Outline
Notes
- Start Screen
- Introduction
- Anatomy of thyroid gland
- The thyroid hormones
- The hypothalamic-pituitary-thyroid axis
- Thyroid hormone synthesis
- What happens with hyperthyroidism?
- What happens with hyperthyroidism?
- How common is feline hyperthyroidism?
- Ectopic tissue
- Clinical signs
- Diagnosing hyperthyroidism
- Biochemistry
- Felimazole and diabetes mellitus
- Total T4 (tT4) test
- Free T4 (fT4) test
- Other testing options
- Other testing options
- Other testing options
- Diagnosis flow chart
- Treating hyperthyroidism
- Medical treatment
- Medical treatment
- Medical treatment
- Unmasking of renal disease
- Predicting unmasking of renal disease
- Long term medical management
- Radioactive iodine treatment
- Radioactive iodine treatment
- Surgical thyroidectomy
- Surgical thyroidectomy
- Felimazole
- Pharmacodynamics of Felimazole
- Pharmacokinetics of Felimazole
- Pre-thyroidectomy stabilisation
- Long-term treatment
- Monitoring treatment
- Monitoring T4 levels
- Why monitor biochemistry?
- Why monitor biochemistry?
- Why monitor haematology?
- References
- Glossary (part one)
- Glossary (part two)
- Glossary (part three)
- Glossary (part four)
- End screen
Start Screen
Welcome to the Dechra Veterinary Products interactive CPD program on the topic of feline hyperthyroidism. This program will last for a total of 2 hours.
When you have completed the program there will be a short self-assessment test to gauge your understanding of what you have learned. You will be able to download a certificate for your CPD record once the course has been completed.
Introduction
In order to understand the clinical signs, diagnosis, and treatment of hyperthyroidism it is important to first discuss the underlying anatomy, physiology and pathophysiology involved.
In the next few sections we will discuss the structure and function of the normal thyroid gland as well as the changes that occur in hyperthyroidism.
Anatomy of thyroid gland
Let's start by discussing the structure and function of the thyroid gland. A cat's thyroid gland is divided into two lobes, which lie on either side of the trachea.
The thyroid gland produces the hormones thyroxine (or T4) and triiodothyronine (or T3). These hormones help control the overall metabolism of the body.
The thyroid hormones
The thyroid hormones thyroxine (T4) and triiodothyronine (T3) affect a huge number of normal body processes. They are essential for normal growth & development, regulate the cellular metabolism of protein, fat and carbohydrate and are involved in the regulation of heat production and oxygen consumption.
Over 99% of circulating T4 and T3 is bound to the plasma proteins albumin and globulin.
However, it is the free or unbound hormones which are metabolically active and can be taken into cells.
T4 is the major secretory product of the thyroid gland, but the metabolic activity of T3 is much greater. T3 is generally considered to be 5 times more metabolically active than T4.
About 80% of the plasma T3 is produced by deiodination of T4 in peripheral tissues, mainly the liver and kidneys.
The hypothalamic-pituitary-thyroid axis
Normal thyroid hormone production is controlled by a negative feedback system.
Thyroid hormone release is stimulated by the hypothalamus secreting thyrotropin releasing hormone (or TRH) which acts on the anterior pituitary and regulates the production of thyroid stimulating hormone (or TSH).
TSH then acts on the thyroid gland and stimulates the production of T4 and T3.
When circulating levels of T4 and T3 exceed a threshold level, they exert a negative feedback effect predominantly on the pituitary (but also on the hypothalamus) to keep the system in balance.
Thyroid hormone synthesis
Thyroid hormones are formed from iodine and thyroglobulin.
When iodine is ingested in the diet it is converted to iodide in the gastrointestinal tract. This iodide is then absorbed into the circulation.
When the iodide reaches the thyroid gland, it is 'trapped' or concentrated by active transport mechanisms of the basolateral plasma membrane of the thyroid follicle cell.
Once inside the thyroid cell, iodide diffuses down a concentration gradient to the apical surface of the cell.
Here, it is oxidised by the enzyme thyroid peroxidase back to iodine and coupled onto tyrosine residues of preformed thyroglobulin. T4 and T3 are then formed.
