly over 10 – 20 minutes.

ii. EKG monitoring advisable.

iii. Do not use calcium chloride

d. Also consider using 5 – 15 ng/kg of calcitriol once a day for vitamin D supplementation.

Recently, ethanol ablation of thyroid adenomas has been reported. Results are preliminary but treatment was successful in eliminating clinical signs and lowering TT4 levels. This option may be used more frequently in the future as experience with the technique increases.

B. Antithyroid medications

i. Medications include propylthiouracil (PTU), methimazole (Tapazole), carbimazole ( a prodrug to methimazole and not yet available in this country).

ii. Act by blocking intrathyroidal conversion of iodothyronines into T3 and T4.

iii. Due to incidence of sideeffects with PTU (hemolytic anemia, thrombocytopenia) Tapazole is most frequently employed.

iv. Animals developing sideeffects to one of these medications should not be treated with the other as crosssensitivity can occur. Sideeffects with Tapazole usually occur within the first month of therapy and include GI upset (anorexia and vomiting are the biggest problems), and agranulocytosis. Reactions usually subside within 2 weeks after stopping medication.

Protocol for Tapazole

1. CBC and platelet count.

2. Start Tapazole

a. mg SID to BID.

3. Recheck TT4 and BUN/creatinine in 7 – 10 days.

4. Check CBC and platelet count every 714 days for the first 30 days.

5. Stop therapy if problems arise (vomiting, diarrhea, leukopenia).

6. Monitor T4 every 23 months or when signs of hypo or hyperthyroidism occur.

A. Advantages to medical therapy

a. Inexpensive (in the short term)

b. Simple and effective

B. Disadvantages

a. Owner compliance.

b. Sideeffects (anorexia in up to 15%).

C. Other medications:

a. Atenolol

i. 1. Beta blocker used to slow heart rate.

ii. 2. 6.25 – 12.5 mg BID.

iii. 3. Use with Tapazole.

iv. 4. Used primarily for short term stabilization prior to definitive therapy.

b. Iopanoic acid (Telepaque)

i. 1. Oral iodine containing contrast agent.

ii. 2. Blocks peripheral conversion of T4 to T3.

iii. 3. Dose is 50 – 200 BID PO.

iv. 4. Have to monitor clinical signs and T3 levels as T4 levels will stay high or increase.

v. 5. Safe, few to no side-effects .

vi. 6. Effective in 60 – 70 % of cats with mild to moderate elevations in TT4.

D. Radioactive Iodine

a. Thyroid concentrates iodine and radioactive iodine will destroy the functioning thyroid cells without destroying non-thyroidal tissue or normal suppressed thyroid tissue.

b. Advantages

1. 95% effective

2. No problem with parathyroid gland function.

3. No anesthesia, no surgery, no pills.

4. T4 normal in 710 days

c. Disadvantages

1. Requires referral centers capable of handling I131

2. Cat needs to be hospitalized while radioactive

3. Usual stay is 13 weeks

4. Fixed dose therapy has allowed for greater use.

Summary

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 treatments 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 or heart disease. Since more than 80% of hyperthyroid cats have 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 quicker than concentrations 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 its important to remove all associated thyroid tissue to prevent the possible recurrence of hyperthyroidism.

Some have been advocating the use of sequential removal of bilaterally affected thyroid glands. Staging a bilateral thyroidectomy presumably allows time for ipsilateral parathyroid tissue to revascularize before the second thyroid gland is removed and the blood supply to the contralateral parathyroid glands is potentially interrupted. However little information has been published to show the long term efficacy and safety of staged thyroidectomies.

Medical management of hyperthyroidism revolves around the use of Tapazole (methimazole), carbimazole (available in Europe and a pro-drug to methimazole) and recently iodine containing agents such as ipodate, iopanoic acid and iodate. These may be used alone or in conjunction with beta blockers such as propranolol.

