Hypothyroidism in dogs (Proceedings)

Background

Thyroid hormones influence many body systems. Thyroid hormones are involved in the development of the nervous and musculoskeletal systems. Thyroid hormones are also important to normal cardiorespiratory function, other hormones and enzyme systems, and red cell synthesis to name a few. The hypothalamus secretes thyrotropin-releasing hormone in response to nervous stimuli. The TRH then stimulates the pituitary gland to secrete thyrotropin-secreting hormone (TSH).1 The follicular cells of the thyroid gland then release thyroid hormone in response to TSH. Thyroxine (T4) and tri-iodothyronine (T3) provide negative feedback primarily at the level of the pituitary. Thyroxine is the primary iodothyronine, or thyroid hormone, released from the thyroid gland.2 Tri-iodothyronine is also released in a much smaller quantity. Thyroid hormones consist of both free and bound fractions. Ninety-nine percent are bound to albumin, prealbumin and thyroid hormone-binding globulin and act as a storage reservoir. It is the free fraction of T4 that can enter cells where it is converted to the biologically active portion, T3 as well as rT3.

Signalment

There are certain breeds that have an increased incidence of hypothyroidism including the golden retriever and Doberman pinscher. Other breeds have a similar incidence as mixed breed dogs. There are also breeds with a higher incidence of autoantibodies to thyroglobulin and thyroid hormones including pointers, English Setter, Old English Sheepdog, Skye Terrier, boxers, giant schnauzers and maltese amongst others.

Etiology

Hypothyroidism is classified as primary (problem in thyroid gland) or secondary (problem in pituitary). Primary hypothyroidism is most commonly due to lymphocytic thyroiditis or idiopathic atrophy with rare cases of neoplasia (mixed tumor, medullary thyroid carcinoma).

Lymphocytic thyroiditis is defined by infiltration of lymphocytes, plasma cells and macrophages throughout the thyroid gland that results in progressive destruction and fibrosis. Clinical signs don't usually appear until over 75% of the gland is destroyed. Antibodies to thyroglobulin and thyroid hormones may be seen prior to clinical signs and at diagnosis. Lymphocytic thyroiditis has occasionally occurred with other autoimmune disorders as part of a polyglandular syndrome.

Idiopathic fibrosis is characterized by replacement of thyroid parenchyma with fat. There are no autoantibodies present and on histopath no inflammatory cells. Idiopathic fibrosis may result from degeneration of thyroid follicles or the progression of LP thyroiditis.This is usually a diagnosis of exclusion so in a dog with primary hypothyroidism that fails to produce autoantibodies, idiopathic atrophy is presumed. Histopathology would be required to differentiate idiopathic atrophy from lymphocytic thyroiditis.

Rarely, neoplasia (discussed above), surgery (bilateral thyroidectomy), dietary iodine deficiency/excess, and hormone dysgenesis can cause primary hypothyroidism.

Secondary hypothyroidism indicates a problem with the pituitary thyrotrophs. The most common cause is suppression of TSH production from the thyrotrophs by exogenous or endogenous glucocorticoids (HAC, illness). Pituitary malformations/cysts and neoplasia can sometimes cause secondary hypothyroidism. Malformation and neoplasia often involve other hormones (CRH, GH, FSH, LH) so other symptoms may be present. Secondary hypothyroidism may also occur with pituitary irradiation and has been reported following hypophysectomy for pituitary-dependent hyperadrenocorticism.

Congenital hypothyroidism is rare but can occur as a result of iodine deficiency (primary), defects in organification of iodine (primary), thyroid dysgenesis (primary), TSH deficiency (secondary) and pituitary dwarfism (secondary).

Goiter refers to an enlarged thyroid gland and is rare in dogs. It can occur with organification defects (primary), thyroid peroxidase defects (primary) and trimethoprim-sulfa administration (primary).

Clinical Signs

Clinical signs typically develop in middle aged dogs because lymphocytic thyroiditis and idiopathic atrophy are responsible for almost all forms of hypothyroidism. Thyroid hormones effect virtually every cell but the most commonly observed clinical signs are related to activity and the skin. Lethargy, exercise intolerance and unwillingness to exercise are commonly reported.A myopathy occurs in dogs with hypothyroidism that is likely responsible for the lethargy and exercise intolerance. Mental dullness, cold intolerance (heat-seeker) and weight gain (normal appetite, intake) are common. Because the signs are insidious in onset and subtle they may go unnoticed for a long period of time.

