Disorders of the thyroid gland (Proceedings)

Anatomy

The thyroid gland is made up of paired lobes on the ventrolateral surface of the proximal trachea. Felines may have accessory thyroid tissue in the neck and thorax. The size of the thyroid gland varies with the size of the dog; with medium-sized dogs having lobes approximately 5 cm. in length, 1.5 cm. in width, and 0.5 cm in thickness. In the average (4.5 kg) cat each lobe is approximately 2 cm. in length, 0.3 cm. in width and 0.5 cm. thick. The thyroid gland is fed by the cranial and caudal thyroid arteries, arising from the common carotid artery. The external parathyroid glands lie on the surface of the thyroid lobes, while the internal parathyroids are embedded within the thyroid tissue. Histologically, the thyroid gland is comprised of rounded follicles that are lined by epithelial cells. The epithelial cells produce colloid, a gel-like glycoprotein which is stored in the follicles. Colloid contains thyroglobulin; the precursor for the synthesis of thyroid hormones.

Physiology

Synthesis of thyroid hormones requires iodine which is absorbed from the small intestine, converted to iodide, bound to plasma proteins and transported to the thyroid gland. Within the thyroid gland, iodide is oxidized and bound to thyroglobulin molecule as tyrosine residues; which in turn result in the synthesis of triiodothyronine (T3) and thyroxine (T4). T3 and T4 are stored extracellularly. In order for T3 and T4 to be released into the circulation, thyroglobulin must re-enter the follicular cell and undergo proteolysis.

In the circulation,T3 and T4 are tightly bound to plasma proteins (~99%), thus <1% are the free hormones, capable of exerting metabolic effects. Most of the hormone produced by the thyroid gland is T4. In the target tissues T4 is metabolized to T3 (metabolically active) or reverse T3 (metabolically inert).

T3 and T4 affect almost all of tissues in the body; increasing the cellular metabolic rate. They are vital for normal fetal development, calorigenesis and carbohydrate, fat and protein metabolism. Other effects of thyroid hormones include: erythropoiesis, formation and resorption of bone, increased heart rate and strength of contraction and increased oxygen consumption by the intracellular mitochondria.

Regulation of the thyroid gland revolves around the hypothalamus (TRF) and anterior pituitary gland (TSH). Increased plasma levels of T3 and T4 will reduce the release of TRF and TSH in a negative feedback manner. Glucocorticoids, androgens and GH (all in supraphysiologic concentrations) will lower the secretion of TSH.

Canine hypothyroidism

This is one of the most common endocrinopathies in the dog and is the result of lowered levels of T3 and T4. Hypothyroidism is most commonly seen in medium to large-sized middle-aged dogs (golden retriever, Labrador retriever, Doberman pinscher, Irish setter, boxers, Great Danes and Airedale terriers). Smaller breeds that are commonly afflicted include: dachshounds, miniature schnauzers and poodles. There does not seem to be a sex predisposition but neutered dogs seem to be at a greater risk.

Etiology

Most dogs develop hypothyroidism as a result of lymphocytic thyroiditis (an immune-mediated disorder) or idiopathic thyroid atrophy. Secondary hypothyroidism due to pituitary disease and lack of TSH secretion is very rare. Excessive cortisolinemia (either iatrogenic or naturally-occurring) can also result in reversible secondary hypothyroidism.

Clinical signs

Hypothyroidism usually progresses gradually and its symptoms are often non-specific. Often the pet owner is unaware of a problem. As the condition progresses lethargy, weight gain (in absence of an increase in food consumed), obesity, depression, are noticed by the pet owner. Dermatologically, a bilateral symmetrical truncal alopecia with a secondary seborrhea, hyperpigmentation and pyoderma may be seen. Occasionally, signs of neuromuscular disease may accompany the clinical picture ( peripheral vestibular disease, facial paralysis, generalized neuromuscular weakness, laryngeal paralysis and megaesophagus). Hypothyroidism may also have a profound effect upon the reproductive tracts of intact males and females (testicular atrophy, decreased sperm production, decreased libido, infertility, silent estus, prolonged interestrus cycles etc.).

Diagnostic plan

A CBC often reveals a low-grade non-regenerative anemia. Hypercholesterolemia is a very common biochemical abnormality (~ 75% of affected dogs). Serum TT4 levels are subnormal but this finding must not be confused with the "sick euthyroid syndrome" ( low TT4 levels as a result of non-thyroid illnesses [ renal failure, diabetes mellitus, CHF, sepsis etc.]). More complete in-depth testing is often required to confirm the diagnosis (FT4, TT3, FT3, TSH, T4 autoantibody, T3 autoantibody etc.).

Management

Thyroid supplementation is required for dogs with confirmed hypothyroidism or as a diagnostic tool when the laboratory results are questionable (achieving a therapeutic diagnosis). Levothyroxine is the drug of choice and should be administered at a dosage of 0.02 mg/kg bid p.o. The dosage should be individualized for each dog ( taking into consideration co-existing disease- especially cardiovascular disease-which usually requires lowering the initial dose [0.005 mg/kg bid] and gradually increasing the dosage.

