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Thyroid function tests (TFTs) are a commonly requested investigation in clinical practice. This guide aims to provide you with the knowledge needed to interpret TFTs and consider underlying pathology.


Thyroid hormonal axis

The ability to interpret thyroid function tests (TFTs) first requires an understanding of the thyroid hormonal axis. Each of the thyroid function tests is assessing different aspects of this axis and understanding the relationship between the results is key to being able to reach a diagnosis.

Thyroid hormonal axis overview

1. The paraventricular nuclei in the hypothalamus release thyroid releasing hormone (TRH).

2. This causes thyrotrope cells in the anterior pituitary to release thyroid stimulating hormone (TSH).

3. The thyroid responds to the TSH by releasing T4 and T3.

4. T4 inhibits the pituitary and hypothalamus in a negative feedback loop. This is the ‘brake system’ which aims to maintain a state of homeostasis.

Thyroid hormonal axis diagram

Thyroid hormonal axis diagram


Thyroid function tests (TFTs)

Thyroid function tests (TFTs) refer to the following investigations:

  • TSH (0.4 – 4 mU/L)
  • Free T4 (9 – 25 pmol/L)
  • Free T3 (3.5 – 7.8 nmol/L)

*There are separate reference ranges for children and pregnant women.

*Reference ranges for TFTs often vary between labs, so always refer to your local guidelines.

 

Important points:

  • Whilst free T3 (fT3) is measured, it is less relevant than free T4 (ft4). This is because the thyroid releases T4 and T3 at a ratio of about 20:1 respectively, with T3 mainly being produced by peripheral conversion of T4. As a result, T4 is a much better marker of thyroid function.
  • Free T4 (fT4) is roughly 1% of the total T4, with the rest being bound to thyroid binding globulin.
  • T4 has a half-life of about one week, therefore to monitor the impact of an intervention (e.g. increasing a patient’s levothyroxine dose) you need to wait several weeks before repeating TFTs.

 

Clinical features of thyroid disease table

Clinical features of thyroid disease table


Hypothyroidism

Primary hypothyroidism

Primary hypothyroidism involves reduced secretion of thyroid hormone from the thyroid gland itself.

Pathology which decreases the thyroid’s ability to release T4/T3 or respond to TSH can, therefore, cause primary hypothyroidism.

Primary hypothyroidism is the most common cause of hypothyroidism, accounting for 99% of all cases.

 

Pathophysiology

1. Less T4 and T3 are produced due to the thyroid’s reduced capacity to produce hormone or respond to TSH

2. As a result, there is reduced negative feedback on the pituitary and hypothalamus

3. The reduction in negative feedback results in increased production of TRH (which we don’t typically measure) and TSH

4. The end result is low T4/T3 and raised TSH

 

Diagnosis

  • Raised TSH (due to absence of negative feedback)
  • Low T4 (due to the thyroid’s inability to produce enough)
  • A normal T4 in the context of a raised TSH may suggest subclinical hypothyroidism (most commonly caused by underlying autoimmune disease)

 

 

Causes of primary hypothyroidism

  • Autoimmune thyroiditis (50%)
  • Iodine deficiency or excess
  • Thyroidectomy
  • Therapy with radioactive iodine – a treatment for hyperthyroidism
  • External radiotherapy
  • Drugs
  • Thyroid agenesis or dysgenesis

 

Secondary hypothyroidism

Secondary hypothyroidism involves a reduction in the hormones that stimulate the thyroid to produce thyroxine.

Pathology that affects the pituitary and hypothalamic glands can result in decreased production of TRH and TSH, causing secondary hypothyroidism.

Secondary hypothyroidism is a rare cause of hypothyroidism, accounting for 1% of all cases.

