- Email: [email protected]
Thyroid Dysfunction After Autologous Hematopoietic Stem Cell Transplant
The American Journal of Medicine (2006) 119, e5-e6
LETTERS The Reply: 1
In our study, we described a 16% prevalence of subclinical hyperthyroidism within 3 months after autologous stem cell transplantation, defining this disorder on the basis of a thyroid hormonal profile characterized by normal serum free triiodothyronine and thyroxine levels, and inhibited thyroid-stimulating hormone (TSH) levels. The space restriction for publishing prevented us from giving a more detailed description of thyroid dysfunctions in our study, which aimed to offer an overview of all endocrine disorders occurring during the first post-transplant year. In transplanted patients, Dr. Carlson properly pointed out that subclinical hyperthyroidism may not be the only plausible explanation for TSH decrease and suggested that previous corticosteroid treatments and “euthyroid sick syndrome” also should be taken into consideration. We are aware that some of the transient post-transplant changes in thyroid function tests may be an expression of a condition previously defined as “euthyroid sick syndrome.” Currently, this disorder is classified as a subtype of acquired transient central hypothyroidism that can have protective effects for patients during severe illness by preventing excessive tissue catabolism.2,3 Moreover, the activity of 5’-monodeiodinase, which catalyses the deiodination of thyroxin, decreases, whereas the activity of 5-monodeiodinase increases during nonthyroidal illnesses and for several treatments, including glucocorticoids. This results in decreased serum triiodothyronine and increased reverse triiodothyronine levels. The authors believe that their small proportion of patients was affected by a transient subclinical hyperthyroidism that was limited to the period of immunological reconstitution occurring within 3 months after the transplant. The following data support their hypothesis: transient thyreotoxicosis was reported during the same period (with a peak at 100 days) after allografting, and an immune-induced injury was claimed as the major pathogenic factor.4 A similar disorder, although less expressed, also may occur after autografting, and the difference in severity can be related to a milder degree of immune system derangement after autologous transplant. After the transplant, we documented an imbalance in the lymphocyte CD4-to-CD8 ratio associated with increased circulating levels of Th-1 cytokines interferon-␥ and tumor necrosis factor-␣. These abnormalities were more expressed in an allogeneic rather than autologous setting.5 Tumor necrosis factor-␣ and interleukin-6 were 0002-9343/$ -see front matter © 2006 Elsevier Inc. All rights reserved.
shown to inhibit 5’-monodeiodinase activity, thus reducing the triiodothyronine production; these findings suggest a possible contribution of the immune system deregulation to the development of early post-transplant “euthyroid sick syndrome.”6 Although the generally accepted definition of subclinical hyperthyroidism consists of suppressed TSH levels and normal serum free thyroid hormone levels in patients without clinical signs of hyperthyroidism,7 only patients with inhibited TSH values and free hormones within the upper half of the normal range were considered to be affected by this disorder.1 Nevertheless, the exact mechanisms resposible for post-transplant transient hyperthyroidism are unclear. Concerning the glucocorticoid influence on the hypothalamic-pituitary-thyroid axis, it suppresses its function and inhibits the thyroxin-to-triiodothyronine conversion in a dose-dependent manner.8 Nevertheless, only auto-transplanted patients were included in our study, and they had withdrawn steroid treatments as a part of chemotherapeutic regimens months before transplant. When evaluation of the thyroid function was undertaken, none of them was on glucocorticoids for reasons different from the physiological replacement in 3 patients with persistent adrenal insufficiency. These patients did not present any abnormalities of the thyroid function. Therefore, the effects of glucocorticoids can be excluded in our population. Moreover, as also specified by Dr. Carlson, free triiodothyronine levels should be low-normal during glucocorticoid treatment. They were significantly higher in our patients with subclinical hyperthyroidism when compared to those with “low T3 syndrome” or inhibited thyroid