Endocrinopathies: Thyroid and Adrenal Disorders

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GERIATRICS

ENDOCRINOPATHIES Thyroid and Adrenal Disorders Sandra R. Merchant, DVM, and Joseph Taboada, DVM

HYPOTHYROIDISM

Hypothyroidism is a commonly diagnosed endocrine disorder in dogs. More than 95% of the cases of canine hypothyroidism are primary: a result of either lymphocytic thyroiditis or idiopathic thyroidal atrophy. 18 The remaining cases are secondary to hypothalamic or pituitary disease. Autoimmune mechanisms are probably involved in the pathogenesis of lymphocytic thyroiditis. Thyroid biopsies taken early in the disease course show a tissue infiltrate consisting of lymphocytes and plasma cells. Idiopathic thyroidal atrophy is characterized by loss of the normal thyroid parenchyma which is replaced with adipose tissue. There is a lack of inflammatory infiltrate. Clinical Features

The onset of clinical signs can occur at any age and in either sex. Breeds predisposed towards hypothyroidism include the Boxer, Dachshund, Doberman Pinscher, Great Dane, Golden Retriever, Irish Setter, Miniature Schnauzer, Poodle, and Old English Sheepdog.18• 36 Familial lymphocytic thyroiditis has been reported in the Borzoi-9 Spontaneous hypothyroidism in the cat is a rare clinical entity. Iatrogenic hypothyroidism secondary to bilateral thyroidectomy or overdose of radioactive iodine or antithyroid drugs is the most common cause. Hypothyroidism is usually insidious in nature. The owner or veterinarian may attribute many of the clinical signs simply to aging, or the signs may be completely overlooked. Because thyroid hormones affect most tissues in the body, the clinical signs are multisystemic in nature, variable, and rarely specific for hypothyroidism. Clinical signs attributed to hypothyroidism include mental

From the Department of Veterinary Clinical Sciences, Louisiana State University, School of Veterinary Medicine, Baton Rouge, Louisiana

VETERINARY CLINICS OF NORTH AMERICA: SMALL ANIMAL PRACTICE VOLUME 27 • NUMBER 6 • NOVEMBER 1997

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dullness, lethargy, exercise intolerance, increase in weight, heat seeking, stiffness, muscle wasting, constipation, diarrhea, vomiting, ocular abnormalities (corneal lipid deposits, corneal ulceration, uveitis), reproductive dysfunction, bradycardia, cardiac arrhythmias, atherosclerosis, vestibular deficits, megaesophagus, laryngeal paralysis, and lower motor neuron signs.32 Dermatologic abnormalities may include a dry and scaly coat, bilaterally symmetrical and nonpruritic truncal alopecia, rat tail, hyperpigmentation (diffuse truncal or ventral neck and abdomen), lichenification, myxedema, vesicular mucinosis, hair coat color change, comedones, hypertrichosis, seborrhea oleosa, seborrhea sicca, Malassezia dermatitis, and recurrent pyoderma. Diagnosis

Laboratory findings associated with hypothyroidism include hypercholesterolemia, hyperlipidemia, and increased creatine phosphokinase as well as a normocytic, normochromic, nonregenerative anemia. The diagnosis of hypothyroidism requires assessment of thyroid function. Many different tests of thyroid function have been reported in the literature. Measurement of basal serum thyroid hormone concentration is the most widely available and practiced method of diagnosing hypothyroidism in the dog. Thyroxine (T4 ) is the primary hormone secreted by the thyroid gland and is present in higher concentrations in the serum than triiodothyronine (T3 ). Basal serum T4 is a more accurate indicator of thyroid status than basal T3 concentration.• Measurement of basal hormone concentrations generally includes the measurement of both the bound and unbound fractions without separation. A T4 concentration that is well within the normal range rules out hypothy. roidism, but erroneous interpretation of borderline low thyroid hormone concentrations may result in misdiagnosis. Numerous f actors can influence thyroid hormone concentration (Table 1). A very low serum T4 concentration in the absence of factors that may lower T4 and signs consistent with hypothyroidism should be sufficient evidence for diagnosis. Further testing is warranted in the dog with questionable signs and a borderline low thyroid hormone concentration. Thyroid releasing hormone (TRH) has been evaluated as a stimulating agent used to test thyroid function. Injection of TRH causes an increase in thyrotropin (TSH) with a resultant release of T4 and T3 • The TRH stimulation test is of limited usefulness, however, because the increases in serum T4 and T3 following TRH injection are small and variable and the influence of nonthyroidal factors on this response have not been well documented. Measurement of free T4 provides a more reliable predictor of thyroid function. Although free thyroid hormone concentrations may also be adversely affected in the euthyroid sick syndrome, evaluating free T4 in conjunction with total T4 reduces the false-positive diagnosis of hypothyroidism by approximately 15%.18 Measurement of endogenous TSH concentration has become a vailable with the recent validation of canine TSH assays. In primary hypothyroidism, the pituitary gland produces high concentrations of TSH as a response to low systemic T4 and T3 concentrations. Therefore, high concentrations of TSH in a patient with low T4 and signs of hypothyroidism should indicate that the patient has primary hypothyroidism. The timing of the thyroid function testing is c ritical in sick patients, because an increase in TSH concentration may be seen a s a rebound phenomenon during the recovery phase of a nonthyroid illness at a time when the T4 concentration is still decreased. Hyperadrenocorticism does

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Table 1. FACTORS AFFECTING TOTAL SERUM THYROXINE CONCENTRATIONS IN THE DOG Factors Age Breed Obesity Hypoproteinemia Drugs that decrease thyroxine levels

Drugs that increase thyroxine levels Acute and chronic illnesses

Thyroxine Concentrations Neonates have increased levels Decreased levels in adult dogs as they age Generally higher levels in small-breed dogs than in large-breed dogs Greyhounds tend to have higher levels Increased levels Increased levels Glucocorticoids Anticonvulsants Penicillin Trimethoprim-sulfa Androgens Phenylbutazone Quinidine Propylthiouracil Salicylates Sulfonylureas Dopamine Insulin May lower levels

not seem to cause an elevation in TSH, but, instead, the TSH concentration is low or normal. 65 In one study, the overall diagnostic accuracy of the canine TSH assay (Coat a Count IRMA; Diagnostic Products Corp., Los Angeles, CA) was 87%.56 A combination of serum TSH and total T4 or free T4 concentrations improves the sensitivityY Antithyroglobulin antibodies are detected in approximately 50% of hypothyroid dogs. 2• 25• 28 Antithyroglobulin antibodies have also been detected in normal dogs and in dogs with nonthyroidal disease.3• 25• 28 Therefore, their presence does not definitively diagnose hypothyroidism. A therapeutic trial with T4 is sometimes useful as a diagnostic test for hypothyroidism; however, response to therapy is often nonspecific. Because of its anabolic nature, thyroid hormone supplementation can create a positive response in some dogs without thyroid dysfunction. Activity level should increase in 10 days, but complete hair regrowth may take as long as 4 to 6 months. Thyroid hormone will cause increased hair growth to some extent in all dogs, regardless of their thyroid status. If all clinical signs resolve and then recur when the drug is stopped, the dog is probably hypothyroid. Therapy

