Dietary pattern and risk of endometrioma in Korean women: a case-control study

Endometriosis is defined as the presence of functioning en - dometrial glands and stromal cells outside the endometrial cavity, affecting 5–15% of women of child-bearing age, among whom 30–50% develop infertility [1,2]. Many theo - ries have been proposed to explain the pathophysiologic development of endometriosis; however, the etiology of the disease is still unclear [3,4]. Most researchers agree that en - dometriosis is an estrogen-dependent chronic inflammatory process in the pelvic cavity. Accordingly, endometriosis is as - sociated with pelvic pain and infertility, especially in the case of ovarian endometrioma, which directly affects the ovarian reserve [5]. Dietary pattern and risk of endometrioma in Korean women: a case-control study Hyun Joo Lee, MD, Hye Kyung Noh, MD, Seung Chul Kim, MD, PhD, Jong Kil Joo, MD, PhD, Dong Soo Suh, MD, PhD, Ki Hyung Kim, MD, PhD Department of Obstetrics and Gynecology, Medical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea

The aim of this study was to investigate and compare the dietary patterns of Korean women diagnosed with endometrioma or other benign ovarian cysts.

A total of 66 patients, comprising 39 patients who were surgically diagnosed with ovarian endometrioma and 27 control patients with other benign ovarian cysts, were included in this case-control study. Trained interviewers identified and interviewed the case patients and controls on the day before the laparoscopic ovarian surgery, using a semiquantitative food frequency questionnaire developed by the Ministry of Health and Welfare of Korea. Statistical analysis was performed using the Wilcoxon sum-rank test for continuous variables and the χ 2 test or Fisher’s exact test for categorical variables.

The calcium intake from daily food consumption was significantly lower in patients with endometrioma than in those with other benign ovarian cysts. The dietary intakes of vitamin D, iron, and zinc were also relatively lower in patients with endometrioma than in patients with other benign ovarian cysts, although they did not reach the statistical significance threshold.

The risk of endometrioma is significantly associated with a lower dietary intake of calcium. Future studies including a larger number of patients on a nationwide scale are urgently required for further clarification.

Diet; Calcium; Endometrioma; Benign ovarian cyst Received: 2020.08.06. Revised: 2020.11.03. Accepted: 2020.11.09. Corresponding author: Jong Kil Joo, MD, PhD Department of Obstetrics and Gynecology, Medical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, 179 Gudeck-ro, Seo-gu, Busan 49241, Korea E-mail: [email protected] https://orcid.org/0000-0002-6338-1512 Articles published in Obstet Gynecol Sci are open-access, distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons. org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright © 2021 Korean Society of Obstetrics and Gynecology Original Article Obstet Gynecol Sci 2021;64(1):99-106 https://doi.org/10.5468/ogs.20230 eISSN 2287-8580 www.ogscience.org100 Vol. 64, No. 1, 2021 The major risk factors based on such estrogen-dependent features of endometriosis include increased estrogen expo - sure frequently leading to early menarche, prolonged dura - tion of menstrual flow, shorter menstrual cycle interval, and nulliparity [1,6,7]. One of the factors that could influence physiologic estrogen activity and exposure is the dietary pattern of a patient, which is a valuable, modifiable factor not only for disease management but also for prevention when well understood [1,8]. A number of studies have been published, although they reported rather inconclusive data. Some studies have reported that a plant-based and high- fiber diet increases estrogen excretion and decreases the concentration of bioavailable estrogen. However, the effects of vegetable consumption on the risk of ovarian endome - trioma are unknown [1,9-11]. Moreover, studies investigating the association between red meat consumption and the risk of endometrioma development have reported contradictory

[12]. When evaluating the relationship between certain diets and diseases, it is important to note that the effect of diet on the hormone levels or inflammatory status of the body could be influenced by the cooking method, storage tech - niques, and/or management of food resources (e.g., use of pesticides) [13]. Because of such variables, the precise evalu - ation of the relationship between dietary patterns and the occurrence of a specific disease requires statistical analysis based on a homogeneous population with a shared culinary culture. Thus, this case-control study investigated the dietary patterns of Korean women diagnosed with ovarian endome - trioma (histologically confirmed after laparoscopic surgery) compared with patients with other benign ovarian cysts with surgical and histologic confirmation.