A study from Australia confirmed the efficacy and safety of carbimazole in the medical management of hyperthyroidism and again showed that the severity of the symptoms of thyrotoxicois appears to be decreasing over time.Twenty-five cats diagnosed as hyperthyroid during a 23-month period participated in the study with owner consent. Therapy with carbimazole was instituted and rechecks were scheduled 2, 6 and 13 weeks after diagnosis. The cats were physically examined and underwent hematological and serum biochemical testing at each re-examination. Owners were also asked to assess clinical signs in their cats in the periods between veterinary examinations. Cats with underlying renal disease were managed by alterations or cessation of carbimazole therapy. A high prevalence of lethargic or inappetent cats without detectable underlying nonthyroidal illness was found. There was also a high prevalence of cats less than 10-years-old and cats in good body condition. Fourteen cats treated with carbimazole and monitored for 13 weeks responded favorably to therapy. Side-effects were minor and uncommon. Cats with underlying renal disease that became apparent during the study, responded well to alterations or cessation of carbimazole therapy.

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 to 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/d, 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, 8 cats responded to treatment and 4 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, and 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 to 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.

Another recent study looked at the combination of potassium iodate and propranolol in cats with hyperthyroidism prior to surgical treatment. Iodate appears to affect thyroid metabolism by blocking the uptake of iodine and leading ultimately to a decrease in TT4 synthesis. Eleven cats (group A) received propranolol from days 1 to 10, followed by propranolol and potassium iodate from days 11 to 20. Ten cats (group B) received the reverse regimen. Group A cats were initially treated with propranolol alone at 2.5 mg, every eight hours. If the heart rate was greater than 200 beats/min after four days, the dose was increased to 5 mg every eight hours, and if it was still more than 200 beats/min on day 7, the dose was increased to 7.5 mg every eight hours. Group B received potassium iodate (42.5 mg, every eight hours) alone on day 1-10, then propranolol was added using the same treatment regimen as Group A. Surgery was carried out on day 21 and propranolol was continued for three days after surgery. Potassium iodate caused intermittent anorexia, vomiting, and mild depression in some cats. When this occurred (seven cats in Group A, six cats in Group B), the dose was reduced to 21.25 mg every eight hours. Blood samples were taken daily for subsequent determination of serum total L-thyroxine (TT4), L-triiodothyronine (TT3) and reverse T3 (rT3) concentrations. The signs of hyperthyroidism improved in all cats over the treatment period. At surgery, 36 per cent of the cats in group A had normal serum TT4 concentrations, while 89 per cent with initially elevated TT3 concentrations had normal concentrations. In group B, 10 per cent of the cats had normal TT4 concentrations, while 75 per cent with initially elevated TT3 concentrations had normalization. The drug regimen used in group A was better tolerated and more effective in normalizing thyroid levels. This approach offers a medial alternative to those cats that cannot tolerate treatment with carbimazole or methimazole. In this study all the cats underwent thyroidectomy, so none were able to be evaluated for long term medical control with this protocol. In addition, the use of iopanoic acid with propranolol should also be investigated as it appears to have fewer GI and hepatic side effects then iodate.

Radioiodine therapy appears to be the safest and most effective form of therapy for hyperthyroidism. Radioiodine may be administered by IV, SQ and PO routes. While all appear effective, the use of oral administration is discouraged due to the risk of exposure and environmental contamination. The largest study on the safety and efficacy of radioiodine treatment was conducted with 524 cats. A scoring system based on 3 factors (severity of clinical signs, size of the thyroid gland, and magnitude of the serum T4 concentration) was used to select the dose of radioiodine to be administered subcutaneously. On the basis of the scoring system, 310 (59%) cats were treated with a low dose of radioiodine (2.5 to 3.4mCi: median, 3.0 mCi), 158 (30%) were treated with a moderate dose (3.5 to 4.4 mCi; median, 4.0 mCi), and 56 (11%) were treated with a high dose (4.5 to 5.4 mCi; median, 5.0 mCi). At time of discharge from the hospital, serum T4 concentration was still high in 80 (15.3%) cats, but by 6 months after administration of radioiodine, the serum T4 concentration had decreased to within or below reference range in all but 8 (1.5%) cats with persistent hyperthyroidism. Many cats had low serum T4 concentrations at some time after radioiodine treatment, but only 11 (2.1%) cats developed clinical and clinicopathologic features of hypothyroidism and required supplementation with L-thyroxine. Thirteen (2.5%) cats had a relapse of hyperthyroidism 1.1 to 6.5 years after initial radioiodine treatment. Overall, the response to treatment was considered good in 94.2% of the cats. Median survival time in the cats was 2.0 years; the percentage of cats alive after 1, 2, and 3 years of treatment was 89, 72, and 52%, respectively.

