DOG CARE

DIAGNOSIS, TREATMENT & PREVENTIVE CARE MANAGEMENT OF HYPOTHYROIDISM IN DOGS

October 28, 2023

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DIAGNOSIS, TREATMENT & PREVENTIVE CARE MANAGEMENT OF HYPOTHYROIDISM IN DOGS

Hypothyroidism is the most frequently diagnosed endocrinopathy in dogs. The disease is characterised by diminished production of the thyroid hormones thyroxine (T4) and thyronine (T3). Thyroid hormones influence large number of metabolic processes in the body and, in the event of disorders in hormone production, symptoms can arise from a number of organ systems. In addition to the most commonly occurring symptoms such as dermatological changes and signs of general metabolic disturbances, a number of neurological manifestations have been reported to occur in hypothyroidism in dogs. Neurological symptoms of hypothyroidism can originate from the central and peripheral nervous systems as well as from the muscles.

In dogs, hypothyroidism is usually primary, i.e., due to atrophy of the thyroid gland. In the majority of cases, this atrophy is associated with acquired autoimmune lymphocytic thyroiditis, similar to Hashimoto‟s thyroiditis in humans, as both are characterized by cellular lymphocytic, as well as humoral autoantibodies against thyroglobulin, T4 and T3 in the thyroid gland (Miller, 2015). The remainders of canine hypothyroid causes are non-inflammatory or of unknown etiology; congenital hypothyroidism is rare (Mooney, 2011). Hypothyroidism is most often diagnosed in middle-aged dogs (approximately 7-8 years old) and is more likely in pure breeds. Graham et al. (2007) revealed that, there was no gender predisposition; however Golden Retrievers, Doberman Pinschers, Labradors and Cocker Spaniels are predisposed.

Clinical Signs

Miller et al (2015) suggested that the thyroxine is needed for normal cellular metabolic functions in all cells of the body, thus a deficiency in thyroxine affects almost all body systems. Clinical signs are therefore very varied and depend on the disease stage and may also differ between breeds. He et al. (2011) observed that the most of the dogs with hypothyroidism have reduced activity and mental states, resulting in exercise intolerance and lethargy. Weight gain is seen in 48 per cent of cases as a result of up to a 15 per cent reduction in calorie expenditure. Their reduced metabolism makes hypothyroid dogs intolerant of cold temperatures (Mooney and Shiel, 2012). The vast majority of dogs with hypothyroidism have dermatological signs (>80 per cent of cases) that vary depending on the duration and the severity of the disease. Thyroid hormones are needed to initiate the anagen phase of hair growth, so their absence leads to persistence of telogen and, as a result, hairs are easy to epilate. Alopecia usually starts over areas of friction, such as the tail (resulting in the classic “rat tail” appearance) and neck, and progresses over time to bilaterally symmetrical truncal alopecia. This usually spares the head and limbs, and is usually non-pruritic. Dorsal nasal alopecia is seen in some breeds, especially Retrievers (Graham et al., 2007). Hyperpigmentation and comedones, with seborrhoea or dry, scaly skin, is commonly seen. Bacterial or Malassezia dermatitis is also common. Mooney and Shiel (2012) stated that the breed-related differences are also noted, with Arctic breeds usually losing the primary hairs, leaving a coarse woolly appearance to the remaining hair. Increased hair coat (hyertrichosis) is sometimes seen in Boxers and Irish Setters. Delayed or poor wound healing is often reported. Neurological signs are commonly seen in association with hypothyroidism, through a variety of mechanisms; these include mucopolysaccharide accumulation around nerves, hyperlipidaemia and central atherosclerosis (He et al., 2011). Generalised muscle weakness is common, leading to weakness, exercise intolerance and reduced reflexes. Abnormal electromyogram (EMG) changes are seen but clinical signs usually improve within three months of treatment. Peripheral vestibular syndrome and facial paralysis are rare complications of hypothyroidism. The relationship between laryngeal paralysis and hypothyroidism is controversial, however treatment generally does not improve laryngeal function. As of yet no causal relationship has been proven (Diaz et al., 2007). The clinical signs of canine hypothyroidism typically develop gradually, affect a number of different organ systems, and range from mild to severe. Clinical signs are summarized below by body system.

