Feline hyperthyroidism

Spontaneous hyperthyroidism (thyrotoxicosis) is a clinical condition resulting from an excessive production and secretion of thyroxine (T₄) and triiodothyronine (T₃) by the thyroid gland. In 98% of cases of feline hyperthyroidism, the hormone excess is caused by a functional thyroid adenomatous hyperplasia (or, less frequently, by an adenoma) involving one, or more often (70-75%) both lobes of the gland. At histology, the thyroid lobes involved have one or more foci of hyperplastic tissue which, by merging, may form palpable nodules ranging between 1 mm and 3 cm in size. In the approximately 2% of remaining cases, the disease is caused by a carcinoma of the thyroid gland.

In the cat, the first isolated cases of hyperthyroidism were described in America in 1979; since then the incidence of the disease has increased exponentially both in America and in other parts of the world, and is currently one of the most common cat diseases. Based on studies and anatomopathological findings preceding these first reports, it is considered probable that feline hyperthyroidism was an extremely rare disease before that time, thus starting a debate on the still unclear pathogenesis of this endocrine disorder.

Although it is believed that feline hyperthyroidism might have a multifactorial aetiology, the hypothesis considered most probable to date is that in these cats a mutation of the thyroid receptors for TSH, or a mutation of the G proteins associated with them, may have occurred.

SIGNALMENT

Hyperthyroidism is the most common endocrine disorder found in elderly or middle-aged cats. The average age of subjects at the time of diagnosis is 12-13 years (range 4-22 years), of which fewer than 5% are under age 8. The disease can strike any subject with no predisposition for breed or gender.

CLINICAL SIGNS

The thyroid gland affected by nodular hypertrophy rarely becomes large enough to be noticed by the owners who, in the majority of cases, bring their cat in for a medical examination because of the progressive onset of symptoms resulting from the thyrotoxic state. The clinical signs are usually multi-organic; however, sometimes, the symptoms of the malfunction of a single system may predominate. The severity of the clinical picture upon presentation mainly depends on the duration of the state of hyperthyroidism and, given the mostly advanced age of the subjects, on the presence or absence of concomitant diseases.

In the clinical history in the majority of cases owners of cats suffering from hyperthyroidism report the presence of a progressive weight loss, almost always associated with polyphagia, which is erroneously interpreted by the owners as a sign of wellbeing. Other commonly reported gastrointestinal signs are vomiting, and occasionally diarrhoea (increased frequency, volume or steatorrhoea).Polyuria, accompanied by polydipsia, is present in around 50%of cats with hyperthyroidism and may reflect the presence not only of a thyrotoxic state, but also of other underlying diseases and especially of chronic kidney disease (CKD); however, this symptom is not always noticed or reported by the owner in the clinical history.

Affected cats are described as particularly hyperactive; during the examination they often manifest a state of agitation that causes them to be intolerant towards being handled or to be aggressive. These cats should always be handled gently, since the stress induced by particularly constrictive procedures like drawing blood can, in some extreme cases, cause cardiovascular insufficiencies.

Excessive leanness and poor condition of the haircoat, which is generally bristled and poorly groomed, are distinctive elements almost always detectable during the physical examination of cats suffering from hyperthyroidism, as are some cardiovascular alterations, which are the most significant clinical findings. Tachycardia, systolic murmur, gallop rhythm and, less frequently, arrhythmias are a frequent finding at the cardiovascular examination. In feline hyperthyroidism, cardiac symptoms are often associated with the presence of a hypertrophic cardiomyopathy which, in more advanced cases, may lead to a state of cardiac insufficiency even in the absence of other underlying heart diseases. Cats suffering from hyperthyroidism with a concomitant congestive heart failure are dyspnoeic, have a cough, and a gallop rhythm may be detected at cardiac auscultation; in these cats treatment is required for both hyperthyroidism and for cardiac insufficiency.

A mild state of hypertension, whose aetiology is often multifactorial (CKD), is commonly found in cats with hyperthyroidism. The hypertrophic cardiomyopathy and the other cardiovascular symptoms are generally reversible with the return to a state of euthyroidism.

Apathetic hyperthyroidism. The term apathetic hyperthyroidism is used to describe an atypical form of hyperthyroidism that occurs in a minority of cats with hyperthyroidism (10%). In these cats the characteristics of polyphagia and hyperactivity are replaced by anorexia and by a state of depression and generalised weakness. In these subjects, after a careful examination, the presence of severe concomitant diseases such as congestive heart failure or chronic renal insufficiency is frequently detected.