In a final step T4 and T3 are either released straight into the bloodstream or stored in lysosomes for later use.
What happens with hyperthyroidism?
Feline hyperthyroidism occurs as a result of overproduction of thyroid hormones from abnormally functioning thyroid tissue. This overproduction occurs in spite of the negative feedback process, since the abnormal thyroid tissue is acting independently of normal pituitary control.
98% of cases are caused by benign adenomatous hyperplasia of the thyroid gland. Hyperplasia is a general term referring to the proliferation of normal cells within an organ or tissue beyond that which is ordinarily seen.
What happens with hyperthyroidism?
Around 70% of cases will have bilateral hyperplasia affecting both lobes of the thyroid gland.
Around 30% of cases will have unilateral hyperplasia where only one lobe of the thyroid gland is affected.
A thyroid carcinoma, which is a malignant tumour, is present in less than 2% of cases, so whilst this type of growth is rare it can occur.
Because T4 and T3 have such profound effects on metabolism, increases in their levels can affect virtually every organ.
If untreated the disease can progress to emaciation, severe cardiac and metabolic disturbances and eventual death.
However, with appropriate therapy the prognosis can be excellent.
How common is feline hyperthyroidism?
Feline hyperthyroidism is an extremely common diagnosis in cats and market research suggests that around 1% of all cats seen in general practice will have this condition. There is no breed or sex predisposition, though studies have reported that Siamese and Himalayan cats are at decreased risk of developing hyperthyroidism.
Hyperthyroidism mostly affects middle aged to older cats, but is also occasionally seen in younger cats.
There is a reported prevalence of 6% in senior cats (those over 10 years of age). Studies suggest that less than 5% of the total number of cats with hyperthyroidism will be under 10 years of age at the time of diagnosis.
Feline hyperthyroidism was first described in 1979 and the prevalence of the disease continues to increase. At the present time the cause of hyperthyroidism remains unknown. Several epidemiological studies have been carried out attempting to uncover risk factors, but to date no one has come up with any conclusive data.
It was found by Kass and colleagues that, amongst other factors, cats fed almost entirely canned food, those using cat litter and those being treated with spot-on flea treatments had an increased risk of developing hyperthyroidism. However, no direct relationship between cause and effect has been found.
Ectopic tissue
In addition to hyperplastic tissue within the thyroid gland, ectopic hyperplastic thyroid tissue may also be present in hyperthyroid cats.
This tissue may be found anywhere from the base of tongue to the base of heart.
The thyroid gland originates in the chest during embryogenesis and then migrates up to the neck as the embryo develops. During this process 'islands' of thyroid tissue may be deposited.
In general practise this tissue is very difficult to detect since it is often located in the thoracic cavity and so is impossible to palpate. It is normally necessary to use scintigraphy to highlight the areas of active ectopic tissue.
This is a scintigraphy scan and the hot areas showing as red, orange and yellow reveal the presence of active thyroid tissue.
Even when the ectopic tissue can be identified it may be difficult to deal with surgically because of its location.
A paper was published in 2009 in the Journal of Feline Medicine and Surgery by Harvey and colleagues. This study showed that in a population of 120 cats seen at the University of Bristol, 23% had ectopic hyperfunctional thyroid tissue.
So the possibility of ectopic tissue is well worth considering when presented with a hyperthyroid cat.
Clinical signs
The most common signs of hyperthyroidism include weight loss despite polyphagia, polyuria and polydipsia, a palpable goitre, tachycardia and other cardiac changes, hyperactivity, vomiting and diarrhoea, skin changes and respiratory abnormalities.
Almost all hyperthyroid cats will exhibit weight loss despite a normal or increased appetite. This is due to an increase in metabolic rate. Indeed in many cases, this weight loss despite polyphagia (possibly along with polyuria and polydipsia) will be the main clinical signs that first alert the owner to the problem and prompt them to seek veterinary attention for their cat.
