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Original Studies |
Division of Endocrinology, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Canada M5G 1X8; and Department of Pediatrics, E. Wolfson Medical Center and Tel-Aviv University Sackler School of Medicine, Tel-Aviv, Israel 69978
Address all correspondence and requests for reprints to: Dr. Denis Daneman, Division of Endocrinology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8. E-mail: denis.daneman{at}sickkids.on.ca
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The etiology of CH may also play an important role in determining both the disease severity at diagnosis as well as its outcome (15). In addition, factors such as lower T4, higher TSH, and greater delay in skeletal maturation may be related to etiology. However, only one previous study has assessed L-T4 therapy longitudinally in children according to the etiology of their hypothyroidism (15). In that study the follow-up period was only 1 yr, and the numbers of subjects with dyshormonogenesis and dysgenesis were small (9 and 13 children, respectively).
The purpose of this study was to evaluate thyroid hormone levels and patterns of L-T4 dose adjustment in a large cohort of children with CH followed from diagnosis to 4 yr of age according to their etiology determined by radionuclide imaging studies. We hypothesized that TSH and T4 concentrations, L-T4 dose requirements, and frequency of dose adjustments in these subjects would differ according to the etiology of the hypothyroidism. We also assumed that if differences exist, these would help determine specific follow-up schedules and dosing levels appropriate for each diagnostic group.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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).
Immediately after confirming the diagnosis,
L-T4 therapy was started at doses of
25, 37.5, or 50 µg/day to provide approximately 10 µg/kg·day. As
part of the routine evaluation of CH at the Hospital for Sick Children,
all infants underwent radionuclide imaging studies at the time of
confirmation of the diagnosis to define the etiology. On the basis of
the technetium 99m thyroid scan results, the CH subjects were divided
into 3 groups. In group 1 athyreosis was diagnosed in infants whose
thyroid scans did not show any radionuclide uptake. This group
consisted of 31 infants (19 females and 12 males). One subject in this
group had no visible thyroid tissue on thyroid scan, but had a
confirmatory TSH concentration of only 2 mU/L. The reason for this
remains uncertain, although the subsequent course (rapid rise in TSH on
stopping L-T4 therapy and the need
for frequent dose changes within the first year of life) confirmed the
diagnosis of CH. In group 2 dysgenesis was diagnosed in infants whose
thyroid scans demonstrated uptake of the tracer at the base of the
tongue (lingual; n = 49 patients) or indicated either small
(n = 2) or hemiagenetic (n = 3) glands on uptake. This group
consisted of 54 patients (42 females and 12 males). In group 3
dyshormonogenesis was diagnosed in infants whose thyroid gland was
enlarged and showed avid uptake of the tracer by a normally located and
shaped thyroid gland (n = 33). Four additional infants (2 pairs of
brothers), who demonstrated no significant technetium 99m uptake were
assigned to the dyshormonogenetic group. In 1 pair there was a
bilobular thyroid gland in the normal location on ultrasound, and in
the other pair, 1 had a small thyroid gland with poor uptake of the
tracer. They were, therefore, considered to have a trapping defect. In
3 additional patients, thyroid scans were not performed because their
older brothers had documented goitrous hypothyroidism, as indicated by
a thyroid scan showing an enlarged gland with increased uptake, or
other family members presented with visible goiter. The
dyshormonogenetic group, therefore, consisted of a total of 40 infants
(14 females and 26 males).
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In many infants, the screening TSH results were reported by the provincial health laboratory as more than 100 or 250 mU/L and the confirmatory TSH as more than 50 or 60 mU/L. For the purposes of data analysis, these results were considered as 100, 250, 50, and 60 mU/L, respectively. Similarly, confirmatory T4 results reported as less than 10 nmol/L at diagnosis were considered as 10 nmol/L. Confirmatory TSH and T4 levels were determined in the Department of Pediatric Laboratory Medicine at the Hospital for Sick Children, using a sensitive third generation TSH immunoassay and homogeneous latex agglutination, respectively (Immuno 1 System, Bayer Corp.). The normal reference ranges for TSH and T4 concentrations did not change throughout the study period.
Statistical analysis
The data were analyzed as follows. Repeated measures ANOVAs were
performed to determine the patterns of T4 and TSH
concentrations in the three CH groups over the 4-yr study period.
Pearson correlation coefficients were used to assess the relationship
between L-T4 dose and therapeutic
outcome. 