Clinical Features of Hypothyroidism in the Adult Dog

General Metabolic Signs

Most adult dogs with acquired hypothyroidism have clinical signs that result from a generalized decrease in metabolic rate. Clinical signs due to the decreased metabolic rate include mental dullness, lethargy, exercise intolerance or unwillingness to exercise, cold intolerance, and a propensity to gain weight without a corresponding increase in appetite or food intake.

Dermatologic Signs

Alterations in the skin and hair coat occur in 60% to 80% of hypothyroid dogs and are the most commonly observed abnormalities in dogs with hypothyroidism. Thyroid hormone is necessary to initiate and maintain the anagen, or growing, phase of the hair cycle [7]. With thyroid hormone deficiency, hair follicles prematurely enter the telogen phase of the hair cycle. Excessive shedding with lack of hair regrowth leads to alopecia. Decreased concentrations of cutaneous fatty acids and prostaglandin E2 in canine hypothyroidism may lead to sebaceous gland atrophy, hyperkeratosis, scale formation, seborrhea sicca, and a dry and lusterless hair coat [8]. In the early stages of hypothyroidism, hair loss is often asymmetric and develops over areas of excessive wear or pressure, such as the caudal thighs, ventral thorax, tail base, and tail (i.e., development of a “rat tail;”. As hypothyroidism becomes more severe or chronic, alopecia becomes more symmetric and truncal, eventually developing into the classic cutaneous finding of bilaterally symmetric, nonpruritic truncal alopecia. Hyperpigmentation is common in hypothyroidism, especially in regions of alopecia and areas of wear, such as the axilla and inguinal regions. In severe cases of hypothyroidism, the hygroscopic glycosaminoglycan, hyaluronic acid may accumulate in the dermis, bind water and result in increased thickness and non-pitting edema of the skin, referred to as myxedema, or cutaneous mucinosis [9]. Myxedema predominantly affects the forehead, eyelids, and lips that contribute to the development of the classic “tragic facial expression” described in hypothyroid dogs.

Reproductive Signs

The classic clinical signs and clinicopathologic abnormalities in hypothyroidism are lack of libido, testicular atrophy, and oligospermia or azoospermia so hypothyroidism appears to be a cause of infertility in male dogs. Additional reproductive abnormalities have been reported as weak or silent estrus cycles, prolonged estrual bleeding, and inappropriate galactorrhea and gynecomastia which may develop following a thyroid hormone deficiency–induced increase in TRH secretion, which in turn stimulates prolactin secretion.

Ocular Signs

Corneal ulceration, uveitis, lipid effusion into the aqueous humor, secondary glaucoma, lipemia retinalis, retinal detachment, keratoconjunctivitis sicca (KCS), and Horner’s syndrome have been reported in hypothyroid dogs .

Gastrointestinal Signs

Clinical signs related to the gastrointestinal system have been described but are not common in hypothyroid dogs. Constipation may occur, presumably as a result of alterations in electrical control activity and smooth muscle contractile responses in the gastrointestinal tract. Diarrhoea has also been reported with hypothyroidism.

Neurologic Signs

Both the peripheral nervous system and CNS may be affected by hypothyroidism. Diffuse peripheral neuropathy characterized by exercise intolerance, weakness, ataxia, quadriparesis or paralysis, deficits of conscious proprioception, and decreased spinal reflexes has been reported to occur in dogs with hypothyroidism.

Other Neurologic Disorders

1) Laryngeal Paralysis and megaesophagus may both occur in association with hypothyroidism.

2) Myasthenia gravis Myasthenia gravis has been identified in dogs with hypothyroidism [and is a wellrecognized cause of acquired megaesophagus in the dog.

(3) Myxedema Coma is an extremely rare syndrome of severe hypothyroidism characterized by profound weakness, hypothermia, bradycardia, and a diminished level of consciousness, which can rapidly progress to stupor and then coma . Clinical signs in addition to the more typical clinical signs of hypothyroidism include mental dullness, depression, unresponsiveness, and weakness. Physical findings include profound weakness, hypothermia, non-pitting edema of the skin, face and jowls (myxedema), bradycardia, hypotension; and hypoventilation.

Diagnosis and clinico-pathologic abnormalities of Hypothyroidism

(1) Blood tests of thyroid gland function Serum T4, both protein-bound and free, comes from the thyroid gland. Therefore tests that measure the serum total and fT4 concentrations, in conjunction with the serum TSH concentration, are currently recommended for the assessment of thyroid gland function in dogs suspected of having hypothyroidism. In contrast, most T3 and rT3 is formed through the deiodination of T4 in extrathyroidal sites-most notably the liver, kidney, and muscle. Serum T3 concentration is a poor gauge of thyroid gland function because of its predominant intracellular location and the minimal amount of T3 secreted by the thyroid gland compared with T4. Thus measurement of serum T3, fT3, or rT3 concentration is not routinely recommended for the assessment of thyroid gland function in dogs.