In hyperthyroid cats, unilateral or bilateral thyroid gland enlargement (or goitre) is invariably present. A recent study published in 2009 in the Journal of Feline Medicine and Surgery by Boretti and colleagues concluded that the likelihood of hyperthyroidism increases with the increasing size of the thyroid gland. However, it is important to note that the presence of a cervical mass is not always associated with hyperthyroidism. Other possibilities include lymph node enlargement and neoplasia or hyperplasia of the parathyroid gland. Some euthyroid cats have an enlarged thyroid gland and these cats should be regularly re-examined for signs of hyperthyroidism.
Tachycardia is a very common finding, and a prominent apex beat, gallop rhythms and a systolic murmur associated with hypertrophic cardiomyopathy can also be seen. The cardiomyopathy is usually reversible following treatment of the hyperthyroidism, but this may not always be the case. Cardiomyopathy may progress (either pre- or post- treatment) to congestive cardiac failure, although this is uncommon.
Respiratory abnormalities, for example tachypnoea and dyspnoea at rest can be seen, this occurs most frequently during a period of stress. However, it is important to rule out symptoms of cardiac failure such as pleural effusion or pulmonary oedema. Respiratory muscle weakness may also occur as a result of chronic thyrotoxic myopathy.
Hyperthyroidism is a common cause of diarrhoea in the adult geriatric cat. The mechanism by which hyperthyroidism causes diarrhoea has not been fully assessed, but rapid gastrointestinal transit may be a factor. Vomiting, typically intermittent, is seen more commonly than diarrhoea.
Finally, skin and coat changes may be seen. Short-haired cats frequently present with an unkempt, stary, matted coat. Longer-haired cats can present with alopecia, possibly as a result of excessive grooming.
Some hyperthyroid cats may exhibit something called apathetic hyperthyroidism.
These cats show unexpected clinical signs, for example anorexia instead of polyphagia and depression instead of hyperactivity. These cases can have significant underlying disease such as renal disease or neoplasia so it is important to look for other complications in these atypical cases.
Diagnosing hyperthyroidism
Compared to some other endocrine disorders the diagnosis of hyperthyroidism is usually straightforward.
A compatible history, clinical signs and a palpable goitre will go a long way to increase your index of suspicion and diagnosis can usually be confirmed with blood tests.
Biochemistry
With feline hyperthyroidism there is usually an elevation in the enzymes alanine aminotransferase (or ALT) and alkaline phosphatase (or ALKP).
However it is important to note that the rise should be proportional to the increase in total T4.
If the increase in ALT and/or ALKP is significantly greater than the increase in total T4 then a diagnosis of primary liver disease should be considered and further tests of liver function may be required. As a guide, the maximum levels of ALT seen in hyperthyroid cats would typically be in the order of 400-500 units per litre.
Renal disease and Diabetes Mellitus can have many similar clinical signs to those of hyperthyroidism, and the presence of renal disease or diabetes mellitus alongside hyperthyroidism can have implications for the treatment of hyperthyroidism. Therefore, it is essential to look for these diseases at the time of the initial investigation.
Felimazole and diabetes mellitus
Hyperthyroidism can cause insulin resistance. This means that some diabetic cats have a decrease in their insulin requirements after treatment for hyperthyroidism. However, this is not the case in all diabetic cats.
In addition, an in vitro study in rats by Ammon and colleagues has shown that thiamazole can increase glucose-induced insulin release. If thiamazole does sensitise the feline pancreatic islet to the insulin-triggering action of glucose, fluctuations of plasma thiamazole concentrations over the day may make insulin requirements in diabetic cats more difficult to ascertain.
Finally, hyperthyroid diabetic cats have significantly lower serum fructosamine concentrations compared to 'normal' diabetic cats due to increased protein turnover.
Fructosamine levels will increase when the hyperthyroidism is treated, but remain lower than the levels in 'normal' diabetic cats. This can make monitoring of diabetes difficult.
Total T4 (tT4) test
As its name suggests the Total T4 test involves measuring the total T4 level in the blood. This includes T4 bound to carrier proteins and T4 that is unbound or 'free'.
Around 99% of the T4 circulating in the blood is bound to the plasma proteins albumin and globulin. It is the free T4 which is metabolically active.
