Hypothyroidism in Animals
In hypothyroidism, impaired production and secretion of thyroid hormones result in a decreased metabolic rate. This disorder is most common in dogs but also develops rarely in other species, including cats, horses, and other large, domestic animals.
Although dysfunction anywhere in the hypothalamic-pituitary-thyroid axis may result in thyroid hormone deficiency, >95% of clinical cases of hypothyroidism in dogs appear to result from destruction of the thyroid gland itself (primary hypothyroidism). The two most common causes of adult-onset primary hypothyroidism in dogs include lymphocytic thyroiditis and idiopathic atrophy of the thyroid gland. Lymphocytic thyroiditis, probably immune-mediated, is characterized histologically by a diffuse infiltration of the gland by lymphocytes, plasma cells, and macrophages and results in progressive destruction of follicles and secondary fibrosis. Idiopathic atrophy of the thyroid gland is characterized histologically by loss of thyroid parenchyma and replacement by adipose tissue. (Also see Organ-Specific Autoimmunity : Autoimmune Thyroiditis.)
In dogs, the most common cause of secondary hypothyroidism is destruction of pituitary thyrotrophs by an expanding, space-occupying tumor. Because of the nonselective nature of the resulting compressive atrophy and replacement of pituitary tissue by such large tumors, deficiencies of other (one or more) pituitary hormones also usually occur.
Other rare forms of hypothyroidism in dogs include neoplastic destruction of thyroid tissue and congenital (or juvenile-onset) hypothyroidism. Congenital primary hypothyroidism may result from one of various forms of thyroid dysgenesis (eg, athyreosis, thyroid hypoplasia) or from dyshormonogenesis (usually an inherited inability to organify iodide). Congenital secondary hypothyroidism (associated with clinical signs of disproportionate dwarfism, lethargy, gait abnormalities, and constipation) has been reported in Giant Schnauzers, Toy Fox Terriers, and Scottish Deerhounds. Congenital secondary hypothyroidism also has been reported in German Shepherds, with pituitary dwarfism associated with a cystic Rathke’s pouch. However, the degree of TSH deficiency in these dogs is variable, and clinical signs are usually caused primarily by deficiency of growth hormone (rather than thyroid hormone).
In cats, iatrogenic hypothyroidism is the most common form. Hypothyroidism develops in these cats after treatment for hyperthyroidism with radioiodine, surgical thyroidectomy, or use of an antithyroid drug. Although naturally occurring hypothyroidism is an extremely rare disorder in adult cats, congenital or juvenile-onset hypothyroidism does also occur. Recognized causes of congenital hypothyroidism in cats include intrathyroidal defects in thyroid hormone biosynthesis (dyshormonogenesis), an inability of the thyroid gland to respond to TSH, and thyroid dysgenesis. All reported cats with hypothyroidism have had the primary (thyroidal) disorder. Secondary (pituitary) or tertiary (hypothalamic) hypothyroidism has not been well described in either juvenile or adult cats but has been reported after severe head trauma.
In foals, congenital hypothyroidism may develop when pregnant mares graze plants that contain goitrogens or are fed diets either deficient in or containing excessive amounts of iodine. Most commonly, congenital hypothyroidism develops in association with a specific syndrome of neonatal foals characterized by thyroid gland hyperplasia together with multiple congenital musculoskeletal anomalies. This syndrome, reported most commonly in western Canada, has been referred to as either thyroid hyperplasia and musculoskeletal deformities syndrome or as congenital hypothyroidism and dysmaturity syndrome and may be related to feeding a high nitrate diet to pregnant mares. In adult horses, hypothyroidism appears to be very rare but, as in other species, is commonly misdiagnosed.
Although onset is variable, hypothyroidism is most common in dogs 4–10 years old. It usually affects mid- to large-size breeds and is rare in toy and miniature breeds.
Breeds reported to be predisposed to hypothyroidism include:
There does not appear to be a sex predilection, but spayed females appear to have a higher risk of developing hypothyroidism than intact females.
