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From the Clinical Research Centers |
University of Tennessee, St. Jude Children’s Research Hospital, and Methodist LeBonheur Children’s Medical Center, Memphis, Tennessee 38103
Address all correspondence and requests for reprints to: Susan R. Rose, M.D., 50 North Dunlap, Fourth Floor, Memphis, Tennessee 38103. E-mail: srose{at}utmem1.utmem.edu
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Abstract |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Most prior endocrine investigations have focused on altered GH secretion as the cause of poor growth among childhood cancer survivors. GH secretory dynamics are often altered after cranial radiation therapy (4, 5, 6, 13, 14, 15). However, even with GH therapy, some childhood cancer survivors do not grow as expected, suggesting that other factors, such as thyroid hormone deficiency, may remain unaddressed. Most prior studies of delayed growth in this population have dealt only superficially with possible hypothalamic-pituitary-thyroid dysregulation (central hypothyroidism). Many studies have used only elevated TSH levels to identify hypothyroidism (8, 11, 16, 17, 18, 19, 20, 21, 22), although TSH levels are commonly normal in central hypothyroidism.
The free T4 (FT4) concentration can also be within normal limits in such patients, albeit in the lowest third of the range (23, 24). Because of this subtle presentation, diagnosis and treatment may be delayed until impaired growth or constitutional symptoms become overt (23). We hypothesized that many children who have received treatment for malignancies have subtle central hypothyroidism. We reasoned that TSH disorders might develop before any other endocrine deficiency in some patients, and that the incidence of TSH dysregulation would increase with total cranial or craniospinal radiation dose and with time elapsed since cancer diagnosis.
Here we report the use of TSH dynamics (the nocturnal TSH surge and the TSH response to TRH) to determine what proportion of central hypothyroidism among symptomatic survivors of childhood cancer is not detected by the use of TSH and FT4 alone. We also assessed how the incidence of central hypothyroidism is related to cranial radiation dose and to time after tumor diagnosis and compared the incidence rate of central hypothyroidism with that of other hormone deficiencies in the same patient group.
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Subjects and Methods |
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Study subjects (n = 208) were drawn from the children and
adolescents referred for endocrinological evaluation during follow-up
at St. Jude Children’s Research Hospital during years 1995 through
1997 after completing therapy for brain tumors, head and neck tumors,
noncranial solid tumors, or leukemia. The histological diagnoses of
these patients are shown in Table 1
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Prior treatment had included surgical excision, chemotherapy, and
radiation therapy. Radiation therapy was delivered in conventionally
fractionated single doses of 180 cGy/day.
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This study did not seek to define the total incidence of thyroid abnormalities after treatment of childhood cancer. Instead, we sought to identify occult central hypothyroidism among survivors who showed signs suggestive of subtle hypothyroidism or hypopituitarism. Patients who developed unambiguous central hypothyroidism (FT4 below the lower limits of the normal range with no TSH elevation) within 6 months after surgery for primary hypothalamic or pituitary tumors and patients with obvious primary hypothyroidism (TSH, >15 mU/L) were excluded from this study. Of the children referred, 208 (68 girls) were selected for dynamic evaluation of TSH secretion because of declining FT4 or FT4 in the lowest one third of the normal range, mild TSH elevation, slow growth velocity, impaired stamina, or altered timing of puberty. In this group, a mean of 6.1 ± 4.1 (SD) yr (range, 1–16 yr) had elapsed since tumor diagnosis.
Procedures
Children were admitted to the metabolic testing unit at Methodist-LeBonheur Children’s Medical Center. Informed consent was obtained from the parents of each child, and assent was obtained from each child as clinically feasible. All tests were performed as part of our routine clinical evaluation of hypothalamic-pituitary function. The study of TSH surge in these patients was also approved by the University of Tennessee institutional review board.
