UNDERSTANDING ENDOCRINE TESTING. David Liss, BA, RVT, VTS (ECC, SAIM) Los Angeles, CA

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1 UNDERSTANDING ENDOCRINE TESTING David Liss, BA, RVT, VTS (ECC, SAIM) Los Angeles, CA Introduction The endocrine system is complex and sometimes poorly understood. Although veterinary technicians are often involved with preparing and submitting endocrine tests and caring for patients with endocrinopathies, it may be difficult to understand what is happening in affected patients. Understanding endocrine testing can greatly enhance a technician s role in helping to manage endocrinopathies. Thyroid Disorders: Hypothyroidism and Hyperthyroidism The thyroid gland, pituitary, and hypothalamus form part of a feedback loop that helps the body regulate thyroid hormone s. The hypothalamus secretes thyrotropin-releasing hormone, which stimulates the pituitary to release thyroid-stimulating hormone (TSH). TSH signals the thyroid gland to release thyroid hormones, with the major ones being triiodothyronine (T 3 ) and thyroxine (T 4 ). Hypothyroidism Hypothyroidism low s of circulating thyroid hormones can cause clinical signs. Hypothyroidism is reportedly the most common canine endocrinopathy. It is also rarely recognized in feline patients. Hypothyroidism is typically caused by thyroid gland failure, in which the gland atrophies (or is attacked by the immune system), causing a decrease in T 3 and T 4 production. Rarely is hypothyroidism caused by a pituitary or hypothalamic condition. In patients suspected of having hypothyroidism, concentrations of the following hormones are typically tested: total T 3, total T 4, free T 3, free T 4, TSH, and anti-thyroid autoantibody hormone. Because total and free T 3 concentrations are not typically used for diagnosing hypothyroidism, they have been excluded from this discussion. The total T 4 concentration is typically used as a screening test, meaning that if the is low, further testing is needed. Because the total T 4 concentration refers to both bound (to proteins) and unbound (biologically available) portions of the total amount of T 4, other factors can affect its measurement. Patients that are critically ill or undergoing certain drug therapies can have a low total T 4 concentration but a normal biologically active free T 4 concentration. Thus, if a patient has a low total T 4 concentration on routine blood work, follow-up tests should be performed. The free T 4 test correlates highly with clinical illness but should be performed only if measurement is by equilibrium dialysis, which is more acccurate for detecting hypothyroidism than the total T 4 test. The TSH can also be measured. If the thyroid gland is not functioning and circulating thyroid hormone s are low, the TSH should be high. However, the accuracy of the

2 TSH assay for detecting hypothyroidism is quite low. Although the TSH would be expected to be high if hypothyroidism is present, this can often be high, low, or normal. Therefore, hypothyroidism cannot be diagnosed based on a TSH alone, and errors may occur when the free T 4 and TSH s are interpreted together; however, a low free T 4 combined with a high TSH is highly predictive of hypothyroidism. Patients with an autoimmune component to hypothyroidism (autoimmune thyroiditis) can have elevated s of thyroid hormone antibodies, which can be measured as a high thyroglobulin autoantibody titer. An elevated T 3 or T 4 autoantibody titer results in a high thyroglobulin autoantibody titer. If a patient has a slightly low total T 4 and a low free T 4, measurement of antithyroid antibodies is indicated. However, these parameters are not routinely measured because the presence of thyroglobulin autoantibodies does not change the approach to treatment. Hyperthyroidism Hyperthyroidism is common in cats. Affected patients often have cachexia, hyperactivity, polyuria, polydipsia, polyphagia, hypertension, tachycardia, thyroid slip which is a palpable thyroid nodule. This thyroid nodule is typically a benign adenoma, however adenocarcinoma s are possible. These neoplasias cause heightened production of thyroid hormones. Most hyperthyroid cats have an elevated total T 4 ; however, this may be in the middle to high range of normal. Therefore, testing the total T 4 is somewhat useful for screening, but additional testing is often required to confirm clinical suspicion. As in dogs, testing the free T 4 can confirm a normal (within reference range) total T 4 in cats. Therefore, in cats, hyperthyroidism is indicated by either an elevated serum total T 4 or a normal total T 4 and an elevated free T 4. Hyperthyroid Hypothyroid Sick euthyroid T 3 Level Guidelines to Thyroid Tests Total T 4 Free T 4 TSH Level Autoantibodies Level Level Elevated Elevated Decreased Not present or normal Present if there is Decreased Decreased or Normal to lymphocytic or normal normal increased thyroiditis Decreased Normal Normal Not present or normal Adrenal Disorders The adrenal glands are part of the interconnected hypothalamus, pituitary, and adrenal system, which is called the hypothalamic-pituitary-adrenal, or HPA, axis. The HPA axis functions to ultimately produce cortisol. Each part of the axis, down to the adrenal glands, secretes a hormone that triggers release of another hormone from a different area within the HPA axis. When cortisol is secreted, the body reacts by ceasing to produce the previous hormones. The hypothalamus secretes corticotropin-releasing hormone (CRH), which stimulates the pituitary to secrete corticotropin (also known as adrenocorticotropic hormone). In turn, corticotropin stimulates the