Changes in the skin and hair coat are most commonly noticed by owners and include hair loss (originally pressure points –> more diffuse), inability to regrow hair, bilateral, symmetric, nonpruritic truncal alopecia (spare head, limbs, rat tail). With hypothyroidism, hair follicles enter and remain in the telogen phase so as they are lost they aren't replaced. In some breeds hair is epilated easily, in others the hair does not shed out normally. Some dogs lose undercoat, some lose guard hairs. Some dogs have coat changes involving the head and extremities, others don't. It is evident there are no consistent changes in hair coat indicative of hypothyroidism but certain breeds have characteristic patterns. Because of fatty acid and prostaglandin alterations in the skin as well as atrophy of the sebaceous glands, scale, seborrhea and hyperkeratosis occur. Hyperpigmentation often occurs in areas of alopecia. Cutaneous infections (pyoderma, folliculitis, impetigo) due to bacteria (usually Staphylococcus spp.) occur secondary to impaired humoral and cell-mediated responses. Malassezia and Demodex may also be found.Myxedema is an uncommon finding in severe cases of hypothyroidism. In cutaneous myxedema, mucopolysaccharides accumulate in the subcutis and pull waterMyxedema is most commonly found on the head (tragic facial expression) but the distal extremities can also be affected.

Neuromuscular signs are central and peripheral in origin. In the central and peripheral nervous system there is segmental demyelination and axonopathy. The central nervous system can also be affected by the accumulation of acids and mucopolysaccharides (myxedema), atherosclerosis and hyperlipidemia but this is rare. Seizures, stupor, coma, ataxia, hypothermia and hypoventilation may be seen with myxedema. Vestibular disease has been reported with hypothyroidism in dogs and be central or peripheral. Hypothyroidism has also been suspected as a cause of facial nerve paralysis in the dog. There are a few reports of dogs with megaesophagus and cricopharyngeal achalasia and hypothyroidism that have responded to thyroid supplementation. Facial paralysis and laryngeal paralysis have also been reported in dogs with hypothyroidism.

Cardiovascular effects are uncommon and typically subclinical but clinical findings include bradycardia and a weak apex beat. Electrocardiography reveals decreased P and R wave amplitude, prolonged P-R interval and heart block (1st and 2nd degree) in some dogs due to decreased contractility. The link between hypothyroidism and atrial fibrillation or dilated cardiomyopathy is controversial. There is, however, one report of a dog with severe hypothyroidism, myxedema, dilated cardiomyopathy, and atrial fibrillation, whose cardiac function improved dramatically with treatment.

Reproductive failure has been described in textbooks to include lack of libido, testicular atrophy and poor sperm quality in males. Females may fail to cycle, exhibit prolonged estrus and abortion. While hypothyroidism continues to be a rule out for infertility in the male and female, there are no good studies that have been done documenting fertility problems secondary to hypothyroidism.

Congenital hypothyroidism in puppies results in disproportionate growth due to the absence of thyroid hormone effects on chondrogenesis (along with growth hormone and insulin-like growth factor-I). These puppies are often dull, lethargic and retain their puppy coat. They might have a poor appetite, problems with constipation and delayed dental eruption. Puppies can have neuromuscular signs (tremors, spasticity, proprioceptive deficits, exaggerated spinal reflexes). Goiter is present in some.

General Laboratory Findings

The most common laboratory abnormalities include non-regenerative anemia, hypercholesterolemia and hyperlipidemia.Anemia may be due to decreased erythropoietin, direct effects of lack of thyroid hormone on bone marrow, decreased RBC survival time, decreased oxygen consumption by tissues and increased 2,3-DPG in RBC's (results in premature oxygen release). Thyroid hormones are involved in the synthesis and degradation of lipids. Insufficiency results in greater decreases in rate of degradation so they accumulate in the blood stream. Cholesterol, VLDL, LDL and HDL are increased. Mild to moderate increases in liver enzymes may also be seen.

Endocrine Testing

The diagnosis of hypothyroidism is dependent on clinical signs and positive endocrine test results. Serum T3, fT3 and rT3 are not routinely measured because little T3 is released from the thyroid gland and most T3 and rT3 are formed in the tissues so measuring these hormones and metabolic products answers questions about tissue metabolism not thyroid function.

Serum TT4 is the most common screening test for hypothyroidism. Serum TT4 is measured by RIA's or ELISA's that have been validated for use in the dog and cat. There is an in-house ELISA that has good correlation with commercial RIA's and ELISA's in the dog and cat. TT4 is a measure of free and bound thyroxine. Factors that affect TT4 include T4 autoantibodies (increase or decrease), euthyroid illness (decrease) and certain drugs. Greyhounds have lower reference ranges for TT4 and fT4 than other breeds.

