Update on canine hypothyroidism and feline hyperthyroidism

PRESENTATION

BROCHURE M.ª Dolores Pérez Alenza Carolina Arenas Bermejo

Update on canine hypothyroidism and feline hyperthyroidism M.ª Dolores Pérez Alenza Carolina Arenas Bermejo

Canine hypothyroidism and feline hyperthyroidism

M.ª Dolores Pérez Alenza Carolina Arenas Bermejo

Update on canine hypothyroidism and feline hyperthyroidism M.ª Dolores Pérez Alenza Carolina Arenas Bermejo

Canine hypothyroidism and feline hyperthyroidism

Update on canine hypothyroidism and feline hyperthyroidism

AUTHOR: María Dolores Pérez Alenza and

Carolina Arenas Bermejo.

FORMAT: 17 × 24 cm.

NUMBER OF PAGES: 100.

NUMBER OF IMAGES: 40.

BINDING: hardcover.

RETAIL PRICE

€45

This clinical manual on thyroid gland conditions offers an update on the concepts and clinical reality of canine hypothyroidism and feline hyperthyroidism, two processes that have been the subject of much case-based reasoning.

Update on canine hypothyroidism and feline hyperthyroidism

Presentation of the book Much of our professional career revolves around endocrinology, which is one of our great passions. It is a very broad speciality of internal medicine that is constantly developing and evolving. However, this speciality is sometimes approached with some apprehension, since it presents many diagnostic dilemmas and therapeutic difficulties.

This book was conceived with the purpose of helping all veterinary surgeons in their daily clinical work. However, it is also a great aid for veterinary surgeons in training or practice and an excellent resource for consultation and updating information in endocrinology.

The book has a simple structure and is written in a simple way, so it may be too simple for those with extensive experience in internal medicine and, more specifically, veterinary endocrinology; however, it addresses all current aspects of thyroid disease.

For this book, we selected diseases of the thyroid gland because they represent one of the great diagnostic dilemmas in the field of veterinary endocrinology. These challenges often lead to incorrect diagnoses and treatment of our patients. This book aims to facilitate this task, and we trust that it will meet your expectations and be of great help in your daily clinical work.

We have included the physiology of the thyroid gland and an approach to the most common thyroid disease in dogs and cats, from their aetiology, pathophysiology and clinical signs to their diagnosis and treatment. All of these aspects are approached from a clinical and practical standpoint.

We hope our experience in this field can be of help to veterinary surgeons in practice.

MarĂ­a Dolores PĂŠrez Carolina Arenas

The authors María Dolores Pérez Alenza She graduated in veterinary medicine from the Complutense University of Madrid (UCM) in 1989, and earned a PhD in veterinary medicine from the same university in 1994. She completed her training in small animal internal medicine with several postdoctoral fellowships at the School of Veterinary Medicine of the University of Utrecht (Netherlands) (1991–1993) and the University of California, Davis (United States) (2002). She is a full professor in the Department of Animal Medicine and Surgery at the School of Veterinary Medicine of the UCM. She is head of the Small Animal Internal Medicine Service of the UCM Veterinary Teaching Hospital and head of the Endocrinology and Mammary Oncology Unit of said service.

She is a member of the Scientific Committee of the Internal Medicine Working Group of AVEPA (Spanish Small Animal Veterinary Association). She has had more than 50 articles published in Spanish and international journals, collaborated in writing book chapters and papers, and is the author of the book Diabetes felina (Feline diabetes) and coauthor of the Manual de endocrinología veterinaria (Manual of veterinary endocrinology).

Update on canine hypothyroidism and feline hyperthyroidism

Carolina Arenas Bermejo She graduated in veterinary medicine from the Complutense University of Madrid (UCM) in 2002, and earned a PhD in veterinary medicine from the same university in 2011. She completed a residency in Internal Medicine at the Queen’s Veterinary School Hospital of the University of Cambridge (United Kingdom). She completed her training in small animal internal medicine at the University of Pennsylvania, Texas A&M University, Animal Endocrine Clinic (New York) and the University of Liverpool.

Previously, she was associate professor of medical and clinical pathology and clinical education at the Alfonso X el Sabio University in Madrid. She was also a collaborating veterinary clinical instructor in endocrinology and mammary oncology in the Department of Internal Medicine and Surgery of the School of Veterinary Medicine of the UCM, in the specialities of endocrinology and mammary oncology.

