The manuscript was drafted by a global expert writing task force comprised of Katleen Van Uytfanghe, Joel Ehrenkranz, David Halsall, Kelly Hoff, Tze Ping Loh, Carole A. Spencer and Josef Köhrle. The document reviews the current clinical use of routine TSH and thyroid hormone (T4 and T3) assays, taking into account geographic differences in disease prevalence, clinical and laboratory practice as discussed and compiled among the writing task force members. The manuscript includes the “Thyroid Hormone Measurement: Clinical Algorithm” table that summarizes key perspectives. The final document integrates feedback from the ATA Board of Directors and Guidelines and Statements Committee, and it underwent formal peer-review in Thyroid^®. Potential author conflict of interest was managed, and transparency maintained in formulating the manuscript.

“This is an extremely important analysis as it reviews the strengths and limitations of the laboratory tests that we have available to assess thyroid function. Understanding these issues allows clinical chemists and health providers to provide evidence-based decisions about the care of patients with thyroid disorders,” said Jacqueline Jonklaas, MD, PhD, Secretary of the American Thyroid Association.

Thyroid hormone-related dysfunction is amongst the most common diseases of the hormone system, especially in women, which is why L-Thyroxine ranks among the top 10 list of medical prescriptions worldwide. Laboratory diagnosis of thyroid status and monitoring of thyroid hormone therapy is based on measurement of the blood TSH concentration as the first line parameter, while determination of the thyroid (pro-)hormone T4 and its bioactive form T3 are only required for further differential diagnosis. Thus, TSH is one of the most frequently measured analytes in the outpatient setting. Over the last five decades, testing for TSH, T4 and T3 has evolved from demanding manual assays to highly automated immunoassay systems with substantial clinical utility. The strengths and limitations of the major thyroid tests currently in use are discussed in this publication. The paper is not a systematic review. There is a need to improve communication between Physicians and the Laboratorians performing these tests in order to understand the limitations of these methods and to optimize ordering and interpretation of thyroid tests. Standardization/harmonization, quality and performance of assays currently used in laboratory thyroid testing needs to be maintained and improved to aid the development and application of emerging assay methodologies and their correct interpretation. Such an approach will enable exchange, application and interpretation of test results within the global medical community for rational and optimal evidence-based state of the art care for patients with thyroid hormone-related diseases.

This review document is expected to be a useful reference tool for the global community. The document does not establish standard procedures for TSH and thyroid hormone measurements. This review does not intend to take the place of physician judgment in ordering and performing diagnostic tests for particular patients.

About the American Thyroid Association^®
The American Thyroid Association^® (ATA) is dedicated to transforming thyroid care through clinical excellence, education, scientific discovery and advocacy in a collaborative and diverse community. ATA^® is an international professional medical society with over 1,700 members from 43 countries around the world. The ATA^® promotes thyroid awareness and information through Clinical Thyroidology^® for the Public, a resource that summarizes research for patients and families, and extensive, authoritative resources on thyroid disease and thyroid cancer in both English and Spanish. The ATA^® website www.thyroid.org serves as a bonafide clinical resource for patients and the public who look for reliable thyroid-related information.

