The clinical challenge of thyroid disease in the dog (Proceedings)

Canine hypothyroidism is the most commonly diagnosed endocrinopathy in the dog.  There is a large incidence of false diagnoses and unnecessary supplementation.  This presentation will discuss the difficulty in correctly diagnosing the disease, recognition of clinical signs, and treatment.

Etiology

Hypothyroidism caused by primary disease at the level of the thyroid is most commonly recognized in dogs.  Lymphocytic thyroiditis probably caused by immune-mediated mechanisms is the most common pathologic finding.  In these cases, the thyroid gland is infiltrated with lymphocytes, plasma cells, and macrophages, and there is progressive destruction of the follicles.  It may need years to have complete destruction of the gland, and that is why hypothyroidism is usually seen in young adults.  Clinical signs occur when 75% of the gland is destroyed.  There is probably a genetic component of the disease since it appears to be inherited by polygenic mode in colony-raised beagles.  Antibodies against the thyroid have been a source of controversy in diagnosing thyroid disease.  In some dogs thyroid antibody titers may rise as antigens are released into the circulation from thyroid gland damage.  These may be measured and in some cases may indicate progressive disease.  Certain breeds may have increased frequency of circulating antibody.  Antibodies against thyroglobulin have been associated with routine vaccination in dogs; however, it is not known whether this is associated with the development of hypothyroid disease.

Other less common causes of hypothyroidism include thyroid atrophy that occurs when the thyroid parenchyma is replaced by adipose tissue with no inflammatory cells.  This is an idiopathic change or may signal endstage lymphocytic thyroiditis.  Neoplastic destruction of thyroid tissue also can result in hypothyroidism.  Congenital thyroid agenesis or dysgenesis may occur rarely.  Trimethoprim-sulfadiazine-induced hypothyroidism has been reported as an example of drug-induced disease and has been postulated to directly interfere with thyroid peroxidase activity and thus directly inhibit thyroid hormone synthesis.  Secondary disease, with hypopituitarism, is rarely reported.

Clinical Signs

Hypothyroidism most often occurs in middle-aged dogs (4-10 years).  Large breed dogs appear to be predisposed including Golden Retrievers, Doberman Pinschers, and Labrador Retrievers (not documented).  Spayed females and castrated male dogs may be at increased risk.

Clinical signs are often subtle and have a gradual onset.  Metabolic signs reflect a decreased cellular metabolism including lethargy, exercise intolerance, heat seeking, weight gain, mental dullness, decreased appetite, and constipation.  Dermatologic signs are often presenting complaints and include bilateral truncal alopecia that is nonpuritic, alopecia of the caudal thighs and a "rat" tail, loss of guard hairs (puppy coat), seborrhea, chronic otitis, hyperpigmentation, failure of hair growth, secondary pyoderma, or myxedema.  Neuromuscular signs including profound lethargy and muscle weakness, peripheral nerve paralysis, slow nerve conduction velocities, type II myofiber atrophy, and loss of peripheral vestibular disease are also reported.  Reproductive signs include prolonged interestrus intervals, failure to cycle, and inappropriate galactorrhea in the female.  Congenital hypothyroidism results in growth retardation, mental retardation, and disproportionate dwarfism (retarded epiphyseal growth) in puppies.  Dilated cardiomyopathy that was responsive to thyroid supplementation has been reported in two Great Danes. 

These animals are also predisposed to development of polyglandular endocrine gland destruction and may also develop hypoadrenococticism, diabetes mellitus, and/or hypoparathyroidism.  Some hypothyroid animals can also present comatose with cerebral myxedema.

Physical examination findings include a mildly overweight to severely obese animal, although some patients may be of normal body condition.  Profound lethargy may be present, as well as, hypothermia, bradycardia, skin disease, myxedema of skin, mostly on head, or stunted growth.

A biochemical database should be performed on every animal suspected of having hypothyroidism.  This is necessary to identify concurrent disease and determine the metabolic status of the animal before potential therapy is initiated.  A CBC may reveal mild/moderate normocytic, normochromic, nonregenerative anemia, potentially from decreased erythropoiesis.  Findings on a routine serum chemistry include fasting hypercholesterolemia that may be severely elevated.  Hypercholesterolemia is seen in approximately 80% of hypothyroid dogs and can help you identify the disease.  Other findings may include fasting hypertriglyceridemia and mild elevations in liver enzymes. Exercise-induced hyperkalemia has been reported in some dogs.  A urinalysis is usually normal.  ECG abnormalities include a sinus bradycardia and decreased amplitude of the P and R waves.

Diagnosis

Hypothyroidism is an overdiagnosed disease!  Baseline hormone measurements can be very helpful in identifying this disease, but are often not interpreted correctly leading to misdiagnosis.  T4 is the major thyroid hormone secreted into the bloodstream and, therefore, would be thought to be the hormone to measure.  However, measurement of serum T4 has consistently confused the diagnosis of the disease because  > 99% of T4 is protein bound in plasma.  The amounts and affinity of binding proteins can change by many physiologic and pharmacologic factors and artificially lower the T4 measurement while thyroid status is actually normal.  Measurement of T4 is useful as a screening test.   If the result is in the middle-high normal range, hypothyroidism would be placed lower on the list of differential diagnoses.  T4 in serum is relatively stable and can be sent to outside laboratories for measurement by RIA.  Interference by anti-T4 antibodies can cause spuriously high readings.  The practitioner must remember that certain breeds of dogs, notably sighthounds, have lower T4 than other dogs.  The correct breed-associated reference range should be used to interpret serum T4 measurements.