Lifelong therapy should be initiated once hypothyroidism has been diagnosed. Synthetic L-thyroxine is the initial therapy of choice. The plasma halflife of L-thyroxine is probably between 12 and 16 hours, with a peak plasma concentration occurring from 4 to 12 hours after administration. Initially, a proprietary product should be used, as some dogs (as is the case with humans) do not respond well to generic brands. The authors recommend a starting dose of 0.01 J.Lg/lb every 12 hours. Clinical signs should begin to resolve in a few

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weeks. Both pre- and 6-hour postpill T4 concentrations should be determined after 3 to 4 weeks of treatment. Both pre- and 6-hour postpill concentrations of T4 should ideally be within the normal range. It is acceptable to have the prevalue within the normal range and the postvalue slightly above the normal range, however. If the prevalue is very low and the postvalue is within the normal range, supplementation should be adjusted upward and pre- and postT4 values should be re-evaluated in 3 to 4 weeks. The opposite holds true for values that are too high. If continued low values are encountered, a problem with administration or bioavailability of the drug should be ruled out. Switching to a different brand of T4 is recommended to rule out poor bioavailability. When the dog is in a stable state, it may be possible to change from twice-daily supplementation to once-daily supplementation. A dose of 0.01 J..Lg/ lb is administered once daily, and pre- and 8- to 10-hour post-T4 values should be evaluated in 3 to 4 weeks. Once stabilized, pre- and postpill T4 values should be evaluated every 6 to 12 months for the remainder of the dog's life, with the dose adjusted accordingly. HYPERTHYROIDISM

Hyperthyroidism is the most common endocrine disorder of middle-aged and older cats. Functional adenomatous hyperplasia involving one or both thyroid lobes is the most common pathologic abnormality associated with feline hyperthyroidism. It is postulated that circulating factors such as immunoglobulins, nutritional factors like iodine, or environmental factors like toxins or goitrogens may interact to cause thyroid disease in cats, but the underlying cause of feline hyperthyroidism remains unknown. Clinical Features

The mean age of onset is 12.5 years old, with a range of 4 to 22 years. There is no breed or sex predilection. There is a broad range of clinical signs, because of the multisystemic nature of the disease. The hyperthyroid state is slowly progressive. The most common clinical sign is weight loss, often in the face of a good appetite. Other clinical signs include polyphagia, vomiting, polyuria, polydipsia, hyperactivity, dyspnea, panting, and increased fecal volume and diarrhea. Less commonly, affected cats may present with decreased appetite, decreased activity, weakness, or complete anorexia. Physical examination findings may include a palpable thyroid mass in most cases, a thin body condition, hyperkinesis, aggression, an unkempt hair coat with increased nail growth and alopecia, tachycardia, and heart murmur or gallop rhythm. Few cats will present with congestive heart failure or ventral neck flexion. Diagnosis

When thyrotoxicosis is suspected, a complete blood count (CBC), biochemical profile, urinalysis, basal T4 profile, echocardiogram, and electrocardiogram should be performed. A stress leukogram is noted in about one third of affected cats. Mild to moderate erythrocytosis and macrocytosis may accompany the stress leukogram. Liver enzyme activity (serum alanine aminotransferase [SALT], serum aspartate aminotransferase [SAST], serum alkaline phosphatase rcA T.ll\ '~ ~;~;t;,..., ,.,+h r inrr"'"""'rl in '10% to 75% of hvoerthvroid cats. Azotemia

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is seen in 20% to 40% of cases secondary to concurrent renal failure. Hyperglycemia, hyperphosphatemia, and hyperbilirubinemia are less common. Cardiomegaly may be noted on thoracic radiographs, but early detection in more recent years .has resulted in the identification of a large percentage of cats with normal cardiac structure and function. Sinus tachycardia, increased QRS complex amplitude, and atrial and ventricular arrhythmias are sometimes identified on electrocardiography. Echocardiography helps in the identification of asymmetrical hypertrophy of the myocardial walls and septum and frequently identifies a hyperdynamic state associated with thyrotoxicosis. The definitive diagnosis of hyperthyroidism is by thyroid testing. Resting T4 values will be increased in most hyperthyroid cats. Nevertheless, in some cats with early or mild hyperthyroidism, concomitant nonthyroidal disease may suppress serum T4 concentrations into the normal range.49 Multiple samples may be required in some cats for a diagnosis. T3 values will also be increased in most hyperthyroid cats, but this increase is more variable than the increased T4 value and offers no advantage as compared with the baseline T4 • The T3 suppression test is used to diagnose early cases of hyperthyroidism, where the T4 is high normal or normal.51 Twenty-five 1-1g of T3 is given orally and repeated every 8 hours for seven doses, with the final dose being given on the morning of the third day. Approximately 4 hours after the last dose, second T4 and T, values are obtained. In normal cats, suppression of T4 concentration by 50% or greater is seen. Hyperthyroid cats will have little or no suppression of T4 concentration. An increased T3 concentration confirms that the cat received and absorbed the administered T3 . The TRH stimulation test has the advantages of being shorter and easier to perform and does not depend on administration of an oral medication. Blood for serum T4 and T3 values is taken before and 4 hours after intravenous administration of 0.1 mg/kg of TRH. Normal cats and cats with nonthyroidal disease should show an increase in serum T4 of greater than 50%, although hyperthyroid cats will not.52 TRH may result in vomiting and weakness in some cats. A free T4 is likely to be increased in a hyperthyroid cat even when the total T4 concentration is normal and may be used for diagnosis in such cases. Some cats with low T4 due to nonthyroidal illness will have a high free T. without being hyperthyroid, however. Thyroid imaging can determine if one or both glands are involved or if the hyperthyroid state is due to ectopic thyroid tissue. Iodine 131, iodine 123, or 99m Tc-pertechnetate can be used for radionucleotide scanning. Therapy

Methimazole (Tapazole) is the drug of choice for treatment of feline hyperthyroidism. Carbimazole is an antithyroid drug that is metabolized to methimazole. Propylthiouracil is an effective drug but has a much higher incidence of side effects and is not recommended when methimazole or carbimazole is available. Ipodate has also been successfully used in treatment of feline hyperthyroidism. 22 Methimazole should be used for long-term control in cats that are not surgical candidates and for short-term control prior to surgery. The goal is to maintain the T4 in the low or low normal range with a dose of 5 mg two or three times a day. Mild side effects of anorexia, vomiting, and lethargy are associated with methimazole use. Severe side effects, including hepatopathy, agranulocytosis and thrombocytopenia with bleeding, are seen in less than 1% to 2% of cases. Excoriation of the head due to methimazole-induced pruritus has been recognized.50 Large doses of iodine will decrease the rate of thyroid hormone synthesis.

