At a Glance
The thyroid gland produces, secrets, and stores 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.
Hypothyroidism is a condition in which the thyroid gland is functionally inadequate. In hypothyroid thyroiditis the functional inadequacy is related to inflammation. 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.
Hashimoto’s disease, also known as chronic lymphocytic thyroiditis, is the most common thyroid disease in the United States. In Hashimoto’s disease, the immune system attacks the thyroid gland, resulting in inflammation that can cause an under active thyroid gland. In response to the decreased thyroid hormone production by the thyroid gland, the anterior pituitary gland increases its production of TSH. This can cause the thyroid to enlarge. Such an enlargement is known as a goiter.
The trigger for the immune system attack on the thyroid in Hashimoto’s disease is not known. Speculation about the trigger includes trauma; environmental exposures, such as cigarette smoke; or a genetic flaw. Hashimoto’s disease is most common in women between 40 and 60 years of age and there is a genetic predisposition. The incidence of the disease is high in the Japanese population, most likely as a result of genetic factors and a diet high in iodine.
Often, there are no symptoms associated with Hashimoto’s disease for many years, and the condition remains undiagnosed until an enlarged thyroid gland or routine blood tests reveal a problem. If symptoms do develop, they are either related to the increased pressure in the neck caused by the goiter or the usual symptoms of hypothyroidism, which include fatigue, cold intolerance, weight gain, depression, and dry skin.
Post-Partum Thyroiditis (PPT) affects 4-10% of postpartum women. The exact cause of postpartum dysfunction is unknown. However, it is speculated to be the result of a modification to the immune system, required during pregnancy. PPT is associated with the development of antithyroid antibodies; antithyroid peroxidase (TPO) and antithyroglobulin (TgAb). Women with autoimmune disorders such as diabetes, positive antithyroid antibodies, history of previous thyroid dysfunction, history of previous PPT, or family history of thyroid dysfunction are more likely to develop PPT. Approximately 20% of women who have PPT develop the disease with subsequent pregnancies. PPT often occurs in stages, with thyrotoxicosis appearing first, followed by hypothyroidism. Not all women experience both stages of PPT. Approximately one-third of women with postpartum thyroid dysfunction exhibit both stages of the disease, whereas one-third of women have only either a thyrotoxic or a hypothyroid stage.
The thyrotoxic stage of PPT usually occurs 1-4 months after delivery and lasts approximately 1-3 months. This stage of PPT is often missed, because symptoms so closely mimic post pregnancy symptoms (i.e., fatigue, insomnia, anxiety, palpitations, and irritability), making it difficult to diagnose. Women will often present with the hypothyroid stage, which usually occurs 4-8 months after delivery and lasts approximately 9-12 months. Symptoms include fatigue, weight gain, and depression. Most women regain normal thyroid function within 12-18 months of the onset of symptoms, but about 20% of women who experience the hypothyroid stage remain hypothyroid.
PPT should be differentiated from lymphocytic hypophysitis. Lymphocytic hypophysitis can also occur postpartum and may cause TSH deficiency along with one or more pituitary hormones, including ACTH. It can be distinguished from PPT by blood tests. Lymphocytic hypophysitis will have normal TSH levels with low FT4 levels, whereas PPT will have increased TSH levels with low FT4.
Atrophic Thyroiditis occurs when bacteria or viruses produce inflammation in the thyroid gland. In response, the gland releases a surge of T3 and T4, thus causing TSH to decrease and consequently T3 and T4 production to decrease. Eventually T3 and T4 stores are depleted.
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 atrophic thyroiditis have 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. Other manifestations are:
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 already impaired. Carpel tunnel and other entrapment syndromes are common. However, these entrapment symptoms are not exclusive to atrophic thyroiditis. They can be seen with any autoimmune disorder.
Sub-Acute Thyroiditis is a painful inflammation of the thyroid that develops suddenly in a patient who has had a viral infection. Pain radiates throughout the neck, so much so that sub-acute thyroiditis can be mistaken for a bad sore throat. It may take several months for normal thyroid function to resume.
Which Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?