Patients had normal meals and remained sedentary during the testing period. For the TSH surge test, blood samples were obtained hourly beginning at 1400 h and ending at 1800 h and again beginning at 2200 h and ending at 0400 h (25). After completion of the TSH surge test, TRH (7 µg/kg up to a maximum dose of 200 µg) was infused iv over 5 min, and blood samples for TSH assay were drawn at 0400 h (baseline) and 10, 15, 30, 45, 60, 90, 120, and 180 min after the infusion began (25).
All patients underwent additional standard endocrine tests for evaluation of hypothalamic-pituitary function during the same admission. These included insulin-like growth factor I (IGF-I), IGF-binding protein-3, GH stimulation tests (arginine and L-DOPA) (26), tests of ACTH secretory adequacy (250 or 1.0 µg ACTH test, metyrapone test) (27, 28), test of pubertal status (GnRH test) (29), and bone age radiograph (30). Overnight GH sampling was performed (every 20 min from 2200–0400 h) (31) if IGF-I and/or IGF-binding protein-3 were low for age and peak stimulated GH concentration was normal.
Assays
Samples were assayed for TSH by using the Abbott Ultrasensitive hTSH kit and the AxSym System (32) (Abbott Laboratories, Abbott Park, IL). Serial serum samples from each patient were assessed in a single TSH assay run to reduce interassay variability. A single sample from each patient was assayed in triplicate for T4 and FT4 concentrations on the AxSym System.
Data analysis
Nadir TSH was computed as the average of the three consecutive lowest afternoon TSH values. Peak TSH was the average of the three consecutive highest TSH values after 2100 h. The nocturnal TSH surge was calculated from peak and nadir TSH levels using the following formula: nocturnal TSH surge = [(peak TSH - nadir TSH) x 100]/nadir TSH. A TSH surge below the 95% confidence interval for normal values (50- 300% rise above nadir) was considered to be blunted (25).
To analyze the response to TRH, we compared the peak TSH, the time from TRH administration to peak TSH, and the rate of TSH decline (measured 60 min after the peak and 180 min after TRH administration) of study patients with those of 76 normal children given TRH (25). In the normal control group, the TSH peak after TRH was between 8–30 mU/L and occurred within 45 min after TRH was given; at 60 min after the TSH peak, TSH declined to 75% or less of the peak value; at 180 min, the TSH value was 3 times or less the basal TSH value.
Diagnostic criteria
The diagnosis of central hypothyroidism required at least one of the following: 1) blunted TSH surge, 2) low or delayed TSH peak after TRH, or 3) delayed TSH decline after TRH.
The diagnosis of mild primary hypothyroidism required either 1) an elevated basal TSH level (4.8–15 mU/L), or 2) an elevated peak TSH in response to TRH plus a normal TSH surge and normal timing of TSH peak and decline after TRH.
Patients who showed evidence of central hypothyroidism plus mildly elevated basal TSH level or elevated peak TSH in response to TRH were defined as having mixed hypothyroidism.
Statistical analysis
The duration of follow-up was calculated from the date of tumor diagnosis. The time that elapsed between tumor diagnosis and development of each hormone deficiency (hypothyroidism, GH deficiency, ACTH deficiency, diabetes insipidus, precocious puberty, or gonadotropin deficiency) was estimated using the method of Kaplan and Meier (33). Outcomes were compared across different radiation treatment groups and cancer diagnosis groups using a stratified Mantel-Haenszel statistic (34). SEs of estimates were calculated using the technique described by Peto et al. (35). All estimates and their SEs are shown as the estimate ± SE (e.g. 32 ± 6%). All reported significance levels are based on two-sided tests. Cumulative incidence rates of hypothyroidism, GH deficiency, ACTH deficiency, diabetes insipidus, precocious puberty, and gonadotropin deficiency were calculated from the date of cancer diagnosis using the method of Kalbfleisch and Prentice (36). Stratified tests were used as described by Gray (37) to compare the cumulative incidence data across radiation treatment groups and oncology diagnosis groups.
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Results |
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Table 1
lists the clinical characteristics of patients grouped by
cancer diagnosis. At the time of evaluation of TSH dynamics, 56
patients were being treated for GH deficiency, and 4 were being treated
with GnRH agonist therapy for precocious puberty. The remaining 148 had
had no prior endocrine evaluation and were receiving no endocrine
therapy at the time of evaluation.
