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Reading TSH Reports Accurately

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.

ASK THE FOLLOWING QUESTIONS

Could this be due to diurnal variations in TSH levels?
Could diet, on-going medications or supplements be the cause of this result?
Is it a case of subclinical hypothyroidism?
Is it because of the difference in the testing platforms between the two labs?

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.

WHY THE ROCHE COBAS PLATFORM, USED AT SUBURBAN DIAGNOSTICS IS MOST SUITED, FOR DETECTING SUBCLINICAL HYPOTHYROIDISM?

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.

Why subclinical hypothyroidism matters?

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

What’s the next recommended step in lab testing, if the report indicates 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).

Why a TSH test done at Suburban Diagnostics is more accurate in diagnosing subclinical hypothyroidism?

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.

Why is it beneficial to test TSH values on the CLIA platform as done by Suburban Diagnostics?

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)

What other factors should you consider, before interpreting a TSH result? Let’s take a closer look at commonly known causes that bring about changes in TSH levels

Causes of variation:

TSH levels exhibit a diurnal variation with the peak occurring during the night and the levels deplete to approximate 50% of the peak value, between 10.00am to 4.00pm in the day
TSH reference interval widens to 0.1-20 µIU/mL; in central hypothyroidism.(Central hypothyroidism refers to thyroid hormone deficiency due to a disorder of the pituitary, hypothalamus, or hypothalamic-pituitary portal circulation)
Very slight changes in the concentrations of free thyroid hormones bring about much greater opposite changes in the TSH levels
Physiologically TSH rises in colder months and drops in warmer months
High fibre diet reduces the ability to absorb thyroid medications, hence variation in TSH results
Variation/erratic time of taking medications can affect TSH levels
Co-ingestion of calcium supplements with thyroid medication causes TSH to rise
Intense surge in estrogen during early pregnancy can increase TSH
TSH levels decline in the first trimester when serum HCG levels are high and rise after 10-12 week of gestation
Serum TSH may be slightly higher in obesity and may be reduced after weight loss

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.