February 10, 2005


In This Issue . . .


New Subclinical Thyroid Dysfunction Guidelines Highlight Screening
Controversies: Evidence-Based Vs. Clinical-Based Perspectives

New Subclinical Thyroid Dysfunction Guidelines Highlight Screening

Arguments surround subclinical disease diagnosis in nearly every field, because the disease is considered mild and presents few or no symptoms. This is indeed the case for subclinical thyroid disease, which is defined as having an abnormal serum thyroid-stimulating hormone (TSH) concentration accompanied by a normal free thyroxine concentration (FT4). Affecting approximately 4% of the general population, especially the elderly, the clinical importance of this disease, as well as the need for prompt diagnosis and treatment, has yet to be defined. While a national task force recommended against routine screening of the general population for this disorder, officials with the top national endocrine societies have recently published guidelines that state otherwise. This month’s Strategies explores the latest chapter on questions surrounding subclinical thyroid dysfunction screening and the effect that a new set of guidelines will have on the clinical laboratory.

In 2002, the three primary U.S. endocrine societies—the American Association of Clinical Endocrinologists (AACE), The Endocrine Society (TES), and the American Thyroid Association (ATA)—sponsored a consensus panel with the U.S. Preventive Services Task Force (USPSTF) to create guidelines that would help clinicians determine what tests to obtain to diagnose subclinical thyroid disease, when to treat patients, and how to determine if test results were abnormal. The panel reported its findings in the Journal of the American Medical Association (JAMA) in the Jan. 14, 2004 issue, but there was dissension among the consensus panel from the AACE, TES, and ATA.

Based on a review of evidence-based medicine, the consensus panel stated that there was insufficient evidence to support population-based screening, especially given that the consequences of this disease are minimal. The panel also recommended only treating patients who were pregnant, planning a pregnancy, or had TSH levels below 0.1 mIU/L or above 10 mIU/L with levothyroxine. Patients with TSH levels outside of these limits have a greater potential of developing clinical thyroid disease.

“What they published independently was not in agreement with what we believe were in the best interest of patients,” said Hossein Gharib, MD, MACE, Past AACE President and Professor of Medicine at the Mayo Clinic College of Medicine (Rochester, Minn.). Gharib headed up a panel of AACE, ATA, and TES representatives that published clinical-based guidelines in the Jan. 24, 2005, issue of the Journal of Clinical Endocrinology and Metabolism (JCEM) in support of routine screening for subclinical thyroid disease. The JCEM article also stated that the endocrinology groups support routine screening of women who are pregnant or planning on becoming pregnant and routine treatment of subclinical hypothyroidism patients with TSH levels of 4.5-10 mIU/L.

“The point of contention was primarily on evidence-based medicine,” he explained. “The consensus panel formed their recommendations primarily, but not exclusively, on evidence-based medicine…They said that if there’s not enough evidence on whether to treat or not to treat, then let’s not treat. We say if there’s not enough evidence either way, we prefer to treat patients. We think that is a safer way to do business.”

Pathology Perspective

It’s unlikely that these new guidelines will cause a spike in the number of thyroid tests ordered, and the emphasis will remain on the clinician’s assessment of the patient’s symptoms, explained Laurence M. Demers, MD, Professor of Pathology and Medicine at the Pennsylvania State University College of Medicine, M.S. Hershey Medical Center in Hershey, Pa.

“It’s really up to the clinician,” he said. “If the patient presents with a constellation of symptoms that would be suggestive of subclinical hypothyroidism, then they can order a thyroid test for that patient.” If the test comes back indicating that the patient’s TSH level is greater than 10 mIU/L, the clinician is going to treat them, regardless of the guidelines set forth by the USPSTF.

The focus needs to be on the reference ranges indicated by both sets of guidelines, added Demers, who predicted that clinicians and laboratorians are going to be looking more closely at these thyroid tests and their reference ranges to determine the proper cutoff that defines true normal and abnormal ranges. Currently, the normal reference range for TSH used by clinicians is 0.45 to 4.12 mIU/L, based on results from the 2002’s third National Health and Nutrition Examination Study (NHANES III). “Who’s to say that 4.5 is abnormal? Who’s to say that 4 is normal? I don’t think there has been a good study done to really look at a true normal population to determine what the reference ranges should be as opposed to where they are now,” he said.

One way to determine a true normal range for TSH would be to do additional tests, such as assays for antithyroid peroxidase antibody (anti-TPO Ab) levels, to gather additional confirmatory data on normal and abnormal reference ranges. For instance, approximately 4% of the population has elevated anti-TPO antibody levels. “You have to ask yourself if these people are really normal,” said Demers. “They have no symptoms, therefore it’s going to put a lot more pressure on the clinical lab to have a test that is accurate and precise, particularly at the decision zones when results are determined to be normal or abnormal.”

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