Feline hyperthyroidism

Feline hyperthyroidism is an endocrine disorder in which the thyroid gland produces too much thyroid hormone. Hyperthyroidism is the most common endocrinopathy of cats. The complete pathogenesis is not fully understood.

Background
In 1979 the first clinical report of a cat with hyperthyroidism was reported. More studies and greater awareness would follow and today hyperthyroidism is a common condition in small animal practice. Whether that is due to increased prevalence or better testing is not entirely agreed upon.

A study in 1987 transplanted thyroid tissue from affected cats into nude mice. The mice were administered levothyroxine, which suppresses thyroid-stimulating hormone. The thyroid cells remained in the hyperthyroid state. This study helped provide evidence for thyroid dysfunction as the cause rather than thyroid stimulation.

Causes
The majority of cases of hyperthyroidism in cats are the result of benign tumours. The most commonly identified abnormalities of the thyroid gland in hyperthyroid cases are follicular cell adenoma and multinodular adenomatous hyperplasia. 1% to 3% of feline hyperthyroid cases are caused by malignant tumours. These are not always able to be distinguished from benign tumours.

It is believed that the cause of hyperthyroidism is multifactorial. Studies have identified different mutations as causing thyroid cell autonomy.

Iodine
Excessive iodine administration has been hypothesised as causing thyrotoxicosis in cats, as it does in humans; however, cats have been shown in multiple long terms studies to be able to regulate their levels of thyroid hormone within safe ranges when administered iodine. Iodide intake and it's effects are unknown.

Soy isoflavones
Soy is often used in commercial cat food diets as a vegetable protein. In one study more than half of commercial cat foods surveyed contained soy isoflavones. Genistein and daidzein, both of which occur in soybeans, inhibit the enzymes thyroid peroxidase and thyroxine 5-deiodinase. This causes decreased thyroxine and triiodothyronine concentrations. In response to decreased triiodothyronine levels the body will produce more thyroid-stimulating hormone to normalise triiodothyronine levels, this has been shown to result in increased thyroxine levels. In addition these effects are heightened when a cat is suffering from iodine deficiency. However, further research is needed to confirm a link between soy isoflavones and hyperthyroidism.

Goitrogens
Goitrogens are chemicals that disrupt thyroid hormone production. Chemicals such as bisphenol A and polybrominated diphenyl ethers have been shown to exist in indoor cats at heightened levels and are hypothesised to be a potential cause of hyperthyroidism. Bisphenol A is common in canned cat foods, although no association between it and hyperthyroidism has currently been demonstrated. Polybrominated diphenyl ethers (PBDEs) are often used as fire retardants and are known to be a goitrogen; however, levels of these chemicals have been shown to be the same in euthyroid cats as hyperthyroid cats. No association has been proven in a study for the association between PBDEs and hyperthyroidism.

Signs and symptoms
Hyperthyroidism is a disease that slowly progresses and symptoms are very subtle at first. It can take up to two years from onset of symptoms for a diagnosis of hyperthyroidism to be made.

The most common symptom is weight loss, occurring in 98% of hyperthyroid cases. Other symptoms that occur more than 50% of the time, include: a palpable thyroid gland (91%); polyphagia (81%), without obesity; restlessness (76%); tachycardia (66%); polydipsia and polyuria (60%); emesis; and cardiac murmur (53%).

Less common symptoms include: diarrhoea (33%), increased volume of faeces (31%), anorexia (26%), polypnoea (25%), myasthenia (25%), muscle tremors (18%), congestive heart failure (12%), excessive nail growth (12%), and dyspnoea (11%).

Systolic hypertension is reported in 10-15% of cats that have been diagnosed with hyperthyroidism. Some normotensive hyperthyroid cats develop hypertension after having their hyperthyroidism treated. The reasons for this are not currently known.

Cachexia is a possible symptom in hyperthyroid cats but due to improved screening and diagnostics it is less common for a cat to become cachectic before starting treatment.

Ventroflexion of the head is a rare symptom observed in hyperthyroid cats but the last case report is from 1994. Due to the rarity the pathogenesis behind this is not known.

Cardiac conditions have become less common over the years in hyperthyroid cats due to earlier diagnosis and improved treatment. The most common cardiovascular issues are tachyarrhythmias, cardiac murmurs, and gallop rhythms. The cause of these conditions is due to how triiodothyronine increases cardiac output.

Symptoms of hyperadrenocorticism can occur in hyperthyroid cats. Adrenocorticotropic hormone levels are raised in some hyperthyroid cats and some studies have documented acromegaly in hyperthyroid cats.

Risk factors
Multiple case control studies have looked at diet and hyperthyroidism. These studies have found associations between commercial diets and hyperthyroidism. Other risk factors identified include non-Siamese related breeds, lack of outdoor access, flea medication, pesticides, certain cat litters, female sex, sleeping on the floor, organic fertiliser, human baby food, carpet cleaners, natural gas, lack of deworming, and a fish diet. These mixed results suggest a multifactoral cause with diet being having an important role.

