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Laboratory Thyroid Function Testing: Do Abnormalities Always Mean CPJ52410.1177/000992281347 4757065706Clinical PediatricsLahoti and Frank Commentary Clinical Pediatrics 52(4) 287 –296 Laboratory Thyroid Function Testing: Do © The Author(s) 2013 Reprints and permissions: sagepub.com/journalsPermissions.nav Abnormalities Always Mean Pathology? DOI: 10.1177/0009922813475706 cpj.sagepub.com Amit Lahoti, MBBS1 and Graeme R. Frank, MD1 Introduction pediatricians with guidelines that will help them distin- Thyroid function tests (TFTs) are the most frequently guish between variants of normal from true thyroid ordered endocrine investigations in children and adoles- pathology, and in doing so, avoid unnecessary parental cents. Abnormalities in TFTs can help in diagnosis of anxiety and unwarranted subspecialist referrals. primary thyroid disorders (i.e. disorders in which the defect is at the thyroid level) as well as secondary or central thyroid disorders (in which defect is at the pitu- Thyroid Hormone: Synthesis, itary level). Hypothyroidism is the most common thy- Secretion, and Regulation roid disorder in the pediatric (as well as adult) population. Iodine is the rate-limiting substrate for synthesis of thy- Although there is a paucity of population studies on the roid hormone and the first step in the synthesis of thyroid prevalence of acquired hypothyroidism in children, the hormone is iodide trapping by the thyroid gland. This few studies that have been done on this subject indicate inorganic iodide is organified by the enzyme thyroid an increase in the prevalence of clinical hypothyroidism peroxidase (TPO) and incorporated into thyroglobulin over the years. A study from the United Kingdom found (Tg), a large glycoprotein synthesized by thyroid follicu- a population prevalence of hypothyroidism in the <22 lar cells, and mono- and diiodotyrosine (MIT and DIT) years age-group of 0.135% for the period of 1993-1995, residues are formed. Subsequent coupling of these iodo- higher than the 0.04% to 0.06% reported prevalence in tyrosines within Tg molecule leads to the formation of prior studies.1 In the United States, reports based on the the thyroid hormones: triiodothyronine (T3) and thyrox- National Health and Nutritional Examination Survey ine (T4) that are stored in follicular colloid, the protein- (NHANES) during a similar time period (1988 and aceous material contained within the thyroid follicular 1994) as well as more recently (1999-2002) found the lumen. Under the effect of thyroid stimulating hormone prevalence of clinical hypothyroidism to be 0.3%.2 This (TSH), there is colloid resorption by the follicular cells higher prevalence in the United States is likely because and enzymatic degradation by lysosomal enzymes the population group studied was ≥12 years and the release MIT, DIT, T4, and T3. Whereas T4 and T3 are prevalence of hypothyroidism increases with age. subsequently released in the circulation, MIT and DIT Symptoms of hypothyroidism are relatively nonspe- get deiodinated for recycling of iodine.4 cific, diverse and often mild. Many children with symp- Only 20% of the total T3 in bloodstream is secreted toms of attention-deficit or hyperactivity, fatigue, by the thyroid gland; the remaining 80% is derived from obesity, constipation and hair loss have TFTs ordered to conversion of T4 by deiodinases, which are enzymes rule out hypothyroidism or thyroid hormone resistance present in peripheral tissues. Most of the thyroid hor- as the cause of these symptoms. The majority of these mone circulating in the bloodstream is bound to carrier patients, however, have normal results.3 proteins: thyroxine-binding globulin (TBG), thyroxine In recent years, there appears to be an increase in the binding prealbumin (TBPA or transthyretin), and albu- use of TFTs by pediatricians during annual health min. Although TBG is the most important carrier protein assessments of healthy children. The frequent thyroid for T4, T3 appears to be equally bound to TBG and function testing and the relatively low prevalence of true thyroid pathologies has led to a high detection rate of 1Cohen Children’s Medical Center of New York, North Shore LIJ values that are minimally outside given normal ranges. Health System, New Hyde Park, NY, USA In general, on finding an “abnormal” TFT, the physician informs the parents of the abnormal values and recom- Corresponding Author: Amit Lahoti, Division of Pediatric Endocrinology, Cohen Children’s mends referral to a pediatric endocrinologist. In many Medical Center of New York, North Shore LIJ Health System, 1991 cases, however, these values represent nonpathologic Marcus Avenue, Suite M100, Lake Success NY 11042, USA normal variants. The aim of this review is to provide Email: [email protected] Downloaded from cpj.sagepub.com at Harvard Libraries on March 8, 2015 288 Clinical Pediatrics 52(4) 1. Thyroid profiling tests to detect or exclude disturbances in thyroid function. This includes TSH and total and free levels of T4 and T3. Additional tests that are often included in “thyroid panels” of commercial laboratories include Tg, TBG, and T3 uptake (T3U) or T3 resin uptake (T3RU). 