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Editorial |
Quest Diagnostics, Nichols Institute, San Juan Capistrano, California 92690
Address all correspondence and requests for reprints to: Delbert Fisher, M.D., Quest Diagnostics, Nichols Institute, 33608 Ortega Highway, San Juan Capistrano, California 92690. E-mail: fisherd{at}questdiagnostics.com.
Newborn screening for congenital hypothyroidism (CH) began in Quebec in 1974. Jean Dussault and Claude Laberge adapted newly available immunoassays for T4 and TSH and new information characterizing thyroid system ontogenesis in the fetus and newborn to the Quebec filter paper blood spot screening program for phenylketonuria (1, 2, 3, 4, 5, 6, 7). Parallel programs were rapidly developed in New England and the northwest United States, leading in 1977 to recommendations for CH screening programs from the Newborn Screening Committee of the American Thyroid Association and publication of results of screening of the first million infants in 1979 (8, 9). A progress report of results covering 489,868 infants screened in 36 centers from 12 European countries was published by the Newborn Committee of the European Thyroid Association in 1980 (10). By 1992 it was estimated that 50 million infants worldwide were screened yearly, and the diagnosis of CH was confirmed in 3000–4000 births (11). There have been continuing questions and studies of CH infants for the optimal dose and timing of replacement therapy with Na-L-T4 (12). Nevertheless, the screening programs have achieved the goal of early detection and therapy and normal or near-normal development of infants with the classical forms of primary CH comprising some 90% of CH infants (11, 13, 14, 15).
The testing strategy has varied among programs with emphasis on detection of primary CH. The initial programs in North America employed a total T4 measurement followed by a TSH assay for specimens with low T4 values; European programs favor primary TSH screening (11, 16). Primary T4 screening is usually conducted using a follow-up TSH measured in infants with T4 values below arbitrary threshold levels. TSH is the most specific test for primary CH, but it does not detect infants with central hypothalamic-pituitary causes of CH. Total T4 measurements are less specific for primary or central CH. In Europe, due to the relatively low prevalence of central CH, it has been recommended that T4 not be included in the screening programs (16). The prevalence of central CH varies from 1:25,000 to 1:100,000 births (13). In the program in the northwest United States, where there is a concerted effort to identify all cases clinically, the prevalence is 1:29,000 births (13). Two-tiered testing (T4 + TSH) can identify suspect cases of central CH if low T4 and normal-low range TSH values are both reported (13). In 1986, Hanna et al. (18) reported 10-yr results from the northwest United States program adding a second screen at 6 wk of age to detect infants with CH missed during the first screening. Although detecting some missed cases of primary CH, central CH was identified in only 8 of 19 infants (11 identified by clinical means only) (18).
Data for the 50 United States, the District of Columbia, and two territories summarized in the latest national newborn screening report (2000) on The National Newborn Screening and Genetics Resource Center web site (http://genes-r-us.uthscsa.edu) lists 41 states conducting primary T4 screening (T4 + TSH), three conducting primary TSH screening (TSH + T4), and nine conducting TSH alone screening (TSH). The total number of infants screened in the listing was 4,125,135, with detection of 1,635 neonates with primary CH (1:2,533 births), 43 with secondary CH (1:95,933 births), and 362 with transient CH (1:11,345 births). The incidences of primary and secondary CH among 653,129 infants screened by eight states conducting a requisite second screen were similar (1:2,533 for primary and 1:130,000 for secondary) to results in the 53 programs, suggesting that a second (T4 + TSH or TSH + T4) screen does not improve detection of central CH.
One of the reasons for the low sensitivity of T4 in the detection of CH is that total T4 measurements largely represent T4 bound to T4 binding globulin (TBG) and, to a lesser extent, albumin and transthyretin (prealbumin). Thus, developmental, genetic, or disease-related variations in TBG artifactually alter T4 concentrations. Free or dialyzable T4 is more specific for the diagnosis of CH. However, free T4 measurements require relatively large serum samples and are not applicable to filter paper samples. One surrogate for free T4 is measurement of the T4/TBG ratio, which has been employed in the Netherlands CH screening program since 1995 (19). In that program, measurement of TBG is conducted in the lowest 5% of T4 values in a three-tier T4, TSH, TBG system; TSH is measured in the lowest 20% of T4 values. The T4/TBG ratio is calculated as T4 (in SD) + 5.1/TBG (in nanomoles per liter serum). A second heel stick filter paper blood sample is collected in cases with a borderline T4 and a low T4/TBG ratio and/or a borderline TSH concentration (19). Using this approach, all known infants with primary CH (n = 393) in the first 1,181,079 infants screened between January 1995 and December 2000 and 92% (66 of 72) of infants with central CH were detected (19). Costs per case detected by testing approaches were similar for primary TSH (T4 measured but not reported), T4 + TSH (both reported), and the T4 + TSH + TBG formats ($6353, $6209, and $6851, respectively). The detection rates for the three formats for primary CH were 94, 96, and 100%, respectively. For central CH, the detection rates were 0, 22, and 92%, respectively (19). The prevalence of primary CH in the 1,181,079 infant samples was 1:3,017 births, and that for central CH was 1:16,404 births. Central CH had a prevalence similar to that of phenylketonuria (1:18,000 births), and the central CH infants detected comprised some 14% of the 459 CH infants detected (19). Thus, the addition of TBG testing to complement T4 and TSH measurement seems to be an effective approach to diagnosis of central CH and also increases detection of primary CH significantly with a minimal increase in cost per infant detected.