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She has published articles in both international and Spanish journals.

Communication services Website Online visualisation of the sample chapter.

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Author´s CV. Sample chapter compatible with iPad.

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M.ª Dolores Pérez Alenza Carolina Arenas Bermejo

Update on canine hypothyroidism and feline hyperthyroidism M.ª Dolores Pérez Alenza Carolina Arenas Bermejo

Canine hypothyroidism and feline hyperthyroidism

Table of contents 1. General thyroid gland concepts Synthesis of thyroid hormones

3. Thyroid tumours and hyperthyroidism in dogs

Regulation of the synthesis and release of thyroid hormones

Incidence and types of thyroid tumours

Hormone transport

Treatment and prognosis

Function of thyroid hormones

References

2. Canine hypothyroidism Types and causes of hypothyroidism Hypothyroidism in young dogs Hypothyroidism in adult dogs

Diagnosis Clinical signs Skin disorders Neuromuscular disorders Cardiac abnormalities Reproductive disorders Other clinical signs

Diagnostic process Complete blood count and biochemical analysis Thyroid function tests Ultrasound evaluation L-thyroxine treatment as a diagnostic method

Treatment of hypothyroidism Dose Monitoring Side effects

References

Clinical signs and diagnostic approach

4. Feline hyperthyroidism Aetiology of hyperthyroidism Epidemiology of hyperthyroidism Intrinsic factors Nutritional factors Environmental factors

Clinical signs of hyperthyroidism Diagnosis of hyperthyroidism Routine diagnostic tests Hormonal tests to confirm the diagnosis Diagnostic imaging

Treatment of hyperthyroidism Medical treatment Diet Radioactive iodine Surgical thyroidectomy Intrathyroid injection of ethanol

References

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UPDATe on CAnIne HYPoTHYroIDIsM AnD felIne HYPerTHYroIDIsM

Figure 1. Cellular processes involved in the synthesis of thyroid hormones.

COLLOID

Thyroglobulin

I2

PND

TP

Endocytosis by pseudopodia

THYROID FOLLICULAR CELL

Apical membrane

H2O2

Colloid vesicle TPrec

I− Lysosomes

I− DIT Deiodination Proteolysis

Ribosomes

I

−

MIT NIS I−

NIS: Na+/I− symporter

T3

T4

Basolateral membrane

2 Na+

BLOOD

TP: thyroid peroxidase PND: pendrin TPrec: thyroglobulin precursor

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GenerAl THYroID GlAnD ConCePTs

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HORMONE TRANSPORT Once released from the thyroid gland, virtually all thyroid hormones circulate in blood bound to plasma protein transporters. Less than 0.05 % of T4 and 0.5 % of T3 circulate freely (fT4 and fT3); this free fraction of hormones is biologically active and available to all tissues. Carrier protein levels may be decreased by some diseases or treatments and may have an effect on the total concentration of hormones in blood. For this reason, the concentration of the free fraction of these hormones is regulated by the hypothalamic–pituitary–thyroid axis so that it remains constant (see Fig. 2). The protein-bound fraction functions as a hormone reservoir.

It is important to be aware of these mechanisms of synthesis, release and transport of thyroid hormones to understand the functional tests for diseases of the thyroid gland.

FUNCTION OF THYROID HORMONES T3 is approximately three to four times more potent than T4 and is primarily responsible for the metabolic effects of thyroid hormones. To perform its functions, T3 binds to specific binding sites in the cell nucleus and stimulates protein synthesis.

Thyroid hormones are involved in numerous cellular processes and play a key role in cellular and tissue metabolism and growth, development, and function of the cardiovascular, nervous and reproductive systems, among others.

The metabolic effects of thyroid hormones include the stimulation of cellular oxygen consumption and increased basal metabolism. These hormones play a fundamental role in lipid and carbohydrate metabolism, since they stimulate the mobilisation of fat deposits, increase the oxidation of fatty acids, regulate the synthesis and degradation of cholesterol and favour gluconeogenesis and glycogenolysis.

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UPDATE ON CANINE HYPOTHYROIDISM AND FELINE HYPERTHYROIDISM

CAnIne HYPoTHYroIDIsM Hypothyroidism is characterised by a deficiency of thyroid hormones and is one of the most common endocrine diseases in dogs. In the cat, however, it is an extremely rare disease.

