Abstract
Background. The prevalence of thyroid cancer in renal transplant population has not been widely studied, and there is no consensus on the management of thyroid cancer in transplant patients. The aim of this study was to evaluate changes in thyroid hormone levels and investigate the incidence of the thyroid cancer after renal transplantation. Materials and methods. From October 1989 to April 2007, 122 renal allograft recipients that were being followed underwent thyroid ultrasonography to determine nodules together with thyroid hormone levels. Ultrasound-guided fine-needle aspiration biopsy (FNAB) was performed to the nodules > 10 mm or those with 8–10 mm diameter but with calcifications. Results. One hundred and eight patients (88.5%) had normal thyroid function. None of the patients had overt hypothyroidism, 2 had subclinical hypothyroidism, 10 subclinical thyrotoxicosis, and 2 low T3 syndrome. Mean thyroid volume was 14.2 ± 7.2 ml. In all, 91.8% was diagnosed with goiter (n = 112). Seventy-two thyroid nodules were detected in 49 kidney allograft recipients (single nodule in 30, multiple in 19 patients). Eighty-four biopsy samples were reported as benign (n = 21, 87.5%), 8 as suspicious (n = 2, 8.3%), and 4 as inadequate (n = 1, 4.1%). After surgery, one of the patients (0.8%) with suspicious FNAB was reported as papillary thyroid carcinoma. Conclusion. Because of the high incidence of thyroid dysfunction in transplant patients, screening of thyroid function should be a part of follow-up. Our results suggest that although frequency of nodules is increased in kidney transplant patients, prevalence of thyroid cancer is slightly, but not significantly, higher than that of the normal population.
INTRODUCTION
Disturbances of thyroid hormone metabolism and morphology are frequent in end stage renal disease (ESRD), but data after renal transplantation (RT) is conflicting. It is proposed that uremia and immunosuppressive medications lead to remarkable immune suppression, and that this may be responsible for increased incidence of thyroid carcinoma in RT patients compared to general population. In one study investistigating the association between thyroid morphology and function in RT recipients, peritoneal or hemodialysis patients, and a normal population, a high rate of goiter (100%), thyroid nodules (43%), and thyroid cancer (11.4%) by ultrasound-guided fine-needle aspiration biopsy (FNAB) was reported. Interestingly, they found a significant association between cyclosporine level and the occurrence of goiter, supporting the idea that medication may be indeed responsible for development of thyroid cancer.Citation[1] However, in a retrospective study by Pond et al., only 0.22% out of a cohort of 10,689 renal transplant recipients had thyroid cancer.Citation[2] Also, Tauchmanova et al. found no patients with thyroid cancer in a prospective follow-up of 50 RT recipients during an average follow-up period of 23 months.Citation[3]
Thus, data are minimal and conflicting regarding thyroid cancer risk after renal transplantation.
The aim of this cross-sectional study was to assess thyroid cancer incidence after renal transplantation, to evaluate the changes in thyroid hormone levels, and also to determine the role of FNAB in the clinical management these patients.
MATERIALS AND METHODS
One hundred and twenty-two patients who underwent renal transplantation between October 1989 and April 2007 were recruited in this cross-sectional study. Data regarding demographical, clinical, and laboratory parameters were obtained from patient charts. The study was performed in accordance with Declaration of Helsinki and approved by the Institutional Review Board of Dokuz Eylul University, Izmir. All patients gave informed consent prior to the study.
At the first visit, a thorough physical examination was performed, primarily focusing in symptoms of thyroid dysfunction (hypothyroidism or hyperthyroidism). An endocrinologist accompanied this first physical examination. Also at this visit, 5 mL of venous blood samples were also obtained for laboratory examinations. Free T3 (normal range 1.8–4.2 pg/mL) and free T4 (normal range 0.8–1.9 ng/dL) levels were measured using a radioimmunoassay (Immulite 2000, Diagnostic Products Corporation, Los Angeles, California, USA). Anti-thyroid peroxidase antibody (Anti TPO), anti-thyroglobulin antibody (Anti Tg), and serum TSH levels were measured using solid phase chemiluminescent immunometric assay (Immulite 2000, Diagnostic Products Corporation).