2 analysis (goodness of fit test) was
used to evaluate the proportion of subjects requiring dose adjustments
at each time interval. The plasma TSH concentrations were normally
distributed, and a Bonferroni correction for multiple comparisons was
used. The SPSS statistical software package (SPSS, Inc.,
Chicago, IL) was used for these analyses. Statistical significance was
established at P < 0.05.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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. A female
preponderance was evident in the athyrotic and dysgenetic groups (61%
and 77%, respectively), whereas only 35% of the patients with
dyshormonogenesis were female (P < 0.001). The median
gestational age, age at onset of therapy, and starting dose of
L-T4, expressed as
micrograms per kg, were similar in all three groups. Screening and confirmatory TSH and T4
Screening TSH values were higher in infants with athyreosis than
in those with either dysgenetic or dyshormonogenetic CH (P <
0.01 and P < 0.02, respectively; Table 1). Median
confirmatory T4 levels were lowest in infants
with athyreosis compared with infants with dysgenesis and
dyshormonogenesis (P < 0.01 and P
< 0.05 respectively; Table 1). The percentage of infants reported to
have screening TSH levels higher than 100 or 250 mU/L was also
significantly higher in athyrotic infants (55%) than in infants with
dysgenetic or dyshormonogenetic CH (29% of the infants in both groups;
P < 0.05). Similarly, the percentage of patients
reported to have T4 concentrations less than 10
nmol/L was higher in the athyrotic group than in the other two
etiological groups (30% vs. 4 and 5%, respectively;
P < 0.001).
Follow-up results
The pattern of TSH concentrations throughout the 48-month
follow-up period varied greatly among the three groups (Table 2). During the first 3 months of therapy,
mean TSH levels were consistently higher in the athyrotic group than in
either the dysgenetic or dyshormonogenetic groups. The differences were
highly significant at 2–4 weeks and 3 months. At the 6-month
follow-up, the mean TSH concentration in the athyrotic group was still
the highest, although a significant difference was now found only
between the athyrotic and dyshormonogenetic groups (P
< 0.05). The higher TSH levels during the first 6 months in athyrotic
patients also corresponded to the number and percentage of infants who
required an increase in
L-T4 dose (Fig. 1). Mean TSH levels normalized by 12
months of age in athyrotic subjects, whereas patients with dysgenetic
CH had an increase in TSH concentrations at 12 months compared with the
other two groups (Table 2) and required a dose increase (Fig. 1). At 18
months, the mean TSH levels in the athyrotic group increased again
compared with those in the other two groups, although the difference
did not attain statistical significance. Thereafter, the mean TSH
levels fluctuated between normal (24 and 36 months) to slightly
elevated levels (48 months), and during this period no significant
differences were observed between the groups. In patients with
dyshormonogenesis, the mean TSH levels normalized earlier (9 months)
despite the fact they received the lowest doses of
L-T4 and required the
fewest dose increases. In addition, their mean TSH values remained
lowest throughout the study period except at 48 months.
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). Levothyroxine dose
During the entire study period, the athyrotic group received the
highest dose of L-T4, and the
subjects with dyshormonogenesis received the lowest dose (Table 3). By 12 months of age, the dose per kg
BW had decreased by about 40–50% from onset of therapy in all three
groups: athyreosis, from 9.4 to 5.6 µg/kg; dysgenesis, from 9.2 to
5.1 µg/kg; and dyshormonogenesis, from 9.3 to 4.2 µg/kg. In
athyrotic patients the T4 doses at 3 and 9 months
of age were significantly higher than those in the other two groups
(Table 3). At 12, 18, 36, and 48 months, significant differences were
found only between the dyshormonogenetic and the other two CH groups
(Table 3).
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). At the 3 and 6 months visits,
respectively, 52% and 48% of subjects with athyreosis required dose
changes, whereas in the dyshormonogenetic group the corresponding
figures were 13% and 22%. The percentage of infants with dysgenetic
CH who needed a dose change at 3 and 6 months was intermediate compared
with those in the other two groups (19% and 31%). Although most
patients who needed dose changes at 3 and 6 months visits were in the
athyrotic group, the majority requiring a dose change at 12 months were
those with dysgenetic CH (37% vs. 16% and 18%; Fig. 1).
Subjects with dyshormonogenesis had the lowest percentage of dose
changes throughout the study period (range, 2.5–22.5%; Fig. 1).