Complete Blood Count

A normocytic, normochromic, nonregenerative anaemia is identified in dogs. Decreased erythropoietin, decreased erythroid progenitor response to erythropoietin, and lack of a direct effect of thyroid hormone on early hemopoietic pluripotent stem cells may all contribute to the anaemia. Erythrocyte survival time is not affected by hypothyroidism. These cells are believed to develop from increased erythrocyte membrane cholesterol loading, a direct result of the concomitant hypercholesterolemia associated with thyroid deficiency.

Serum Biochemistry Panel

The classic abnormality seen on a screening biochemistry panel is fasting hypercholesterolemia, which is present in approximately 75% of hypothyroid dogs. Thyroid hormones stimulate virtually all aspects of lipid metabolism, including synthesis, mobilization, and degradation. Both the synthesis and degradation of lipids are depressed in hypothyroidism, with degradation affected more than synthesis. The net effect is an accumulation of plasma lipids in hypothyroidism and the potential for development of atherosclerosis.

Urinalysis

Results of urinalysis are usually normal in dogs with hypothyroidism. In dogs with lymphocytic thyroiditis, concurrent immune-complex glomerulonephritis may result in proteinuria .

Conventional Radiography

In congenital hypothyroidism, radiographic abnormalities include delayed epiphyseal ossification, epiphyseal dysgenesis (i.e. irregularly formed, fragmented, or stippled epiphyseal centers), most common in the humeral, femoral, and proximal tibial condyles; short broad skulls; shortened vertebral bodies; and delayed maturation.

Ultrasonography

Ultrasound may also be helpful for confirmation of hypothyroidism. The normal thyroid gland is homogenous and well delineated with a hyperechoic capsule. The parenchyma is hyperechoic to the surrounding muscles, and the size is correlated with the size (body surface area) of the dog .

Nuclear Imaging

Thyroid scintigraphy is useful for evaluating the size, shape, and location of thyroid tissue. Either technetium-99m pertechnetate (99mTcO4) or iodine-123 (123I) can be used for scintigraphy in dogs is the most commonly used isotope used for thyroid scintigraphy in veterinary medicine because of its low cost, short half-life, and safety. On scintigraphy, normal canine thyroid lobes appear as two uniformly dense, symmetric ovals in the mid-cervical area, although asymmetrical uptake has been reported in some euthyroid dogs Baseline Serum Total Thyroxine Concentration Baseline serum T4 concentrations are lower in healthy dogs than in humans (1.0 to 3.5 versus 4.0 to 10.0 μg/dL respectively) because of weaker protein binding in dogs. The serum T4 concentration in healthy dogs ranges between 1.0 and 3.5 μg/dl. Baseline Serum Total Triiodothyronine Concentration Serum total T3 concentrations are the sum of the proteinbound and free levels circulating in the blood. Almost all commercial laboratories currently use either RIA or chemiluminescent techniques for measuring T3 concentrations in the blood. Most human RIAs for T3 are suitable for use in the dog, because blood concentrations are similar for both species. Using the RIA technique, an approximate normal range for blood T3 concentrations is 0.8 to 2.1 nmol/L..

Baseline Serum Free Thyroxine Concentration

Although the gold standard technique for measurement of fT4 is equilibrium dialysis, this technique is expensive and time consuming and is only performed in research laboratories. In commercial laboratories, canine serum fT4 is measured by one of three methods: modified equilibrium dialysis (MED), analog RIA, or analogue chemiluminescent assay. MED techniques are regarded as the most accurate commerciallyavailable technique for determining serum fT4 concentrations in dogs. fT4 in dogs ranges from 0.52 to 2.7 ng/dl.

Thyrotropin Stimulation Test

The TSH stimulation test evaluates the thyroid gland responsiveness to exogenous TSH administration and is a test of thyroid gland reserve. The TSH stimulation test is indicated in dogs with low basal thyroid hormone concentrations to differentiate hypothyroidism from nonthyroidal illness syndrome (NTIS). The biologic activity of the TSH molecule is not species-specific so human recombinant TSH can be used for the test.