1. Study population The current case-control study included a total of 66 patients referred to a single, tertiary, national university hospital from September 2018 to August 2019. Of these, 39 patients diag - nosed with unilateral or bilateral ovarian endometrioma were assigned as the case group. Another 27 patients with other benign ovarian cysts, such as teratomas or cystadenomas, were selected as the control group. The other benign ovar - ian cysts were not further distinguished because they were less likely to be associated with estrogen exposure [14]. All patients underwent routine preoperative examinations and medical history taking for laparoscopic surgery, after which the ovarian pathology was diagnosed with histologic confir - mation. In the review of the patients’ medical records, men- strual irregularity was defined as a menstrual cycle length of less than 21 days and/or more than 35 days with varying intervals, and history of smoking included both present and previous smoking. For the case group, only patients who were diagnosed with endometrioma for the first time were included; those with recurring endometrioma were excluded. Patients who had been previously requested to restrict food intake because of their medical history, such as diabetes, were also excluded, as were women who had been taking hormonal contraceptives for contraception or dysmenorrhea treatment. The control group was composed of patients with surgically and histologically confirmed ovarian teratomas or serous or mucinous cystadenomas. Patients who were diag - nosed with coexisting endometriosis during the operation were excluded from the control group, as were those who had been preoperatively diagnosed with comorbid myoma uteri and/or adenomyosis with imaging modalities such as computed tomography or magnetic resonance imaging. 2. Dietary assessment Food intake data were collected using a validated semiquan- titative food frequency questionnaire (SQFFQ) about the patients’ dietary patterns for the previous year. The SQFFQ, which covered 112 food groups derived from the Korean National Health and Nutrition Examination Survey, was de - veloped by the Ministry of Health and Welfare [15]. Food intake frequency was divided into the following 9 categories for all 112 items: never or seldom, once per month, 2 to 3 times per month, once or twice per week, 3 to 4 times per week, 5 to 6 times per week, once per day, twice per day, and 3 or more times per day. The participants indicated the frequency of intake of each food item based on the pro - vided definitions of portion sizes. The respondents indicated whether the amount of food they consumed in 1 sitting was more than, equal to, or less than 1 portion, based on pictures of the food items. Daily intake was calculated using the midpoint of the assigned frequencies of each category for each food item. Food intake was calculated by multiply - ing the midpoints of the frequencies for each food category by the number of times each food item was consumed. By www.ogscience.org 101 Hyun Joo Lee, et al. Dietary pattern and risk of endometrioma using the SQFFQ food intake data, the consumption of en - ergy and nutrients, such as protein, carbohydrates, fat, fiber, total vitamin A, vitamin B1, vitamin C, calcium, and iron, was calculated using Can-Pro 2.0 software (The Korean Nutrition Society, Seoul, Korea) [16]. Trained interviewers identified and supervised the patients throughout the completion of the questionnaire. All interviews were conducted in a hospi - tal setting. 3. Statistical analysis Statistical analyses were performed using SAS software (ver - sion 9.4; SAS Institute, Cary, NC, USA). The frequency distri- butions of categorical demographic and personal behavior- related variables were obtained according to the presence of endometrioma or other benign ovarian cysts, and statistical significance was determined using the χ 2 test. The median and interquartile range (IQR) of the dietary intake of each nutrient, as determined using the SQFFQ method, were calculated. Statistical significance was determined using the Wilcoxon rank-sum test for continuous variables.

1. Patient characteristics of the endometrioma and other benign cyst groups The background characteristics of the patients are presented in Table 1. No statistical differences were found in the pa - tients’ age, body mass index, age at menarche, and parity between the groups. The median serum level of carbohy - drate antigen 125 in the endometrioma group was 34.80 U/ mL that in the benign ovarian cyst group was 18.20 U/mL. None of the patients in either group had a history of diabe - tes, hypertension, or dyslipidemia. 2. Results of semiquantitative food frequency questionnaire in the endometrioma and other benign cyst groups Table 2 shows the results of the SQFFQ in both groups. The dietary calcium intake was significantly lower in the endome- trioma group than in the other benign ovarian cyst group, with median (IQR) values of 530.83 (406.89–725.23) mg and 779.40 (518.52–867.18) mg, respectively (P=0.047). Vitamin D, iron, and zinc intakes were also relatively lower in the endometrioma group than in the other benign cyst group, but without statistically significant differences. No other statistically significant difference was observed in the rest of the evaluated nutrients: carbohydrates, lipids, proteins (both plant-based and animal-based), dietary fibers (both soluble and insoluble), vitamins, minerals (including phosphorus, so - dium, chlorine, potassium, and magnesium), cholesterol, to - tal fatty acids, saturated fatty acids, unsaturated fatty acids, other fatty acids (including caproic acid, caprylic acid, and palmitic acid), and amino acids (including isoleucine, cyste - ine, phenylalanine, and aspartate).

In this study of a homogeneous population of Korean wom- Table 1. Patient characteristics in the endometrioma group and the other benign ovarian cyst group Characteristics Endometrioma group (n=39) Other benign ovarian cyst group (n=27) P-value Age (yr) 33.18 (9.35) 35.67 (11.27) 0.350 Height (cm) 160.66 (4.58) 160.64 (5.59) 0.991 Weight (kg) 54.40 (8.06) 56.91 (8.14) 0.221 BMI 21.08 (3.04) 22.08 (3.18) 0.207 Nulliparous (%) 29 (74.36) 15 (55.56) 0.186 b) Age at menarche (yr) 13.33 (1.58) 13.48 (1.60) 0.712 CA-125 (U/mL) a) 34.80 (23.10–60.10) 18.20 (12.05–28.85) 0.001 c) Menstrual irregularity (%) 7 (17.95) 5 (18.52) 1.000 b) Smoking (%) 1 (2.56) 0 (0.00) 1.000 b) Data are presented as mean (standard deviation) or median (interquartile range). a) P<0.05; b) χ 2 test or Fisher’s exact test for categorical variables; c) Wilcoxon rank-sum test for continuous variables. www.ogscience.org102 Vol. 64, No. 1, 2021 Table 2. Dietary intake of each nutrient in the endometrioma group and the other benign ovarian cyst group Characteristics Endometrioma group (n=39) Other benign ovarian cyst group (n=27) P-value Energy (kcal) 2,235.43 (1,795.43–2,658.01) 2,495.67 (1,811.78–3,298.20) 0.217 Carbohydrate (g) 325.33 (246.10–391.47) 364.93 (275.13–507.93) 0.164 Lipid (g) 62.08 (49.26–84.29) 67.74 (42.27–107.69) 0.717 Vegetable lipid 31.94 (23.57–40.83) 30.48 (22.32–48.31) 0.756 Animal lipid 29.77 (25.16–42.35) 29.99 (19.05–53.84) 0.877 Protein (g) 74.84 (61.63–93.08) 82.45 (62.39–121.77) 0.287 Vegetable protein 40.31 (32.36–46.35) 44.07 (30.80–56.69) 0.318 Animal protein 38.32 (25.75–50.11) 38.38 (23.70–66.60) 0.525 Fiber (g) 25.71 (20.01–36.46) 31.29 (22.49–40.99) 0.350 Soluble dietary fiber 3.43 (2.52–5.23) 4.78 (2.63–6.29) 0.248 Insoluble dietary fiber 14.22 (11.36–20.28) 17.62 (11.18–20.85) 0.414 Vitamins Vitamin A (µg RAE) 602.61 (410.65–949.52) 656.85 (442.93–893.96) 0.707 β-Carotene (µg) 3,859.46 (3,066.85–4,910.98) 4,506.81 (3,065.18–5,404.64) 0.399 Vitamin D (µg) 2.58 (1.90–3.86) 3.49 (2.29–5.72) 0.149 Vitamin E (mg) 20.68 (16.92–28.38) 26.20 (17.60–33.04) 0.385 Vitamin K (µg) 165.36 (116.86–215.94) 203.76 (114.16–283.23) 0.305 Vitamin C (mg) 115.64 (79.33–198.67) 144.29 (86.26–287.52) 0.264 Thiamin (mg) 2.19 (1.69–2.82) 2.39 (1.80–3.07) 0.452 Riboflavin (mg) 1.63 (1.36–2.38) 1.98 (1.51–2.56) 0.232 Niacin (mg) 12.77 (10.53–16.81) 16.53 (11.24–19.79) 0.185 Vitamin B6 (mg) 2.04 (1.50–2.45) 2.42 (1.53–3.28) 0.128 Folate (µg) 586.10 (445.53–856.39) 677.76 (523.42–1,000.34) 0.337 Vitamin B12 (µg) 8.99 (6.02–11.18) 7.22 (5.96–15.50) 0.766 Pantothenic acid (mg) 5.49 (4.62–6.84) 6.60 (4.90–9.82) 0.138 Vitamin B7 (µg) 2.63 (1.42–4.98) 3.40 (1.33–6.66) 0.437 Minerals Ca (mg) a) 530.83 (406.89–725.23) 779.40 (518.52–867.18) 0.047 P (mg) 1,195.35 (944.14–1,480.49) 1,410.78 (1,103.60–1,853.43) 0.152 Na (mg) 3,664.52 (3,058.92–4,994.28) 4,723.70 (3,243.69–5,720.62) 0.141 Cl (mg) 122.35 (59.89–180.92) 134.85 (72.26–281.58) 0.357 K (mg) 2,860.00 (2,353.87–4,419.42) 3,769.45 (2,872.51–5,199.46) 0.152 Mg (mg) 141.09 (95.72–177.36) 143.61 (106.71–187.22) 0.452 Fe (mg) 17.39 (13.47–20.02) 21.32 (15.03–27.09) 0.141 Zn (mg) 11.40 (9.36–13.94) 14.24 (9.04–18.13) 0.198 Cu (µg) 819.59 (562.48–1,117.10) 937.58 (650.70–1,182.37) 0.517 Cholesterol (mg) 416.89 (299.02–552.22) 443.85 (266.84–686.51) 0.484 Total fat (g) 40.22 (29.97–51.67) 42.73 (25.45–66.49) 0.669 Saturated fat (g) 11.14 (8.39–14.36) 11.54 (7.57–18.81) 0.542 Monounsaturated fat (g) 13.55 (10.52–18.27) 15.29 (8.92–24.79) 0.613 Polyunsaturated fat (g) 14.05 (11.30–19.24) 15.52 (8.89–23.31) 0.727 www.ogscience.org 103 Hyun Joo Lee, et al. Dietary pattern and risk of endometrioma Characteristics Endometrioma group (n=39) Other benign ovarian cyst group (n=27) P-value Fatty acids (g) n3 fatty acid 0.66 (0.44–0.99) 0.50 (0.32–1.27) 1.000 n6 fatty acid 4.42 (3.22–5.72) 4.46 (2.62–7.60) 0.707 Caproic acid 0.01 (0.00–0.01) 0.01 (0.00–0.03) 0.701 Caprylic acid 0.01 (0.00–0.01) 0.01 (0.00–0.02) 0.895 Lauric acid 0.12 (0.07–0.25) 0.12 (0.05–0.29) 0.969 Myristic acid 1.17 (0.86–1.75) 1.60 (0.85–2.18) 0.281 Myristoleic acid 0.20 (0.13–0.27) 0.23 (0.10–0.32) 0.429 Palmitic acid 38.79 (31.64–47.00) 41.63 (28.29–54.57) 0.476 Palmitoleic acid 3.31 (2.38–4.72) 3.66 (2.72–6.57) 0.305 Stearic acid 10.71 (7.68–13.50) 12.24 (6.42–17.63) 0.414 Oleic acid 52.26 (38.78–63.20) 59.50 (32.41–84.62) 0.444 Linoleic acid n6 44.73 (34.03–55.30) 46.96 (27.32–52.17) 0.604 Linoleic acid n3 4.83 (3.95–6.28) 5.06 (3.32–6.78) 0.678 γ linoleic acid 0.00 (0.00–0.00) 0.00 (0.00–0.00) 0.938 Stearidonic acid 0.02 (0.01–0.05) 0.02 (0.01–0.07) 0.201 Arachidic acid 0.28 (0.23–0.37) 0.31 (0.18–0.45) 0.660 Eicosenoic acid 0.88 (0.61–1.20) 0.95 (0.70–1.57) 0.392 Docosanoic acid 0.16 (0.01–0.27) 0.17 (0.03–0.68) 0.185 Tetracosanoic acid 0.02 (0.01–0.03) 0.02 (0.01–0.03) 0.492 Other fatty acid 1.68 (1.13–2.08) 1.89 (0.97–2.62) 0.500 Amino acids (mg) Isoleucine 1,883.74 (1,543.83–2,196.70) 2,164.41 (1,591.59–2,991.26) 0.305 Leucine 3,605.33 (2,888.95–3,951.05) 3,881.38 (2,889.01–5,644.90) 0.330 Lysine 2,411.76 (1,935.49–3,217.77) 2,540.66 (1,845.83–3,938.08) 0.509 Methionine 822.83 (667.78–992.84) 983.05 (715.21–1,338.48) 0.189 Cysteine 497.84 (401.54–622.37) 545.18 (389.52–943.23) 0.350 Phenylalanine 2,053.00 (1,670.79–2,259.90) 2,236.80 (1,602.91–3,223.99) 0.437 Tyrosine 1,536.10 (1,221.48–1,660.01) 1,642.90 (1,231.48–2,396.93) 0.378 Aromatic amino acids 474.97 (360.99–651.23) 479.12 (285.65–930.04) 0.846 Threonine 1,638.82 (1,349.37–2,009.12) 1,739.02 (1,294.78–2,652.56) 0.460 Tryptophan 388.88 (309.66–513.61) 405.13 (338.92–608.15) 0.650 Valine 2,271.37 (1,872.81–2,562.71) 2,604.35 (1,910.10–3,561.50) 0.194 Histidine 1,260.01 (1,006.30–1,556.34) 1,389.06 (1,089.44–2,014.45) 0.287 Arginine 3,227.83 (2,443.01–3,697.55) 3,406.15 (2,299.44–5,259.51) 0.551 Alanine 2,459.03 (1,962.48–2,891.14) 2,580.99 (1,838.04–3,872.93) 0.421 Aspartic acid 4,332.92 (3,443.94–5,561.76) 4,561.69 (3,277.35–6,916.76) 0.569 Glutamic acid 8,246.09 (7,098.08–9,473.94) 9,252.80 (6,689.90–13,033.56) 0.437 Glycine 1,756.50 (1,329.30–2,147.21) 1,785.72 (1,171.84–2,841.09) 0.746 Proline 2,672.18 (2,383.42–3,307.90) 3,177.45 (2,527.83–3,789.80) 0.217 Serine 1,945.67 (1,658.40–2,238.09) 2,166.25 (1,524.05–3,081.65) 0.460 Taurine 119.53 (73.52–202.41) 127.72 (65.55–192.33) 0.877 Data are presented as median (interquartile range). a) P<0.05. Table 2. Continued www.ogscience.org104 Vol. 64, No. 1, 2021 en living in a local city with a shared culinary culture, the dietary intake of calcium was significantly lower in the endo- metrioma group. Moreover, although statistical significance was not reached, the dietary intakes of vitamin D, iron, and zinc were relatively lower in the endometrioma group than in the control group. Our data did not provide supporting evidence for a relationship between endometriosis and any of the other nutrients or food groups examined, except for calcium, vitamin D, iron, and zinc. The lower intakes of calcium in our patients with endo - metrioma are partially consistent with previously reported data from different ethnicities and population pools. Harris et al. [17] reported that calcium, vitamin D, and magnesium intakes from