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Iodine therapy can be used for 10 to 14 days prior to surgery but is not ideal for long-term treatment. Radioactive iodine (131 I as a single dose) administered subcutaneously or intravenously is a highly effective treatment for hyperthyroidism in the cat. Thyroidectomy is a highly effective means of treating hyperthyroidism but can be associated with significant morbidity. Prior to surgery, an euthyroid state should be achieved with medical management, and a beta-blocker should be administered if significant thyrotoxic heart disease is present. With bilateral disease, postoperative hypocalcemia and, more rarely, hypothyroidism can be seen. With any of the above treatments for hyperthyroidism, azotemia may worsen in older cats with chronic renal disease. 12 In some instances, thyrotoxicosis might completely mask underlying chronic renal insufficiency.26 It may be prudent not to treat cats with mild hyperthyroidism and renal disease.

THYROID TUMORS IN THE DOG

Thyroid tumors are uncommon in the dog and account for approximately 10% to 15% of all head and neck tumors.6 Thyroid carcinomas are identified clinically far more often than thyroid adenomas. Thyroid carcinomas and adenomas may arise from ectopic mediastinal thyroid tissue and occasionally arise from the base of the tongue.61 The most common site of metastases are the lung and cervical lymph nodes and cervical vertebrae, followed by the adrenal glands, kidneys, myocardium, liver, and brain.

Clinical Features

The average age of dogs with thyroid adenomas and adenocarcinomas is approximately 9 to 10 years old, with a range of 7 to 18 years. Boxers have been reported to be predisposed to adenomas, with Beagles, Boxers, and Golden Retrievers possibly having a higher prevalence of carcinomas.47 The majority of the tumors are malignant and nonfunctional.

History

Owners are usually prompted to present their dogs with thyroid carcinomas because of a palpable cervical mass. Dysphagia, dyspnea, and a change in vocalization may be seen. Regurgitation, precaval syndrome, weight loss, or disseminated intravascular coagulation may be present. The duration of clinical signs prior to presentation is usually le ss than 3 months. Clinical signs in dogs with an actively secreting thyroid tumor include polydipsia, polyuria, increased appetite, panting, restlessness, heat intolerance, and occasional weakness. A rapid heart rate with bounding pulses may be noted on physical examination. Hypothyroid signs secondary to aunilateral tumor may result from the production of biologically inactive thyroid hormone which causes a n egative feedback inhibition and subsequent atrophy of the normal thyroid tissue.

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Diagnosis

When a cervical mass is present, a fine-needle aspirate and cytology may aid in the diagnosis. Histopathology is necessary to confirm the diagnosis. When surgical removal is contemplated, thoracic radiography should be performed to ensure that there is no metastatic disease. Cervical radiography, ultrasonography, and computed tomography (CT) may help identify the location of the mass and other vital structures in the area. Nuclear scans using radioactive iodine or sodium pertechnetate can be helpful in identifying the location and extent of primary and metastatic neoplasia. Scintigraphy does not appear to offer any additional benefit when compared with thoracic radiography for detection of pulmonary metastases.41 When thyroid assessment is made, a resting T4 should be performed.

Therapy

Complete surgical excision is the treatment of choice for adenomas and carcinomas. The cervical lymph nodes should be examined and biopsied when possible. Treatment for hypothyroidism and hypoparathyroidism may be necessary postsurgery if a bilateral thyroidectomy has been performed. For nonresectable tumors, use of doxorubin has resulted in partial remission in some cases.33- 39 Radiation therapy has also been used.43 Dogs that have adenomas completely excised have an excellent prognosis. Dogs that have small, noninvasive, freely movable, encapsulated carcinomas completely excised also have excellent survival times. Dogs that have large tumors fixed to underlying structures have a poor prognosis.

CANINE HYPERADRENOCORTICISM

Hyperadrenocorticism or Cushing's syndrome refers to the constellation of clinical and chemical abnormalities resulting from chronic exposure to excess glucocorticoids either endogenously or exogenously supplied. Excessive endogenous glucocorticoid production may be secondary to increased corticotropin (ACTH) release from the pituitary gland (pituitary-dependent hyperadrenocorticism [PDH]) or from an autonomously secreting adrenal tumor (adrenal-dependent hyperadrenocorticism). The underlying cause of 85% to 90% of dogs with spontaneous hyperadrenocorticism is excessive secretion of ACTH by the pituitary gland. The remaining 10% to 15% of the animals with spontaneous hyperadrenocorticism have a functional glucocorticoid-producing adrenal adenoma, or adenocarcinoma. Excessive ACTH production causes bilateral adrenal gland enlargement which results in increased cortisol release. The negative feedback mechanism normally controlling the hypothalamic pituitary adrenal axis is markedly reduced. PDH can result from tumors (adenomas or, rarely, carcinomas) or hyperplasia of the cells of the anterior pituitary lobe (corticotrophs) or intermediate pituitary lobe (A or B cells). Ninety percent of affected dogs probably have a pituitary tumor.66 Glucocorticoid treatment is the cause of iatrogenic hyperadrenocorticism in the dog and represents more than half of the total cases.

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Clinical Features

Spontaneous hyperadrenocorticism is largely a disease of middle-aged and older dogs. Dogs with PDH have a median age of 7 to 9 years.18 Dogs with adrenal tumors are older, with a median age at the time of diagnosis between 9 and 13 years. 18 There is no sex predilection for dogs with PDH, but female dogs seem to be overrepresented with adrenal tumors with a ratio of 3:1. Dachshunds, Boston Terriers, Poodles, Boxers, and Beagles are breeds most commonly predisposed to PDH, with large-breed dogs more commonly developing adrenal tumors. Spontaneous hyperadrenocorticism is insidious in onset and slowly progressive. Most owners when questioned have noted the presence of some alteration indicative of hyperadrenocorticism for 1 to 6 years before the diagnosis is made. It is common for owners to believe that most of these signs are simply due to aging. Common presenting clinical complaints include polyuria, polydipsia, polyphagia, weight gain, behavior changes, lethargy, reluctance to exercise, panting, and truncal hair loss. Some owners may complain of recurrent bacterial infections that were never seen when the animal was young. A lack of estrus may be noted in the intact female. A common physical examination finding is abdominal enlargement. This results from a combination of factors, including fat redistribution, hepatomegaly, muscle wasting and weakness, and true obesity. Panting may be noted on physical examination, which is secondary to one or more of the following conditions: increased fat deposition over the thorax, muscle wasting and weakness of the respiratory muscles, increased pressure on the diaphragm due to fat redistribution, and hepatomegaly and interstitial calcification. An increased incidence of thromboembolism may cause more acute respiratory distress. Obesity may be noted. Some animals will look heavier because of fat redistribution but some do gain weight because of polyphagia. Truncal obesity occurs at the expense of muscle and fat wasting from the extremities. Muscle atrophy may be evident, especially in muscles of the extremities and masseters. On testicular evaluation in the intact male dog, the testicles are often small, soft, and spongy. Dermatologic abnormalities may be quite striking. Classic changes include hair loss that is usually bilaterally symmetrical, but focal hair loss may also be seen. Comedones, especially on the ventral abdomen and thin, inelastic skin, are also usually seen. Other changes include hyperpigmentation, seborrhea sicca, telangiectasia, increased prominence of surgical scars, lack of hair regrowth after shaving, and adult onset generalized demodicosis. One dramatic manifestation seen in 5% of dogs is calcinosis cutis. 63 Adult dogs that have never had bacterial skin disease may show a marked predisposition to recurrent staphylococcal skin infections. Diagnosis

