Trends Associated with Hemorrhoids in Japan: Data Mining of Medical

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Vol. 43, No. 12 Biol. Pharm. Bull. 43, 1831–1838 (2020) 1831 Regular Article

Trends Associated with Hemorrhoids in Japan: Data Mining of Medical Information Datasets and the National Database of Health Insurance Claims and Speciﬁc Health Checkups of Japan (NDB) Open Data Japan Ririka Mukai,a Kazuyo Shimada,a Takaaki Suzuki,a Satoshi Nakao,a Mizuki Tanaka,a Kiyoka Matsumoto,a Yu Yoshida, a Fumiya Goto,a Misaki Inoue,a Riko Satake,a Yuri Nishibata,b Honami Sugihara,c and Mitsuhiro Nakamura*,a a Laboratory of Drug Informatics, Gifu Pharmaceutical University; 1–25–4 Daigaku-Nishi, Gifu 501–1196, Japan: b Division of Pharmacy, Japanese Red Cross Wakayama Medical Center; 4–20 Komatsubaradori, Wakayama 640–8558, Japan: and c Division of Pharmacy, Anjo Kosei Hospital; 28 Higashihirokute, Anjocho, Anjo, Aichi 446–8602, Japan. Received February 21, 2020; accepted September 12, 2020

Hemorrhoids are a common anorectal disease. Epidemiological studies on medication trends and risk factors using information from real-world databases are rare. Our objective was to analyze the relationship between hemorrhoid treatment prescription trends and several risk factors using the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB) Open Data Japan and related medical information datasets. We calculated the standardized prescription ratio (SPR) based on the 2nd NDB Open Data Japan from 2015. The correlation coefficients between the SPR of antihemorrhoidals and those of “antispasmodics,” “antiarrhythmic agents,” “antidiarrheals, intestinal regulators,” “purgatives and clysters,” “hypnotics and sedatives, antianxietics,” “psychotropic agents,” and “opium alkaloids preparations” were 0.7474, 0.7366, 0.7184, 0.6501, 0.6320, 0.4571, and 0.4542, respectively. The correlation coefficient between the SPR of antihemorrhoidals and those of “average annual temperature,” “percentage of people who were smokers,” and “percentage of people who drank regularly” were 0.7204, 0.6002, and 0.3537, respectively. The results of cluster analysis revealed that Hokkaido and Tohoku regions tended to have low average annual temperature values and high percentage of people who were smokers and had comparatively high SPRs of “antispasmodics,” “antiarrhythmic agents,” “antidiarrheals, intestinal regulators,” “purgatives and clysters,” “hypnotics and sedatives, antianxietics,” “psychotropic agents,” and “opium alkaloids preparations.” Antihemorrhoidals are frequently used in Hokkaido and Tohoku, Japan; thus, it is important for these prefectural governments to focus on these factors when taking measures regarding health promotion. Key words hemorrhoid; national database; Standardized Prescription Ratio; e-Stat

INTRODUCTION Several drugs have been implicated in the development of constipation.12,13) Furthermore, the everyday lifestyle guidance As the most common anal disease, hemorrhoids are charac- provided to patients includes taking precautions when work- terized by the symptomatic enlargement and distal displace- ing at cold temperatures. The patients are instructed to avoid ment of the anal cushions,1–3) via projections of anal mucosa letting their bodies get too cold.1,15) However, the data are formed by loose connective tissues, smooth muscle, and arte- inconsistent, and these factors have not been well investigated. rial and venous vessels.4) Hemorrhoids are commonly asymp- The Ministry of Health, Labour and Welfare (MHLW) has tomatic but can be complicated by painless bleeding, prolapse, been conducting the “Comprehensive Survey of Living Condi- soiling, and pruritus ani.5) Symptomatic hemorrhoidal disease tions (CSLC)” every year since 1986 based on the “Statistics is one of the most prevalent ailments associated with a signifi- Law.”16) The CSLC was conducted with approximately 277000 cant effect on a patient’s QOL.6) households from across the country in 2016.16,17) The purpose The risk factors for the development of hemorrhoids include of the survey is to understand the actual living conditions of aging, constipation, obesity, abdominal obesity, a sedentary the participants and use basic statistical methods to draw con- lifestyle, depressive mood, and pregnancy.7–9) Some types of clusions for the population in Japan. The CSLC provides re- food and lifestyles, including smoking, alcohol intake, low sults such as family composition, health status, income status, fiber diet, and spicy foods, are suspected to be associated with employment situation, and nursing care status. Furthermore, the development of hemorrhoids and the aggravation of acute the MHLW conducts other official statistical surveys, such hemorrhoidal symptoms.8,10,11) Constipation is suspected to as “Vital Statistics (VS)” and “National Health and Nutrition be associated with hemorrhoids. Therefore, the relationship Survey in Japan (NHNS).” All medical information datas- between the use of purgatives and clysters for the treatment ets from National Database of Health Insurance Claims and of constipation and hemorrhoids was examined.12,13) Anti- Specific Health Checkups of Japan (NDB) Open Data Japan, cholinergic agents that possess a high affinity for muscarinic CSLC, VS, and NHNS are open for public use and can be ob- cholinergic receptors are also known to cause constipation.14) tained from the MHLW and e-Stat websites.18)

