Global FT4 immunoassay standardization: an expert opinion review

Kratzsch, Juergen; Baumann, N; Ceriotti, Ferruccio; Lu, Zhong X.; Schott, M.; Herwaarden, Antonius E. van; Vieira, José Gilberto H.; Kasapic, Dusanka; Giovanella, Luca

doi:10.1515/cclm-2020-1696

Cited by 14 publications

(5 citation statements)

References 46 publications

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“…Standardization will improve the comparability of the fT4 assays enabling worldwide generalized reference intervals, will improve interpretation and will prevent miscommunication regarding fT4 results. However, there are other methodological quality aspects (like matrix effects in a pregnant population as demonstrated in this study) that need to be addressed in addition to implementation of standardization 29 . Although less than in healthy controls, most IAs measured significantly lower fT4 concentrations in serum of pregnant women compared to the LC-MS/MS as well.…”

Section: Discussionmentioning

confidence: 99%

Pregnancy disrupts the accuracy of automated fT4 immunoassays

Jansen

Herwaarden

Huijgen

et al. 2022

European Thyroid Journal

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Objective: Thyroid hormone measurements are often performed in pregnant women, as hypo- and hyperthyroidism during pregnancy can severely affect the fetus. Serum free thyroxine (fT4) measurements are well known for their analytical challenges, due to low serum concentrations and the subtle equilibrium between free and bound T4 (to thyroid-binding globulin (TBG), transthyretin and albumin). Pregnant women have high TBG concentrations due to an increase in human chorionic gonadotropin (hCG) and estrogen and lower albumin concentrations which changes the equilibrium and may affect the validity of fT4 measurements in their samples. As accurate serum fT4 measurements in pregnant women are important for the long-term health of the fetus, we aimed to evaluate the accuracy of several fT4 immunoassays in serum of pregnant women. Methods: FT4 was measured in healthy controls and pregnant women using a candidate-reference method (LC-MS/MS) and 5 commercially available automated immunoassays (Alinity (Abbott), Atellica (Siemens), Cobas (Roche), Lumipulse (Fujirebio) and UniCel DXI (Beckman Coulter)). Method comparisons (Bland Altman plots and Passing and Bablok analyses) were performed. Results: Serum samples from both healthy controls (n=30) and pregnant women (n=30; mean gestational age 24.8 weeks) were collected. The fT4 immunoassays deviated +7 to +29% more from the LC-MS/MS in serum samples of pregnant women vs healthy controls (falsely high). Conclusions: Our results indicate that immunoassays overestimate fT4 in pregnant women, which might lead to an overestimation of thyroid status. Physicians and laboratory specialists should be aware of this phenomenon to avoid drawing false conclusions about thyroid function in pregnant women.

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Section: Discussionmentioning

confidence: 99%

Pregnancy disrupts the accuracy of automated fT4 immunoassays

Jansen

Herwaarden

Huijgen

et al. 2022

European Thyroid Journal

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“…Another pitfall that should be acknowledged is that not all groups benefit from using the same TSH and FT4 reference intervals. Clinical studies in euthyroid patients using L-T4 showed that FT4 concentrations in this group are significantly higher, and more often above the upper reference interval, than in non L-T4 treated people (32,48,49) indicating that in this group a higher upper reference limit may apply. In addition, FT3 concentrations and FT3/ FT4 ratios are lower in this group compared to non-L-T4 users, a finding probably more outspoken in athyreotic patients due to the absence of any endogenous T3 production.…”

Section: Pitfalls Of Biochemical Measurements In Primary (Subclinical...mentioning

confidence: 76%

Hypothyroidism: The difficulty in attributing symptoms to their underlying cause

et al. 2023

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Common symptoms of overt hypothyroidism are non-specific and include fatigue, lethargy, and dry skin. Although the diagnosis is considered to be straightforward, no single symptom can be used to identify patients with overt hypothyroidism, while many patients with subclinical hypothyroidism are asymptomatic. A large population-based study on the spectrum of symptoms in subclinical hypothyroidism showed similar rates of thyroid disease-related symptoms compared with euthyroid subjects, while the TSH concentration had no impact on symptom score. Together, these findings make it challenging to attribute symptoms to their underlying cause. This is also true in the case of unexplained persistent symptoms in levothyroxine-treated patients. Although generally considered a life-long replacement therapy, successful thyroid hormone discontinuation resulting in euthyroidism has been reported in approximately one third of patients. Thus, we overtreat patients with (subclinical) hypothyroidism, highlighting the importance of reliable diagnostic criteria. The diagnostic process, including the implementation of robust TSH and FT4 reference intervals, is especially challenging in specific situations including aging, pregnancy, non-thyroidal illness, and central hypothyroidism. There is a clear need for improved adherence to current guidelines from scientific societies and for willingness to manage symptoms without a clear pathological correlate, especially in the case of mild TSH elevations. This review will highlight recent literature on this topic and offers some practice points.

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“…The international federation of clinical chemistry and laboratory medicine (IFCC) committee for standardization of thyroid function tests (C-STFT) has attempted to harmonize commercially available TSH immunoassays and also to standardize free thyroxine measurements in order to enable manufacturers to achieve more uniform reference intervals [43,44]. Current FT4 immunoassays vary in their sensitivity to alterations in binding proteins that occur during pregnancy and re-establishment of trimester-and method-specific reference intervals is crucial for the successful implementation of standardized FT4 testing [45]. Recently in Japan the coefficients were determined for each of the TSH assay kits from 10 manufacturers who participated in the TSH harmonization study using healthy Japanese adults except pregnant or lactating women [46,47].…”

Section: Discussionmentioning

confidence: 99%

Gestational trimester-specific reference ranges for serum thyrotropin and free thyroxine in Japanese

et al. 2022

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Thyroid diseases in pregnant and lactating women may result in adverse outcomes for both mothers and infants. A reference range for thyroid function is required in different areas; however, few studies on the gestational change or reference ranges of thyrotropin (TSH) and free thyroxine (FT4) concentrations for Japanese pregnant women have been reported. To establish the gestational trimester-specific reference ranges of serum TSH and FT4 concentrations, our previously published data on 481 pregnant women with the mean age of 30.8 years who provided serum samples as early as gestational week (GW) 6 was compiled by using their percentile values. The overall median urinary iodine concentration (UIC) during pregnancy was 201 μg/L suggesting adequate iodine intake. The prevalence of positive serum thyroid autoantibody (ThAb), i.e., antithyroid peroxidase antibody (TPOAb) and antithyroglobulin antibody (TgAb), was 11.4%. The reference ranges (2.5-97.5th percentile) of serum TSH and FT4 concentration calculated for samples with negative TgAb and TPOAb were 0.04-6.06 mIU/L in the first trimester (T1), 0.31-3.11 mIU/L in the second trimester (T2) and 0.48-3.93 mIU/L in the third trimester (T3) for TSH, and 1.10-1.87 ng/dL (T1), 0.76-1.56 ng/dL (T2) and 0.76-1.14 ng/dL (T3) for FT4. Compared to published data around the world in the 2017 American Thyroid Association (ATA) guideline, both the upper and lower limits of our TSH and FT4 reference ranges in the first trimester were higher than those in other countries. Further research is necessary in larger samples.

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Global FT4 immunoassay standardization: an expert opinion review

Cited by 14 publications

References 46 publications

Pregnancy disrupts the accuracy of automated fT4 immunoassays

Pregnancy disrupts the accuracy of automated fT4 immunoassays

Hypothyroidism: The difficulty in attributing symptoms to their underlying cause

Gestational trimester-specific reference ranges for serum thyrotropin and free thyroxine in Japanese

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