Canine Pseudohypothyroidism and Covert Hypothyroidism
by C. B. Chastain, DVM, MS
From the Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri, Columbia, Missouri.
Address correspondence to C. B. Chastain, DVM, Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211.
Source: Problems in Veterinary Medicine, pp. 693-716.
Primary hypothyroidism is perhaps the most common endocrinopathy of the dog. Unfortunately, a paradox exists. Many cases of mild to moderately severe hypothyroidism are unrecognized, while many euthyroid dogs are misdiagnosed as having hypothyroidism. Uncommon manifestations resulting from earlier stages of primary hypothyroidism, from secondary/tertiary hypothyroidism, or from a unique interplay between thyroid hormone deficiency and the age, sex or breed affected can obscure the clinical suspicion of hypothyroidism. Conversely, nonthyroidal diseases and drug therapy can alter thyroid hormone metabolism in ways that mimic hypothyroidism and can lead to erroneous diagnosis. Misinterpretation of clinical signs and laboratory findings are also causes for an incorrect diagnosis of hypothyroidism. The level of confidence in the diagnosis of hypothyroidism should be reflected as "suspected," "probable," and "definitive" hypothyroidism. Screening laboratory evaluations should be serum T4 and free T4 levels. The most reliable current evaluation for equivocal cases is the thyroid-stimulating hormone (TSH) stimulation test. Intramuscular or subcutaneous administration of TSH provides a greater separation between normal and abnormal post-TSH response. A definitive diagnosis of hypothyroidism in an adult dog is a retrospective assessment based on complete recovery after appropriate thyroid hormone replacement.
Hypothyroidism is the most commonly diagnosed endocrinopathy in the dog. The disease and its therapy was well defined more than 100 years ago. Today, some dogs in which hypothyroidism is diagnosed are not truly affected, whereas others that really have hypothyroidism, remain undiagnosed, particularly if the disease is masked by concurrent nonthyroid illnesses or if in an early stage of hypothyroidism. Thus, the true incidence of hypothyroidism in dogs is not known, however, there still is no doubt that hypothyroidism is among the most common endocrine disorders in the dog.
Primary hypothyroidism is the most common type of hypothyroidism in the dog. It is usually the result of lymphocytic thyroiditis or thyroid atrophy. Thyroid atrophy can be the end-result of lymphocytic thyroiditis.1 Severe primary hypothyroidism affects practically every organ of the body and is easily recognized by most veterinarians. Middle- age dogs (4-10 years of age) of mid- to large-sized breeds are at increased risk. The golden retriever, Doberman pinscher, Irish setter, miniature schnauzer, dachshund, cocker spaniel, Airedale terrier, Great Dane and Old English Sheepdog are especially susceptible.2,3 German shepherd dogs and mongrels are at low risk.3 Common clinical signs are alopecia with or without hyperpigmentation, physical lethargy, mental dullness, dry flaky hair coat, cold intolerance, slow heart rate, infertility in males and females, constipation and weight gain.4 Myxedema of the skin may be evident on the head, particularly over the eyes.4 Laboratory findings often include hypercholesterolemia and normaochromic normocytic anemia. Serum creatine kinase (CK) is occasionally elevated. Oligospermia may occur in hypothyroid dogs.4
The benefits of replacement hormone therapy in severe primary hypothyroidism without complications are clear to all observers. Within days of beginning treatment, hypothyroid dogs are noticeably more active and mentally alert. New hair growth is evident by 4-6 weeks. Complete regrowth of hair occurs and remains as long as replacement therapy continues. Associated hypercholesterolemia and anemia are completely corrected.
CAUSES OF COVERT HYPOTHYROIDISM
An Early Stage of Development
Not all dogs with hypothyroidism have the classical clinical signs and laboratory findings described above. The development of thyroid hormone deficiency of primary origin is slow and insidious. The clinical signs and laboratory findings of mild to moderate hypothyroidism are nonspecific, mild and incomplete manifestations of the complete spectrum of problems that occur with severe hypothyroidism. Dogs with developing hypothyroidism that have highly observant owners or veterinarians may have signs detected in an early stage of development. Those with owners and veterinarians that have a low index of suspicion for hypothyroidism will have undiagnosed or incorrectly diagnosed maladies stemming from hypothyroidism.
Atypical Presenting Signs
Another group of causes of covert hypothyroidism are the atypical presenting signs: myopathy, neuropathy, impaired mental state, hypothermia, stunted growth, bleeding and signs of other endocrine diseases (Table 1). Severe hypothyroidism can cause pseudomyotonia and profound muscle weakness. Some dogs exhibit slow, stiff locomotion, often described by owners as muscle cramps. Affected dogs have elevated serum CK values and usually hypercholesterolemia. Other more characteristic signs of hypothyroidism are present but may be overshadowed by the degree of muscular weakness.
The most common finding in affected dogs is a metabolic dysfunction in type II fibers leading to type II fiber atrophy.5 However, myopathic findings in dogs with hypothyroidism and neuromuscular abnormalities are inconsistent and vary with the severity of hormone deficiency. Additional findings can be high-frequency discharges on electromyography and a type I myofiber atrophy with a periodic acid-Schiff (PAS)-positive material in type I fibers.6
Dogs with hypothyroidism occasionally have central or peripheral nerve disturbances. The clinical signs can be dragging of the front feet, hearing impairment or nystagmus.7,8 Electromyography may reveal fibrillation potentials and positive sharp waves.8 Motor nerve velocity can be slowed.6 Lesions in affected dogs include segmental demyelination, peripheral nerve entrapment from myxedema in surrounding soft tissue and central nervous system (CNS) vascular accidents resulting from atherosclerosis.8
Impaired Mental State
An impaired mental state resulting from associated atherosclerosis, cerebral myxedema or a hypothalamic or hypophyseal tumor can be a presenting sign of hypothyroidism. Atherosclerosis can lead to cerebral infarction, seizures, disorientation, coma, circling to one side, head tilt and amaurosis.9,10 Moderate to severe atherosclerosis developing mainly in the coronary and renal arteries has been observed in related hypothyroid beagles and sporadically in other breeds.8,10 Serum triglycerides are generally elevated and serum cholesterol levels usually exceed 400 mg/dl.10 Other effects of atherosclerosis such as hypertension, retinopathy and renal failure also may be present.
The most dangerous possible sequelae of severe hypothyroidism is myxedema coma. Most recognized cases have involved Doberman pinschers.11,13 Associated mortalities are high. Severe hypothyroidism can cause an obtunded mental state, stupor and then coma. Myxedema coma is further characterized by hypothermia, usually without shivering, hypoventilation, hypotension and bradycardia, in addition to signs of classic hypothyroidism such as alopecia or seborrhea. Laboratory findings may include hypoxia, hypercarbia, dilutional hyponatremia, hypocortisolemia and hypoglycemia.12,13
Precipitating factors of myxedema coma are respiratory depressant drugs,infectious disease (especially those of the respiratory system), heart failure, decreased blood volume (due to diuretic therapy) or exposure to a cold environment.