Thyrotropin-Releasing Hormone Stimulation Test

The TRH stimulation test evaluates the pituitary gland respon siveness to TRH and the thyroid gland responsiveness to TSH secreted in response to TRH administration. Dogs with primary hypothyroidism have a lower change in TSH concentration after TRH administration than the healthy dogs [18]. This finding has been attributed to TRH receptor desensitization due to persistent stimulation of the pituitary thyrotrophs by the negative feedback loop [19]. In dogs, the TRH stimulation test has been used to differentiate between hypothyroidism and the NTIS in dogs with low basal thyroid hormone concentrations.

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Tests for Lymphocytic Thyroiditis

During the inflammatory phase of lymphocytic thyroiditis, antibodies are released into the circulation. In dogs, the predominant antibody that arises is directed against Tg. Tg is a large complex protein molecule with several epitopes and antibodies formed against it are heterogenous. The thyroid hormones T3 and T4 are haptens and do not elicit an antibody response unless attached to a larger protein molecule . Thus the Tg autoantibody test is a more sensitive test for lymphocytic thyroiditis than is measurement of anti-T3 and anti-T4 antibodies. Circulating Tg autoantibodies are detected in approximately 50% of hypothyroid dogs .

Concurrent illness (Nonthyroidal illness Syndrome)

The nonthyroidal illness syndrome (NTIS, Euthyroid Sick Syndrome) refers to suppression of serum thyroid hormone concentrations that occur in euthyroid patients due to concurrent illness. Decreased serum thyroid hormone concentrations are believed to be a physiologic adaptation that decreases cellular metabolism during illness. Generally, the magnitude of the change in serum thyroid hormone concentrations is not related to the specific disorder but rather reflects the severity of the illness, with more severe systemic illness resulting in more severe suppression of serum thyroid hormone concentrations . Disorders that are frequently associated with NTIS in dogs include neoplasia, renal disease, hepatic disease, cardiac failure, neurologic disease, inflammatory disorders, and diabetic keto-acidosis.

Thyroid Hormone

Thyroxine (T4) and 3, 5, 3′-triiodothyronine (T3) are iodine–containing amino acids. Thyroid hormone synthesis requires iodine and is dependent upon ingestion of adequate iodide from the diet. Iodide is actively transported from the extracellular fluid into the thyroid follicular cell by the sodium-iodine symporter (NIS), where it is rapidly oxidized by thyroid peroxidase (TPO) into a reactive intermediate. At the apical membrane, iodine is incorporated into the tyrosine residues of Tg . TPO also catalyzes the coupling of the non-biologically active iodinated tyrosine residues (monoiodotyrosine [MIT], and diiodotyrosine [DIT]) to form the biologically active iodothyronines-T4 and T3. These iodination reactions are referred to as organification.

Hypothyroidism Classification

Hypothyroidism is the most common thyroid disorder in dogs and may be acquired or congenital. Hypothyroidism is classified as primary if it is due to an abnormality at the level of the thyroid gland, secondary if it is due to decreased TSH secretion and tertiary if it is due to TRH deficiency.

(A) Acquired Hypothyroidism

(1) Primary Hypothyroidism It is the most common cause of naturally occurring thyroid failure in the adult dog, accounting for more than 95% of cases. Two histologic forms of primary hypothyroidism are recognized in dogs- lymphocytic thyroiditis and idiopathic atrophy. Other much more rare causes of primary hypothyroidism include iodine deficiency, goitrogen ingestion, congenital hypothyroidis m, thyroid gland destruction by neoplasia, drug therapy, surgical

(b) Idiopathic Atrophy

It is characterized microscopically by progressive reduction in the size of the thyroid follicles, and replacement of the degenerating follicles with adipose tissue. The parathyroid glands are not affected, and variable numbers of parafollicular cells remain. Idiopathic thyroid atrophy may be either a primary degenerative disorder , or an end stage of lymphocytic thyroiditis as evident by initial degenerative thyroidal parenchymal changes, which progressed to progressively worsening inflammation, subsequent fibrosis, and thyroid gland destruction.

(c) Neoplastic Destruction Clinical signs of hypothyroidism may develop following destruction of more than 80% of the normal thyroid gland by an infiltrative tumour. Tumours may arise from the thyroid gland or unlike for may metastasize to or invade the thyroid gland from adjacent tissues. Interpretation of thyroid hormone concentrations in dogs with thyroid tumours is complicated by the effects of concurrent illness on serum thyroid hormone concentration.