PALPATION OF THE THYROID GLAND

The presence of a goitre (neoformation) is only occasionally macroscopically visible, while in most cases palpation of the gland is instead necessary for its detection.Palpation of the thyroid gland is easily performed and should be considered an integral part of the physical examination in all cats, especially when they are over 8 years old. In the cat, the best technique for exploring the thyroid gland requires positioning the animal with its front limbs in extension and the neck in line with the limbs and kept slightly extended. In this position, holding the head with one hand, the second hand is to be passed gently along the trachea with thumb and index finger on opposite sides, with a top-down movement and vice versa, going from the larynx to the entrance of the chest near the manubrium. Under normal conditions, the thyroid gland cannot be explored through palpation; in the presence of nodules, these are felt as relatively movable structures ranging from 1 mm to 3 cm in size that will slide through the fingers.

Approximately 90% of cats with hyperthyroidism have one or more palpable nodules that involve one, or more often (70%) both lobes of the gland. Recent studies have shown that the larger the nodule(s) and the older the cat, the greater the probability that hyperthyroidism is indeed present; however, the presence of a nodule or even of a mass in the cervical region may also occur in a high percentage of euthyroid cats, or in cats with other non-thyroidal diseases (parathyroid hyperplasia, tumours); for this reason, the diagnostic suspicion should always be confirmed through laboratory tests or scintigraphy.

From: Feldman and Nelson: Canine and Feline Endocrinology and Reproduction, Saunders, 2004.

LABORATORY FINDINGS

Routine haematobiochemical tests and urinalysis usually do not reveal constant alterations specific for this disease; in spite of this, these tests are of considerable diagnostic aid especially for excluding or indicating the presence of other diseases which may be present in view of the advanced age of the subjects.

Complete blood count
The complete blood countof cats with hyperthyroidism may allow to detect a mature neutrophilic leucocytosis, which may be associated with lymphopenia and eosinopenia, considered indications of a state of stress in the animal; other detectable alterations are a slight increase in the haematocrit (HCT) and in mean corpuscular volume( MCV). Rarely, in some severe forms of hyperthyroidism, anaemia may be present, possibly caused by the depletion of the medullary reserves of iron or of other microelements as a result of excessive chronic stimulation.

Biochemical profile
The most noticeable alteration in the biochemical profile of cats with hyperthyroidism is the increase in liver enzymes (ALT, AST, ALP, LDH), which in some cases can be quite marked. In the case of ALP, the degree of the increase is positively correlated to the T₄ value. At histological examination, the liver of these subjects usually presents only mild, non-specific signs of damage; these signs, as well as their related laboratory alterations, are usually reversible following the treatment of the endocrine disorder. However, in those cases in which a strong increase in liver enzymes is only accompanied by a slight/moderate increase in thyroid hormones or if, following treatment, these values remain altered, it is reasonable to suspect and investigate the possible presence of a concomitant liver disease.

Twenty percent (20%) of cats with hyperthyroidism show a slight/moderate hyperazotaemia, generally alongside normal creatinine values. In around 40% of cats with hyperthyroidism a concomitant chronic kidney disease is present; nevertheless, in these subjects urea and especially creatinine are not sufficiently reliable parameters for a correct evaluation of kidney function, since their concentrations are affected by metabolic changes and by an increase in GFR secondary to the state of thyrotoxicosis.

In a high percentage of cats suffering from hyperthyroidism, serum fructosamine concentrations are lower than the reference range due to the increased protein catabolism, regardless of the total concentration of plasma proteins. In spite of this, blood glucose values may also be increased, indicating a state of stress in the animal.

Urinalysis
Urinalysis should always be included in the diagnostic protocol of cats with suspected hyperthyroidism, as it allows to investigate the possible presence of polyuria and to exclude or confirm eventual other diseases such as diabetes mellitus or a urinary tract infection. In cats with hyperthyroidism, the urine specific gravity (USG) has proven to be particularly variable, with a range between 1009 and 1050; in the majority of cases, this parameter does not change significantly following treatment of the endocrine disorder. In addition, preliminary studies have also shown that a pre-treatment USG below 1030 may be considered as a predictive factor for the presence and subsequent post-treatment manifestation of a chronic kidney disease.

The presence of proteinuria (in the absence of urinary tract infections) is another frequent finding, also among non-hyperazotaemic cats with hyperthyroidism; the severity of proteinuria is reduced considerably with the treatment of hyperthyroidism.