Hypophyseal or hypothalamic tumors can cause secondary or tertiary hypothyroidism, respectively. An altered mental state caused by intracranial compression can accompany or overshadow signs of hypothyroidism in such cases.14
Thyroid hormones are essential for normal musculoskeletal growth. Untreated congenital or juvenile-onset hypothyroidism will result in stunted physical growth.
Most dogs and cats with congenital hypothyroidism probably die before weaning. The two most common causes include thyroid dysgenesis and dyshormonogenesis (usually an inability to organify iodine). Other forms of dyshormonogenesis, serum transport abnormalities, congenital thyroid-stimulating hormone (TSH) deficiency, goitrogens and severe iodine deficiency are also possible causes. If the condition is mild or the puppy is reared by hand, it can survive.
Goitrous congenital cretinism has been reported in a German shepherd dog and St. Bernard crossbred pup.15 Nongoitrous congenital cretinism from apparent thyroidal dysgenesis has been reported in a German shepherd dog and Alaskan malamute crossbred pup16 and Scottish deerhounds.17,18
Nongoitrous congenital or juvenile cretinism from unestablished causes also has been reported in a bull mastiff19 and giant schnauzers.20
Clinical signs may go unnoticed until the period after weaning, when impaired growth and maturation of the skeletal and nervous systems become obvious. Severe congenital hypothyroidism causes disproportionate (short-legged) dwarfism and subnormal mentality. Other physical signs can include short-broad skull, shortened mandible, protruding tongue, lateral strabismus, exophthalmos, alopecia, hypothermia, bradycardia, muscular weakness, delayed dental eruption and (depending on the cause) goiter.15-20
Suggestive laboratory findings can include hypercholesterolemia, nonregenerative anemia, elevated serum CK levels, impaired secretion of growth hormone and hypoglycemia.15,16,18,19 Thyroid dysgenesis is made evident by abnormal findings in a thyroid scan. A defect in organification is substantiated by abnormal findings in a perchlorate discharge test.15
Radiographic evidence of epiphyseal dysgenesis (ragged epiphyses with few foci of calcification) is pathognomonic for congenital hypothyroidism. Other radiographic findings include delayed epiphyseal closure, shortened vertebral bodies, deformities of the open cranial sutures joints, kyphosis and arthritis.15-20
Although administration of thyroid hormones can promote significant physical growth after prolonged cretinism, treatment must be begun in the first few weeks of life to preserve normal intelligence levels.15
A relationship between bleeding tendencies, particularly von Willebrand's disease, and hypothyroidism has been proposed.21 Laboratory changes that resemble von Willebrand's disease can occur in hypothyroidism in humans, but bleeding is mild.22 However, untreated hypothyroidism can make von Willebrand's disease more severe, perhaps converting a subclinical bleeding tendency into a clinical tendency, as thyroxine amplifies the production of factor VIII and factor VIII-related antigen.4,22 Most of the canine breeds at high risk for hypothyroidism also have high risk for von Willebrand's disease so that hypothyroidism concurrent with von Willebrand's disease is not surprising.21
Other Signs of Endocrine Disease
Other endocrine gland dysfunction concurrent with hypothyroidism can mask the presence of hypothyroidism. For example, in myxedema coma there can be impaired secretion of adrenocorticotropic hormone (secondary hypoadrenocorticism) and enhanced secretion of antidiuretic hormone (the syndrome of inappropriate ADH).12
Hyperprolactinemia occurs in dogs with severe hypothyroidism and is caused by an excess of thyrotropin-releasing hormone (TRH) and deficient concentrations of hypothalamic dopamine as documented in humans.23,24 The resulting hyperprolactinemia may cause inappropriate galactorrhea in at least 25% of hypothyroid, sexually intact bitches.23 Galactorrhea induced by hypothyroidism depends on the mammae being adequately primed earlier for lactation. This phenomenon must be differentiated from other possible causes of galactorrhea, particularly pregnancy, pseudocyesis and mammary trauma. Hyperprolactinemia may also be at least partially responsible for infertility in dogs with severe hypothyroidism, as prolactin may interfere with gonadotropin-releasing hormone (GnRH) or directly with gonadal production of steroids.23
Secondary hypothyroidism and tertiary hypothyroidism are rare in dogs. In juvenile dogs, secondary hypothyroidism can result from a cystic Rathke's pouch producing compression of the hypophysis.25 Pituitary dwarfism from cystic Rathke's pouch is inheritable in German shepherd dogs and Carelian bear-dogs.25 Congenital secondary or tertiary hypothyroidism has been reported in giant schnauzers.20 In adults, secondary hypothyroidism is usually caused by adenohypophyseal adenomas.14
Clinical signs of secondary hypothyroidism in juvenile dogs may be accompanied by multiple adenohypophyseal hormone deficiencies. Growth hormone deficiency is always concurrent, either because of compression of the hypophysis or secondary to the deficiency of thyroxine's permissive effect on growth hormone secretion. Hypophyseal compression from enlarging cysts may cause secondary hypogonadism or secondary hypoadrenocorticism.25
Clinical signs suggestive of adult-onset canine secondary hypothyroidism are indications of hypothyroidism concomitant with signs of intracranial disease. Adenohypophyseal hormone deficiencies in addition to TSH deficiency and progressive neurologic abnormalities are to be expected.14 Clinical signs may include stumbling, head pressing, bradycardia, episodic blindness and behavioral changes in addition to secondary hypothyroidism.14 Suggestive laboratory abnormalities are hypercholesterolemia or hyposthenuria (diabetes insipidus).14
The diagnosis of secondary or tertiary hypothyroidism can be confirmed by showing the lack of colloid vacuoles in biopsies of the thyroid, along with radiographic evidence of adenohypophyseal enlargement shown by cranial sinus venography or cranial tomography. Typically, baseline serum tetraiodothyronine (T4) levels are low, and serum T4 levels are normal or near normal after 3-8 days of injections of thyroid-stimulating hormone (TSH).14 Images produced by thyroid scans also will increase in response to the administration of TSH for 3 days, if secondary or tertiary hypothyroidism is the cause of low baseline T4 levels.
Dogs with hypothyroidism caused by lymphocytic throiditis can concurrently develop hypoadrenocorticism, hypoparathyroidism, primary hypogonadism or diabetes mellitus. These concurrent endocrinopathies often represent autoimmune (lymphocytic) destruction of multiple endocrine glands. Dogs with hypoadrenocorticism or diabetes mellitus have been reported to have antithyroglobulin antibodies in 60% and 37.5% of cases, respectively.2 This was not confirmed by a later study, however.26
Hypothyroidism and hypoadrenocorticism have been reported in a dog with antibodies demonstrated against thyroid microsomes and adrenocortical cells.11 This is identical to type II autoimmune polyglandular syndrome of humans (Schmidt's syndrome).