Antithyroid antibodies are often helpful in the diagnosis of an autoimmune thyroid disorder. There are three 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 made up of the essential amino acid tyrosine 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. Presence of antithyroid antibodies is the single most specific test for Hashimoto’s disease. They are present in 95% of cases. However, anti-thyroid antibodies are also present in 65- 85 % of patients with PPT; and they can sometimes be found in patients without an autoimmune thyroid problem. Usually, a combination of TPOAb and TgAb testing is used to add more specificity. Up to 20% of patients with one of the autoimmune hypothyroid diseases have antibodies against TSH receptor, which prevent binding with TSH. TSH receptor blocking antibodies are difficult to analyze and generally not available.
Normally, 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 in TSH. But TSH levels without a baseline are not helpful. Reference ranges are not as tightly set as individual set points, so TSH may be normal, elevated, or depressed.
In a patient with unstable thyroid status of any type, free T4 is the more reliable indicator; however, it is possible for high TSH stimulation to keep T4 levels within normal limits for quite some time. (Table I)
Atrophic Thyroiditis is really the end stage of destruction and shows a decrease in TSH T3 and T4. (Table II)
TSH, free T4, or other analytes will not identify the cause of the hypothyroidism or the individual classification.
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 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.
Trimester specific reference ranges should be used in 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 itself altered during pregnancy. TSH is decreased in the first trimester due to 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.
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.
Pregnancy is associated with lower albumin levels. Therefore, albumin-dependent methods are not suitable for accessing thyroid status during pregnancy.
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 malfunction of central inhibition of hypothalamic releasing hormone. The National Academy of Clinical Biochemistry has published guidelines for testing of hospitalized patients with nonthyroid illness.
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, so understanding the effect of timing is crucial
For a change in analyte value to have clinical significance, the difference should take into consideration analytical and biological variabilities. The magnitude of difference in thyroid testing values reflecting 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
During the hyperthyroid stage of PPT, a radioactive iodine uptake test may be performed if the mother is not breast feeding to distinguish PPT from Grave’s disease. Radioactive iodine uptake is decreased in women with PPT.
If there is a question about the cause of a goiter associated with hypothyroidism, a fine needle aspiration examined cytologically can confirm the presence of autoimmune thyroiditis.
It is important that Hashimoto’s disease be treated appropriately. If replacement therapy is inadequate, the thyroid gland will continue to enlarge and cholesterol levels may increase. Such hypercholesterolemia is generally seen as an increase in low density lipoprotein, which places the patient at greater risk of atherosclerosis. Hypothyroidism can also lead to an enlarged heart and, in rare cases, heart failure. Hashimoto’s disease is also associated with an increased rate of birth defects, if inadequately treated. If replacement therapy is too strong, symptoms of hyperthyroidism can develop, placing excessive strain on the heart and increasing the risk of osteoporosis.
Patients with hypothyroidism caused by a disorder of the immune system have a statistically increased risk of developing other autoimmune disorders, such as insulin dependent diabetes, rheumatoid arthritis, pernicious anemia, Addison’s disease, early menopause, vitiligo, thrombocytopenic purpura, or lupus erythematosis.
Interferences may obscure the diagnosis of hypothyroidism 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 auto-antibodies 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 auto-antibodies, 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 they affect simple competitive immunoassays. In immunometric assays HAMA and HAAA can form a bridge between the capture and signal antibodies. Auto-antibodies 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. Physiological shifts toward greater total hormone binding will 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 furosemide compete with thyroid hormone for protein binding sites and, thus, acutely increase free hormones and reduce total hormones. Eventually, a normal equilibrium is reestablished where 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.
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.
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.
A combination of high free T4 and high TSH may be an indication 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 because of a “lag effect”. Free T4 is the 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. 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 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.
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 re-equilibrate to the new thyroid hormone status. Similar periods of unstable thyroid status may occur following an episode of thyroiditis.
What's the Evidence?
Demers, LM, Spencer, CA. ” Laboratory Medicine Practice Guidelines: Laboratory Support for the Diagnosis and Monitoring of Thyroid Disease”. Clin Endocrinol (Oxf). vol. 58. 2003 Feb. pp. 138-40.
Spencer, C. ” Clinical Implications of New TSH Reference Range AACC Expert Access”.
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