Despite this, the current incidence of this disease in dogs is less than that estimated a few years ago, since hypothyroidism was diagnosed in some animals that were not truly hypothyroid. In fact, the great challenge of hypothyroidism is its diagnosis; it is sometimes difficult to establish because clinical signs are highly variable and nonspecific, and the diagnostic tests have limitations.

The diagnosis is especially complicated in animals with other diseases and in those receiving certain medications that can affect the results of thyroid hormone tests.

TYPES AND CAUSES OF HYPOTHYROIDISM Hypothyroidism may occur in young animals or in adults.

Hypothyroidism in young dogs When the disease affects young animals, it may be congenital or acquired.

Thyroid hormones are essential for the postnatal development of tissues, especially the skeletal and nervous systems. When hypothyroidism occurs in growing animals, signs include those seen in adults as well as developmental delays, both physical and mental, resulting in disproportionate dwarfism.

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Congenital hypothyroidism Congenital hypothyroidism in the dog is uncommon and may be primary, due to thyroid dysgenesis and defective synthesis of thyroid hormones, or central, due to a lack of pituitary TSH secretion, as seen in miniature Schnauzer dogs.

Thyroid dysgenesis is characterised by the appearance of ectopic thyroid tissue due to the descent of the primitive thyroid tissue together with the aortic sac during embryonic development. In fact, approximately 50 % of adult dogs have thyroid tissue in the fat of the intrapericardial aorta, and this may occasionally be associated with an absence of normal thyroid tissue, as there is insufficient ectopic tissue to prevent hypothyroidism.

Signs of thyroid hormone deficiency appear as early as in the first 3 months of life: ■ Enlarged fontanelle.

■ Hypothermia.

■ Hypoactivity.

■ Difficulty in suckling.

■ Decreased response to stimuli.

As the puppy grows, its head becomes relatively large and broad, its face widens and its tongue becomes large and thick. Growth is delayed, and animals develop disproportionate dwarfism and show minimal physical activity. Mental development is delayed, and hair can be fine and the primary coat may be absent.

Another cause of hypothyroidism in young animals is defective hormone synthesis caused by different enzyme deficiencies, although this is rare in dogs. In this species, lack of response to TSH (thyroid-stimulating hormone, or thyrotropin) and deficiency of the peroxidase enzyme involved in the synthesis of thyroid hormones have been described. Animals can concentrate iodine in the thyroid gland, but they cannot use it adequately in the synthesis of thyroid hormones (organification defect). This alteration is variable; in some animals the defect is complete, while in others it is partial. These cases are usually associated with an enlargement of the thyroid gland, or goitre. The severity of both hypothyroidism and goitre is highly variable and goitre may be difficult to assess by palpation.

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UPDATE ON CANINE HYPOTHYROIDISM AND FELINE HYPERTHYROIDISM

Ultrasound evaluation Ultrasound evaluation of the thyroid gland may be useful in the diagnosis of hypothyroidism. Although diagnosis requires experience and adequate equipment, in hypothyroid dogs the parenchyma of the thyroid gland is hypoechoic to the neck muscles, unlike what is observed in euthyroid dogs and dogs with euthyroid sick syndrome.

The size, shape, echogenicity, and homogeneity of the thyroid gland can be evaluated by ultrasound. In most euthyroid dogs, the thyroid lobes are longitudinally spindle-shaped and triangular in the transverse plane, and in euthyroid dogs with nonthyroid diseases (euthyroid sick syndrome) there are no changes in the shape, size, or echogenicity of the thyroid lobes.

In hypothyroid dogs, the thyroid lobes most often have a round to oval shape in the transverse plane. The thyroid parenchyma is hypoechoic with respect to the adjacent musculature, and the lobes and thyroid gland appear smaller in size and volume when compared with euthyroid dogs.

Other common findings in hypothyroid dogs include a thyroid capsule with an irregular surface, heterogeneous thyroid parenchyma and differences in echogenicity between the right and left lobes.

In addition, the size of the thyroid continues to decrease during treatment with levothyroxine.