food sources were inversely related to endo - metriosis. In their study, participants with a higher quintile intake of calcium from food sources had a lower risk of en - dometriosis, with a trend of statistical significance. Moreover, Trabert et al. [1] suggested inverse associations between en - dometriosis and dairy product intake or calcium intake from food sources, although the difference was not statistically significant (odds ratio, 0.7; 95% confidence interval, 0.4–1.2). The authors suggested the ability of calcium and vitamin D to downregulate growth-promoting factors, such as insulin- like growth factor-I, and to upregulate negative growth fac - tor regulators, such as transforming growth factor β. Further- more, according to their study, dietary factors such as dairy products and several specific nutrients may be related to the physiologic processes associated with endometriosis through their effects on systemic inflammation. The association between vitamin D and endometrioma seems more compli - cated to analyze than the association of other nutrients with endometrioma. As mentioned earlier, the dietary intake of vitamin D was inversely related to endometriosis, although only a small proportion of vitamin D is obtained from dietary sources [17]. Nevertheless Ciavattini et al. [18] also reported that a relatively high proportion of women with ovarian en - dometrioma showed hypovitaminosis D. Similarly, Abbas et al. [19] observed that vitamin D treatment induced a reduc - tion in the endometriosis cyst dimension in a rat model. To clarify the role of vitamin D in endometriosis, further studies are urgently required. In our study, the dietary intake of zinc was also lower in the endometrioma group (median [IQR] = 11.40 [9.36–13.94] mg in the case group and 14.24 [9.04–18.13] mg in the control group, P=0.198). Similar patterns were observed in the study by Messalli et al. [20], who reported that patients with endo - metriosis presented a lower serum zinc concentration than the control group (1,010±59.24 µg/L vs. 1,294±62.22 µg/L, P<0.05). They also suggested that zinc interferes in the pathogenic processes of endometriosis, such as inflammation and immunity. Other important dietary factors known to be related to the risk of endometriosis development are red meat, trans fats, and omega-3 fatty acids. Large studies have been con - ducted to reveal such relationships, and their results have shown that increased intakes of red meat and trans fats, and decreased intake of omega-3 fatty acids were related to an increased risk of endometriosis [2,8,21]. In our study, the intake of animal fat and protein showed no difference between the 2 groups. Such results may be due to the small number of patients included in this study; however, they could also result from the inclusion in the current study of an East Asian population with eating habits that differ from those of Western populations analyzed in previous studies. Traditionally, Asian populations are known to consume lower amounts of meat than their Western counterparts. Although the general dietary patterns have been showing similarities worldwide, owing to the increasing cultural exchanges and the faster and easier internal trades of food products, the daily eating habits still considerably differ across different countries [22,23]. Thus, the red meat consumption in our Korean population may have been too low to present any significant effect on the risk of endometriosis, compared with previous data from Western populations. Moreover, the current study was conducted in a local port city in South