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Predictors of Early Remission of Hyperthyroidism in Children¹

Department of Pediatrics, Section of Endocrinology, University of California, Davis School of Medicine, Sacramento, California 95817

Address all correspondence and requests for reprints to: Dennis M. Styne, M.D., Department of Pediatrics, Section of Endocrinology, University of California Davis Medical Center, 2516 Stockton Boulevard, Sacramento, California 95817.

	Abstract

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Children with hyperthyroidism often require prolonged courses of antithyroid medication to achieve remission, and long-term compliance is problematic. To determine which clinical and laboratory features predict early remission, we reviewed the records of 191 patients less than 19 yr old with Graves’ disease. We compared patients achieving remission within 2 yr (group 1, n = 27) with those who completed more than 2 yr of medical therapy but did not achieve a remission (group 2, n = 79). Patients who were in neither of the above categories (n = 85) were excluded from the statistical analysis. Variables that were measurable at the time of diagnosis, recorded in more than 50% of the study population and associated with early remission in the univariate analysis (P 0.05), were entered into a stepwise multiple logistic regression analysis. Variables retaining a significant association with early remission (P < 0.05) were considered independent predictors of early remission. Patients achieving early remission were older (mean, 12.5 vs. 10.9 yr, P = 0.039) and had higher body mass indexes (BMI, 19.0 vs. 16.6, P = 0.002), higher BMI SD scores (-0.03 vs. -0.60, P = 0.004), lower heart rates (110 vs. 121, P = 0.023), smaller goiters (group 1: 60% with moderate/large goiter; group 2: 83%, P = 0.050), lower platelet counts (272 vs. 339 K/µL, P = 0.006), lower serum T₄ and T₃ concentrations at presentation (T₄: 18.3 vs. 22.5 µg/dL, P = 0.015; T₃: 439 vs. 613 ng/dL, P = 0.008), and were less likely to have a positive test for thyroid stimulating Igs (group 1: 50% vs. group 2: 93%, P = 0.008). Regression analysis identified BMI SD score and goiter size as independent predictors of early remission (P < 0.05). Eighty-six percent of patients with BMI SD score above -0.5 SD and minimal/small goiters achieved early remission, compared with 13% of those with BMI SD score below -0.5 SD and moderate/large goiters. We conclude that, of multiple clinical and laboratory variables associated with early remission, BMI SD score and goiter size are independent predictors. Algorithms employing these two variables can be used to facilitate counseling of patients and expedite therapeutic decisions.

	Introduction

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THE OPTIMAL treatment of hyperthyroidism in children is a subject of controversy. The three therapeutic options (antithyroid medications, subtotal thyroidectomy, and ablation with radioactive iodine) all carry a risk of serious complications (1). In children, medical therapy frequently is chosen as the initial treatment to avoid surgery and possible long-term teratogenic or carcinogenic effects of radioiodine (2). Most children require relatively long periods of medical therapy, as only 25% of children achieve remission with every 2 yr of medical treatment (3, 4). It is frequently difficult, however, to achieve long-term compliance. Therefore, elucidation of prognostic factors for the outcome of medical therapy would improve patient counseling and expedite appropriate therapeutic decisions.

We examined the prognostic value of clinical and biochemical variables for determining the likelihood of remission of hyperthyroidism within 2 yr on medical treatment. Multivariate statistical methods identified independent predictors of remission within 2 yr, and a predictive model based on factors available at the time of diagnosis was developed.

	Materials and Methods

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Study sample

We reviewed the medical records of all patients 1–19 yr old (n = 191) with a diagnosis of hyperthyroidism caused by Graves’ disease, treated between 1976–1996 at five pediatric referral hospitals in California. All patients presented with elevated serum T₄, free T₄ (fT₄), and/or T₃ concentrations and suppressed TSH concentrations. Patients with palpable thyroid nodules or evidence of autonomously functioning thyroid adenomas on thyroid scintiscan were excluded.