A presumptive diagnosis of canine hyperadrenocorticism can be made based upon historical information, consistent physical examination findings, and supportive abnormalities in the CBC, serum biochemistry panel, and urinalysis. CBC abnormalities include a mature leukocytosis, neutrophilia, lymphopenia, eosinopenia, erythrocytosis, and nucleated red blood cells. Serum biochemistry abnormalities include an increased alkaline phosphatase, increased alanine aminotransferase, increased cholesterol, increased fasting blood glucose, decreased blood urea nitrogen, and lipemia, and urinalysis may show a specific gravity

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less than 1.015 and often less than 1.008. A urinary tract infection (bacteriuria may be noted without inflammation) may be seen. Additional laboratory investigation should proceed through two stages. The screening stage is to confirm (or exclude) the diagnosis of hyperadrenocorticism. Once the diagnosis is confirmed, the second stage is to differentiate PDH from that caused by an adrenal tumor. Screening Tests Basal or Resting Plasma or Serum Cortisol

Basal resting plasma or serum cortisol levels are of minimal diagnostic value when attempting to differentiate normal dogs from dogs with hyperadrenocorticism. Single basal cortisol concentrations in dogs with hyperadrenocorticism overlap with cortisol concentrations in normal dogs. Only 10% of dogs with hyperadrenocorticism have an elevated plasma cortisol concentration on random morning sampling.tB Urinary Cortisoi:Creatinine Ratio Determinations

Urinary cortisol:creatinine ratio is of value as a screening test for ruling out canine hyperadrenocorticism. 19• 34• 55 Two consecutive morning urine samples are collected and measured for concentrations of cortisol and creatinine, and a cortisol:creatinine ratio is then calculated. This test is highly sensitive in that a dog with a normal cortisol: creatinine ratio is unlikely to have hyperadrenocorticism. On the other hand, the test has low specificity in that many diseases besides hyperadrenocorticism will cause an abnormally high cortisol:creatinine ratio. ACTH Stimulation Test

The ACTH stimulation test is a screening test for hyperadrenocorticism. This test is the only one that will distinguish spontaneous hyperadrenocorticism from iatrogenic hyperadrenocorticism. This test is also utilized to monitor the response to medical manipulation of the pituitary adrenal axis. Dogs with spontaneous (not iatrogenic) hyperadrenocorticism have enlarged adrenal(s) secondary to hyperplasia (PDH) or neoplasia (adrenal tumor). Therefore, they have a large cortisol reserve and the potential for hyperresponsiveness to maximal ACTH stimulation. The test is a 1- to 2-hour test depending upon the species tested and the type of exogenous ACTH administered. The aqueous ACTH gel (repository corticotrophin injection, HP Acthar Gel; RhonePoulenc Rorer Pharm, Collegeville, P A) is given intramuscularly at a dose of 2.2 IU /kg, and cortisol is measured pre-ACTH and 2 hours post-ACTH stimulation. Alternatively, 0.25 mg of synthetic ACTH (Cortrosyn, Organon, West Orange, NJ) is given intravenously, and pre- and 1-hour postsamples are taken. Cortrosyn can be given intramuscularly with pre- and 2-hour postsamples taken. Doses of synthetic ACTH between 1 and 10 f.Lg/kg have produced maximal cortisol response in the dog. 53 Normal values will vary between laboratories. In our laboratory, a postvalue above 20 p..g/ dL (550 nmol/L) is consistent with a diagnosis of hyperadrenocorticism in the dog. Values may be lower in the cat but will also vary among laboratories. ACTH stimulation tests are abnormal in 85% of dogs with PDH

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but in only 50% of dogs with adrenal tumors. Exaggerated responses to ACTH have also been documented in dogs with chronic illness. In dogs or cats with a recent history of glucocorticoid therapy, the ACTH stimulation test is the recommended initial screening procedure. Dogs with nonadrenal disease can hyperrespond to ACTH, giving false-positive test results. Care must be taken in interpreting test results in dogs with other systemic diseases. 35 Low-Dose Dexamethasone Suppression Test

Dogs with a normal pituitary adrenal axis will respond to the negative feedback from exogenously administered dexamethasone. Dogs with hyperadrenocorticism will be resistant to this negative feedback. A morning baseline serum/plasma sample is obtained. A total of 0.01 to 0.015 mg/ kg of dexamethasone is administered intravenously with 3- or 4-hour and 8-hour postinjection samples taken. Approximately 90% to 95% of dogs with hyperadrenocorticism will fail to show normal suppression of cortisol at 8 hours. If the 8-hour sample cortisol level is less than 1 to 1.5 J..Lg/dL (27-41 nmol/dL), then the test indicates that the dog is normal. Lack of suppression at 8 hours does not distinguish PDH from adrenal tumor, except when a dog is suppressed at 3 to 4 hours (< 1.0-1.5 J..Lg/dL) and escapes the suppression at 8 hours (cortisol levels > 1.0-1.5 J..Lg/dL). Dogs showing this pattern of suppression probably have PDH, and further testing to differentiate PDH from adrenal tumor need not be performed. In all other instances, a high-dose dexamethasone test, blood ACTH concentration, or adrenal ultrasonography needs to be performed to distinguish PDH from adrenal tumor. Dogs with nonadrenal illness are more likely to have false-positive test results when the low-dose dexamethasone suppression test is used compared with the ACTH response test. Differentiating Tests

Endogenous Plasma ACTH Levels

Plasma ACTH will be normal to high in dogs with pituitary-dependent disease but low in dogs with adrenal tumors. Unfortunately, some dogs have values in a gray zone, requiring several samples taken at different collection times to obtain a sample that truly reflects the underlying disease process. A plasma sample is collected in an EDTA tube, aprotinin (a proteinase inhibitor) is added, the sample is centrifuged within 30 minutes of collection, the plasma is separated and placed in a plastic tube, and the sample is shipped in insulated mailing containers containing frozen refrigeration packs using next-day or second-day delivery.37 Proper handling of the specimen is paramount, as ACTH is very labile; however, the use of aprotinin allows for extended time between collection and measurement of the ACTH concentration. High-Dose Dexamethasone Suppression Test

Dogs with a normal pituitary adrenal axis will respond to the negative feedback from exogenously administered dexamethasone. Most dogs with PDH will also respond to the negative feedback from a high dose of dexamethasone. Dogs with adrenal tumors will be resistant to this negative feedback. The protocol is the same as for the low-dose dexamethasone test, except that 0.1 mg/kg of dexamethasone is administered. If the dog is suppressed at 8 hours, this is indicative of PDH. If the dog does not suppress at 8 hours, the test is inconclusive, because 20% of PDH cases and 100% of adrenal tumors do not

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suppress. If the 3- to 4-hour sample shows suppression but it escapes at 8 hours, this is indicative of PDH. If the test results are inconclusive (nonsuppression at 3-4 and 8 hours), further evaluation is indicated. Further Tests to Differentiate PDH from Adrenal Tumor and to Localize the Tumor Abdominal Radiography