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1. Dr. Philip G. Clerc, of the Brooke Army Medical Center, San Antonio, Texas will present a poster on Thursday, October 31, 2019, “Prevalence of Laboratory Thyroid Dysfunction Prior to First Dispense of Levothyroxine,” (Poster 60) to address prescribing practices for levothyroxine. Providers often prescribe this medication for patients who present with nonspecific symptoms, even though they show no laboratory confirmation of thyroid dysfunction. Dr. Clerc and his colleagues conducted a retrospective data analysis for 9,400 patients in a military health system who had obtained their first dispense of levothyroxine in 2018 and had had thyroid function tests during the preceding 6 months. Of these patients, only 15% had a thyroid-stimulating hormone level higher than 10 mU/L. This may be the first estimate of prescribing practices for levothyroxine compared with clinical practice guideline recommendations.
2. Dr. Freddy Jean Karlo Toloza Bonilla, of the University of Arkansas for Medical Sciences, Little Rock, Arkansas and Mayo Clinic, Rochester, Minnesota will present a poster on Thursday, October 31, 2019, “Association of Thyroid Function with Posttraumatic Stress Disorder: A Systematic Review and Meta-analysis.” (Poster 94) Dr. Bonilla and his colleagues searched several databases for studies reporting mean values and standard deviation of thyroid hormone levels in patients with posttraumatic stress disorder (PTSD), compared with controls. Studies published from the databases’ inception through July 20, 2018, were included. The systematic review and meta-analysis included ten observational studies with a total of 675 participants. The meta-analysis revealed significant differences in mean thyroid hormone levels between patients with PTSD and control patients. The clinical implications of this finding are unknown.
3. In Poster 86 on Thursday, October 31, 2019, Dr. Daniella Araujo Muniz, of the Faculdade de Medicina de Marilia, São Paulo, Brazil, will present the results of a cross-sectional analysis assessing potential associations between thyroid and kidney function. The analysis included 1,110 participants aged 30 years and older who were free of thyroid disease and medications in a prospective, population-based study. Kidney function was determined based on estimated glomerular filtration rate (eGFR), and chronic kidney disease was defined as eGFR lower than 60 mL/min/1.73 m2. After adjustment for several risk factors associated with chronic kidney disease, logistic regression models identified subclinical hypothyroidism and low-normal thyroid function as independent risk factors for chronic kidney disease in this population. The poster is titled, “Subclinical Hypothyroidism and Low-Normal Thyroid Function Are Associated with Increased Risk of Chronic Kidney Disease: A Population-Based Study.”
4. Ms. Carol Chiung-Hui Peng, of the University of Maryland Medical Center, Midtown Campus, Baltimore, Maryland will present  Poster 56 on Thursday, October 31, 2019, “Association of Hypothyroidism and Mortality in the Elderly Population: A Systematic Review with Meta-Analysis.” The systematic review and meta-analysis included 27 cohort studies evaluating associations between hypothyroidism and mortality among a total of 1,122,891 older adults total. The meta-analysis found a significantly higher risk for all-cause mortality among older adults with hypothyroidism than among those with euthyroidism. No links between hypothyroidism and cardiovascular mortality were identified.
5. In an oral presentation on Thursday, October 31, 2019, Dr. Ying Yang, of the National Research Institute for Health and Family Planning, National Human Genetic Resources Center, Beijing, China will present an update to her study, “Preconception Thyroid Stimulating Hormone Level and Risk of Preterm Birth in Over 4.3 Million Rural Chinese Women Aged 20-49 Years: A Population-based Cohort.” (Oral 15) Dr. Yang and his colleagues conducted this historical cohort study among 4,324,810 reproductive-aged women who had participated in the National Free Pre-pregnancy Checkups Project (NFPC) between 2013 and 2016. The NFPC system collected data on preconception TSH levels, family history, and history of pregnancy, among other variables, and information on pregnancy outcomes were documented during the follow-up period before December 2017. Preterm births were defined as live births occurring at 28 to 37 weeks. The study documented 287,288 preterm birth events, for a prevalence of 6.64%. The study identified a U-shaped relationship between preconception TSH levels and risk for preterm birth, with both decreasing and increasing preconception TSH levels increasing the risk for preterm birth.

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The American Thyroid Association^® (ATA) is dedicated to transforming thyroid care through clinical excellence, education, scientific discovery and advocacy in a collaborative community. ATA^® is an international professional medical society with over 1,700 members from 70 countries around the world. Celebrating its 96^th anniversary, the ATA^® delivers its mission — transforming thyroid care through clinical excellence, education, scientific discovery and advocacy in a collaborative community — through several key endeavors:

• The publication of the highly regarded professional journals Thyroid^®, Clinical Thyroidology^®, and VideoEndocrinology
• Annual scientific meetings
• Biennial clinical and research symposia
• Research grant programs for young investigators
• Support of online professional, public, and patient educational programs

• Development of guidelines for clinical management of thyroid disease and thyroid cancer

The ATA^® promotes thyroid awareness and information through its online Clinical Thyroidology^® for the Public (distributed free of charge to over 12,000 patients and public subscribers) and extensive, authoritative explanations of thyroid disease and thyroid cancer in both English and Spanish. The ATA^® website www.thyroid.org serves as a bonafide clinical resource for patients and the public who look for reliable information on the Internet.

