Skip to main content

Advertisement

SpringerLink
Log in

Environmental factors, medical and family history, and comorbidities associated with primary biliary cholangitis in Japan: a multicenter case–control study

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Background

Primary biliary cholangitis (PBC) is considered to be caused by the interaction between genetic background and environmental triggers. Previous case–control studies have indicated the associations of environmental factors (tobacco smoking, a history of urinary tract infection, and hair dye) use with PBC. Therefore, we conducted a multicenter case–control study to identify the environmental factors associated with the development of PBC in Japan.

Methods

From 21 participating centers in Japan, we prospectively enrolled 548 patients with PBC (male/female = 78/470, median age 66), and 548 age- and sex-matched controls. These participants completed a questionnaire comprising 121 items with respect to demographic, anthropometric, socioeconomic features, lifestyle, medical/familial history, and reproductive history in female individuals. The association was determined using conditional multivariate logistic regression analysis.

Results

The identified factors were vault toilet at home in childhood [odds ratio (OR), 1.63; 95% confidence interval (CI), 1.01–2.62], unpaved roads around the house in childhood (OR, 1.43; 95% CI, 1.07–1.92), ever smoking (OR, 1.70; 95% CI, 1.28–2.25), and hair dye use (OR, 1.57; 95% CI, 1.15–2.14) in the model for lifestyle factors, and a history of any type of autoimmune disease (OR, 8.74; 95% CI, 3.99–19.13), a history of Cesarean section (OR, 0.20; 95% CI, 0.077–0.53), and presence of PBC in first-degree relatives (OR, 21.1; 95% CI, 6.52–68.0) in the model for medical and familial factors.

Conclusions

These results suggest that poor environmental hygiene in childhood (vault toilets and unpaved roads) and chronic exposure to chemicals (smoking and hair dye use) are likely to be risk factors for the development of PBC in Japan.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

PBC:

Primary biliary cholangitis

OR:

Odds ratio

CI:

Confidence interval

AMA:

Antimitochondrial autoantibodies

GWAS:

Genome-wide association studies

UTI:

Urinary tract infection

FDR:

First-degree relative

BMI:

Body mass index

References

  1. Lleo A, Wang GQ, Gershwin ME, et al. Primary biliary cholangitis. Lancet. 2020;396:1915–26.

    Article  CAS  Google Scholar 

  2. Carbone M, Milani C, Gerussi A, et al. Primary biliary cholangitis: a multifaceted pathogenesis with potential therapeutic targets. J Hepatol. 2020;73:965–6.

    Article  Google Scholar 

  3. Gulamhusein AF, Hirschfield GM. Primary biliary cholangitis: pathogenesis and therapeutic opportunities. Nat Rev Gastroenterol Hepatol. 2020;17:93–110.

    Article  Google Scholar 

  4. Rosa R, Cristoferi L, Tanaka A, et al. Geoepidemiology and (epi-)genetics in primary biliary cholangitis. Best Pract Res Clin Gastroenterol. 2018;34–35:11–5.

    PubMed  Google Scholar 

  5. Terziroli Beretta-Piccoli B, Mieli-Vergani G, Vergani D, et al. The challenges of primary biliary cholangitis: what is new and what needs to be done. J Autoimmun. 2019;105:102328.

    Article  Google Scholar 

  6. Selmi C, Gershwin ME, Lindor KD, et al. Quality of life and everyday activities in patients with primary biliary cirrhosis. Hepatology. 2007;46:1836–43.

    Article  Google Scholar 

  7. Cordell HJ, Han Y, Mells GF, et al. International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways. Nat Commun. 2015;6:8019.

    Article  CAS  Google Scholar 

  8. Hirschfield GM, Liu X, Han Y, et al. Variants at IRF5-TNPO3, 17q12-21 and MMEL1 are associated with primary biliary cirrhosis. Nat Genet. 2010;42:655–7.

    Article  CAS  Google Scholar 

  9. Hirschfield GM, Liu X, Xu C, et al. Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants. N Engl J Med. 2009;360:2544–55.

    Article  CAS  Google Scholar 

  10. Hirschfield GM, Xie G, Lu E, et al. Association of primary biliary cirrhosis with variants in the CLEC16A, SOCS1, SPIB and SIAE immunomodulatory genes. Genes Immun. 2012;13:328–35.