Total T4 (or TT4) is the main diagnostic test used for hyperthyroidism and should be used as the first screening test. It is cost effective and establishes baseline levels prior to treatment. A total T4 of over 60 nannomoles per litre is generally considered to be diagnostic of hyperthyroidism, though it is important to note that the reference ranges may differ between individual laboratories.
Measurement of an elevated total T4 will confirm approximately 90% of cases of hyperthyroidism. However, that means the total T4 can be normal in approximately 10% of hyperthyroid cats. This is most often seen in early cases or cats with concurrent (non-thyroidal) illness for example renal failure.
Any non-thyroidal illness can artificially lower the T4 level. This is called 'euthyroid sick syndrome'. Normally the more severe the illness the lower the T4, so it is essential to rule out other diseases where possible.
Free T4 (fT4) test
If a diagnosis has not been confirmed with a total T4 test, a free T4 test could be performed. The free T4 (or fT4) test only measures the fraction of T4 that is not bound to carrier proteins and so is metabolically active. Levels of free T4 are less affected by non-thyroidal illness.
Measuring free T4 involves a more complex technique called equilibrium dialysis and so is normally more expensive.
Some non-hyperthyroid cats can have a high free T4, so it is important to measure free T4 in conjunction with total T4 to enhance the diagnostic specificity. For example, some euthyroid cats with another illness can have elevated free T4 concentrations. These cats normally have a corresponding total T4 in the lower half or below the reference range. Measurement of free T4 alone could have yielded a false positive result of hyperthyroidism. So, it is really important that free T4 is measured in conjunction with total T4 rather than used as the sole diagnostic test.
Generally speaking if you have compatible clinical signs and a total T4 that is mid to high end of the normal reference range and the free T4 is elevated then this is indicative of hyperthyroidism.
Other testing options
In the vast majority of cases the use of total T4 and free T4 testing will be enough to confirm a diagnosis.
However, other testing options are available. The main alternative tests are the T3 suppression test and TRH stimulation test.
The T3 suppression test involves collecting a basal blood sample for total T4 and total T3, giving oral T3 supplementation and then collecting a second blood sample to measure total T4 and total T3 levels again. A normal animal will show a marked reduction in T4 because production is being blocked by the negative feedback effect of this T3 on the hypothalamus and pituitary. Hyperthyroid cats would have little or no decrease in serum T4 because the thyroid gland is secreting T4 independent of normal control. It is important to measure total T3 as well as total T4 to confirm that the cat actually absorbed the oral T3 dose. A detailed testing protocol can be obtained from your laboratory.
Other testing options
TRH stimulation can be associated with adverse side effects and should be used with caution. The basic principle is that administration of artificial TRH should increase TSH and so increase T4 production. The response produced by a hyperthyroid cat will be lower as negative feedback will have shut down this pathway because the thyroid is autonomously producing T4. Hyperthyroid cats therefore generally show little or no rise in total T4 from a high or high-normal baseline. There is a grey area in result interpretation and this test cannot differentiate sick euthyroids from hyperthyroids. Again, a detailed protocol for this test can be obtained from your laboratory.
Other testing options
Early reports suggest that the assay for measuring canine TSH is capable of measuring feline TSH, and that this test may be useful in evaluating early cases of hyperthyroidism. Hyperthyroid cats will have low levels of TSH, because the high levels of T4 and T3 have a negative feedback effect on the hypothalamus and pituitary gland. Finding detectable levels of TSH in a cat using the canine TSH assay would exclude hyperthyroidism.
However, this test has poor sensitivity at the low end of the reference range, and therefore if a zero result or a very low result is obtained, this may not be accurate. Various studies are currently evaluating a feline specific TSH assay.
Diagnosis flow chart
This flow chart shows the recommended process for diagnosing hyperthyroidism.
In an animal with a compatible history and clinical signs, you are looking to measure total T4, haematology and biochemistry.
If the total T4 is elevated, then this confirms your diagnosis.
If the total T4 is within the reference range but you are still suspicious that the cat is hyperthyroid based on the clinical signs, there are three options.
The first step would be to rule out concurrent disease. Since the majority of cats with hyperthyroidism are middle aged or older the frequency of concurrent disease can be high. These concurrent diseases are often potentially serious and so this must be investigated before any other steps are taken.