Age of onset
The age of onset has been reported to be between 4–22 years with an average of 13 years, with some individual cases occurring in cats below the age of 4 years. More than 95% of cases occur in cats 8 years and older.

Diagnosis
Testing for hyperthyroidism is routine for elderly cats and standard blood tests that can be performed in clinic allow for measurement of serum thyroxine levels. With this advancement diagnosis is often made before clinical signs are well noticeable and severe.

Diagnosing hyperthyroid cats is not just to confirm the presence of the condition but also what symptoms are present. For example more serious cardiac conditions require special treatment compared to a cat without any serious cardiac abnormalities. Cats with hyperthyroidism should have a complete blood count test, a biochemistry profile of blood serum, urinalysis, measurement of thyroxine serum levels, thoracic radiography, and measurement of blood pressure. If heart disease is suspected electrocardiography and echocardiography should be performed.

Measurement serum thyroxine levels is the best method of confirming hyperthyroidism. Measurement of serum concentrations triiodothyronine are not useful for diagnosing hyperthyroidism and neither is measurement of serum thyroid-stimulating hormone levels. Thyroxine levels on their own should not be used to diagnose hyperthyroidism: if a patient is displaying no symptoms of hyperthyroidism but test results show heightened serum thyroxine levels the possibility of other causes such as an error in the test have to be considered and excluded before establishing a diagnosis.

Complete blood count
Common findings of a complete blood count on a hyperthyroid cat include a small increase in packed cell volume (40-50%), macrocytosis (20%), and Heinz bodies. Anaemia is rare. Increased erythrocyte count is due to thyroid hormone stimulating erythropoietin secretion. Leukocytes and thrombocytes usually have normal results, some changes may occur but these are not specific and are not consistent.

Serum chemistry
The most commonly noticed change in serum chemistry is a non-major increase in liver enzymes. More than 90% of hyperthyroid cats have an increase in either serum concentration of alanine aminotransferase and alkaline phosphatase, with more than 75% of cats having an increase in both. These increases are small and typically below 500 IU/L. Higher increases may be due to hepatic disease, although many other conditions can cause an increase in liver enzymes.

Fructosamine concentrations are lowered by serum protein metabolism, which is increased in hyperthyroid cats. Fructosamine concentrations are significantly lower in hyperthyroid cats, with half of hyperthyroid cats having levels outside the reference range. Following treatment for hyperthyroidism these concentrations rise to normal levels. Diabetes mellitus also affects fructosamine concentration and this should not be relied on in diabetic cats. Hyperglycaemia can occur in hyperthyroid cats independent of diabetes mellitus. Frucotsamine measurement cannot reliably differentiate non-diabetes related hyperglycaemia.

Blood urea and creatinine
In roughly 10% of hyperthyroid cats serum creatinine levels are increased to the point of azotemia. In 10-20% of cats increased serum concentration of blood urea nitrogen is observed. Although the prevalence of hyperthyroid cats with chronic kidney disease is higher than this due to how hyperthyroidism results in an increase to the glomerular filtration rate. Most cats with chronic kidney disease and hyperthyroidism have the kidney disease go undiagnosed until after treatment for hyperthyroidism has begun. Between 15% and 49% of non-azotemic hyperthyroid cats will develop azotemia following treatment for hyperthyroidism. Further complicating the diagnosis is the shared symptoms between the conditions. It is not currently known whether the effects of hyperthyroidism cause or worsen renal disease. Chronic kidney disease is not an uncommon condition in elderly cats further complicating determination of a relationship between the two conditions.

Urinalysis
Common abnormalities found during urinalysis of hyperthyroid cats include: decreased urine specific gravity, proteinuria, symptoms of urinary tract infections, and ketonuria.

Decreases to urine specific gravity are likely not the result of hyperthyroidism but instead due to chronic kidney disease. In a 2009 study most cats that had been treated for hyperthyroidism with radioactive iodine did not have changes to urine specific gravity levels.

Proteinuria is reported in 75–80% of cats with hyperthyroidism. Likely causes of this are glomerular hyperfiltration and glomerular hypertension, and structural changes in the glomerular filtration barrier.

Radiography
Thoracic radiographs do not help diagnose hyperthyroidism, instead they help diagnose concurrent illnesses like thoracic neoplasia. If respiratory distress, tachypnoea, tachycardia, arrhythmia, or heart murmur are observed then thoracic radiographs should be taken. Congestive heart failure is uncommon. The most common finding is cardiomegaly.

Echocardiography
The most common echocardiographic abnormalities in hyperthyroid cats is hypertrophy of the left ventricular caudal wall and interventricular septum. The effects of thyroid hormone are known and explain most cardiac abnormalities; however, one study found only 37% of hyperthyroid cats to have an echocardiographic abnormality, with 32% having abnormalities following treatment.

Clinical examination
Multiple clinical signs that support a diagnosis can be observed in hyperthyroid cats during a clinical exam. The most useful symptoms for this is weight loss with concurrent polyphagia and tachycardia.

A goitre is swelling from an enlarged thyroid gland. This does not occur in all cases of hyperthyroidism, even those caused by adenoma; however it occurs in most cases and is a common way to support a hyperthyroid diagnosis caused by adenoma. Other conditions can cause a cervical mass that may resemble a goitre.

