T4 Total - Kresser Institute Membership Site

Marker Name: Total T4
REFERENCE RANGES FOR TOTAL T4 (THYROXINE):

Laboratory reference range: 4.5–12 µg/dL

Functional reference range: 6–12 µg/dL

DESCRIPTION:

T4 (thyroxine) is one of two biologically active thyroid hormones.¹ T4 is the molecular precursor of T3 (triiodothyronine), which is the substantially more potent thyroid hormone; T3 binds to thyroid hormone-responsive receptors with 10 to 15 times greater affinity than T4.² Given this difference in potency, T4 may be considered a prohormone to T3. The abbreviations T4 and T3 reflect the number of iodine atoms found in the respective thyroid hormone molecules.

t4-total-a

t4-total-b

T4 is produced solely by the thyroid gland and is stored in large quantities within the gland.¹ T4 is bound to thyroglobulin within the thyroid gland, mostly within the lumen of thyroid follicles.¹ Thyroid-stimulating hormone (TSH) acting on the thyroid gland causes T4 to be released into the bloodstream.³

T4 is enzymatically converted to T3 in the peripheral tissues. In fact, roughly 80 percent of T3 is produced by deiodination of T4 outside of the thyroid gland. This deiodination is performed by thyroxine-5′-deiodinases found largely in the liver and kidney, but also present in muscle, brain, pituitary, skin, and placenta.⁴ Interestingly, the deiodinases are selenoproteins (selenium-containing proteins), and selenium deficiency exacerbates autoimmune thyroid disease and endemic cretinism.⁵

Greater than 99 percent of T4 circulating in the bloodstream is bound to a serum protein.⁶ Three-quarters of circulating T4 is bound to thyroxine-binding globulin (TBG), 12 percent is bound to albumin, and 10 percent is bound to transthyretin.^1,6 Less than one-tenth of 1 percent of serum T4 is not bound to proteins, yet only the unbound portion of T4 is biologically active. The laboratory assay “total T4” measures both bound and unbound T4. T4 that is not bound to any serum protein is “free T4.” The relative levels of these serum proteins can make a considerable difference on thyroid function status. Total T4 provides a better estimate of thyroid function when TBG levels are normal.⁷

Elevated total T4 levels may occur in patients with hyperthyroidism but do not necessarily define hyperthyroidism. For instance, euthyroid hyperthyroxinemia is a condition in which T4 levels are elevated in the absence of abnormal TSH levels or clinical signs of hyperthyroidism.⁸ Drugs that increase TBG levels will also tend to increase total T4 levels, as this state creates additional binding sites for thyroxine in the blood. Iodine-containing drugs such as amiodarone can inhibit the conversion of T4 to T3, causing a relative increase in the prohormone T4.⁹ Normal pregnancy changes thyroid physiology; total T4 concentrations rise during the first half of pregnancy and reach a new steady state at approximately 20 weeks of gestation.¹⁰

Decreased total T4 levels in the serum usually indicate hypothyroidism or chronic or subacute thyroiditis. Conditions that affect serum protein levels will also affect total T4 concentrations. For instance, nephrotic syndrome is a protein wasting condition in which thyroid hormone bound to serum proteins can be filtered and excreted in the urine, causing overall reductions in total T4.¹¹ The same is true for drugs that increase T4 clearance, mainly antiepileptic drugs. Likewise, any drug that can inhibit the synthesis or release of thyroxine will lower total T4 levels. Importantly, these conditions may or may not alter TSH levels.¹²Overt hyperthyroidism with high T4 and low TSH is rare during pregnancy; it occurs in 0.1 to 0.4 percent of all pregnancies.¹⁰

Total T4 is primarily used to monitor treatment with synthetic hormones or antithyroid drugs, such as thiouracil.⁷ While free T4 is used more often than total T4 to evaluate thyroid function, no clinical laboratories offer a truly direct measure of free T4.^12,13 Instead, serum free T4 is calculated from total T4 and other indices. Therefore, any free T4 level involves measurement of total T4 and either TBG or T3 resin uptake. Total T4 may also be measured with serum TSH, total T3, free T3, reverse T3, or markers for thyroid antibodies.¹²

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^7,9,10,12

Normal pregnancy
Hyperthyroidism
Euthyroid hyperthyroxinemia
TSH-mediated hyperthyroidism
Acute thyroiditis
Familial dysalbuminemic hyperthyroxinemia
Drugs that increase TBG (e.g., estrogens, tamoxifen, opioids)
Drugs that decrease T4 conversion to T3 (e.g., amiodarone)

Low in:^7,12

Hypothyroidism
Chronic thyroiditis
Subacute thyroiditis
Congenital thyroid agenesis, dysgenesis, or defects in hormone synthesis
Nephrosis/nephrotic syndrome
Synthetic triiodothyronine treatment
Drugs that decrease TBG (e.g., anabolic steroids, glucocorticoids)
Drugs that increase T4 clearance (e.g., phenytoin, carbamazepine, phenobarbital)
Drugs that inhibit T4 synthesis/release (e.g. thionamides, lithium, perchlorate)

FUNCTIONAL RANGE INDICATIONS:

High in:

Hyperthyroidism
Facetious hyperthyroidism (excess thyroid hormone replacement)
Hepatitis

Low in:

Hypothyroidism
T3 replacement therapy

References: