When it comes to laboratory testing, children are not just small adults. Clinical interpretation of many laboratory tests requires age-specific data. This is particularly important with thyroid function testing, as specific thyroid tests change with age, organ growth, and development.
Thyroid function abnormalities are among the most common endocrine problems in children. Because proper thyroid function is essential for brain and bone growth, detection of any issues is especially critical in children.
The thyroid gland is an important endocrine gland located at the front of the neck, just below the Adam’s apple. The thyroid produces hormones that are responsible for the rate of all metabolic and chemical processes affecting every cell, tissue, and organ in the body. The thyroid gland is, therefore, essential for life, growth, and development.
Signs and symptoms of thyroid disease are general and nonspecific and may be silent or difficult to detect. Although the prevalence of thyroid disorders is most common in adults, diseases of the thyroid can occur at any age, from newborn through adolescence and adulthood.
Pediatric-specific reference intervals (See sidebar below) for thyroid tests enable proper interpretation of test results for optimal patient care for the smallest patients. However, few studies have been published to provide this information, and hospital laboratories may find establishing their own pediatric reference intervals challenging due to resourcing issues; lack of sufficient, well-characterized samples; and blood-volume constraints. Further, general published intervals are not always accurate for each instrument and assay. Instrument- and assay-specific pediatric reference intervals are preferred for the accurate interpretation of thyroid results.
Thyroid function assays
When the thyroid gland produces too much thyroid hormone (overactive), the condition is called hyperthyroidism. When the thyroid gland produces too little thyroid hormone (underactive), the condition is called hypothyroidism. Diagnosis and management of hyper- and hypothyroidism require accurate laboratory testing. Tests used to aid in the clinical assessment of thyroid status include thyroid-stimulating hormone (TSH), free and total thyroxine (T4), and free and total triiodothyronine (T3).
TSH is a hormone produced by the anterior pituitary gland that stimulates the thyroid gland to synthesize and secrete thyroid hormones T4 and T3. Measurement of TSH is the best initial screening test for the presence of primary hyper- or hypothyroidism. The capability of a TSH assay to distinguish between normal and subnormal concentrations is essential for thyroid testing strategy. Quantification of TSH at a lower value of 0.01 mlU/L yields information that is useful to clinicians referring patients with subnormal TSH concentrations. An abnormal TSH measurement leads to additional testing, which may include free or total T3 and/or free or total T4.
Both T3 and T4 play an important role in regulating metabolism. In the circulation, 99.7 percent of T3 is reversibly bound to transport proteins. Unbound T3 (free T3) is metabolically active. The free T3 test helps determine whether the thyroid is functioning properly. It is ordered primarily to help diagnose a form of hyperthyroidism called T3 thyrotoxicosis, in which only T3 is elevated. It may also be ordered to help monitor the progress of a patient with this disorder. Free T3 is usually ordered following abnormal TSH and T4 tests.
Like T3, T4 is a hormone synthesized and secreted by the thyroid gland. In the circulation, 99.95 percent of T4 is reversibly bound to transport proteins. The remaining T4 is not bound to transport proteins but is free in circulation. This unbound fraction, free T4, is the metabolically active hormone.
Free T4 is used as a follow-up test to an abnormal TSH. Patients with hypothyroidism have decreased levels of free T4 and elevated levels of TSH. In contrast, patients with hyperthyroidism have increased levels of free T4 and low levels of TSH.
Less-common thyroid function tests include thyroglobulin antibodies (anti-TG), antibodies to thyroid peroxidase (anti-TPO), thyroid receptor antibodies (TRAb), and thyroid-
stimulating immunoglobulins (TSI). These antibody assays are used for the diagnosis of various autoimmune diseases affecting the thyroid gland.
Thyroid disease in the neonate
Congenital hypothyroidism affects one in 1,500 to 3,000 newborns in the U.S. each year. The condition most often occurs for no known reason, due to the thyroid gland failing to develop normally, but 10 percent to 20 percent of the time, it is inherited.1 If the diagnosis is delayed and immediate treatment is not given, congenital hypothyroidism can lead to growth and developmental defects and severe mental retardation.
Because most newborns show no signs of it, the condition is usually detected during routine newborn screening. At U.S. hospitals, routine testing for thyroid function in newborns has been mandatory since 1976. Within the first week of life, a heel-stick blood sample is taken to assess an infant’s thyroid (most commonly with a TSH test). If any abnormality is found, confirmatory thyroid testing is performed. If test results show elevated levels of TSH and decreased levels of free T4, the infant is immediately given thyroid hormone-replacement therapy. There is usually no cure for congenital hypothyroidism, but replacement therapy and continued monitoring will ensure proper growth and development of the infant.
Congenital hyperthyroidism is less common in neonates but is critical to detect early, as consequences can be very serious and complex. While thyroid hormones produced by or given to the mother cross the placenta in only limited amounts, both thyroid antibodies and antithyroid drugs (ATDs) readily cross the placenta and affect fetal thyroid function. If the mother has the autoimmune disease Graves’ disease (GD), the thyroid-stimulating antibodies or immunoglobulin in maternal blood can cross the placenta and stimulate the unborn child’s thyroid gland, resulting in hyperthyroidism in the neonate.
Because neonatal Graves’ disease is caused by maternal antibodies, it is self-limited and usually resolves when the child is aged three to four months. However, symptoms of hyperthyroidism can persist longer, depending on the clearance of the stimulating antibodies. In rare circumstances, the levels of stimulating antibodies are high enough to cause severe hyperthyroidism in the newborn. This can be a potentially life-threatening medical condition, and immediate treatment with antithyroid medication is necessary to lower thyroid hormone levels.