axis. Thyroxin levels were also higher in subclinical hyperthyroidism than in patients with inhibited thyroid axis. Values of thyroid hormones and TSH according to different disorders of the thyroid function are summarized in the Table. Patients included in our study were apparently in good clinical conditions. Nevertheless, 3 months after autografting, “low T3 syndrome” was observed in 25% of them. Inhibited thyroid axis was detected in another 5%, suggesting an incomplete recovery of the clinical conditions, which could have led to the development of “euthyroid sick syndrome” in about 30% of cases. Due to the limit on number of words, these patients were pooled into the category of “low T3 syndrome” in the original article. To our knowledge, mildly inhibited TSH levels associated with high-normal thyroid hormones have
e6
The American Journal of Medicine, Vol 119, No 6, June 2006
Table
Values of Thyroid Hormones and TSH in 95 Patients Divided According to Different Disorders
Disorder
Number of patients (%)
Triiodiothyronin (pg/mL)
Thyroxin (pg/mL)
TSH (mUI/mL)
Subclinical hyperthyroidism “Low T3 syndrome” Subclinical hypothyroidism Inhibited thyroid axis No abnormality Normal range
15 24 9 5 42
3.4 1.98 3.3 1.7 3.2
⫾ 0.6* ⫾ 0.4 ⫾ 0.5* ⫾ 0.4 ⫾ 1* 2.8-5.6
11.6 ⫾ 2.4† 9.2 ⫾ 4.2 8.2 ⫾ 2.4 5.6 ⫾ 4.3 9.3 ⫾ 4.3 6.6-18
0.23 ⫾ 0.2‡ 1.3 ⫾ 0.7 5 ⫾ 2§ 0.4 ⫾ 0.2 1.8 ⫾ 0.6 0.35-3.5
(16%) (25%) (9%) (5%) (44%) -
The data is expressed as mean ⫾ SDS. Significance: *P ⬍.001 vs patients with low T3 syndrome and those with inhibited thyroid axis. †P ⬍.001 vs patients with inhibited thyroid axis. ‡P ⬍.001 vs patients with low T3 syndrome, subclinical hypothyroidism, inhibited thyroid axis, and those with no abnormality. §P ⬍.05 vs patients with subclinical hyperthyroidism, low T3 syndrome, inhibited thyroid axis and those with no abnormality.
not been described as an expression of “euthyroid sick syndrome” yet. Hyperthyroidism of various degrees was also reported as a late consequence of radiotherapy9 and an early consequence of chemotherapy.10 These conditions should also be considered in neoplastic patients with inhibited TSH levels. The authors hope that this letter sufficiently supports their hypothesis that subclinical hyperthyroidism can occur in a small percentage of patients during immunological reconstitution after stem cell transplant. Larger longitudinal studies are necessary to clarify the pathogenetic mechanism. Libuse Tauchmanova, MD, PhD Annamaria Colao, MD, PhD Department of Molecular and Clinical Endocrinology and Oncology “Federico II” University of Naples Naples, Italy
Carmine Selleri, MD Gennaro De Rosa, MD Bruno Rotoli, MD Division of Hematology “Federico II” University of Naples Naples, Italy
doi:10.1016/j.amjmed.2005.09.017
References 1. Tauchmanovà L, Selleri C, De Rosa G, et al. Endocrine dysfunctions during the first year after autologous stem cell transplant for hematological malignancies. Am J Med. 2005;118:664-670. 2. Chopra IJ. Clinical review 86: euthyroid sick syndrome: is it a misnomer? J Clin Endocrinol Metab. 1997;82:329-334. 3. Utiger RD. Altered thyroid function in nonthyroidal illness and surgery. To treat or not to treat? N Engl J Med. 1995;333:1562-1563. 4. Kami M, Tanaka Y, Chiba S, et al. Thyroid function after bone marrow transplantation: possible association between immune-mediated thyreotoxicosis and hypothyroidism. Transplantation. 2001;71:406-411. 5. Tauchmanovà L, Matarese G, Colao A, et al. High serum leptin in patients with chronic graft versus host disease after hematopoietic stem cell transplantation. Transplantation. 2004;78:1376-1383. 6. Lee WY, MI Kang, Oh KW, et al. Relationship between circulating cytokines levels and thyori function following bone marrow transplantation. Bone Marrow Transplant. 2004;33:93-98. 7. Cooper DS. Subclinical thyroid disease: a clinician’s perspective. Ann Intern Med. 1998;129:135-138. 8. Chopra IJ, Huang TS, Beredo A, Solomon DH, Chua Teco GN, Mead JF. Evidence for an inhibitor of extrathyroidal conversion of thyroxin to 3,5,3’ triiodothyronine in sera of patients with nonthyroidal illness J Clin Endocrinol Metab. 1985;60:666-672. 9. Sklar C, Whitton J, Mertens A, et al. Abnormalities of the thyroid in survivors of Hodgkin’s disease: data from the childhood Cancer survivor Study. J Clin Endocrinol Metab. 2000;85:3227-3232. 10. Al-Anazi KA, Inam S, Jeha MT, Judzewitch R. Thyrotoxic crisis induced by cytotoxic therapy. Support Care Cancer. 2005;13:196-198.
