Thyroid and Parathyroid Disease In the Dog and Cat. Darren Fry MA VetMB, FANZCVS, Registered Specialist, Small Animal Medicine,

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1 Thyroid and Parathyroid Disease In the Dog and Cat Darren Fry MA VetMB, FANZCVS, Registered Specialist, Small Animal Medicine, Introduction Brisbane Veterinary Specialist Centre. June 2015 Canine and feline thyroid and parathyroid disorders represent a disparate and interesting group of diseases. There are quite marked differences between cats and dogs in terms of the types and incidence of disease seen, clinical presentation and often, treatment options and prognosis. In cats of course, hyperthyroidism predominates. The vast majority of feline thyroid tumours are benign and functional. The rarer malignant tumours seen are also generally functional. Most thyroid tumours in the dog, in contrast, are malignant and non-functional. This fact means that unfortunately, the majority of canine thyroid tumours are diagnosed late once they become a space occupying lesion or are palpated. Parathyroid tumours are commonly recognised in the dog and occasionally in the cat. The majority of these tumours are benign and extremely small. The clinical presentation is due to the resultant hypercalcaemia due to hypersecretion of parathyroid hormone (PTH). Hypothyroidism is a relatively common but almost definitely over-diagnosed condition in the dog. Whilst hypothyroidism is seen occasionally spontaneously in cats, iatrogenic hypothyroidism following the treatment of hyperthyroidism is the most well-recognised presentation and is an area of ongoing interest and controversy. Canine Hypothyroidism The vast majority (95%) of hypothyroidism in the dog is caused by autoimmune thyroiditis. There the prolonged subclinical phase and eventually clinical disease results. The textbook presentation of hypothyroidism is well recognised and easily diagnosed and treated. However, significant difficulties lie in diagnosing non-classical cases and more significantly, mis-diagnosis of euthyroid dogs as being hypothyroid. A major source of potential overdiagnosis is the addition of total T4 testing to routine clinicopathological testing panels. It is very important that thyroid testing is carried out once a clinical diagnosis of hypothyroidism is suspected rather than backing in to a diagnosis based on low thyroid levels on a screening test. As well as sensitivity and specificity of testing, positive and negative predictive values must be taken into account. There are many causes of a low total T4 on a screening test apart from hypothyroidism. Most commonly, non-thyroidal disease is recognised as a significant cause of low total T4 result in a dog with normal thyroid function. In addition, there are several drugs which are known to reduce thyroid levels including: Glucocorticoids (both endogenous and exogenous)

2 Phenobarbitone Sulphonamides Potassium bromide Non-steroidal anti-inflammatory drugs As thyroid supplementation is lifelong it is vitally important that a robust diagnosis is made before treatment is instituted A robust diagnosis would include: An initial clinical suspicion Exclusion of other disease processes which could be causing similar clinical signs A low total T4 and a low free T4 by equilibrium dialysis A high endogenous TSH assay. This is probably the least important of the tests as it lacks sensitivity with a significant proportion of confirmed hypothyroid dogs having a normal result. The reason for this is uncertain. As well as the classical presentation of hypothyroidism there are several other disease syndromes/symptoms which have been associated with hypothyroidism including: Poor reproductive function Bradycardia and dilated cardiomyopathy Laryngeal paralysis Mega-oesophagus Neurological abnormalities including peripheral neuropathy, myopathy, dysfunction of multiple cranial nerves, facial nerve paralysis and vestibular dysfunction. Rarely, cerebrocortical dysfunction is seen. Because of the confounding effect of euthyroid sick syndrome, it is vitally important in these non-classical presentations, that other causes of the symptoms are rigorously ruled out before hypothyroidism is pursued as a cause of the symptoms. Although concurrent hypothyroidism is recognised in dogs with laryngeal paralysis and mega-oesophagus, current evidence would seem to suggest that there is no obvious causative association. In most cases, dilated cardiomyopathy in the dog is an idiopathic disease. However, it may be worth assessing thyroid function in some unusual breed presentations. There has been a case report of two Great Danes whose cardiac function responded dramatically to thyroid supplementation.

