¹³¹I SUCCESSFULLY TREATED A CASE OF HYPERTHYROIDISM AFTER ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION

Abstract

Hematopoietic stem cell transplantation (HSCT) is an effective treatment for various types of hereditary hematologic disease, hematological malignancy, primary immunodeficiency and metabolic disease. Thyroid dysfunction is a common complication of HSCT, which situation is mainly manifested as hypothyroidism and rarely as hyperthyroidism. This report presents a 28-year-old man who developed hyperthyroidism 9 years after sibling allogeneic HSCT, which was most likely caused by chronic GVHD. In the meantime, the patient also suffered from liver dysfunction and pancytopenia, for which he was inappropriate to take antithyroid drugs (ATD) for treatment of hyperthyroidism. The patient was orally administered 259 MBq ¹³¹I, an individualized dose. The symptoms of hyperthyroidism were mitigated by ¹³¹I treatment.

Introduction

Thyroid dysfunction is a common complication of hematopoietic stem cell transplantation (HSCT), of which the most common condition is hypothyroidism (incidence: about 40%), mostly occurred in 12-19 months after transplantation. Hyperthyroidism, however, is rarely seen, and in many cases manifested as transient subclinical hyperthyroidism (1,2). According to related clinical research, the risk factors of post-HSCT disturbance of thyroid function include HLA-A2-B46-DR9 positivity, female donor, total body irradiation (TBI) before transplantation, and the persistence of chronic graft versus host disease (GVHD) (3,4). Some research also reported possible contribution of post-transplantation cytomegalovirus (CMV) infection to hyperthyroidism (5).

Here, we report a case of Graves’ disease after allogeneic HSCT successfully cured with ¹³¹I therapy.

Case Report

A 28-year-old man sought medical care in May 2010 for epistaxis, and was diagnosed with myelodysplastic syndrome (MDS-RAEB II, high risk). HLA matching found his full elder sister a 6/6 match with compatible blood type (O/O). In October the same year, the patient received sibling allogeneic HSCT (conditioning regimen: Busulfan combine Cyclophosphamide, GVHD prophylaxis regimen: Mycophenolate mofetil combine Cyclosporin, total number of nucleated cells infused was 5.84x10⁸/kg, the number of CD34+ cells infused was 2.71 x10⁵/kg). Neutrophil recovered 12 days after transplantation; platelet recovered 13 days after transplantation; and red blood cells recovered 24 days after transplantation. On day 30 after transplantation, according to STR-PCR of bone marrow, the bone marrow of the recipient was completely matched with the donor’s. On day 29 after transplantation, the patient had skin rash and was diagnosed as acute GVHD I, which was ameliorated after glucocorticoid treatment. On day 42 after transplantation, the patient was infected by cytomegalovirus, which turned negative after being treated with ganciclovir. The patient also suffered from hypopigmentation 8 months after the transplantation and liver dysfunction 1 year after the transplantation, which we considered to be chronic GVHD (generalized). In view of these, the methylprednisolone and immunosuppressive therapy was introduced. Although the patient’s liver dysfunction was improved later, there was gradual aggravation of the hypopigmentation. Later, the patient’s situation was followed up at the clinic. In April 2019, the patient reported feeling hungry fast, increased amount of food intake, trembling hands, and other symptoms of hypermetabolism. At the same time with the above symptoms, his pulse rate was 110 beats/min, other vital signs were within normal range. His physical examination revealed a soft and diffusely enlarged thyroid gland (grade I). Thyroid hormone levels, liver function, and routine blood tests were shown in Table 1. Free triiodothyronine (FT3) and free thyroxine (FT4) were elevated while thyrotropin (TSH) was reduced; thyroglobulin antibody (TgAb) >500.00IU/mL↑ (reference range: 0.00-60.00IU/mL), thyroid peroxidase antibody (TPoAb) >1300.00IU/mL↑ (reference range: 0.00-60.00IU/mL), thyrotropin receptor antibody (TRAb) was 2.18U/L (reference range: 0.00-5.00 IU/mL). Thyroid ultrasonography showed mild thyroid enlargement. The sizes of the left and right lobes were 15 x 18 x 45 mm and 16 x 21 x 50 mm respectively (vertical length reference range: 35-45mm, horizontal length reference range: 20-25mm), with a hyperechoic nodule of 4.0x3.7mm in the lower right lobe and a cystic nodule of 2.2x1.2mm in the upper right lobe. The values of 2 hour and 24 hour Radioactive iodine uptake (RAIU) were 64% and 99.9%, respectively. The 99mTcO₄-thyroid scintigraphy showed a diffusely enlarged thyroid gland, the estimated weight was approximately 33.4g (reference range: 20-25g). Therefore, he was diagnosed with Graves’ hyperthyroidism. At the same time, the result of bone marrow puncture indicated that the patient had complete remission of MDS. According to routine blood test, the numbers of WBC, RBC and PLT were slightly lower than references. Moreover, the patient still showed hypopigmentation, which could be the result of chronic GVHD.

Table 1.