LETTERS The Reply: 1
In our study, we described a 16% prevalence of subclinical hyperthyroidism within 3 months after autologous stem cell transplantation, defining this disorder on the basis of a thyroid hormonal profile characterized by normal serum free triiodothyronine and thyroxine levels, and inhibited thyroid-stimulating hormone (TSH) levels. The space restriction for publishing prevented us from giving a more detailed description of thyroid dysfunctions in our study, which aimed to offer an overview of all endocrine disorders occurring during the first post-transplant year. In transplanted patients, Dr. Carlson properly pointed out that subclinical hyperthyroidism may not be the only plausible explanation for TSH decrease and suggested that previous corticosteroid treatments and “euthyroid sick syndrome” also should be taken into consideration. We are aware that some of the transient post-transplant changes in thyroid function tests may be an expression of a condition previously defined as “euthyroid sick syndrome.” Currently, this disorder is classified as a subtype of acquired transient central hypothyroidism that can have protective effects for patients during severe illness by preventing excessive tissue catabolism.2,3 Moreover, the activity of 5’-monodeiodinase, which catalyses the deiodination of thyroxin, decreases, whereas the activity of 5-monodeiodinase increases during nonthyroidal illnesses and for several treatments, including glucocorticoids. This results in decreased serum triiodothyronine and increased reverse triiodothyronine levels. The authors believe that their small proportion of patients was affected by a transient subclinical hyperthyroidism that was limited to the period of immunological reconstitution occurring within 3 months after the transplant. The following data support their hypothesis: transient thyreotoxicosis was reported during the same period (with a peak at 100 days) after allografting, and an immune-induced injury was claimed as the major pathogenic factor.4 A similar disorder, although less expressed, also may occur after autografting, and the difference in severity can be related to a milder degree of immune system derangement after autologous transplant. After the transplant, we documented an imbalance in the lymphocyte CD4-to-CD8 ratio associated with increased circulating levels of Th-1 cytokines interferon-␥ and tumor necrosis factor-␣. These abnormalities were more expressed in an allogeneic rather than autologous setting.5 Tumor necrosis factor-␣ and interleukin-6 were 0002-9343/$ -see front matter © 2006 Elsevier Inc. All rights reserved.
shown to inhibit 5’-monodeiodinase activity, thus reducing the triiodothyronine production; these findings suggest a possible contribution of the immune system deregulation to the development of early post-transplant “euthyroid sick syndrome.”6 Although the generally accepted definition of subclinical hyperthyroidism consists of suppressed TSH levels and normal serum free thyroid hormone levels in patients without clinical signs of hyperthyroidism,7 only patients with inhibited TSH values and free hormones within the upper half of the normal range were considered to be affected by this disorder.1 Nevertheless, the exact mechanisms resposible for post-transplant transient hyperthyroidism are unclear. Concerning the glucocorticoid influence on the hypothalamic-pituitary-thyroid axis, it suppresses its function and inhibits the thyroxin-to-triiodothyronine conversion in a dose-dependent manner.8 Nevertheless, only auto-transplanted patients were included in our study, and they had withdrawn steroid treatments as a part of chemotherapeutic regimens months before transplant. When evaluation of the thyroid function was undertaken, none of them was on glucocorticoids for reasons different from the physiological replacement in 3 patients with persistent adrenal insufficiency. These patients did not present any abnormalities of the thyroid function. Therefore, the effects of glucocorticoids can be excluded in our population. Moreover, as also specified by Dr. Carlson, free triiodothyronine levels should be low-normal during glucocorticoid treatment. They were significantly higher in our patients with subclinical hyperthyroidism when compared to those with “low T3 syndrome” or inhibited thyroid axis. Thyroxin levels were also higher in subclinical hyperthyroidism than