3 Canine Thyroid Carcinoma Dogs with thyroid carcinoma may be presented for evaluation of hyper or hypothyroidism. Approximately 20% of cases are reported to be hyperfunctional although not all of these are clinical. A similar percentage of dogs may be hypofunctional with or without accompanying clinical signs. However, the majority of cases are assessed unfortunately at a relatively advanced stage of disease with space occupying signs which may include a palpable mass, coughing, gagging and stridor. 30 to 40% of dogs have gross metastatic disease at the time of initial evaluation. In addition, the situation can be complicated by the fact that ectopic thyroid tissue can become neoplastic independent of the thyroid gland itself. Ultrasonography, CT and MRI or play an important role in the diagnosis and assessment of local invasiveness of thyroid tumours. A recent study 1 suggested that although ultrasound is a useful screening tool for evaluation of the degree of invasiveness of tumours, CT or MRI were much more reliable. The study also suggested that palpation of a thyroid mass is a poor indicator of tumour invasion and capsule disruption. Fine needle aspiration cytology can be a useful tool to provide further diagnostic information. Incisional biopsy is fraught with the complications of excessive haemorrhage and biopsy tract seeding and is usually not performed. The best chance of long term remission or cure for thyroid carcinoma is with surgical excision. However, this is usually only likely to be successful with smaller, freely mobile, noninvasive tumours. Median survivals for this group of tumours (even with bilateral disease) have been reported in excess of three years. The optimal treatment for invasive, poorly mobile or metastatic tumours is yet to be defined. The evidence for efficacy of chemotherapy is not compelling. Doxorubicin may have antitumour effect in some dogs but there are no good studies confirming a long term survival advantage with chemotherapy. One of the potential reasons for the lack of efficacy of chemotherapeutic agents is the possible over expression of membrane efflux pump proteins such as P-glycoprotein and multidrug resistance related protein-1. A recent study 2 evaluated the expression of these proteins and also other potential therapeutic targets. This study looked at 74 thyroid carcinoma samples of both the follicular cell form and medullary thyroid carcinomas. Immunohistochemical assessment revealed some interesting findings. The large majority of both tumour types over expressed vascular endothelial growth factor (VEGF). This is a major stimulator of angiogenesis and may potentially be a therapeutic target for tyrosine kinase inhibitors such as toceranib. The same study showed that p 53 mutations were uncommon and so not a potential therapeutic target. The authors however did confirm significant P-glycoprotein expression in the majority of the medullary thyroid carcinomas but only a small percentage of the follicular tumours. It is possible that tyrosine kinase inhibitors may be helpful in inhibiting P-glycoprotein expression and possibly improving chemotherapy sensitivity in the medullary thyroid carcinomas. The final immunohistochemical assay that was performed was for cyclo-oxygenase 2 which may be a therapeutic target for piroxicam or other non-steroidal anti-inflammatories. Again, cyclo-

4 oxygenase 2 expression was noted in approximately 50% of the medullary tumours and a much lower percentage of the follicular tumours. Anecdotally, carbimazole or methimazole may have some palliative effects on thyroid tumours but this has not been rigourously studied. Exogenous thyroid hormone supplementation may be theoretically beneficial due to the effect of reducing endogenous TSH levels which may stimulate further tumour growth. However, studies have not been performed to investigate this. Feline Hyperthyroidism Feline hyperthyroidism is a relatively "new" disease first recognised by Dr Mark E Peterson in the late 1970s. It is not known whether this is actually a "new" disease as such or whether it had been present previously and not recognised. Dr Peterson noticed a pattern of older cats in the USA losing weight without obvious explanation. It may have been that previously these cats were thought to be suffering from cancer or renal failure and were not investigated further. However, when he started to research, he found that the cause of the symptoms was a functional thyroid adenoma with a small proportion of cases being caused by