Study Population
The subjects of this study were Japanese men and women living near the Fukushima Daiichi Nuclear Power Plant in Fukushima prefecture, in communities including Tamura City (2010 Census population, 42,085), Minami-Soma City (71,661), Kawamata-machi (16,065), Hironomachi (5495), Naraha-machi (7927), Tomioka-machi (15,854), Kawauchi-mura (3074), Okuma-machi (11,553), Futaba-machi (7171), Namie-machi (21,551), Katsurao-mura (1582), Iitate-mura (6584) and Date City (67,684), with a total 2010 population of 278,286 (19). After the disaster, the government designated the 20-km radius around the Fukushima Daiichi Nuclear Power Plant a restricted area requiring compulsory evacuation. The government subsequently designated the 20- to 30-km area around the plant as an evacuation-prepared area in case of emergency, and areas near the 30-km radius where high-level radiation exposure was expected (> 20 mSv/y) as deliberate evacuation areas (evacuation over a period of roughly one month). As a result, all residents of Hirono-machi, Naraha-machi, Tomioka-machi, Kawauchi-mura, Okuma-machi, Futaba-machi, Namie-machi, Katsurao-mura, and Iitate-mura evacuated from their homes; this was also the case for some areas of Tamura City, Minami-Soma City, Kawamata-machi, and Date City (19).
In this study, a total of 123,314 residents (62,161 men and 61,153 women) between 40 and 74 years old were registered from the above areas in fiscal year 2011. A total of 33,559 participants (14,135 men and 19,424 women) aged 40 to 74 years completed the Comprehensive Health Check of the FHMS in fiscal year 2011. Among them, 9,502 participants who did not respond to the Mental Health and Lifestyle Survey and nine participants without serum uric acid data were excluded. Moreover, those who met the diagnosis of hyperuricemia at baseline, those who did not undergo the Comprehensive Health Check of the FHMS from fiscal years 2012 to 2017, and participants without evacuation status data were excluded (5,908 participants). Thus, 18,140 participants (6,961 men and 11,179 women) were included in the final analysis. (Fig. 1). This corresponded to approximately 14.7% of the population between 40 and 74 years of age who were registered in the above areas in fiscal year 2011 (approximately 11.2% of men and 18.3% of women). The Comprehensive Health Check, which was conducted by the FHMS, evaluated subjective symptoms, family history, smoking and drinking history, and laboratory findings, such as blood counts, liver function, kidney function, and lipids. Detailed descriptions of the survey methods have been summarized in previous literature (13). The Mental Health and Lifestyle Survey was conducted by the FHMS to evaluate changes in mental status and living conditions after the disaster.
This study protocol was approved by the Ethics Committee of the Fukushima Medical University School of Medicine (approval numbers 1319, 2020 − 239, 29064) and conformed to the ethical guidelines of the 1975 Declaration of Helsinki. Informed consent was obtained from community representatives to conduct an epidemiological study based on the guidelines of the Council for International Organizations of Medical Science (22).
Study Design
This was a prospective longitudinal study. The primary outcome was new-onset of hyperuricemia defined as serum uric acid levels > 7.0 mg/dL for men and > 6.0 mg/dL for women, respectively. Those who did not have hyperuricemia as of fiscal year 2011 were followed until fiscal year 2017 to examine the factors associated with new-onset hyperuricemia, using multivariate analyses based on the results of medical examinations and interview items. In particular, we examined whether "evacuation" poses a significant risk of new-onset hyperuricemia, even after adjusting for multiple models. Due to the large sex-related differences in uric acid levels, the analysis was conducted separately for men and women.