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1. 1. Dr. Maia Banige will give a presentation titled “Prediction of fetal and neonatal dysthyroidism,” showing how imperfect development and function of the thyroid in fetuses (FD) and newborns (ND) can be predicted from perinatal variables. Dr. Banige is from the Department of Pediatrics-Neonatology and Pediatric Emergency of the French-British Hospital Institute, Levallois-Perret, Ile-de-France.She and her colleagues conducted a retrospective, multicenter study using data from the medical records of all patients monitored for pregnancy from 2007 to 2014 in 10 obstetric centers of the Assistance Publique des Hôpitaux de Paris. Women with Graves’ disease who were positive for thyrotropin receptor antibodies (TRAb) at least once during pregnancy were included. Among 280,000 births, 2,288 medical records of women with thyroid dysfunction were selected and screened, and 417 women with Graves’ disease who were positive for TRAb during pregnancy (0.15%) were finally included in the study.

      Analysis revealed that the TRAb level in the mother and child was the strongest independent predictor of thyroid dysfunction. The risk of FD and ND increases with maternal hormonal imbalance and is also greater in the patients receiving antithyroid drugs (ATDs) during pregnancy. In pregnant women with TRAb levels ≥2.5 IU/L, fetal ultrasound monitoring is essential until delivery. All newborns with TRAb levels ≥6.8 IU/L should be examined by a pediatrician with special attention for thyroid dysfunction.

1. 1. A presentation titled “Pre-conception thyroid stimulating hormone level and risk of preterm birth in over 4.3 million rural Chinese women aged 20-49 years: a population-based cohort study” will be given by Dr. Ying Yang of the National Research Institute for Health and Family Planning and the National Human Genetic Resources Center. Dr. Ying and his colleagues studied the association between the pre-conception thyroid stimulating hormone (TSH) levels of women planning for pregnancy and the risk of preterm births (PTB).Researchers conducted a historical cohort study of 4,320,584 rural reproductive-age women who had participated in free National Free Pre-pregnancy Checkups (NFPC) in 2013-2016 in China. Data on preconception TSH, history of pregnancy and diseases, and other variables were obtained from the physical examination record in NFPC. Successful conception and pregnancy outcomes were documented during the follow-up period, June 2013 to December 2017. PTB is defined as any birth within 28 to 37 weeks of gestational age. Participants who failed to become pregnant within 6 months, suffered from fetal death or stillbirth, or had multiple gestations during the period of study were excluded from the analysis. The data documented 283,854 PTB events (6.57%).

      The study identified a V-shaped relationship between maternal pre-conception TSH levels and PTB risk. Either decreasing or increasing pre-conception TSH levels can significantly increase the risk of preterm birth.

1. 1. Dr. George Kahaly of the Department of Medicine at Johannes Gutenberg University Medical Center in Mainz, Germany, and colleagues have undertaken a three-phase clinical trial of the drug teprotumumab. Results from the first phase—a 24-week randomized, double-masked, placebo-controlled treatment trial of the drug, which is an insulin-like growth-factor-1 receptor inhibitory antibody—were reported in the New England Journal of Medicine (NEJM 2017; 376:1748). Compared with a placebo (69% versus 20%), teprotumumab reduced protopsis (protrusion of the eyeballs) significantly beginning at week 6 and continuing over the 24 weeks of the trial. This second-phase report is an assessment of clinical status at weeks 28 and 72.At week 28 (4 weeks after the treatment period), proptosis response was 73.8% in the teprotumumab group versus 13.3% in controls. At week 72 (48 weeks after treatment), 53% of week 24 teprotumumab proptosis responders maintained ≧ 2 mm improvement relative to baseline. Compared to baseline and placebo, clinical activity also decreased at week 28 and was relatively unchanged in the teprotumumab group at week 72. These results indicate no acute rebound of disease following the 24-week treatment.

      Dr. Kahaly’s group conclude that teprotumumab may represent a disease-modifying therapy in TAO by reducing proptosis and clinical activity, with sustained effects seen in most patients 48 weeks after treatment. In phase 3 of the trial, the research group will investigate whether patients would benefit from longer treatment or retreatment with teprotumumab.

1. Dr. Mats Holmberg of Institute of Medicine, Sahlgrenska Academy, and the Karolinska University Hospital, ANOVA, both in Stockholm, Sweden, will present a study titled “Structural brain changes in Graves’ hyperthyroidism may be of autoimmune origin.”  During the hyperthyroid state of Graves’ disease (GD), the volumes of medial temporal lobe (MTL) structures, e.g., the hippocampi, are reduced. This has been attributed to high thyroid hormone levels, but Dr. Holmberg and his colleagues hypothesized that the structural changes and mental symptoms may be due to autoimmunity per se. The aim of their study was to determine the relationship between nonthyroid autoimmunity and MTL volumes during hyperthyroidism in GD.Dr. Holmberg’s project is a longitudinal, observational, prospective case-controlled study in which 65 premenopausal women were evaluated within 2 weeks after a diagnosis of GD and again after 15 months of antithyroid treatment. Thyroid-stimulating hormone receptor antibodies, thyroid-stimulating immunoglobulins, and several additional antibodies were measured in the hyperthyroid state. MTL structures were scanned to determine hippocampal and amygdala volumes. This presentation reports preliminary data on the nonthyroid antibodies at baseline. Data on the thyroid antibodies will be reported separately.

   The data so far support the hypothesis that autoimmunity that is not directly connected to the thyroid may be involved in the impairment of brain function in GD, introducing a new concept that needs further study.

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The American Thyroid Association (ATA) is the leading worldwide organization dedicated to the advancement, understanding, prevention, diagnosis, and treatment of thyroid disorders and thyroid cancer. ATA is an international membership medical society with over 1,700 members from 43 countries around the world. Celebrating its 95^th anniversary, the ATA continues to deliver its mission of being devoted to thyroid biology and to the prevention and treatment of thyroid disease through excellence in research, clinical care, education, and public health.  These efforts are carried out via several key endeavors:

• The publication of the highly regarded professional journals Thyroid, Clinical Thyroidology, and VideoEndocrinology
• Annual scientific meetings
• Biennial clinical and research symposia
• Research grant programs for young investigators
• Support of online professional, public, and patient educational programs
• Development of guidelines for clinical management of thyroid disease and thyroid cancer

The ATA promotes thyroid awareness and information online through Clinical Thyroidology for the Public and extensive, authoritative explanations of thyroid disease and thyroid cancer in both English and Spanish. The ATA website serves as the clinical resource for patients and the public who look for reliable information on the Internet. Every fifth year, the American Thyroid Association joins with the Latin American Thyroid Society, the European Thyroid Association, and the Asia and Oceania Thyroid Association to cosponsor the International Thyroid Congress (ITC).

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We welcome your feedback and suggestions. Let us know what you want to see in this publication.

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Previous evidence clearly supports a link between altered thyroid function and cardiovascular disease. A new study demonstrating that higher levels of thyroxine-stimulating hormone (free T4) — still within the normal range and in individuals with normal thyroid stimulating hormone (TSH) levels — are associated with increased risk of sudden cardiac death. Layal Chaker, Erasmus Medical Center, Rotterdam, The Netherlands, presents the data to support this finding in the poster “Thyroid Function and Sudden Cardiac Death: A Population-Based Cohort Study.”

Subclinical hypothyroidism in elderly individuals can improve symptoms of depression, according to the findings of Letician Teixeira, Federal University of Rio de Janeiro, Brazil, detailed in the poster, ‘Longitudinal Evaluation of a Geriatric Population — Relationship Between Depressive Symptoms and Subclinical Hypothyroidism Defined by Age-Adjusted Criteria for Serum TSH.” Furthermore, higher free T4 levels, associated with greater thyroid activity, had a negative impact on various outcomes related to depressive symptoms in this older population.

Olga Yeliosof, Goreyb Children’s Hospital, Morristown, NJ, presents “Endemic Goiter in a Vegan Toddler in the US,” in which she describes a 23-month-old boy diagnosed with hypothyroidism due to iodine deficiency. The child had been breastfed until 16 months of age and was then fed a homemade vegan diet containing no cow’s milk or iodinated salt, and he took no vitamins. Administration of thyroxine-stimulating hormone and iodized salt to the child’s diet restored normal thyroid function.