A deficiency of thyroid hormone affects the function of all organ systems; as a result, clinical signs are diffuse, variable, often nonspecific, and rarely pathognomonic. Although the disorder should be highly suspect, overdiagnosis should be avoided, because many diseases, especially those of the skin, can easily be misdiagnosed as hypothyroidism.
Many of the clinical signs associated with canine hypothyroidism are directly related to slowing of cellular metabolism, which results in development of mental dullness, lethargy, exercise intolerance, and weight gain without a corresponding increase in appetite. Mild to marked obesity develops in some dogs. Difficulty maintaining body temperature may lead to frank hypothermia; the classic hypothyroid dog is a heat-seeker. Alterations in the skin and coat are common. Dryness, excessive shedding, and retarded regrowth of hair are usually the earliest dermatologic changes. Nonpruritic hair thinning or alopecia (usually bilaterally symmetric) that may involve the ventral and lateral trunk, the caudal surfaces of the thighs, dorsum of the tail, ventral neck, and the dorsum of the nose is seen in about two-thirds of dogs with hypothyroidism. Alopecia, sometimes associated with hyperpigmentation, often starts over points of wear. Occasionally, secondary pyoderma (which may produce pruritus) is seen.
In moderate to severe cases, thickening of the skin occurs secondary to accumulation of glycosaminoglycans (mostly hyaluronic acid) in the dermis. In such cases, myxedema is most common on the forehead and face, resulting in a puffy appearance and thickened skin folds above the eyes. This puffiness, together with slight drooping of the upper eyelid, gives some dogs a “tragic” facial expression. These changes also have been described in the GI tract, heart, and skeletal muscles.
In intact dogs, hypothyroidism may cause various reproductive disturbances: in females, failure to cycle (anestrus) or sporadic cycling, infertility, abortion, or poor litter survival; and in males, lack of libido, testicular atrophy, hypospermia, or infertility.
A variety of neurologic disorders, including megaesophagus, laryngeal paralysis, facial nerve paralysis, and vestibular disease, have been related to hypothyroidism. However, all such peripheral and central nervous disease is uncommon, at least compared with the metabolic and dermatologic changes commonly seen in hypothyroid dogs. In addition, such neurologic signs do not always resolve after thyroid hormone replacement therapy.
Myxedema coma, a rare syndrome, is the extreme expression of severe hypothyroidism. The course can develop rapidly; lethargy progresses to stupor and then coma. The common signs of hypothyroidism (eg, hair loss) are usually present, but other signs, such as hypoventilation, hypotension, bradycardia, and profound hypothermia, are usually seen as well.
During the fetal period and in the first few months of postnatal life, thyroid hormones are crucial for growth and development of the skeleton and CNS. Therefore, in addition to the well-recognized signs of adult-onset hypothyroidism, disproportionate dwarfism and impaired mental development (cretinism) are prominent signs of congenital and juvenile-onset hypothyroidism. In primary congenital hypothyroidism, enlargement of the thyroid gland (goiter) also may be detected, depending on the cause of the hypothyroidism. Radiographic signs of epiphyseal dysgenesis (underdeveloped epiphyses throughout the long bones), shortened vertebral bodies, and delayed epiphyseal closure are common.
In dogs with congenital hypopituitarism (pituitary dwarfism, see Juvenile-onset Panhypopituitarism in Dogs), there may be variable degrees of thyroidal, adrenocortical, and gonadal deficiency, but clinical signs are primarily related to growth hormone deficiency. Signs include proportionate dwarfism (rather than the disproportionate form of dwarfism characteristic of congenital hypothyroidism), loss of primary guard hairs with retention of the puppy coat, hyperpigmentation of the skin, and bilaterally symmetric alopecia of the trunk.
In adult cats, clinical signs associated with advanced or severe hypothyroidism include:
Obesity may develop, especially in cats with iatrogenic hypothyroidism, but it is not a consistent sign. Bilaterally symmetric alopecia, except for pinnal involvement, does not appear to develop, but focal areas of alopecia over the craniolateral carpi, caudal hocks, and dorsal and lateral tailbase have occasionally been seen. However, in many cats with mild iatrogenic hypothyroidism, very mild or no obvious clinical signs are seen. In young cats with congenital or juvenile-onset hypothyroidism, the clinical signs are more obvious and include disproportionate dwarfism, severe lethargy, mental dullness, constipation, inappetence, and bradycardia.