L-thyroxine treatment as a diagnostic method Occasionally, if repeated tests do not confirm a diagnosis of hypothyroidism, treatment may be used as a diagnostic method. If this option is chosen, first try to confirm that there are no other nonthyroid diseases and that the animal is not receiving medication. Next, establish an objective criterion to judge the success or failure of the therapy (e.g. resolution of apathy, alopecia, high cholesterol levels, and anaemia). Then, administer the correct dose of thyroxine and decide on the right moment to reassess the patient; for example, at 15 days and one month initially, and then once a month, by evaluating the clinical response and the levels of tT4 after medication. If the response to treatment is unclear within 1 to 3 months, thyroxine administration should be discontinued completely (no need for gradual withdrawal). Subsequently, 1 or 2 months after treatment interruption, the dog should be clinically evaluated and thyroid function tests should be performed again if there are any signs of hypothyroidism.

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SUMMARY OF DIAGNOSTIC TESTS ■

To confirm a clinical suspicion of hypothyroidism it is advisable to perform a combination of thyroid tests such as determination of tT4 and TSH or tT4, fT4, and TSH. In fact, the diagnosis of hypothyroidism should not be established solely on the basis of low tT4 levels.

■

A low level of tT4 and a high level of TSH confirms the diagnosis in dogs with clinical signs of hypothyroidism and decreases the false positive results obtained with tT4.

■

Only 2 % of euthyroid dogs have both low tT4 levels and high TSH levels. However, the combination of tT4 and TSH levels does not have a high diagnostic sensitivity, since 1 in 3 or 4 hypothyroid dogs shows TSH levels within the reference range, so a normal TSH level does not rule out hypothyroidism. In these cases, it is necessary to determine fT4 levels.

■

A complete thyroid panel (tT4, fT4 by dialysis, TSH, TgAA, T4AA and T3AA) is only necessary when the tT4/TSH combination is not conclusive and to confirm or rule out lymphocytic thyroiditis.

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UPDATE ON CANINE HYPOTHYROIDISM AND FELINE HYPERTHYROIDISM

THYroID TUMoUrs AnD HYPerTHYroIDIsM In DoGs INCIDENCE AND TYPES OF THYROID TUMOURS Tumours of the thyroid gland account for 1.2 % to 3.7 % of all neoplasms in the canine species.

In the dog, most thyroid tumours diagnosed in life are malignant (90 %); however, in postmortem studies, the proportion of malignant tumours is 50– 70 %, the rest being benign. In the cat, on the contrary, only 2 % of thyroid neoplasms are malignant, although adenomatous hyperplasias that cause hyperthyroidism can become malignant with time, becoming carcinomas.

Thyroid carcinomas tend to be larger and multinodular in comparison with adenomas. They are attached to adjacent tissues and usually have a central necrotic or haemorrhagic region (Fig. 1). Carcinomas often show rapid and invasive growth and are poorly encapsulated. They invade the trachea, neck muscles, oesophagus, larynx, and nerves and blood vessels in the area. They also frequently metastasise to the regional (retropharyngeal and cervical) lymph nodes and invade the cranial and caudal thyroid veins, leading to lung metastases even before invasion of the regional lymph nodes. Unilateral involvement is the most common (more than double the incidence of bilateral), and when both lobes are affected it is usually due to tumour progression. In some cases there is ectopic thyroid tissue, located anywhere from the base of the tongue to the base of the heart, that can become neoplastic.

Figure 1. Thyroid tumour in an 8-year-old German shepherd, cross section, showing areas of necrosis and haemorrhage.

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THYroID TUMoUrs AnD HYPerTHYroIDIsM In DoGs

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Histologically, thyroid tumours may originate from follicular cells (follicular carcinomas) or parafollicular C-cells (medullary carcinomas). Follicular cell carcinomas are often well-differentiated and can be classified into several types, although a relationship between histological diagnosis and prognosis has not been established (Figs. 2 and 3). Medullary carcinoma (parafollicular, C-cell) is rare (less than 5Â % of all carcinomas) and has a better prognosis than other thyroid carcinomas, since it is usually easily excised and does not usually metastasise.

Figure 2. Histological image of a solid follicular thyroid carcinoma in a dog. There is a proliferation of follicular cells forming solid cords, with scarce connective stroma and rare mitotic figures. H&e stain.

Figure 3. Histological image of a solid follicular thyroid carcinoma in a dog.

A moderate pleomorphism is observed.

H&e stain.

