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Original Studies |
Quest Diagnostics, Inc.-Nichols Institute (D.A.F., J.C.N., E.I.C.), San Juan Capistrano, California 92690-6130; Kaiser Permanente Medical Care Program of Northern California (E.J.S., J.H.G.), Oakland, California 94611; Oregon Health Sciences University Center (S.L.F.), Loma Linda, California 97201-3011; and Kaiser Permanente Northwest (S.H.M.), Beaverton, Oregon 97005
Address correspondence and requests for reprints to: D. A. Fisher, Quest Diagnostics, Inc.-Nichols Institute, 33608 Ortega Highway, San Juan Capistrano, California 92690-6130.
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Abstract |
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Introduction |
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This relative hyperthyrotropinemia in many treated CH children has been variously attributed to suboptimal therapy and/or an abnormal setting of the T4 negative feedback control of pituitary TSH secretion (12, 13). Abnormal feedback control has been demonstrated early in some CH infants by an associated augmentation of PRL responses and paradoxal GH responses to TRH (5). Permanent resetting of T4 feedback control of TSH secretion has been documented in rodents rendered transiently hypothyroid in the neonatal period by propylthiouracil treatment (14). Whether the abnormal setpoint for TSH regulation in CH infants represents a transient maturational delay or a permanent resetting in some CH infants is not known.
To assess feedback control of TSH in treated CH infants, we measured serum free T4 by direct dialysis and TSH by third-generation immunochemiluminometric assay (ICMA) in CH infants, children, and adolescents, for comparison with values in normal newborn infants and children. Our results suggest that abnormal maturation of feedback control of TSH secretion in treated CH infants persists in about 10% of cases.
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Subjects and Methods |
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Serum free T4, TSH, T3, and thyroglobulin (Tg) concentrations were measured in 42 infants and 63 children with CH detected and treated through the Northwest Newborn Regional Screening Program or the Northern California Kaiser Permanente Medical Care Program (KPNC), respectively. The infants (30 females, 12 males) ranged from 2–9 months of age. Of the 37 for whom data were available, 24 were Caucasian, 11 were Hispanic, 1 was Oriental, and 1 native American. Birth weight was 3445 ± 271 g (mean ± SD). The initial screening filter paper T4 was 4.71 ± 2.48 µg/dL (61 ± 32 nmol/L); all TSH levels exceeded 220 mU/L. Thyroid scintigraphy was not routinely carried out in these infants. The initial starting T4 dose was 47.6 µg, or 13.8 µg/kg·day. The children ranged from 1–18 yr of age and were managed by participating pediatricians and/or pediatric endocrinologists at several KPNC sites. All had thyroid scanning in the neonatal period and were classified as athyrotic (A) or having an ectopic (E) or eutopic (N) thyroid gland. Children with known transient disease have been excluded. The 63 patients were derived from a group of 164 CH patients screened and followed at KPNC between March, 1980 and July, 1996. Of the total group,138 had thyroid scintigraphy [43 (31%) were athyrotic, 33 (24%) ectopic, and 62 (42%) eutopic]. This distribution is similar to that published by one of the authors (E. J. Schoen) in a smaller series(15). The male/female ratios for the athyroid, ectopic, and eutopic groups in the present study were 8/7, 5/15, and 9/18, respectively. Treatment was begun in all infants at a mean postnatal age of 14 days; all were treated within 40 postnatal days, with one exception (120 days). Thyroid hormone dosage usually was given in the morning. Growth and development were considered normal in all cases. Single blood samples were collected between 0900 and 1700 h at the time of routine follow-up outpatient visits for disease management.
To develop normal feedback control axis data, free T4 and TSH concentrations were measured by Quest Diagnostics, Inc. - Nichols Institute Diagnostics in 589 healthy subjects, 2 months to 54 yr of age; 83 hypothyroid patients; 116 hyperthyroid patients; and 40 normal term infants, 1–4 days of age. Healthy pediatric subjects and thyroid patients were examined at Loma Linda University Medical Center or White Memorial Medical Center in Southern California. All of these samples were drawn with individual patient or parent permission after approval by relevant institutional review boards. The normal subjects were screened to exclude thyroid disease and nonthyroidal illnesses by history, examination, and thyroid autoantibody measurements. Much of this normative data has been published previously (16). The hypothyroid patients were untreated, with serum TSH concentrations ranging from 10–1095 mU/L. The hyperthyroid patients also were untreated, with serum free T4 values ranging from 2.6–30 ng/dL (33.5–386 pmol/L) and TSH concentrations ranging from undetectable to 0.04 mU/L.