a carcinoma. There are concerns that long term medical treatment of benign adenomas can result in transformation to carcinoma. Feline hyperthyroidism is a fascinating and unusual disease of older cats. The most unusual aspect of the disease is that despite the serious clinical signs, it is possible to cure a large proportion of these cats. Despite many years of research, the exact underlying cause for feline hyperthyroidism is not known. The clinical signs of hyperthyroidism are well recognised and not the subject of this presentation. However, with increased awareness of this condition, much more subtle cases are being diagnosed. Diagnosis in most cases is relatively straightforward being based on a combination of clinical signs and total T4 levels. Evaluation for concurrent disease in these older patients is of course very important. Treatment Options There are many possible treatment options both palliative and curative. Palliative treatment options are: Medical treatment with carbimazole or methimazole and Hills y/d diet. Curative treatment options are surgical thyroidectomy and I 131 treatment. Thyroidectomy When facilities for radioiodine are not available, thyroidectomy is a reasonably good option. This can be curative when unilateral disease is present but bilateral disease may require staged surgeries to reduce the risk of iatrogenic hypoparathyroidism. The major concern regarding thyroidectomy is the necessity to anaesthetise a geriatric patient with potentially significant cardiovascular concerns and possibly, concurrent disease. Medical Treatment Probably the most common treatment currently recommended for hyperthyroidism is medical treatment with either carbimazole or methimazole. Although this is the most common

5 treatment it is not necessarily the best treatment in most cases. The drugs work by reducing the amount of thyroid hormone produced by the overactive thyroid gland and can be very effective. However, the treatment does not stop growth of the thyroid gland and there are concerns that over time, malignant transformation can occur. Peterson has presented data from over 2000 cats that he treated for hyperthyroidism. All received scintigraphy for treatment planning. 85% of cats received radio iodine therapy within one year of diagnosis. 228 cats were treated for 1-6 years medically and 31 cats were treated for 4 to 6 years. The volume of the thyroid increased with time. The incidence of thoracic lesions increased with time. The incidence of carcinoma increased significantly over time. The incidence of ectopic tissue did not increase over time. The overall incidence of carcinoma was 1.7%. Within one year of diagnosis, the incidence was 0.6%. Over four years, the incidence was 25%. Other disadvantages of medical treatment include the necessity to administer a pill or transdermal medications to a cat daily for life, potential direct side effects of the medication and over the life of the cat, and increased expense compared to radio iodine therapy. Methimazole is one of the few transdermal medications that has been studied scientifically and does seem to be relatively effective although expense is a concern long term. Recent publications have however raised concern regarding long term efficacy. Dietary Management Recently, Hills have developed a new prescription diet (Hills y/d) that shows some promise for the palliative management of hyperthyroidism. The principle of this diet is that it has very low iodine levels. This effectively "starves" the overactive thyroid of "fuel" to produce the excessive thyroid hormone. This approach has been shown to be effective in experimental cats and there is also a published study in clinical cases showing that in some cats, it can be quite effective. Although this is potentially a very attractive option for the treatment of hyperthyroidism and it may be very suitable for some cats, there are concerns regarding this approach. Firstly, it seems that it is very difficult to achieve a very low iodine level in the diet and small amounts of other foods can potentially lead to reduced effectiveness of the diet. This may well become a problem for multi cat households or fussy cats. Secondly, as with medical treatment this treatment is palliative only. Thirdly, the need to administer y/d rules out the possibility of later using other prescription diets should for example, diabetes mellitus develop. For the large majority of hyperthyroid cats, I 131 treatment is the treatment of choice and should be considered the first