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UPDATE ON CANINE HYPOTHYROIDISM AND FELINE HYPERTHYROIDISM

felIne HYPerTHYroIDIsM Hyperthyroidism is a multisystem disease that occurs as a result of excess secretion of the thyroid hormones thyroxine (tetraiodothyronine, T4) and triiodothyronine (T3) by the thyroid gland. It is a relatively recently discovered disease, as the first cases of feline hyperthyroidism were described in the late 1970s and early 1980s in new York and Boston, respectively.

since the first cases, the incidence of the disease has been increasing, and it is currently the most common endocrine disease in cats and one of the most common feline geriatric diseases.

At present, a greater number of hyperthyroid cats are detected and in earlier stages thanks to testing to determine tT4 levels in senior and diseased cats.

This increase in incidence may be due in part to better knowledge of the disease in the veterinary community, to the greater availability of diagnostic tests for thyroid diseases, and to the ageing of the feline population (a higher proportion of cats that are over 10 years of age). For example, over a 7-year period (from 1979 to 1985) the prevalence of hyperthyroidism in the United States increased from 0.3 % to 4.5 %. More recent studies also in the United States indicate an increase in prevalence from 0.61 cases per 1,000 patients (1978–1982) to 29.6 cases per 1,000 patients (1993–1997).

Similar data have also been observed in other countries such as Germany, where prevalence increased from 0.2 % in 1987–1994 to 2.6 % in 1998.

The increase in cases of the disease is due to not only the above factors, but also to a real increase in its incidence and prevalence. Some studies have compared the increase in the prevalence of feline hyperthyroidism to that of other feline diseases, such as diabetes mellitus and chronic kidney failure. All have increased in prevalence in recent years, but this increase is greater for hyperthyroidism than for either of the other two diseases.

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The prevalence (proportion of individuals in a population with a given characteristic at a given time or period) and the incidence (number of new cases of a disease in a given population and in a given period) of the disease vary geographically. For example, the annual incidence in the United Kingdom reaches 11.4 % compared with 1.53 % in Spain among feline populations of similar age. Similarly, prevalence reaches 12 % in countries where the disease is considered prevalent (New Zealand, Australia, Japan, Germany, Canada, United States), compared with a prevalence of less than 4 % in places where it is considered rare, such as Hong Kong or Spain. However, in a recent study in Spain, a frequency of hyperthyroidism of 10 % has been reported, although prevalence studies are needed to determine the actual number of cases in that country.

AETIOLOGY OF HYPERTHYROIDISM The most common cause of feline hyperthyroidism is functional adenomatous hyperplasia (adenoma). In 70 % of cases, bilateral enlargement of the thyroid lobes is observed, whereas in the remaining 30 % there is involvement of only one of the two lobes. Histopathological studies show that these enlarged thyroid lobes contain one or more foci of hyperplasia (Fig. 1), sometimes forming actual nodules between 1 mm and 3 cm in diameter.

Thyroid carcinomas are a less common cause of hyperthyroidism, seen in less than 5 % of cases.

Some hyperthyroid cats have been reported to have areas of adenoma along with areas of carcinoma in the same thyroid lobe. Some authors postulate that in cats that have had hyperthyroidism for a long time, altered thyroid tissue may undergo a histopathological transformation from hyperplasia or adenoma to carcinoma. In addition, adenoma and carcinoma are probably not two separate entities, but rather the result of one malignancy process. It has recently been shown that the probability of thyroid carcinoma increases in hyperthyroid cats treated with methimazole over time.

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UPDATE ON CANINE HYPOTHYROIDISM AND FELINE HYPERTHYROIDISM

Figure 1. Thyroid hyperplasia.

H&e stain.

Histologically and clinically, the disease is similar to toxic nodular goitre in humans. However, the benign nature and involvement of both lobes may indicate that the disease is caused by an immune disorder, as is the case with Graves’ disease in humans (the most common cause of hyperthyroidism). Unlike in humans, hyperthyroidism is not of immune origin in cats.

Although the presence of antibodies that stimulate the thyrotropin hormone (TSH) receptor has been reported in hyperthyroid cats, and these antibodies may mimic the effect of thyrotropin hormone (which occurs in Graves’ disease), genetic studies have demonstrated that these immunoglobulins are not capable of actually stimulating the TSH receptor.

In the cat this disease is not considered analogous to Graves’ disease; instead, the problem is located in the thyroid gland and caused by hyperthyroid cells that function autonomously and give rise to uncontrolled growth, similar to what happens in human toxic nodular goitre.

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