Abdominal radiography may be helpful in diagnosing an adrenal tumor and localizing the side of involvement. Radiographic documentation of a mass craniomedial tumor to either kidney or calcification of the adrenal gland is supportive of an adrenal tumor. Unfortunately, the tumor must be of a large size (or calcified) to be radiographically apparent. Ultrasonography of the Abdomen

Ultrasonography is a sensitive, noninvasive method that aids in defining location, size, and organ involvement of adrenal masses. Results help to define if both adrenals are enlarged (probable PDH) or if one adrenal is enlarged (probable adrenal tumor). In addition, other organ involvement, e.g., hepatic involvement or vascular invasion or compression, may be detected. 54 In a recent study, sonographic differences between PDH-induced bilateral cortical hyperplasia and functional adrenocortical neoplasia were appreciated as well as differences in sonographically determined adrenal size between healthy dogs and dogs with PDH.27

CT In human medicine, CT is currently considered to be the best approach to image the adrenal and pituitary glands in patients with hyperadrenocorticism. It has proved successful in visualization of pituitary tumors and detection of unilateral and bilateral adrenal gland enlargement in the dog. 1• 17• 58 It is not possible to differentiate between malignant and benign adrenal masses on the basis of size. Magnetic Resonance Imaging

Superior soft tissue contrast is afforded by magnetic resonance (MR) imaging as compared with CT. In human medicine, it is more accurate for the identification of pituitary neoplasms than CT, because the latter routinely produces a beam-hardening artifact that obscures the pituitary fossa. MR imaging has provided accurate information on tumor size and the extent of tumor expansion into the surrounding structures in dogs with pituitary macrotumors with central nervous system signs.16 MR imaging has also detected visible pituitary masses in approximately 50% of imaged dogs with PDH with no clinical signs suggestive of an intracranial mass.5 MR imaging can also be used for identification of adrenal masses.64 Therapy

Treatment depends upon the underlying cause of the hyperadrenocorticism. In all cases, a good rapport with the client is essential if management of the

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disease is to be successful. In general, treatment modalities include medical, surgical, and radiation therapy.

PDH Medical management is the most common therapeutic modality used for the treatment of PDH. Therapy is aimed at decreasing cortisol production by the adrenal cortex. Drugs used for this purpose include mitotane (Lysodren), ketoconazole, aminoglutethimide, metyrapone, and deprenyF The most commonly used drug is Lysodren. Lysodren is adrenocorticolytic, causing severe progressive necrosis of the zona fasciculata and reticularis. The zona glomerulosa, the zone responsible for mineralocorticoid production, is relatively resistant but can be affected. Lysodren therapy is divided into two phases: loading and maintenance. The loading phase is initiated by giving 25 to 50 mg/ kg/ d of Lysodren. In dogs that are polyuric and polydipsic, water consumption is monitored daily, and drug therapy should be discontinued if water consumption drops precipitously. Unfortunately, 20% of cases are not polyuric and polydipsic. In these cases, medication is given for 5 to 14 days, and the animal is monitored for side effects of glucocorticoid insufficiency. If no side effects are seen after 10 to 14 days of therapy, the animal should be re-evaluated with an ACTH stimulation test. Side effects of Lysodren therapy include listlessness, decreased appetite, vomiting, and diarrhea. At the first sign of side effects, Lysodren therapy should be discontinued. Some animals will experience vomiting as a direct effect of Lysodren. This can be prevented by giving the medication with food or dividing the dose and giving it twice daily. If side effects related to glucocorticoid insufficiency are seen by the owner, prednisone or prednisolone can be administered orally at a dose of 0.2 to 0.4 mg/kg until the dog can be evaluated. Generally, the signs will resolve within a few hours of glucocorticoid supplementation. When an end point is reached, re-evaluation of the pituitary adrenal axis is accomplished by performing an ACTH stimulation test. This test should be delayed for 24 to 48 hours if prednisone or prednisolone has been given. The goal of therapy is to have the post-ACTH cortisol value in the low normal to slightly below normal range. If there is a continued exaggerated response, then continued daily administration of Lysodren is necessary. If the ACTH response is too low, prednisone or prednisolone therapy at the above dose can be given. Intermittent ACTH stimulation tests should be used to monitor the dog until cortisol values rise to the low normal or slightly below normal range. In one study, Lysodren decreased mineralocorticoid production in 5.5% of dogs after a median of 4.6 months of therapy.38 Dogs with decreased mineralocorticoid production will not respond to glucocorticoid administration alone, and serum sodium and potassium concentrations should be monitored. The urine cortisol:creatinine ratio has been utilized to monitor response to Lysodren therapy. A morning urine sample is collected before Lysodren therapy is initiated and also at the completion of the loading dose regimen.34 This test can differentiate elevated from basal levels of cortisol but lacks sensitivity to differentiate basal from reduced states of cortisol secretion. The clinical implication is that a glucocorticoid-insufficient animal may have a normal cortisol:creatinine ratio. When ACTH stimulation is in the appropriate range, maintenance therapy should be initiated. The dose to be given each week is equal to the daily loading dose. This total dose is usually divided in half and given twice weekly. An ACTH stimulation test should be repeated 1 month after initiation of mainte-

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nance Lysodren therapy and subsequently every 3 to 6 months. It should be performed sooner if problems are noted. Approximately 50% of the dogs will relapse within 12 months and need to be reloaded or have their maintenance dose increased. Ketoconazole decreases cortisol biosynthesis and is not adrenolytic. Mineralocorticoid production is not affected. Enzyme inhibition is reversible and cortisol concentration will return to its baseline value within 8 to 24 hours after drug discontinuation. Ketoconazole has been used as an alternative to Lysodren therapy, particularly when Lysodren is unsuccessful because of drug resistance or severe side effects. Ketoconazole is generally less effective and more expensive than Lysodren. The initial dosage is 5 to 10 mg/ kg given orally two times daily for 7 to 14 days. The animal is monitored as for Lysodren, with an ACTH stimulation test repeated when water consumption decreases precipitously, when side effects are noted, or after 14 days of therapy. Higher doses will be required in many dogs. Direct side effects of the drug include anorexia, vomiting, and lightening of the hair coat. Lifelong twice-daily therapy must be maintained in most cases. There is a reported lack of efficacy in approximately 20% of treated dogs. This may be secondary to poor gastrointestinal absorption of the drug. L-Deprenyl has been used successfully to treat canine PDH. In one study, 71% of dogs were treated successfully using a dose of 2 mg/kg, and no untoward effects or laboratory abnormalities were seen.8 In a second study, 79% of dogs were treated successfully with 1 mg/kg, and side effects were noted in less than 3% of the cases.8 Radiation therapy has been used to treat pituitary tumors. Cobalt irradiation has been used successfully in cases of macroadenoma to reduce the size of the pituitary tumor.14• 44 Although cobalt therapy can reduce the size of the tumor and ameliorate neurologic complications, it does not appear to decrease pituitary ACTH secretion. Therefore, Lysodren or ketoconazole therapy must be used concurrently. Adrenocortical Tumors