2. Definitive tests of thyroid to identify the eti- ology of thyroid disease. These tests mainly include antibodies against various thyroid antigens, which are markers of autoimmune thyroid disease—both hypothyroidism and hyperthyroidism, namely, antithyroglobulin antibody, antithyroperoxidase antibody, TSH receptor antibody, and thyroid-stimulating immunoglobulin. Several comprehensive reviews in the past have dis- cussed abnormalities in these tests, which suggest hyperthyroid or hypothyroid states. This review will focus on “abnormalities” in these lab tests that do not necessarily indicate a pathologic state. Abnormalities in TSH Levels Elevated TSH with normal thyroid hormone level in the neonate Figure 1. Thyroid hormone secretion is regulated by feedback Case 1: The newborn screen in a full-term male loops working at the level of pituitary and hypothalamus drawn on the second day of life shows the fol- Abbreviations: TRH, thyrotropin-releasing hormone; TSH, thyroid- lowing results: stimulating hormone; T4, thyroxine; T3, triiodothyronine. Analyte Result Reference Range albumin. These bound hormones are in equilibrium with Thyroxine: Screen negative >6 µg/dL their free forms and in euthyroid state, free T4 accounts TSH: 37.5 µIU/mL <20 µIU/mL for <0.1% of the total T4 and free T3 accounts for ~0.3% 5 of total T3. The state newborn screening report includes Thyroid hormone synthesis and secretion is closely the statement: Possible hypothyroidism. The regulated by the hypothalamic–pituitary–thyroid axis. mother had an uneventful pregnancy, had no Thyrotropin-releasing hormone (TRH) synthesized in history of thyroid disease, and on examination, the paraventricular nucleus of the hypothalamus trav- the infant has no goiter and no clinical features els across the medial eminence to the anterior pituitary of hypothyroidism. through the hypophyseal portal venous system. TRH stimulates secretion of TSH from the pituitary. TSH is An elevated TSH level on a newborn screen should released into the systemic blood circulation and trans- alert a practitioner to the possibility of congenital hypo- ported to the thyroid gland where it stimulates thyroid thyroidism. However, awareness of the thyroid adapta- hormone synthesis and release. Regulatory feedback tion in the immediate period after birth is very important loops working at the level of pituitary and hypothala- for careful interpretation of this “screening” test. mus modulate thyroid hormone secretion (Figure 1). An abrupt increase in pituitary TSH secretion Measures of Th yroid Function occurs soon after birth and reaches a peak of about 60 to 80 µIU/mL at 25 to 30 minutes of A number of tests are available to assess thyroid function life. Serum TSH concentration decreases rap- and these can be broadly divided into 2 main categories: idly over the first 24 hours of life, and there- Downloaded from cpj.sagepub.com at Harvard Libraries on March 8, 2015 Lahoti and Frank 289 Table 1. Normal Range for Thyroid Function Tests for 9, although above the lab reference range, is Different Age-Groups. within the age adjusted normal range of 1.7 to Age TSH (µIU/mL) T4 (µg/dL) T3 (ng/dL) Free T4 (ng/dL) 9.1 µU/mL (Table 1). The family is therefore reassured that patient’s TFTs are normal for age Cord blood 1.0-17.4 7.4-13.0 15-75 0.9-2.2 1-4 days 1.0-39.0 14.0-28.4 100-740 2.2-5.3 and no further endocrine follow-up is needed. 2-20 weeks 1.7-9.1 7.2-15.7 105-245 0.9-2.3 5-24 months 0.8-8.2 7.2-15.7 105-269 0.8-1.8 Hence, if the first screen is drawn at less than 48 hours 2-7 years 0.7-5.7 6.0-14.2 94-241 1.0-2.1 8-20 years 0.7-5.7 4.7-12.4 80-210 0.8-1.9 of life and the TSH is moderately elevated (20-50 µIU/mL), 21-45 years 0.4-4.2 5.3-10.5 70-204 0.9-2.5 repeat sampling is appropriate, which may be a repeat NBS or serum specimen to a commercial lab based on Abbreviations: TSH, thyroid-stimulating hormone; T4, thyroxine; T3, triiodothy- ronine. clinical situation and/or state policies. In general, the Adapted from Marks and LaFranchi6 with kind permission from Springer Sci- commercial laboratories will provide a result within 24 ence and Business Media. hours, while repeat NBS screens sent to the state lab may take several days. after more slowly and generally falls to below 10 µIU/mL by 1 month.4,6 Therefore, results Elevated TSH with normal thyroid hormone level in young should be compared with the age-appropriate children and adolescents normal ranges for interpretation (Table 1). Newborn screen (NBS) for hypothyroidism Case 2: A 9-year-old obese girl has TFTs done may use a primary TSH test or a primary T4 at her annual visit, which show the following test and this varies from state to state.
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