Once concurrent disease has been ruled out there is a choice between repeating the measurement of total T4 after two to three weeks or measuring free T4. Repeating the total T4 will be most applicable if you think that it may be an 'early' case and the cat is otherwise clinically stable.
Treating hyperthyroidism
The aim of treating hyperthyroidism is to reduce the high circulating concentration of thyroid hormones by either inhibiting thyroid hormone production or by destroying or removing the abnormally functioning thyroid tissue.
Treatment for hyperthyroidism can be either reversible or permanent.
The three treatment options currently available are medical treatment (which is reversible) and surgery or radioactive iodine which are both permanent treatments.
Treatment is usually selected on a case by case basis taking into account many individual factors such as the presence of any underlying disease, the severity of the condition, the facilities available, owner and cat compliance and also the owner's wishes.
Medical treatment
The drugs currently licensed for medical treatment of hyperthyroidism in the UK are thiamazole (which is often called methimazole especially in American references) and carbimazole.
Both drugs belong to a group called the thioureylene antithyroid drugs. In fact, once carbimazole is ingested it is converted to thiamazole and only exerts its antithyroid effect once converted.
Medical treatment
These drugs actively concentrate in the thyroid gland and work by inhibiting the enzyme thyroid peroxidase which in turn blocks T4 and T3 synthesis.
Medical treatment
Initial medical management to achieve euthyroidism is indicated for virtually all cases, even if surgery or radioactive iodine are likely to be selected for long-term treatment. Initial medical management has some key advantages.
One key benefit is a reduction of the risks and dangers associated with surgery and anaesthesia in an unstable hyperthyroid cat.
In addition, all treatments for hyperthyroidism can unmask renal disease. These cases will need careful management and this issue is discussed further in future sections.
The recommended initial treatment plan for any cat diagnosed with hyperthyroidism should therefore involve an induction phase to establish euthyroidism.
At the end of the induction phase you should measure total T4, take routine bloods and discuss with clients about how their cat is doing and how they are managing with the medication.
A decision can then be made about the long-term management of the case.
Unmasking of renal disease
Hyperthyroidism causes an increase in renal blood flow. This leads to increased glomerular filtration rate and so improved renal function.
Glomerular filtration rate is the volume of fluid filtered from the kidney glomerular capillaries per unit time.
This means that in cats with Hyperthyroidism, underlying subclinical renal dysfunction may be masked.
Once treatment has started and the cat becomes euthyroid, renal blood flow will decrease and this leads to reduced glomerular filtration rate and so "unmasking" of any underlying renal problem.
It is also worth noting that serum creatinine is often low before treatment in hyperthyroid cats, even if there is underlying renal dysfunction, as these animals are often cachexic and creatinine originates from muscle protein. Creatinine levels often rise during treatment and following establishment of euthyroidism.
Predicting unmasking of renal disease
A recently published paper by Riensche and colleagues looked for evidence of a way to predict renal insufficiency in hyperthyroid cats. This paper retrospectively looked at data including serum total T4, urea and creatinine levels and also urine specific gravity prior to treatment of hyperthyroidism.
They divided animals into 2 groups: Group 1 comprised 19 hyperthyroid cats which showed no evidence of renal insufficiency following six months of treatment. Group 2 included 20 cats that developed renal insufficiency within six months of treatment. Renal insufficiency was judged to be present by the existence of azotaemia and a urine Specific Gravity which was less than 1.030.
The researchers found no significant difference in pre treatment values of total T4, creatinine, urea and urine Specific Gravity between the two groups and so concluded that there was no reliable predictor of renal insufficiency.
The group also found that cats with a urine specific gravity greater than 1.035 prior to treatment can still develop renal insufficiency.
However, this was a relatively small study and the investigators stated that additional research would be useful to look at this issue in more depth with a prospective study. This would involve both a larger study population and measuring additional factors such as blood pressure, urine protein:creatinine ratio (UP:CR) and condition score.
Until further work is done, the authors advocate initial medical therapy as the best option to assess the effect of euthyroidism on renal function prior to embarking on permanent therapy.