Data collection

We collected information on the following variables at diagnosis: 1) Clinical features: age, gender, family history of autoimmune thyroid disease, height, weight, body mass index [BMI; weight in kg/(height in meters)²], heart rate, blood pressure, pulse pressure, presence or absence of exophthalmos, and goiter size. To standardize BMI for age and gender, we calculated the BMI SD score:

To correct for variations in methods of assessment of goiter size, as well as for age-related differences in the volume of the normal thyroid, we constructed Table 1 based on pathologic studies (6, 7). Goiter size was classified as minimal, small, moderate, or large goiter, based on these standards. 2) Laboratory values: serum T₄, fT₄, T₃, and fT₄ index, complete blood count, presence of thyroid-stimulating Igs (TSI), antimicrosomal antibodies (AMA), antithyroglobulin antibodies (ATG), and antinuclear antibodies. To correct for differences in the normal ranges of various thyroid hormone assays, we calculated the percent elevation of each hormone concentration as:

We also recorded the following treatment-related factors: medication, treatment regimen, initial and maintenance dose of antithyroid medication, and duration of treatment. A titration regimen designation indicated that the dosage of antithyroid medication was adjusted to maintain serum T₄ or fT₄ concentrations within the normal range and replacement oral T₄ was not used. A block-replace regimen designation indicated that, when serum T₄ concentrations fell below normal, T₄ was administered, rather than adjusting the dose of antithyroid medication. Maintenance dose was defined as the first dose of antithyroid medication on which the patient was able to maintain serum T₄ concentrations within the normal range for a period more than 6 months.

Outcome definitions

We defined remission as maintenance of normal serum T₄ or fT₄ concentrations without medication for more than 6 months. Our main outcome variable was early remission, defined as remission within 2 yr of beginning medical treatment.

For purposes of analysis, patients were assigned to one of three outcome groups: 1) patients who achieved early remission (n = 27); 2) patients who were treated with antithyroid medications for more than 2 yr, but did not achieve early remission (n = 79); 3) (a) patients who chose initial treatment with I¹³¹ or surgery, or (b) patients who did not achieve early remission and discontinued medical therapy or were lost to follow-up before 2 yr (n = 85).

Patients in group 3 were excluded from statistical analysis.

Statistical analysis

Univariate analysis. Differences between groups 1 and 2 in normally distributed continuous variables were analyzed using Student’s t test. Continuous variables with nonnormal distributions were analyzed using the Wilcoxon rank-sum test. Categorical variables were analyzed using Fisher’s exact test. Goiter size was analyzed as a dichotomous, rather than a categorical variable, because of small numbers of patients in some categories. All statistical tests were conducted based on two-tailed alternatives. P-values 0.05 were considered significant differences and P-values between 0.05 and 0.10 were considered to represent a trend.

Multivariate analysis. Forward, stepwise multiple logistic regression analysis was used to identify independent predictors of early remission. Variables entered into the regression analysis fulfilled the following criteria: 1) measurable or obtainable at diagnosis; 2) recorded in 50% or more of the study population; and 3) univariate association (P 0.05) with early remission. In the case of colinear variables, (BMI and BMI SD score, T₄, and T₄%), one variable of each pair was entered into the regression equation. Because BMI SD score and T₄% were standardized to correct for age-related differences in BMI and differences among T₄ assays, these variables were chosen. Variables retaining a significant association with early remission (P < 0.05) after regression analysis were considered independent predictors of early remission. All statistical computations were performed using STATA 4.0 statistical software (8).

	Results

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Patient population

The characteristics of the study population (n = 191) are summarized in Table 2. Fifty-two patients (28% of those who initially chose medical treatment) achieved remission with antithyroid medication after a mean of 29 ± 17 months of treatment. Six percent of patients who continued medical treatment achieved a remission within 1 yr, 25% within 2 yr, 46% within 3 yr, and 69% within 4 yr. A summary of the outcomes for the study population is shown in Fig. 1.

View larger version (29K): [in this window] [in a new window]   Figure 1. *, Includes patients who discontinued medical treatment because of complications of medications and those who discontinued treatment because of preference for alternative therapy; +, includes patients who are currently continuing medical treatment and those who were lost to follow-up; Rx, treatment.

Of the initial 191 patients, 106 met the criteria for inclusion into the analysis: 27 patients who achieved remission within 2 yr (group 1) and 79 who continued medical therapy for 2 yr or more but did not achieve remission within 2 yr (group 2). The patients who met the criteria for analysis were younger (11.3 ± 4.0 yr vs. 13.2 ± 3.3 yr, P = 0.005) and had lower BMI (17.3 ± 3.4 vs. 19.3 ± 4.0, P = 0.001) and lower BMI SD (-0.44 ± 0.83 vs. -0.091 ± 0.88, P = 0.014) scores than those who did not. There were no other statistically significant differences between patients who did and did not meet the criteria for inclusion (data not shown).