Echogenicity aspects and presence of thyroid nodules were assessed by the same operator by using an ultrasonography (HDI-5000; ATL, Bothell, Washington, USA) equipped with a 7.5-MHz linear-array transducer.
Ultrasound-guided fine-needle biopsy was performed in all detected nodules greater than 1 cm in diameter and in nodules greater than 8 mm in diameter but with calcification. Each cytological specimen was smeared on a slide immediately after aspiration. All specimens were cytologically categorized as benign, suspicious (possible carcinoma), malignant, or inadequate. Nodules were considered to be definitively benign if two consecutive FNABs were histopathologically benign. All patients with suspicious nodules underwent surgery.
A search of Pubmed for the incidence and prevalence of thyroid cancer in Turkish transplant patients was performed by entering the words Turkey, Turkish, transplantation, incidence, and prevalence.
Statistical Analysis
Results are reported as mean±SD. Comparison of means and percentages was estimated by the unpaired two Student's t-test or Mann-Whitney U test, as appropriate. p value < 0.05 was considered as statistically significant. All calculations were performed using SPSS, version 12.0.
RESULTS
The demographical, clinical, and biochemical characteristics of patients are presented in .
Table 1 Characteristics of the renal transplant patients in study
Underlying diseases were glomerulonephritis in 46 (37.7%), hypertension in 17 (13.9%), and other causes in 59 (48.4%) cases. Mean period of dialysis prior to RT was 22.6 ± 25.1 months (range: 0–114). Mean age was 39.8±12.2 years (range: 19–69 years), post-transplantation follow-up was 59.9 ± 49.5 months (range: 6–372)m and 46 (38%) were female. Sixty-six (54%) of RT were from living, and 56 (46%) were from cadaveric donors. Median post-transplant creatinine level was 1.4 mg/dL, considered as satisfactory (see ).
Sixty-seven patients received induction therapy, 40 anti-CD25 monoclonal antibody (basiliximab 40 mg intravenously) and 27 antithymocyte globulin treatment. Maintenance immunosuppressive protocols included oral tacrolimus/cyclosporine or sirolimus and steroids and mycophenolate mofetil or azathioprine.
Type of pre-transplant thyroid surgery was bilateral subtotal resection in 5 patients for thyroid nodule enlargement, and severe refractory secondary hyperparathyroidism in 4 patients.
One hundred and eight patients (88.5%) had normal thyroid function. None of these patients demonstrated overt hypothyroidism. Subclinical hypothyroidism was diagnosed in 2 patients, subclinical thyrotoxicosis (low TSH with normal free T3, free T4) in 10, and low T3 syndrome in 2 patients. Circulating thyroid autoantibodies were negative in all cases with normal thyroid function at the time of evaluation.
Mean thyroid volume was 14.2 ± 7.2 mL. Goiter was diagnosed in the majority of cases (91.8%, n = 112/122). Seventy-two thyroid nodules were found on sonography in 49 kidney allograft recipients (30 patients, single; 19, multiple). Nodules were larger than 2 cm diameter in 2 patients (4%), between 1 and 2 cm in 20 (40.8%), and were less than 1 cm in diameter in 27 (55.2%). Of the patients who had nodules, 43 patients had normal thyroid function, subclinical hyperthyroidism was diagnosed in 4 patients, and the low T3 syndrome occurred in one. The biopsy samples were cytologically interpreted as benign (87.5%), suspicious (8.3%), or inadequate for diagnosis (4.1%). One of the suspicious nodules was a 1.5 cm heterogeneous nodule in the right lobe of the thyroid, and there were multiple nodules with calcifications in the left lobe. The other suspicious nodule showed an iso-echoic irregular nodule of 1.7 cm in the left lobe with some micro-calcifications. All patients with a biopsy diagnosis of suspicious cytology underwent total thyroidectomy with lymph node dissection. Histological examination revealed multicentric papillary thyroid cancer. There was no distant metastasis. Adjuvant radioiodide treatment was applied. The patient has been previously received inductive therapy of basiliximab 40 mg and antithymocyte globulin for steroid-resistant acute rejection and maintenance treatment with cyclosporine plus steroid plus mycophenolate mofetil. There were no signs of recurrence at 8 months after surgery. A second suspicious nodule was underwent hemi-thyroidectomy alone. Histological examination revealed benign cytology.