Various large-scale medical information databases have grasping the situation in each prefecture.23) Because NODJ been used for clinical and epidemiological research in is open data, it has only a few labor, cost, and ethical con- Japan.19,20) In 2009, the MHLW developed the NDB, which straints, and research using it can be conducted in a relatively covers over 95% of current insurance claim information pro- short time. To the best of our knowledge, hemorrhoid surveil- vided by health insurance in Japan.21,22) The NDB contains lance using NODJ has not been performed. Therefore, our data that has been prepared to optimize medical expenses. objective was to analyze the relationship between hemorrhoids However, as the NDB contains most of the available data treatment prescription trends based on the standardized pre- in the national healthcare insurance system and reflects the scription ratio (SPR)24) using the population of each prefecture trends in medical care in Japan, it can be used to inform gov- and several risk factors using NODJ and related databases. ernment policy and clinical research. Recently, the MHLW released the “NDB Open Data Japan (NODJ)” online; it pro- MATERIALS AND METHODS vides various summary tables from the NDB that are freely available for use by the general public. The NDB is based on claims from outpatients, inpatients, Compared to the data obtained by sampling survey, NDB diagnosis procedure combinations, prescriptions, dental treat- data comprise a comprehensive dataset from individuals ments, and specific checkup data.21) We obtained data from who have received a specific health checkup in Japan. As the the MHLW website for NODJ25) and the e-Stat website for VS, survey covers the entire country, it is considered suitable for CSLC, and NHNS (Fig. 1). We extracted data on drug usage

Fig. 1. Flowchart of Data Analysis Vol. 43, No. 12 (2020) Biol. Pharm. Bull. 1833

(prescription) and speciﬁc medical checks [abdominal circum- out-of-hospital prescription/hospital prescription) using the data ference, body mass index (BMI), etc.] from the second NODJ tables (0000177287.xls, 0000177288.xls, 0000177289.xls, from 2015. In this study, we summed up the number of prescrip- 0000177290.xls, 0000177291.xls, 0000177292xls, 0000177293.xls, tion drugs (internal/external/injection, outpatient/hospitalization, 0000177294.xls, 0000177296.xls, and 0000177297.xls) from the

Table 1. Therapeutic Categories with p-Values Less than 0.05 in the Linear Regression Analysis of the SPR of Antihemorrhoidals

Code Therapeutic categories described by Standard Commodity Classiﬁcation Number of Japan Correlation coeﬃcient p-Value

