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Learn to answer troublesome questions about thyroid tests.

Does your medical staff repeatedly ask about discordant thyroid test results? This primer will help you respond.

One hectic Monday morning, you are up to your elbows in work when you receive a call from a family practitioner who recently joined the hospital's medical staff.

"Good morning, Dr. Leonard. How can I help you?"

"I'm in the CCU with Mrs. Rodriguez. She was admitted with a mild heart attack. She's better now, and we're about to move her out of the unit, but I can't explain her lab test results. Her TSH is 0.09, which is low, but her free [T.sub.4] is 1.5, which is normal. What's wrong with your TSH test? This woman doesn't look hyperthyroid - she shouldn't have a low TSH. And her EKG is fine."

You take a deep breath and ask what medication she's taking.

"Heparin, digoxin, prednisone, Lasix, Premarin ...."

"Okay, the problem is the prednisone. Since it suppresses TSH, it makes TSH assays unreliable. But free [T.sub.4] works for those patients, and it agrees with your clinical impression. Just ignore the TSH and use the F[T.sub.4]."

You make a note to write a memo for the medical staff about medications that affect thyroid tests. Using one test instead of two would reduce costs for some patients. The hospital administration would like that. Before writing anything, though, you'll check with the pathologists about whether to write that memo and what to include.

Meanwhile, you wish you knew more about those assays. And you wonder why Dr. Leonard ordered free [T.sub.4] (F[T.sub.4]) and thyrotropin (thyroid-stimulating hormone, or TSH) tests for a patient who was admitted with a heart attack.

AN APPARENT DISCREPANCY

In many hospital laboratories, this scenario is repeated several times a week. The calls may come to the pathologist, section supervisor, clinical chemist, laboratory manager, or anyone else who answers the phone. Doctors complain about thyroid test results that don't seem to agree, thyroid test results that don't support their clinical impression, and a TSH that's too high in patients taking the usual dosage of levothyroxine (Levothroid, Levoxine, Synthroid). A patient with severe dehydration may show abnormal thyroid test results, such as free [T.sub.4] greater than 6.0 ng/dL and TSH less than 0.01 mU/L. Often the doctor wants the test repeated at no charge. The repeat analysis provides the same answer.

In fact, third-generation TSH assays may present more problems than the old [T.sub.4] and [T.sub.3] tests ([T.sub.4] and [T.sub.3] uptake). Lab directors are expanding their test menus by adding the new F[T.sub.4] and TSH tests. Reference intervals are quickly confirmed with specimens from lab staff volunteers. When results fall within the recommended ranges, the normal ranges are accepted.

The apparent simplicity of setting up these new thyroid tests is misleading because test interpretation is not so easy. Thyroid test data must be interpreted carefully in the context of myriad complex factors that affect results.

Let's review the reasons doctors order thyroid function tests and the factors that affect test results. The concepts are simple and the facts will update your skills beyond what you still remember from training.

NORMAL THYROID PHYSIOLOGY

[T.sub.4] is a storage form of thyroid hormone, a stable structure for transport in the blood. The thyroid gland secretes [T.sub.4] and [T.sub.3] in a ratio of 10:1 with 80% of [T.sub.3] arising later from peripheral deiodination of circulating [T.sub.4]. The two hormones travel in the blood bound to proteins with a very small fraction free to enter cells. Only the free fraction is metabolically active.

At peripheral tissues, free [T.sub.4] and free [T.sub.3] enter cells. At the cell surface and within the cell, [T.sub.4] is converted to [T.sub.3], the active hormone that migrates into the cell nucleus to bind DNA.

In a normal individual, thyroid gland function and the level of free [T.sub.4] and free [T.sub.3] in the blood are carefully regulated by hormones from two other endocrine glands: the pituitary and the hypothalamus. When circulating levels of [T.sub.4] and [T.sub.3] fall, the hypothalamus releases thyrotropin-releasing hormone (TRH). TRH stimulates the pituitary thyrotrope cells to release TSH, causing synthesis and release of new [T.sub.4] and [T.sub.3] by the thyroid to maintain homeostasis.