Surgery remains the treatment of choice for an adrenal tumor. Approximately 50% of the tumors are benign adenomas, and the animal is cured by adrenalectomy. Radiography or ultrasonography of the thorax and abdomen should be performed to check for metastatic disease prior to surgery. Intensive monitoring is needed during and after surgery to prevent acute adrenocortical insufficiency. Glucocorticoids (dexamethasone, 0.1-0.2 mg/ kg intravenously or subcutaneously, or prednisolone sodium succinate, 1-2 mg/kg intravenously) should be given at anesthetic induction.42 Maintenance of postoperative glucocorticoid support is ideally accomplished using a continuous intravenous infusion of hydrocortisone hemisuccinate (625 J.Lg/kg/h) for 48 hours. Alternatively, dexamethasone (0.1-0.2 mg/kg subcutaneously two to three times daily) can be given. After the initial 48 to 72 hours of parenteral glucocorticoid support, oral prednisone should be initiated at 0.5 mg/kg twice daily, and this should be tapered over 2 to 3 months. Oral mineralocorticoid supplementation (fludrocortisone acetate, 0.02 mg/kg orally once a day) may be required for the first couple of weeks following surgery in a minority of cases. Medical therapy should be considered if there is metastatic disease, if the owner does not elect surgery, if the animal is a very poor surgical risk, or if a nonresectable tumor is found at surgery. Lysodren has the potential to destroy the cancerous tissue. Ketoconazole can also be used to block the cortisol synthetic

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pathway and decrease the signs associated with excess cortisol production. Medical treatment can also be used to stabilize the patient in preparation for surgery. Higher doses of Lysodren and ketoconazole are usually needed to control dogs with adrenal tumors compared with dogs with PDH. FELINE HYPERADRENOCORTICISM Clinical Features

Hyperadrenocorticism is a relatively rare disease in the cat as compared with the dog. The average age of onset is 10.4 years. It is more frequently seen in female cats (78%),45 and there is no apparent breed predilection. Polyuria, polydipsia, polyphagia, and a pendulous abdomen with hepatomegaly, muscle wasting, and weight gain are the most common signs noted. Depression and weight loss are seen in less than 25% of cases. Dermatologic abnormalities include truncal and abdominal alopecia, unkempt hair coat, thin skin, comedones, hyperpigmentation bruising, and abscesses. In some cats, excessively fragile skin leads to tearing following normal manipulation or handling.30• 67 Diagnosis

Approximately 81% of cats with hyperadrenocorticism have overt diabetes. CBC abnormalities include neutrophilia, eosinopenia, and lymphopenia in approximately two thirds of cases. Serum biochemical abnormalities include hyperglycemia and hypercholesterolemia in over 75% of cases, with increased alanine aminotransferase and serum alkaline phosphatase in approximately 50% of cases. The diagnosis of hyperadrenocorticism is difficult in cats. Diagnostic test results are often inconsistent, and testing has not been standardized. The ACTH stimulation test is probably the best test for the diagnosis of hyperadrenocorticism in the cat. Cortisol concentration is measured both before and 1 and 2 hours after intramuscular injection of ACTH gel (2.2 U / kg), or synthetic ACTH (Cortrosyn) at 125 flog per cat may be administered intramuscularly or intravenously with samples collected at 30 and 60 minutes after administration. It is important to obtain both post-ACTH samples with either protocol, because peak cortisol response is highly variable. 67 It has been shown recently that 1.25 to 12.5 flog of synthetic ACTH administered per cat will maximally stimulate the adrenal cortex. 48 If the smaller doses are given, it is important to realize that plasma cortisol concentration tends to peak earlier (30 minutes) and returns to its baseline value more quickly. After reconstitution, a vial of Cortrosyn will be fully stable in 5 flog of saline solution per milliliter for at least 4 months.U Urine cortisol:creatinine ratios have been shown to be significantly higher in cats with PDH than in normal cats.24 As is the case with their canine counterparts, however, sick cats will also have a significantly higher urine cortisol:creatinine ratio. 31 If the ACTH stimulation test is normal but hyperadrenocorticism is still suspected, a high-dose dexamethasone suppression test may be helpful using 0.1 mg/kg of dexamethasone given intravenously. This high-dose test is utilized as a screening test in the diagnosis of feline hyperadrenocorticism. A certain percentage of normal cats will have an escape of serum cortisol suppression at the 8-hour sample.

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A high-dose dexamethasone suppression test using 1 mg/kg of dexamethasone given intravenously may be appropriate for distinguishing PDH from adrenal tumors in cats. Many cats with PDH will have plasma ACTH concentration in the low (adrenal tumor) range, making ACTH concentrations of questionable value in confirming a functional adrenal tumor.57 Because the current recommendation for treatment of feline hyperadrenocorticism of either pituitary or adrenal origin is bilateral adrenalectomy, a test to differentiate between the two types of hyperadrenocorticism may not be as crucial as it is in the dog. More information is needed before firm diagnostic recommendations can be made.

Therapy Surgical, medical, and radiation therapies have been used to treat feline Cushing's syndrome. These therapies have met with varying degrees of success. Lysodren therapy, ketoconazole, cobalt irradiation, metyrapone therapy, and bilateral adrenalectomy have been used for the treatment of PDH. Bilateral adrenalectomy followed by mineralocorticoid and glucocorticoid replacement therapy has been used as a treatment for feline PDH. Postoperative complications include abnormal serum electrolyte concentrations, pancreatitis, skin lacerations, hypoglycemia, pneumonia, and venous thrombosis.15 Surgical excision is the treatment for an adrenal tumor. During surgery, dexamethasone (0.05 mg/kg) should be infused with intravenous fluids and administered over 6 hours. This dose should be repeated every 12 hours until the cat is eating and drinking. The cat is further supplemented with prednisone at a dosage of 1 mg/kg every 12 hours for 2 to 4 days, after which the dosage can be gradually reduced. If a bilateral adrenalectomy is performed, daily administration of prednisone at a dose of 2.5 mg/ d and mineralocorticoid supplementation (fludrocortisone (Florine£]) at a dose of 0.05 mg every 12 hours are necessary. At the time of bilateral adrenalectomy, hydrocortisone hemisuccinate or hydrocortisone sodium succinate can be used at a dose of 2 mg/kg every 6 hours, then at 1 mg/ kg every 6 hours on the second day, and then at 1 mg/kg every 12 hours thereafter until oral medication can be initiated. 46 In cats exhibiting extremely fragile skin that tears easily during manipulation, metyrapone should be initiated at 65 mg/kg every 12 hours until cortisol levels are normal and skin lesions have healed. 1° Ketoconazole at a dose of 5 to 10 mg/kg every 8 hours may be used if the response to metyrapone is not adequate. 67

PHEOCHROMOCYTOMA Pheochromocytoma is a functional tumor that arises from the adrenal medulla and secretes catecholamines. It is rare in dogs and cats; 48% of cases are detected postmortem. The pattern of secretion of pheochromocytomas can be persistent but more often is paroxysmal. The pharmacologic effects of catecholamines excreted can be numerous and variable, often causing vague and unusual signs. The tumor usually does not metastasize and is locally invasive into the vena cava, liver, and kidney. Metastasis has been seen in the lung, liver, spleen, kidney, bone, heart, and pancreas.23 Pheochromocytomas have been seen in dogs with concurrent hyperadrenocorticism.59

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Clinical Features

There is no sex or breed predisposition. Dogs have a mean age at the time of diagnosis of 10.5 years. Most of the clinical signs produced result from either the direct presence of the space-occupying nature of the tumor or are secondary to the excretion of excessive amounts of catecholamines. Clinical signs include polypnea, dyspnea, weakness, anorexia, cough, collapse, weight loss, lethargy, vomiting, diarrhea, restlessness, anxiety, polyuria, polydipsia, ataxia, seizures, abdominal distension, epistaxis, cyanosis, tremors/ shaking, and adipsia.40 Many of these clinical signs are subtle, often vague, and sometimes overlooked by most owners. Duration of clinical signs can range from days to years before presentation.