Patients were grouped by serum FT4 concentrations (23, 38). Our normal reference range for FT4 was 0.71–1.85 ng/dL (9 to 24 pmol/L). Five patients had FT4 slightly less than 0.71 ng/dL (range, 0.6–0.7 ng/dL, 7.5–8 pmol/L), 155 had FT4 in the lower portion of the normal range (0.71–1.2 ng/dL, 9–15 pmol/L), and 48 had FT4 in the upper portion of the normal range (1.2–1.85 ng/dL, 16–24 pmol/L).
TSH surge and TRH test results
Among 208 patients who had dynamic TSH evaluation, 160 patients had FT4 levels of 1.2 ng/dL or less. Of these, 51 (32%) had a blunted TSH surge, and 40 (25%) had a low or late TSH peak or delayed decline after TRH (30 had a blunted TSH surge only, 19 had abnormal TRH response only, and 21 had both). Altogether these patients could be placed into 2 diagnostic groups: 55 patients (34% of the lower FT4 group) had central hypothyroidism, and 15 (9% of the lower FT4 group) had mixed hypothyroidism. In addition, 26 (16% of the lower FT4 group) had mild primary hypothyroidism. Of the 160 cancer survivors with FT4 in the lowest third of the normal range, only 64 (41%) had no discernable thyroid dysfunction.
Forty-eight of the 208 had FT4 values above 1.2 ng/dL. Of them, 2 (4%) had a blunted TSH surge, and 5 (10%) had late peak or delayed decline after TRH; thus, 14% of the higher FT4 group had altered TSH dynamics, as seen in central hypothyroidism. Seven (15% of the higher FT4 group) had mild primary hypothyroidism. None met the criteria for mixed hypothyroidism.
In the study group as whole, 62 patients had central hypothyroidism;
40% of these were identified only by a blunted TSH surge, 29% only by
a low or late TSH peak or a delayed TSH decline after TRH, and 31% by
abnormalities on both tests (Table 2). Of
15 patients who had mixed hypothyroidism, 60% had elevated basal TSH,
34% had elevated peak TSH after TRH, and 6% had both; in addition,
54% had a blunted TSH surge, 40% had a late TSH peak or a delayed
decline after TRH, and 6% had both. All 33 patients who had mild
primary hypothyroidism were identified by both elevated basal TSH and
normal dynamic TSH test (TSH surge and TRH) results; 74% also had an
elevated peak TSH response to TRH (Table 2).
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Of the 62 patients who had central hypothyroidism, only 5 (8%) had FT4 below 0.71 ng/dL (lower limits of the normal range). Of the 15 with mixed hypothyroidism, none had FT4 below normal; 11 (73%) of these patients would have been diagnosed as having only mild primary hypothyroidism because of TSH elevation. Of the 33 patients with mild primary hypothyroidism, none had FT4 below the normal limits, although all had elevated basal TSH.
Thus, 57 (92%) of the diagnoses of central hypothyroidism and 4 (27%) of the diagnoses of mixed hypothyroidism would have been missed by reliance on FT4 and basal TSH values alone. If TRH testing had been used without the TSH surge test, 25 (40%) of the diagnoses of central hypothyroidism would have been missed, and 8 (54%) of the patients with mixed hypothyroidism would have been undiagnosed or incompletely diagnosed.
Pattern of other endocrine deficiencies
Fifteen (24%) of the patients with central hypothyroidism showed no evidence of other endocrine deficiency, 41 (66%) had GH deficiency, and another 6 (10%) had only ACTH deficiency or precocious puberty when central hypothyroidism was identified. Of the 15 patients with mixed hypothyroidism, 3 had no other endocrine dysfunction, 1 had ACTH deficiency, and 11 had GH deficiency. Of the 33 patients with mild primary hypothyroidism, only 6 (18%) had no other endocrine dysfunction; 23 (70%) had GH deficiency, and 4 (12%) had ACTH deficiency, precocious puberty, or gonadotropin deficiency.