There was no difference in values of TSH among patients with or without nodules or in patients with goiter. Nodule prevalences were similar with respect to induction therapy, maintenance immunosuppressive regimens, and rejection history. shows characteristics of patients with and without nodules. Only the thyroid volume was greater in patients with thyroid nodules than in those without (16.3 ± 8.4 vs. 12.9 ± 5.9; p < 0.05) (see ).
Table 2 Demographic features of renal transplant patients with and without nodules
DISCUSSION
Patients with renal transplantation are at increased risk for developing thyroid cancer, primarily due to impaired immune surveillance, secondary hyperparathyroidism, nutritional deficiencies, and altered DNA repair. There is conflicting data in the literature regarding thyroid cancer in the renal transplant population.Citation[1–5] The fact that the majority of studies are retrospective investigations of transplant patients who were surgically treated is also another disadvantage when evaluating these studies. The prevalence of thyroid cancers has been reported to be between 0 and 11.4% in these studies.Citation[1–5] We found no reported thyroid cancer in Turkish transplant patients in Pubmed database. However, in a study of 2817 chronic renal failure patients from Turkey, which is considered an iodine-deficient country, only 10 papillary thyroid cancer and 3 unspecified thyroid cancers have been reported.Citation[6] In our study population, the prevalence of thyroid cancer was found to be lower compared to general population (0.8 vs 2.6%, respectively).Citation[7] Recently, a study was performed to determine the prevalence and clinicopathological characteristics of thyroid cancers in the dialysis population in Turkey. They conclude that the prevalence of thyroid cancer undergoing dialysisCitation[8] was not higher than that in the background population. This finding was in accordance with the results of our study showing a similiar prevelance of thyroid cancer in Tx patients. Both this relatively low number in regard to general and other transplant population may due to differences in background population, genetic predisposition, and/or environmental factors.
We also found a higher prevalence of thyroid nodules (40%) and goiter (91.8%) in transplant patients compared to the general Turkish population (33% and 20–76%, respectively).Citation[9] Our results support the previous reports that show that the presence of thyroid nodules is not related to age, duration of dialysis, or TSH.Citation[1] Contrary to these results, Tauchmanova et al.Citation[3] described that duration of dialysis increased the occurrence of thyroid nodules. We did not demonstrate any effect of duration of dialysis on the development of thyroid nodules. In our study, the thyroid volume was greater in patients with thyroid nodules than in those without. We also found that there was no difference in nodule prevalence with respect to immunosuppressive regimens, inductive therapy, and rejection history.
Other studies have reported conflicting results regarding thyroid dysfunction, with a majority of them not reporting any specific functional disturbances and some reporting increased incidence of hypothyroidism after kidney transplantation. In our study, subclinical hypothyroidism and low T3 syndrome were diagnosed only in two patients. The occurrence of hyperthyroidism in transplant recipients receiving immunosuppressive therapy is extremely rare.Citation[10,Citation11] Furthermore, in end-stage renal disease, hyperthyroidism may occur with a frequency similar to that of the general population.Citation[12] However, we observed a high prevalence of hyperthyroidism in transplant patients. The higher prevalence of thyrotoxicosis may be caused by iodine-induced hyperthyroidism and/or steroid therapy. In our study, in five of the ten patients that received steroid therapy because of rejection, serum TSH levels showed a marked decrease caused by high dose steroid administration during rejection period. In the remaining five patients who did not receive steroid, thyroid scintigraphy with 99mTc pertechnetate showed at least one hyperfunctioning nodule in the gland. There is a negative correlation between levels of iodine intake and serum TSH concentration. Endemic goiter patients develop a mild clinical and laboratory picture of hyperthyroidism when they move to an urban area where iodine intake is higher than in the rural villages (like most of the transplant patients in our study). These patients were treated by cessation of excessive iodine intake. After depletion of the excess iodine, thyroid functions returned to normal levels.
In conclusion, the prevalence of thyroid cancer in renal transplant patients is not higher than the background population. Because of the high incidence of thyroid dysfunction in transplant patients, screening of thyroid function should be considered in the evaluation of these patients. Our results also suggest that thyroid nodules are highly overestimated in these patients.
DECLARATION OF INTEREST
The authors declare no conflict of interest. The authors alone are responsible for the content and writing of the paper.
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