Cats with thyroid carcinoma are also candidates for radioiodine therapy especially following surgical debulking. Seven cats with thyroid carcinomas that had previously undergone surgical removal of neoplastic tissue were treated with 30 mCi of radioactive iodine (131I). Six of the cats had clinical signs of hyperthyroidism; 1 did not. There were no complications associated with 131I treatment, and clinical signs resolved in all cats. Technetium scans of 4 cats made after treatment did not have evidence of isotope uptake. In the remaining 3 cats, small areas of isotope uptake, the intensity of which was equal to or less than the intensity of uptake in the salivary glands, were seen. All 7 cats became hypothyroid after treatment; 4 required L-thyroxine supplementation. One cat was alive 33 months after treatment. The other 6 cats were euthanatized because of unrelated diseases 10 to 41 months after treatment.

Most doses of radioiodine are determined either from past experience, a combination of clinical and hormonal data (as above) or by determination of radioiodine uptake and thyroid volume in a given patient. A recent study looked at the practicality and accuracy of thyroid volume estimates in cats with hyperthyroidism as a means of calculating the dose of radioiodine. Hyperthyroidism was diagnosed in 80 cats with thyroid scintigraphy using technetium pertechnetate. These cats were subsequently treated with radioiodine using a modified fixed dose method based on the volume of hyperfunctioning thyroid tissue calculated from the pertechnetate scans. The medical records and thyroid scintigrams were evaluated retrospectively. Follow-up was obtained on the cats to evaluate treatment success. Several parameters were evaluated in an attempt to identify a difference between treatment success and failure. Cats that failed to become euthyroid after one dose of radioiodine had a significantly higher pretreatment serum thyroxine level, had a significantly larger volume of hyperfunctioning thyroid tissue on scintigrams, and were more likely to have received oral radioiodine therapy. Based on these results the authors concluded that the administration of a dose of radioiodine based solely on the volume of hyperfunctioning thyroid tissue as estimated from the pertechnetate scan may be inadequate for those patients with extremely elevated serum thyroxine levels or large thyroid glands, and that oral administration of radioiodine should not recommended for the treatment of feline hyperthyroidism.

Recently novel non-medical treatments for hyperthyroidism have been attempted with the use of ethanol ablation of thyroid nodules. This is done under US guidance with the animals under heavy sedation. In one case-report an 8 ½ year old female spayed domestic shorthair was treated with intrathyroid injections of ethanol. The cat had been only partially responsive to I131 treatment 4 weeks previously. The percutaneous ethanol injections were given 4 times over a 6-week period. The cat became acutely dyspneic shortly after the last treatment. Bilateral laryngeal paralysis was diagnosed and surgically corrected. Repeated serum thyroxine measurements and thyroid scintigraphy showed a marked decrease in the size and function of the treated thyroid lobe. A more recent paper described the use of ethanol ablation in 4 cats. All cats had increased serum thyroxin (T4) concentrations (4.0,5.2, 7.0, and 8.4 mg/dl, reference range: 1.1-3.9 mg/dl), a palpable thyroid nodule and clinical signs consistent with hyperthyroidism. Unilateral disease was diagnosed based on nuclear scintigraphy with unilateral uptake of pertechnetate ( 99m Tc). An enlarged solitary thyroid mass was identified ultrasonographically in all 4 cats using a 10MHz transducer. One cat had a mass with a cystic appearance. The thyroid mass volumes were 0.20, 0.33, 0.74, and 0.84 cm3 . Intravenous propofol sedation was utilized to prevent movement during the injection procedure which lasted approximately 10minutes. A 27 gauge needle was inserted into the thyroid mass with ultrasound guidance. Ethanol (96%) was slowly injected until diffusion throughout the mass was observed or a volume of ½ of the calculated mass volume was achieved. All 4 cats received a single injection. Serum T4 and free T4 concentrations became normal or subnormal in all cats within 48 hours of the injection. These values remained below or within the reference range for the duration of the 6 month study. All clinical signs of hyperthyroidism were reported by the owners to have resolved within one week of the treatment. No cats exhibited clinical signs of hypothyroidism or required thyroid supplementation. Repeat nuclear scintigraphy performed in all cats 3 months after the injection procedure was normal in 1 cat and showed evidence of faint residual increased 99m Tc uptake in 3 cats. No severe biochemical or clinical complications were observed as a result of the injection or during the study. A transient voice change was noted by the owners of 2 out of the 4 cats. This occurred within a few days of the injection and resolved 6-8 weeks later.