Materials and methods
The hormone assays were conducted at the Quest Diagnostics, Inc. - Nichols Institute Diagnostics reference laboratory. Serum free T4 was measured by direct equilibrium dialysis and RIA (17). The sample was dialyzed for 20 h at 37 C in a special dialysis chamber, after which free T4 was assayed directly in the dialysate, employing a highly sensitive T4 RIA. The interassay coefficient of variation was 8.5% at 1.56 ng/dL (20 pmol/L). Total T3 concentration in serum was measured by RIA, employing a high-affinity polyclonal rabbit antibody. Bound/free separation was achieved using a goat antirabbit second antibody. The interassay coefficient of variation was 7.8% at 165 ng/dL (2.54 nmol/L). Serum TSH was measured by third-generation ICMA, employing acridinium-labeled signal antibody and biotin-coupled capture antibody to effect avidin-biotin solid-phase separation of the antibody-TSH-antibody sandwich complex. Light generated from the acridinium substrate is directly proportional to TSH concentration. The interassay coefficient of variation was 20% at 0.01 mU/L. Serum Tg was measured by an ICMA, employing a polyclonal capture antibody and an acridinium-labeled monoclonal signal antibody. The acridinium ester complex emits light in the presence of hydrogen peroxide and hydroxyl ion and the light emitted is proportional to the Tg concentration. The interassay coefficient of variation was 13% at 32 ng/mL.
Means, SDs, statistical significance of differences between
means by Student t test, simple regression analyses,
correlation coefficients, and ANOVA at a significance of 0.05 were
obtained using SYSTAT software (SPSS, Inc., Chicago, IL).
The 99-percentile range of plotted free T4 and
TSH data from 309 healthy pediatric and 280 healthy adult controls, 83
untreated primary hypothyroid patients, and 116 untreated hyperthyroid
patients was determined based on the negative linear relationship
between free T4 concentration (plotted as the
dependent variable x on a linear scale) and TSH concentration (plotted
as the dependent variable y on a logarithmic scale). This line was
moved up and to the right, and
down and to the left, until 0.5% of
the data fell outside the range on either side. This provided the solid
99-percentile reference lines shown in Figs. 1
, 2, and 3.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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. Previously published values in normal
infants and children are shown for comparison (16). Both the free
T4 and TSH values in the treated children show
wider variation than control children, as expected in patients on
exogenous hormone. Serial samples were available during the first 3
months in 11 of the 42 treated infants. Serum free
T4 and TSH concentrations in these infants, at a
median postnatal age of 23 days (14–30 days) and at 3 months, are
shown in Table 2. There was wide
variation in both the free T4 and TSH
concentrations (minimum and maximum) at both 23 days and 3 months. The
(median) free T4 values at 23 days and 3 months
were 3.0 and 2.5 ng/dL (38.6 and 32.2 pmol/L) with corresponding TSH
levels of 34 and 1.2 mU/L. The serum TSH concentration exceeded 30 mU/L
in 6 of 11 infants (range, 34–824 mU/L) at 23 (14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30) days and was
less than 10 mU/L in all 11 infants at 3 months of age.
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, relative to thyroid gland
classification by initial thyroid scan (A = athyreosis, E =
ectopia, N = eutopia). There were no statistically significant
differences among the mean free T4, TSH, or
T3 values vs. thyroid gland
classification. The overall mean T3 for the
treated hypothyroid children was 112 ng/dL, range 19–206 (1.72, range
0.29–3.17 nmol/L). This value was significantly lower
(P < 0.001) than the mean level in the normal children
(150 ng/dL, range 72–228; 2.3 nmol/L, range 1.10–3.51). The mean Tg
concentrations vary significantly; normal values in children, 3–16 yr
old, range from 2–42 ng/mL (2–42 µg/L). Individual free
T4, TSH, T3, and Tg values
are plotted vs. disease type in Figs. 4, 5, 6, and 7.
Control values (95% range) are shown by the dotted lines.
