To help diagnose hypothyroidism and hyperthyroidism—and to monitor thyroid cancer recurrence—physicians rely on laboratory results. The problem is, thyroid testing is a source of confusion for many laboratories and clinicians alike.
“Thyroid testing can be perplexing,” says Anthony W. Butch, Ph.D., Professor of Pathology & Laboratory Medicine; Director, Clinical Chemistry & Toxicology; and Director, Clinical Immunology Research Laboratories at the Geffen School of Medicine, University of California, Los Angeles. “It's important for labs to stay on top of what's going on.”
The two most common issues: what tests to run and what reference interval to apply to the patient test result.
Which Tests? And When?
When it comes to testing for thyroid disorders, physicians have a panel of assays to choose from. The most common, of course, are thyroid-stimulating hormone (TSH), free thyroxine (free T4), free triiodothyronine (free T3) and TPO antibody (TPOAb).
TSH alone—not as part of a thyroid panel—is the recommended first step. One of the chief benefits of TSH is that it provides a magnified reflection of changes in T4 levels. For instance, a two-fold change in T4 can result in a 100- to 150-fold change in TSH level.
“The key is to have a third-generation TSH assay with a functional sensitivity of less than or equal to 0.02 mIU/L,” says Dr. Butch. “In other words, the test has to deliver a between-day imprecision not more than 20 percent at the 0.02 mIU/L cutoff. And it's important for laboratories to establish their own functional sensitivity based on independent studies.”
If a patient's TSH is normal, a thyroid condition can usually be ruled out, assuming there are no confounding factors (pregnancy, serious illness or certain medications). These factors, including even routine hospitalizations, can produce results not reflective of the patient's actual thyroid function, so in-patients should be evaluated after discharge.
If the TSH is abnormal, the next step is free T4. This can go one of two ways: if the free T4 is normal but TSH is abnormal, it could indicate a mild or subclinical thyroid disease. On the other hand, if both TSH and free T4 are abnormal, it could signal disease.
What about free T3? While some physicians order free T4 and free T3 at the same time, this is usually unnecessary.
“If you are conducting a routine evaluation of suspected hyper- or hypothyroidism, free T3 is not recommended,” says Dr. Butch. “The free T4 usually gives physicians the information they need to make a diagnosis.”
Free T3 does however play an important role in screening for T3 thyrotoxicosis. For example, if the patient has symptoms of hyperthyroidism and TSH levels are low but free T4 is normal, physicians may want to check free T3 levels.
If autoimmune disease is suspected, the TPO antibody assay is critical. And because TPO antibody (TPOAb) is the most sensitive biochemical marker of autoimmune thyroid disease, it is typically the only test that is needed.
Thyroglobulin autoantibodies (TgAb) are often present in patients with autoimmune thyroid disease but are generally not recommended for monitoring treatment. When thyroglobulin (TG) assays are used to monitor differentiated thyroid carcinoma, sensitive TgAb methods play an essential role in detecting the presence of TG autoantibodies, which can interfere with the TG measurements used to monitor cancer recurrence.
Identifying the Right Reference Intervals
Determining the order of tests is one issue; it's another matter to define reference intervals—particularly when it comes to TSH.
One issue is that TSH levels—like most biomarkers—differ from individual to individual, making it difficult to label what's “normal” for the general population.
In many laboratories, the TSH reference interval is 0.5 to 5.0 mIU/L. But over the past several years, evidence has shown that people who are at the upper end of the interval tend to develop hypothyroidism more often than people at the lower end of the interval.
Noticing this trend, researchers took a hard look at the validity of the 0.5 mIU/L to 5.0 mIU/L reference interval. In late 2002, the NACB (the National Academy of Clinical Biochemistry, the academy of the American Association for Clinical Chemistry), found that the upper limit of the reference interval was likely too high. When establishing the historical range, researchers inadvertently included people who had mild or subclinical thyroid disease and this pushed the upper limit higher than appropriate.
Based on their reassessment, the NACB predicted that a 2.5 mIU/L upper limit is likely to be used in the future, because 95 percent of rigorously screened volunteers have serum TSH values between 0.4 and 2.5 mIU/L. Now the NACB guideline states: “Ambulatory patients with a serum TSH above 2.5 mIU/L, when confirmed by a repeat TSH measurement made after three weeks, may be in the early stages of thyroid failure, especially if TPOAb is detected.”
Over the past few years, many studies have supported an upper-limit of 3.0 to 4.0 mIU/L . And in January 2003, the American Association of Clinical Endocrinologists (AACE) formally suggested an interval of 0.3 to 3.0 mIU/L.
For now, it is up to individual healthcare organizations to determine what is right for their practice—and until a standard is established, the debate will continue. But it's important to understand that ultimately, there is no single point at which treatment is “always” or “never” recommended. The key is to look for other clinical symptoms, as well as risk factors such as family history and increased blood lipids.
In fact, because the rules are not clear cut, thyroid testing provides an opportunity for the lab and physicians to partner and work closely on the testing strategy. Early diagnosis is critical because even mild thyroid disease may play a role in elevated cholesterol, osteoporosis, depression and other serious conditions.
When it comes to thyroid disease, the symptoms may be vague, but the actions in the laboratory should be anything but. By understanding which tests should be ordered, and what to consider when interpreting the test results, clinical laboratory scientists can serve as valuable partners, providing insight when it's needed most.
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