The patient should be evaluated in 4-6 weeks after commencement of levothyroxine therapy. Usually improvement in mentation occur within the furst 10 days of therapy and TT3 and TT4 levels normalize within a month. However, dermatological abnormalities may take up to 6 months to improve; while reproductive and neuromuscular problems may take up to 12 months to improve.

Signs of levothyroxine overdosage ( iatrogenic thyrotoxicosis ) include PU/PD, polyphagia, nervousness, excessive weight loss, hyperactivity and tachycardia. If the above signs are noted by the owner a TT4 level should be run and the dosage lowered accordingly.

Prognosis-Dogs that are properly managed with levothyroxine have a good to excellent prognosis; especially if the neuromuscular abnormalities resolve.

Feline hyperthyroidism- his very common feline endocrinopathy results from the production of supraphysiologic amounts of T3 and T4; causing the clinical signs of thyrotoxocosis. Of interest feline hyperthyroidism was virtually unheard of 30 years ago. It is usually a disease of older cats (mean age- 13 yrs., range 4-22 yrs.). There appears to be no predisposition with regards to sex or breed.

Pathophysiology

Excessive levels of T3 and T4 are usually the result of a functional thyroid adenoma, adenomatous hyperplasia or rarely a thyroid adenocarcinoma. Recent studies have pointed to goiterogenic compounds in commercial cat foods as a possible etiology (excessive iodine, soy flavonoids, etc.) and the overexpression of the c-ras oncogene in the regions of follicular hyperplasia of the feline thyroid glands. Mutation of this gene may play a role in neoplastic formation.

Excessive synthesis and release of T3 and T4 are responsible for the clinical signs and laboratory abnormalities seen in this disorder. Clinical signs progress gradually and may not be obvious to the pet owner for 6-12 months. Weight loss occurs in nearly all affected cats, despite marked polyphagia. In less than 8% of affected cats inappetence is reported. Other common signs include: nervousness, vocalization, PU/PD, a thin, unkempt haircoat, vomition and diarrhea (hyperdefecation due to overeating and overloading the pancreatic digestive enzymes). Less frequently, decreased activity, weakness, tremors, panting, dyspnea ( due to secondary Hypertrophic Cardiomyopathy) are exhibited by affected cats. A thyroid nodule may be palpated in the neck of 75% of patients and occasionally bilaterally enlarged lobes may be felt. Other findings on the physical examination may include: tachycardia, gallop rhytmn, cardiac murmurs and undersized kidneys.

Diagnosis

Hyperthyroidism should be suspected in any older cat that is presented for weight loss, (despite a good appetite), hyperexcitability, PU/PD and diarrhea. A CBC often reveals erythrocytosis. Biochemical abnormalities include: increased levels of ALT, AST. SAP. Because these patients are elderly, the clinician should als be on the alert for diabetes mellitus and renal disease. A serum TT4 that is above the normal limits is diagnostic for feline hyperthyroidism. Some affected cats with concomitant diseases (diabetes mellitus, renal failure) may have a hgh-normal TT4 level. In these patients, a T3 suppression test can be perfprmed, especially if a thyroid nodule is not palpated. (a baseline TT4 is drawn and labeled and 25 micrograms of T3-Cytomel is administered bid for 5 doses and a post T4 is drawn-little or no suppression of TT4 confirms the diagnosis).

Cats with documented hyperthyroidism should also have a blood pressure measurement, thoracic radiogaphs, ECG and echocardiography (to check for CHF due to HCM).

Therapy-Cats with hyperparathyroidism can be managed with oral anti-thyroid drugs, surgery or radioactive I131. It is equally important for the clinician to manage concomitant diseases (renal failure, CHF/HCM, diabetes mellitus etc.).

Methimazole (Tapazole) is the oral anti-thyroid drug of choice in the management of affected felines. Methimazole is inexpensive and reversible which is important if the patient has renal insufficiency, because rapid lowering of T4 may cause a decline in renal function. Disadvantages of methimazole administration include: difficulty in administering an oral medication to a cat sid or bid for the remainder of its life, vomition and diarrhea, blood dyscrasias (leukopenia, thrombocytopenia and anemia) and liver disease (often accompanied by icterus). These side effects usually occur within 2-3 months after commencement of therapy. The usual beginning dose is 5 mg. bid, but but some clinicians prefer to begin with 2.5 mg. bid. If no side effects are encountered, the cat should be rechecked in 4 weeks and a CBC, biochemical panel and TT4 should be run. Some cats can be managed indefinitely on 5-10 mg. sid.