If the levels of stimulating antibodies are low, newborns may hardly be affected and no treatment may be necessary, as the mother’s antibodies will soon clear from the baby’s bloodstream. If the mother is taking antithyroid drugs, infants are usually born asymptomatic. Signs and symptoms of hyperthyroidism may develop when the antithyroid medications that have crossed the placenta are cleared from the infant’s bloodstream and the thyroid-stimulating antibodies have not yet cleared. The hyperthyroidism, although transient, can be serious. Neonates born to mothers with GD must be carefully monitored with both thyroid function tests and TSI or TRAb assays and managed with medication if needed.
In childhood and adolescence
Both hypothyroidism and hyperthyroidism can develop during childhood. Children with Down syndrome are at increased risk of thyroid disorders, including congenital hypothyroidism, GD, and another autoimmune disease, Hashimoto’s thyroiditis.2
Hypothyroidism in childhood and adolescence is more common in females and in those with a family history of autoimmune disorders. They usually undergo testing because of the detection of a goiter (enlarged thyroid gland) on routine examination or because of poor growth rate present for several years. In adolescence, these children may experience delayed puberty if not diagnosed and treated. Worldwide, iodine deficiency continues to be an important cause of hypothyroidism in children and adults, but it is a less common cause in North America.
The most common cause of hypothyroidism in children and adolescents is Hashimoto’s thyroiditis. The treatment for Hashimoto’s thyroiditis in children and adolescents is the same as in adults. Thyroid hormone replacement is taken daily for life. The dosage of thyroid hormone must be age-appropriate, as the body’s demands for thyroid hormone vary with age. Regular thyroid function tests must be assessed by a doctor to ensure that normal hormone levels are maintained and adjusted as needed.3
Hyperthyroidism, like hypothyroidism, can produce symptoms that are often vague and nonspecific and can mimic other conditions. These symptoms include goiter, anxiety and irritability, heat sensitivity and increased perspiration, weight loss (despite normal eating habits), rapid or irregular heartbeat, and ophthalmopathy. The most common cause of hyperthyroidism is GD, and although it is much less common in childhood than in adults, it can occur at any age.
The clinical diagnosis of hyperthyroidism is made by the finding of decreased TSH and increased concentrations of circulating thyroid hormones (T4, or preferably free T4, and free T3). In hyperthyroidism, the circulating T3 concentration may be elevated out of proportion to the T4 because TSH receptor antibodies stimulate increased conversion of T4 to T3. The diagnosis of GD is confirmed by the demonstration of TSH receptor antibodies in serum. Treatment of GD is with antithyroid drugs (ATDs) or by removal of the thyroid gland by surgery or radioablation. Following either medical treatment or thyroid gland removal, child patients become hypothyroid and require lifelong thyroid replacement therapy and thyroid hormone monitoring.
Thyroid disorders in pregnancy, neonates, and childhood can be complex. Patients require frequent laboratory testing and follow-up treatment, often throughout their lives. Along with endocrinologists, the lab plays a vital role in managing their challenging conditions.
Pediatric reference intervals
To ease the challenges presented by a lack of age-specific reference intervals for infants and pediatrics, a study was designed and conducted to establish such intervals for thyroid hormones for four instrument systems. The study included FT4, FT3, T4, and T3 (on four systems) and the third-generation TSH (on two systems) for three age groups: infants (1–23 months), children (2–12 years), and adolescents (13–20 years). Stringent inclusion criteria were used to ensure a well-characterized subject selection and a significant sample size. Statistical analysis used to derive the thyroid reference intervals for these subgroups were based on the CLSI C28-A3 and Horn and Pesce’s Reference Intervals: A User’s Guide.
Eight collection sites across the United States were used to collect samples, which were aliquoted and shipped frozen to one laboratory for testing. Testing was conducted using assay-specific runs on the instruments, and samples were tested with the handling conditions recommended for each assay in its Instructions for Use (IFU).
For the infant group, the lower and upper reference limits were estimated as the 2.5th and 97.5th percentiles of the distribution produced by the robust method. For the children and adolescents groups, the lower and upper reference limits were established as the 2.5th and 97.5th percentiles of the test result distribution.
The sample size totals (391, 421, 407, and 435) for each of the four analyzers included in the study were significant, and stringent inclusion criteria were used for well-characterized subject selection as well as a statistical package recommended by CLSI and Horn and Pesce.4,5
The pediatric reference ranges thus established are reflected in the IFUs for the respective assays. For more information and study details, please visit usa.siemens.com/pediatricthyroid.
REFERENCES
- Bahn RS, Burch HB, Cooper DS, et al. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the ATA and AACE. Endocr Pract. 2011;17(3)457-520.
- Zori RT, Schatz DA, Ostrer H, Williams CA, Spillar R, Riley WJ. Relationship of autoimmunity to thyroid dysfunction in children and adults with Down syndrome. American Journal of Medical Genetics—Supplement. 1990;7:238-241.
- Raymond J, LaFranchi SH. Fetal and neonatal thyroid function: review and summary of significant new findings. Curr Opin Endocrinol Diabetes Obes. 2010;17(1):1-7.
- CLSI. Defining, Establishing and Verifying Reference Intervals in the Clinical Laboratory; Approved Guideline—Third Edition. Volume 28, Number 30, Guideline C28-A3c, 2010.
- Horn PS, Pesce AJ. Reference Intervals: A User’s Guide. Washington, DC: AACC Press; 2005.
Linda C. Rogers, PhD, DABCC, FACB, serves as Senior Clinical Consultant, Scientific & Clinical Affairs, Siemens Healthineers.