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The American Thyroid Association (ATA) is the leading worldwide organization dedicated to the advancement, understanding, prevention, diagnosis, and treatment of thyroid disorders and thyroid cancer. ATA is an international membership medical society with over 1,700 members from 43 countries around the world. Celebrating its 92^nd anniversary, the ATA delivers its mission — of being devoted to thyroid biology and to the prevention and treatment of thyroid disease through excellence in research, clinical care, education, and public health — through several key endeavors: the publication of highly regarded professional journals, Thyroid, Clinical Thyroidology, and VideoEndocrinology; annual scientific meetings; biennial clinical and research symposia; research grant programs for young investigators, support of online professional, public and patient educational programs; and the development of guidelines for clinical management of thyroid disease and thyroid cancer. The ATA promotes thyroid awareness and information through its online Clinical Thyroidology for the Public (distributed free of charge to over 11,000 patients and public subscribers) and extensive, authoritative explanations of thyroid disease and thyroid cancer in both English and Spanish. The ATA website serves as the clinical resource for patients and the public who look for reliable information on the Internet. Every fifth year, the American Thyroid Association joins with the Latin American Thyroid Society, the European Thyroid Association, and the Asia and Oceania Thyroid Association to co-sponsor the International Thyroid Congress (ITC). This year the ITC is hosted by the American Thyroid Association at the Walt Disney World Swan and Dolphin Resort. More information about the 15^th ITC can be found at http://www.thyroid.org/itc2015/.

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What is the thyroid gland?

The thyroid gland is a butterfly-shaped endocrine gland that is normally located in the lower front of the neck. The thyroid’s job is to make thyroid hormones, which are secreted into the blood and then carried to every tissue in the body. Thyroid hormone helps the body use energy, stay warm and keep the brain, heart, muscles, and other organs working as they should.

Function

How does the thyroid gland function?
The major thyroid hormone secreted by the thyroid gland is thyroxine, also called T4 because it contains four iodine atoms. To exert its effects, T4 is converted to triiodothyronine (T3) by the removal of an iodine atom. This occurs mainly in the liver and in certain tissues where T3 acts, such as in the brain. The amount of T4 produced by the thyroid gland is controlled by another hormone, which is made in the pituitary gland located at the base of the brain, called thyroid stimulating hormone (abbreviated TSH). The amount of TSH that the pituitary sends into the blood stream depends on the amount of T4 that the pituitary sees. If the pituitary sees very little T4, then it produces more TSH to tell the thyroid gland to produce more T4. Once the T4 in the blood stream goes above a certain level, the pituitary’s production of TSH is shut off. In fact, the thyroid and pituitary act in many ways like a heater and a thermostat. When the heater is off and it becomes cold, the thermostat reads the temperature and turns on the heater. When the heat rises to an appropriate level, the thermostat senses this and turns off the heater. Thus, the thyroid and the pituitary, like a heater and thermostat, turn on and off. This is illustrated in the figure below:

T4 and T3 circulate almost entirely bound to specific transport proteins, and there are some situations which these proteins could change their level in the blood, producing also changes in the T4 and T3 levels (it happens frequently during pregnancy, women who take control birth pills, etc).

Another measurement done to assess the thyroid status of patients is the Free T4 measurement. The Free T4 avoids any change the proteins could have, giving us a more accurate value for the T4 level (see below).

Tests

Blood tests to measure TSH, T4, T3 and Free T4 are readily available and widely used. Tests to evaluate thyroid function include the following:

TSH Tests
The best way to initially test thyroid function is to measure the TSH level in a blood sample. A high TSH level indicates that the thyroid gland is failing because of a problem that is directly affecting the thyroid (primary hypothyroidism). The opposite situation, in which the TSH level is low, usually indicates that the person has an overactive thyroid that is producing too much thyroid hormone (hyperthyroidism). Occasionally, a low TSH may result from an abnormality in the pituitary gland, which prevents it from making enough TSH to stimulate the thyroid (secondary hypothyroidism). In most healthy individuals, a normal TSH value means that the thyroid is functioning normally.