Rising blood levels of [T.sub.4] and [T.sub.3] exert negative feedback on the pituitary and hypothalamus, reducing further output of TSH and TRH. This exquisite control mechanism maintains most people in a euthyroid, eumetabolic condition. A dynamic equilibrium is maintained; TSH and TRH are secreted in a pulsatile fashion throughout the day. TSH shows a circadian variance, with the highest levels late at night and the lowest levels around noon.[1]

THYROID DISEASE

The normal physiology of thyroid hormones changes vastly when disease is present. For example, in the most common thyroid disorder, primary hypothyroidism, the thyroid gland fails to respond to rising TSH. The first physical changes are so subtle that they are barely noticeable to the patient or the physician.

The disease progresses insidiously; the pituitary generates more and more TSH while circulating [T.sub.4] drops to subnormal concentrations. Although TSH is still secreted in a pulsatile fashion, it no longer displays a circadian pattern but remains abnormally elevated at all times.

The failing thyroid gland partially compensates by increasing the ratio of secreted [T.sub.3] to [T.sub.4]. If this last attempt to restore homeostasis fails, the patient's metabolic rate drops to subnormal levels. Now the unflattering physical and mental changes become manifest, and the clinical picture of myxedema evolves relentlessly. (Myxedema describes the disfiguring dry, waxy swelling caused by abnormal mucin deposits in the skin. The striking facial changes shared by most patients include dry skin and swelling around the eyes, lips, and nose.) At this stage of hypothyroidism, all laboratory tests of thyroid function become abnormally distorted, so that the TSH is too high and the [T.sub.4] and F[T.sub.4] are too low.[2]

The opposite condition, thyrotoxicosis, is caused by too much circulating thyroxine. Graves' disease, an autoimmune disorder caused by an antibody to TSH receptors, leads to gradual destruction of the thyroid. The result is uncontrolled release of intracellular components, including [T.sub.4], [T.sub.3], and microsomal proteins.

Too much [T.sub.3] and [T.sub.4] suppress circulating TSH to undetectable levels. The thyroid gland doesn't receive the TSH stimulus and continues to spew hormones autonomously. Hormone production goes out of control. The laboratory picture of hyperthyroxinemia reveals F[T.sub.4], F[T.sub.3], [T.sub.3], and [T.sub.4] at two or three times the upper limit of normal while TSH is suppressed to immeasurably low levels. In spite of a voracious appetite, the restless patient loses weight, has a rapid, irregular heart rate, and complains of feeling hot, jittery, and weak.[3]

Some older patients have an unusual form of hyperthyroidism called apathetic hyperthyroidism, in which the only symptom is unexplained arrhythmia. That may have been a condition Dr. Leonard was trying to rule out when he admitted Mrs. Rodriguez to the CCU.

LAB TESTS FOR THYROID DISEASE

Thyroid tests run on patients with florid thyrotoxicosis or obvious myxedema are reliable. The problematic tests are those run on patients with acute or chronic illnesses that are not associated with thyroid disease yet display unexpectedly abnormal thyroid test results. These patients are described as "euthyroid sick," with nonthyroidal illnesses (NTIs) or poor nutrition.

The puzzling test results of these patients lead to calls to the laboratory for help. Explaining their test results presents an opportunity to educate the physicians about using laboratory services appropriately.

As much as 10% of a euthyroid population may show transient abnormalities of TSH, with either high or low values.[4] Seventeen percent of hospitalized adults show abnormal elevations or depressions in TSH.[5,6] Similarly, a small percentage of an ambulatory population will have unexplained abnormal thyroid test results. Half have underlying thyroid disease. The rest have thyroid test results outside normal reference ranges but no thyroid disease.

PRINCIPLES OF THYROID FUNCTION TESTING

Thyroid testing is done 1) to estimate overall metabolic status, 2) to distinguish between different types of thyroid disease, and 3) to monitor therapy.

Thyroid tests quantify serum analytes, which indirectly reflect a patient's metabolic status and are influenced by variables other than thyroid disease. The selection of any thyroid test is based on the clinical question: Is the purpose to exclude of confirm disease?

Other variables that affect test results include 1) the patient's age and sex, 2) whether the patient is hospitalized or ambulatory, and 3) medications.

Before diagnostic tests are ordered, the patient's clinical status is always considered along with the clinical history, physical examination, and medications. The same information is required to interpret tests of thyroid function. It is imperative to know the context in which the test was ordered. Clinical decisions are made based on clinical presentation and lab data - they are never based solely on laboratory test results.

