TFT Interpretation
The Hypothalamic-Pituitary-Thyroid (HPT) Axis
The interpretation of thyroid function tests (TFTs) is entirely dependent on understanding the Hypothalamic-Pituitary-Thyroid (HPT) axis. This system operates on a classic negative feedback loop:
- Hypothalamus releases Thyrotropin-Releasing Hormone (TRH).
- TRH stimulates the Anterior Pituitary to release Thyroid-Stimulating Hormone (TSH).
- TSH stimulates the Thyroid Gland to produce and release Thyroxine (T4) and Triiodothyronine (T3).
- T4 and T3 circulate in the blood (mostly bound to proteins) and exert negative feedback on both the pituitary and the hypothalamus, suppressing TSH and TRH release, respectively.
Because of this feedback, TSH is the most sensitive marker for primary thyroid dysfunction. A small change in free T4 (FT4) leads to a large, logarithmic change in TSH.
The Key Thyroid Tests
- TSH (Thyroid-Stimulating Hormone): The single best screening test for thyroid dysfunction in ambulatory patients.
- FT4 (Free Thyroxine): Measures the metabolically active, unbound portion of T4. It reflects the thyroid gland's output. Total T4 (TT4) is less reliable as it is affected by changes in binding proteins (e.g., in pregnancy or with oral contraceptive use).
- FT3 (Free Triiodothyronine): Measures the active, unbound T3. T3 is the more potent hormone, mostly derived from peripheral conversion of T4. It is primarily useful for diagnosing hyperthyroidism (thyrotoxicosis), as it can be elevated earlier or more significantly than FT4 (known as T3-toxicosis).
- Thyroid Antibodies:
- TPOAb (Thyroid Peroxidase Antibodies): A marker of autoimmune thyroid damage. Its presence is diagnostic for Hashimoto's thyroiditis (the most common cause of primary hypothyroidism) and is also found in a majority of patients with Graves' disease.
- TRAb (TSH Receptor Antibodies): These are diagnostic for Graves' disease. They can be stimulating (causing hyperthyroidism) or, rarely, blocking (causing hypothyroidism).
- TgAb (Thyroglobulin Antibodies): Primarily used as a follow-up marker for differentiated thyroid cancer after thyroidectomy and radioiodine ablation. Their presence can also interfere with Thyroglobulin (Tg) assays.
Common Patterns of Thyroid Function Tests
Interpretation relies on matching the TSH and FT4 results.
| TSH | Free T4 (FT4) | Free T3 (FT3) | Interpretation | Common Causes |
|---|---|---|---|---|
| High | Low | Low / Normal | Overt Primary Hypothyroidism | Hashimoto's thyroiditis, post-thyroidectomy, radioiodine therapy, drug-induced (e.g., Lithium). |
| High | Normal | Normal | Subclinical Hypothyroidism | Early Hashimoto's, insufficient levothyroxine replacement. |
| Low | High | High / Normal | Overt Primary Hyperthyroidism (Thyrotoxicosis) | Graves' disease, toxic multinodular goiter (MNG), toxic adenoma, thyroiditis (destructive phase). |
| Low | Normal | High | T3-Toxicosis | Early Graves' disease, toxic MNG. |
| Low | Normal | Normal | Subclinical Hyperthyroidism | Graves', MNG, over-replacement with levothyroxine. |
| Low | Low | Low / Normal | Central Hypothyroidism | Pituitary mass (e.g., adenoma), Sheehan's syndrome, infiltrative disease, severe illness (NTI), suppressive drugs (e.g., glucocorticoids, dopamine). |
| High / Normal | High | High | Secondary Hyperthyroidism | TSH-secreting pituitary adenoma (TSH-oma), thyroid hormone resistance. |
| Normal | Normal | Normal | Euthyroid | Healthy individual. |
Key Clinical Scenarios and Confounders
Interpreting TFTs requires clinical context, as several conditions and substances can alter the results.
1. Non-Thyroidal Illness (NTI)
Also known as Euthyroid Sick Syndrome, this is a critical consideration in hospitalized or critically ill patients.
- Pathophysiology: An adaptive response to illness, starvation, or stress, not a true thyroid disorder. It involves altered peripheral deiodinase activity and suppressed TSH.
- Classic Pattern:
- Mild/Moderate Illness: Low FT3 (and low Total T3) is the earliest and most common finding, due to decreased conversion of T4 to T3. TSH and FT4 are often normal.
- Severe Illness: Low FT3, Low FT4, and Low/Normal TSH. The TSH is "inappropriately normal" or low for the low FT4 level, mimicking central hypothyroidism.
- Recovery Phase: As the patient recovers, TSH may transiently rise (sometimes >20 mIU/L) before FT4 normalizes.
- Clinical Pearl: Routine TFT screening in hospitalized patients is discouraged. Reverse T3 (rT3) is typically high in NTI (due to reduced clearance), whereas it is low in central hypothyroidism, but this test is rarely used.
2. Drug Interference
Many common medications can interfere with TFTs.
- Amiodarone: Due to its high iodine content and direct cellular toxicity, it can cause:
- Amiodarone-Induced Hypothyroidism (AIH): More common in iodine-sufficient areas (Wolff-Chaikoff effect).
- Amiodarone-Induced Thyrotoxicosis (AIT): Type 1 (Jod-Basedow effect in underlying thyroid disease) or Type 2 (destructive thyroiditis).
- Glucocorticoids (high dose) & Dopamine: These drugs suppress TSH secretion, leading to a pattern of central hypothyroidism (Low TSH, Low FT4).
- Lithium: Can cause goiter and primary hypothyroidism by inhibiting thyroid hormone release.
- Biotin (Vitamin B7): This is a major source of assay interference, not a physiological effect. High doses of biotin (common in hair/nail supplements) interfere with streptavidin-biotin-based immunoassays.
- Typical Interference: Falsely Low TSH and Falsely High FT4/FT3. This pattern dangerously mimics Graves' disease.
- Action: Biotin should be stopped for at least 48 hours (or longer) before thyroid testing.
3. Pregnancy
Thyroid physiology changes significantly during pregnancy.
- First Trimester: High hCG levels weakly stimulate the TSH receptor, causing a physiologic suppression of TSH and a slight rise in FT4.
- Second/Third Trimester: Estrogen increases Thyroxine-Binding Globulin (TBG), which raises Total T4 (but FT4 remains relatively stable).
- Key Point: Trimester-specific reference ranges for TSH must be used for all pregnant patients.