Table 3 shows the cumulative incidence of
endocrine deficiencies identified 2, 5, and 10 yr after cancer
diagnosis. The cumulative incidence rate of hypothyroidism (central,
mixed, and mild primary) was nearly as high as that of GH deficiency at
all time points after cancer diagnosis. Gonadotropin deficiency, which
has no clinical manifestation before the expected age of puberty, was
the last hypothalamic-pituitary deficiency to develop or to be
identified.
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The time of emergence and the cumulative incidence of central,
mixed, and mild primary hypothyroidism varied with the specific tumor
diagnosis (Fig. 1). At 5 yr after cancer
diagnosis, central hypothyroidism had been identified in about 50% of
patients who had suprasellar or nasopharyngeal tumors, in about 35% of
patients who had supratentorial or posterior fossa tumors or after BMT,
and in 20% of patients with noncranial tumors. At 5 yr, mixed
hypothyroidism had been identified in about 20% of patients after BMT.
At 5 yr, primary hypothyroidism had been identified in about 20% of
patients with nasopharyngeal or posterior fossa tumors or after
BMT.
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Irradiation of the thyroid gland as the result of spinal or total
body irradiation was significantly related to development of mild
primary hypothyroidism (P < 0.0001) and mixed
hypothyroidism (P = 0.05; Table 4 and Fig. 2). In contrast, the cumulative incidence
of central hypothyroidism was unaffected by irradiation of the thyroid
gland (P = 0.31), but was strongly related to the total
cranial radiation dose (P < 0.0001; Fig. 3). Both mixed and mild primary
hypothyroidism were also strongly related to the total cranial
radiation dose (P < 0.0001). Because radiation dose
and fields are disease-dependent variables, the presence of central and
other forms of hypothyroidism may not be independent of tumor
diagnosis. However, because the study population was not randomly
chosen, we did not stratify the thyroid abnormalities by tumor
diagnosis. Of note, 27% of the patients who developed central
hypothyroidism had undergone surgical excision of brain tumor (n =
5), chemotherapy alone (n = 10), or both (n = 2), but had
received no radiation therapy.
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), that of mixed hypothyroidism was
15% (Fig. 3B), and that of mild primary hypothyroidism was 22% (Fig. 3C) by 10 yr after tumor diagnosis. Thus, 76% of these patients had
some form of mild hypothyroidism by 10 yr after tumor diagnosis.
In contrast, administration of 15–29 Gy cranial or craniospinal
radiation was associated with a cumulative incidence of central
hypothyroidism of 8% (Fig. 3A), mixed hypothyroidism of 2% (Fig. 3B),
and mild primary hypothyroidism of 10% (Fig. 3C) by 10 yr after tumor
diagnosis. Thus, 20% of these patients had some form of mild
hypothyroidism by 10 yr after tumor diagnosis.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The higher frequency with which we identified central hypothyroidism in childhood cancer survivors compared to rates reported by others reflects our high index of suspicion and the recognition that FT4 levels in the lowest third of the normal range are compatible with thyroid dysfunction. Past studies of thyroid function after radiation therapy have used only single TSH and T4 assays or TRH tests to identify TSH disorders. Neither approach is as sensitive as the TSH surge test for identifying central hypothyroidism (25). In the current study, the TSH surge used in combination with the TRH test provided maximal sensitivity for confirmation of central hypothyroidism.
The TSH response to TRH has been the standard test used to identify central hypothyroidism. However, 30–90% of patients with central hypothyroidism may have a normal response to TRH (a normal amplitude TSH peak, normally timed) (23, 25, 39, 40). The nocturnal TSH surge is a demonstrably more sensitive indicator of idiopathic or isolated central hypothyroidism (23, 25). Both children and adults normally experience a nocturnal surge in TSH of 50–300% as a normal circadian event (41, 42, 43). The TSH surge is frequently blunted or absent in patients with central hypothyroidism despite normal basal TSH values. Blunting of the TSH surge reduces the daily total production of TSH by approximately one third, causing a subtle decrease in thyroid hormone production that is sufficient to slow the growth of some children (23).