 

 

Pathophysiology

1. Decreased production or secretion of TRH/TSH results in decreased stimulation of the thyroid gland

2. The thyroid gland, therefore, produces less T3 and T4

3. The low T3 and T4 would normally stimulate the pituitary and hypothalamic glands to increase TRH/TSH production, however, they are unable to increase production

4. The end result is low T4/T3 and a normal/low TSH

 

 

Diagnosis

  • Normal/low TSH (due to a lack of production)
  • Low T4 (due to the absence of any positive feedback from TSH)

 

Causes of secondary hypothyroidism

Pituitary:

  • Adenoma – most common
  • Surgery or radiotherapy which damages the tissue

 

Hypothalamus:

  • Hypothalamic or suprasellar tumour
  • History of hypothalamic surgery or radiation

 

TRH is not measured as part of thyroid function tests, as it is only released locally between the hypothalamus and pituitary (so it is not present in representative quantities within the peripheral circulation).

Both structures are commonly grouped together into ‘secondary’ because an issue with TRH gives the same blood test results as an issue with TSH, however, some literature may refer to the hypothalamus as a ‘tertiary’ cause.


Hyperthyroidism

Primary hyperthyroidism

Primary hyperthyroidism involves excessive production of T3/T4 by the thyroid gland as a result of pathology within the thyroid gland itself.

 

Pathophysiology

1. The thyroid produces excessive amounts of T4 and T3

2. The excessive T4 and T3 cause negative feedback on the pituitary and hypothalamus, resulting in decreased production of TRH/TSH

3. The end result is a raised T3/T4 and a low TSH

 

 

Diagnosis

  • Raised T3/T4 (due to excessive production)
  • Low TSH (due to negative feedback on the pituitary/hypothalamus)

 

 

Causes of primary hyperthyroidism

  • Graves’ disease (75% of all cases)
  • Toxic multinodular goitre
  • Toxic adenoma
  • Iodine-induced (rare)
  • Trophoblastic tumour (very rare)

 

Secondary hyperthyroidism

Secondary hyperthyroidism involves stimulation of the thyroid gland by excessive thyroid stimulating hormone (TSH).

Pathophysiology

1. TSH production is increased by either the pituitary/hypothalamus or another source (known as ectopic production)

2. The excess TSH causes overstimulation of the thyroid gland, resulting in high levels of T3/T4 production

3. Normally a raised T3/T4 level would cause negative feedback, decreasing TSH production, however, in this instance, the TSH production is not responsive to any negative feedback, resulting in continued excess production

 

 

Diagnosis

  • Raised T3/T4 (due to excess production driven by a raised TSH level)
  • Raised TSH (due to excess production)

 

 

Causes of secondary hyperthyroidism

Pituitary:

  • TSH-secreting tumour
  • Chorionic-gonadotropin secreting tumours (hCG secreting)
  • Thyroid hormone resistance (usually euthyroid) – TSH is resistant to T3/T4 negative feedback

Summary

Below is a flowchart that summarises the key points discussed in this article.

 

TFT interpretation flow chart

TFT interpretation flow chart

Thyroid function interpretation flow chart


References

1. The endocrine system at a glance, 3rd edition; B.Greenstein D.Wood; Wiley-Blackwell; ISBN 978-1-4443-3215-5; 2011

2. Comprehensive Clinical Endocrinology 3rd ed., G.Besser, M. Thorner; 2002; 0-7234-3185-X; Elsevier science limited

3. Willims Textbook of Endocrinology 10th ed.; Larsen, Kronenberg, Melmed, Polonsky; 0-7216-9184-6; 2003

4. De Leo, Lee, Braverman; Hyperthyroidism; Lancet. 2016 Aug 27; 388(10047): 906–918; available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5014602/

5. Kostoglou-Athanassiou, Ntalles; Hypothyroidism – new aspects of an old disease; Hippokratia, 2010 Apr-Jun; 14(2): 82-87

6. Dr Lousie Newson; Thyroid Function Tests. 2015 Dec 23. [LINK]

 

Acknowledgement

With thanks to Professor Levy (Consultant Endocrinologist) for checking the accuracy of the facts.


 

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