Univariate analysis (Table 3)

Clinical variables. Patients achieving early remission (group 1) were older and had higher BMI’s and BMI SD scores and lower heart rates at presentation than those in group 2. Patients with minimal or small goiters were more likely to achieve early remission, compared with those with moderate or large goiters. No other clinical variables were significantly associated with early remission; however, there was a trend towards association (P < 0.10) for absence of exophthalmos.

Treatment regimens. There were no significant associations between the type of medication or regimen used and early remission. The initial dose of PTU was lower in patients who achieved early remission, compared with those who did not (6.9 ± 3.6 vs. 8.2 ± 3.5 mg/kg·day, P = 0.05); however, the initial dose of methimazole and maintenance doses of both medications were not significantly different between the two groups (data not shown).

Clinical course. Changes in goiter size during treatment were significantly associated with early remission. No patient in group 1 had an increase in goiter size, and 42% had complete resolution of the goiter. In group 2, 18% had an increase in goiter size, and only 9% had complete resolution of the goiter (P = 0.003). In group 1 patients, serum T₄ and T₃ concentrations also returned to the normal range more rapidly after beginning therapy.

Multivariate statistical analysis

The following variables met the criteria defined previously for inclusion in the regression analysis: age, BMI SD score, heart rate, goiter size, and T₄%. T₃, platelet count, and TSI could not be included because they were recorded in less than 50% of the study population. Among the variables entered into the regression analysis, only BMI SD score (P = 0.003) and goiter size (P = 0.043) were identified as independent predictors of early remission. The adjusted odds ratio for a 1-SD increase in BMI SD score was 4.15 (95% confidence interval 1.63–10.59). The adjusted odds ratio for moderate/large vs. minimal/small goiter was 0.22 (95% confidence interval 0.05–0.96) (Table 4).

View larger version (22K): [in this window] [in a new window]   Figure 2.

View larger version (47K): [in this window] [in a new window]   Figure 3.

	Discussion

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According to our univariate analysis, a number of variables have prognostic value for determining early remission, including age, BMI, heart rate, goiter size, serum T₄ and T₃ concentrations, platelet count, TSI, changes in goiter size, and time required for serum T₄ and T₃ concentrations to normalize. These findings indicate that the severity of disease at diagnosis, as assessed by multiple clinical and laboratory variables, is an important determinant of likelihood of early remission.

Using multivariate statistical methods, we derived a simple model to predict likelihood of achieving remission within 2 yr. Of the variables available at diagnosis and recorded in more than 50% of our study population, we found BMI SD score and goiter size to be independent predictors of early remission. When the study population was stratified into prognostic categories based on these two variables, 86% of those in the best prognostic category (i.e. BMI SD score above -0.5 and minimal/small goiter) achieved remission within 2 yr, compared with only 13% of those in the worst prognostic category (i.e. BMI SD score below -0.5 and moderate/large goiter).

Previous studies of prognostic factors in hyperthyroidism mainly involved adult patients and yielded variable results. Some adult studies found that initial serum T₃ and T₄ concentrations and/or the T₃/T₄ ratio were of prognostic importance (9, 10, 11), but these findings were challenged in other studies (12, 13, 14, 15). Information regarding goiter size has been somewhat more consistent, with many studies supporting the contention that larger goiter size is a poor prognostic sign (10, 13, 14, 15, 16, 17, 18). High titers of TSH receptor antibodies (TSI, TRAb, TBII) at the time of diagnosis, and persistence of these antibodies throughout the treatment period, also indicate a low likelihood of achieving remission in adults (10, 12, 13, 14, 16, 17, 18, 19). AMA and ATG, however, were not found to be prognostically useful in most studies (10, 11, 13, 16, 18), nor were age, gender, and presence of exophthalmos (11, 13, 16, 20, 21, 22, 23). Information regarding the value of human leukocyte antigen-type, in determining prognosis, is variable (10, 12, 16, 21, 24).

Variations in treatment regimens also have been evaluated in adults. Hashizume et al. (25) demonstrated improved remission rates, using treatment with methimazole plus T₄, compared with methimazole alone. More recent studies, however, failed to confirm these results (22, 26, 27). The reason for the variability among these studies is unknown.