Hypothyroidism is probably one of the most overdiagnosed diseases in dogs. Many diseases and conditions can mimic hypothyroidism, and some of the clinical signs, even in dogs with normal thyroid function, can improve after administration of exogenous thyroid hormone. In addition, a variety of nonthyroidal factors (eg, nonthyroidal illness and prior administration of certain drugs) can lead to low serum thyroid hormone measurements in euthyroid dogs, cats, and other species. Definitive diagnosis of canine hypothyroidism requires careful attention to clinical signs and results of routine laboratory testing. Tests that may confirm the diagnosis include measurement of the serum concentrations of total T4, free T4, and TSH; provocative thyroid function tests (eg, TSH stimulation test); thyroid gland imaging; and response to thyroid hormone supplementation. Choice and interpretation of diagnostic tests is based heavily on the index of suspicion for hypothyroidism.
There are well-recognized clinicopathologic abnormalities associated with hypothyroidism, the severity of which usually correlates with the severity and chronicity of the hypothyroid state. These changes are nonspecific and may be associated with many other diseases in dogs. Their presence, however, adds supportive evidence for a diagnosis of hypothyroidism in a dog with relevant clinical signs. The classic hematologic finding associated with hypothyroidism, found in 40%–50% of cases, is a normocytic, normochromic, nonregenerative anemia. The classic serum biochemical abnormality is hypercholesterolemia, which occurs in ~80% of dogs with hypothyroidism. The value of serum cholesterol determination as a screening test for hypothyroidism cannot be overemphasized, because cholesterol concentrations are a sensitive and inexpensive biochemical marker for this disease in dogs. Other clinicopathologic abnormalities may include high serum concentrations of triglycerides, alkaline phosphatase, and CK.
Total T4 concentration is the most commonly performed static thyroid hormone measurement and is a good initial screening test for hypothyroidism, with a diagnostic sensitivity of ~90%. A dog or cat with a T4 concentration well within reference range limits may be assumed to have normal thyroid function. However, a subnormal basal T4 concentration alone is not diagnostic; it may indicate an animal that is normal, hypothyroid, or suffering from a nonthyroidal illness with a secondary decrease in the basal T4 concentration (sick euthyroid syndrome; see below).
Because only the unbound fraction of serum T4 is biologically active, measurement of free T4 has been hypothesized to be more useful to differentiate euthyroid dogs from hypothyroid dogs than total T4 concentrations. However, most single-stage solid phase (analogue) commercial assays for free T4 do not appear to be superior to measurement of total T4 in dogs, probably because of differences in serum binding proteins. A free T4 assay that uses an equilibrium dialysis step (direct dialysis) has better accuracy than the analogue methods. Compared with the total T4 assay, the free T4 assay by dialysis has greater diagnostic sensitivity and specificity.
Because T3 is the most potent thyroid hormone at the cellular level, it would seem logical to measure its concentration for diagnostic purposes. However, serum T3 concentrations may be low, normal, or (occasionally) high in dogs with documented hypothyroidism. The diagnostic value of a serum T3 determination is particularly weak during early thyroid failure because the “failing” thyroid tends to increase the relative synthesis and secretion of T3 versus T4. In hypothyroid dogs in which values for serum T3 are high, anti-T3 antibodies, which produce spurious results in most T3 radioimmunoassays, should be suspected.
Determination of serum TSH concentrations by use of a valid species-specific TSH assay can be a useful adjunctive test for hypothyroidism in dogs, cats, and horses. Animals with primary hypothyroidism (by far the most common type) would be expected to have low serum T4 and/or free T4 concentrations with high endogenous TSH concentrations. Unfortunately, serum TSH concentrations remain within the reference range in 20%–40% of dogs with confirmed hypothyroidism. Although a few dogs with normal serum TSH concentrations have secondary hypothyroidism, pituitary TSH deficiency is extremely rare, and most dogs with normal TSH concentrations (ie, a false-negative result) have primary hypothyroidism. In contrast, falsely high serum TSH concentrations (ie, a false-positive result) are occasionally found in euthyroid dogs with nonthyroidal illness. Thus, serum TSH determinations should never be evaluated alone but always in conjunction with the dog’s history, routine laboratory abnormalities, and total or free T4 concentrations.
