What are the optimal TSH ranges for reflex Free T4 testing. How can laboratories rationalize thyroid function testing. What is the significance of TSH with reflex to FT4 in thyroid disorder diagnosis. How do different TSH cutoffs impact the need for additional Free T4 testing.

Understanding TSH with Reflex to FT4 Testing

TSH with Reflex to FT4 is a two-step thyroid function test that begins with measuring thyroid-stimulating hormone (TSH) levels. If the TSH result falls outside the specified reference range, the laboratory automatically performs a Free T4 (FT4) test on the same blood sample. This reflex testing approach aims to provide a comprehensive assessment of thyroid function while minimizing unnecessary testing.

Key Features of TSH with Reflex to FT4 Test

• Initial TSH screening followed by conditional FT4 testing
• Applicable for patients 1 year of age or older
• Requires serum sample (1.0 mL, minimum 0.7 mL)
• Collected in a gel-barrier tube (SST)
• Results available in 1 to 3 days

Why is TSH with Reflex to FT4 considered an efficient screening method? This approach leverages the sensitivity of TSH as an initial indicator of thyroid dysfunction. TSH levels respond dynamically to changes in thyroid hormone concentrations, making it an excellent first-line test for detecting potential thyroid disorders.

Clinical Significance and Applications

TSH with Reflex to FT4 testing plays a crucial role in assessing thyroid function, particularly when pituitary disease is not suspected. How does this test aid in the diagnosis of thyroid disorders? By providing a two-tiered approach:

1. TSH screening identifies potential thyroid dysfunction
2. Reflex FT4 testing helps distinguish between subclinical and overt thyroid disorders

In cases of suspected hyperthyroidism or hypothyroidism, TSH testing serves as the initial diagnostic step. An abnormal TSH result triggers the reflex FT4 test, offering additional information to guide diagnosis and determine if further testing is necessary.

Interpreting TSH and FT4 Results

• Elevated TSH + Low FT4: Indicative of primary hypothyroidism
• Elevated TSH + Normal FT4: Suggests subclinical hypothyroidism
• Low TSH + High FT4: Consistent with hyperthyroidism
• Low TSH + Normal FT4: May indicate subclinical hyperthyroidism

It’s important to note that result interpretation should always consider the patient’s clinical context, including symptoms, medical history, and physical examination findings.

Optimizing TSH Cutoffs for Reflex Testing

The study by Henze et al. aimed to evaluate different TSH cutoffs for triggering reflex FT4 testing. What was the primary goal of this research? The investigators sought to determine if widening the normal TSH range could reduce the need for additional FT4 testing without compromising the detection of thyroid disorders.

Current TSH Reference Ranges

Most laboratories report a normal TSH reference range between:

• Lower limit: 0.4-0.5 mU/L
• Upper limit: 4-5.5 mU/L

How might adjusting these cutoffs impact thyroid function testing? By potentially reducing the number of reflex FT4 tests performed while maintaining diagnostic accuracy. This optimization could lead to more cost-effective and efficient thyroid screening processes.

Factors Affecting TSH and FT4 Measurements

Several factors can influence TSH and FT4 test results, potentially impacting the interpretation and reliability of thyroid function assessments. What are some key considerations when collecting and analyzing samples for TSH with Reflex to FT4 testing?

• Timing of specimen collection: For patients on hemodialysis, collection should be delayed for 2 weeks
• Interference from medical procedures: Specimen collection after fluorescein dye angiography should be delayed for at least 3 days
• Presence of heterophile antibodies: Can lead to interference in TSH measurements
• Sample stability: Proper storage and handling are crucial for accurate results

How can laboratories ensure the reliability of TSH and FT4 measurements? By adhering to strict collection, storage, and analysis protocols, as well as being aware of potential interfering factors that may affect test results.

The Role of Additional Thyroid Tests

While TSH with Reflex to FT4 testing provides valuable information about thyroid function, additional tests may be necessary in certain situations. When might healthcare providers consider ordering supplementary thyroid tests?

• Suspected Hashimoto’s thyroiditis: Thyroid peroxidase antibody testing
• Potential Graves’ disease: TSH receptor antibodies testing
• T3 thyrotoxicosis: Free T3 measurement

These additional tests can help refine the diagnosis and guide treatment decisions in cases where TSH and FT4 results are inconclusive or suggest specific thyroid disorders.

Implications for Clinical Practice

The optimization of TSH cutoffs for reflex FT4 testing has significant implications for clinical practice. How might these findings impact thyroid function screening and diagnosis?

1. Potential reduction in unnecessary FT4 testing
2. Cost savings for healthcare systems and patients
3. Streamlined thyroid function assessment workflows
4. Improved allocation of laboratory resources

However, it’s crucial to balance the desire for efficiency with the need for diagnostic accuracy. Healthcare providers must carefully consider the potential risks and benefits of adjusting TSH cutoffs in their clinical practice.

Future Directions in Thyroid Function Testing

As research in thyroid function assessment continues to evolve, what are some potential areas for future investigation and improvement?

