TOTAL THYROXINE (T4)
Total serum thyroxine includes both free and protein-bound thyroxine and is usually measured by competitive immunoassay. Normal level in adults is 5.0-12.0 μg/dl.
Test for total thyroxine or free thyroxine is usually combined with TSH measurement and together they give the best assessment of thyroid function.
Causes of Increased Total T4
- Hyperthyroidism: Elevation of both T4 and T3 values along with decrease of TSH are indicative of primary hyperthyroidism.
- Increased thyroxine-binding globulin: If concentration of TBG increases, free hormone level falls, release of TSH from pituitary is stimulated, and free hormone concentration is restored to normal. Reverse occurs if concentration of binding proteins falls. In either case, level of free hormones remains normal, while concentration of total hormone is altered. Therefore, estimation of only total T4 concentration can cause misinterpretation of results in situations that alter concentration of TBG.
- Factitious hyperthyroidism
- Pituitary TSH-secreting tumor.
Causes of Decreased Total T4
- Primary hypothyroidism: The combination of decreased T4 and elevated TSH are indicative of primary hypothyroidism.
- Secondary or pituitary hypothyroidism
- Tertiary or hypothalamic hypothyroidism
- Hypoproteinaemia, e.g. nephrotic syndrome
- Drugs: oestrogen, danazol
- Severe non-thyroidal illness.
Free Thyroxine (FT4)
FT4 comprises of only a small fraction of total T4, is unbound to proteins, and is the metabolically active form of the hormone. It constitutes about 0.05% of total T4. Normal range is 0.7 to 1.9 ng/dl. Free hormone concentrations (FT4 and FT3) correlate better with metabolic state than total hormone levels (since they are not affected by changes in TBG concentrations).
Measurement of FT4 is helpful in those situations in which total T4 level is likely to be altered due to alteration in TBG level (e.g. pregnancy, oral contraceptives, nephrotic syndrome).
Total and Free Triiodothyronine (T3)
- Diagnosis of T3 thyrotoxicosis: Hyperthyroidism with low TSH and elevated T3, and normal T4/FT4 is termed T3 thyrotoxicosis.
- Early diagnosis of hyperthyroidism: In early stage of hyperthyroidism, total T4 and free T4 levels are normal, but T3 is elevated.
A low T3 level is not useful for diagnosis of hypothyroidism since it is observed in about 25% of normal individuals.
For routine assessment of thyroid function, TSH and T4 are measured. T3 is not routinely estimated because normal plasma levels are very low.
Normal T3 level is 80-180 ng/dl.
Free T3: Measurement of free T3 gives true values in patients with altered serum protein levels (like pregnancy, intake of estrogens or oral contraceptives, and nephrotic syndrome). It represents 0.5% of total T3.
Thyrotropin Releasing Hormone (TRH) Stimulation Test
- Confirmation of diagnosis of secondary hypothyroidism
- Evaluation of suspected hypothalamic disease
- Suspected hyperthyroidism
This test is not much used nowadays due to the availability of sensitive TSH assays.
- A baseline blood sample is collected for estimation of basal serum TSH level.
- TRH is injected intravenously (200 or 500 μg) followed by measurement of serum TSH at 20 and 60 minutes.
- Normal response: A rise of TSH > 2 mU/L at 20 minutes, and a small decline at 60 minutes.
- Exaggerated response: A further significant rise in already elevated TSH level at 20 minutes followed by a slight decrease at 60 minutes; occurs in primary hypothyroidism.
- Flat response: There is no response; occurs in secondary (pituitary) hypothyroidism.
- Delayed response: TSH is higher at 60 minutes as compared to its level at 20 minutes; seen in tertiary (hypothalamic) hypothyroidism.
Box 864.1 Thyroid autoantibodies
Various autoantibodies (TSH receptor, antimicrosomal, and antithyroglobulin) are detected in thyroid disorders like Hashimoto’s thyroiditis and Graves’ disease. Antimicrosomal (also called as thyroid peroxidase) and anti-thyroglobulin antibodies are observed in almost all patients with Hashimoto’s disease. TSH receptor antibodies (TRAb) are mainly tested in Graves’ disease to predict the outcome after treatment (Box 864.1).
Radioactive Iodine Uptake (RAIU) Test
This is a direct test that assesses the trapping of iodide by thyroid gland (through the iodine symporters or pumps in follicular cells) for thyroid hormone synthesis. Patient is administered a tracer dose of radioactive iodine (131I or 123I) orally. This is followed by measurement of amount of radioactivity over the thyroid gland at 2 to 6 hours and again at 24 hours. RAIU correlates directly with the functional activity of the thyroid gland. Normal RAIU is about 10-30% of administered dose at 24 hours, but varies according to the geographic location due to differences in dietary intake.
Causes of Increased Uptake
- Hyperthyroidism due to Graves’ disease, toxic multinodular goiter, toxic adenoma, TSH-secreting tumor.
Causes of Decreased Uptake
- Hyperthyroidism due to administration of thyroid hormone, factitious hyperthyroidism, subacute thyroiditis.
RAIU is most helpful in differential diagnosis of hyperthyroidism by separating causes into those due to increased uptake and due to decreased uptake.
An isotope (99mTc-pertechnetate) is administered and a gamma counter assesses its distribution within the thyroid gland.
- Differential diagnosis of high RAIU thyrotoxicosis:
– Graves’ disease: Uniform or diffuse increase in uptake
– Toxic multinodular goiter: Multiple discrete areas of increased uptake
– Adenoma: Single area of increased uptake
- Evaluation of a solitary thyroid nodule:
– ‘Hot’ nodule: Hyperfunctioning
– ‘Cold’ nodule: Non-functioning; about 20% cases are malignant.
Interpretation of thyroid function tests is shown in Table 164.1.
Table 864.1 Interpretation of thyroid function tests
|1. TSH Normal, FT4 Normal||Euthyroid|
|2. Low TSH, Low FT4||Secondary hypothyroidism|
|3. High TSH, Normal FT4||Subclinical hypothyroidism|
|4. High TSH, Low FT4||Primary hypothyroidism|
|5. Low TSH, Normal FT4, Normal FT3||Subclinical hyperthyroidism|
|6. Low TSH, Normal FT4, High FT3||T3 toxicosis|
|7. Low TSH, High FT4||Primary hyperthyroidism|
Neonatal Screening for Hypothyroidism
Thyroid hormone deficiency during neonatal period can cause severe mental retardation (cretinism) that can be prevented by early detection and treatment. Estimation of TSH is done on dry blood spots on filter paper or cord serum between 3rd to 5th days of life. Elevated TSH is diagnostic of hypothyroidism. In infants with confirmed hypothyroidism, RAIU (123I) scan should be done to distinguish between thyroid agenesis and dyshormonogenesis.
- Demers LM. Thyroid disease: pathophysiology and diagnosis. Clin Lab Med 2004;24:19-28.
- Heuck CC, Kallner A, Kanagasabapathy AS, Riesen W. Diagnosis and monitoring of diseases of thyroid. World Health Organization. 2000 WHO/DIL/0.004.
- Kaplan MM. Clinical perspectives in the diagnosis of thyroid disease. Clin Chem 1999;45:1377-83.
- Lazarus JH, Obuobie K. Thyroid disorders—an update. Postgrad Med J 2000;76:529-36.
- McDermott MT. Endocrine Secrets (4th Ed). Philadelphia. Mosby, 2005.
- US Preventive Services Task Force: Screening for thyroid disease: Recommended statement. Ann Intern Med 2004;140:125-7.
- Woeber KA. The year in review: the thyroid. Ann Intern Med 1999;131:959-62.
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