2 analysis showed significant group
differences in the percentage of subjects needing a dose change at 2–4
weeks (P < 0.05), 3 months (P <
0.01), and 12 months (P < 0.05). To assess the function of the hypothalamic-pituitarythyroid axis, we performed correlations between current TSH concentration and L-T4 dose at the previous follow-up visit. We found significant negative correlations in the athyrotic group, but not in the other two groups: 2–4 weeks, r = -0.46; P < 0.02; 3 months, r = -0.43; P < 0.05; 9 months, r = -0.4; P < 0.05; and 12 months, r = -0.54; P < 0.01. In fact, in the dyshormonogenetic group, we found a significant positive correlation between TSH levels and the dose at previous follow-up visit at 9 and 12 months only (r = 0.40 and r = 0.43, respectively; P < 0.05), reflecting the low levels of both TSH and L-T4 dose during these visits.
TSH and T4 correlations at diagnosis and follow-up
In all three groups, there was a significant inverse correlation between TSH and T4 concentrations at most time intervals after initiation of therapy (r = -0.31 to -0.63; P < 0.05). However, there was no correlation between TSH and T4 concentrations in the athyrotic group at the 2–4 week evaluation.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Despite rapid normalization of mean T4 levels in all three groups, mean TSH levels at screening and during the first 6 months of follow-up were consistently higher in those with athyreosis than in those with dysgenetic or dyshormonogenetic etiologies. The athyrotic group also had the lowest total T4 levels at diagnosis and 3 months of age. At 1 yr of age, we found that the mean TSH levels of dysgenetic CH patients became significantly higher than those in the other groups. By 24 month of age and at all subsequent visits, the dyshormonogenetic group showed significantly lower total T4 levels than the other two groups.
Previous studies in which the disease severity was related to etiological category either were not longitudinal (18, 19, 20, 21) or were limited by their short duration of follow-up and small cohort size (15). As in this report, most of these studies found the lowest screening and pretreatment T4 levels in the athyrotic (agenesis) group (18, 19, 20, 21). One study reported significantly higher pretreatment T4 levels in those with a dysgenetic hypothyroidism than in those with athyreosis or dyshormonogenesis (21). The latter study included only 11 infants with athyreosis, 2 with dyshormonogenesis, and 28 with dysgenetic thyroid glands. This is not the usual etiological distribution and may reflect sampling bias.
Differences between TSH concentrations determined at screening and diagnosis in the three etiological groups have been even less consistent. Only 1 study reported that the screening TSH level was highest in the athyrotic group (20). Another reported that TSH concentrations did not significantly differ from those in the other 2 groups; however, only 13 patients with dysgenetic thyroids and 9 with dyshormonogenesis were included (15).
Follow-up data and etiology: dose relationships
Our study demonstrates that a clear difference in the severity of CH depends on etiology not just at diagnosis but also during follow-up to age 4 yr. During the first 6 months of life, the athyrotic group was the most severely affected. The mean TSH concentrations during this period were highest in the athyrotic group, intermediate in the dysgenetic group, and lowest in those with dyshormonogenesis. At 6 months of age, the mean TSH levels of all groups were still abnormally high (>7 mU/L), even though there was normalization of T4 levels. Despite early treatment, elevated plasma TSH concentrations in the first year of life are very common in infants with CH regardless of their etiological group (13, 14, 22, 23). Accumulating data from these and other studies in which the severity of hypothyroidism was determined by parameters such as the degree of skeletal delay and T4 and TSH concentrations suggest that the increase in TSH concentrations is related to a lower L-T4 dose and that TSH inhibition can be attained by higher doses (11, 13, 14, 22, 23, 24, 25). Despite having received a higher L-T4 dose, the percentage of patients who required a dose increase in the first 6 months was significantly higher in the athyrotic group. Furthermore, in this group, TSH levels correlated inversely with L-T4 dose at the previous visit. These findings provide strong support for the view that the etiology should be considered as an important determinant of treatment schedules in patients with CH. Accordingly, in those patients with athyreosis, more frequent follow-up visits and a higher dose of L-T4 both at initiation of therapy and at follow-up may be required, particularly during the first 6 months of life. Other recent data also support this view (11, 16).
Our patients with athyreosis began treatment at a median age of 12 days and an initial dose of 9.4 µg/kg·day (range, 7–14). Van Vliet et al. studied 8 patients for 18 months, initiated therapy at 14 days of age, and used a median L-T4 dose of 11.6 µg/kg·day, which was slightly higher than our dose (11). They found the developmental outcome of infants with severe CH (defined by the degree of skeletal delay and T4 concentrations) was indistinguishable at 18 months from that of children with less severe hypothyroidism. However, some subtle differences may appear over time, especially with the use of more sophisticated neuropsychological tests (9).