SPECIFIC THYROID FUNCTION DIAGNOSTIC TESTS

The diagnosis of hyperthyroidism is confirmed by increased concentrations of circulating thyroid hormones or by an increased uptake of radioisotopes during the scintigraphic examination.

Basal hormone concentrations
The increase in basal thyroid hormone concentration is indicative of a state of hyperthyroidism; in most cases there is an increased concentration of both T₄ and of free T₄and T₃,reaching values that exceed by many times the upper limits of reference ranges. In some cases, however, the concentration of T₃ may stay within the reference range, and hence the determination of this parameter for diagnostic purposes is not advised; the measurement of T_4, and possibly of the more sensitive but less specific (more false positives compared to T4) free T₄  by equilibrium dialysis, are instead indicated for the diagnosis. At the time of examination, only around 5% of cats with hyperthyroidism have normal T₄ concentrations (within the range), which can occur in the initial stages of the disease, as a result of considerable hormonal fluctuations during the day, or as a result of the presence of concomitant non-thyroidal diseases that can suppress the circulating levels of T₄. The finding of decreased T₄ and increased free T₄ values should instead be interpreted with caution, since in some subjects with euthyroid sick syndrome this latter parameter may result increased (false positive result).

In doubtful cases in which, based on the clinical findings, a strong suspicion of hyperthyroidism is present, it is advisable to perform an additional hormonal assay after 2-6 weeks, or to rely on dynamic thyroid function tests (T₃ suppression test).

Thyroid gland scintigraphy
In cats with hyperthyroidism, the percentage of thyroid uptake of radioisotopes (I_¹³¹ or I_¹²³or preferably of TcO₄-_^99m) 20 and 60 minutes after their intravenous administration is significantly higher  compared to euthyroid subjects, and is positively correlated with the circulating levels of T₄. Scintigraphy allows to detect the possible presence of hyperfunctioning ectopic thyroid tissue or the presence of distant metastases in the rare cases of thyroid gland carcinoma. Compared to hormonal evaluations, thyroid scintigraphy is a more sensitive diagnostic technique in the early stages of the disease or in the presence of concomitant non-thyroid conditions. Thyroid scintigraphy also allows to exclude hyperthyroidism in subjects with a false free T₄ measurement.

The main limitations of scintigraphy are correlated with the need for sophisticated equipment in order to perform the examination and with the high costs. Treatment with methimazole may alter the results of the scintigraphic examination (false negative results), hence in such cases results must be interpreted with caution.

TREATMENT

In 98% of cases feline hyperthyroidism is a disorder due to a benign neoplasm; although benign, if not properly treated it may result in a severe and progressive impairment of the animal, as a result of the state of thryrotoxicosis. The aetiopathogenetic mechanisms capable of causing the disease in cats are still unknown, and thus treatment is aimed at directly controlling excessive hormone production by the thyroid neoplasia. To this end, three therapeutic options are available, each of which presenting advantages and disadvantages that should be carefully evaluated for each individual patient.

• Destruction of the neoplastic tissue with radioactive iodine
• Surgical thyroidectomy
• Inhibition of hormone secretion with antithyroid drugs

Treatment with radioactive iodine
In view of its high therapeutic efficacy and the relative absence of complications, radioactive iodine therapy is considered the treatment of choice for feline hyperthyroidism. However, due to the radioactive potential of the agent used, this treatment can only be carried out in authorised facilities, which explains why its use is still limited.

The β radiations of I_¹³¹ selectively destroy hyperfunctioning thyroid cells, sparing normal thyroid tissue. The radioactive agent may be administered orally, intravenously or subcutaneously and a single administration is usually sufficient to attain the therapeutic effect (a second treatment is needed in only 5% of cases). The treatment requires hospitalisation and isolation of the cat for at least one week after the administration of I_¹³¹ because of the high degree of elimination of radiation through faeces and urine.

Radioactive therapy is especially advantageous in cats with bilateral thyroid lobe involvement, in the presence of pathological ectopic thyroid tissue, or in the rare cases of carcinoma of the thyroid gland. The possible complications associated with the use of this treatment are related to the possible onset of a nephropathy, not caused by the treatment itself but by the return to a euthyroid state in subjects in whom the hyperthyroidism present before treatment was masking the presence of the disease. Before implementing this treatment it is therefore advisable to first check, with the aid of medical antithyroid treatment, whether the concentration of T₄ can be reduced safely without causing renal failure.