The TSH stimulation test evaluates the response of the thyroid gland to exogenously administered TSH and is a test of thyroid reserve. It is an accurate test of thyroid function in dogs, but its use is limited by the expense and limited availability of TSH. The protocol requires collection of a serum sample for measurement of a basal T4, followed by administration of bovine TSH given IV at a dosage of 0.1 U/kg (maximum dose 5 units). A second sample for measurement of T4 is collected 6 hours later. Human recombinant TSH is available, although expensive, and may be frozen for at least 8 weeks with no loss of potency. The recommended dose is 75 mcg, IV, with collection of 0- and 6-hour samples. Results are similar to those obtained using the bovine product. Results may reveal a normal response, a blunted response (sick euthyroid syndrome), or no response (hypothyroidism).
Both ultrasonography and scintigraphy of the thyroid gland have been evaluated as diagnostic tests for hypothyroidism in dogs. With an experienced radiologist, use of thyroid sonography (ie, decreased echogenicity and decreased thyroid volume) can be an effective ancillary diagnostic tool to differentiate between canine hypothyroidism and euthyroid sick syndrome. The best imaging technique may be the use of technetium 99m (99mTc) uptake and imaging of the thyroid gland. With quantitative measurement of thyroidal 99mTc uptake, there is little to no overlap between dogs with primary hypothyroidism and dogs with nonthyroidal illness.
In some cases, the most practical approach to confirming the diagnosis of hypothyroidism is a therapeutic trial using appropriate guidelines. Every attempt should be made to exclude nonthyroidal illness before starting a therapeutic trial. There is no evidence that thyroid hormone supplementation is beneficial in dogs with sick euthyroid syndrome, and it may be detrimental.
Thyroxine supplementation should be started at a dosage of 20 mcg/kg (administered without food, on an empty stomach), once to twice daily. Objective criteria should be used to assess the response to treatment. If response to treatment is positive, the clinician should be prepared to withdraw therapy to confirm that clinical signs return. This will ensure that dogs with thyroid-responsive diseases (ie, those in which the clinical signs improve because of the nonspecific effects of thyroid hormone or unrelated to therapy) do not remain on thyroid supplementation for life. If therapy is unsuccessful, therapeutic monitoring should be performed to identify the cause of treatment failure. Because an incorrect diagnosis is the most common cause of treatment failure, the clinician should be prepared to withdraw therapy and pursue other diagnoses.
In cats, hypothyroidism can also be diagnosed on the basis of finding low to low-normal serum concentrations of total T4, free T4, and T3, with high serum TSH concentrations. A feline-specific TSH assay is not available, but the canine TSH assay can be used as a test for feline hypothyroidism.
Circulating antithyroglobulin antibodies can be detected in as many as half of dogs with hypothyroidism and are believed to reflect a state of autoimmune thyroiditis. Measurement of these antibodies in breeding studs and bitches has been proposed as a method to identify dogs with autoimmune thyroid disease. Serum thyroglobulin autoantibody determinations may be a useful adjunctive diagnostic aid for hypothyroidism. However, the test can never be used alone to confirm a diagnosis of hypothyroidism because a positive antithyroglobulin antibody titer may occur in euthyroid dogs with early stages of lymphocytic thyroiditis. Identification of these autoantibodies supports the diagnosis if the dog has clinical signs and other laboratory data consistent with the disorder.
Although extremely rare in dogs, circulating thyroid hormone autoantibodies (anti-T3 or anti-T4 antibodies) are occasionally detected and also are believed to reflect a state of autoimmune thyroiditis. These antibodies, which can be formed against either T3 or T4 (or both), produce a spurious increase in the apparent T3 or T4 concentrations, into the hyperthyroid range in most dogs. Of all the thyroid hormones, only measurement of free T4 (by dialysis) is not affected by autoantibodies directed at T4 or T3, because the serum autoantibodies are removed in the dialysis step. Therefore, if hypothyroidism is suspected in a dog with circulating thyroid hormone autoantibodies, serum free T4 concentration should be determined to help confirm the diagnosis.
