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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 12 5981-5986
Copyright © 2004 by The Endocrine Society

Long-Term Follow-Up of Thyroid Function in Patients Who Received Bone Marrow Transplantation during Childhood and Adolescence

Hiroyuki Ishiguro, Yukiharu Yasuda, Yuuichiro Tomita, Tsuyoshi Shinagawa, Takashi Shimizu, Tsuyoshi Morimoto, Kinya Hattori, Masae Matsumoto, Hiroyasu Inoue, Hiromasa Yabe, Miharu Yabe, Osamu Shinohara and Shunichi Kato

Departments of Pediatrics (H.Is., Y.Y., Y.T., T.Shin., T.Shim., T.M., K.H., M.M., H.In., H.Y., M.Y., O.S., S.K.) and Cell Transplantation and Regenerative Medicine (S.K.), Tokai University School of Medicine, Kanagawa 259-1193, Japan; and Department of Pediatrics (T.Shim.), University of Tsukuba, Tsukuba 305-8577, Japan

Address all correspondence and requests for reprints to: Hiroyuki Ishiguro, M.D., Department of Pediatrics, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa 259-1193, Japan. E-mail: h-ishi{at}is.icc.u-tokai.ac.jp.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
An increasing number of long-term surviving bone marrow transplant (BMT) recipients have recovered from their primary disease but are at risk of developing failure of endocrine organs. We investigated 147 patients who underwent allogeneic BMT. Thyroid function was evaluated by serial measurement of basal TSH and free T4 levels as well as by TRH provocative test. Thyroid ultrasound examination was performed for evaluation of thyroid tumor after BMT. Five patients were found to have overt thyroid dysfunction (hypothyroidism in four patients and hyperthyroidism in one patient). Twenty-three patients in the under 9-yr-old group at BMT and 16 patients in the over 10-yr-old group at BMT had subclinical compensated hypothyroidism. Younger age at BMT was the strongest factor for developing thyroid dysfunction, compared with older age (P < 0.001). Only in patients with subclinical compensated hypothyroidism did median basal and peak TSH increase to the upper half of the normal range by 8 yr after BMT and then returned slightly to the middle of the normal range spontaneously. These results suggest that thyroid dysfunction in long-term BMT survivors depends on age at BMT, with a greater risk among younger patients, indicating the need for life-long surveillance.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
BONE MARROW TRANSPLANTATION (BMT) has improved the prognosis of children with malignant and nonmalignant fatal diseases. An increasing number of long-term survivors have recovered from their primary disease, but they are at risk of developing failure of other organs, affected by the aggressive treatment of their disease or conditioning regimen before BMT. These treatments consist of both cytotoxic drugs and irradiation, and endocrine organs are well known to be sensitive to both (1, 2). Among the endocrine complications that have been described after BMT (3), thyroid disorders have frequently occurred in long-term survivors (4).

Although thyroid dysfunction occurs in both children (5, 6, 7) and adults after total body irradiation (TBI) (8), a recent report demonstrated that the thyroid gland was especially sensitive to the effects of irradiation at a very young age (9). In a previous study, we reported that short-term changes (less than 3 months) after BMT in thyroid function reflect euthyroid sick syndrome rather than tertiary hypothyroidism (10). However, the most frequent type of thyroid dysfunction in long-term survivors is subclinical compensated hypothyroidism or overt hypothyroidism, a complication whose frequency seems to be closely related to the use of the conditioning regimen including TBI. In the light of the latter risk, some endocrinologists would treat a patient with an elevated TSH level with levothyroxine because there are a considerable number of animal studies to suggest that lowering a previously raised TSH level into the normal range in a child who has received irradiation to the thyroid gland is likely to reduce the risk of thyroid malignancy (11). However, the long-term natural history of irradiation-induced thyroid dysfunction is unknown, and there are no long-term follow-up data to support this strategy in patients treated with levothyroxine.

The risk of thyroid tumors after irradiation is real and dose related (12). The latency period between thyroid irradiation and clinical presentation with thyroid tumor may be many years. In a recent report of second malignancies after BMT for malignant disorder, five (0.2%) thyroid carcinomas occurred among 3182 children with a strong relationship between the age at BMT and the occurrence of thyroid cancer (9). However, the number of reports of thyroid cancer after TBI is limited (13, 14).