Long term medical management
Long term medical treatment has several advantages compared to other treatment options.
Firstly, medical treatment will treat hyperthyroidism no matter where the abnormal thyroid tissue is located. This means it is also effective against ectopic thyroid tissue which we discussed earlier.
Medical treatment is also reversible within 24 to 72 hours of stopping administration of the drug and this is important if any underlying renal disease is present.
Furthermore, medical management avoids the risks of anaesthesia which will be higher for this older population, and the treatment is widely and readily available.
The main disadvantage of medical treatment is that it is not curative and so will need to be continued for the rest of the cat's life. It is also possible that the dose may need to be increased over time.
In addition, medical treatment is less suitable for suspected carcinomas as these cases ideally need an intervention that addresses the underlying lesion rather than just controlling the excessive hormone production.
Another issue is that for medical management to work, owner (and cat) compliance with the treatment has to be good. In those cases where clients find it difficult to pill their cats a more permanent solution (such as surgery or radioactive iodine) could be more appropriate.
Permanent, one-off treatments may also be more appropriate for those rare younger cats that develop hyperthyroidism.
Radioactive iodine treatment
As we demonstrated earlier the thyroid hormones are synthesised from iodine in the blood.
In this treatment radioactive iodine is injected subcutaneously and travels to the thyroid gland.
The thyroid cells take up the radioactive iodine, but the abnormal thyroid cells take up more of the radioactive iodine than normal cells.
The radioactive iodine emits radiation that only travels a maximum of 2 millimetres in tissue and so destroys the abnormal tissue, but spares the surrounding normal tissue.
Radioactive iodine treatment
As with Medical Management of hyperthyroidism, Radioactive iodine treatment has both pros and cons.
The positive aspects of radioactive iodine are that it is simple (requiring a straightforward subcutaneous injection), effective (with success rates generally quoted as being 95% or above) and permanent (with a reported recurrence rate of less than 1%).
In addition it only destroys abnormal thyroid tissue and is effective against both ectopic tissue and thyroid carcinomas.
The negative aspects of radioactive iodine include the fact that treatment requires referral and there are only a few centres that offer this treatment in the UK. This can mean lengthy waiting lists.
In addition there is a requirement for extensive post treatment hospitalisation in an isolation ward with minimal human contact because treated cats will be radioactive. The current minimum stay in the UK is 3 weeks. The need for isolation means that radioactive iodine is not suitable for cats with some underlying conditions. Because handling of these cats post injection must be minimal for human safety, animals requiring regular medication for other conditions do not make good candidates.
Cats will need a full diagnostic work up prior to treatment and isolation to ensure that there is no underlying disease present that would need attention urgently during the period when they can't be handled.
Another factor is the cost. The current cost of this treatment is in the region of £1250-£1650.
Surgical thyroidectomy
Surgical thyroidectomy involves the removal of either one thyroid gland lobe in a unilateral thyroidectomy or both lobes in a bilateral thyroidectomy. Both options have their pros and cons.
Since 70% of cases involve bilateral hyperplasia it might seem sensible to opt for a bilateral procedure as standard. However care must be taken to preserve the parathyroid glands & their blood supply.
The parathyroid glands produce Parathyroid Hormone (PTH) which regulates calcium & phosphorus concentrations in the body. If the parathyroid glands are damaged during the procedure, then the cat may develop life threatening hypocalcaemia.
If opting for a unilateral procedure it is possible for the other lobe of the thyroid gland to become hyperplastic at a later date. If this happens a second surgery will be needed.
Surgical thyroidectomy is complicated further if ectopic tissue is present. Ectopic tissue can only be reliably detected by scintigraphy, and in any case, is frequently difficult to access surgically.
Surgical thyroidectomy
The advantages of surgical thyroidectomy are that it can be curative and that the procedure is offered in general practice.
However, all surgical procedures have their risks and these are generally higher in older patients that are more likely to have other concurrent diseases. Most hyperthyroid cats are senior cats over 10 years of age and as hyperthyroidism can affect the cardiovascular system the anaesthetic risk is further increased.
