At a Glance

The thyroid gland produces two related hormones, thyroxine (T4) and triiodothyronine (T3), which play a critical role in thermogenic and metabolic homeostasis. T4 and T3 are normally synthesized and released in response to a combined hypothalamic pituitary signal mediated by thyroid stimulating hormone (TSH) from the anterior pituitary and thyrotropin releasing hormone from the hypothalamus. There is a negative feedback from thyroid hormone concentration, primarily T3, to TSH production, causing total T4, total T3, free T4, and free T3 concentrations to move in opposition to TSH concentration.

Iodide trapping in the thyroid is accomplished via the Na+/I symporter. The selective activity of the Na+/I symporter in the thyroid allows radioactive I131 ablation of the thyroid to be employed to treat hyperthyroidism and thyroid cancer without significant effect on other organs. Radioiodine is the most popular treatment for hyperthyroidism in the United States. Ablation may also be performed post thyroidectomy for certain thyroid cancers to remove residual tumor or thyroid cells. The absence of thyroid cells in the body lessens the potential for recurrence of the cancer and makes subsequent scans and thyroglobulin assays used to monitor possible cancer reoccurrence more interpretable.

In most cases, hypothyroidism develops within the first 3 months after irradiation. Although it should be noted that, prior to the development of hypothyroidism, hyperthyroidism may worsen because of a release of thyroid hormones from the dying cells. Generally, hypothyroidism occurs within the first year post ablation and worsens over time. Six years post ablation, the replacement dose of levothyroxine (L-T4) required is almost double what was required initially.

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Patients with hypothyroidism post ablation present with the same signs and symptoms as other hypothyroid conditions (i.e., fatigue, cold intolerance, weight gain, depression, and dry skin).

Other symptoms of post ablation hypothyroidism include the usual array of hypothyroid symptoms ie., brittle nails, coarsening and thinning hair, puffy eyes, weakness, and constipation.

Symptoms expressing themselves later in the course of hypothyroidism are hoarseness; menstrual disorders; puffy hands, face, and feet; thickening of the skin; thinning of the eyebrows; increased cholesterol levels; muscle and/or joint aches and stiffness; and decreased hearing.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

TSH of 0.5-2.0 mIU/L is the usual target post ablation. It is particularly important to suppress TSH when the ablation was performed as a treatment for thyroid cancer. A suppressed TSH is thought to discourage reoccurrence of the cancer. It is also more important in children to maintain this target zone.

Patients taking rifampin or anticonvulsants may require higher doses to maintain TSH at the target level, since these drugs increase the breakdown of L-T4.

A serum free T4 in the upper third of the reference range is the target for free T4. A typical titration involves L-T4 increased in 25 μg increments each 6-8 weeks until the target levels are reached.

T3 should also be monitored, since some patients lose their ability to convert T4 to T3.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

Interferences may complicate the monitoring of the effectiveness of thyroid replacement therapy post ablation.

Most thyroid testing today is performed by either immunoassay in which labeled and unlabeled ligands compete for a limited number of antibody sites or immunometric assays in which an antibody is bound to a solid surface rather than an antibody. Cross reactivity of autoantibodies or heterophilic antibodies can affect diagnostic accuracy of competitive binding based tests.

The term heterophilic antibodies is often loosely applied to relatively weak antibodies with multiple activity sites, known as autoantibodies, seen in auto immune disorders; broadly reactive antibodies induced by infections or exposure to therapy containing monoclonal mouse antibodies (HAMA); or human anti-animal immunoglobulins produced against well defined, specific antigens following exposure to therapeutic agents containing animal antigen or by coincidental immunization through exposure to animal antigens.

The latter, human anti-animal antibodies (HAAA), are strong reactors. HAMA and HAAA affect immunometric assays more than simple competitive immunoassays. In immunometric assays HAMA and HAAA can form a bridge between the capture and signal antibodies. Autoantibodies and heterophilic antibody interferences can sometimes be detected by simply using a different manufacturer’s method that employs a slightly different antibody. Tests in which dilutions are acceptable, such as total T4, total T3, or TSH, but not free T4 or free T3, may be checked for linearity of response to help identify heterophilic antibody interference.