option over other treatments. Cure rates are in excess of 95%. The other very practical advantages include: The fact that cats will no longer need to be pilled or have transdermal medication applied or have frequent monitoring tests. Long term, I 131 is by far the most cost effective treatment option. The risk of malignant transformation of the thyroid adenoma is removed. Special diets are not required no need to choose between Hills y/d and k/d? There are no concerns regarding availability of medical treatments I 131 therapy I 131 therapy is a simple and elegant treatment without any direct side effects for the cat. The principle and theory of the treatment is very simple. However, due to concerns regarding

6 human exposure to radiation, the development of a treatment facility is an involved and complicated process. There are concerns regarding exposure of veterinarians, nurses and owners to radiation. However, with a properly designed facility and techniques, this exposure can be kept to extremely low levels. The principle of radio iodine therapy is the use of a radioactive isotope of iodine (1 131). This isotope behaves biologically exactly the same as regular iodine and is taken up into the thyroid gland when administered to the cat as normal iodine would be. Once taken up into the thyroid gland, the radioactive isotope then releases beta radiation. This is low energy, poorly penetrating radiation that only travels 1 to 2 mm in tissue. This is ideal in that this enables the abnormal thyroid cells to be killed by the radiation. Normal thyroid cells have suppressed function due to the hyperthyroid state and so do not take up the iodine and are relatively spared. I 131 can be administered either by injection or oral liquid or capsules. The latter is usually chosen in Australia as injections can be prohibitively expensive. Although the radio iodine treatment does not result in any side-effects for the cat, careful precautions need to be taken to reduce the radiation exposure to veterinarians, nurses and owners. There are two sources of radiation exposure. Firstly, there is high energy gamma radiation that is released from the radio iodine capsule/injection and also from the iodine within the cat. The second source of exposure is vapourised iodine from cat urine. This can be inhaled or ingested and can result in some exposure to beta radiation which longer term, in theory, could increase the risk of thyroid cancer. Because of these concerns, it is mandatory that cats are hospitalised after treatment until the radiation levels are significantly decreased (usually 5 to 10 days under Australian regulations). Specialised and fully licensed treatment facilities are required. Broadly speaking, two approaches are possible with the radioiodine facility. Firstly, a dedicated, shielded room can be used to house the cats. A second, more innovative approach is to house the cat in a custom made lead cage such as that manufactured by Gammasonics. This is the approach used at BVSC. This approach completely eliminates exposure of staff to gamma radiation during the hospitalisation period and significantly reduces the level of potential exposure to beta radiation. The other benefit of this approach is that there is a possibility of owners visiting the cat in hospital. This is not possible with a more conventional approach and can be a source of potential stress to cat owners. Dosing of I 131 Curing hyperthyroidism caused by thyroid adenoma is relatively easily achieved by administering a large dose of I 131. However, this can also potentially cause hypothyroidism which is being recognised as a significant concern regarding long term renal function. For this reason, there has been much debate recently in the literature and amongst experts in this field regarding I 131 dosing. Traditionally, a relatively large, fixed dose has been administered ( MBq). Although very effective, this has been associated with hypothyroidism in some cats. A recent abstract at ECVIM reported a very high success rate with a much lower fixed dose (125 MBq) and overall there is a move towards lower dosing generally. Generally speaking, the currently best accepted approach is to "tailor" the dose to the individual patient This is best achieved by scintigraphy. However, as this is not very widely available, the alternative approach and that used at BVSC is to take into account the severity of clinical signs, thyroid size and the T4 level and base dosing decisions on overall assessment of the severity of disease.