Surgical complications for thyroidectomies include potential damage to the parathyroid glands, which leads to post-operative hypocalcaemia. Less commonly nerve damage can occur.
Other disadvantages include the fact that surgery may not resolve the condition. This can occur if ectopic tissue is present or in cases where a unilateral procedure has been selected and the remaining lobe of the thyroid gland was either already hyperfunctional, but relatively normal in appearance, or becomes hyperplastic at a later date.
It is good practice to warn the owner prior to surgery of the possibility of ectopic thyroid tissue and the possibility that the condition may recur, even if a bilateral procedure has been performed.
Felimazole
Felimazole was the first medical treatment for feline hyperthyroidism licensed in the UK and Europe. It is indicated for both stabilisation of hyperthyroidism in cats prior to surgical thyroidectomy and long-term treatment of feline hyperthyroidism.
Felimazole tablets contain the active ingredient thiamazole (which is also sometimes referred to as methimazole).
Felimazole tablets are small and sugar coated for ease of administration. The main purpose of the sugar coating is to protect the owner from exposure to the active ingredient, and the sugar coating also masks the taste of thiamazole. The sugar coating is not an enteric coating.
The tablets are available in two strengths which are colour coded - 2.5mg tablets are pink and 5mg tablets are orange.
This colouring enables clear differentiation of tablet strengths.
Pharmacodynamics of Felimazole
Thiamazole acts as a substrate for the enzyme thyroid peroxidase, blocking the synthesis of T4 and T3.
As medical treatment has no effect on pre-formed stores of T4 and T3, it takes a few weeks for there to be a marked reduction in the T4 levels measured.
If treatment is stopped, inhibition is reversed and T4 levels recover in 24 to 72 hours. This means that it is important that a cat has all the tablets due on the day that a monitoring blood test is taken and for the 2-3 days prior to the blood test.
This is also why compliance with medication is important. If there is poor compliance, the level of T4 will rapidly climb back to pre-diagnosis levels.
Pharmacodynamics of Felimazole
Although plasma concentration correlates with tissue concentration and duration of drug action for many drugs, this is not true for drugs such as thiamazole that are actively concentrated at their target sites.
Elimination of the drug from cat plasma is rapid, with a terminal elimination half life of three and a half to four hours. However, in the second edition of "Small Animal Clinical Pharmacology" published by Elsevier in 2008, Dr Carmel Mooney states "Thiamazole is actively concentrated by the thyroid gland within minutes of absorption. Thus the effect of thiamazole is likely to be more prolonged than the half-life suggests. The intra-thyroidal residence time may be 20 hours in cats as it is in humans".
Therefore, in summary, even if thiamazole cannot be detected in the serum, this doesn't mean that it isn't working in the thyroid gland.
Pre-thyroidectomy stabilisation
The recommended dosing regime for pre-thyroidectomy stabilisation is one 2.5mg tablet morning and evening. This is independent of body weight and Total T4 levels.
A clinical study carried out as part of the regulatory submission for Felimazole showed that after 3 weeks, 81% of cats had stabilised on 2.5mg twice daily.
This graph shows the changes in the average Total T4 for 52 cats being treated with Felimazole as part of this clinical study.
Mean average total T4 was measured prior to starting treatment and then after 3 weeks, 6 weeks, 10 weeks, 15 weeks and 20 weeks of treatment.
After 3 weeks of treatment, the average T4 level had dropped to within the reference range and remained within the reference range for the duration of the study.
Long-term treatment
The recommended dosing regime for long-term treatment with Felimazole is one 2.5mg tablet morning and evening. This is again independent of body weight and Total T4.
After three weeks haematology, biochemistry and Total T4 should be assessed and the dose titrated to effect.
If after three weeks the Total T4 level is within the reference range and there are no signs of adverse reaction then this dose should be continued until the next follow up appointment.
The availability of 2.5mg and 5mg sizes of Felimazole enables flexible dosing. If the Total T4 level is below the reference range, then the dose should be reduced by 2.5mg.
If on the other hand the Total T4 level is still above the reference range but the level has decreased significantly from the pre treatment level then the current dose should be continued for a further three weeks and then reassessed.
