VARIATIONS IN TSH: A CASE STUDY

Patient Details: 29 year-old female, from Mumbai.

Medical History: No major systemic disorder, healthy patient.

Clinical presentation: The patient presented to her family physician to get basic lab tests done as she wanted to conceive shortly and evaluate her fitness.

Clinical Action: The doctor ordered basic blood tests. In particular, the doctor was keen to assess thyroid function prior to conception. Thyroid assessment was also done as it is a key parameter for women who want to conceive.

Tests done: CBC, LFT, Blood sugar, HbA1c, AMH, urinalysis and lipid profile. Thyroid tests included free T3/T4 and TSH. She gave the sample for TSH testing at one of our centres in the morning.

Results: We performed TSH testing on the CLIA platform. The patient’s result was 7.6 microIU/mL and reported as elevated as per the reference range of the CLIA platform. No other tests showed any derangements.

Clinical Problem: As the patient did not have any symptoms, the clinician was not sure whether the TSH result was correct. The same patients, 2 days later, gave another sample for TSH testing at another lab. The sample was given in the evening. The other lab performed the test by the CMIA method. As per that platform, the patient was reported to have a normal TSH level with a value of 4.5 microIU/mL.

Clinical Question: The clinician and the patient were confused and did not know which report to consider true and correct as there was a 40% difference in the TSH values between the 2 reports.

Points to Note: The patient gave samples for TSH testing in the two labs at different times of the day (morning and evening). Besides, the second sample was given two days later. Both labs used a different method to test TSH levels. Diurnal variations can cause large fluctuations in TSH levels. So also, different platforms that labs use for testing TSH can cause wide variations in the result.

Let’s delve deeper to precisely understand the reasons for TSH variations and why is it that a large number of hypothyroid patients may actually have elevated TSH and not show any apparent features

UNDERSTANDING TSH VARIATION AND THE TREATMENT ALGORITHM FOR SUBCLINICAL HYPOTHYROIDISM

CAUTION – VARIATIONS IN THYROID STIMULATING HORMONE CAN MISLEAD DIAGNOSIS!!

In the context of the clinical and laboratory diagnosis of hypothyroidism, the frequent variations that occur in the levels of TSH need to be factored in.

Biological rhythm, weather, medications, diet, alcohol, other associated disorders and stress are among the many extraneous factors that can significantly alter TSH levels
The diagnosis of hypo and hyperthyroidism cannot solely depend upon TSH levels. Testing also needs to be performed for T3, T4 and other metabolic parameters for a conclusive diagnosis
The lab profile of the patient needs to be accurately correlated with clinical features and with history – in order to arrive at a conclusive diagnosis

Ref: Biological Variation: From Principles to Practice-Callum G Fraser (AACC Press)

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 am to 4 pm in the day. (TSH measurement, Review paper, Medscape at http://www.medscape.com/viewarticle/452667_4 )
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)(Indian J Clin Biochem. 2014 Apr; 29(2): 189–195)
Very slight changes in the concentrations of free thyroid hormones bring about much greater opposite changes in the TSH levels (Surks MI, Chopra IJ, Mariash CN, et al. American Thyroid Association Guidelines for the Use of Laboratory Tests in Thyroid Disorders. JAMA 1990;263:1529-1532)
Physiologically TSH rises in colder months and drops in warmer months (http://www.thyroidinfo.com/articles/tsh-fluctuating.htm)
High fibre diet reduces the ability to absorb thyroid medications, hence variation in TSH results (http://www.apiindia.org/pdf/medicine_update_2005/ch apter_63.pdf)
Variation/erratic time of taking medications can affect TSH levels Co-ingestion of calcium supplements with thyroid medication causes TSH to rise (http://www.apiindia.org/pdf/medicine_update_2005/ch apter_63.pdf)
Intense surge in estrogen during early pregnancy can increase TSH (http://www.apiindia.org/pdf/medicine_update_2005/ch apter_63.pdf)
TSH levels decline in the first trimester when serum HCG levels are high and rise after 10-12 weeks of gestation (MolsheHod et al. Textbook of Diabetes and Pregnancy, Third Ed)
Serum TSH may be slightly higher in obesity and may be reduced after weight loss (Indian J EndocrinolMetab. 2016 Jul-Aug; 20(4): 554–557)

Inter-Instrument Variation:

At Suburban Diagnostics, we report TSH values by the Chemiluminescence Immunoassay (CLIA). The other commonly used methodology is Chemiluminescent Microparticle Immunoassay (CMIA).

What are the reference ranges of the CLIA and CMIA platforms used for measuring TSH?

CLIA reference range for TSH (0.27–4.20 µIU/mL) is actually on the narrower side than the range of the CMIA assay (0.35–4.94 µIU/mL) Indian J Clin Biochem 2014 Apr; 29(2): 189–195 (Note: The lab uses its own derived ranges)

Why do the CLIA and CMIA platforms have different reference ranges?

The CLIA platform used at Suburban diagnosticsis based on a 95% central interval limit which means that while determining the biological reference range for this assay, 95% central values of the general population were taken into consideration – excluding 2.5% values at the bottom and 2.5% values at the top of the range, from the general population.

This is the central interval limit recommended by the regulating authority – Clinical Laboratory Standards Institute (CLSI)

On the other hand, the CMIA platform is based on a 99% central interval which means that while determining the biological reference range for this assay, 99% central values of the general population were taken into consideration – excluding 0.5% values at the bottom and 0.5% values at the top of the range, from the general population.

Ref: Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory, 3rd Edition

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)

HOW TO INTERPRET TSH VALUES FOR DIAGNOSING AND MANAGING SUBCLINICAL HYPOTHYROIDISM?

TREATMENT ALGORITHM FOR SUBCLINICAL HYPOTHYROIDISM

Ref: Harrison – Textbook of Medicine 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.