The extensive menu of laboratory thyroid tests is shown in Table 1. It includes tests that measure hormone function and transport, overall hormone action, and etiology and specialized applications.

One of the most overutilized tests is [T.sub.3]. Before the advent of improved TSH assays, [T.sub.3] tests were used to confirm hyperthyroidism. The improved reliability of TSH assays, however, has made that application obsolete. The [T.sub.3] test is still used to assess patients with hyperthyroid appearance, normal F[T.sub.4], and subnormal TSH.[3] [T.sub.3] confirms the rare condition of [T.sub.3] toxicosis in which [T.sub.3] is selectively produced by the thyroid gland.

THYROID TESTING IN EUTHYROID PATIENTS

The American Thyroid Association recommends using F[T.sub.4] and TSH tests to screen patients for thyroid disease and to document suspected thyroid disease.[7] The best single test to exclude thyroid disease is TSH.

Community screening detects new thyrotoxicosis or hypothyroidism in approximately 0.5% of the general population, with the best yield in women over 40 years old.[8] Thyroid tests are not indicated for community screening programs or for patients hospitalized with acute medical or psychiatric illnesses.

Physicians follow specific guidelines for ordering thyroid tests in euthyroid patients. Absolute and relative indications for thyroid surveillance are shown in Table 2. Two of the absolute indications deal specifically with thyroid medications: replacement therapy for hypothyroidism and suppression therapy for hyperthyroidism. Physicians prescribing thyroid medications should understand the sequence of changes in test values [ILLUSTRATION FOR FIGURES 1A AND 1B OMITTED].

Figure 1a shows developing hypothyroidism. The attendant change in TSH occurs first, long before the F[T.sub.4] drops below the euthyroid reference interval. Once therapy has been initiated, F[T.sub.4] returns to normal long before TSH recovers. This delayed recovery in patients receiving adequate thyroid replacement is called "pituitary lag." It takes a minimum of 6-8 weeks after starting therapy for TSH to accurately reflect thyroid status.[2,9]

When blood tests are performed too soon after replacement therapy begins, the F[T.sub.4] test is reliable but the TSH does not reflect true thyroid status. Clinical decisions based on this premature sampling lead to increased medication. The increased dosage leads to higher F[T.sub.4] levels and the eventual suppression of TSH to subnormal concentrations. The ultimate result is overmedication.

This pituitary lag phase occurs whenever a thyroid supplementation dose is changed. F[T.sub.4] and [T.sub.4] adjust quickly, but adjustment of TSH is delayed. The requisite period of 6-8 weeks is always necessary to reestablish regulation of the pituitary-thyroid axis.

Figure 1b shows similar changes occurring in developing hyperthyroidism. TSH becomes abnormally suppressed long before F[T.sub.4] and [T.sub.4] become elevated above the reference range. Once the condition is diagnosed and treatment has begun, F[T.sub.4] recovers long before TSH returns to normal. When propylthiouracil (PTU) is used, TSH suppression may persist long after serum [T.sub.4] and F[T.sub.4] levels are corrected. Therefore, therapeutic efficacy and dosage adjustment are best assessed by routinely monitoring symptoms and [T.sub.4] levels.[10]

The lab may receive fewer calls about the treatment of patients with hyperthyroid disease because it is less common than hypothyroid disease and because treatment is usually directed by an internist, endocrinologist, oncologist, or other clinical specialist who is likely to be more familiar with these issues than a general practitioner. Patients on supplementation therapy, however, are commonly encountered. Physicians who call about perceived test discrepancies should wait at least two months after initiating therapy or changing dose before checking thyroid function tests again.

TSH TESTING

Historically, TSH was used to diagnose hypothyroidism. Methods were focused on optimizing accuracy and precision at the upper limit of normal and were reliable to 1 or 2 mU/L. The advent of radioimmunoassay (RIA) allowed TSH measurement as low as 0.1 mU/L. Then, during the past 10 years, the newest technology employing chemiluminescence detection (CLIA) brought more sensitive TSH assays that accurately detect concentrations as low as 0.01 mU/L.