Surgical treatment
Uni- or bilateral thyroidectomy is a quick, effective and relatively easy procedure, and is often the preferred treatment approach for the disease in clinical practice. In 70% of cases adenomatous hyperplasia involves both thyroid lobes, even though bilateral involvement is not always recognised in view of the small size of the neoformations. In these cases, if a unilateral thyroidectomy is performed, a recurrence of the disease can be observed months later.

Before performing the surgical operation, treatment with antithyroid drugs for at least two weeks is indicated, in order to stabilise the patient especially from the cardiovascular point of view.

Thyroidectomy can be performed using extra- or intracapsular techniques; however, the latter technique is preferable, as it reduces the risk of impairment (damage or removal) of the adjacent parathyroid gland. If a bilateral thyroidectomy is performed the main postoperative complication is the onset of iatrogenic hypoparathyroidism, which is generally temporary; for this reason, after this type of operation serum calcium concentrations should be monitored for at least one week. Hypocalcaemia should only be treated if clinical signs are present or if serum calcium concentrations are below 6.5 mg/dl, even in the absence of clinical symptoms.

Medical treatment
Medical treatment is a practical option that does not require the use of special equipment and, at least initially, is not expensive. With the exception of the rare cases of thyroid gland carcinomas, medical treatment has few contraindications, mostly connected above all with the onset of side effects.

The more commonly used drugs in both human and veterinary medicine for the long-term control of hyperthyroidism are the thiouracil derivatives: carbimazole and methimazole (thiamazole). These drugs inhibit the action of the thyroid peroxidase enzyme and consequently block the synthesis of thyroid hormones. When hormone production is inhibited a rapid return to a condition of euthyroidism is generally observed, in around 2-4 weeks after the start of treatment. Compared to the treatment with radioactive iodine and to thyroidectomy, these drugs allow a reversible control of the disease: 24-72 hours after discontinuation of the drug, the cat returns to a state of hyperthyroidism. Although this is considered a negative aspect, in some situations this result may be considered advantageous: it can be used to test whether with the return of euthyroidism the cat develops an overt renal failure or before thyroidectomy to stabilise the patient.

In Europe, the drug registered for veterinary use for the treatment of hyperthyroidism is carbimazole. After oral administration the drug is metabolised and converted into methimazole, the molecule with antithyroid properties. A 5 mg dose of carbimazole is equivalent to approx. 3 mg of methimazole.

The initial dosage of carbimazole is 2.5-5 mg/cat (or 1.25-2.5 mg/cat of methimazole) once or twice a day. Methimazole, like carbimazole, is a drug that, if well tolerated by the subject, has an efficacy greater than 90% in the treatment of hyperthyroidism. The most common side effects of methimazole are anorexia, vomiting and lethargy. These symptoms generally arise within the first 4 weeks from the beginning of treatment and they can be resolved by reducing the dosage or by using the transdermal formulation of methimazole. In some cases more severe adverse reactions to the drug have been reported, including: blood dyscrasia (thrombocytopenia, leukopenia), facial excoriations from self-trauma and liver disease. In these cases the administration of the drug should be discontinued.

Transdermal methimazole: in the cat, methimazole may be more easily administered transdermally, using a pharmaceutical preparation expressly formulated with PLO (pluronic lecithin organogel). The owner, wearing gloves, should apply the ointment 2 times a day, to the inner pinna. The starting dose is 2-2.5 mg/cat every 12 hours. The bioavailability of the drug is inferior compared to that of the formulation for oral administration, and hence the efficacy is lower. Nevertheless, this formulation is especially advantageous for those cats in whom tablets are difficult to administer, and especially if tablets are associated to the appearance of gastrointestinal effects.

Therapeutic monitoring
The first control after the beginning of treatment is at 2-4 weeks, to test the concentration of T₄, to exclude the onset of possible drug adverse reactions and to monitor renal function. It is important to evaluate renal function and T₄ concentration simultaneously during treatment, to make sure that the latter is maintained even with GFR values associated with a state of euthyroidism. Hormonal monitoring may be carried out independently from the moment of drug administration; concentrations of T₄ within the lower half of the reference range are generally associated with a good control of the disease. However, if with the recovery of euthyroidism the cat becomes azotaemic and symptomatic, the drug dosage may be reduced to ensure that the concentration of T₄ remains within the upper half of the reference range.

Suggested readings

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