The solid horizontal line in Fig. 7 indicates the level of
analyte detectability in the Tg assay; nine patients demonstrated
undetectable levels. The three CH patients classified as athyroid, but
with elevated Tg concentrations (Fig. 7), presumably were misclassified
on the basis of the initial thyroid scan. One other patient, initially
classified as athyroid by scan and with detectable serum Tg, was
reclassified as eutopic when rescanned at 3 yr of age. The other three
patients have not been rescanned.
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) from data of the 589 healthy subjects (adult data not shown)
and the 84 hypothyroid and 116 hyperthyroid patients (not shown). The
solid diagonal lines in Fig. 1 encompass the 99 percentile
range of plotted data from these 789 subjects. The individual plotted
values (circles) represent results in 299 of the healthy
subjects, 2 months to 20 yr of age, for comparison with the current
cohort of CH children and adolescents. Fig. 1 also plots free
T4 vs. TSH in 69 patients with
untreated thyroid hormone resistance, mostly provided by Dr. Samuel
Refetoff of the University of Chicago. Fig. 3 shows the plotted serum
free T4 vs. TSH concentration data in
the 63 children in the present study; values in the 42 infants are
plotted in Fig. 2. Most of the values in children (57 of 63, or 90%)
fall within the 99 percentile range of subjects with a normal
hypothalamic-pituitary-thyroid negative feedback control axis. There
are only 6 values clearly outside (to the right) of the 99
percentile range. Two of these children had ectopic glands (a 2-yr-old
male and a 3-yr-old female), 2 were athyroid (Tg values < 0.05
ng/mL; a 3-yr-old male and an 8-yr-old female), and 2 were eutopic (a
2-yr-old male and a 15-yr-old female). Among the infants, 18 of the 42
values (43%) clearly plot to the right of the 99 percentile
range (Fig. 2). The serum Tg concentrations were plotted against serum TSH values for the group of children with ectopic glands (data not shown). There was a significant positive correlation of Tg and TSH (r2 = 0.708, P < 0.001 for the ectopic gland group).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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and 3), as are the patients with
thyroid hormone resistance (Fig. 1). Several of the children manifested
elevated serum TSH concentrations with free T4
levels within the normal range. In these patients, the serum TSH
exceeded 10 mU/L, ranging to more than 100 mU/L (Figs. 2 and 3), but
the TSH values extrapolate to the normal range as free
T4 is increased (Fig. 2). These patients
presumably represent inadequate treatment. TSH levels are suppressed
below 1 mU/L in several children with normal range free
T4 concentrations (Figs. 2 and 3). These patients
presumably reflect overtreatment.
There was a shift to the right of the normal range of the
free T4/TSH plot for 24 of the infants and
children (Figs. 2 and 3), indicating thyroid hormone resistance at the
hypothalamic-pituitary level. One patient from the children’s group
(Fig. 3) plotted to the left of the normal axis 99
percentile range, and the TSH was suppressed. This patient is
presumably overtreated, but the significance of the left shift is
unclear.
Exogenous thyroid hormone administration, to children with CH, increases serum free T4 levels by about 30% by 5 h, with a reciprocal decrease in TSH values of about 40% by 6 h (18). Thus, T4 ingestion rapidly adjusts serum TSH within the normal range, and the timing of T4 treatment vs. blood sampling would not account for a right shift in the plotted free T4 vs. TSH. The prevalence of apparent thyroid hormone resistance in the present patients decreased with age, from 43% in the group less than 1 yr of age to about 10% in the 1- to 20-yr-old group. This is in agreement with earlier reports indicating frequently elevated serum TSH, relative to T4 or free T4 values, in CH infants early in the course of treatment and infrequent inappropriately elevated TSH levels in older children (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12).