T4 Tests
T4 circulates in the blood in two forms:

1) T4 bound to proteins that prevent the T4 from entering the various tissues that need thyroid hormone.

2) Free T4, which does enter the various target tissues to exert its effects. The free T4 fraction is the most important to determine how the thyroid is functioning, and tests to measure this are called the Free T4 (FT4) and the Free T4 Index (FT4I or FTI). Individuals who have hyperthyroidism will have an elevated FT4 or FTI, whereas patients with hypothyroidism will have a low level of FT4 or FTI.

Combining the TSH test with the FT4 or FTI accurately determines how the thyroid gland is functioning.

The finding of an elevated TSH and low FT4 or FTI indicates primary hypothyroidism due to disease in the thyroid gland. A low TSH and low FT4 or FTI indicates hypothyroidism due to a problem involving the pituitary gland. A low TSH with an elevated FT4 or FTI is found in individuals who have hyperthyroidism.

T3 Tests
T3 tests are often useful to diagnosis hyperthyroidism or to determine the severity of the hyperthyroidism. Patients who are hyperthyroid will have an elevated T3 level. In some individuals with a low TSH, only the T3 is elevated and the FT4 or FTI is normal. T3 testing rarely is helpful in the hypothyroid patient, since it is the last test to become abnormal. Patients can be severely hypothyroid with a high TSH and low FT4 or FTI, but have a normal T3. In some situations, such as during pregnancy or while taking birth control pills, high levels of total T4 and T3 can exist. This is because the estrogens increase the level of the binding proteins. In these situations, it is better to ask both for TSH and free T4 for thyroid evaluation.

Thyroid Antibody Tests
The immune system of the body normally protects us from foreign invaders such as bacteria and viruses by destroying these invaders with substances called antibodies produced by blood cells known as lymphocytes. In many patients with hypothyroidism or hyperthyroidism, lymphocytes make antibodies against their thyroid that either stimulate or damage the gland. Two common antibodies that cause thyroid problems are directed against thyroid cell proteins: thyroid peroxidase and thyroglobulin. Measuring levels of thyroid antibodies may help diagnose the cause of the thyroid problems. For example, positive anti-thyroid peroxidase and/or anti-thyroglobulin antibodies in a patient with hypothyroidism make a diagnosis of Hashimoto’s thyroiditis. If the antibodies are positive in a hyperthyroid patient, the most likely diagnosis is autoimmune thyroid disease.

Thyroglobulin
Thyroglobulin (Tg) is a protein produced by normal thyroid cells and also thyroid cancer cells. It is not a measure of thyroid function and it does not diagnose thyroid cancer when the thyroid gland is still present. It is used most often in patients who have had surgery for thyroid cancer in order to monitor them after treatment. Tg is included in this brochure of thyroid function tests to communicate that, although measured frequently in certain scenarios and individuals, Tg is not a primary measure of thyroid hormone function.

Non-Blood Tests

Radioactive iodine uptake
Because T4 contains much iodine, the thyroid gland must pull a large amount of iodine out from the blood stream in order for the gland to make an appropriate amount of T4. The thyroid has developed a very active mechanism for doing this. Therefore, this activity can be measured by having an individual swallow a small amount of iodine, which is radioactive. The radioactivity allows the doctor to track where the iodine molecules go. By measuring the amount of radioactivity that is taken up by the thyroid gland (radioactive iodine uptake, RAIU), doctors may determine whether the gland is functioning normally. A very high RAIU is seen in individuals whose thyroid gland is overactive (hyperthyroidism), while a low RAIU is seen when the thyroid gland is underactive (hypothyroidism). In addition to the radioactive iodine uptake, a thyroid scan may be obtained, which shows a picture of the thyroid gland (see Thyroid Nodules brochure).

Further Information

Further details on this and other thyroid-related topics are available in the patient information section on the American Thyroid Association website at www.thyroid.org.

Thyroid Function Tests Brochure for Saving and Printing (PDF File, 592 KB)

Thyroid Function Tests Brochure for Saving and Printing (PDF File, 258 KB)

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