(d) Miscellaneous Causes Acquired primary hypothyroidism may rarely result from ingestion of goitrogens, administration of anti-thyroid medications (e.g., propylthiouracil and methimazole), and chronic use of high doses of potentiated sulfonamides. A palpable goiter may develop in dogs treated chronically with potentiated sulfonamides .

(2) Secondary Hypothyroidism Secondary hypothyroidism results from failure of pituitary thyrotrophs to develop due to pituitary malformation or acquired dysfunction of the pituitary thyrotrophs causing impaired secretion of TSH. Deficiency of TSH leads to decreased thyroid hormone synthesis and secretion and thyroid gland hypoplasia . Potential causes of secondary hypothyroidism include congenital malformations of the pituitary gland, pituitary destruction, and pituitary suppression. In the dog, secondary hypothyroidism caused by naturally acquired defects in pituitary thyrotroph function or destruction of pituitary thyrotrophs (e.g., pituitary neoplasia) is uncommon.

(3) Tertiary Hypothyroidism

Tertiary hypothyroidism is defined as a deficiency in the secretion of TRH by peptidergic neurons in the supraoptic and paraventricular nuclei of the hypothalamus. Lack of TRH secretion causes deficiency of TSH secretion and follicular atrophy of the thyroid gland. Neurologic signs and additional pituitary dysfunction may be present, depending on the cause. Tertiary hypothyroidism is assumed to be rare in dogs.

(B) Congenital Hypothyroidism Congenital hypothyroidism is rare in dogs. Unfortunately, congenital hypothyroidism frequently results in early puppy death, and the cause of death is rarely documented. A defect anywhere in the hypothalamic-pituitary-thyroid axis or of the thyroid hormone receptor can result in congenital hypothyroidism. Congenital hypothyroidism with goiter (CHG) develops if the hypothalamic-pituitary-thyroid gland axis is intact; TSH binds appropriately with its receptor, but there is an intra-thyroidal defect in thyroid hormone synthesis (dyshormonogenesis). Increased serum TSH concentrations result in development of thyroid hyperplasia and a goitre.

Therapeutics Drugs

Levothyroxine is the only hormone that appears necessary for treatment of hypothyroidism (Jonklass and Talbert, 2014). The frequency of levothyroxine dosing is controversial, and the only study to closely evaluate the response to treatment showed that once daily treatment is adequate. However, in clinical practice some dogs seem to respond better to twicedaily treatment. The initial starting dose is 0.02 mg/kg PO q 24 h. In general you will never have to exceed 0.8 mg as an initial daily dosage even in very large dogs. If the dog has significant cardiovascular disease, diabetes mellitus, or hypoadrenocorticism, treatment should be instituted at 25% of the standard dose, with the dosage increased by 25% every 2 weeks based on clinical response and post-pill testing. Most dogs show improvement within the first 1-2 weeks, with increased activity, improved attitude, and partial or complete resolution of neurologic signs. The cutaneous manifestations of hypothyroidism may take several weeks to months to resolve. Post treatment monitoring may be carried out but clinical response is the most important monitoring tool. Peak T4 concentrations generally occur 4-6 hours after administration of levothyroxine and should be in the high normal to slightly above normal range (40- 70 nmol/L). However, the bioavailability of thyroxine ranges from 13 to 87% in the same dog from day to day bringing into the question the utility of random post pill monitoring of TT4. It is likely more meaningful (though more expensive) to measure TSH (especially if the TSH concentration was elevated pre-treatment) or fT4 concentrations after replacement therapy has been started, especially in animals that show a poor clinical response to therapy. Serum TSH concentrations should be in the normal range or undetectable and fT4 concentrations should be in the normal range (Diaz et al.,2007). Serum concentrations of TSH and fT4 should not be performed until the patient has been on supplementation for at least 2 weeks. If the patient was initially started on twice daily therapy, treatment can be reduced to once daily treatment when a good clinical response has been obtained. Hyperthyroidism is the most common complication of treatment with levothyroxine, but it is rare in dogs. Clinical signs are similar to those of hyperthyroidism in cats and the diagnosis is confirmed by documenting a substantial elevation of serum T4. Treatment consists of stopping levothyroxine treatment for 2- 3 days, then instituting treatment at a lower dose.