The design of this study did not permit us to ascertain the time at which deficiencies emerged. Although many patients were referred in anticipation of altered growth or at the first oncology clinic visit showing an altered growth rate, most deficiencies were identified only after poor growth was observed. Nevertheless, our use of the TSH surge plus the TRH test allowed us to identify central hypothyroidism much earlier than would have otherwise been expected and often well before any alteration of GH secretion. GH deficiency has been reported to be the first hypothalamic-pituitary deficiency to emerge, followed by gonadotropin, ACTH, and TSH (7, 16, 44, 45). However, TSH secretory alterations may have been recognized last only because relatively insensitive tests, such as single measures of TSH and T4, or TSH response to TRH, were used. In 34% of our patients diagnosed with central hypothyroidism, dysregulation of TSH secretion preceded development of GH deficiency. If TSH secretion had not been tested until GH deficiency became apparent, the diagnosis of hypothyroidism would have been delayed in a third of our patients. Although such a delay may be acceptable in an asymptomatic adult, the lost growth opportunities and potential functional implications (e.g. in school) of hypothyroidism in pediatric patients signify a need for early intervention (23).
A careful review of prior studies supports our thesis that TSH secretory dysregulation after irradiation may precede other endocrine disorders. For example, of 31 patients examined 5 yr after receiving cranial irradiation for nasopharyngeal carcinoma, 64% had GH deficiency, 31% had gonadotropin deficiency, 27% had ACTH deficiency, and 15% were diagnosed as having central hypothyroidism, representing only those 4 who had T4 values below the normal range (16). However, review of their test results shows that 28 of the 31 had a delayed peak TSH response to TRH by 1 yr after therapy. Thus, 90% of these patients showed evidence of altered TSH dynamics suggestive of central hypothyroidism. In a prospective study of 7 children with brain tumors, Spoudeas et al., performed endocrine testing of all pituitary axes 0, 6, and 12 months after administration of more than 30 Gy cranial radiation. They found that in many patients, the TSH surge became blunted before the onset of reduced GH levels (46).
The hypothalamus is thought to be even more sensitive to radiation damage than the pituitary itself (45, 47, 48) and may be more vulnerable in children than in adults (49). Central hypothyroidism has been clearly related to radiation dose in both our study and prior reports. Higher total doses of cranial or craniospinal radiation are associated with earlier development of hypothyroidism and a higher long term probability of abnormal thyroid function. Because intracranial solid tumors are treated with higher total doses of radiation, the incidence of central hypothyroidism is also related to the type of tumor. In adults who had received cranial radiation 5 yr previously, central hypothyroidism was diagnosed in 9% of patients after a total dose of 20 Gy, in 22% after 30–37 Gy, in 35% after 40 Gy, and in 52% after 42–45 Gy (50). In children, central hypothyroidism was most often associated with total radiation doses more than 40 Gy to the hypothalamic-pituitary region (51).
Chemotherapy, especially the regimens used for BMT, may exacerbate the effects of radiation on hypothalamic-pituitary-thyroid function (17) as well as exert endocrine effects of its own; 9% of patients have been reported to develop primary hypothyroidism after busulfan and cyclophosphamide therapy with no radiation (22), and poor growth has been observed after chemotherapy alone (52, 53). Of our 62 patients with central hypothyroidism, 10 (16%) had received only chemotherapy; none of these had hypothalamic tumors that would be clearly associated with endocrine dysfunction. Patients in our study who had been treated with a BMT preparatory regimen (total body irradiation and chemotherapy) were as likely to have central hypothyroidism as those who had received more than 30 Gy of cranial radiation. This finding illustrates the impact of combined radiation and chemotherapy on the hypothalamic-pituitary-thyroid axis.