At first, these assays were called sensitive TSH assays to distinguish them from existing methods. Subsequent terms were "ultrasensitive" or "supersensitive" methods. To resolve the confusing terminology, they were called first-, second-, and third-generation assays based on functional [TABULAR DATA FOR TABLE 3 OMITTED] sensitivity. There is even a new fourth-generation assay for research applications [ILLUSTRATION FOR FIGURE 2 OMITTED].[6]

Functional sensitivity is defined as the lowest TSH concentration that is reproducibly measured with an interassay coefficient of variation (CV) of 20% or less. Second-generation assays have a functional sensitivity of less than 0.1 to 0.2 mU/L. Third-generation assays allow accurate, reproducible determination of TSH concentrations less than 0.01 mU/L.

Studies of the third-generation assays revealed that TSH was in fact suppressed in hyperthyroidism. This extended the clinical applications for the TSH assay to cover the full spectrum of thyroid disease. The TSH test had become the accepted standard test to estimate thyroid status.

Because TSH is exquisitely sensitive to changes in metabolic status, a twofold change in [T.sub.4] or F[T.sub.4] concentration causes a tenfold change in TSH concentration. This log/linear relationship, shown in Figure 2, explains why TSH is an earlier, superior indicator of subclinical or pre-clinical abnormalities of thyroid homeostasis.

The second- and third-generation TSH assays, however, are not without flaws. Along with their exquisite sensitivity and improved diagnostic capability came attendant problems of nonspecificity. Low TSH concentrations are not always indicative of hyperthyroidism. TSH is not specific for thyroid disease; it is an indirect assessment of thyroid status, an indicator of abnormalities. As with all laboratory tests, correct application and interpretation depend on knowledge of the multiple factors that affect the circulating concentrations.

The utility of the third-generation assays is their ability to distinguish extremely low TSH concentrations associated with true hyperthyroidism from suppressed values seen in nonthyroidal illnesses. Having the results of a third-generation assay is mandatory to establish and monitor the thyroxine dosage required to obliterate residual tumor cells in patients with thyroid cancer. But is a third-generation TSH assay needed for most applications? That is debatable.

Although some experts recommend the exclusive use of third-generation TSH assays, financial considerations are a strong argument for routine use of second-generation assays, which are adequate for most clinical applications. Keep in mind that the analytical goals - timeliness, cost, convenience, or accuracy - vary with the clinical situation.

Turnaround time and timeliness. How soon is the answer needed? Is the patient acutely ill? Is abnormal cardiac activity present? Is the patient scheduled for surgery? Is myxedema coma a possible diagnosis? Is the clinician trying to role out thyroid disease or confirm a clinical diagnosis of thyroid disease?

Cost or convenience may outweigh precision. If the test is used for screening an asymptomatic ambulatory population in a low-risk group, a fully automated economical assay may be adequate. A second-generation assay would meet this need.

Accuracy expectations relate to patient care decisions. The accuracy and precision required for diagnosing hypothyroidism or Graves' disease and suppressing thyroid cancer differ.

For diagnosing hypothyroidism, a first-generation assay is sufficient because one is looking at the difference between TSH concentrations of 5 and 10 mU/L. Specificity is optimal at results over 10 mU/L. Values falling in the range of 5 to 10 mU/L usually are early or preclinical hypothyroidism, but may represent the influence of nonthyroidal illness or euthyroid individuals falling outside the Gaussian distribution.

For diagnosing Graves' disease, a second-generation assay is required to know whether the TSH is less than 0.10 mU/L. A reliable TSH result less than 0.1 mU/L may be sufficient if the patient has a history of thyroid disease and attendant symptoms. TSH values between 0.10 and 0.40 may represent nonthyroidal illness or hyperthyroidism. True hyperthyroidism is associated with markedly suppressed TSH. A second-generation assay distinguishes TSH levels of 0.25 from those less than 0.10. If the TSH is less than 0.1 mU/L, the clinician may not need the exact value (i.e., whether it is 0.05, 0.01, or lower). With an interpretation made in light of the clinical presentation, and attended by abnormally elevated F[T.sub.4], [T.sub.4], and/or [T.sub.3], decisions for intervention and treatment can be made.

A third-generation assay is required to titrate suppression therapy in thyroid cancer. The therapeutic goal is to obliterate the residual gland to prevent recurrence. It is vital to know if the TSH is 0.05 or less than 0.01.