    Article  CAS  Google Scholar 

  11. Juran BD, Hirschfield GM, Invernizzi P, et al. Immunochip analyses identify a novel risk locus for primary biliary cirrhosis at 13q14, multiple independent associations at four established risk loci and epistasis between 1p31 and 7q32 risk variants. Hum Mol Genet. 2012;21:5209–21.

    Article  CAS  Google Scholar 

  12. Kawashima M, Hitomi Y, Aiba Y, et al. Genome-wide association studies identify PRKCB as a novel genetic susceptibility locus for primary biliary cholangitis in the Japanese population. Hum Mol Genet. 2017;26:650–9.

    CAS  PubMed  Google Scholar 

  13. Liu JZ, Almarri MA, Gaffney DJ, et al. Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis. Nat Genet. 2012;44:1137–41.

    Article  CAS  Google Scholar 

  14. Liu X, Invernizzi P, Lu Y, et al. Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis. Nat Genet. 2010;42:658–60.

    Article  CAS  Google Scholar 

  15. Mells GF, Floyd JA, Morley KI, et al. Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis. Nat Genet. 2011;43:329–32.

    Article  CAS  Google Scholar 

  16. Nakamura M, Nishida N, Kawashima M, et al. Genome-wide association study identifies TNFSF15 and POU2AF1 as susceptibility loci for primary biliary cirrhosis in the Japanese population. Am J Hum Genet. 2012;91:721–8.

    Article  CAS  Google Scholar 

  17. Qiu F, Tang R, Zuo X, et al. A genome-wide association study identifies six novel risk loci for primary biliary cholangitis. Nat Commun. 2017;8:14828.

    Article  CAS  Google Scholar 

  18. Dong M, Li J, Tang R, et al. Multiple genetic variants associated with primary biliary cirrhosis in a Han Chinese population. Clin Rev Allergy Immunol. 2015;48:316–21.

    Article  CAS  Google Scholar 

  19. Cordell HJ, Fryett JJ, Ueno K, et al. An international genome-wide meta-analysis of primary biliary cholangitis: novel risk loci and candidate drugs. J Hepatol. 2021;75:572–81.

    Article  CAS  Google Scholar 

  20. Asselta R, Paraboschi EM, Gerussi A, et al. X chromosome contribution to the genetic architecture of primary biliary cholangitis. Gastroenterology. 2021;160:2483-2495.e26.

    Article  CAS  Google Scholar 

  21. Juran BD, Lazaridis KN. Environmental factors in primary biliary cirrhosis. Semin Liver Dis. 2014;34:265–72.

    Article  CAS  Google Scholar 

  22. Tanaka A, Leung PS, Gershwin ME. Environmental basis of primary biliary cholangitis. Exp Biol Med (Maywood). 2018;243:184–9.

    Article  CAS  Google Scholar 

  23. Howel D, Fischbacher CM, Bhopal RS, et al. An exploratory population-based case-control study of primary biliary cirrhosis. Hepatology. 2000;31:1055–60.

    Article  CAS  Google Scholar 

  24. Prince MI, Ducker SJ, James OF. Case-control studies of risk factors for primary biliary cirrhosis in two United Kingdom populations. Gut. 2010;59:508–12.

    Article  CAS  Google Scholar 

  25. Gershwin ME, Selmi C, Worman HJ, et al. Risk factors and comorbidities in primary biliary cirrhosis: a controlled interview-based study of 1032 patients. Hepatology. 2005;42:1194–202.

    Article  Google Scholar 

  26. Parikh-Patel A, Gold EB, Worman H, et al. Risk factors for primary biliary cirrhosis in a cohort of patients from the United States. Hepatology. 2001;33:16–21.

    Article  CAS  Google Scholar 

  27. Corpechot C, Chrétien Y, Chazouillères O, et al. Demographic, lifestyle, medical and familial factors associated with primary biliary cirrhosis. J Hepatol. 2010;53:162–9.

    Article  Google Scholar 

  28. Kim KA, Kim YS, Park SH, et al. Environmental risk factors and comorbidities of primary biliary cholangitis in Korea: a case-control study. Korean J Intern Med. 2021;36:313–21.

    Article  Google Scholar 

  29. Kobayashi Y, Ohfuji S, Kondo K, et al. Association between dietary iron and zinc intake and development of ulcerative colitis: a case-control study in Japan. J Gastroenterol Hepatol. 2019;34:1703–10.

    Article  CAS  Google Scholar 

  30. Kobayashi Y, Ohfuji S, Kondo K, et al. Association of dietary fatty acid intake with the development of ulcerative colitis: a multicenter case-control study in Japan. Inflam Bowel Dis. 2021;27:617–28.

    Article  Google Scholar 

  31. Kondo K, Ohfuji S, Watanabe K, et al. The association between environmental factors and the development of Crohn’s disease with focusing on passive smoking: a multicenter case-control study in Japan. PLoS ONE. 2019;14: e0216429.

    Article  CAS  Google Scholar 

  32. Kondo K, Suzuki K, Washio M, et al. Association between coffee and green tea intake and pneumonia among the Japanese elderly: a case-control study. Sci Rep. 2021;11:5570.

    Article  CAS  Google Scholar 

  33. Working Subgroup (English version) for Clinical Practice Guidelines for Primary Biliary Cirrhosis. Guidelines for the management of primary biliary cirrhosis: The Intractable Hepatobiliary Disease Study Group supported by the Ministry of Health, Labour and Welfare of Japan. Hepatol Res. 2014;44:71–90.

    Article  Google Scholar 

  34. Tanaka A, Leung PSC, Gershwin ME. Pathogen infections and primary biliary cholangitis. Clin Exp Immunol. 2019;195:25–34.

    Article  CAS  Google Scholar 

  35. Hardy CJ, Palmer BP, Muir KR, et al. Smoking history, alcohol consumption, and systemic lupus erythematosus: a case-control study. Ann Rheum Dis. 1998;57:451–5.

    Article  CAS  Google Scholar 

  36. Heliövaara M, Aho K, Aromaa A, et al. Smoking and risk of rheumatoid arthritis. J Rheumatol. 1993;20:1830–5.

    PubMed  Google Scholar 

  37. Prummel MF, Wiersinga WM. Smoking and risk of Graves’ disease. JAMA. 1993;269:479–82.

    Article  CAS  Google Scholar 

  38. Tanaka A, Mori M, Matsumoto K, et al. Increase trend in the prevalence and male-to-female ratio of primary biliary cholangitis, autoimmune hepatitis, and primary sclerosing cholangitis in Japan. Hepatol Res. 2019;49:881–9.

    Article  CAS  Google Scholar 

  39. Dyson JK, Blain A, Foster Shirley MD, et al. Geo-epidemiology and environmental co-variate mapping of primary biliary cholangitis and primary sclerosing cholangitis. JHEP Rep. 2021;3:100202.

    Article  Google Scholar 

  40. Probert PM, Leitch AC, Dunn MP, et al. Identification of a xenobiotic as a potential environmental trigger in primary biliary cholangitis. J Hepatol. 2018;69:1123–35.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We deeply appreciate the secretarial assistance of Ms. Kayono Unno.

Funding

This work was supported by the MHLW Research Program on Intractable Hepatobiliary Disease, Grant Number JPMH20FC1023.

Author information

Authors and Affiliations

  1. Department of Medicine, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-ku, Tokyo, Japan

    Kosuke Matsumoto, Yamato Tamura, Ryo Miura, Toshihiko Arizumi, Yoshinari Asaoka & Atsushi Tanaka

  2. Department of Public Health, Osaka City University Graduate School of Medicine, Osaka, Japan

    Satoko Ohfuji

  3. Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan

    Masanori Abe

  4. Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Nagasaki, Japan

    Atsumasa Komori

  5. Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan

    Atsushi Takahashi & Hiromasa Ohira

  6. Department of Premier Preventive Medicine, Graduate School of Medicine, Osaka City University, Osaka, Japan

    Hideki Fujii

  7. Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan

    Hideki Fujii & Norifumi Kawada

  8. Hepatology Division, Department of Internal Medicine II, Hamamatsu University School of Medicine, Shizuoka, Japan

    Kazuhito Kawata & Hidenao Noritake

  9. Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Kagawa, Japan

    Tomoko Tadokoro & Tsutomu Masaki

  10. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan

    Akira Honda & Tadashi Ikegami

  11. Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, Saitama, Japan

    Maiko Asami & Satoshi Mochida

  12. Department of Gastroenterology, Nara Medical University, Nara, Japan

    Tadashi Namisaki & Hitoshi Yoshiji

  13. Department of Gastroenterology and Hepatology, Kurashiki Central Hospital, Okayama, Japan

    Masayuki Ueno & Youichi Morimoto

  14. Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Masayuki Ueno

  15. Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Gunma, Japan

    Ken Sato

  16. Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Iwate, Japan

    Keisuke Kakisaka & Yasuhiro Takikawa

  17. Department of Gastroenterology, Faculty of Medicine, Oita University, Oita, Japan

    Mie Arakawa

  18. Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Aichi, Japan

    Takanori Ito

  19. Center for Gastroenterology, Teine-Keijinkai Hospital, Hokkaido, Japan

    Kazunari Tanaka & Takeshi Matsui

  20. Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

    Toru Setsu, Masaaki Takamura & Shuji Terai

  21. Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Gifu, Japan

    Satoshi Yasuda

  22. Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan

    Tomohiro Katsumi & Yoshiyuki Ueno

  23. Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan

    Jun Itakura

  24. Division of Gastroenterology, Department of Internal Medicine, Kurume University School of Medicine, Fukuoka, Japan

    Tomoya Sano

  25. Teikyo Academic Research Center, Teikyo University, Tokyo, Japan

    Kiyoko Uno & Ai Nishitani

Authors
  1. Kosuke Matsumoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Satoko Ohfuji
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Masanori Abe
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Atsumasa Komori
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Atsushi Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hideki Fujii
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kazuhito Kawata
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hidenao Noritake
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Tomoko Tadokoro
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Akira Honda
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Maiko Asami
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Tadashi Namisaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Masayuki Ueno
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Ken Sato
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Keisuke Kakisaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Mie Arakawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Takanori Ito
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Kazunari Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Takeshi Matsui
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Toru Setsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Masaaki Takamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Satoshi Yasuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Tomohiro Katsumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Jun Itakura
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Tomoya Sano
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Yamato Tamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. Ryo Miura
    View author publications

    You can also search for this author in PubMed Google Scholar

  28. Toshihiko Arizumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  29. Yoshinari Asaoka
    View author publications

    You can also search for this author in PubMed Google Scholar

  30. Kiyoko Uno
    View author publications

    You can also search for this author in PubMed Google Scholar

  31. Ai Nishitani
    View author publications

    You can also search for this author in PubMed Google Scholar

  32. Yoshiyuki Ueno
    View author publications

    You can also search for this author in PubMed Google Scholar

  33. Shuji Terai
    View author publications

    You can also search for this author in PubMed Google Scholar

  34. Yasuhiro Takikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  35. Youichi Morimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  36. Hitoshi Yoshiji
    View author publications

    You can also search for this author in PubMed Google Scholar

  37. Satoshi Mochida
    View author publications

    You can also search for this author in PubMed Google Scholar

  38. Tadashi Ikegami
    View author publications

    You can also search for this author in PubMed Google Scholar

  39. Tsutomu Masaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  40. Norifumi Kawada
    View author publications

    You can also search for this author in PubMed Google Scholar

  41. Hiromasa Ohira
    View author publications

    You can also search for this author in PubMed Google Scholar

  42. Atsushi Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kosuke Matsumoto.

Ethics declarations

Conflict of interest

The authors have no conflicts of interests to declare.

Ethical approval

All the procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study protocol was approved by the Institutional Ethics Committee of Teikyo University, School of Medicine (20-602).

Informed consent

Informed consent was obtained from all individual participants included in the study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 19 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Matsumoto, K., Ohfuji, S., Abe, M. et al. Environmental factors, medical and family history, and comorbidities associated with primary biliary cholangitis in Japan: a multicenter case–control study. J Gastroenterol 57, 19–29 (2022). https://doi.org/10.1007/s00535-021-01836-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-021-01836-6

Keywords

Search

Navigation