Misinterpretation of the Response to Trial Therapy
Hypothyroidism may be suspected and then rejected because of what is thought to be a failure to respond to therapy. An erroneous assumption of failed therapy in a true hypothyroid dog generally is due to owner failure to administer therapy as instructed, an insufficient dose of thyroxine or an insufficient length of time for treatment response.
Owner failure can be substantiated in some cases by testing after the owner has reportedly administered replacement therapy. An insufficient dose of thyroxine is rare except when a human dose schedule is applied to dogs. Therapy should be continued for a minimum of 6 weeks before possible failure to respond is considered.
PSEUDOHYPOTHYROIDISM AND ITS CAUSES
An Oversimplified Understanding of Thyroid Physiology
The diagnosis of hypothyroidism has been greatly facilitated by newer specific and precise serum hormone assays. However, care must be taken not to assume that low levels of serum thyroid hormones always have a direct relationship on the health of the thyroid glands.
Although the thyroid gland is normal there are many potential causes for low serum levels of thyroid hormones. For example, not all thyroid-derived hormones in the blood stream are directly produced by the thyroid gland. The majority of the serum tri- iodothyronine (T3) and reverse (r)T3 are produced at peripheral cells by deiodination of T4. Most of the serum thyroid hormones measured are usually inactive, being bound to serum proteins. A decline in protein-bound thyroid hormone does not directly alter the free hormone concentration that is necessary for target cell effects. Finally, nonthyroid illnesses can temporarily modify the hormone production by the thyroid gland, the degradation and elimination of thyroid hormones, and the use of circulating thyroid hormones by target cells.27
Confusing Endocrine Assay Terminology and Methodology
The units in which endocrine laboratories report thyroid hormone values are not standardized. This can cause an incorrect interpretation of results. For example, some laboratories report serum T4 in nanograms per milliliter. A normal value would be about 20 ng/ml, but if this is reported in ug/dl, the value would be 2 ug/dl (normal, 1-4 ug/dl). If the reported value of 2 ug/dl is assumed to be in nanograms per milliliter, an erroneous diagnosis of hypothyroidism would result. The units have nothing to do with the accuracy of the results. Most laboratories prefer to report in units that allow normal values to be in single digits before the decimal, ie, ug/dl.
There is currently a well-intentioned effort being made to change the traditional units from ug/dl to the Systeme International (SI) units, moles. This may have common usage in the future, but while routine laboratory test values and manufactured drugs remain in traditional units, it may be premature to attempt to isolate hormone value conversion. Plus, as long as journals and textbooks continue to use traditional units, reporting in SI units is unnecessarily confusing.
The designations T3 and T4 (T[Total]T4, TT3) infer that total serum values are being reported. At least 99% of circulating T3 and T4 are bound to plasma proteins. About 0.1% of serum T4 and 1% of serum T3 are free.4 Free T4 (FT4) or FT3 values are protein- unbound hormone values. It is this form that is more readily used by peripheral cells. Free hormone values are sometimes referred to as fractions. Fractional FT4 or FT3(%FT4, %FT3) are the percentages of free hormones compared with the total values. Therefore, the FT4 value may decrease even though the fractional FT4 increases if hypothyroidism and hypoproteinemia occurs in the same dog.
The terms T3, total (T)T3, FT3, reverse(r)T3, and T3 uptake can be confusing. TT3 and T3 are used interchangeably. These terms refer to the bound and unbound T3 levels. FT3 is the unbound portion of circulating T3, the form that most easily enters target cells. The FT3 levels parallel the changes in the TT3 levels.4 Reverse T3 is a metabolically inactive metabolite of T4 deiodination at peripheral cells. The T3 uptake is an indirect and very insensitive test of thyroid hormone binding to plasma proteins in the dog.4
Free T4 and FT3 may be determined by several means. Equilibrium dialysis is considered to be the most reliable method, but this method is used primarily for research, as it is too time consuming and expensive for commercial laboratories. Most free thyroid hormone assays are direct radioimmunoassays (RIA). These do not always correlate with free values by equilibrium dialysis.4
Euthyroid Sick Syndrome
Many nonthyroidal illnesses are associated with a reduction in serum T3 and T4 levels (Table 2). Almost all critically ill dogs in an intensive care unit will have low serum T3 and T4 levels.4
The first change in critical nonthyroidal illnesses is usually a subnormal level of T3 and FT3 resulting from decreased peripheral monodeiodination of T4. Sustained moderate to severe nonthyroidal illnesses result in low serum total T4 and finally FT4 levels.27,28 Causes include reduced thyroxine-binding prealbumin (TBPA) levels, release of an inhibitor of thyroid hormone binder, increased serum clearance of thyroid hormones, and a lowered set point for T3 feedback on TSH secretion.27,29
Serum T4 levels do not change following surgery in dogs, but plasma T3 levels are significantly suppressed for 24-31 hours. Levels of rT3 increase 50% for 6-31 hours. All values return to normal by 48 hours.30
Fasting for up to 2 weeks does not significantly alter T4 levels in dogs. Serum T3 declines significantly after 2 days of fasting. Serum rT3 does not seem to rise in dogs and even will transiently decrease in the first 24 hours of fasting.31,32 Thyroid- stimulating hormone secretion can be attenuated by poor caloric intake, leading to decreased serum T3, T4 and FT4.27 Serum T3 declines in fasting to spare muscle protein and perhaps fat stores.27
Diabetic ketoacidosis can significantly depress serum T3 and T4 levels. Levels may vary with the severity, adequacy of treatment, or the present concurrent illnesses.4 In most cases, serum rT3 increases with diabetes mellitus. Serum T3 drops, whereas serum T4 is normal to decreased. Thyroxine-binding prealbumin may be normal to increased with decreased T4. The decrease in T4 is due to factors other than a decrease in available plasma-binding protein.29 A depressed TSH response also can occur in dogs with diabetes mellitus.33
The majority of dogs with hyperadrenocorticism have either low serum T4 or T3, or both.4,34 Low serum T3 levels may be due to direct suppression of thyroid gland or decreased deiodination of T4 to T3.34 In almost one-third of affected cases, FT4 and rT3 are low, indicating decreased TSH secretion or increased clearance of thyroid hormones.4 Thyroxine-binding prealbumin increases, but %FT4 increases in more than 20% of cases indicating decreased plasma protein binding.29 The slope of the TSH response remains normal, but absolute pre- and post-TSH serum T4 values are lower. Recovery of normal absolute pre- and post-TSH serum T4 values follow successful treatment of hyperadrenocorticism.34 Hypoadrenocorticism in dogs depresses baseline serum T4 levels in half of cases.4
Renal or liver diseases can reduce serum T4 levels.4,29,33 Renal disease may cause loss of thyroid hormone plasma-binding proteins, and hepatic disease may impair production of the binding proteins, especially TBPA.29 Serum TT3 may be normal to decreased, and serum rT3 is usually increased with liver and renal diseases.29,33 Serum FT4 remains normal in renal insufficiency.4 Plasma thyroid hormone- binding proteins also should decrease in protein-losing enteropathies and severe hookworm burdens.