Diagnosis

Hypertension is a common feature, but a normal blood pressure measurement will not rule out a pheochromocytoma, and multiple measurements may be required in cases that are highly suspect. Survey abdominal radiographs may reveal an abdominal mass. Ultrasonography can identify adrenal tumors, detect renal invasion, and identify intracaval tumor thrombus. CT, MR imaging, and scintigraphic localization have also been used. Demonstration of increased circulating concentrations of catecholamines and increased urinary excretion of catecholamine metabolites may be helpful in the definitive diagnosis of this disease.

Therapy

Surgical exos10n of the tumor is the treatment of choice. Medical management may be necessary to stabilize the animal from a metabolic and cardiovascular standpoint. The cornerstone of medical management is the use of alpha- and beta-adrenergic blockers. Beta-blockers should not be used without alpha-blockers because of the possibility of resulting severe hypertension.

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cism: A spontaneous animal model for neurodegenerative disorders and their treatment with L-deprenyl. Prog Brain Res 106:207-215, 1995 8. Bruyette DS, Darling LA, Griffin D, et al: L-Deprenyl for canine pituitary dependent hyperadrenocorticism pivotal clinical trial. In Proceedings of the 14th American College of Veterinary Internal Medicine Forum, San Antonio, TX, 1996, p 764 9. Conaway DH, Padgett GA, Bunton TE, et al: Clinical and histological features of primary progressive, familial thyroiditis in a colony of Borzoi dogs. Vet Pathol22:439446, 1985 10. Daley CA, Zerbe CA, Schick RO, et al: Use of metyrapone to treat pituitary-dependent hyperadrenocorticism in a cat with large cutaneous wounds. JAVMA 202:956-960, 1993 11. Dickstein G, Shechner C, Nicholson WE, et al: Adrenocorticotropin stimulation test: Effects of basal cortisol level, time of day, and suggested new sensitive low dose test. J Clin Endocrinol Metab 72:773-778, 1991 12. DiBartola SP, Broome MR, Stein BS, et al: Effect of treahnent of hyperthyroidism on renal function in cats. JAVMA 208:875-878, 1996 13. Dixon RM, Graham PA, Mooney CT: Serum thyrotropin concentrations: A new diagnostic test for canine hypothyroidism. Vet Rec 138:594-595, 1996 14. Dow SW, LeCouteur RA: Radiation therapy for canine ACTH-secreting pituitary tumors. In Kirk RW (ed): Current Veterinary Therapy X. Philadelphia, WB Saunders, 1989, pp 1031-1037 15. Duesberg CA, Nelson RW, Feldman EC, et al: Adrenalectomy for treatment of hyperadrenocorticism in cats: 10 cases (1988-1992). JAVMA 207:1066-1070, 1995 16. Duesberg CA, Feldman EC, Nelson RW, et al: Magnetic resonance imaging for diagnosis of pituitary macrotumors in dogs. JAVMA 206:657- 662, 1995 17. Emms SG, Wortman JA, Johnston DE, et al: Evaluation of canine hyperadrenocorticism, using computed tomography. JAVMA 189:432-439, 1986 18. Feldman EC, Nelson RW: Canine and Feline Endocrinology and Reproduction, ed 2. Philadelphia, WB Saunders, 1996 19. Feldman EC, Mack RE: Urine cortisol:creatinine ratio as a screening test for hyperadrenocorticism in dogs. JAVMA 200:1637-1641, 1992 20. Ferguson DC: The effect of nonthyroidal factors on thyroid function tests in dogs. Compend Contin Educ Pract Vet 10:1365- 1377, 1988 21. Ferguson DC: Thyroid function tests in the dog. Vet Clin North Am Small Anim Pract 14:783- 808, 1984 22. Ferguson DC, Jacobs GJ, Hoenig M: Ipodate as an alternative medical treahnent for feline hyperthyroidism. In Proceedings of the American College of Veterinary Internal Medicine Forum, Washington, DC, 1988, p 718 23. Gilson SD, Withrow SJ, Wheeler SL, et al: Pheochromocytoma in the dog. A retrospective review of 50 cases. Veterinary Cancer Society Newsletter 16:607, 1992 24. Goossens MMC, Meyer HP, Voorhout G, et al: Urinary excretion of glucocorticoids in the diagnosis of hyperadrenocorticism in cats. Domest Anim Endocrinol 12:355-362, 1995 25. Gosselin SJ, Capen CC, Martin SL, et al: Biochemical and immunological investigations on hypothyroidism in dogs. Can J Comp Med 44:158-168, 1980 26. Graves TK, Olivier NB, Nachreiner RF, et al: Changes in renal function associated with treahnent of hyperthyroidism in cats. Am J Vet Res 55:1745-1749, 1994 27. Grooters AM, Biller DS, Theisen SK, et al: Ultrasonographic characteristics of the adrenal glands in dogs with pituitary-dependent hyperadrenocorticism: Comparison with normal dogs. J Vet Intern Med 10:110-115, 1996 28. Haines DM, Lording PM, Penhale WJ: The detection of canine autoantibodies to thyroid antigens by enzyme-linked immunosorbent assay, hemagglutination and indirect immunofluorescence. Can J Comp Med 48:262- 267, 1984 29. Hall IA, Campbell KL, Chambers MD, et al: Effect of trimethoprim/sulfamethoxazole on thyroid function in dogs with pyoderma. JAVMA 202:1959-1962, 1993 30. Helton-Rhodes K, Wallace M, Baer K: Cutaneous manifestations of feline hyperadrenocorticism. In Proceedings of the Second World Congress of Veterinary Dermatology, Montreal, Quebec, Canada, 1992, p 109

