The Diagnosis and Management of Subclinical Hypothyroidism Is Assay-Dependent

Implications for Clinical Practice

Tejas Kalaria; Anna Sanders; Jonathan Fenn; Helen L. Ashby; Pervaz Mohammed; Harit N. Buch; Clare Ford; Rousseau Gama


Clin Endocrinol. 2021;94(6):1012-1016. 

In This Article


Subclinical hypothyroidism (SCH), which indicates mild to moderate thyroid failure, is defined as a serum thyroid-stimulating hormone (TSH) level above the upper reference limit with a normal level of serum free thyroxine (fT4).[1] SCH is common affecting up to 10% of the population,[1] and 90% of patients with SCH have a TSH less than 10 mIU/L.[2] In 60% patients with SCH, TSH returns to within the reference range when the initial TSH is <10 mIU/L, whereas progression to overt hypothyroidism is 2% to 4% per annum, particularly in patients who have thyroid peroxidase antibodies.[1] Guidelines recommend regular monitoring of thyroid function and consideration for levothyroxine replacement if the patient is symptomatic or if the TSH is ≥10 mIU/L irrespective of symptoms.[2–4]

Different physiological and pathological factors affecting TSH result, such as age, are often considered while interpreting the results[5] but not usually any assay-related differences. Variations between assays and their reference ranges are well recognized including those pertaining to TSH and fT4 assays.[6–8] Understanding of impact, however, of these differences in the diagnosis and clinical management of SCH is limited[8] and not considered in clinical guidelines of thyroid disorders.[2–4,9] Over-diagnosis of SCH, in addition to causing patient anxiety, would incur unnecessary expenditure by generating thyroid peroxidase antibody test requests and periodic follow-ups and could lead to inappropriate treatment.[2–4] On the other hand, under-diagnosis of SCH would delay treatment in symptomatic patients and would also potentially delay the identification of progression from SCH to overt hypothyroidism.

The International Federation of Clinical Chemistry (IFCC) working group for the standardization of thyroid function tests (C-STFT) has been working for over a decade to reduce between-method variability for thyroid assays.[7,10] This led to the development of conventional reference measurement procedure for fT4 based on equilibrium dialysis isotope dilution-liquid chromatography-tandem mass spectrometry.[11] However, compared to the automated immunoassays, measurement of fT4 by mass spectrometry has many limitations; labour-intensive manual processing, slow throughput, delay in availability of results, high cost and often less precision compared to immunoassays. Currently, therefore, immunoassay is preferred over mass spectrometry by most clinical laboratories for a high-volume test like fT4 where clinicians often expect results in real time. Whereas for TSH, C-STFT opted for statistical harmonization of immunoassays since it was considered unlikely that a reference measurement procedure would be available soon.[10,12]

TSH and fT4 immunoassays manufactured by Roche Diagnostics and Abbott Laboratories are commonly used since nearly 75% of clinical laboratories in the UK provide thyroid results based on these two analytical platforms[13] largely due to overall performance, cost, efficiency, throughput, scalability and manufacturer reputation. In our regional pathology network of five hospitals, two provide thyroid tests using Roche assays and three using Abbott assays. Since differences between Roche and Abbott TSH assays have been reported,[8] we assessed commutativity of Roche and Abbott TSH and fT4 assays in the diagnosis of SCH and its management.