3 adrenal glands to secrete steroids. The major steroids in the body are cortisol (an endogenous glucocorticoid) and aldosterone (an endogenous mineralocorticoid). When s of endogenous steroids increase, their predecessor hormones decrease; this is called a negative feedback loop. When the cortisol is high, CRH is inhibited and the corticotropin decreases. Conversely, when the cortisol is low, CRH is secreted and the corticotropin increases. Hypoadrenocorticism Hypoadrenocorticism (also known as Addison disease) usually results from immune-mediated destruction of the adrenal glands. Clinical signs appear as affected patients become deficient in not only cortisol (a natural glucocorticoid) but also aldosterone (a natural mineralocorticoid). Rarely, dogs develop secondary Addison disease due to failure of the pituitary to secrete corticotropin, resulting in adrenal failure. In addition, hyperadrenocorticism patients receiving antiadrenal therapy can develop iatrogenic Addison disease. Adrenal dysfunction can be detected by measuring how well the adrenal glands respond to stimulation; therefore, the corticotropin stimulation test (also known as the adrenocorticotropic hormone [ACTH] stimulation test) is performed to diagnose this disorder. Corticotropin is released from the pituitary during times of stress. When synthetic corticotropin or a gel form of corticotropin is administered, it stimulates the adrenal glands to produce cortisol. This response can be measured in an assay. Diagnosis of Addison disease involves measurement of an inappropriately low response to corticotropin stimulation. This definitively diagnoses hypoadrenocorticism because affected patients with a low basal cortisol have no reserve when forced to respond to corticotropin stimulation. Hyperadrenocorticism Hyperadrenocorticism (also known as Cushing disease) involves overproduction of glucocorticoids and mineralocorticoids in the body. It is a complicated disease that can be caused by steroid therapy, a pituitary adenoma, or a functioning adrenal adenoma or adenocarcinoma. Most cases involve pituitary-dependent hyperadrenocorticism (PDH); fewer cases involve adrenal-dependent hyperadrenocorticism (ADH). Several approaches may be used to test for hyperadrenocorticism. The differences are due to disagreement regarding which test should be used first and which tests should be used for confirmation. These tests have different sensitivity and specificity, so some are arguably better screening tests and others are better for confirming a result. It may be beneficial to distinguish between PDH and ADH because a unilateral adrenal tumor may be surgically excised. The corticotropin stimulation test detects adrenocortical reserve and, therefore, sometimes reveals an elevated basal cortisol and an exaggerated poststimulation cortisol. Eighty-five percent of dogs with PDH have exaggerated postcorticotropin results, while 55% of dogs with ADH have the same results. Diagnosis of hyperadrenocorticism not only relies on excess cortisol production but also must show decreased sensitivity to exogenous glucocorticoid administration. When Cushing disease is suspected, a spontaneously obtained resting cortisol is not diagnostic because many factors can elevate a single cortisol measurement. The primary test used to investigate the ability of the