Dogs with diseases causing Horner's syndrome, facial paralysis, congestive cardiomyopathy, laryngeal paralysis, or intervertebral disk protrusion may have lowered levels of serum T3 or T4.7,35-37 The underlying disease is usually the cause of the secondary lowered serum thyroid hormone levels. When a TSH stimulation test is used as the criterion for diagnosis, there is no relationship between hypothyroidism and Horner's syndrome, congestive cardiomyopathy, or facial neuropathy.35,38,39 Some dogs with laryngeal paralysis may have hypothyroidism, but it is not a triggering factor for laryngeal paralysis.40
Primary and secondary pyoderma diseases can lower serum T3 levels in dogs. The incidence of low baseline serum T3 levels in one survey of 71 dogs with pyoderma was greater than 50%.41 After treatment of the underlying cause of pyoderma, the response to TSH stimulation is normal in euthyroid dogs that have had pyoderma.
Treatment with thyroid hormones is not beneficial and probably detrimental in euthyroid sick syndrome. For example, 24 of the dogs in a retrospective study were initially diagnosed as being hypothyroid based on low T3 with a normal T4. Using more than a physiologic dose of sodium levothyroxine (22 ug/kg body weight twice per day), 60% of all levothyroxine-treated dogs in the study failed to have a good clinical response in 2 months.42 The detrimental effects of unnecessary thyroid hormones in euthyroid sick dogs are from increased catabolism of needed protein and energy.
Several drugs may lower serum T4 or T3 levels (Table 3). Levels of total hormone concentrations can be lowered by inhibiting plasma protein binding, by inhibiting the synthesis of binding proteins, by speeding the clearance of free hormone or binding proteins, by inhibiting the secretion of TSH, or by directly inhibiting the secretion of hormones by the thyroid.
Serum T4 concentration can be lowered in dogs by the anticonvulsants phenobarbital and phenytoin.43,44 However, binding may not be significantly affected by phenobarbital.44
Nonsteroidal anti-inflammatory drugs such as salicylates and flunixin lower serum T4 levels.43,44 Phenylbutazone inhibits T4 binding to plasma proteins, increasing the percentage of free T4 and causing lowered total T4, but the effect may be insignificant.43,44 The response to TSH stimulation is not decreased.4
Serum T4 and T3 can be decreased by repeated daily administration of glucocorticoids. Alternate-day therapy also can decrease serum levels of both hormones. The first effect of glucocorticoid administration on serum thyroid hormone levels is decreased serum T3 within 8 hours and a rise in rT3 within 24 hours because of inhibition of peripheral deiodination of T4 to T3.32,45 However, a single administration of a short-duration form does not cause suppressed serum T4 levels.32,44,45 Secretion of endogenous TSH is probably inhibited in more severe cases. A normal TSH response slope remains, but absolute pre- and post-TSH serum T4 values are suppressed.34,45 Even though it is used to suppress excessive adrenocortical secretion of glucocorticoids, mitotane also may lower serum thyroid hormone levels.43
Anesthesia with halothane or thiopental and methoxyflurane significantly depresses serum T4, T3 and rT3 30 hours after administration, apparently because of suppressed TSH secretion.4 Ratios of T3 and rT3 to T4 are increased, indicating decreased peripheral deiodination. Thiopental may be more suppressive than methoxyflurane.4
Sex hormones affect thyroxine-binding protein concentrations. Anabolic steroids decrease T4 binding to plasma proteins in dogs and may lower serum T4 levels.43 Chronic estrogen stimulation may increase or buoy serum T4 levels in hypothyroidism. Dogs with early hypothyroidism and hyperestrogenism could have TT4 levels in normal range because of increased binding. After ovariectomy in dogs, estradiol levels drop for 2 weeks, TT4 levels decrease 30% in 3-5 weeks and FT4 levels (by RIA, not dialysis) decrease nearly one fourth in one week.46 Hyperestrogenism also blunts the TSH response.33
Other drugs that may lower thyroid hormone concentrations include furosemide, oleic acid, and ipodate. Furosemide significantly inhibits thyroxine binding to plasma proteins, in vitro.44 Serum oleic acid concentration increases with lipolysis, heparin therapy, or nonthyroidal illnesses. Elevated concentrations of oleate significantly inhibit thyroxine binding to plasma proteins.44 Ipodate, a radiocontrast dye for cholecystography, inhibits T4 plasma protein binding.44 However, acute effects of a single large dose of ipodate in dogs are a decline in serum T3 levels and an increase in serum T4 levels.32
Propranolol is a weak inhibitor of T4 deiodination to T3. However, at common dosages propranolol does not alter baseline or post-TSH serum levels of T4, T3 or rT3 in dogs.44
Misleading Physical Findings
Physical findings are important initial clues to the possibility of hypothyroidism. Some, such as hypothermia without shivering, have a relatively reliable association with hypothyroidism. Other physical abnormalities have become linked with a supposed association with hypothyroidism and are unreliable: obesity, Horner's syndrome, facial paralysis, megaesophagus, laryngeal paralysis, congestive cardiomyopathy, and diarrhea (Table 4).
The myth that obesity is often caused by hypothyroidism dies hard. Although 60% of hypothyroid dogs have been reported to have weight gain or obesity,4 weight gain and obesity are not synonymous. Obesity is a body weight that exceeds 15% above the optimum range.47 Based on earlier records of body weight, modest weight gains do occur with hypothyroidism, but hypothyroidism is not a common cause of obesity. The incidence of obesity in the general population of pet dogs in affluent societies is 24-44%,47 whereas the incidence of hypothyroidism is less than 1%. The incidence of obesity in hypothyroid dogs does not exceed the incidence of obesity in the general population.
Because hypothyroidism can cause neuropathies and myopathies, hypothyroidism has been associated with the development of certain neuromuscular disease syndromes, including Horner's syndrome, facial paralysis, megaesophagus, laryngeal paralysis, and congestive cardiomyopathy.7,36-40 However, when a TSH stimulation test was used as the criterion for diagnosis, there was no relationship between hypothyroidism and Horner's syndrome for facial paralysis.39 No data have been presented to support the proposal that megaesophagus is associated with hypothyroidism. Although 3 of 11 dogs with laryngeal paralysis evaluated by TSH stimulation in one study were interpreted as having hypothyroidism,37 hypothyroidism has not been established as a triggering factor.40 In 5 of 13 Doberman pinschers with congestive cardiomyopathy, baseline serum T4 levels were abnormally low. However, 4 of the 5 had normal responses to TSH stimulation.35
Hypothyroidism can cause constipation due to decreased electrical and motor activity of the digestive tract.4 Diarrhea does not occur from hypothyroidism, but it is a potential cause for euthyroid sick syndrome.