Ultrasound guided heat ablation of thyroid nodules is also being investigated as a treatment for hyperparathyroidism and its use has been recently described in dogs with primary hyperparathyroidism. The use of ethanol and heat ablation for hyperthyroidism will likely have limited use given the success of medical and radioiodine therapy

Renal Disease and Hyperthyroidism

It had been recognized that many cats following successful treatment for hyperthyroidism experienced a decrease in renal function although only a small percentage of cats experienced severe azotemia or clinical signs. The first paper to look at the effect of treatment of renal function examined 58 hyperthyroid cats. Urine specific gravity, serum creatinine (SCr), BUN, and T4 concentrations were determined before and 30 and 90 days after treatment of hyperthyroidism with radioactive iodine, methimazole, or surgical bilateral thyroidectomy. Mean SCr and BUN concentrations determined 30 and 90 days after treatment were significantly higher than those measured before treatment. Mean SCr, BUN, and T4 concentrations were not different among groups before treatment or 30 and 90 days after treatment. This was important as it showed that the treatment itself was not the problem rather the worsening azotemia may have been the result of reversal of the hyperthyroid and hypermetabolic state. Reduction of serum T4 concentrations after treatment of hyperthyroidism may result in azotemia in older cats with chronic renal disease. The authors concluded that treating azotemic (or in fact all) hyperthyroid cats with methimazole until it can be determined whether correction of the hyperthyroid state will result in clinically significant reductions in renal function, may be prudent.

Similar result were found in another study of 22 cats treated with radioiodine alone. Serum T4, SCr, BUN and urine specific gravity were measured before treatment and 6 and 30 days after treatment. Twenty-two cats had pretreatment and 21 cats had 6 day post-treatment measurement of glomerular filtration rate (GFR) using nuclear medicine imaging techniques. There were significant declines in serum T4 at 6 days following treatment, but the changes in GFR, SCr and BUN were not significant. At 30 days following treatment, there were significant increases in BUN and serum creatinine and further significant declines in serum T4. Nine cats were in renal failure prior to treatment and 13 cats were in renal failure 30 days following treatment. Renal failure was defined as BUN greater than 30 mg/dl and/or serum creatinine greater than 1.8 mg/dl with concurrent urine specific gravity less than 1.035. These 13 cats included eight of 9 cats in renal failure prior to treatment and 5 cats not previously in renal failure. Follow up information beyond 30 days following treatment on 9 of these 13 cats indicated that all remained in renal failure. Based on analysis of pretreatment glomerular filtration rate (GFR) in predicting post-treatment renal failure, a value of 2.25 ml/kg/min as a point of maximum sensitivity (100%) and specificity (78%) was derived. Fifteen of 22 cats had pretreatment GFR measurements of less than 2.25 ml/kg/min. These 15 cats included all 9 cats in renal failure and 5 cats with normal renal clinicopathologic values prior to treatment. At 30 days following treatment, 13 of these 15 cats were in renal failure. The 2 cats not in renal failure had persistently increased serum T4 values. Seven of 22 cats had pretreatment GFR measurements greater than 2.25 ml/kg/min. None of these 7 cats was in renal failure at 30 days following treatment. It was concluded that significant declines in renal function occur after treatment of hyperthyroidism and this decline is clinically important in cats with renal disease. Pretreatment measurement of GFR is valuable in detecting subclinical renal disease and in predicting which cats may have clinically important declines in renal function.