It is not clear whether the results of adult studies are applicable to pediatric populations. Hyperthyroidism in adults follows a more benign course than in children, with 49–75% of adults achieving remission after short courses (24 months) of antithyroid medication, compared with only 25% of children (3, 4, 9, 17, 18, 25, 26). Therefore, it may not be appropriate to apply results of adult studies to pediatric patients.

Children with hyperthyroidism were studied less extensively than adults and, before our study, few variables were shown to predict outcomes. In agreement with our findings, several studies demonstrated that initial goiter size and changes in goiter size during treatment are of prognostic importance (28, 29, 30). Buckingham et al. (28) found that patients with goiters less than three times normal size at diagnosis and less than two times normal size at the conclusion of therapy were more likely to achieve remission. Similarly, Barnes and Blizzard (30) found that a decrease in goiter size to normal or near-normal, predicted remission. Gorton et al. (29) did not find a significant correlation between initial goiter size and ability to achieve remission; however, they noted that 67% of those with small goiters achieved remission within 2 yr and 66.5% of those with large goiters required longer than 2 yr to achieve remission.

Variables other than goiter size were evaluated in fewer studies. Collen et al. (3) found no factors that identified patients who achieved remission within 54 months. There was a tendency toward earlier remission, however, in patients older than 13 yr, in males, and in patients with initial serum T₃ concentrations less than 645 ng/dL. The authors followed the same cohort for a longer period in a second study. In this analysis, only initial serum T₄ concentration was found to correlate with time to remission (4). Gorton et al. (29) found no significant differences in serum T₄ and T₃ concentrations, T₃/T₄ ratio, AMA, and ATG titers among patients who did and did not achieve remission on medical therapy.

The variation between our findings and those cited above are likely the result of a number of factors, including sample size, variable selection, and outcome definitions. First, our study population was large, allowing the detection of significant differences of smaller magnitude. Second, we evaluated a number of clinical indicators of disease severity (i.e. BMI, heart rate, and alterations in the complete blood count), which were not previously investigated. Finally, we chose to define our outcome variable as achievement of remission within 2 yr. Because previous studies showed that most patients treated with antithyroid medication eventually achieve remission if therapy is continued (3, 4), studies that define the outcome as ability to achieve remission, without specifying treatment duration, would be unlikely to identify predictive factors. We also chose not to assess the correlation of variables with time to remission, because we felt that this type of design in a retrospective study would be unreliable.

The current study has some limitations, mainly because of its retrospective nature. First, we had limited follow-up of the study population. Patients who were euthyroid for greater than 6 months after discontinuation of medication were considered to have achieved remission. Because many patients were lost to follow-up thereafter, we cannot exclude the possibility that some patients experienced a late relapse. Second, some laboratory variables were measured in less than 50% of patients. Although some of these variables, including TSI, T₃, and platelet count, were significant predictors of early remission in the univariate analysis, they could not be included in the multivariate analysis without excessively restricting the sample size. Therefore, we could not determine whether these variables are independent predictors of early remission. We also were unable to study some variables that are of theoretical interest, such as antibody titers (i.e. TSI, AMA, and ATG). The assays used to measure antibody titers in different institutions and during different time periods varied and could not be standardized. Future prospective studies will help to assess the prognostic value of these variables.

In summary, this study of a large population of children with hyperthyroidism demonstrates that severity of disease at diagnosis, as measured by multiple clinical and laboratory variables, is important in predicting remission within 2 yr. Among the variables measurable at the time of diagnosis and recorded in more than 50% of the study population, BMI SD score and goiter size are independent predictors of early remission. These two variables can be used to stratify patients according to probability of early remission and provide useful information for counseling patients and therapeutic decision-making.

	Acknowledgments

 
We gratefully acknowledge the assistance of Matthew Connors, M.D., and Sobha Kollipara, M.D. (University of California, Davis School of Medicine); Frank Gareis, M.D. (Children’s Hospital, Oakland); Kenneth Lee Jones, M.D. (University of California, San Diego, School of Medicine); and Bagher Sheikholislam, M.D. (Sutter General Hospital, Sacramento) in the implementation of this project. We also wish to thank Nathan Kuppermann, M.D., for his helpful guidance in the design of this study and his thoughtful review of the manuscript.

	Footnotes

 
¹ This work was supported in part by fellowship research training grants from Eli Lilly and Company and the Pharmacia-Upjohn Corporation (to N.S.G.).

Received December 3, 1996.

Revised February 3, 1997.

Accepted February 21, 1997.

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