The relationship between secondary hyperparathyroidism and thyroid
cancer in end stage renal disease: A population based cohort study
Shih-Yi Lin a,b, Wei-Ming Linc,d, Cheng-Li Lin e,f, Tse-Yen Yang g, Fung-Chang Sung e,f,
Yuan-HungWang h,i, Chia-Hung Kao j,k,⁎
1. Introduction
End stage renal disease (ESRD) patients have shown suppressed immunity, originating from impaired antigen recognition, impaired
phagocytosis, altered T-Cell function, and B cell lymphopenia in uremic milieu, which account for their high prevalence of infection and malignancy [1,2]. Maisonneuve et al. reported that dialysis patients have a
higher incidence of kidney, bladder, and thyroid cancer than is typical in western populations [3]. Lin et al. and Kao et al. [4,5] reported similar fndings in Asian dialysis patients. Although ESRD patients have a higher incidence of a specifc malignancy than the general population, few studies have investigated which characteristic among dialysis patients carries a higher risk of developing cancer [6].
In addition to immune dysfunction, secondary hyperparathyroidism (HPT) is another prevalent complication observed in ESRD patients [7].
Secondary HPT left untreated can cause certainmorbidity in dialysis patients, including osteodystrophy, anemia, pruritus, and atherosclerotic
vascular disease [8–10]. The parathyroid hormone is also reported to exert adverse effects on immune function [11]. Although several studies have observed the association between HPT and certain malignancy, including breast and genitourinary tract cancer [12–14], most of these studies have been confned to researching the general population and primary HPT. Whether secondary HPT also modifes the risk of cancer development in the ESRD population, which carries an extremely high prevalence of malignancy, remains unknown. Therefore, conducting a cohort study using a nationwide database to investigate the association between secondary HPT and cancer in ESRD patients is worthwhile.
2. Materials andmethods 2.1. Study design
We conducted a population-based retrospective cohort study based on the original claims data of 1 million benefciaries randomly sampled
fromthe TaiwanNationalHealth Insurance ResearchDatabase (NHIRD).
All personal identifcations were encrypted by the National Health Research Institutes (NHRI) before data was released. We also obtained
the approval of the Institutional ReviewBoard of ChinaMedical University Hospital (CMU-REC-101-012). Previous papers have presented related information about the NHIRD [5,6] and demonstrated diagnosis accuracy and validity, such as that of cardiovascular and autoimmune disease [15,16].
2.2. Study population
We used the International Classifcation of Disease, Ninth Revision (ICD-9), for diagnostic codes and identifed ESRD diagnoses and other cancer types by using records from the Registry of Catastrophic Illness Patient Database (RCIPD). Fig. 1 shows the study framework.We identifed 5360 patients with an ESRD diagnosis (ICD-9 code 585) from
1997 to 2010. Patients with newly diagnosed HPT (ICD-9 codes 252.0, 227.1; receiving operation ICD-9 06.81, 06.89; treated with calcitriol;
or receiving a sestamibi parathyroid scan) were selected for the HPT group. The HPT diagnosis date was defned as the index date. The non-HPT group was randomly selected from the remaining ESRD patients without a history of HPT. For each patient in the HPT cohort, 3
comparisons were randomly selected, frequency-matched by years since ESRD diagnosis, and year of HPT diagnosis.We excluded patients with a medical history of cancer (ICD-9 codes 140–195, 200–208) before the index date, and those with incomplete age or sex information.
Both cohorts were followed until they were diagnosed with cancer, or until the patients were censored because of loss to follow-up, withdrawal from the NHI system, or the end of 2010.
2.3. Comorbidity variables
The following diseases were considered as probable comorbidities associated with ESRD. Patients diagnosed with these diseases made at least 3 claims before the index date with a principal or secondary diagnosis, such as hypertension (ICD-9 codes 401–405) and hyperlipidemia
(ICD-9 272). Those making at least 2 claims for diabetes (ICD-9 code 250) within 1 year of the index date received principal or secondary diagnoses.
2.4. Statistical analysis
We described and compared the distributions of age, sex, and comorbidities between the case and control groups by using χ2 tests. To
estimate the effects of age on the relative and absolute risks of cancer, we analyzed patients aged 20–49 years, 50–64 years, and ≥65 years at the index date of HPT. We calculated the incidence densities (per 1000 person-years) and person-years from the index date to the date of cancer diagnosis, loss to follow-up, or the end of 2010. We used the Cox proportional-hazards regression to assess the hazard ratio (HR) of developing cancer. We performed all statistical analyses by using the SAS statistical package (version 9.2 for Windows; SAS Institute, Inc., Cary, NC, USA). We set the statistical signifcance at α = .05 and depicted the survival curves with R statistical software (version 2.14.1 for Windows).