In this study, we analyzed 147 patients who underwent BMT for various diseases in a single institution. The aim of this study was to investigate thyroid disorders in long-term survivors receiving BMT during childhood and adolescence.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients

We investigated 147 patients (80 males and 67 females) who underwent allogenic BMT at Tokai University Hospital between 1982 and 1997, survived at least 1 yr after BMT, and had no history of thyroid disorder before BMT. At admission, informed consent was obtained from either patients or their parents. Patient characteristics are shown in Table 1Go. The median age of the whole group at BMT was 9.8 yr (range, 0.3–30.5 yr), and the median follow-up duration after BMT was 11.1 yr (range, 5.8–21.5 yr).


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  		TABLE 1. Patient characteristics

 
Transplantation procedure

Patient conditioning regimens are shown in Table 1Go. Conditioning regimens for 128 patients consisted of irradiation combined with/without cyclophosphamide and/or other drugs; 6–12 Gy of TBI was given in three to six fractions, and 3–10 Gy thoracoabdominal irradiation (TAI) in one to five fractions. Only 19 patients received conditioning without irradiation. Prophylaxis against graft-vs.-host disease varied during the time period; methotrexate, cyclosporine, or a combination of both drugs was used.

Thyroid function tests

Thyroid function was evaluated before and annually after BMT by serial measurement of basal serum TSH levels, serum free T3 (FT3) levels, and free T4 (FT4) levels. Normal values in our hospital were: TSH, 0.30–4.00 µU/ml; FT3, 2.50–4.50 pg/ml; and FT4, 0.75–1.75 ng/dl. In addition, all patients had TRH provocative test, during which a dose of 300 µg/m2 body surface area of TRH (maximum 500 µg) was given iv and TSH was measured before and at +30, +60, +90, and +120 min. The normal response to TRH provocation should not exceed 30 µU/ml. The peak response occurred in the patients as expected at +30 to +60 min. Therefore, only peak TSH levels at either +30 or +60 min after TRH provocation are presented. All analyses were performed in the routine clinical laboratory of our hospital.

Definition of thyroid dysfunction

Normal thyroid profile was defined as FT3 and FT4 levels within the normal range and TSH levels also normal; primary hypothyroidism was considered present if TSH was elevated concomitant with low FT4 levels; subclinical compensated hypothyroidism was defined as elevated TSH levels but normal FT4 levels with no clinical symptoms.

Thyroid ultrasound examination

Thyroid ultrasound examination was performed in recent follow-up visits in 47 of those 147 patients for evaluation of tumor after BMT.

Statistical analysis

Because the data had a skewed distribution, median and range were used throughout the text, tables, and figures. The results are presented in box and whisker plots in the figures. The box contains the middle 50th percentile of the value. The lower and upper boundaries of the box show the 25th and the 75th percentiles, respectively. The top and bottom of the bar show maximum and minimum values, respectively. The Mann-Whitney U test was used to compare the differences between groups. The {chi}2 test and Fisher’s exact probability test were used to assess the association between endocrine dysfunction and particular clinical features. Kaplan-Meier survival curve was constructed to assess the probability of thyroid dysfunction, and the log-rank test was used to compare survival curves. This statistical analysis was carried out using the GraphPad PRISM statistical package (GraphPad Software, Inc., San Diego, CA). Values of P < 0.05 were considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Overt thyroid dysfunction

Among the 147 patients who underwent BMT and survived more than 1 yr after transplantation, five patients were found to have thyroid dysfunction with clinical symptoms. The characteristics of all patients with overt thyroid dysfunction are listed in Table 2Go. The underlying primary disease of four patients with primary hypothyroidism was acute myelogenous leukemia (AML) in one patient, Fanconi anemia in two patients, and aplastic anemia (AA) in one patient. The median age at BMT was 7.6 yr (range 5.1–23.9 yr). The median time from transplantation to diagnosis of primary hypothyroidism was 2.7 yr (range 1.0–5.0 yr). Hormone replacement therapy with oral levothyroxine was given to all patients with symptomatic primary hypothyroidism. Only one patient was found to have overt hyperthyroidism. A 10-yr-old boy with adrenoleukodystrophy received BMT twice. Conditioning regimens consisted of TAI+busulfan (Bu) + cyclophosphamide (CY) + antithymocyte globulin (ATG) for the first BMT and Bu+CY+ATG for the second BMT. Although subclinical compensated hypothyroidism was demonstrated after the first BMT, overt hyperthyroidism occurred 3.4 yr after the first transplantation.