Measurements
Sex, age at examination, height, body weight, body mass index (BMI), systolic blood pressure, diastolic blood pressure, use of antihypertensive medication, hemoglobin A1c (HbA1c), fasting blood glucose, use of hypoglycemic agents, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides, use of drugs for dyslipidemia, aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyl transpeptidase (γ-GT), uric acid, and serum creatinine were measured during the Comprehensive Health Check that was conducted in 13 municipalities in the evacuation zone. Body weight (kg) and height were measured without shoes and in light clothing. BMI was calculated by dividing body weight (kg) by height squared (m2). Obesity was defined as a BMI ≥ 25.0 kg/m2. Hypertension was defined as systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg, or being treated for hypertension. Diabetes was defined as fasting blood glucose ≥ 126 mg/dL or random blood glucose ≥ 200 mg/dL, and/or hemoglobin A1c (HbA1c) ≥ 6.5%, or being treated for diabetes. Dyslipidemia was defined as low-density lipoprotein cholesterol (LDL-C) ≥ 140 mg/dL, fasting triglycerides ≥ 150 mg/dL, and/or high-density lipoprotein cholesterol (HDL-C) < 40 mg/dL, or being treated for dyslipidemia. Abnormal liver function was defined as AST ≥ 31 U/L, ALT ≥ 31 U/L, or γ-GT ≥ 51 U/L. Abnormal renal function was defined as an estimated glomerular filtration rate (eGFR) of < 60 mL/min/1.73 m2 or urine protein ≥ + 1. Since hyperuricemia has different cutoff values for men and women according to previous literature (23–25), hyperuricemia was defined as serum uric acid levels > 7.0 mg/dL for men and > 6.0 mg/dL for women, respectively.
In the Mental Health and Lifestyle Survey, the Japanese versions of the Kessler 6-item scale (K6) (26) and Post-traumatic Stress Disorder Checklist (PCL) (15) were used to assess the participants’ mental health. The K6 consists of six brief questions about depressive and anxiety symptoms during the past 30 days, with overall scores ranging from 0 to 24. We defined psychological distress as corresponding to a K6 score ≥ 13 (27). The PCL is a tool used to evaluate symptoms of post-traumatic stress disorder (PTSD) during the past 30 days. The PCL consists of 17 items, and the overall score ranges from 17 to 85. We classified participants as having probable PTSD if their overall PCL score was ≥ 44 (15). In addition to the K6 and PCL, data on medical history and various lifestyle factors, such as cigarette smoking status, drinking status, physical activity, sleep satisfaction, and changes in work situation were obtained from other questionnaires. Changes in work situation included unemployment or a job change after the accident. Furthermore, because this study was disaster-related, we assessed the presence of changes in residence and evacuation, and the subjects’ experiences of the tsunami, as well as their experiences of the nuclear accident.
Definition of Evacuees and Non-Evacuees
The term “evacuees” was defined as residents of the nine towns and villages who were directed to evacuate by the government, except for those in the four cities and towns that fell under non-evacuation orders.
Non-evacuees were defined as the residents of Tamura City, Minamisoma City, Kawamata-machi, and Date City, whose residence at the time of the survey was not a shelter or temporary housing. However, among the non-evacuation categories, those whose residence at the time of the survey was a shelter or temporary housing were defined as evacuees.
Statistical Analysis
We first conducted t-tests for continuous variables and χ2 tests for categorical variables to perform comparisons between evacuees and non-evacuees for analysis of the characteristics of the target population who did not have hyperuricemia at baseline.
Next, Cox proportional hazards regression model analyses with the onset of hyperuricemia as the dependent variable were performed separately for men and women. Referring to previous cross-sectional studies (21), we adjusted for the independent variables of age, evacuation, BMI, systolic blood pressure, fasting blood glucose, triglycerides, eGFR, smoking status, drinking status, and unemployment in Model 1. In addition to Model 1, sleep dissatisfaction, physical activity, tsunami experience, nuclear accident experience, and PTSD were adjusted as independent variables for Model 2. Since HDL-C, LDL-C, and triglycerides statistically strongly correlate with each other, triglyceride level was adopted as representative of dyslipidemia, as in previous reports (28). Since there was a strong correlation between K6 score and PCL score, PTSD (PCL score ≥ 44) was adopted as an independent factor in this study.
In multivariate analysis, the missing values were replaced by dummy variables, and the missing values were included in the aggregate to ensure representativeness.
All analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA). A two-tailed test was performed, with a significance level of p < 0.05.