In this issue of the JCEM, van Tijn et al. (20) report a 2-yr prospective multicenter study (April 1994 to April 1996) of infants with central CH diagnosed in the Netherlands T4, TSH, TBG screening program. Among 385,000 infants screened during the 2-yr period, there were 19 cases of permanent central CH detected, with 13.5% of the permanent CH cases detected during the same period, for a prevalence of central CH of 1:20,263 births. Presumptive central CH was diagnosed if the T4 was less than –1.6 SD, the T4/TBG ratio was less than 8.5, and the TSH result was less than 20 µU/ml (20 mU/liter) (20). The 8.5 T4/TBG cutoff was determined in a pilot study. Infants with borderline TSH (20–50 µU/ml) and/or borderline T4 (–1.6 to 2.9 SD) and/or T4/TBG results below 8.5 underwent a second heel stick sample. A total of 26 infants with presumptive CH were detected. On subsequent testing, 20 infants met the criteria for central CH [plasma free T4 < 0.93 ng/dl (12 pmol/liter), TSH < 15 µU/ml, and minimal TSH response to TRH]. Clinical features, cerebral magnetic resonance imaging, and pituitary adrenocorticotropic, somatotropic, and gonadotropic axes were studied. For TRH testing (10 µg/kg TRH with TSH measurements at 15–180 min), an "adequate" response was considered to be a 30-min peak TSH level greater than 15 µU/ml with a return to baseline by 3 h. The central CH patients showed either a diminished (TSH < 15 µU/ml) or a delayed (60–120 min) but excessive (16–70 µU/ml) increase with delayed (>180 min) decrease of the plasma TSH level. The six infants with false-positive central CH (free T4 values > 0.93 ng/dl) had adequate TRH test results. One of the 20 infants proved to have transient central CH with a normal TRH test result and normal thyroid function at age 13 months. Fifteen (78%) of the 19 infants with central CH had multiple pituitary hormone deficiencies, and nine (53%) had pituitary malformations on magnetic resonance imaging. Seven of these nine had delayed and excessive TSH responses to TRH.
This is the first comprehensive study of the effectiveness of newborn screening for CH, including central CH, related to testing strategy. Test results were evaluated after 5 yr follow-up so that the total cases, those detected and missed by the screening program, could be quantified. Assuming similar prevalence in Europe and North America, an estimation of missed cases in screening programs (TSH alone and T4 + TSH strategies) could reach 15–20% (5% primary CH and 14% central CH). The T4, TSH, TBG format appears capable of reducing missed cases to less than 5% and detecting most cases of central CH, reducing the morbidity and mortality associated with pituitary hormone deficiencies in the neonatal period. Although central hypothyroid may be less severe than primary CH, the free T4 cutoff criterion used for diagnosis in the Netherlands study [<0.93 ng/dl (<12 pmol/liter)] approximates –2 SD for cord blood values in full-term infants and is well below the 2 SD range in 7-d-old term infants recently reported by Williams et al. (21) [20.1–49.3 ng/dl (259–634 pmol/liter)]. There has been no detailed study of treatment effects on IQ and psychomotor development in newborn infants with severe central CH, but there is no reason to believe that congenital hypothyroidism affects central nervous system development differently whether primary or secondary. The T4, TSH, TBG testing strategy increases total screening costs somewhat, but the increased cost per case detected is minimal.
Thus, moving to the T4, TSH, TBG testing strategy to include central CH in newborn screening programs can be justified as fulfilling generally accepted screening criteria:
1. The disorder is relatively frequent, approximating the prevalence of phenylketonuria, the first newborn screening target.
2. A practical testing approach is available and relatively inexpensive.
3. Readily available and effective treatment is available.
4. Screening will allow early detection and treatment and reduce neonatal morbidity and mortality associated with pituitary hormone deficiencies and the central nervous system developmental damage associated with untreated congenital hypothyroidism.
Footnotes
Abbreviations: CH, Congenital hypothyroidism; TBG, T4 binding globulin.
Received April 18, 2005.
Accepted April 27, 2005.
References
This article has been cited by other articles:
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  D. A. van Tijn, E. J. Schroor, H. A. Delemarre-van de Waal, J. J. M. de Vijlder, and T. Vulsma Early Assessment of Hypothalamic-Pituitary-Gonadal Function in Patients with Congenital Hypothyroidism of Central Origin J. Clin. Endocrinol. Metab., January 1, 2007; 92(1): 104 - 109. [Abstract] [Full Text] [PDF]
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M. J. E. Kempers, C. I. Lanting, A. F. J. van Heijst, A. S. P. van Trotsenburg, B. M. Wiedijk, J. J. M. de Vijlder, and T. Vulsma Neonatal Screening for Congenital Hypothyroidism Based on Thyroxine, Thyrotropin, and Thyroxine-Binding Globulin Measurement: Potentials and Pitfalls J. Clin. Endocrinol. Metab., September 1, 2006; 91(9): 3370 - 3376. [Abstract] [Full Text] [PDF]
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