FreeT4 (fT4) measurement is that in which the free hormone is separated by equilibrium dialysis and measured by RIA.  This factors out influence of nonthyroidal illness and drugs that lower the concentration of T4 serum binding proteins and subsequently decrease the total T4.  It is more expensive and takes longer than T4 measurement; however, it more accurately diagnoses the disease.  In one study, 98% of hypothyroid dogs had low fT4, although a small percentage of euthyroid dogs with concurrent nonthyroidal illness have low serum fT4.

TSH measurement (cTSH) is used to diagnose hypothyroidism in people and takes advantage of measuring the negative feedback (or lack thereof) of fT4 and fT3 on pituitary secretion of TSH.  As fT4 and fT3 decrease in primary hypothyroidism, TSH levels will increase due to lack of negative feedback.  In dogs and cats,this test has been hampered by availability of good assay reagents.  As is stands now it is not valid as a test on its own.  Studies show that 25-38% of hypothyroid dogs had normal TSH levels.  In euthyroid dogs with concurrent illness, only 12% had elevated TSH levels.  This test has low sensitivity, but can be very specific when combined with fT4 or T4 measurement.

TSH-stimulation test is the gold standard of testing for hypothyroidism.  It tests for reserve in a hypofunctioning gland.  In normal dogs, cats, and birds serum T4  rises in response to TSH administration.  Hypothyroid dogs have a blunted response.  Injectible bovine source TSH is available as a research grade compound which may cause anaphylaxis.  Human recombinant TSH is available and has been shown to be effective in dogs.  However, its high cost makes routine use prohibitive.

Thyroid biopsy is another way to diagnose thyroid disease.  It gives histologic evaluation of gland, but no information on function.  These glands are usually atrophied and a surgical biopsy is required.  Usually it is not necessary in order to obtain a diagnosis.

Thyroid autoantibodies are circulating antibodies to T3, T4, and thyroglobulin in the serum. Elevations of these antibodies may indicate early immune-mediated destruction of the gland.  However, there are problems with specificity of antibody production.  In a recent large study, 6.3% of samples submitted from dogs with clinical signs of hypothyroidism were positive for thyroid hormone antibodies.

Problems with the diagnosis of hypothyroidism occur when concurrent illness results in euthyroid sick syndrome.  This is a syndrome defined in humans.  It is a physiological adaption to decrease cell metabolism during periods of illness.  Serum levels of T4 and T3 are depressed, although the animal is euthyroid at the cellular level.  Levels of fT3 and fT4 appear to be affected less, but may also be decreased.  In addition this can be due to changes in thyroid hormone binding proteins, changes in activation of the 5-deiodinase or 5'-deiodinase enzymes, changes in TSH secretion, or increased metabolism of thyroid hormones.  Things that can cause this in dogs include hyperadrenocorticism, exogenous glucocorticoid treatment, diabetes mellitus, starvation, systemic diseases, and pyoderma.  These animals are euthyroid and do not need to be supplemented with thyroid hormone.  Other factors that can affect thyroid hormone measurement include drugs (especially glucocorticoids, phenobarbitol, and clomipramine) and fasting.

So how does the clinician diagnose hypothyroidism.  It can be difficult and confusing.  First the clinician should have a clinical index of suspicion.  Basal T4, fT4, T4 autoantibodies, and TSH can be measured at the same time.  Alternatively, measurement of TSH and T4 or  fT4 is quicker and gives the same specificity, although the antibody status of the animal is not determined.  If clinical index of suspicion is high and initial thyroid testing comes back as normal, the animal should be retested in 1-2 weeks.  Animals should be off thyroid supplementation for 6-8 weeks before thyroid testing is attempted.

Treatment

In an emergency situation with myxedema stupor or coma, treat with intravenous L-thyroxine, and supportive care.  Oral sodium levothyroxine (L-thyroxine) is the treatment of choice for longterm management of hypothyroidism.  Use a good generic or brand name (Soloxine-Daniels pharmaceuticals).  Some generics may have less hormone than is printed on the label or may vary pill to pill.  The dose is 0.01-0.02 mg/kg PO q 12 -24 hours.  Start at a lower dose for dogs with cardiac illness, severly debilitated dogs, or geriatric patients and raise the dose slowly if necessary.  Monitor and adjust dose by measuring T4 4-8 hours post-pill; dogs should be in the high-normal to slightly-high range at that time if on the correct dose.  Monitor for signs of hyperthyroidism.  Side effects are few.   Levothyroxine (0.02 mg/kg) given once per day may be sufficient for most dogs after they are initially controlled.  Obtain a pre-pill T4 to determine whether once/day dosing is appropriate for this patient.