• Development of more sensitive and specific TSH assays
• Exploration of population-specific TSH reference ranges
• Integration of artificial intelligence in result interpretation
• Investigation of novel biomarkers for thyroid dysfunction

These advancements could further enhance the accuracy and efficiency of thyroid function testing, ultimately leading to improved patient care and outcomes.

Conclusion and Key Takeaways

TSH with Reflex to FT4 testing remains a cornerstone in the assessment of thyroid function. The optimization of TSH cutoffs for reflex testing presents an opportunity to enhance the efficiency of thyroid screening while maintaining diagnostic accuracy. Key points to remember include:

• TSH is a sensitive initial marker for thyroid dysfunction
• Reflex FT4 testing provides valuable additional information when TSH is abnormal
• Adjusting TSH cutoffs may reduce unnecessary FT4 testing
• Result interpretation should always consider the clinical context
• Ongoing research aims to further improve thyroid function testing methodologies

As the field of thyroid diagnostics continues to evolve, healthcare providers and laboratorians must stay informed about the latest developments to ensure optimal patient care and resource utilization.

TSH with Reflex to FT4

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NEW YORK DOH APPROVED: YES

CPT Code: 84443

Order Code: C513

For patients 1 year of age or older, Free T4 will be performed at an additional charge (CPT code 84439) when TSH result exceeds age specific reference range.

ABN Requirement:  No
Synonyms: Thyroid Stimulating Hormone with Reflex
Specimen: Serum
Volume: 1.0 mL
Minimum Volume: 0.7 mL
Container: Gel-barrier tube (SST)

Collection:

1. Collect and label sample according to standard protocols.
2. Gently invert tube 5 times immediately after draw. Do not shake.
3. Allow blood to clot 30 minutes.
4. Centrifuge for 10 minutes.

Special Instructions: Specimen collection after fluorescein dye angiography should be delayed for at least 3 days. For patients on hemodialysis, specimen collection should be delayed for 2 weeks. According to the assay manufacturer Siemens: “Samples containing fluorescein can produce falsely depressed values when tested with the Advia Centaur TSh4 Ultra assay.”

Transport: Store serum at 2°C to 8°C after collection and ship the same day per packaging instructions included with the provided shipping box.

Stability:

Ambient (15-25°C): 7 days
Refrigerated (2-8°C): 7 days
Frozen (-20°C): 28 days

Causes of Rejection: Specimens other than serum; improper labeling; samples not stored properly; samples older than stability limits

Methodology: Immunoassay (IA)

Turn Around Time: 1 to 3 days

Reference Range:

Thyroid Stimulating Hormone (TSH): See individual test

Thyroxine (T4), Free: See individual test

Clinical Significance: This test may be useful in assessing thyroid dysfunction when pituitary disease is not suspected. In patients with clinical suspicion of hyperthyroidism or hypothyroidism, testing thyroid stimulating hormone (TSH) is the initial step [1]. An abnormal TSH result will reflex to a free thyroxine (T4) test to aid in diagnosis and guide further testing if needed.

TSH stimulates the thyroid gland to synthesize and secrete triiodothyronine (T3) and T4. TSH production is reduced in response to high T3/T4 levels and increased in response to low T3/T4 levels. When pituitary disease is not suspected, TSH serves as a sensitive marker for screening for thyroid dysfunction [1,2]. A normal TSH result excludes most cases of primary overt thyroid disease. When the TSH level is elevated, measurement of free T4 level may help diagnose subclinical or overt hypothyroidism. Thyroid peroxidase antibody testing may be needed to aid in the diagnosis of Hashimoto thyroiditis. When the TSH level is decreased, measurement of free T4 and free T3 may help identify hyperthyroidism or T3 thyrotoxicosis. In patients with thyrotoxicosis, TSH receptor antibodies testing helps confirm Graves disease [1-3].

Note: Interference due to heterophile antibodies has been known to occur [1].

The results of this test should be interpreted in the context of pertinent clinical and family history and physical examination findings.

References:

1. Demers LM, et al. The thyroid: pathophysiology and thyroid function testing. In: Burtis CA, et al. eds. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 4th ed. Elsevier; 2006:2053-2095.

2. Ross DS, et al. Thyroid. 2016;26(10):1343-1421.

3. Vasileiou M, et al; Guideline Committee. BMJ. 2020;368:m41.

The CPT codes provided are based on AMA guidelines and are for informational purposes only. CPT coding is the sole responsibility of the billing party. Please direct any questions regarding coding to the payer being billed.

Determination of optimal TSH ranges for reflex Free T4 testing

CLINICAL THYROIDOLOGY FOR THE PUBLIC
A publication of the American Thyroid Association

Summaries for the Public from recent articles in Clinical Thyroidology

Table of Contents | PDF File for Saving and Printing

THYROID HORMONE TESTS
Determination of optimal TSH ranges for reflex Free T₄ testing

BACKGROUND
TSH measurement is generally regarded as the most sensitive initial laboratory test for screening individuals for thyroid hormone abnormalities. This is due to the fact that small changes in Free T₄ levels result in larger changes in TSH values. Many clinicians and laboratories check TSH alone as the initial test for thyroid problems and then only add a Free T₄ measurement if the TSH is abnormal (outside the laboratory normal reference range). When the laboratory adds the Free T₄ test to the blood sample automatically based on an abnormal TSH result, it referred to as “reflex” testing. Although laboratories vary, most report a normal TSH reference range between 0.4-0.5 mU/L on the lower end and 4-5.5 mU/L on the upper end of the range. The goal of this study was to evaluate different TSH cutoffs leading to reflex Free T₄ testing, with the purpose to determine whether a widened normal range could decrease the need for additional Free T₄ testing and not lead to missing cases of thyroid problems.