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  		TABLE 2. Characteristics of patients who developed overt thyroid dysfunction after transplantation

 
Subclinical thyroid dysfunction

We excluded the above five patients from evaluation of thyroid dysfunction because they were being treated with levothyroxine or antithyroid drug after BMT. We evaluated the remaining 142 patients. Changes in basal TSH, peak TSH, and FT4 levels before and after BMT are shown in Fig. 1Go. Median basal TSH, peak TSH, and FT4 levels remained in the normal range throughout the follow-up period (12 yr) after BMT. We evaluated the relationship between thyroid dysfunction and patient characteristics shown in Table 1Go. There were no differences regarding sex of patients, primary disease, and conditioning regimen. However, younger age at BMT was strongly correlated with developing thyroid dysfunction (< 9 yr old vs. >10 yr old, P < 0.001). Therefore, changes of thyroid function were re-sorted by age at BMT (Fig. 2Go). All patients had normal median FT4 levels before and during follow-up after BMT. The difference in results between the under 9-yr-old group and the over 10-yr-old group is statistically significant (P < 0.005) for median basal TSH levels 2 yr after BMT. Furthermore, the difference between groups is statistically significant (P < 0.05) for median peak TSH levels by TRH provocation 2, 6, and 10 yr after BMT. Of the remaining the 142 patients, 23 patients in the under 9-yr-old group (n = 72) and 16 patients in the over 10r-old group (n = 70) had subclinical compensated hypothyroidism. The median age at transplantation in the under 9-yr-old group and the over 10-yr-old group was 4.1 and 12.7 yr (range 0.7–9.1 and 10.0–18.4), respectively, and the median time from transplantation to diagnosis of subclinical compensated hypothyroidism was 2.5 and 4.3 yr (range 1–10 and 1–8), respectively, although there was no statistical significance between groups. Using Kaplan-Meier curves (Fig. 3Go), probability of subclinical compensated hypothyroidism was statistically increased in the under 9-yr-old group, compared with the over 10-yr-old group (P < 0.05). Changes of thyroid function only in patients with subclinical compensated hypothyroidism are shown in Fig. 4Go. Median basal TSH and peak TSH increased to the upper half of the normal range by 8 yr after BMT and then returned slightly to the middle of the normal range spontaneously.



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  		FIG. 1. Changes in basal TSH (top), peak TSH after TRH provocative test (middle), and basal FT4 (bottom) levels after BMT in all patients who received BMT. Shaded area shows the normal range. The box contains the middle 50th percentile of the value. The lower and upper boundary of the box shows the 25th and the 75th percentile, respectively. The bottom and top of the bar show maximum and minimum values, respectively. To convert to SI units, multiply TSH by 1.0 (result in milliunits per liter) and FT4 by 12.87 (result in picomoles per liter).

 


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  		FIG. 2. Changes in basal TSH (top), peak TSH after TRH provocative test (middle), and basal FT4 (bottom) levels after BMT in patients by age at BMT. Patients were divided into two groups: patient younger than 9 yr old at BMT (left) and older than 10 yr old at BMT (right). Significant differences are shown (*, P < 0.005; **, P < 0.05).

 


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  		FIG. 3. Probability of subclinical compensated hypothyroidism. Dotted and solid lines indicate patients younger than 9 yr old at BMT and older than 10 yr old at BMT, respectively.

 


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  		FIG. 4. Changes in basal TSH (top), peak TSH after TRH provocative test (middle), and basal FT4 (bottom) levels after BMT only in patients with subclinical compensated hypothyroidism.

 
Thyroid tumor

Among the 147 patients, 49 patients were evaluated for thyroid tumor by thyroid ultrasound. Of the 49 evaluated cases, 22 patients were found to have thyroid adenoma. The majority of these patients (n = 17) received TBI as a part of pretransplant conditioning, three patients received TAI, and another two patients received no irradiation. There were no differences regarding sex of patients, age at BMT, primary disease, and conditioning regimen. Furthermore, there was no relationship between thyroid dysfunction and the incidence of thyroid tumors: seven of 12 in subclinical compensated hypothyroid patients and 15 of 37 in normal thyroid function patients.

Malignant characteristics were pointed out by thyroid ultrasound examinations in patient 061, and the tumor was growing rapidly in 041. Therefore, surgical resection was indicated in these two patients (pathologically papillary carcinoma in 061 and follicular adenoma in 041).