Laboratory results of thyroid hormone levels, liver function and routine blood test before and after ¹³¹I treatment

	Before	1 month after	3 months after	6 months after	10 months after	14 months after
FT3 (pmol/L, reference: 3.50-6.50 pmol/L)	13.63	4.18	1.37	8.55	5.53	4.66
FT4 (pmol/L, reference: 11.50-22.70 pmol/L)	44.93	22.71	2.91	29.72	20.55	18.26
TSH (mU/L, reference: 0.55-4.78 mU/L)	0.002	<0.0050	>100	0.014	0.010	0.026
Alanine aminotransferase (IU/L, reference: 0-50 IU/L)	65	33	107	82	37	41
Aspartate aminotransferase (IU/L, reference: 0-40 IU/L)	59	31	136	73	36	41
Alkaline phosphatase (IU/L, reference: 40-150 IU/L)	430	337	647	468	325	393
Glutamyl transpeptidase (IU/L, reference: 7-50 IU/L)	358	298	720	525	404	223
Total bilirubin (umol/L, reference: 3.4-20.5 umol/L)	10.3	9.8	12.4	10.9	7.0	7.6
WBC (x109/L, reference: 3.5-9.5 x109/L)	3.32	3.51	3.72	3.82	4.66	4.89
RBC (x1012/L, reference: 3.8-5.1 x1012/L)	3.11	4.04	3.75	3.46	3.42	3.09
PLT (x109/L, reference: 125-350 x109/L)	95	123	85	89	88	90
Hb (g/L, reference: 115-150 g/L)	93	112	92	108	103	110

To determine the cause, this patient’s sister received thyroid examination at our hospital. Her thyroid hormone levels were normal, TgAb 262.2 IU/mL↑, TPoAb 226.2 IU/mL↑, TRAb 9.21 U/L. Her thyroid ultrasonography showed heterogeneous echogenicity with a hypoechoic nodule of 7×4mm in the right lobe, which suggested chronic lymphocytic thyroiditis (CLT). As retrieved from previous medical records, the patient’s thyroid function and related antibodies were normal.

Due to the patient’s complications such as liver dysfunction and pancytopenia, it was inappropriate to treat him with antithyroid drugs (ATD). The patient was given individualized oral dose of 259 MBq ¹³¹I. His related laboratory tests after ¹³¹I treatment were summarized in Table 1. After the treatment, his thyroid hormone levels decreased gradually. Three months later, the patient experienced early hypothyroidism, and started taking levothyroxine sodium as alternative treatment. Six months later, levothyroxine sodium was stopped as his thyroid function returned to normal. Ten months after ¹³¹I treatment, TSH, FT3, FT4 and WBC returned to normal, while alanine aminotransferase and aspartate aminotransferase both declined to normal values. Other results of laboratory tests had no obvious improvement, which was related to the existence of chronic GVHD.

Discussion

Related clinical research has summarized the risk factors for post-HSCT disturbance of thyroid function, including HLA-A2-B46-DR9 positivity, female donor, total body irradiation (TBI) before transplantation, and the persistence of chronic graft versus host disease (GVHD) (3,4). In addition, it is pointed out in some research that post-transplantation cytomegalovirus (CMV) infection might also contribute to hyperthyroidism (5). According to a recent study, administration of anti-thymocyte globulin (ATG) might induce severe T cell depletion, thereby leading to Graves’ disease (13).

The specific mechanism of post-transplantation hyperthyroidism could be related to reactive lymphocytes-caused adoptive immunity in the donor, or secondary immune disorders and immune reconstruction of the body because of GVHD after transplantation (6,7). Such cases have been reported in related literature (8,9). In this case, the patient suffered from hyperthyroidism 9 years after transplantation. The conditioning regimen was Busulfan combined Cyclophosphamide, not including TBI, therefore at low risk of post-transplantation disturbance of thyroid function. The patient also experienced CMV infection on day 42 after transplantation, which turned and remained negative after antiviral therapy, therefore of remote possibility of hyperthyroidism secondary to viral infection. Later, the patient received long-term oral administration of glucocorticoids and immunosuppressant for the chronic GVHD that occurred in 12 months after transplantation. In view that the donor is his elder sister who was then diagnosed with chronic lymphocytic thyroiditis, there is the possibility of adoptive immunity. However, according to previous research, post-HSCT autoimmune thyroid disease caused by adoptive immunity is mostly found within several years after transplantation (10). Adoptive immunity seems less likely in the current case since the interval time was very long. In the end, chronic GVHD is believed to be the most likely reason for the patient’s post-transplantation hyperthyroidism. Chronic GVHD is a major late complication of HSCT, and a state of immune disorders. It can involve multiple systems, while showing varied clinical manifestations and the characteristics of autoimmune disease. In chronic GVHD, helper T cell 2 (Th2) gives immune response to antigens in the body, and releases interleukin-4, interleukin-5, interleukin-6, interleukin-10 and other cytokines to induce B cell proliferation and differentiation to generate antibodies for humoral immunity, thus causing organ-specific autoimmune disease such as Graves hyperthyroidism (11,12). In this case, the patient’s long-term pancytopenia might be related to the complex immune response of the body after HSCT. In addition, the long-term administration of immunosuppressant might also contribute to pancytopenia.

As the first-line therapy for Graves’ hyperthyroidism in adults, ¹³¹I treatment can effectively control the state of hyperthyroidism in patients. It is particularly suitable for those not fit for ATD treatment and with contraindications in operation. It is rare to see reports on ¹³¹I treatment of hyperthyroidism after allogeneic hematopoietic stem cell transplantation. In this case, the patient suffered from hyperthyroidism 9 years after HSCT, and showed liver dysfunction and pancytopenia, therefore not suitable for ATD. After ¹³¹I treatment, his hyperthyroidism symptoms are gradually relieved, and his liver function and white blood cell recovered to some extent in the follow-up visits. Therefore, ¹³¹I treatment for post-HSCT hyperthyroidism is safe and effective, and can be applied as the first choice treatment.

Conflict of interest

The authors declare that they have no conflict of interest. Funding Sources

This work was supported by“the Fundamental Research Funds for the Central Universities”(grant numbers WK9110000192).