7 I 131 and Renal Function Another controversial area in the treatment of feline hyperthyroidism generally is that of concurrent renal disease. Of course, most of the patients that we see are geriatric and comorbid disease is very common including chronic renal insufficiency. It is well recognised that the hyperthyroid state can "prop up" failing kidneys by increasing renal blood flow and GFR. Once a euthyroid state has been achieved, the renal insufficiency is "unmasked" and is now "visible" biochemically. In addition, increased muscle mass in the treated cat can increase serum creatinine levels. This can occur whether treatment is medical, surgical or radioactive. However, in the vast majority of cases, the azotaemia that develops is IRIS stage II or early stage III and is very well tolerated. It has been demonstrated in more than one large study, that the development of this mild azotaemia subsequent to successful treatment of the hyperthyroidism does not appear to affect long-term survival compared to cats that do not develop an azotaemia. The euthyroid state does not change the underlying histological disease in the kidney but it is merely the altered blood flow which has an effect on the measured biochemical parameters. The other factor that must be borne in mind is that the hyperthyroid state in itself is potentially very damaging to the kidneys long term. It could be looked at another way in that this "unmasking" of renal insufficiency could influence the clinician to then assess the kidneys in more detail and possibly discover treatable disease such as pyelonephritis. There does appear to be a relatively high incidence of positive urine cultures in hyperthyroid cats. Hypothyroidism can contribute to long term worsening of renal function and if this does develop post-treatment, then thyroid hormone may have to be supplemented orally (often only transiently but sometimes permanently). Mark E Peterson presented some data on this at ECVIM in His conclusion was that post-treatment hypothyroidism is common (20% when either increased TSH or low T4 was used) and increases with increased dose. However, when looking at only those cats that had a low T4, the incidence was closer to 10%. Clinical signs were not common in this group but 60% were azotaemic. In many of these cats, the azotaemia improved or resolved with thyroid supplementation. This is an emerging field but it does seem prudent to consider thyroid supplementation in cats that develop a low T4 and become azotaemic. Several questions arise though are we just treating a number, how do long do we treat for and are the lower end of the feline reference ranges appropriate? Liquid Leventa (Merck) is used by Peterson at a dose of either 100mcg SID or 75mcg BID on an empty stomach if possible. BID seems to be preferred. Currently, we recommend a one month post treatment follow up with a total T4 and creatinine and then continued monitoring should an abnormality be detected. Difficult cases Overall, response rate to I 131 therapy is very high. However, there are some treatment failures and it is useful to possibly be able to predict which cases may be more difficult to achieve a cure in. It seems that cats with very high T4 levels (>250nmol/L) may be associated with an increased risk of treatment failure and will also require a higher dose. At the RVC in the UK, no treatment failures have yet been recorded with cats with a T4 <250nmol/L. With a T4 >250nmol/L, treatment success is only 80%.

8 Carcinomas (which account for 1-3% of cases) are known to be more difficult to treat. Generally, they tend to be larger with a higher total T4 and don't tend to respond to medical therapy or standard I 131 doses. However, differentiation from adenomas is not always straightforward without histology. Scintigraphy is very useful with heterogenous, irregularly margined or mediastinal masses often being carcinomas. Some tumours can be mixed, possibly due to malignant transformation. Regardless of histologic type it does seem that lager goitres can be more problematic to treat. Some cats that have been treated medically long term can suffer from quite severe thyrotoxic symptoms during medication withdrawal prior to I 131 therapy. The above concerns really stress the importance of early curative treatment of this condition which hopefully will become more common as I 131 therapy becomes more widespread. More commonplace early treatment of younger cats may also increase the possibility of further, de novo adenomatous lesions developing as the cat gets older?! If a cat has received intravenous iodinated contrast agents then I 131 therapy should be postponed for at least 2 months as the high levels of iodine will inhibit radioactive isotope uptake. Contra-indications for I 131 therapy Although I 131 therapy is the recommended treatment for the vast majority of hyperthyroid cats, there are certain situations where this treatment is not ideal including: 1. Cats with pre-existing azotaemia. 2. Situations where owners are not comfortable with possible exposure to very low levels of radiation after discharge in the home environment and do not wish the cat to be boarded for this time. 3. Some owners are not comfortable with separation from the cat for 5-10 days (although at BVSC, visits are possible). 4. Cats which require ongoing medical treatment or potential interventions during the treatment period such as diabetic cats or cats on medication that has to be administered daily. We feel that this could expose our staff to unnecessary radiation. Discontinuation of medical treatment prior to I131 Another controversial area in the field of radio iodine therapy is whether to discontinue medication with methimazole/carbimazole/hills y/d diet before treatment with I 131. However, this area is becoming less controversial in that the broad consensus is now that it is very important to discontinue medication for at least five days and probably up to 10 days before treatment. The data regarding whether medical treatment interferes with uptake of I 131 is conflicting. However, the main concern appears to be the increased risk of the development of hypothyroidism. It is thought that in animals with medically well controlled hyperthyroidism, the non-adenomatous thyroid tissue starts to regain its function. This means that it is more likely to take up the isotope and be damaged, leading potentially to hypothyroidism.