124 Antispasmodics 0.7474 <0.0001 212 Antiarrhythmic agents 0.7366 <0.0001 231 Antidiarrheals, intestinal regulators 0.7184 <0.0001 223 Expectorants 0.7002 <0.0001 259 Other agents for uro-genital and anal organ 0.6791 <0.0001 214 Antihypertensives 0.6653 <0.0001 235 Purgatives and clysters 0.6501 <0.0001 332 Hemostatics 0.6484 <0.0001 122 Skeletal muscle relaxants 0.6465 <0.0001 391 Agents for liver disease 0.6428 <0.0001 112 Hypnotics and sedatives, antianxietics 0.6320 <0.0001 225 Bronchodilators 0.6067 <0.0001 319 Other vitamin preparations 0.6031 <0.0001 114 Antipyretics, analgesics and anti-inflammatory agents 0.5916 <0.0001 722 Reagents for various function tests 0.5603 <0.0001 395 Enzyme preparations 0.5549 <0.0001 213 Diuretics 0.5467 <0.0001 133 Antimotionsickness agents 0.5370 <0.0001 211 Cardiotonics 0.5325 0.0001 216 Vasoconstrictors 0.5315 0.0001 396 Antidiabetic agents 0.5222 0.0002 232 Agent for peptic ulcer 0.5176 0.0002 132 Agents for otic and nasal use 0.5158 0.0002 449 Other antiallergic agents 0.5066 0.0003 421 Alkylating agents 0.4939 0.0004 217 Vasodilators 0.4826 0.0006 719 Other agents for dispensing use 0.4818 0.0006 322 Mineral preparations 0.4803 0.0006 711 Excipients 0.4706 0.0008 249 Other hormone preparations (including antihormone preparations) 0.4698 0.0009 117 Psychotropic agents 0.4571 0.0012 811 Opium alkaloids preparations 0.4542 0.0013 264 Analgesics, anti-itchings, astrigents and anti-inflammatory agents 0.4416 0.0019 441 Antihistamines 0.4385 0.0021 613 Antibiotic preparations acting mainly on Gram-positive, Gram-negative bacteria −0.4245 0.0029 239 Other agents affecting digestive organs 0.4222 0.0031 229 Other agents affecting respiratory organs 0.4164 0.0036 224 Antitussives and expectorants 0.4036 0.0049 236 Cholagogues 0.4022 0.0051 313 Vitamin B preparations (except Vitamin B1) 0.3907 0.0066 218 Agents for hyperlipidemias 0.3885 0.0070 119 Other agents affecting central nervous system 0.3643 0.0118 323 Saccharide preparations −0.3554 0.0142 59 Other crude drug and chinese medicine formulations −0.3472 0.0168 325 Proteins, amino acid and preparations 0.3343 0.0216 339 Other agents relating to blood and body fluides 0.3317 0.0227 333 Anticoagulants 0.3298 0.0236 234 Antacids −0.3228 0.0269 123 Autonomic agents 0.3199 0.0284 131 Agents for ophthalmic use 0.3093 0.0344 263 Dermatics for purulence 0.3058 0.0366 399 Agents affecting metabolism, n.e.c. 0.3029 0.0385 616 Antibiotic preparations acting mainly on acid-fast bacteria −0.2961 0.0433 233 Stomachics and digestives 0.2929 0.0457 1834 Biol. Pharm. Bull. Vol. 43, No. 12 (2020)