EFFECTS OF DRUGS

Drug interference with laboratory tests is a subject of encyclopedic complexity. Medications that affect [T.sub.4] by altering the concentration of binding proteins, such as drags containing estrogens and androgens, are largely overcome by the F[T.sub.4] assay. Interference is dosage dependent and shows wide variation among patients. The most common offenders (because they are used the most) are lithium, amiodarone, dopamine, glucocorticoids, phenytoin, carbamazepine, estrogens, and iodides (see Table 3).[11]

DAILY CONSIDERATIONS

Constant change in the clinical laboratory affects thyroid function testing in several ways. New technology is important, as is the advent of less costly reagents and faster and more highly automated tests. Laboratorians should stay abreast of changes in technology and be prepared to answer questions.

The usefulness of screening for thyroid dysfunction varies with the clinical setting. Thyroid test results can be interpreted properly only in light of the patient's clinical history and laboratory data.

Table 1

Tests for assessing thyroid function

Total thyroxine ([T.sub.4]) Free thyroxine (F[T.sub.4]) Triiodothyronine ([T.sub.3]) Free triiodothyronine (F[T.sub.3]) [T.sub.3] resin uptake ([T.sub.3]U) or [T.sub.4]U Free thyroxine index (FTI) or T7 Thyrotropin, thyroid-stimulating hormone (TSH) Thyrotropin-releasing hormone (TRH) Reverse triiodothyronine, reverse (r[T.sub.3]) Thyroid peroxidase antibodies (TPO) TRH stimulation test Thyroglobulin Thyroglobulin antibodies

Table 2

Indications for thyroid testing in euthyroid patients

Absolute indications

Newborn Goiter History of chronic thyroiditis History of radioiodine therapy History of head and neck irradiation Graves' disease Monitoring thyroid replacement or suppression therapy Atrial fibrillation or flutter History of taking thyroid medications

Relative indications

History of nonthyroid autoimmune disease Family history of thyroid or autoimmune disease Unexplained weight change Females older than 50 Patients (male or female) older than 50 and hospitalized

References

1. Keffer JH. Preanalytical considerations in testing thyroid function. Clin Chem. 1996; 42:125-134.

2. Ridgeway EC. Modern concepts of primary thyroid gland failure. Clin Chem. 1996; 42:179-182.

3. Figge J, Leinung M, Goodman AD, et al. The clinical evaluation of patients with subclinical hyperthyroidism and free triiodothyronine toxicosis. Am J Med. 1994;96:229-234.

4. Ehrmann DA, Same DH. Serum thyrotropin and the assessment of thyroid status. Ann Intern Meal 1989;110:179-181.

5. Spencer CA, Eigen A, Shen D, et al. Specificity of sensitive assays of thyrotropin (TSH) used to screen for thyroid disease in hospitalized patients. Clin Chem. 1987;33:1391-1396.

6. Nicoloff JT, Spencer CA. Clinical review 12. The use and misuse of the sensitive thyrotropin assays. J Clin Endocrinol Metab. 1990:71:553-558.

7. Surks MI, Chopra J, Mariash CN, Nicoloff JT, Solomon DH. American Thyroid Association guidelines for use of laboratory tests in thyroid diseases. JAMA. 1990;263:1529-1532.

8. Helfand M, Crapo LM. Screening for thyroid disease. Ann Int Med. 1990;112:840-849.

9. Toft AD. Thyroxine therapy. N Engl J Med. 1994;331:174-180.

10. Singer PA, Cooper DS, Levy EG, et al. Treatment guidelines for patients with hyperthyroidism and hypothyroidism. JAMA. 1995; 273:808-812.

11. MacAdams MR. Effects of medication and nonthyroidal illness on thyroid function testing. Medical Rounds. 1988;1:31-43.

12. Spencer CA. New roles for TSH measurement in thyroid testing. Kodak Thyroid Information Service. Kodak Clinical Diagnostics. Monograph 4. Rochester, NY: Eastman Kodak Co; 1992.
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Copyright 1996 Gale, Cengage Learning. All rights reserved.

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Author:Trundle, Diana
Publication:Medical Laboratory Observer
Date:Oct 1, 1996
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