Transient hyperthyroxinemia resulting from a relatively high dose regimen does not appear to produce any harmful effects (11, 12, 15, 24). Although an earlier study did report increased temperamental difficulties among infants started on a higher dose of L-T4 (26), this dose was subsequently found to be beneficial for intellectual outcome at 7 yr of age (27). Although a high initial dose of L-T4 therapy may be beneficial for patients with severe hypothyroidism, the advantage of this therapeutic approach over the long term remains to be proven.
It has been suggested that despite early treatment of CH, disease severity (determined mostly by T4 concentrations and the degree of skeletal delay) has a threshold effect on prenatal brain development (7, 8). In those studies that evaluated the intellectual outcome in children with CH at 5 yr of age, the initial dose of L-T4 ranged between 8 and 10 µg/kg (7, 8). These dose differences may explain to some degree the different conclusions reached by different investigators. In a study evaluating later neuropsychological outcome of children with CH, where the etiology was available, children with athyreosis had the lowest scores (9). These data strengthen our view that children with athyreosis need more careful evaluation and a more aggressive treatment schedule. Only long-term follow-up studies evaluating the intellectual outcome in children with CH due to different diagnostic categories will confirm whether the outcome is affected by the etiology and whether it is consistently worse in athyreosis (28). An ongoing study on a subset of our sample in whom thyroid hormone measurements and neuropsychological abilities were measured at 7–12 yr of age will provide relevant data on the clinical significance of our current findings.
An interesting finding in our study was the significant increase in TSH concentrations at 12 months in children with dysgenetic CH compared with those in the other two groups. This rise corresponds to the high proportion of patients requiring a dose increase at this time. T4 concentrations in the dysgenetic group decreased, reaching a nadir (from 171 to 131 nmol/L) at the same time. Based on a 40% decrease in T4 levels between screening and diagnosis, Delange et al. proposed the term vanishing thyroid tissue to explain the progressive decrease in serum T4 in infants with thyroid dysgenesis (19). One explanation for our findings may be the loss of functional capacity of the thyroid tissue not only in the first few weeks of life but throughout the first year. In particular, the partially functioning thyroid gland of children with thyroid dysgenesis may no longer meet the metabolic needs of rapid growth by 12 months of age.
The female preponderance found in our patients with dysgenetic CH is also noteworthy. This is consistent with the observations in a recent report from Devos et al. suggesting that the molecular mechanisms resulting in athyreosis or defective thyroid migration may be "modulated by the genetic make-up of the embryo and/or the hormonal milieu of the fetus" (29).
In our patients with dyshormonogenesis, there was a prompt response to L-T4 therapy, with serum TSH concentrations decreasing significantly by 2–4 weeks of age and remaining lowest during the first 9 months. In these patients the low TSH levels persisted throughout this time despite the fact that they received the lowest dose (micrograms per kg/day) of L-T4, and their serum T4 concentrations levels did not differ from those in the other two groups. In normal individuals, TSH secretion is inversely proportionate to the concentration of thyroid hormones (30). Thus, the early and marked suppression of TSH in response to therapy in the dyshormonogenetic CH group, as opposed to lack of suppression in response to a similar dose in the athyrotic group, suggests that the sensitivity of the hypothalamic-pituitary-thyroid axis to circulating T4 may differ in the various etiological groups (15).
In children with dyshormonogenetic hypothyroidism, ongoing thyroid stimulation by normal or slightly elevated TSH concentrations may be a risk factor for the development of nodular hyperplasia later in life (31, 32). In our patients with dyshormonogenesis, slightly increased TSH levels were found later at 48 months. Thus, closer follow-up of these patients may become necessary at older ages.
The follow-up schedules in our study were similar to those employed by other groups (12, 16), but were slightly less frequent than recommended by the American Academy of Pediatrics guidelines (33). We conclude, therefore, that treatment and follow-up schedules for CH need to consider the unique hormonal patterns and different responses to therapy in the three primary etiological categories. This implies that an etiological diagnosis is advisable before initiation of therapy but without delaying it, a procedure that is not routine in most centers. Although the need for close supervision in children with CH, especially those with athyreosis, is crucial, particularly during early life, those with dysgenetic and dyshormonogenetic CH may also require more attention later life.
Received February 10, 2000.
Revised July 31, 2000.
Revised September 26, 2000.
Accepted September 29, 2000.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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, patients in the dysgenetic group; 
,
patients in the dyshormonogenetic group.