9 Pre-evaluation of I 131 cases There is no accepted minimum data base that is required prior to I 131 therapy and this will vary between institutions. Some treatment centres insist on medical pre-treatment of hyperthyroid cats before I 131 therapy to assess renal function. However, taking into account the factors above, many centres (including BVSC) do not require this before treatment. It is important however, that serum creatinine is known before treatment. Cats with pre-existing azotaemia tend to have a much poorer prognosis. We do recommend that these patients are treated medically. However, if euthyroidism is achieved medically and renal parameters are stable for 2-3 months, then I 131 treatment can still be considered although long term survival is less likely regardless of which treatment option is used. Philosophically, 2 approaches can be taken: 1. It can be decided to fully evaluate the patient for co-morbidity (common in the older cats that we see) and secondary effects of hyperthyroidism prior to treatment. This could potentially involve (depending on the patient): CBC, biochemistry, urinalysis and culture, UPC. Blood pressure measurement and management. Abdominal ultrasound and echocardiography. Trial medical treatment and re-assessment A fully informed decision can then be made as to whether to proceed with treatment and also an understanding can possibly be arrived at as to whether all the clinical signs seen are due to the hyperthyroidism (for example a cat with concurrent hyperthyroidism and small cell lymphoma). The disadvantages of this approach include the extra time and expense and the difficulty in performing some of these procedures in a poorly controlled or uncontrolled hyperthyroid cat. 2. The second approach and that favour at BVSC is to obtain the minimum required data that will allow safe I 131 treatment and allow rapid and effective return the euthyroid state. Once this has been achieved then the cat is a much better candidate for further investigations should ongoing symptoms be present. The marked deleterious effects of excessive thyroid hormone on various body systems can then be taken out of the equation. Our pre-treatment recommendations are: Full history, clinical examination, CBC and serum biochemistry to identify obvious comorbidities. A total T4 to confirm the diagnosis and help with dosing estimate. If there is delay between this and the I 131 treatment, we insist on a repeat serum creatinine within one month of the treatment date. We do not insist on a USG unless there is an azotaemia. Urine can be difficult to obtain from a hyperthyroid cat and a low USG would not influence our decision to treat a non-azotaemic cat.

10 Using this approach, we can usually see the patient in the morning, make a final assessment and treat the same day. Discharge Precautions After discharge, the cat is deemed safe to be handled at home. However, low levels of radiation are emitted for a couple weeks. During that time, it is important that there is minimal close contact between the cat and the owner. Some owners find this difficult to cope with and the option can be given for further hospitalisation during that period. Discharge regulations will again vary from State to State. Parathyroid Neoplasia Parathyroid neoplasia is recognised but rarely seen in the cat. In the dog, it is also reported as an uncommon neoplasm. However, anecdotally in our practice, parathyroid neoplasia is a relatively common cause of chronic, mild hypercalcaemia. The vast majority of canine parathyroid tumours are benign and often extremely small lesions. They are usually discovered during evaluation for ionised hypercalcaemia or lower urinary tract signs caused by calcium oxalate urolithiasis. Definitive diagnosis requires assessment of PTH and PTH-rp levels in conjunction with hypercalcaemia. However, sonographic evaluation of the thyroid and parathyroid glands with high-frequency linear transducers in our experience tends to be an accurate and much more rapid diagnostic test which can facilitate earlier surgical resection. Prognosis with surgical resection is very good. Post-operative hypocalcaemia is a well recognised complication of surgery. It was previously thought that dogs with higher pre-operative calcium levels were at increased risk of developing post-operative hypocalcaemia. However, recent studies appear to have refuted this. It may be that chronicity of hypercalcaemia is more important. Careful monitoring of ionised serum calcium after surgery is very important but prophylactic calcium or calcitriol supplementation is probably not recommended.