MHLW website for NODJ.25) The percentage of individuals SPR of 100 is equivalent to the national average. If the SPR is who were smokers and percentage of individuals who drank greater than 100, it indicates that, even when adjusted for sex regularly were obtained from the CSLC in 2016.26,27) A person and age in the prefecture, the prescribed amount of the drug was defined as a smoker based on the following two criteria: is greater than the national average. Conversely, if the SPR is “smoking every day” and “occasional smoking.” A person who less than 100, it indicates that the prescribed amount of the drinks more than 3 d a week was defined as “people who drank drug is less than the national average. regularly.” The average steps per day, salt intake, and vegetable A linear regression analysis was performed. The p-value intake were obtained from the NHNS in 2016.28) The average was used to test the hypothesis that there is no relationship annual temperature was obtained from “natural environment” between the predictor and response, that is, to test the hypoth- of e-Stat,29) and the temperature difference was calculated as esis that the true slope coefficient is zero. the difference between the highest temperature (highest monthly To investigate the regional similarity in factors considered average of daily maximum temperature) and lowest tempera- to be associated with hemorrhoidal disease, a hierarchi- ture (lowest monthly average of daily lowest temperature) from cal cluster analysis of the SPR of drugs of other therapeutic “natural environment” of e-Stat.29) categories that did not include antihemorrhoidals (code: 255) According to the region categories in the NHNS, we strati- and the associated factors with p values less than 0.05 in the fied 47 prefectures into 12 regions: Hokkaido (Hokkaido), above-mentioned linear regression analysis was performed. Tohoku (Aomori, Iwate, Miyagi, Akita, Yamagata, and Fuku- Clusters were formed using the Ward’s method with Euclidean shima), Kanto I (Saitama, Chiba, Tokyo, and Kanagawa), distance. The number of clusters was determined based on the Kanto II (Ibaraki, Tochigi, Gunma, Yamanashi, and Nagano), characteristics of each cluster.32) Due to the 2016 Kumamoto Hokuriku (Niigata, Toyama, Ishikawa, and Fukui), Tokai (Gifu, earthquake, there is no survey data of people who drank regu- Shizuoka, Aichi, and Mie), Kinki I (Kyoto, Osaka, and Hyogo), larly, people who were smokers, and salt intake. Kumamoto Kinki II (Nara, Wakayama, and Shiga), Chugoku (Tottori, prefecture is excluded from the cluster analysis. Shimane, Okayama, Hiroshima, and Yamaguchi), Shikoku The data were integrated in a relational database system (Tokushima, Kagawa, Ehime, and Kochi), Kita-Kyushu (Fuku- using FileMaker Pro 13 software (FileMaker, Santa Clara, CA, oka, Saga, Nagasaki, and Oita), and Minami-Kyushu (Kuma- U.S.A.). Data analyses were performed using JMP 13.0 (SAS moto, Miyazaki, Kagoshima, and Okinawa). Institute, Cary, NC, U.S.A.). Furthermore, we obtained population data for each prefecture stratified by age and sex from the VS in 2015.30) We RESULTS calculated the SPR using the population of each prefecture.24) Age class was calculated every 5 years. A summary of regression coefficients between the SPR of Prescription amount  A antihemorrhoidals (code: 255) and those of other therapeutic SPR = =×100 categories is presented in S1 Table. One hundred and thirty- Expected value  B six therapeutic categories of drugs were reported in the 2nd where, A is the number of prescriptions by age group and NODJ (S1 Table). There were 54 therapeutic categories with B = (population of age group) × (prescription incidence by age p-values less than 0.05 in the linear regression analysis of the group in Japan). We used the therapeutic categories described SPR of antihemorrhoidals (Table 1). The correlation coeffi- by the Standard Commodity Classification Number of Japan.31) cients between the SPR of antihemorrhoidals and those of “an- All generic names of drugs were verified and subsequently tispasmodics (code: 124),” “antiarrhythmic agents (code: 212),” linked to the corresponding therapeutic category codes. Ac- “antidiarrheals, intestinal regulators (code: 231),” “purgatives cording to the therapeutic category, all drugs were classified and clysters (code: 235),” “hypnotics and sedatives, antianxiet- (S1 Table). The SPR of each prefecture was calculated. The ics (code: 112),” “psychotropic agents (code: 117),” and “opium

Table 2. Regression Coeﬃcients between the SPR of Antihemorrhoidals and the Speciﬁc Medical Checks from the 2nd NODJ and Other Factors from CSLC, NHNS, and Natural Environment with p-Values Less than 0.05

Correlation coeﬃcient p-Value Data set

Average annual temperature on 2016 (°C) −0.7204 <0.0001 ES Percentage of people who were smokers 0.6002 <0.0001 ES Alanine aminotransferase (ALT) in male (U/l) 0.5869 <0.0001 NODJ Aspartate aminotransferase (AST) in male (U/I) 0.5472 <0.0001 NODJ Aspartate aminotransferase (AST) in female (U/I) 0.5108 0.0002 NODJ Alanine aminotransferase (ALT) in female (U/I) 0.4369 0.0021 NODJ Salt intake (g/d) 0.4198 0.0037 ES Triglyceride in male (mg/dL) 0.3875 0.0071 NODJ γ-GTP in male (U/l) 0.3798 0.0085 NODJ Percentage of people who drank regularly 0.3537 0.0159 ES Diastolic blood pressure in female (mmHg) 0.3478 0.0166 NODJ γ-GTP in female (U/l) 0.3422 0.0186 NODJ Temperature diﬀerence on 2016 (°C) 0.3014 0.0395 ES Diastolic blood pressure in male (mmHg) 0.2970 0.0427 NODJ

NODJ: NDB Open Data Japan; ES: e-Stat. Vol. 43, No. 12 (2020) Biol. Pharm. Bull. 1835

