At a Glance
The thyroid gland produces 2 related hormones, thyroxine (T4) and triiodothyronine (T3). T3 and T4 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 on TSH production from thyroid hormone concentration, primarily T3, causing total T4, total T3, free T4, and free T3 concentration to move in opposition to TSH.
Thyroid gland dysfunctions can result in hyper- or hypoactivity of the thyroid. Hypothyroidism is a condition in which the thyroid gland is functionally inadequate. Symptoms of hypothyroidism may include brittle fingernails, coarsening and thinning of hair, puffy eyes, weakness, and constipation, as well as the cold intolerance and fatigue associated with the thyroid gland’s critical role in thermogenic and metabolic homeostasis. 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; slowed speech; and decreased hearing.
Causes of hypothyroidism include autoimmune disorders, such as Hashimoto’s thyroiditis, atrophic thyroiditis, and postpartum thyroiditis; iodine deficiency, the most common cause of hypothyroidism in underdeveloped areas; congenital defects; medications or treatments that can result in hypothyroidism; central hypothyroidism in which the thyroid is not stimulated by the pituitary or hypothalamus; and infiltrative processes that may damage the thyroid, pituitary, or hypothalamus. These different causes of hypothyroidism are often interrelated. Usually, the exact cause of the hypothyroidism cannot be definitively determined.
Both Hashimoto’s thyroiditis and atrophic thyroiditis, also known as primary myxedema, are autoimmune disorders. Hashimoto’s thyroiditis is the more common of the two. Atrophic thyroiditis may be viewed as the later stages of autoimmune hypothyroidism in which there is minimal residual thyroid tissue. In this stage, fibrosis of the thyroid gland is quite extensive. Myxedema is the result of increased dermal glycosaminoglycan content, which traps water resulting in skin thickening, pitting, and swelling.
Often, there are no symptoms associated with atrophic hypothyroiditis for many years, and the condition remains undiagnosed until a small, palpably hard thyroid gland or abnormalities on routine thyroid function blood tests reveal the problem. If symptoms do develop, they are the usual ambiguous symptoms of hypothyroidism (i.e., fatigue, cold intolerance, weight gain, depression, and/or dry skin).
Patients presenting in the latter stage of autoimmune thyroiditis may have:
thinning of the epidermis
hyperkeratosis of the stratum cornea
yellow tinged skin due to an accumulation of carotene
Since atrophic thyroiditis manifests itself late in its progression, cardiac and neurological functions are often impaired. Carpel tunnel and other entrapment syndromes are common. However, these entrapment symptoms are not exclusive to atrophic thyroiditis, but rather can be seen with any autoimmune disorder.
The trigger for the immune system attack on the thyroid is not known. Speculation about the trigger includes trauma; environmental exposures, such as cigarette smoke; a genetic flaw; or virus or bacterium, although infection as a trigger is now thought of as less likely. Heredity, sex, and age are predisposing factors.
What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?
TSH and free T4 are the usual laboratory diagnostic tools in the diagnosis of hypothyroidism. In hypothyroidism due to atrophic thyroiditis, free T4 is decreased and TSH is increased. T3 is not generally reliable in the diagnosis of hypothyroidism. Measuring TSH, free T4, or other analytes will not identify the cause of the hypothyroidism as atrophic thyroiditis. (Table 1)
|TSH||free T4||blocking TSH receptor antibodies|
|increased (the more reliable test for hypothyroidism in stable thyroid status)||decreased (the more reliable test for hypothyroidism in unstable thyroid status)||presence (consistent with atrophic thyroiditis)|
In a patient with stable thyroid status, TSH is the more sensitive test in the diagnosis of hypothyroidism, since the relationship between TSH and free T4 is log/linear. Intraindividual variation for free T4 is quite small, so any small deficiency of free T4 will be sensed by the anterior pituitary relative to the individual’s set point and cause an amplified, inverse response of TSH.
In a patient with unstable thyroid status, free T4 is the more reliable indicator.
Antithyroid antibodies are often useful in the diagnosis of hypothyroidism caused by an autoimmune disorder. There are 3 different antithyroid antibodies: thyroperoxidase antibody (TPOAb), an antibody to a follicular enzyme involved in oxidation and organification of iodine; thyroglobulin antibody (TgAb), an antibody to thyroglobulin, the protein to which the iodine is attached; and TSH receptor inhibiting immunoglobulin, which competes with TSH for receptor binding sites but does not activate them.
If an antithyroid antibody is present, it is often indicative of a prior attack on thyroid tissue. Antithyroid antibodies are not present in all cases, and they sometimes can be found in patients without an autoimmune thyroid problem. Sixty percent of patients with atrophic thyroiditis have blocking thyroid stimulating receptor antibodies. TPOAb and TgAb are more frequently seen together in Hashimoto’s thyroiditis.
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 obscure the diagnosis of atrophic thyroiditis or complicate the monitoring of the effectiveness of thyroid replacement therapy.
Most thyroid testing 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 both of these 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 autoimmune disorders
Broadly reactive antibodies induced by infections or exposure to therapy containing monoclonal mouse antibodies (HAMA)
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 they affect 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 which 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 will decrease available free hormone. Theoretically free T3 and free T4 are not affected analytically by binding. 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 hormones and reduce total hormones. Eventually, a new 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 elevate free T4.
Free fatty acids are known to affect some methods.
Liver disease, androgens, and nephrotic syndrome decrease TBG, decreasing total thyroid hormones.
Estrogens increase TBG, increasing 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. But 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?
There is no confirmatory test for atrophic thyroiditis as a cause of hypothyroidism.
It has been suggested that the best confirmation of hypothyroidism is an evaluation of response to a trial administration of thyroid supplement in patients with symptoms of hypothyroidism.
Lone TSH testing may not be predictive of autoimmune disorders in which TSH may be normal, elevated, or depressed.
What Factors, If Any, Might Affect the Confirmatory Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?
A combination of high free T4 and high TSH may be indicative of therapeutic noncompliance. Acute ingestion of missed levothyroxine (L-T4) just prior to a clinic visit will raise the free T4 but fail to normalize the TSH due to 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 of day 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. Medication should be stored away from humidity, light, and increased temperatures. When ordering medication, it is best to avoid the 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 treatment for hyper- or hypothyroidism or after changing the dose of L-T4. It takes 6-12 weeks for pituitary TSH secretion to re-equilibrate 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 where 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 central inhibition of hypothalamic releasing hormone. The National Academy of Clinical Biochemistry guidelines for testing of hospitalized patients with nonthyroid illness recommendations 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 the hospitalized patients should have a functional sensitivity of 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 testing. 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 low total T4 levels in hospitalized patients 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 in which 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 in pregnancy.
During pregnancy, estrogens increase TBG to 2 or 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 from the increased TBG. 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, 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 midgestation through completion of puberty. In adulthood, TSH increases in the elderly. Therefore, 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 should 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 are:
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 (0/1 ng/dL)
TSH: 0.75 mIU/L
Tg: 1.5 μg/L
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- At a Glance
- What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?
- 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?
- What Lab Results Are Absolutely Confirmatory?
- What Factors, If Any, Might Affect the Confirmatory Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?