Most circulating thyroid hormones are bound to protein. Only that hormone that is free is biologically active. Variations in binding protein will cause variations in concentrations of total hormones. In general, serum TSH is less affected by binding issues than T3 and T4, and T4 is bound more tightly than T3. T3 and T4 circulate in the body bound to thyroid binding globulin (TBG); transthyretin, formally known as thyroxine binding prealbumin; and serum albumin. Physiologically, shifts toward greater total hormone binding decrease available free hormone. Theoretically, free T3 and free T4 are not affected analytically by binding, but in reality, all of the free methods are binding dependent to varying degrees.

Phenytoin, carbamazepine, aspirin, and furosimide compete with thyroid hormone for protein binding sites and, thus, acutely increase free hormone and reduce total hormones. Eventually, a normal equilibrium is reestablished in which free levels normalize at the expense of total levels.

Heparin stimulates lipoprotein lipase, liberating free fatty acids, which inhibit total T4 protein binding and elevates free T4.

Free fatty acids are known to affect some methods.

Estrogens increase TBG, increasing total thyroid hormones.

Liver disease, androgens, and nephrotic syndrome decrease TBG, decreasing total thyroid hormones.

Indole acetic acid, which accumulates in uremia, may interfere with thyroid binding.

Pregnancy is associated with lower albumin levels. Therefore, albumin dependent methods are not suitable for accessing thyroid status during pregnancy.

TSH levels decline in the first trimester of pregnancy partly because of the increase in total T3 and T4 from increased TBG. Total T3 and T4 are also increased in the first trimester by increased human chorionic gonadotropin (HCG), which is structurally and to some extent functionally similar to TSH.

Glucocorticosteroids can lower T3 and inhibit TSH production. This interaction is of particular concern in sick, hospitalized patients in whom the elevated TSH in primary hypothyroidism may be obscured.

Propanolol has an inhibitory effect on T4 to T3 conversion. Eighty percent of T3 is produced enzymatically in nonthyroid tissue by 5-monodeiodination of T4.

Free T3 and free T4 are often method dependent.

Methods that use fluorescent tags may be affected by the presence of fluorophore-related therapeutic or diagnostic agents.

What Lab Results Are Absolutely Confirmatory?

Thyroid function testing in post ablation patients is more to guide replacement therapy than a diagnostic tool.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Thyroglobulin is a sensitive test for recurrence of thyroid cancer because thyroglobulin is made only by thyroid cells. Thyroglobulin, in the absence of antibodies, which could interfere with the assay, correlates well with tumor burden in post thyroidectomy-ablation patients. About one-fourth of patients make antibody against thyroglobulin, which will cause the thyroglobulin level to be artificially suppressed. Thyroglobulin and thyroglobulin antibody are usually performed together to determine if antibody is present. If antibody is present, a more specific method should be used to follow thyroglobulin levels.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

TSH may remain elevated for long periods post ablation due to the dramatic increase in TSH receptor antibodies.

A high free T4 and a high TSH may be indicative of therapeutic noncompliance. Acute ingestion of missed L-T4 just prior to a clinic visit will raise the free T4 but fail to normalize the TSH because of a “lag effect.” Free T4 is a short-term indicator, whereas TSH is a long-term indicator. Since TSH is the long-term indicator, it is not influenced by time of L-T4 ingestion.

When testing free T4, the daily dose of L-T4 should be withheld until after sampling, as free T4 is significantly increased above baseline for up to 9 hours after ingesting L-T4. Ideally, L-T4 should be taken prior to eating, at the same time each day, and at least 4 hours apart from other medications. Many medications and even vitamins and minerals can influence L-T4 absorption. L-T4 should not be taken with iron supplements. Patients should not switch from brand to brand of L-T4, and prescriptions should not be written generically, as doing so will allow brand to brand switches.

Although stated concentrations of L-T4 may be the same, slight variations exist between pharmaceutical manufacturers in terms of bioavailability. Also, medication storage recommendations should be scrupulously followed. Medicine should be stored away from humidity, light, and increased temperatures. When ordering medication, it is best to avoid summer for shipping.