Thyrotropin-releasing hormone stimulation
Following a test for blood serum thyroxine levels thyrotropin-releasing hormone can be administered to cats intravenously and after 4 hours another blood test can be taken to measure thyroxine serum levels. If the thyroxine levels have increased this indicates the cat is euthyroid but if levels remain stagnant it suggests hyperthyroidism. This test is rarely performed due to side effects. The most common side effects being: emesis, tachypnoea, and defecation.

Scintigraphy
Scintigraphy helps to show information on the thyroid gland and tumours affecting it. It is useful for identifying the size of the tumour, whether it is unilateral or bilateral, and how much radiation is required for treatment. Iodine-131, Iodine-123, and technetium-99m pertechnetate are all used for this. Pertechnetate is the most commonly used due it's low cost, quick uptake, and short half-life. Scintigraphy can also be used to confirm hyperthyroidism when clinical symptoms are present but serum thyroxine levels remain within reference. Drugs such as methimazole and anaesthetics can influence results if not discontinued before scintigraphy.

Ultrasonography
Ultrasonography is an alternative option to scintigraphy. Ultrasounds provide less information than scintigraphy but is easier and cheaper to conduct. Ultrasonography allows for the state of the thyroid gland to be evaluated and for an estimation of the volume but does not allow for evaluation of tissue.

Differential diagnosis
Polyphagia and weight loss are two concurrent symptoms that have multiple causes, including: diabetes mellitus, malnutrition, malabsorption, and maldigestion. If these symptoms occur serum thyroxine levels should be tested to confirm or exclude a diagnosis of hyperthyroidism.

Therapy
Currently, three therapy options are available for hyperthyroidism in cats: the use of thyrostatic drugs, surgical removal of the diseased thyroid tissue, and radioiodine therapy. Regardless of the procedure selected, subsequent treatment of concomitant and secondary diseases (e.g., kidney damage, high blood pressure, heart disease) is typically necessary. In order to ascertain the potential adverse effects of reduced thyroid hormone levels on renal function, a 30-day course of medication is recommended prior to the implementation of more radical measures such as thyroidectomy or radioiodine therapy.

Thyreostatics
Therapy with thyrostatic agents is relatively straightforward and is therefore the most commonly used. Thyrostatic drugs inhibit the formation of thyroid hormones, but, in contrast to other methods, do not eliminate the pathologically altered tissue. Nevertheless, these drugs can usually be used in long-term therapy without any problems or can also be used to stabilize patients before a surgical procedure. In veterinary medicine, thiamazole (syn. methimazole, trade names Felimazole, Felidale and Thiamatab) or carbimazole (trade name Vidalta) are employed. Carbimazole is rapidly converted into methimazole when administered orally. According to the manufacturer, side effects (including vomiting, lethargy, itching, liver disease, and blood count changes) occur in approximately 20% of cats, particularly with long-term treatment. However, these typically resolve once the drug is discontinued. Additionally, thiamazole cannot be used in cats with concomitant liver disease, diabetes, or blood clotting disorders.

Iopanoic acid may also be employed in the event of intolerance to thiamazole. It inhibits the conversion of T4 to T3 and has a negligible incidence of side effects.

Thyroidectomy
Although surgical removal (thyroidectomy) is an effective treatment, it is also associated with a high risk of complications, particularly in cats with severe hyperthyroidism, due to the inherent risks associated with anesthesia. Prior to the surgical procedure, it is common practice to administer thyrostatic drugs. There are several techniques for the removal of the thyroid gland, with the objective of preserving the epithelial cells to the greatest extent possible. Additionally, there is a potential risk of injury to crucial cervical nerves (recurrent laryngeal nerve, vagosympathetic trunk) during surgery. A total thyroidectomy results in a deficiency of thyroid hormones, which must be compensated for by lifelong administration. In the event of unilateral removal, a transient hypothyroidism frequently develops postoperatively, although this is typically not a cause for concern. Furthermore, there is a risk of recurrence with surgical removal, particularly in the presence of ectopic thyroid tissue.

Radioiodine therapy
Radioiodine therapy is the treatment of choice due to its efficacy and tolerability. A single treatment is typically sufficient, eliminating the need for long-term drug treatment (which can be problematic in some cats) and the risks associated with surgical removal. However, it is associated with significant radiation protection requirements and is currently only available at two veterinary facilities in Germany. In addition to the limited availability, the associated costs and the need for hospitalization represent a disadvantage. In close consultation with the responsible supervisory authorities, it has been possible to reduce the required duration of hospitalization from approximately three weeks to a few days. The necessary duration of hospitalization is determined by dosimetry and is seven to ten days.

Thermal or chemical destruction of the thyroid gland
Destruction of the thyroid tissue using a radiosurgical device under ultrasound control (thermal ablation) or by injection of 96% ethanol (chemical ablation) is practically no longer relevant. Both forms of treatment have increased side effects such as laryngeal paralysis or Horner's syndrome.