The mechanism(s) for the thyroid hormone resistance in CH infants and children is not clear. The molecular events involved in setpoint maturation are complex, involving hypothalamic TRH secretion, pituitary TRH receptors, thyrotroph T3 nuclear receptors and receptor cofactors, thyrotroph iodothyronine monodeiodinase activities, and TSH biosynthetic and secretory mechanisms. Imprinting of the feedback control axis has been shown in rodents, wherein transient neonatal administration of T4 or propylthiouracil produces permanent resetting of the TSH feedback control system (14, 19, 20, 21). Adult rats, exposed transiently to neonatal T4 administration, manifest hypothyroidism, decreased hypothalamic TRH and pituitary TSH levels, and decreased serum TSH concentrations, with an obtunded TSH response to TRH (19, 20, 21). They resemble rats with bilateral anterior hypothalamic lesions in the thyrotropic area (14). Pituitary iodothyronine monodeiodinase activity also is increased (21). After transient neonatal propylthiouracil administration, adult rats demonstrate low serum T4 levels, increased serum and pituitary TSH levels, and an impaired response to TRH (14). Pituitary monodeiodinase activity was not studied. Cavaliere and co-workers (22) have shown that adult patients with treated CH require larger doses of exogenous T4 to block the TSH response to TRH than do treated adult onset hypothyroid patients. Both patient groups were maintained on 200 µg (0.2 mg) T4 daily before TRH testing; the peak TSH response in the CH group was 24 mU/L vs. 5.7 mU/L in the patients with acquired hypothyroidism (22).
The pathogenesis of the thyroid resistance in infants with CH, however,
remains unclear. TSH/free T4 values in normal
neonates, during the first 1–2 weeks, plot to the right of
the normal range because of the neonatal TSH surge secondary to
neonatal cooling and presumably mediated by increased TRH secretion
(23). Thus, increased TRH secretion or mutation of the
T3 nuclear receptor gene, with decreased
effective hypothalamic-pituitary T3 feedback,
shift the TSH/free T4 plot to the
right (Fig. 1). This transient neonatal hypothalamic-pituitary
T4-resistant state remits rapidly in most
infants, and the serum TSH decreases rapidly with treatment (Table 2).
However, in a significant number of patients, hypothyroxinemia with
increased TRH/TSH secretion produces a more prolonged state of
pituitary thyrotroph hyperplasia-hypertrophy or otherwise alters
maturation of hypothalamic-pituitary feedback control in the
hypothyroid fetus (Figs. 1 and 2). Whatever the mechanism, the feedback
resistance is corrected in most of these children by 1–3 yr.
It is well known in adults on T4 replacement therapy for hypothyroidism that higher serum T4 concentrations are required than in the normal euthyroid state to maintain normal serum TSH concentrations (24). This is believed to reflect the additional T4 necessary to replace the approximately 20% of T3 production derived from thyroidal T3 secretion. Our data are consistent with this observation. The mean serum T3 concentration in the present treated hypothyroid children with increased mean T4 concentrations was 112 ng/dL (1.72 nmol/L), a value reduced 25% below that of normal children (150 ng/dL, 2.31 nmol/L), but this reduction would have a limited impact on prevailing serum TSH concentrations. T4-to-T3 conversion, mediated by type 2 iodothyronine monodeiodinase in the hypothalamus and pituitary glands, provides about half of the local T3 in these tissues; and serum T3 must be increased about 2-fold to replace T4-to-T3 conversion as a source of pituitary nuclear T3 (25).
The serum Tg concentration results in the present patients are of
interest. Three of the 13 athyroid children for whom Tg measurements
were available had normal serum concentrations, indicating the presence
of residual thyroid tissue (Fig. 7). Repeat scans are not available, so
whether these children were misclassified is not clear. Most values in
patients in the ectopic group (Fig. 7) are within the normal range,
suggesting significant secretion, in spite of replacement dosage of
T4, indicating that about 90% of the patients
have residual thyroid tissue capable of Tg synthesis; and the positive
correlation of serum Tg and TSH concentrations indicates responsiveness
of Tg production to TSH stimulation. Measurable serum Tg concentrations
have been reported in most patients with CH (26, 27, 28, 29, 30, 31, 32, 33). The absence of
measurable serum Tg is considered, in association with thyroid scanning
and ultrasound, for the diagnosis of thyroid agenesis (27, 28, 29). There
are several reports of prolonged persistence of measurable serum Tg
levels in CH children with residual thyroid tissue, and these data
indicate roughly proportional variations of serum TSH and Tg levels
during therapy (30, 31, 32, 33).
The prevalence of eutopic glands in the KPNC children (42%) is higher than in earlier reports. All of the children with normal glands, by scan, have been taken off T4 replacement therapy and the hypothyroidism confirmed by significant increases in their serum TSH concentrations (to >20 mU/L). The cause(s) of the impaired thyroid hormone production in these children is not known.
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Acknowledgments |
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Received November 10, 1999.
Revised February 2, 2000.
Accepted February 4, 2000.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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