The effects of methimazole therapy on renal function was examined in 12 hyperthyroid cats. The study assessed renal function with a single-injection plasma iohexol clearance (PIC) test ( a measurement of GFR), along with routine serum biochemical and urine analyses, before and after treatment with methimazole. Twelve cats with naturally occurring hyperthyroidism were studied and 10 clinically normal cats served as controls. After initial evaluation, all hyperthyroid cats were treated with methimazole at a starting dose of 5 mg orally every 12 hours with dose adjustments made until euthyroidism was achieved. The mean pretreatment GFR, as estimated by PIC, was significantly higher for the hyperthyroid cats than for the control cats. Control of hyperthyroidism resulted in significantly decreased GFR when compared to pretreatment values. There was no significant difference between the mean GFR for the post treatment hyperthyroid cats and the mean GFR for the control cats. In the hyperthyroid group, the mean increases in BUN and SCr concentrations, and the mean decrease in urine specific gravity after treatment were not statistically significant when compared to pretreatment values. Two of the 12 hyperthyroid cats developed abnormally high serum creatinine concentrations following treatment. Both of these cats were isothenuric on pretreatment urinalyses and had post treatment GFR values of less than 1 ml/kg per minute. It was felt that post treatment reductions in GFR most likely unmasked latent renal dysfunction in these two cats. The authors concluded that a trial course of methimazole with follow-up serum biochemical and urine analyses may be prudent initial steps in the treatment of hyperthyroid cats suspected of having renal dysfunction prior to selecting a nonreversible treatment modality (i.e., thyroidectomy, radioactive iodine).

The effects of hyperthyroidism on renal function was also evaluated in a group of 10 normal adult cats where hyperthyroidism was induced with exogenous administration of thyroxine. Baseline serum T4 concentrations, clinicopathologic data (CBC, serum chemistry panel, urinalysis), and nuclear medicine determinations of GFR, effective renal plasma flow (ERPF), and effective renal blood flow (ERBF) were measured in 10 normal adult cats. Cats were then injected with T4 (50 micrograms/kg SQ) daily for 30 days to induce hyperthyroidism. Clinicopathologic and nuclear medicine studies were repeated at 30 days. Cats injected with thyroxine had significant increases in T4, GFR, and ERBF and significant declines in SCr and BUN values.

The clinical importance of these various studies seems to be that hyperthyroidism induces an artificial state of increased GFR resulting in a decrease in serum concentrations of BUN and creatinine. Treatment of the hyperthyroidism (surgery, methimazole or radioiodine) results in a decrease in the GFR and results in the unmasking or progression of underlying chronic renal disease. With the possible exception of measuring GFR prior to treatment, no reliable clinical or laboratory predictor currently exists to help the clinician determine which cat may exhibit a clinically important deterioration in renal function following therapy. It is important to emphasize that the number of cats with severe or clinically relevant declines in renal function post-treatment appears to be small.

Several studies have documented a decline in renal function following successful treatment for hyperthyroidism. This effect is seen with medical and surgical treatments as well as following radioiodine therapy. In over 95% of the cats, the decline in renal function is mild and clinically insignificant. However, in a small percentage of cats the decline in renal function can be dramatic. To attempt to avoid this complication we initially treat all hyperthyroid cats with low dose Tapazole therapy (2.5 mg once or twice a day) and recheck laboratory values (TT4, BUN, creatinine) in 7 – 10 days. Long term definitive therapy may undertaken in those cats with stable renal function following initial medical management. In a few cats we may need to weigh the risk/benefit ratio of treating the hyperthyroidism vs promoting significant deterioration in renal function.