Potentially Misleading Laboratory Findings or Interpretations
Support for a tentative diagnosis of hypothyroidism has been sought through a variety of laboratory assessments on the plasma or serum. Each of these assessments can be misleading. Interpretation of the results of most laboratory assessments are often controversial.
Approximately 2/3 of hypothyroid dogs have abnormally elevated serum cholesterol values. Hypercholesterolemia also may be caused by many other factors, including high-fat diets, postprandial testing, hyperadrenocorticism, diabetes mellitus, nephrotic syndrome, primary dyslipoproteinemia, and cholestatic disorders. Dogs with hypercholesterolemia of unknown cause should be investigated for hypothyroidism.
Laboratories that routinely assay serum thyroid hormone levels in humans cannot use the same methodology to accurately determine canine thyroid hormone levels. Normal TT4 levels in dogs are 1/3 to 1/4 that of humans. This necessitates the use of a different standard curve to read the lower normal range of dogs. Validation of assays is required because of serum binding proteins that differ among different species, which may interfere with the RIA procedure used.4,48
Normal serum T4 concentrations in dogs are approximately 1-4 ug/dl, depending on the assay used and the laboratory performing the assay. Normal serum T4 values may differ among breeds of dogs.49 However, the degree of difference among breeds is of doubtful significance.
An in-office enzyme-linked immunosorbent assay (ELISA) for semi- quantitation of serum T4 levels has recently become commercially available. Previously, a study on baseline T4 by ELISA in dogs concluded that the ELISA used in that study did not differentiate normal from hypothyroid dogs unless combined with an exogenous TSH response.29
A circadian cycle of serum T4 does not occur in dogs.50 Nevertheless, erratic fluctuations of serum T3 and T4 do occur in sick and normal euthyroid dogs. Fluctuations into low ranges are particularly common in sick dogs.50
In hypothyroid dogs, serum T3 is within normal range half of the time.51 Serum T4 is decreased in hypothyroidism more often than serum T3, and serum T4 fluctuations into normal range are rare and transient.
Most aging studies in dogs indicate there are slight decreases in basal T4 of about 0.1 ug/dl/year.52,53 Decreases may be due to decreased binding to plasma proteins, decreases T4 production, increased T4 clearance, increased degradation, or increased T4 receptors. Thyroid-stimulating hormone-stimulated serum T4 responses decline slightly with age. Older dogs do not respond to TRH stimulation as well as younger dogs.54
Normal serum T3 levels in dogs are about 50-150 ng/dl. However, there is normally 20 times more T4 in the serum than T3. In addition, 60% of serum T3 is generated through peripheral monodeiodination of T4 to T3 by the enzyme, thyroxine 5'-deiodinase.55
A single determination of baseline serum T3 levels is inferior to the single measurement of baseline T4 for the diagnosis of hypothyroidism.4 Many dogs with nonthyroidal diseases have low T3 levels, whereas half of dogs with hypothyroidism have normal T3 serum levels.51 In dogs, serum T3 returns to normal in 10 days after partial thyroidectomy, while serum T4 will remain low for more than 2 months.56 Triiodothyronine is secreted preferentially under acute TSH stimulation, as occurs in developing hypothyroidism.57
A noncritical nonthyroidal disease that can lower serum T3 in dogs is pyoderma.41 Serum T3 is expected to be low in critical nonthyroidal illness or catabolic states.
Antithyroglobulin Antibodies (ATGA)
Antithyroglobulin and antithyroid microsomal antigen antibodies have been determined in hypothyroid dogs and in the general canine hospital population by ELISA, chromic chloride passive hemagglutination (CCPH), and indirect immunofluorescence assay (IFA).2,26,33,58 Antithyroglobulin antibodies can occur in euthyroid dogs as well as hypothyroid dogs. Using current methods, at least 40% of hypothyroid dogs do not have ATGA.2
The clinical usefulness of ATGA tests are limited to possible use in genetic screening of families with a high incidence of hypothyroidism and to help differentiate the cause of hypothyroidism when it is discovered to be present by other means.58 For example, a hypothyroid dog with an ATGA can be presumed to have primary hypothyroidism. However, if no ATGA are present, a primary cause for hypothyroidism cannot be ruled out.
Antithyroglobulin antibodies are detectable before the serum T4 drops to an abnormally low level. The unaffected general canine hospital population have ATGA by ELISA in 13.2%2 to 18.7%.58 By ELISA, 59% of hypothyroid dogs were found to have ATGA2; by chronic chloride passive hemagglutination (CCPH), 34%26 and 48%33 of hypothyroid dogs were reported to have ATGA. Fifty percent had ATGA by ELISA in a later study.58 Preparation with glutaraldehyde resulted in antibody detection in 24% of hypothyroid dogs, but this method may be more accurate than the CCPH.26 The CCPH and indirect fluorescent antibody (IFA) were technically unreliable and time- consuming.2 Antibodies to thyroidal microsomal antigens were found in 4% of hypothyroid dogs.33
Anti-T3 and Anti-T4 Antibodies
Among dogs suspected of having hypothyroidism based on clinical signs, 0.2% have been found to have elevated serum T3 levels above 500 ng/dl with or without reductions in serum T4 levels.59 The cause is auto-antibody binding of T3. Less commonly, auto- antibodies against T4 may occur.