Certain breeds have normal thyroid hormone ranges that differ from most other breeds. Few have been evaluated, but Greyhounds have serum total T4 and free T4 concentrations that are considerably lower than those of most other breeds. Scottish Deerhounds also have total T4 concentrations that are well below the mean concentration of dogs in general, and other sight hounds may have similar findings. Alaskan sled dogs have serum total T4, T3, and free T4 concentrations that are below the reference range of most pet dogs, particularly during periods of intense training or racing.
Illness not involving the thyroid gland can alter thyroid function tests and has been labeled “nonthyroidal illness” or “euthyroid sick syndrome.” Any illness can alter thyroid function tests, causing a fairly consistent decrease in total T4 and T3 concentrations in proportion to the severity of illness. Serum TSH concentration is increased in 8%–10% of dogs with nonthyroidal illness. Serum free T4 measured by equilibrium dialysis is less likely to be affected but can be increased or decreased. However, in dogs with substantial nonthyroidal illness, the free T4 is likely to be decreased. Testing of thyroid function should be postponed until the nonthyroidal illness is resolved. If this is not possible, measurement of T4, TSH, and free T4 are indicated.
Glucocorticoids, phenobarbital, sulfonamides, clomipramine, and aspirin are known to commonly alter thyroid function tests. Glucocorticoids suppress total T4 and sometimes free T4 concentrations. Phenobarbital causes decreased total T4 and mildly increased TSH. Sulfonamides can induce overt primary hypothyroidism with clinical signs and thyroid function tests that support the diagnosis. All changes are reversible when the medication is discontinued. Dozens of drugs affect thyroid function and thyroid function tests in people, so many others likely affect animals as well.
Synthetic levothyroxine (L-T4) is the thyroid hormone replacement compound of choice in dogs and cats. With few exceptions, replacement therapy is necessary for the remainder of the animal's life; careful initial diagnosis and tailoring of treatment is essential. The reported replacement dosages for L-T4 in dogs and cats range from a total dosage of 0.01–0.02 mg/lb (0.02–0.04 mg/kg), daily, given once or divided twice daily without food (on an empty stomach).
The most important indicator of the success of therapy is clinical improvement. Reversal of changes in coat and body weight should be assessed only after 1–2 months of therapy. When clinical improvement is marginal or signs of thyrotoxicosis are seen, the clinical observations can be supported by therapeutic monitoring of serum thyroid hormone concentrations (“post-pill testing”). With once-daily administration of T4, the peak serum concentration of T4 generally should be slightly high to high-normal 4–6 hours after dosing and should be low-normal to normal 24 hours after dosing. Animals on twice-daily administration probably can be checked at any time, but peak concentrations can be expected at the middle of the dosing interval (4–6 hours) and the nadir just before the next dose. After the dosage is stabilized, serum T4 (with or without T3) concentrations should be checked 1–2 times per year.
If clinical signs of hypothyroidism remain despite the use of reasonable doses of thyroid hormone, the following must be considered:
the dosage or frequency of administration is improper
the owner is not complying with instructions or is not successfully administering the medication
the animal is not absorbing the medication well, or is metabolizing and/or excreting it too rapidly
the medication is outdated
the diagnosis is incorrect
Hypothyroidism, an underactive thyroid condition, is a relatively common endocrine disorder in dogs. It is less common in other species.
Hypothyroidism causes the bodily functions to slow down. Clinical signs of the disorder include lethargy, weight gain, and haircoat and skin changes.
Synthetic thyroid hormone replacement (L-T4) is the preferred treatment for hypothyroidism. Though L-T4 is man-made, it is the exact same hormones as produced in the animal's body.
In almost all cases, treatment for hypothyroidism is lifelong. Fortunately, L-T4 is effective and safe and will improve the animal's quality of life.