Assessment of thyroid function in intensive care unit patients by liquid chromatography tandem mass spectrometry methods☆,☆☆
Introduction
Hospitalized patients suffer from a number of medical conditions and receive many medications that cause typical changes in thyroid function tests. These changes are referred to as “non-thyroidal illness” or the “euthyroid sick syndrome.” Patients with non-thyroidal illness are reported to have decreased total 3,5,5′-triidothyronine (TT3) and free 3,5,5′-triidothyronine (FT3), increased reverse 3,5,5′-triidothyronine (rT3), and may have normal or decreased total thyroxine (TT4) and free thyroxine (FT4) [1] when measured by immunoassay. Thyroid stimulating hormone (TSH) is usually normal, and thus these patients are considered “euthyroid.” These changes in thyroid status are reported to occur in over 70% of hospitalized patients [1]. The marked abnormalities in thyroid hormone tests that occur in non-thyroidal illness are generally considered to reflect a response to systemic illness rather than clinical thyroid dysfunction, and treatment with thyroid hormone is currently not recommended by most Endocrinology organizations including the American Thyroid Association [2], [3]. Furthermore, routine testing for thyroid function in hospitalized patient in the absence of suspected thyroid disease is not recommended by most guidelines.
Thyroid hormones are measured by automated immunoassay platforms in the majority of clinical laboratories. However, a number of studies have shown discrepancies in free and total thyroid hormone measurement by immunoassay when compared to a reference method such as liquid chromatography-tandem mass spectrometry (LC-MSMS) in several populations (reviewed in [4], [5]). Multiple studies have shown falsely normal values for TT3, FT3, and FT4 by immunoassays that are below the reference interval when measured by reference LC-MSMS in a number of patient populations [3], [6], [7], [8]. Furthermore, several disease and physiologic conditions are known to cause interference in thyroid hormone measurement by immunoassay. Specifically, changes in the thyroid hormone binding proteins thyroxine-binding globulin (TBG) and albumin that occur in a number of conditions cause unreliable immunoassay free thyroid hormone measurements [9], [10]. Many commonly used drugs such as heparin, furosemide, anti-epileptics, and salicylates displace thyroid hormone binding from serum proteins [11], [12], [13]; immunoassays that use a dilution step cause a reduction in competing drugs, resulting in increased in vitro free thyroid hormone binding to proteins and a falsely decreased measure of free thyroid hormone [4]. Hospitalized patients, especially those in intensive care units (ICU), have a number of conditions that cause low protein states and are frequently on a large number of medications known to cause artifactual values in thyroid hormone assays. Thus, it is not clear if the abnormalities seen in non-thyroidal illness reflect physiologic conditions or if they are at least partially artifact due to analytical issues.
To our knowledge, no study has extensively studied thyroid hormone measurement by gold standard, validated LC-MSMS methods in a population of ICU patients. This study evaluates plasma FT3, FT4, TT3, TT4, and rT3 determined by reference method LC-MSMS in a cohort entirely of ICU patients. The results are further compared to a common automated immunoassay platform. Marked discrepancies were found by the immunoassay method in this population with multiple medical comorbidities, low binding proteins, and on multiple medications. These results have important implications for clinical studies evaluating patients with non-thyroidal illness syndrome.
Section snippets
Patient population
The Clinical Center at the National Institutes of Health is a 200 bed research facility. Fifty patients were selected from the ICU who were hospitalized for at least seven days between May 2016–July 2016. Patients were excluded if they had known thyroid disease, were receiving thyroid hormone replacement therapy, or if they were positive for anti-thyroperoxidase antibodies. Clinical characteristics including demographics, length of hospitalization, mortality, and number of medications were
Results
Characteristics of the patient population are shown in Table 1. The patient age range was 21–74 years, and 18.0% of patients died in the hospital. Length of hospitalization ranged from 7 to 252 days. Medical comorbidities were frequent, and the majority of patients were on substantial numbers of medications, ranging from 3 to 27. Decreases in binding proteins were found in most patients; 34/50 patients (68%) had albumin levels below the reference interval (3.5–5.0 g/dL) and 16/50 (32%) had
Discussion
Marked discrepancies in both total and free thyroid hormones were identified using a common automated immunoassay platform compared to LC-MSMS, a reference method. Total thyroid hormones were lower when measured by LC-MSMS; however, FT4 was more likely to be normal or elevated compared to immunoassay. Accurate measurement of thyroid hormones is essential for the identification of patients with undiagnosed thyroid disease superimposed on non-thyroidal illness syndrome as well as studies
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2020, Annales d'EndocrinologieCitation Excerpt :However, technically, this assay is not free of difficulties because of its dependence on, often unknown, quantitative and qualitative variations of its binding proteins. This is, for example, observable in the intensive care unit where the free thyroxine assay after ultrafiltration and LCMS shows double concentrations compared to an unbiased immunoassay for non-ICU subjects [29]. In addition, the correlation between thyroxine immunoassays and ultrafiltration and LCMS assay worsens for concentrations moving away from baseline values, where, however, analytical precision is important [30].
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Declaration of interests: The authors have no conflicts of interest that could be perceived as prejudicing the impartiality of the research reported.
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The authors are supported by the National Institutes of Health Intramural Research Award.