Lymphocytic thyroiditis or subsequent thyroid atrophy is the most frequent cause of spontaneous primary hypothyroidism in the dog. Thyroglobulin contains T3 and T4 in its primary structure and is highly antigenic. While in the follicular colloid, it is relatively sequestered from immune surveillance. Damage to the thyroid often results in the development of antithyroglobulin antibodies.60 Affected dogs may be euthyroid or hypothyroid. Most, if not all, will eventually become hypothyroid.4
The thyroid hormones, T3 and T4, are simple iodinated amino acids of low molecular weight. Probably with thyroglobulin acting as a hapten, antibodies can be produced during the development of lymphocytic thyroiditis, which will bind T3 or T4.60
Antithyroid hormone autoantibodies can interfere with RIA of thyroid hormones if the titer is high enough to bind a significant fraction of the radioactive-labeled hormone used in the RIA procedure. With solid-phase procedures and double antibody procedures, in which the second antibody does not precipitate the autoantibody complex, the apparent hormone concentration value will be spuriously elevated. With charcoal extraction methods and double- antibody procedures, in which the second antibody precipitates the autoantibody complex, the value will be spuriously reduced.59
Serum Reverse T3 (rT3)
Normal serum rT3 values in dogs are about 20-60 ng/dl. About 90% of rT3 is derived outside the thyroid in the dog.57
Many severe nonthyroidal illnesses and some drugs will inhibit peripheral deiodination of T4 to T3, shifting the degradation of T4 toward rT3. This is true in cases of untreated diabetes mellitus, chronic renal or liver diseases, acute dexamethasone administration, following surgery, and as a result of aging.29,30,32,33
Serum levels of rT3 in dogs can decline in chronic hyperadrenocorticism, transiently in 24 hours of fasting, for at least 30 hours after halothane or thiopental and methoxyflurane anesthesia, and as a middle-age-related change between 3 and 9 years of age.4,32
Serum Free T4(FT4)
Normal FT4 levels by RIA in dogs are nearly identical to humans, being approximately 0.5-2 ng/dl.61,62 Free T4 assays by direct RIA should be validated against the standard, equilibrium dialysis RIA. Unfortunately, FT4 by equilibrium dialysis is time-consuming and expensive and requires a relatively large amount of serum. Therefore, it is not practical for routine clinical use. Free T4 by direct RIA that require dilution of serum underestimates the %FT4, especially when plasma protein binding inhibitors or drugs are present.4,27,63
Endogenous Canine TSH (c-TSH)
A reliable assay for endogenous c-TSH is not currently available. Antibodies against human TSH (h-TSH) do not cross-react sufficiently to detect c-TSH.29 An assay for c-TSH using antibodies to h-TSH met some of the criteria for validation with bovine TSH as the standard.64 However, when c-TSH was attempted to be measured before and after TSH stimulation, the measured c-TSH values did not at least double after stimulation, as would be expected with a specific and sensitive antibody against c-TSH.
A homologous antibody for c-TSH used in a double-antibody RIA for research purposes has met validation criteria.54 A currently available homologous antibody RIA for c-TSH has not been reliable.4,29,65 Cross-reactions with other adenohypophyseal glycoproteins with identical alpha subunits may occur. Increased measured TSH values are not diagnostic of hypothyroidism, especially in a neutered animal that would have elevated plasma gonadatropins.66
Thyrotropin-Releasing Hormone (TRH) Response
The TRH response test is used in humans to differentiate secondary (hypophyseal) from tertiary (hypothalamic) hypothyroidism. Thyrotropin-releasing hormone is given and the resulting change or lack of change in the endogenous TSH level is determined. In dogs, as there is not a reliable c-TSH assay, TRH has been given and the response in serum T4 evaluated.
Drugs such as glucocorticoids and non-thyroidal illnesses can impair the response to TRH in euthyroid dogs.4 Although TRH is potentially less antigenic than bovine TSH, allergic reactions to bovine TSH have not been reported in dogs.
Administered TSH is better tolerated than TRH. Thyrotropin- releasing hormone is given intravenously (IV) at 300-600 ug.56,64 Dosages of 250 ug or more can cause signs of cholinergic overstimulation, such as salivation, defecation, urination, emesis, miosis, tachycardia, and tachypnea.66-68 Thyrotropin-releasing hormone in humans also often causes headache and nausea, which cannot be determined in dogs given TRH, but may occur.63
Post-TRH serum T4 samples are taken at 4-8 hours.49,56,64,68,69 Response as determined by the change in serum T4 levels of normal dogs is variable but is rarely less than 0.5 ug/dl.64,68,69 Many do not double baseline levels, and response is always much less than that produced by TSH simulation.49,56,64,68 Serum T3 response to TRH is even more inconsistent.67
The TRH response test may differentiate secondary from tertiary hypothyroidism in some cases. After arriving at a diagnosis of hypothyroidism, if the serum T4 level elevates at least 0.5 ug/dl above the baseline 6 hours after the intraveous injection of 0.1 mg of TRH/kg body weight, the response is consistent with that expected from tertiary hypothyroidism.68
Thyroid-Stimulating Hormone (TSH) Stimulation Test
There is universal agreement that the most definitive method currently available for diagnosing hypothyroidism in dogs is exogenous TSH stimulation.4,29,43,70 Conversely, there is much disagreement and confusion on the ideal method of TSH stimulation and the interpretation of results. Serum T4 levels are monitored before and after exogenous TSH administration. Changes in serum T3 levels after TSH administration are of less magnitude and are less consistent than the changes with T4.4,70,71
The recommended dosage of TSH has ranged from 0.1 U/kg body weight IV43 to 0.4 U/kg body weight intramuscularly (IM),61 and 2.5 U IV72 to 10 U IV, IM, subcutaneously (SC).53,63,70,73 The recommended route and post-TSH sampling time has been IV from 1.574 up to 12 hours.43,49,53,62,70-72 IM from 8 to 12 hours.53,61,75 and SC at 16 hours.73 Peak values of serum T4 after TSH stimulation have been observed after IV, IM, and SC administrations to be 5-12 hours,70,72 8-12 hours61,75 and at 16 hours,73 respectively.
The time of peak response in serum T4 for the TSH dose range of 2.5 to 10 U appears to be affected by the dose used. With lower doses of TSH, within 2.5 to 10 U, the peak serum T4 value is of less magnitude and earlier than with larger doses.70,72
The magnitude of response is increased by more prolonged stimulation achieved by IM or SC routes as compared with IV administration.71 For instance, the peak response in post-TSH- stimulated T4 values after IV administration of 0.1 U/kg body weight to 10 U TSH is 2-3 times baseline levels.43,49,53,72,74 After 0.3-0.4 U/kg body weight to 10 U TSH, IM or SC, the expected
T4 level should rise 4-6 times the baseline level.61,73,75 Peak serum T4 responses are decreased from normal by some drug therapy and illnesses. However, the slope of the serum T4's rise in response to TSH stimulation in these cases is near normal.34,51
Interpretation should not be based solely or primarily on being able to at least double baseline T4 levels.51,62,71 The best criterion is the absolute level of T4 attained after TSH stimulation. Normal dogs usually have a rise of at least 2 ug/dl from the baseline. Absolute peak values in normal dogs generally exceed 5 ug/dl and always exceed 4 ug/dl if 10 U, or sometimes less, is given IV,70 IM,61 or SC.73 If prior treatment with l-thyroxine has occurred, withdrawal from therapy is necessary for at least 4 weeks before TSH response returns to normal.67
Misinterpretation of the Response to Trial Therapy
The presumptive diagnosis of hypothyroidism is ultimately validated on clinical improvement in problems attributed to hypothyroidism. In some instances, improvement does not substantiate a diagnosis of hypothyroidism. Temporary improvement in problems such as alopecia can be a pharmacologic response to thyroid hormones. Thyroid hormones initially stimulate anabolic processes such as hair growth, even in euthyroid dogs.76 If hypothyroidism is not the cause of the alopecia, hair regrowth will not be complete and will worsen after 2-3 months.