Fig. 2. Dendrogram Report of Standardized Prescription Ratios Stratified by Therapeutic Categories, Including Antihemorrhoidals, and the Associ- ated Factors alkaloids preparations (code: 811)” were 0.7474, 0.7366, 0.7184, observations in each cluster (Fig. 3). These plots connected 0.6501, 0.6320, 0.4571, and 0.4542, respectively (Table 1). line segments that represent each raw data in a data table Regression coefficients between the SPR of antihemor- and demonstrated how the clusters differ. Cluster 1 included rhoidals and the results of specific medical checks from the Hokkaido and six prefectures in Tohoku and tended to have 2nd NODJ and other factors from CSLC, NHNS, and natural low average annual temperature values and high percentages environment are summarized in S2 Table. The number of ap- of people who were smokers. The SPRs of “antispasmodics plicable factors was 33 (S2 Table). There were 14 factors with (code: 124),” “antiarrhythmic agents (code: 212),” “antidiarrhe- p-values less than 0.05 in the linear regression analysis of the als, intestinal regulators (code: 231),” “purgatives and clysters SPR of antihemorrhoidals shown in S2 Table (Table 2). The (code: 235),” “hypnotics and sedatives, antianxietics (code: correlation coefficients between the SPR of antihemorrhoid- 112),” “psychotropic agents (code: 117),” and “opium alkaloids als and those of “average annual temperature,” “percentage preparations (code: 811)” in cluster 1 were comparatively high of people who were smokers,” and “percentage of people who (Fig. 2). Clusters 2 and 3 included the Kanto I, Kanto II, drank regularly” were −0.7204, 0.6002, and 0.3537, respec- Hokuriku, Kinki I, Kinki II, Chugoku, Shikoku, Kita-Kyushu, tively (Table 2). The correlation coefficient between the SPR and Minami-Kyushu regions; the average annual temperature of antihemorrhoidals and average steps per day was −0.2504 values, percentage of people who were smokers, and the SPRs (S2 Table). In the Hokkaido and Tohoku regions, the SPR of of therapeutic categories were moderate. Cluster 4 included antihemorrhoidals was greater than 100, indicating that anti- the Okinawa prefecture and tended to have high average annu- hemorrhoidals were prescribed more in these regions than in al temperature values and low percentage of people who were the other prefectures. In addition, the SPR of purgatives and smokers. The SPRs of “antispasmodics (code: 124),” “antiar- clysters was greater than 100 in the Hokkaido and Tohoku re- rhythmic agents (code: 212),” “antidiarrheals, intestinal regula- gions (data not shown). The lowest SPR of hemorrhoid prepa- tors (code: 231),” “purgatives and clysters (code: 235),” “hyp- rations and the highest abdominal circumference and BMI notics and sedatives, antianxietics (code: 112),” “psychotropic were observed in Okinawa prefecture in the Minami-Kyushu agents (code: 117),” and “opium alkaloids preparations (code: region. 811)” were comparatively low in the Okinawa prefecture. A cluster analysis of the SPR of drugs of other therapeutic categories that did not include antihemorrhoidals (Table 1) and DISCUSSION the associated factors (Table 2) was performed. The clustering analysis results were demonstrated as a dendrogram report In this study, we aimed to determine the relationship be- (Fig. 2). The cluster means plots displayed the structure of tween drug prescription trends based on SPR values using the 1836 Biol. Pharm. Bull. Vol. 43, No. 12 (2020)