THE FULL ARTICLE TITLE:
Henze M et al. Rationalizing thyroid function testing: Which TSH cutoffs are optimal for testing Free T4?. J. Clin Endocrinol. Metab. 2017. 102 (11): 4235-4241.

SUMMARY OF THE STUDY
These investigators evaluated TSH and Free T₄ measurements in two populations. One group of 120,403 individuals (named the clinical group) had thyroid tests performed in a single laboratory in Western Australia over a 12 year period of time. This group was compared to community group of 4568 individuals participating in the Busselton Health Study. All individuals had both TSH and Free T₄ measured. They excluded people with known pituitary disease, thyroid disease and other factors known to affect thyroid function tests. These investigators quantified the number of individuals at different TSH values that had high, low or normal Free T₄ levels. They measured the effect of changing the TSH reference range cutoffs on the number of reflex Free T₄ tests. They determined how many times an abnormally high or low Free T₄ would have gone undetected if the TSH cutoffs for reflex testing had been changed. The normal reference range for the TSH was 0.4-4 mU/L in this study. They found in the clinical group that if the TSH normal range that led to reflex Free T₄ testing was changed to from 0.4-4 mU/L to 0.3-5 mU/L, this would have led to a 22% reduction in the number of Free T₄ tests performed. As expected, if the TSH normal reference range was widened even more to 0.2-6 mU/L, even fewer reflex Free T₄ tests would have been done.

They then examined how many of those Free T4 levels that would not have been done were abnormal. When the TSH lower limit was reduced from 0.4 to 0.2 mU/L, a high Free T₄ would have been missed in 4.2% of people who had a TSH between 0.2 and 0.4 mU/L. When the TSH upper limit was raised from 4 to 6 mU/L, a low Free T₄ would have been missed in 2.5% of the people who had a TSH between 4 and 6 mU/L.

The authors noted that this was a relatively small number of people that would have been missed and that the majority had only very slight abnormalities of Free T₄. They suggested that these mild abnormalities were unlikely to be associated with clinically important overt hyper- or hypothyroidism. The vast majority of people (97%) with a TSH in the normal range of 0.4-4 mU/L also had normal Free T₄ values. The findings were similar but of lesser magnitude in the smaller community group of patients. The authors concluded that the TSH reference range leading to reflex Free T₄ testing could likely be widened to decrease the number of unnecessary Free T₄ measurements performed. This would reduce overall costs to the medical system without likely causing negative consequences in terms of missing the detection of people with thyroid hormone abnormalities.

WHAT ARE THE IMPLICATIONS OF THIS STUDY?

These results indicate that by widening the normal reference range for TSH, the need for additional reflex testing for Free T₄ values could be reduced. The authors suggested that fewer unnecessary Free T₄ measurements would be performed and thus these changes would be cost saving for the health care system. The results indicated that the TSH normal reference range could be altered with minimal clinical effects. In other words, few cases of overt hyper- or hypothyroidism would go undetected if the TSH cutoffs leading to reflex Free T₄ testing were only slightly changed. It is important to note, that this study refers to the finding of overt thyroid disease and does not address the concept of “subclinical” or mild thyroid disorders. Additionally it is important to remember that TSH testing alone is inadequate or misleading in some conditions (such as central hypothyroidism or other abnormal thyroid conditions). This study primarily addresses the utility of isolated TSH measurements when screening people for new thyroid disease. When screening the general population for thyroid disease, the majority of people with a TSH in the normal reference range will also have a normal Free T₄, making the new diagnosis of a thyroid disorder unlikely when a person has a normal TSH.

— Whitney W. Woodmansee MD

ATA THYROID BROCHURE LINKS

Thyroid Function Tests: https://www.thyroid.org/thyroid-function-tests/

Hypothyroidism (Underactive): https://www.thyroid.org/hypothyroidism/

Hyperthyroidism (Overactive): https://www.thyroid.org/hyperthyroidism/

ABBREVIATIONS & DEFINITIONS

TSH: thyroid stimulating hormone — produced by the pituitary gland that regulates thyroid function; also the best screening test to determine if the thyroid is functioning normally.

Thyroxine (T4): the major hormone produced by the thyroid gland. T₄ gets converted to the active hormone T₃ in various tissues in the body.

Hypothyroidism: a condition where the thyroid gland is underactive and doesn’t produce enough thyroid hormone. Treatment requires taking thyroid hormone pills.

Subclinical Hypothyroidism: a mild form of hypothyroidism where the only abnormal hormone level is an increased TSH. There is controversy as to whether this should be treated or not.