In dogs non-thyroidal illness, considered a protective mechanism during disease, can falsely decrease TT4. This may be due to changes in the quantity of carrier proteins, alterations in metabolism of thyroxine, the ability to transport thyroxine into cells and the binding of T4 within the cells.Anti-thyroxine antibodies are uncommon but can falsely elevate TT4. Tests for fT4 using equilibrium dialysis (ED) are recommended when non-thyroidal illness or antibodies may be complicating interpretation of the TT4.2 Because ED is time-consuming and expensive, human radioimmunoassay's (RIA) have been used in dogs. These RIA's consistently measure a lower fT4 than ED and are of no diagnostic value over TT4. Because fT4 ED is a more sensitive test in the dog it seems logical to use it as a screening test but unfortunately a few euthyroid sick dogs have a low fT4. So although the fT4 is more sensitive it is not a perfect test. FT4 by ED is often used concurrently with TT4 and an endogenous TSH (eTSH) or to follow-up a questionable TT4 in dogs with suspected hypothyroidism.

Endogenous TSH is measured by immunoradiometric, chemiluminescent and enzyme immunometric assays with good correlation between the three in the dog. In primary hypothyroidism the TSH should be high due to absence of negative feedback. Unfortunately it can be difficult to differentiate hypothyroid and euthyroid dogs based solely on TSH because of overlap in values and endogenous TSH has been shown to have a poorer sensitivity than TT4 and fT4ed. Serum TSH should be used with clinical signs, TT4 and fT4 by MED in dogs with suspected hypothyroidism.

Autoantibodies can be measured against T4, T3 and thyroglobulin (TG). T3 and T4 autoantibodies are rare in hypothyroid dogs. They can interfere with measurement of TT3 and TT4 artifactually increasing (more common) or decreasing them depending on the test method.TG autoantibodies can be measured in up to 50% of hypothyroid dogs. All autoantibodies must be used in addition to measurements of thyroid hormones because increases in autoantibodies themselves do not indicate hypothyroidism. Antithyroglobulin antibodies are used by some breeders to screen younger animals that could potentially develop hypothyroidism.

The TSH stimulation test is not routinely done because the diagnosis is often made with more routine tests and TSH is often not available. TSH is given IV and a pre and 6 hour post TT4 are measured. TSH stimulation test of a normal dog should result in stimulation and an increase in TT4. When stimulating a dog with hypothyroidism, the thyroid gland is not able to respond to stimulation due to the lack of functional follicular cells.

The TRH stimulation test is also not routinely done for the reasons above. This test provides less dramatic increases with stimulation than the TSH stimulation making interpretation more difficult. TRH is given IV and a pre and 4 hour sample are evaluated for TT4. Normal dogs increase, dogs with hypothyroidism are below the reference range on the post.

The diagnosis of hypothyroidism is firstly made in a dog with appropriate clinical findings (history, physical, routine laboratory evaluation). A normal TT4 rules out hypothyroidism in almost all dogs. A low TT4, with clinical signs, is diagnostic and treatment should be instituted. If the TT4 is questionable and clinical signs questionable (euthyroid sick, drugs, signs not classic) then a fT4 by MED and TSH can be done. Measurement of TT4, fT4 (MED) and TSH concurrently is commonly done as an initial screening test in suspect hypothyroid dogs. Autoantibodies can be measured (particularly thyroglobulin antibodies) to evaluate for lymphocytic thyroiditis. Stimulation testing is rarely needed for diagnosis.

Treatment

Synthetic levothyroxine (T4) is given at 0.02 mg/kg once to twice daily (some dogs on BID therapy can eventually be placed on once daily) to a maximum of 0.8 mg/dose. Both tablet and liquid formulations are available and effective in dogsAttitude improves within a few days. Dermatologic and neuromuscular abnormalities may take weeks to months to improve. In fact as hair enters anagen phase they might look worse. Levels are checked 3 to 4 weeks after initiating therapy and a 4 to 6 hour post pill sample is taken to measure TT4 ± TSH. TT4 should be high normal to mildly increased with a normal TSH.

Liothyronine sodium (T3) is used in dogs unresponsive to levothyroxine (poor absorption). Supplementing T3 provides feedback to the pituitary and subsequent decrease in T4. T3 is measured 2 to 4 hours after administration. Liothyronine sodium typically has to be given three times a day.

Prognosis

The prognosis is excellent with treatment.

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