RECOMMENDATIONS FOR THE DIAGNOSIS AND TREATMENT OF HYPOTHYROIDISM
Screening Laboratory Exams
Therapeutic trials are not recommended to supplant serum hormone assays, as validated serum hormone assays are usually diagnostic, if properly interpreted. A trial that fails is an unnecessary expense and an unnecessary delay in finding the true cause of clinical problems. A levothyroxine therapeutic trial requires a minimum of one month to evaluate treatment and a minimum of one month without treatment to recover from thyroid suppression caused by the previous treatment.4,67 Baseline serum T4 and FT4 determinations by validated RIA are the preferable laboratory assessments for screening the possibility of hypothyroidism (Table 5). If either the serum T4 or FT4 levels are within normal range, hypothyroidism is not likely. Serum FT4 concentration may be more accurate in detecting hypothyroidism than is TT4.61
Antithyroglobulin antibodies tests may be used as genetic marker for familial lymphocytic thyroiditis and probable impending hypothyroidism. Normal dogs also may have ATGA, so ATGA-positive dogs are the only suspects that should have repeated serum T4 and the FT4 determinations done on at least a yearly basis. Autoimmune thyroiditis and hypothyroidism is inherited in the borzoi,1 Great Danes,2 Doberman pinschers,58 and beagles.77 The transmission is apparently an autosomal recessive trait in the borzoi.1
Laboratory Studies for Confirmation
If the baseline serum T4 and FT4 levels are abnormally low, a probable diagnosis of hypothyroidism is appropriate. Should only one or neither of the baseline hormone values be abnormally low, the possibility of hypothyroidism may be pursued further by a TSH stimulation test.
The protocol for the TSH stimulation should be as inexpensive as possible. It should take as little time as is feasible. More importantly though, the results obtained should be reliable and accurately interpreted.
In an effort to reduce expense, dosages in units per kilogram of body weight have been recommended. Most veterinary practices will rarely have the need to perform a TSH stimulation on more than one dog in 3 weeks. Based on current knowledge, reconstituted TSH should be discarded in 3 weeks.78 Therefore, to insure reliable bioactivity, it is recommended to use TSH doses in increments of 5 units, the minimum quantity of lyophilized sterile TSH available. The dosage of 5 units for dogs under 10 kg and 10 units for dogs over 10 kg will meet or exceed recommended dosages using previously reported protocols.
To maximize the ability to differentiate normal dogs from those with hypothyroidism, the widest separation between the two is required. The administration routes of TSH that produce the highest and most prolonged elevation in serum T4 levels are the IM and SC routes.61,71,73,75
Using 0.1 units of TSH per kilogram body weight up to a maximum of 5 units given IV and sampled at 6 hours, a normal TSH response is an increase of at least 2 ug/dl above the baseline or an absolute level that exceeds the normal baseline range.4 Because serum T4 levels in normal dogs is approximately 1-4 ug/dl, an adequate response to this TSH protocol should be at least an absolute post- TSH serum T4 value of 3 ug/dl. Using a TSH dose of 5 U/10 kg body weight or less and 10 U for dogs above 10 kg body weight given IM or SC and sampled at the appropriate time for the response peak, a minimum absolute post-TSH serum T4 level of 4 ug/dl should be expected.61,73,75 Recommended protocols and interpretation of the TSH response are summarized in Table 6.
Concern may develop over the volume of the TSH that must be injected IM. Although 5 ml of diluent is provided, 5 units of lyophilized hormone can be diluted with only one ml of diluent.
If available, serum rT3 determination can be helpful in cases of discordant or equivocal screening assays for serum T4 and FT4. If serum rT4 levels are high, hypothyroidism not present.
Exams for Differentiation of Causes
There is no currently available safe, reliable, and inexpensive method of differentiating the cause of hypothyroidism in dogs. A reliable, inexpensive endogenous c-TSH assay would be a valuable means of differentiating primary hypothyroidism from secondary or tertiary hypothyroidism. At present, cases of hypothyroidism suspected to be hypophyseal or hypothalamic in origin must be confirmed by morphologic exams (CT or MRI), response to repeated TSH injections, a TRH response, ATGA determination, and thyroid biopsy. Daily TSH injections for 3 or more days may eventually stimulate a serum T4 concentration within normal range if hypothyroidism is secondary or tertiary in origin.
The TRH response test can be used to rule out secondary hypothyroidism. After a diagnosis of hypothyroidism of unknown origin, if the serum T4 elevates at least 0.5 ug/dl above the baseline 6 hours after the intravenous injection of 0.1 mg of TRH/kg of body weight, the response is consistent with tertiary hypothyroidism.
The presence of ATGA in a dog with hypothyroidism of unknown origin is suggestive of primary hypothyroidism, although secondary or tertiary hypothyroidism cannot be ruled out.
Biopsy of the thyroid may be used to differentiate primary hypothyroidism from secondary or tertiary causes.14
Replacement Hormone Type, Dose and Frequency of Administration
Thyroid hormone preparations are either animal-origin or synthetic products. Sodium levothyroxine, a synthetic product, is the treatment of choice in the dog.4 It is less expensive than other synthetic preparations. It has the longest serum half-life, so the required frequency of administration is the least. Its conversion to T3 can be modulated by the body during other drug therapy, caloric deprivation, or critical illness, so that the peripheral cellular metabolic rate is dampened and protein loss is reduced.
The most meaningful method of determining an adequate dosage is by the clinical response. To determine if the dosage is excessive, the endogenous TSH levels should be measured. A physiologic replacement dose should not completely inhibit endogenous TSH secretion. Unfortunately, a reliable c-TSH assay is not available. The adequate dose of levothyroxine in the dog is known by clinical observations, but the dosage at which the physiologic effects are exceeded is not known.
An adequate initial replacement dosage of levothyroxine is 0.02 mg/kg body weight/day or 0.5 mg/m2/day for extremely small dogs or extremely large dogs. This will completely reverse all clinical signs of hypothyroidism and generally normalize serum T4 levels.4,79 This dose per kilogram body weight in dogs is far in excess of the necessary dosage required in hypothyroid humans. The serum half-life of T4 is less than 1/10 the length of the half-life in humans. Greater doses per kilogram body weight and more frequent administration is therefore necessary in dogs than in humans.
Dosing twice per day is generally not necessary. No difference was found in average serum T4, FT4, or T3 levels when T4 was administered once per day or divided twice per day.80 The half-life of T4 in the dog has been estimated to be between 10 and 16 hours.4 However, serum T4 is not yet affecting peripheral cells. The tissue response of cellular bound thyroxine is maintained throughout the day, allowing for once-per-day treatment for maintenance.4
The dosage may be gradually raised or the dose divided into twice- per-day administration in the few instances that it may be desirable. When other medications that enhance the elimination of administered thyroxine by inhibiting serum protein binding (glucocorticoids, phenytoin, salicylates, furosemide, or androgens) are given concurrently with levothyroxine, administration of the levothyroxine in two divided doses may be indicated. Likewise, if concurrent diseases are present that lower thyroid hormone-binding plasma protein levels (protein-losing enteropathies, glomerulonephritis, severe hookworm diseases, liver diseases, or anorexia/starvation with cachexia), dividing the levothyroxine dose may be advisable.