This author's preference is to utilize methimazole for stabilization of the patient's TT4, blood pressure and ECG, etc. for 4 weeks and then surgically remove the affected gland(s). Surgery in this author's experience has been quite successful. It is usually a quick procedure and the patient recovers quite rapidly. Isoflurane/oxygen are administered via mask and then the patient is intubated. During surgery (approximately 30 min.), the patient with a blood pressure cuff, pulse oximetry and ECG monitor. Care must be taken to spare the parathyroid glands, recurrent laryngeal nerve, jugular vein and carotid artery. Post-surgically the patient should be monitored for signs of hypocalcemia (tremors, weakness, seizures, restlessness etc.). Patient with bilateral thyroid adenomas require bilateral thyroidectomies and levothyroxine supplementation (usually 0.05 mg. sid or bid). Approximately 10% that have had one thyroid gland removed will experience hyperthyroidism again in about 30 months after surgery. These cats can be managed with methimazole, radioactive I131 or a second surgery to remove the other thyroid gland which has become adenomatous. Cats with severe CHF (due to HCM) or renal failure are not surgical candidates.

Radioactive I131 therapy has been gaining popularity in the past decade. There are usually no severe side effects. The most important disadvantages include: referral to a center that performs the procedure, prolonged hospitalization of the cat (1-4 weeks depending upon state laws for the clearance of the radioisotope via the urine and feces), expense of the procedure and the reoccurrence of hyperthyroidism in cats with markedly enlarged thyroid glands. Approximately 5-10% of treated cats will develop hypothyroidism (again, managed with 0.05 mg. levothyroxine sid or bid).

Prognosis for uncomplicated feline hyperthyroidism is usually good to excellent, however the median survival period is 2 years. This is because the patients are elderly and can develop concominant diseases (renal failure, diabetes mellitus, CHF, etc.).

Thyroid neoplasia

Clinically important canine thyroid tumors are almost always malignant. They are rare in cats and are seen in middle-aged to older dogs. The breeds most commonly affected include: beagles, Labrador retrievers, golden retrievers, German Shepherds and boxers. There appears to be no sex predisposition. The etiology of these tumors is unknown.

Clinical signs

Usually affected dogs will have ventral cervical swelling, dyspnea, coughing, dysphagia and high-pitched bark. Upon physical examination, a non-painful cervical mass is detected that is usually adhered to the adjoining tissues.Less than 10% of affected dogs will display signs of hyperthyroidism (PU/PD, cachexia, weight loss, nervousness, panting etc.), because most canine thyroid tumors are non-functional.

A FNA (ultrasound-guided) and cytological examination will diagnose canine thyroid neoplasia in approximately 60% of patients.

Management

The major options in the treatment of thyroid neoplasia are surgery/chemotherapy. If there is no evidence of distant (thoracic) metastases, surgical debulking/complete excision (uncommon in the dog) is indicated. The surgeon must be aware that these tumors are very vascular and invasive to vital surrounding tissues (carotid artery, jugular vein, parasympathetic nerve trunk, etc.) and proceed with caution.

Chemotherapy is indicated for the majority of patients because it is often impossible to achieve complete removal of the tumor and at the time of diagnosis micrometastases have already occurred. Although complete remission is often difficult to achieve, this author's preferred protocol is BAP (bleomycin, doxorubricin and cisplatin). In patients with inoperable tumors with distant metastases, a trial with I131 radiotherapy may be indicated.

Prognosis

If the neoplasm is movable and completely excised some dogs can live up to 48 months with surgery/chemotherapy, if no visible signs of metastases are present at the time of diagnosis. Most dogs have a median survival period of 9 months.

Infrequently-encountered thyroid disorders

Canine hyperthyroidism is very rare, especially when compared to its feline counterpart. Canine functional thyroid tumors tend to be benign. Clinical signs are similar to those of cats, (PU/PD, polyphagia, panting, restlessness and weight loss). Diagnosis is achieved by documenting an elevated TT4 level and palpating a fluctuant cervical mass.The treatment of choice appears to be surgical excision but a few dogs have been successfully treated with radioactive I131. Supplementation with levothyroxine is necessary after either treatment.

Feline hypothyroidism

This is a rare naturally-occurring endocrinopathy. The most common causes are iatrogenic ( bilateral thyroidectomy, I131 irradiation or methimazole overdosage). Congenital hypothyroidism can be recognized in 6-8 week-old kittens when they begin to display skeletal malformations (dwarfism), failure to thrive, enlarged heads, short limbs and short, thickened necks. Serum TT4 levels are subnormal. Often it is advisable to perform a TSH-response test (pre-TT4 sample, TSH- 0.1U/kg. IV and collect a post-6 hrs. TT4 sample). If there is a "flat" response the diagnosis is confirmed. Treatment is levothyroxine at a dose of 0.05 mg to 0.1 mg/cat sid or bid.

References

Drazner, FH: Small Animal Endocrinology Churchill Livingstone. 1984.

Drazner, FH: A Case Report of a Dog with Gastrinoma, Resembling the Zollinger-Ellison Syndrome. California Veterinarian. 1978.

Mooney, CT. and Peterson ME (eds) BSAVA Manual of Canine and Feline Endocrinology. BSAVA. 2004.

Monroe, WE: Disease of the Endocrine Pancreas and Pituitary Gland in: Leib MS.and Monroe WE.:(eds.) Practical Small Animal Internal Medicine, WB Saunders. 1997.