If the Total T4 level is still above the reference range and there hasn't been a significant decrease in this level then the dose should be increased by 2.5mg.
The total dose administered must not exceed 20mg/day.
After any dose adjustment the monitoring program should be restarted with a follow up appointment after three weeks.
Wherever possible, the total daily dose should be divided into two and administered morning and evening. However, once a day dosing with a 5mg tablet is acceptable for reasons of compliance.
Felimazole Tablets should not be split or crushed to ensure that the owner is not exposed to the active ingredient.
The aim should be to achieve the lowest possible dose rate and the animal should be treated for life.
Monitoring treatment
As part of the long-term treatment of hyperthyroidism with Felimazole it is important that the cat is monitored on a regular basis.
Haematology, biochemistry and Total T4 should be assessed before initiating treatment.
These parameters should then be assessed after 3 weeks, 6 weeks, 10 weeks, 20 weeks and thereafter every 3 months.
The dose should be titrated as necessary based on the results of these tests and if a dose adjustment is made you should return to the start of the monitoring protocol.
Monitoring T4 levels
It has been shown that when measuring T4 levels with the total T4 test, the timing of the test in relation to tablet administration is not important.
However it is important that the owner has given all the tablets due on the day of the test and all those for 2-3 days prior to the blood test because Total T4 levels will increase within 24-72 hours if tablets are missed.
The aim is to achieve total T4 within reference range, preferably the lower half of the reference range. The dose should be titrated to effect according to the serum Total T4, in increments of 2.5mg, if this has not been achieved.
Why monitor biochemistry?
All hyperthyroidism treatment regimes can 'unmask' renal disease as discussed earlier in this program.
Taking a blood sample for biochemistry at the time of the initial investigation of hyperthyroidism allows assessment of renal function prior to treatment.
The data sheet for Felimazole states that 'Use of the product in cats with renal dysfunction should be subject to careful risk: benefit assessment by the clinician. Due to the effect thiamazole can have on the glomerular filtration rate, the effect of therapy on renal function should be monitored closely as deterioration of an underlying condition may occur'.
It is important to judge the effect of treatment on the animal clinically.
The aim is to achieve a balance between treatment of hyperthyroidism and maintenance of adequate renal function.
Consideration should also be given to additional appropriate treatment for renal insufficiency.
Why monitor biochemistry?
Over 90% of hyperthyroid cats have elevations in alanine aminotransferase (ALT), alkaline phosphatase (ALKP), lactate dehydrogenase (LDH) and aspartate aminotransferase (AST).
These should be proportional to the increase in Total T4. Presence of concurrent hepatopathy should be considered if there is a marked elevation of liver enzymes with only a mild increase in Total T4.
It is also worth remembering that serum liver enzyme half-lives in cats are short. The half-life for ALT is approximately 6hrs and that for ALKP is just minutes. Therefore, the levels of these enzymes should decline and may return to reference range with successful induction of euthyroidism.
Felimazole is contraindicated in primary liver disease. While the metabolism of thiamazole in cats has not been investigated, the liver is important for the metabolic degradation of the compound in humans. Therefore, if there is significant elevation in hepatic enzymes with only a mild increase in total T4, further tests of liver function, for example the bile acid stimulation test, should be considered prior to commencement of Felimazole therapy. The appearance of the liver could also be assessed with an ultrasound scan.
Finally, icterus associated with hepatopathy is a known adverse reaction to Felimazole, and it is important to consider this possibility if hepatic enzymes are rising whilst on treatment. Progression of underlying primary hepatic disease would be another possible explanation for a rise in hepatic enzymes while on treatment.
Why monitor haematology?
Haematological abnormalities are known adverse reactions to thiamazole.
Mild abnormalities include subclinical eosinophilia, lymphocytosis, lymphopenia and slight leucopenia.
More severe abnormalities include neutropenia, agranulocytosis, thrombocytopenia, and haemolytic anaemia.
Agranulocytosis is also known as granulocytopenia and involves a decrease in levels of neutrophils, basophils and eosinophils.
Monitoring haematology allows you to check for the abnormalities that are known adverse reactions to Felimazole and to modify or cease treatment accordingly.