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Thyroid dysfunction has been recognized as one of the potential aftereffects of the intensive treatment in patients receiving BMT. Hypothyroidism is a relatively early complication in patients after BMT, but it can also manifest itself years after BMT. The role of irradiation in causing thyroid dysfunction was clearly shown in various studies. Boulad et al. (15) reported a lowered incidence of thyroid dysfunction by hyperfractionating TBI (22 of 150 patients, 14.7%; three patients with overt hypothyroidism and 19 with subclinical compensated hypothyroidism). In our study, among 147 patients who underwent BMT mainly during childhood, five patients (3.4%) developed overt hypothyroidism 1–5 yr after BMT and 39 patients (26.5%) developed subclinical compensated hypothyroidism 1–10 yr after BMT. The incidence of subclinical compensated hypothyroidism was statistically higher in the under 9-yr-old age at BMT group than in the over 10-yr-old age at BMT group. The probability of thyroid dysfunction after BMT noted in our study is similar to other studies (15).

Treatment with levothyroxine or antithyroid drug is indicated in those cases of overt primary hypothyroidism or hyperthyroidism. Dosage should be tailored to each individual patient and adjusted according to the basal TSH and free thyroid hormone levels performed every 3–6 months. There is a debate on whether to treat patients with subclinical compensated hypothyroidism. Borgstrom and Bolme (7) reported that treatment with levothyroxine was given to patients with subclinical compensated hypothyroidism. The main reason for treating these patients, even though they have no clinical signs of hypothyroidism, is to diminish the risk of thyroid adenoma and carcinoma (16, 17), especially in children in whom hypothyroidism can lead to growth failure and delayed development (18). On the other hand, the assumption that a high TSH level increases the risk of thyroid carcinomas in humans, and suppression with levothyroxine reduces it, has not been proven, and the majority of cases with subclinical compensated hypothyroidism after BMT were found to be mild, compensated, and resolved spontaneously. In this study, we did not treat patients with subclinical compensated hypothyroidism. Two of 47 patients who developed clinically significant thyroid tumor (papillary carcinoma and follicular adenoma) had normal TSH and free thyroid hormone levels during follow-up and at diagnosis. Changes of thyroid function in patients with subclinical compensated hypothyroidism revealed that median basal TSH and peak TSH increased to the upper half of the normal range by 8 yr after BMT and then returned slightly to the middle of the normal range spontaneously. Some authors (19, 20) also emphasize the evidence that thyroid gland may recover spontaneously in a substantial proportion of patients. Therefore, our policy in patients with subclinical compensated hypothyroidism is to carefully follow up the TSH and thyroid hormone levels every 3–6 months in these patients and start treatment with levothyroxine only if TSH remains high or it increases.

The transplant recipients were at significantly higher risk of new malignancy than the general population (21). Moreover, the risk was higher for recipients who were younger at the time of transplantation than for those who were older. The risk of developing secondary thyroid tumor after BMT has been only marginally reported as part of retrospective multicenter studies (19, 20, 21), and the incidence was low. In a recent report of second malignancies after BMT for acute leukemia, five thyroid carcinomas occurred among 3182 children with a strong relationship between the age at transplant and the occurrence of thyroid cancer (9). In our study, a high frequency of thyroid adenoma after BMT was well documented, and the incidence of thyroid carcinoma was rare. The relatively high incidence of secondary thyroid adenoma found in our study, compared with other multicenter studies, can be related to the close attention of the endocrinological follow-up, which consists of an annually performed thyroid ultrasound examination in many patients, including asymptomatic patients with normal thyroid function. Based on this study, we recommend that thyroid ultrasound examination be carried out on all BMT survivors, especially those who had transplants at younger ages.

In conclusion, patients who underwent BMT deserve life-long attention to detect, prevent, and treat symptoms and disorders of endocrine dysfunction.


   Acknowledgments
 
We thank all the medical staff in Tokai University Hospital for patient care.


   Footnotes
 
This work was partially supported by a research grant on human genome and tissue engineering from the Ministry of Health, Welfare, and Labor (Japan).

Abbreviations: AA, Aplastic anemia; AML, acute myelogenous leukemia; ATG, antithymocyte globulin; BMT, bone marrow transplant; Bu, busulfan; CY, cyclophosphamide; FT3, free T3; FT4, free T4; TAI, thoracoabdominal irradiation; TBI, total body irradiation.

Received May 5, 2004.

Accepted September 7, 2004.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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