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Thyroid function tests are a critical tool in diagnosing and managing hypothyroidism. However, various factors can influence these tests, including the all-too-common presence of heterophile antibodies. These antibodies can lead to inaccurate results and potentially inappropriate treatment decisions for your underactive thyroid. In this article, we’ll look at heterophile antibodies and how they can affect your thyroid tests.

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Heterophile antibodies are weak antibodies that target multiple external antigens or allergens. About 30 to 40% of the general population has heterophile antibodies. A substantial percentage of heterophile antibodies are caused by Epstein-Barr infection. These antibodies are present in about 30-40% of the general population. Heterophile antibodies are produced in response to certain viral infections, with the most common cause being the Epstein-Barr virus (EBV), which leads to infectious mononucleosis. Other viruses, including Cytomegalovirus (CMV) and hepatitis E, can also cause heterophile antibodies to develop.

Heterophile antibodies can interfere with a wide range of laboratory tests, leading to false results that can potentially mislead clinical diagnoses and treatments. This process -- called assay interference -- can cause false elevation or, less commonly, false reduction of values in various tests.

Some of the medical tests that can be affected by heterophile antibodies include:

• Sandwich Immunoassays: Heterophile antibodies can cause false-negative and false-positive results for Follicle Stimulating Hormone (FSH), Luteinizing Hormone (LH), Prolactin, Thyroid Stimulating Hormone (TSH), Ferritin, and several other specialized tests.
• Thyroglobulin Levels: False lowering of thyroglobulin levels may occur due to the presence of heterophile antibodies.
• Endocrine Tests: These heterophilic antibodies can interfere with endocrine tests, leading to false results that can misguide the diagnosis and treatment of endocrine disorders.
• Tumor Marker Tests: Heterophile antibodies can cause false elevation of tumor markers, potentially leading to incorrect diagnoses of cancer or inaccurate monitoring of cancer progression[1].
• Cardiac Injury Marker Tests: Heterophile antibodies can falsely elevate cardiac injury markers, potentially leading to misdiagnosis of heart conditions.
• Drug Level Tests: These antibodies can affect the accuracy of drug level tests, potentially leading to incorrect assessments of medication effectiveness or toxicity.
• Serum Cortisol Levels: Heterophile antibodies can cause tests to show low serum cortisol levels, potentially leading to incorrect diagnosis of hypothalamic-pituitary-adrenal axis insufficiency and inappropriate and possibly harmful replacement with steroid drugs.
• Steroid Hormones and Digoxin: Heterophile antibodies can interfere with these assays, causing false results.

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The presence of heterophile antibodies can cause false measurements of TSH, Free Thyroxine (Free T4), and Free Triiodothyronine (Free T3). The impact can be significant and may lead to misdiagnosis and inappropriate treatment. Specifically, the following tests can be affected:

Falsely high TSH levels: Heterophile antibodies that artificially increase TSH levels can lead to a potential misdiagnosis of hypothyroidism.

Falsely low TSH levels: In some cases, negative interference from heterophile antibodies can lead to artificially low TSH levels, potentially resulting in a misdiagnosis of hyperthyroidism.

Inaccurate free thyroxine (T4) and free triiodothyronine (T3) measurements: The presence of heterophile antibodies can also cause falsely high or low measurements of Free T4 and Free T3, further complicating the assessment of thyroid function.

The impact of heterophile antibodies on thyroid function tests can be significant, potentially leading to misdiagnosis and inappropriate treatment. For instance, a patient’s thyroid function measurements may appear abnormal despite the absence of clinical symptoms, leading to unnecessary investigation and potentially incorrect treatment. Similarly, levels may appear normal when they are actually low or elevated and require changes to the treatment.

Your thyroid practitioners need to be aware of this possible interference, especially when the results of thyroid function tests don’t match a patient’s clinical signs and symptoms of thyroid dysfunction.

In one case from the medical literature, a patient was receiving higher-dose treatment to suppress thyroid levels after thyroid cancer surgery. The patient had elevated TSH levels, indicating that the levels were not suppressed. However, after the samples were pretreated with a heterophilic antibody blocker, the TSH measurements showed significant decreases, confirming that heterophile antibodies in the patient samples interfered with accurate TSH measurements.

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The diagnosis of heterophile antibody interference in thyroid testing can be challenging. There are no physical symptoms. Instead, this situation is typically identified when test results don’t correlate to your clinical signs and symptoms.

When there is a high degree of suspicion, this is followed by careful evaluation of the clinical and laboratory data. Several approaches can be used to assess the potential for heterophile antibody interference in thyroid testing.

Clinical presentation

Practitioners need to carefully evaluate the patient’s clinical presentation and symptoms as they relate to the thyroid function test results. When there’s a mismatch between the clinical findings and the biomarkers -- such as abnormal thyroid function test results without any corresponding symptoms -- a practitioner should suspect the possibility that heterophile antibodies are interfering with the assay.

Laboratory evaluation

Laboratory professionals can use several techniques to assess the potential for heterophile antibody interference. This may include using heterophile antibody blocking tubes and conducting parallel testing on different platforms to identify discrepancies that could indicate interference.

Heterophile antibody testing

In some cases, direct testing for heterophile antibodies may be warranted. This can involve specific assays designed to detect the presence of heterophile antibodies in the patient’s blood, providing direct evidence of their potential to interfere with laboratory tests.

Interestingly, some of the most common heterophile antibodies are produced by the immune system in response to Epstein-Barr virus (EBV) infection, the virus that causes mononucleosis. One way to determine if you have this type of heterophile antibodies is a Monospot test. This test, also known as the heterophile antibody test, is a common way to detect EBV-related heterophile antibodies (as well as diagnose mononucleosis.) Note, however, that there are many other heterophile antibodies apart from those triggered by EBV, and this test doesn’t detect them.

By carefully evaluating the patient’s clinical presentation, evaluating the existing laboratory results, and considering the potential for heterophile antibody interference, practitioners can work to ensure the accuracy and reliability of thyroid function test results.

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Once the potential for heterophile antibody interference in thyroid function tests is identified, it is essential to correlate this information with the patient’s clinical history and other laboratory test results. This integrated approach can help ensure that further testing or treatment decisions are based on a comprehensive understanding of the patient’s unique circumstances.

Several methods can be used to address this heterophile antibody interference and get more accurate thyroid test results. These include:

• Pretreating samples with heterophilic antibody blockers.
• Sample dilution
• Using alternative analytical platforms to confirm the differences in results

If your practitioner suspects heterophile antibodies are affecting your thyroid test results, they can determine the best way to ensure that testing assesses your actual thyroid values.

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As discussed, both practitioners and patients need to be aware of the potential for heterophile antibodies to interfere with TSH, Free T4, and Free T3 thyroid function tests, particularly when the results of thyroid function tests do not fit the patient’s clinical signs and symptoms. Results may be misleading in the presence of heterophile antibodies, which can complicate diagnosis and treatment decisions.

Becoming a Paloma Health member can significantly improve the entire diagnosis and treatment process for your hypothyroidism. Paloma Health offers a patient-centered approach, providing access to a dedicated care team of practitioners specializing in hypothyroidism. The team works collaboratively to oversee and interpret your thyroid function testing, ensuring a comprehensive understanding of your condition. By leveraging advanced technology, such as at-home thyroid test kits and telemedicine appointments, Paloma Health streamlines the process of monitoring and managing your hypothyroidism, allowing for more frequent and convenient interactions with your thyroid care professionals. The comprehensive support and resources offered by Paloma Health empower you to take a more active role in your care and experience improved outcomes in treating your hypothyroidism.