TSH or free T4 levels may be diagnostically misleading during transition periods of unstable thyroid function. Often, these transition periods occur in the early phase of treating hyper- or hypothyroidism or changing the L-T4 dose. It takes 6-12 weeks for pituitary TSH secretion to reequilibrate to the new hormone status. Similar periods of unstable thyroid status may occur following an episode of thyroiditis.

TSH or free T4 levels may also be diagnostically misleading in cases of abnormalities in hypothalamic or pituitary function in which the usual negative feedback is not seen, and TSH may remain within normal ranges.

Free T4 and TSH have reduced specificity in hospitalized patients with nonthyroid illness. Most hospitalized patients have low serum total T3 and free T3. These abnormalities are seen with both acute and chronic nonthyroid illness and are thought to be the result of a malfunction of the central inhibition of hypothalamic releasing hormone. The National Academy of Clinical Biochemistry guidelines for testing of hospitalized patients with nonthyroid illness are as follows:

  • Acute or chronic nonthyroid illness has complex effects on thyroid function testing. Whenever possible, diagnostic testing should be deferred until the illness has resolved, except in cases in which there is a suggestion of presence of thyroid dysfunction.

  • Physicians should be aware that some thyroid tests are inherently not interpretable in severely ill patients or patients receiving multiple medications.

  • TSH in the absence of dopamine or glucocorticoid therapy is the more reliable test.

  • TSH testing in a hospitalized patient should have a functional sensitivity less than 0.02 mIU/L; otherwise, sick, hyperthyroid patients with profoundly low TSH cannot be differentiated from patients with mild transient TSH suppression caused by nonthyroid illness.

  • An abnormal free T4 in the presence of serious somatic disease is unreliable. In hospitalized patients, abnormal free T4 testing should reflex to total T4. If both free T4 and total T4 are abnormal in the same direction, a thyroid condition may exist. Discordant free T4 and total T4 abnormalities are more likely the result of illness, medication, or a testing artifact.

  • Total T4 abnormalities should be considered in conjunction with the severity of the patient’s illness. A low T4 in patients not in intensive care is suspicious of hypothyroidism, since, in hospitalized patients, low total T4 levels in nonthyroid illness are most often seen in sepsis. If a low total T4 is not associated with an elevated TSH and the patient is not profoundly sick, hypothyroidism secondary to pituitary or hypothalamic deficiency should be considered.

  • Reverse T3 formed by the loss of an iodine group from T4 where the position of the iodine atoms on the aromatic ring is reversed is rarely helpful in the hospital setting, because paradoxically normal or low values can result from impaired renal function and low binding protein concentrations.

Trimester-specific reference ranges should be used during pregnancy.

During pregnancy, estrogens increase TBG to 2-3 times prepregnancy levels. This shifts binding such that total T3 and total T4 are approximately 1.5 times nonpregnant levels at 16 weeks gestation.

TSH is also altered during pregnancy. TSH is decreased in the first trimester because of the thyroid stimulating activity of HCG. The decline in TSH is associated with a modest increase in free T4. In approximately 2% of pregnancies, the increase in free T4 leads to a condition known as gestational transient thyrotoxicosis. This condition may be associated with hyperemesis.

In the second and third trimester of pregnancy, free hormone levels decrease 20-40% below reference ranges.

Pregnant patients receiving L-T4 replacement may require increased dose to maintain a normal TSH and free T4.

TSH has a very short half-life of 60 minutes and is subject to circadian and diurnal variation peaking at night and reaching a nadir between 10 AM and 4 PM. T4 has a much longer half-life of 7 days.

It should be noted that there is a continuous decrease in the TSH/free T4 ratio from mid-gestation through completion of puberty. In adulthood, TSH increases in the elderly. Age-related reference ranges, or at least ratio-adjusted reference ranges, should be used for these analytes.

For a change in value to have clinical significance, the difference must take into consideration analytical and biological variabilities. The magnitude of difference in thyroid testing values reflecting a clinical significance when monitoring a patient’s response to therapy is:

T4 28 nmol/L ( 2.2 μg/dL)

free T4 6 pmol/L ( 0.5 ng/dL)

T3 0.55 nmol/L (35 ng/dL)

free T3 1.5 pmol/L (1.5 ng/dL)

TSH 0.75 mIU/L