in patients with inhibited thyroid axis. Values of thyroid hormones and TSH according to different disorders of the thyroid function are summarized in the Table. Patients included in our study were apparently in good clinical conditions. Nevertheless, 3 months after autografting, “low T3 syndrome” was observed in 25% of them. Inhibited thyroid axis was detected in another 5%, suggesting an incomplete recovery of the clinical conditions, which could have led to the development of “euthyroid sick syndrome” in about 30% of cases. Due to the limit on number of words, these patients were pooled into the category of “low T3 syndrome” in the original article. To our knowledge, mildly inhibited TSH levels associated with high-normal thyroid hormones have
e6
The American Journal of Medicine, Vol 119, No 6, June 2006
Table
Values of Thyroid Hormones and TSH in 95 Patients Divided According to Different Disorders
Disorder
Number of patients (%)
Triiodiothyronin (pg/mL)
Thyroxin (pg/mL)
TSH (mUI/mL)
Subclinical hyperthyroidism “Low T3 syndrome” Subclinical hypothyroidism Inhibited thyroid axis No abnormality Normal range
15 24 9 5 42
3.4 1.98 3.3 1.7 3.2
⫾ 0.6* ⫾ 0.4 ⫾ 0.5* ⫾ 0.4 ⫾ 1* 2.8-5.6
11.6 ⫾ 2.4† 9.2 ⫾ 4.2 8.2 ⫾ 2.4 5.6 ⫾ 4.3 9.3 ⫾ 4.3 6.6-18
0.23 ⫾ 0.2‡ 1.3 ⫾ 0.7 5 ⫾ 2§ 0.4 ⫾ 0.2 1.8 ⫾ 0.6 0.35-3.5
(16%) (25%) (9%) (5%) (44%) -
The data is expressed as mean ⫾ SDS. Significance: *P ⬍.001 vs patients with low T3 syndrome and those with inhibited thyroid axis. †P ⬍.001 vs patients with inhibited thyroid axis. ‡P ⬍.001 vs patients with low T3 syndrome, subclinical hypothyroidism, inhibited thyroid axis, and those with no abnormality. §P ⬍.05 vs patients with subclinical hyperthyroidism, low T3 syndrome, inhibited thyroid axis and those with no abnormality.
not been described as an expression of “euthyroid sick syndrome” yet. Hyperthyroidism of various degrees was also reported as a late consequence of radiotherapy9 and an early consequence of chemotherapy.10 These conditions should also be considered in neoplastic patients with inhibited TSH levels. The authors hope that this letter sufficiently supports their hypothesis that subclinical hyperthyroidism can occur in a small percentage of patients during immunological reconstitution after stem cell transplant. Larger longitudinal studies are necessary to clarify the pathogenetic mechanism. Libuse Tauchmanova, MD, PhD Annamaria Colao, MD, PhD Department of Molecular and Clinical Endocrinology and Oncology “Federico II” University of Naples Naples, Italy
Carmine Selleri, MD Gennaro De Rosa, MD Bruno Rotoli, MD Division of Hematology “Federico II” University of Naples Naples, Italy
doi:10.1016/j.amjmed.2005.09.017
References 1. Tauchmanovà L, Selleri C, De Rosa G, et al. Endocrine dysfunctions during the first year after autologous stem cell transplant for hematological malignancies. Am J Med. 2005;118:664-670. 2. Chopra IJ. Clinical review 86: euthyroid sick syndrome: is it a misnomer? J Clin Endocrinol Metab. 1997;82:329-334. 3. Utiger RD. Altered thyroid function in nonthyroidal illness and surgery. To treat or not to treat? N Engl J Med. 1995;333:1562-1563. 4. Kami M, Tanaka Y, Chiba S, et al. Thyroid function after bone marrow transplantation: possible association between immune-mediated thyreotoxicosis and hypothyroidism. Transplantation. 2001;71:406-411. 5. Tauchmanovà L, Matarese G, Colao A, et al. High serum leptin in patients with chronic graft versus host disease after hematopoietic stem cell transplantation. Transplantation. 2004;78:1376-1383. 6. Lee WY, MI Kang, Oh KW, et al. Relationship between circulating cytokines levels and thyori function following bone marrow transplantation. Bone Marrow Transplant. 2004;33:93-98. 7. Cooper DS. Subclinical thyroid disease: a clinician’s perspective. Ann Intern Med. 1998;129:135-138. 8. Chopra IJ, Huang TS, Beredo A, Solomon DH, Chua Teco GN, Mead JF. Evidence for an inhibitor of extrathyroidal conversion of thyroxin to 3,5,3’ triiodothyronine in sera of patients with nonthyroidal illness J Clin Endocrinol Metab. 1985;60:666-672. 9. Sklar C, Whitton J, Mertens A, et al. Abnormalities of the thyroid in survivors of Hodgkin’s disease: data from the childhood Cancer survivor Study. J Clin Endocrinol Metab. 2000;85:3227-3232. 10. Al-Anazi KA, Inam S, Jeha MT, Judzewitch R. Thyrotoxic crisis induced by cytotoxic therapy. Support Care Cancer. 2005;13:196-198.