If you see a TSH report showing elevation and the patient shows no apparent symptoms and T3/T4 is normal, please do not ignore the case or regard it as a false TSH elevation or a wrong report, especially if another lab gives a normal result.
Over the years, thyroid testing has greatly evolved. The history of thyroid testing can be traced back to the era of Enzyme based mmunoassay (EIA), Radioimmunoassay (RIA), followed by immunometric assay (IMA); to the more recent Chemiluminiscence immunoassays (CLIA), its more advanced form electro Chemiluminiscence immunoassays (eCLIA) and the state-of-the-art LC-MS.
As a large diagnostic lab, we are spoilt for choices as far as the selection of a technology platform for one of our testing procedures is concerned, especially when it comes to a routinely and commonly ordered test like thyroid.
At Suburban Diagnostics, we perform around 1 lakh TSH tests per year. Hence, we wanted to select the best platform for testing of thyroid disorders, in the interest of our clinicians and patients. After a series of discussions with our internal and external thought leaders, we chose the Roche Cobas platform for thyroid testing at Suburban Diagnostics.
The Hypothalamic Pituitary Axis Operates via a well-established Negative Feedback Loop
Thyroid disorders affect millions of people worldwide. Thyroid gland produces the hormones thyroxine (T4) and triiodothyronine (T3). T4 is peripherally converted to T3 by deiodinases. Hypothalamic thyrotropin releasing hormone (TRH) stimulates pituitary production of thyroid stimulating hormone (TSH), which, in turn, stimulates thyroid hormone synthesis and secretion. Thyroid hormones act via negative feedback to inhibit TRH and TSH production.
Subclinical hypothyroidism is characterized by a serum TSH above the upper reference limit along with a normal free T4 (Garber, et al., 2012). Though called subclinical, some patients may have minor symptoms. This is a phase of compensation wherein as the thyroid function is reduced, normal thyroid hormone levels are maintained by a rise in TSH (Jameson, et al., 2014).
Later, free T4 levels fall and TSH levels rise further; symptoms become more readily apparent at this stage (usually TSH >10 mIU/L), which is referred to as clinical or overt hypothyroidism (Jameson, et al., 2014).
In India, up to 20% hypothyroid patients are estimated to have subclinical hypothyroidism whereas the prevalence of overt hypothyroidism is about 3.5-4% (Kalra, et al., 2015).
Hence, if you see a TSH report showing elevation and the patient shows no apparent symptoms and T3/T4 is normal, please do not ignore the case or regard it as a false TSH elevation or a wrong report.
It could well be a case of subclinical hypothyroidism
If TSH is high, T3/T4 normal, the next step recommended by American Association of Clinical Endocrinologists and the American Thyroid Association guidelines is to check for anti-thyroid antibody titres, anti-thyroglobulin antibodies (TgAb) and anti-thyroid peroxidase antibodies (TPOAb) Consider the algorithm below
In patients with subclinical hypothyroidism, those with elevated TPOAb progress to overt hypothyroidism at a faster rate of 4.3% per year compared to 2.6% per year in those without elevated TPOAb titers (Garber, et al., 2012).
This higher risk of developing overt hypothyroid¬ism in TPOAb-positive patients has prompted several professional societies to recommend measurement of TPOAbs in those with subclinical hypothyroidism (Garber, et al., 2012).
At Suburban we use the Roche platform for performing thyroid function tests. The assay performed on this platform is based on the Chemiluminiscence Immunoassay (CLIA) method.
This platform and method is based on what is called as 95% central interval limit. This simply means that while developing the reference range for this assay, values of 95% of the general population were taken into account. This, in turn means, that values falling beyond this 95% interval are reported as abnormal or deranged on this assay.
However, platforms used by other labs, use platforms that consider 99% values of the general population as normal and report only 1% of the values as abnormal (method used, Chemiluminiscence microparticle immunoassay or CMIA). Hence, as the normal range for the other assays is large, they may end up missing a case of subclinical hypothyroidism. On the other hand, due to a smaller normal range, the Roche based assay at Suburban Diagnostics can pick up a greater number of subclinical cases.
The CLIA platform has a narrower reference range as compared to the CMIA platform (95% central interval of CLIA versus 99% of CMIA).
As a result, a certain proportion of patients which are shown to have abnormal values by the CLIA method at Suburban, could be reported as normal by the CMIA method (due to difference in reference intervals)
This subgroup of subclinical hypothyroid patients (laboratory evidence of hypothyroidism with no apparent symptoms) which actually has deranged TSH, gets reported as normal on the CMIA method and goes undetected
Consequently, no follow-up is done for these patients. Over time, these patients could worsen and move from subclinical hypothyroidism to overt disease
Had the same patients been tested on the CLIA platform as done at Suburban Diagnostics, these patients would be reported to have deranged TSH and would have received follow-up and monitoring
Treatment is necessary only when elevations above 10 mU/L are sustained over a 3-month period. (Harrison, Textbook of Medicine)
In conclusion, timely identification of the patients of subclinical hypothyroidism and knowledge of their antithyroid antibody status is important, in view of the high probability of progression to overt hypothyroidism.
Once identified, making the right decision as to treatment or follow up is imperative. It is important to bear in mind that repeated measurements of TSH over weeks are essential to establish a diagnosis of subclinical hypothyroidism due to an array of causes leading to transient elevations.
As per recommendations, treatment need not be initiated if TSH levels are below 10 mU/L Any elevations above this level can be considered for treatment. However, lab-based evidence of such elevations above 10 mU/L, sustained for at least a period of 3 months; should be available before treatment is begun.