3. Results
3.1. Patient characteristics and comorbidity
Table 1 shows the distribution of demographic characteristics in the
study patients. The HPT group and non-HPT group showed no signifcant differences in the distribution of sex. Patients in the HPT group
were predominantly less than 65 years of age. The non-HPT group primarily included the elderly, with a much higher mean age than that of
the HPT group (58.9 ± 14.0 years vs 54.4 ± 13.2 years). However, comorbidities such as diabetes (53.0% vs 30.9%; p b 0.001), hypertension
(86.3% vs 85.7%; p = 0.68), and hyperlipidemia (45.0% vs. 41.7%;
p = 0.09) were more prevalent in the non-HPT group than in the HPT group. 3.2. Incidence densities and HR for cancer between HPT and non-HPT patients
Table 2 shows the incidence densities and risks of all cancer types in
the case and control groups. During the 14-year follow-up period, 51 patients in the ESRDwith HPT group and 158 patients in the ESRDwithout HPT group developed cancer. The overall incidence rate of all cancer was 8% lower in the ESRD with HPT group than in the control group (16.8 vs 18.3 per 1000 person-years), with an adjusted HR of 1.00 (95% confdence interval (CI), 0.72–1.38). Stratifed by sex, the female incidence density rates were 16.0 and 19.0 per 1000 person-years in the ESRD with and without HPT groups. Compared with the non-HPT patients over 65 years of age, the incidence density was lower in the HPT cohort (26.9 per 1000 person-years vs 10.6 per 1000 personyears;
incidence rate ratio = 0.40, 95% CI = 0.22–0.71). However,
these relationships were non-signifcant when we adjusted covariates in the multivariate Cox proportional hazards regression analyses
(HR = 0.46, 95% CI = 0.18–1.16 for≥65 years of age). Table 3 presents a further analysis of cancer risk for the case and control groups. For the ESRD with HPT group, the highest incidence rate of bladder cancer was 4.29 per 1000 person-years. For the ESRDwithoutHT group, the highest incidence rate of kidney cancer was 4.64 per 1000 person-years. However, compared with the non-HPT group, the adjusted HR of the statistically signifcant development of thyroid cancer was 10.1-fold higher for patients with HPT (95% CI = 1.12–91.0). Fig. 2 shows the results of the log-rank test and Kaplan–Meier survival analysis. During the study period, the risk of all cancer was not signifcant between the HPT group and the non-HPT cohort (log-rank p = .582). 4. Discussion This is the frst retrospective cohort study based on nationwide data to evaluate the relationship between HPT and malignancy in the ESRD population. Using ESRD patients as controls,we observed that ESRD patients with secondary HPT have a 10.2-fold higher risk of developing
thyroid cancer than ESRD patients without secondary HPT.
Primary HPT and thyroid cancer have an established relationship among the general population inwestern countries [17]. The established casual factors account for the correlation between the primary HPT and thyroid cancer, including previous neck irradiation, positive family history, and multiple endocrine neoplasia [18,19]. However, no studies
have reported the association between secondary HPT and thyroid cancer. High levels of the parathyroid hormone are reported to effect phagocytosis, T-cell sensitivity, and B-cell function, thus accounting for the immune dysfunction of ESRD patients [20,21]. Immune suppression caused by higher levels of the parathyroid hormone (PTH) cannot fully explain why the incidence of thyroid cancer in ESRD patients with secondary HPT is considerably higher than that of other cancers. Kao et al.
and Lin et al. indicated that themost prevalent cancers among ESRD patients are urinary tract cancer and liver cancer, rather than thyroid cancer
[4,5]. Therefore, we assumed that secondary HPT might exert
stimulatory or synergistic effects on thyroid carcinogenesis. The underlying pathophysiological mechanism of our clinical fnding remained
unclear and required further investigation.
In patients with symptomatic primary HPT, a parathyroidectomy eradicates this disease [22]. However, standard therapies for secondary or tertiary HPT in ESRD patients consist of reduced phosphate intake, medical treatment, and a parathyroidectomy [23,24]. Because of the
trend of minimal invasive parathyroidectomy, an occult thyroid lesion
in patientswith either primary or secondary/tertiary hyperparathyroidismmight not be detected [25]. Thus, Arciero et al. recommended using
preoperative thyroid sonography in patients with primary HPT [26].
Based on our results, we suggest thyroid sonography in ESRD patients with secondary or tertiary HPT.
This study has several strengths. First,we used a nationwide population database that covers more than 99% of Taiwanese residents and is validated by NHRI in Taiwan. Second, we compared the risk of cancer development between HPT and non-HPT cohorts among the ESRD population which this relationship has never been investigated. In conclusion,
this study demonstrates a link between secondary or tertiary
HPT and thyroid cancer in ESRD patients. We suggest clinician alertness for possible thyroid cancer in ESRD patients with secondary HPT.