Although the basis for such a high dose has not been explained, 20 mcg of T4 per kilogram of body weight twice per day has often been recommended.43,81 As a result post-pill serum T4 values after this dosage are frequently above normal. For example, 50% of dogs on 20 ug of levothyroxine/kg body weight twice per day have serum T4 levels in excess of 5 ug/dl; 20% have levels above 7.5 ug/dl.81 This excess hormone is either bound to additional serum protein- binding sites or peripheral cells, or it is eliminated in the urine or feces as waste.
Thyroid hormones in excess of physiologic levels are catabolic, leading to increased gluconeogenesis, protein break-down, and nitrogen wasting.4 Overt signs of overdosage are uncommon, but include polyuria, polydipsia, nervousness, weight loss, increased appetite, panting, weakness and fatigue, seeking cool areas, restlessness, elevated resting heart rate, and fever.4 Thyroid hormones administered in excess also can cause a marked decrease in muscle and liver glycogen stores.82 Hypoglycemia can occur in dogs from thyroxine-induced glycogen depletion when there are demands for exercise for prolonged periods.83
The overt signs of hypothyroidism usually are not evident until the serum T3 is elevated. Elevations of serum T3 above normal are more indicative of toxicity than is an elevated serum T4 level.84 It has been recommended not to reduce the dose of levothyroxine until the serum level exceeds 10 ug/dl.81 However, liver damage85 and reduced bone density86 has been attributed to long-term overdosage with levothyroxine in humans. Thinning of the hair coat and weight loss in dogs on excessive levothyroxine that improved with proper dosage adjustment has been observed by the author.
The treatment of myxedema stupor or coma must begin before the results of measuring serum T4 levels are received. Treatment consists of IV levothyroxine, mechanical respiratory support, intravenous administration of glucocorticoids, broad-spectrum antibiotics, and passive rewarming with blankets. Fluid administration, respiratory depressant drugs, diuretics, vasopressors, and active attempts to warm should be avoided or used sparingly with caution until T4 has been administered and a response noted.
The initial dose of levothyroxine should be decreased and the frequency increased in cases of diabetes mellitus or heart disease to allow gradual adaptation to the increased metabolic rate.4,43,81 If concurrent with hypoadrenocorticism, thyroid replacement should be preceded by adrenocortical hormone replacement therapy to preclude the increased risk of a hypoadrenocortical crisis.4
The most important criterion of adequate therapy and a correct diagnosis is improvement in the clinical signs of hypothyroidism as perceived by all trained and untrained observers. Six weeks is a reasonable time to wait to assess for improvement in the skin and hair coat. Attitude and activity should improve in the first week.
Post-pill testing should be reserved for dogs that have been on therapy at least 1 month and no response has been apparent. One month of therapy also is required to reach a steady state with increased clearance of thyroxine that occurs.4,81 Serum T4 should be in the low normal range just before the next dosing.4 Peak concentrations are expected at 4-8 hours.4,81
Based on endogenous TSH levels, humans on appropriate replacement doses of levothyroxine have serum T4 levels that are slightly high and serum T3 levels that are within the normal range.84,87 The ratio of serum T4 to T3 is greater in treated euthyroid humans than normal euthyroid humans.84 The altered ratio may result from the lack of thyroidal contribution to serum T3 levels. Treated euthyroid cases derive all serum T3 from peripheral deiodination. Therefore, dosage adjustments for l-thyroxine replacement in otherwise healthy dogs should be based on peak serum T3 levels, which should be within normal range. If post-pill serum T3 levels exceed normal range, the replacement dosage of levothyroxine should be reduced.
Failure to satisfactorily respond to treatment of hypothyroidism may occur for several reasons. The most common cause is an erroneous diagnosis, pseudohypothyroidism. Other potential causes are overdosage of replacement therapy, a failure to receive prescribed replacement therapy, an inadequate dose or frequency of administration, an inactive preparation, poor gastrointestinal absorption, and peripheral tissue resistance.
A definitive clinical diagnosis of hypothyroidism is a retrospective assessment that is based on a complete and persistent remission of pretreatment abnormalities attributable to hypothyroidism, with replacement therapy using levothyroxine. Clinical signs and, in some cases, hypercholesterolemia are sufficient for a tentative, "suspected" diagnosis of hypothyroidism. A suspected diagnosis should be pursued further with serum thyroid hormone levels. If baseline serum T4 and FT4 levels are abnormally low, a probably diagnosis can be made and therapeutic trial with levothyroxine begun. If baseline serum T4 and FT4 are discordant or equivocal, a TSH stimulation test should be used to differentiate between normal and probable hypothyroidism. The definitive diagnosis requires complete remission of all signs associated with hypothyroidism and continued maintenance of normalcy after 3 months, or more, of appropriate replacement therapy.
Table 1. Atypical Presenting Signs of Hypothyroidism
Impaired Mental State
Signs of other endocrine diseases, particularly
Syndrome of inappropriate antidiuretic hormone
Table 2. Some Known Causes of Euthyroid Sick Syndrome in Dogs
Calorie or protein deficiency
Surgery (or anesthesia)
Debilitating diseases such as:
Intervertebral disk disease
Certain neuromuscular diseases
Table 3. Drug-Induced Suppression of Serum Thyroid Hormone in Dogs
Phenytoin Thiopental and methoxyflurane
Flunixin Fatty acids
Anabolic steroids Phenylbutazone*
*May not be significant decrease
Table 4. Selected Physical Abnormalities with Poor-to-No Presently Confirmed Association with Hypothyroidism
Table 5. Diagnostic Recommendations for Suspected Hypothyroidism
Testing equivocal or discordant screening test results
Tests for differentiating the cause
Repeated TSH stimulation
Tests for genetic counseling
*Normal dogs may also have antithyroglobulin antibodies
Table 6. Recommended Protocols* for Performing a TSH Stimulation Test and Interpretation of the Results
Same Day Method (IM TSH)
Give 5 U to dogs up to 10 kg body weight and
10 U to dogs more than 10 kg body weight
Sampling times for serum T4 levels:
Baseline time and 8 hr later
Normal dogs post-TSH T4 value is more than 4
ug/dl or at least 2 ug/dl above baseline levels
Overnight Method (SC TSH)
Same as above
Sampling time for serum T4 levels:
Baseline time and 16 hr later
Same as above.
*IV TSH administration methods can be successfully used but result in lower post TSH T4 peak values with more transient peak periods. IM and SC TSH administration produces wider separation between baseline and post-TSH T4 values in normal dogs.
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