Mixed hypothyroidism has not been previously described. We used this term to refer to mild TSH elevation combined with a blunted TSH surge, a TSH peak that was delayed in onset, or a delayed TSH decline after TRH. We consider this condition to be related to central hypothyroidism. Mixed hypothyroidism may reflect either separate injuries to the thyroid gland and hypothalamus (such as radiation injury of both structures) or central hypothyroidism in which the biological activity of the secreted TSH is reduced. A bioinactive TSH molecule has been described in a few patients with no history of radiation or chemotherapy (39, 54). Irradiation of the pituitary gland has been proposed to reduce the biological activity of the secreted TSH molecule (17, 55, 56). In the current study, mixed hypothyroidism was most prevalent in patients who had received total cranial or craniospinal radiation doses of more than 30 Gy or a BMT preparatory regimen. Mixed hypothyroidism was not always associated with elevated basal TSH; thus, both the TSH surge test and the TRH test were required for diagnosis.
In children, studies of thyroid function after treatment of brain tumors (17, 57) have emphasized identification of TSH elevation. Most patients with elevated TSH have been considered to have compensated hypothyroidism. The clinical significance of mild primary hypothyroidism (compensated or subclinical) has been a subject of controversy. Such mild hypothyroidism is characterized by slight TSH elevation and T4 values that, as in central hypothyroidism, remain in the low part of the normal range. Several studies have found clinically significant differences between adults with normal thyroid function and those with mild hypothyroidism (58, 59, 60) and have observed that treatment of mild hypothyroidism can produce meaningful clinical benefit (61, 62, 63, 64). In growing children, treatment of mild hypothyroidism may have even greater clinical importance. Although fewer studies have been performed in children, levothyroxine treatment of four infants with mild TSH elevation returned the basal metabolic rate to normal (65).
As expected (66), we found that mild primary hypothyroidism was most likely to occur in patients who had received irradiation of the neck. This deficiency was rarely isolated in our patients. Only 18% had mild TSH elevation alone; the rest had other hypothalamic-pituitary hormone deficiencies as well. Children with mild TSH elevation and T4 levels within normal limits typically grow less well than other children, and their growth improves with thyroid replacement therapy (23). Thyroid hormone replacement has been recommended for patients who have elevated TSH, as has GH for patients who have slow growth (11). TSH elevation is a sign of possible thyroid dysfunction and should not be disregarded, particularly during slowed growth in childhood, lest the opportunity to improve the growth rate be missed.
We suggest that most prior studies have failed to accurately identify many cases of central or mixed hypothyroidism because of diagnostic criteria that require a T4 or FT4 value below the normal range in addition to a low TSH value. However, patients with central hypothyroidism most often have normal TSH values and T4 or FT4 levels within the low part of the normal range. In most of these patients, T4 or FT4 concentrations decline by about 25%, whereas normal individuals usually maintain a fairly constant FT4 level throughout life. To optimize clinical benefit, hypothyroidism should be suspected in patients whose FT4 level declines or is in the lowest third of the normal range in the presence of symptoms such as slow growth rate, dry skin, constipation, or low energy.
The cause of poor growth in childhood cancer survivors cannot always be
identified. Although often caused by toxic effects of chemotherapy or
radiation on bone growth centers or by GH deficiency, poor growth may
in many cases be caused by undiagnosed central hypothyroidism. The use
of our FT4 screening criterion and confirmatory
testing that combines the TSH surge test with the TRH test should
improve the sensitivity with which central hypothyroidism is diagnosed.
We recommend growth surveillance, yearly measurement of TSH and
FT4, and treatment of childhood cancer survivors
as shown in Table 5. The TSH surge and
TRH tests should be used to assess thyroid status in survivors whose
FT4 is in the lowest third of the normal range,
whose basal TSH concentration is normal, and whose growth rate is
slowed. Other hypothalamic-pituitary axes should be evaluated
concurrently as clinically indicated. Improved diagnosis of mild
hypothyroidism will allow treatment that enhances patients’ growth
velocity and sense of well-being.
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Acknowledgments |
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Footnotes |
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Received February 11, 1999.
Revised June 15, 1999.
Accepted July 12, 1999.
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