Korea, where the population had easy and frequent access to fish products containing omega-3 fatty acids. Accordingly, both the case and control groups had been exposed to and consumed higher levels of omega-3 fatty acids than the gen - eral population, which could have affected the results of the current study. The current study had several limitations. As this was a retrospective study that reviewed previously obtained medi - cal records, the baseline characteristics of the patients were limited to 9 categories for the risk factors of endometrioma. Although such categories included major risk factors, more detailed features of the patients still need to be investigated in future studies. In addition, most studies evaluating popu - lation dietary patterns in association with endometriosis use self-questionnaires; thus, some of the data are vulnerable www.ogscience.org 105 Hyun Joo Lee, et al. Dietary pattern and risk of endometrioma to recall bias. However, in our study, all questionnaires were completed by medical professionals who had been educated about the purpose and outline of the study. In addition, in epidemiologic studies, the diagnosis or exclusion of endo - metriosis is typically determined solely by evaluating the patients’ medical records. In our study, all patients were diag - nosed with or ruled out from having endometriosis by lapa - roscopic surgery and histologic confirmation, thus obtaining a more precise medical status for each patient. Other limitations include the potentially compromised ef - fects of a single nutrient according to the cooking method, even with the same amount of ingredients. Such variations are difficult to standardize in epidemiologic studies. However, it may be important to implement in certain areas in persons with similar lifestyles, and our study included a homoge - neous population of only Korean women and local area resi- dents. Finally, the number of patients included in the present study was relatively small. To offset the size limitation, all patients included in the study were surgically diagnosed with the ovarian pathology (endometrioma or a benign ovarian cyst), with histologic confirmation, and every food frequency questionnaire interview was supervised by a medical profes - sional. Additionally, to our knowledge, this is the first study to analyze the effect of dietary patterns on the risk of endo - metriosis in a Korean population. In summary, the risk of endometriosis is significantly associ- ated with a lower intake of calcium, and despite being statis- tically insignificant, lower intakes of vitamin D, magnesium, and zinc were observed in patients with ovarian endome - trioma. Further studies including a larger number of patients on a nationwide scale with detailed statistical analysis of significant nutrients are urgently required to determine the link between dietary patterns and the risk of endometriosis, to enable the establishment of patient education programs and lifestyle consultation on population-based strategies for preventing the disease. Conflict of interest No potential conflict of interest relevant to this article was reported. Ethical approval The current study was officially exempted from ethical ap - proval by the institutional review board of the Human Re - search Protection Committee of Pusan National University Hospital (committee reference No. 1912-014-086). Patient consent All patients provided informed consent to the use of their medical records and completed questionnaires for research purposes. Funding information None.

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