Fig. 3. Cluster Means Plots of Cluster Analysis The axis ranges from two standard deviations above and below the mean. If a cluster mean falls beyond this range, the axis is extended to include it. population of each prefecture and several risk factors using In this study, we interpreted the association between the the NODJ and related databases. In the present study, we incidence of hemorrhoids and regional characteristics in Japan demonstrated a relationship between the amounts of antihem- using cluster analysis. Antihemorrhoidals are frequently used orrhoidals (code: 255) and purgatives and clysters (code: 235) in the cold regions of Hokkaido and Tohoku in Japan. The that might be used to treat constipation. Antispasmodics (cade: lowest SPR of hemorrhoid preparations and the highest BMI 124), such as scopolamine butylbromide, and antiarrhythmic and abdominal circumference were observed in the Okinawa agents (code: 212), such as cibenzoline and disopyramide, Prefecture (data not shown). The treatments for hemorrhoids which are considered to have anticholinergic effects, frequent- range from dietary and lifestyle modifications to radical sur- ly cause constipation as an adverse effect. Psychotropic agents gery, depending on the degree and severity of symptoms.34–36) (code: 117) were associated with the SPR of antihemorrhoid- It is important for these prefectural governments to focus on als. Benzodiazepines, which are anticholinergic drugs, were the above factors when taking measures for health promotion. included in the “psychotropic agents (code: 117)” category. Lifestyle guidance on avoiding working in cold conditions The correlation coefficient between the SPRs of psychotropic may be particularly useful in Hokkaido and Tohoku. agents (code: 117) and purgatives and clysters (code: 235) was Cluster analysis helps in grouping similar observations and 0.5316 (data not shown). Opium alkaloids preparations (code: classifying them into homogeneous clusters.32) As cluster anal- 811), which are known to cause constipation,12,13) were asso- ysis does not include objective variables, it is a method of data ciated with the SPR of hemorrhoid preparations. Our results summarization, compared with other multivariate analysis support the findings of previous studies5,7,11,33) reporting that methods, and an exploratory data analysis method. Therefore, constipation might be associated with an increased risk of data can be divided into any number of cluster formations, hemorrhoids. We examined the effects of drugs based on the based on the subjectivity or viewpoint of a researcher, using therapeutic categories according to the Standard Commodity cluster analysis. The validity of results can be judged only by Classification Number of Japan.31) As the symptoms of consti- external knowledge; if a researcher can interpret the results of pation are considered to differ with the type of drugs, future data division, then it can be said that the number of clusters research should examine differences among drugs based on is “correct.”32) We finally set the number of cluster formations pharmacological action. to 4. The determined characteristics for each cluster indicate Vol. 43, No. 12 (2020) Biol. Pharm. Bull. 1837 the tendency of occurrence of factors common to the regions we did not further investigate the influence of these OTC belonging to the cluster. medications in the present study. Several lifestyle modifications, such as exercising regu- In this study, we investigated the correlation at the regional larly, refraining from a sedentary lifestyle, refraining from level. Regional correlation studies cannot show an association straining on the toilet, improving anal hygiene, increasing the between individual-level exposure and outcome and cannot intake of dietary fiber and oral fluids, and avoiding drugs that elucidate causal relationships and risk assessment of hemor- cause constipation or diarrhea, might be useful to decrease rhoid at the individual level. Overall, it is important for pre- the incidence of hemorrhoids; however, the evidence for these fectures to pay attention to these factors when formulating strategies is poor.34,35,37) As the SPR of antihemorrhoidals health promotion measures. demonstrated a negative correlation with the average number of steps per day, regular exercise may slightly lower the risk CONCLUSION of hemorrhoids. Smoking causes both arterial and venous vascular injuries.9) Several possible influencing factors were examined based An association between smoking and hemorrhoids has been on NODJ. Antihemorrhoidals are frequently used in Hokkaido reported, with the risk of developing hemorrhoidal vascular and Tohoku in Japan; thus, it is important for these prefectural injuries among smokers being 2.4 times greater than that governments to focus on these factors when taking measures among nonsmokers.9) Our results also suggested an association regarding health promotion. Our study will make a valuable between smoking and hemorrhoids. A previous study reported contribution to information available for clinicians and will that alcohol consumption is not associated with the risk of help improve the management of hemorrhoids. developing hemorrhoids.38) Our results suggested a significant association between hemorrhoids and the percentage of people Acknowledgments This research was partially supported who drank regularly. Obesity has been reported to be related by the Japan Society for the Promotion of Science (JSPS) to hemorrhoids;8,38,39) however, our results did not show a clear KAKENHI [Grant No. 17K08452]. association between hemorrhoids and abdominal circumference or BMI (S2 Table). Conflict of Interest The authors declare no conflict of Although hemorrhoids are recognized as a common cause interest. of rectal bleeding and anal discomfort, the true epidemiol- ogy of this disease is unknown because patients tend to Supplementary Materials The online version of this ar- self-medicate rather than seek proper medical attention.3) The ticle contains supplementary materials. biggest advantage of research using NODJ and e-Stat is that it is possible to clarify the current state of medical care in REFERENCES Japan. Although the NODJ does not contain data on individual patients and disease, the annually prescribed numbers of phar- 1) The Japan Society of Coloproctology. Clinical practice guidelines maceutical products and specific medical examinations, such for anorectal diseases in Japan 2014: hemorrhoids, anal fistulas, as BMI and laboratory data, are available. and anal fissures. Nankodo Co., Ltd., Tokyo (2014). 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