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31. Henry CJ, Clark TP, Young DW, et a!: Urine cortisol:creatinine ratio in healthy and sick cats. JVet Intern Med 10:123-126, 1996 32. Jaggy A, Oliver JE, Ferguson DC, eta!: Neurological manifestations of hypothyroidism: A retrospective study of 29 dogs. J Vet Intern Med 8:328-336, 1994 33. Jeglum KA, Whereat A: Chemotherapy of canine thyroid carcinoma. Compend Cantin Educ Pract Vet 5:96-98, 1983 34. Jones CA, Refsal KR, Lippert AC, et a!: Changes in adrenal cortisol secretion as reflected in the urinary cortisol/ creatinine ratio in dogs. Domest Anim Endocrinol 7:559-572, 1990 35. Kaplan AJ, Peterson ME, Kemppainen RJ: Effects of disease on the results of diagnostic tests for use in detecting hyperadrenocorticism in dogs. JAVMA 207:445-451, 1995 36. Kemppainen RTJ, MacDonald JM: Canine hypothyroidism. In Griffin CE, Kwochka KW, MacDonald JM (eds): Current Veterinary Dermatology; The Science and Art of Therapy. St. Louis, Mosby Year Book, 1993, pp 265-272 37. Kemppainen RJ, Clark TP, Peterson ME: Preservative effect of aprotinin on canine plasma immunoreactive adrenocorticotropin concentrations. Domest Anim Endocrinol 11:355-362, 1994 38. Kintzer PP, Peterson ME: Mitotane (op'DDD) treatment of 200 dogs with pituitarydependent hyperadrenocorticism. J Vet Intern Med 5:182-190, 1991 39. Loar AS: Canine thyroid tumors. In Kirk RW (ed): Current Veterinary Therapy IX. Philadelphia, WB Saunders, 1986, pp 1033-1039 40. Maher ER: Pheochromocytoma in the dog and cat: Diagnosis and management. Semin Vet Med Surg 9:158- 166, 1994 41. Marks SL, Koblik PD, Hornof WJ, et a!: 99mTc-Pertechnetate imaging of thyroid tumors in dogs: 29 cases (1980- 1992). JAVMA 204:756-760, 1994 42. Matthieson DT, Mullen HS: Problems and complications associated with endocrine surgery in the dog and cat. Probl Vet Med Endocrinol 2:627-667, 1990 43. Mauldin GN: Radiation therapy for endocrine neoplasia. In Kirk RW, Bonagura D (eds): Current Veterinary Therapy XI. Philadelphia, WB Saunders, 1992, pp 319-321 44. Mauldin GN, Burk RL: The use of diagnostic computerized tomography and radiation therapy in canine and feline hyperadrenocorticism. Probl Vet Med Endocrinol 2:557564, 1990 45. Myers NC, Bruyette DS: Feline adrenocortical diseases: Part !- hyperadrenocorticism. Semin Vet Med Surg 9:137- 143, 1994 46. Nelson RW, Feldman EC: Hyperadrenocorticism. In August JR (ed): Consultation in Feline Internal Medicine. Philadelphia, WB Saunders, 1991, pp 267-270 47. Ogilvie GK: Tumors of the endocrine system. In Withrow SJ, MacEwen EG (eds): Small Animal Clinical Oncology. Philadelphia, WB Saunders, 1996, pp 316-346 48. Peterson ME, Kemppainen RJ: Dose-response relation between plasma concentrations of corticotropin and cortisol after administration of incremental doses of cosyntropin for corticotropin stimulation testing in cats. Am J Vet Res 54:300-304, 1993 49. Peterson ME, Gamble DA: Effect of nonthyroidal illness on serum thyroxine concentrations in cats: 494 cases (1988). JAVMA 197:1203- 1208, 1990 50. Peterson ME, Ferguson DC: Thyroid diseases. In Ettinger SJ (ed): Textbook of Veterinary Internal Medicine. Philadelphia, WB Saunders, 1989, pp 1632-1675 51. Peterson ME, Graves TK, Gamble DA: Triiodothyronine (T3) suppression test, an aid in the diagnosis of mild hyperthyroidism in cats. J Vet Intern Med 4:233-238, 1990 52. Peterson ME, Broussard JD, Gamble DA: Use of the thyrotropin releasing hormone stimulation test to diagnose mild hyperthyroidism in cats. J Vet Intern Med 8:279286, 1994 53. Peterson ME, Wallace MS, Kerl ME, et al: Dose-response relation between plasma concentrations of ACTH and cortisol after administration of incremental doses of cosyntropin for ACTH stimulation testing in dogs. In Proceedings of the 14th American College of Veterinary Internal Medicine Forum, San Antonio, TX, 1996, p 768 54. Poffenbarger EM, Feeney DA, Hayden DW: Gray-scale ultrasonography in the diagnosis of adrenal neoplasia in dogs: Six cases (1981- 1986). JAVMA 192:228-232, 1988 55. Rijnberk A, van Wees A, Mol JA: Assessment of two tests for the diagnosis of canine hyperadrenocorticism. Vet Rec 122:178- 180, 1988

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56. Scott-Moncrieff JC, Nelson RW, Bruner JM, et a!: Serum canine thyrotropin concentration (cTSH) in euthyroid, hypothyroid, and sick euthyroid dogs. In Proceedings of the 14th American College of Veterinary Internal Medicine Forum, San Antonio, TX, 1996, p 768 57. Smith MC, Feldman EC: Endogenous ACTH and plasma cortisol response to synthetic ACTH and dexamethasone sodium phosphate in normal cats. Am J Vet Res 48:17191724, 1987 58. Turrel JM, Fike JR, LeCouteur RA, et a!: Computed tomographic characteristics of primary brain tumors in 50 dogs. JAVMA 188:851-856, 1986 59. von Dehn BJ, Nelson RW, Feldman EC, eta!: Pheochromocytoma and hyperadrenocorticism in dogs: Six cases (1982-1992). JAVMA 207:322-324, 1995 60. Voorhout G, Lubberink AAME, van Waes PFGM: Computed tomography in the diagnosis of canine hyperadrenocorticism not suppressible by dexamethasone. JAVMA 192:641-646, 1988 61. Walsh KM, Diters RW: Carcinoma of ectopic thyroid in a dog. JAm Anim Hosp Assoc 20:665- 668, 1982 62. Wenzel KW: Pharmacological interference with in vitro tests of thyroid function. Metabolism 30:717-732, 1981 63. White SD, Ceragioli KL, Bullock LP, et a!: Cutaneous markers of canine hyperadrenocorticism. Compend Contin Educ Pract Vet 11:446-465, 1989 64. Widmer WR, Guptill L: Imaging techniques for facilitating diagnosis of hyperadrenocorticism in dogs and cat. JAVMA 206:1857-1864, 1995 65. Wolfsheimer KJ, Brady C: Thyroid testing in dogs. Canine Pract 20:12- 16, 1995 66. Zerbe CA: Etiology of pituitary dependent hyperadrenocorticism: Parts I and II. In Proceedings of the lOth American College of Veterinary Internal Medicine Forum, San Diego, CA, 1992, pp 360-361 67. Zerbe CA, MacDonald JM: Canine and feline Cushing's syndrome. In Griffin CE, Kwochka KW, MacDonald JM (eds): Current Veterinary Dermatology; The Science and Art of Therapy. StLouis, Mosby Year Book, 1993, pp 273-287

Address reprint requests to Sandra R. Merchant, DVM Department of Veterinary Clinical Sciences Louisiana State University School of Veterinary Medicine Baton Rouge, LA 70803