4 adrenal system to manage exogenous steroid administration is the low-dose dexamethasone suppression test (LDDST), which uses the potent steroid dexamethasone at a dose that elicits a diagnostic response without affecting the laboratory machine measurement of cortisol, as dexamethasone does not cross-react with the assay. In a healthy dog, because the corticotropin system is based on negative feedback, administration of exogenous glucocorticoids suppresses the corticotropin system, resulting in lowered cortisol measurements. However, in an affected patient, the low dose of steroids fails to suppress the hypothalamic-pituitary-adrenal axis, resulting in elevated cortisol measurements. Therefore, LDDST results showing failure to suppress (i.e., the cortisol is elevated) at 4 and 8 hours after administration are diagnostic of hyperadrenocorticism. This test is fairly accurate for diagnosing hyperadrenocorticism. In 65% of cases, the LDDST can differentiate between PDH and ADH through observation of the response (i.e., the cortisol ) at 4 and 8 hours after administration. In patients with pituitarydependent hyperadrenocorticism, cortisol production is temporarily suppressed after exogenous dexamethasone is administered. Thus, some suppression can be detected at 4 hours after administration, but the cortisol (i.e., escape ) is exaggerated again at 8 hours. A noninvasive option to help diagnose hyperadrenocorticism is the urinary cortisol:creatinine ratio (UCCR) test. This test reflects several hours of cortisol production even though the UCCR sample is collected from one urination. This test is highly sensitive making it a good screening test. Patients with normal UCCR values (ref range: <13 normal) are unlikely to have hyperadrenocorticism. Typically, the client collects the UCCR sample by free catch at home. This can eliminate falsely elevated test results due to the stress of a veterinary visit. It is recommended to collect two samples on two consecutive mornings, with the second sample collected on the day of the veterinary appointment. The results are analyzed and averaged. An elevated urinary cortisol concentration in relation to the creatinine concentration suggests hyperadrenocorticism, but this should be confirmed with another test, such as the LDDST or corticotropin stimulation test. Stress or concurrent infection can raise the patient s cortisol, resulting in false-positive results. The UCCR test does not differentiate between PDH and ADH. Because test results from two consecutive days are averaged, diagnosis may be missed in patients with mildly elevated cortisol s. If initial diagnostic tests confirm a diagnosis of hyperadrenocorticism but are not definitive for differentiating between PDH and ADH, a high-dose dexamethasone suppression test (HDDST) can be used. This test administers 10 times more dexamethasone than the LDDST. The HDDST works on the premise that a high of dexamethasone suppresses the corticotropin system in the presence of a pituitary-dependent tumor, based on negative corticotropin feedback, but does not suppress the corticotropin system in the presence of an adrenal tumor. With this test, if suppression is seen (i.e., cortisol s are decreased from the baseline at 4 and 8 hours after administration), a diagnosis of PDH can be made. However, suppression does not occur in 25% of cases; therefore, if suppression is not detected at 4 or 8 hours, the test cannot differentiate between PDH and ADH. The preferred method for differentiating between ADH and PDH is visualization of the adrenal glands by abdominal ultrasonography. The plasma corticotropin can also be used to differentiate between PDH and ADH. Patients with pituitary tumors have elevated corticotropin s because their pituitary oversecretes corticotropin. Patients with adrenal tumors have decreased corticotropin s due to negative

5 feedback mechanisms. The plasma corticotropin test is expensive and difficult to perform because of the requirements for sample handling. However, this test can be useful as a final laboratory test. Differentiating Between PDH and ADH Test Results Indicative of Hyperadrenocorticism Basal Cortisol Level Poststimulation Cortisol Level Suppression at 4 Hours? Suppression at 8 Hours? UCCR test Elevated cortisol in relation to creatinine Corticotropin (ACTH) stimulation test post-stimulation cortisol Elevated: exaggerated response LDDST Elevated at 4 and 8 h Yes: 65% No [Maybe?] Pituitary Dependent HDDST Corticotropin test ; suppression evident only if PDH is present Yes: 75% Yes: 75% UCCR test Elevated cortisol in relation to creatinine Adrenal Tumor Corticotropin stimulation test LDDST HDDST Elevated: exaggerated response Elevated at 4 and 8 h No No Elevated No No Corticotropin test Low