Skip to main content

Advertisement

SpringerLink
Log in

Mechanisms of Fibrosis in Primary Biliary Cholangitis

  • Autoimmune, Cholestatic, and Biliary Diseases (S Gordon and C Bowlus, Section Editors)
  • Published:
Current Hepatology Reports Aims and scope Submit manuscript

Abstract

Background

Primary biliary cholangitis (PBC) is an autoimmune liver disease featured with bile duct injury, ductopenia and proliferation, periportal inflammation and fibrosis. Clinical manifestations of PBC vary from almost no symptoms to different degrees of pruritus plus symptoms of liver dysfunction.

Purpose of Review

This review intends to update our understanding in the mechanisms of hepatic fibrogenesis under chronic biliary injury.

Recent Findings

Underlying mechanisms are proposed for a better understanding and more effective therapeutic targets. With genetic predisposition, lesions from bile ducts cause damage to biliary epithelial cells (BECs); and simultaneous autoimmunity reinforces a vicious cycle of BEC damage, inflammatory infiltration, BEC proliferation and fibrogenic responses. Therapeutic efficacy of immunosuppressive agents has been unsatisfactory.

Summary

As a major variable in PBC progression, fibrosis has been paid a great deal of attention but has not been responsive to various treatments.

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

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

α-SMA:

α-smooth muscle actin

AIH:

Autoimmune hepatitis

ALP:

Alkaline phosphatase

AMA:

Anti-mitochondrial antibody

ANA:

Antinuclear antibodies

APRI:

AST-platelet ratio index

ATP:

Adenosine triphosphates

BCL-2:

B cell lymphoma 2

BECs:

Biliary epithelial cells

BTSCs:

Biliary tree stem/progenitor cells

cAMP:

Adenosine 3′,5′-cyclic monophosphate

CDCA:

Chenodeoxycholic acid

CTFR:

Cystic fibrosis transmembrane conductance

DCA:

Deoxycholic acid

sECM:

Extracellular matrix

EMT:

Epithelial-mesenchymal transition

FGF-7:

Fibroblast growth factor-7

FIB-4:

Fibrosis-4

FXR:

Farnesoid X receptor

GGT:

Gamma-glutamyl transpeptidase

GPI:

Glycophosphatidylinositol

HA:

Hyaluronic acid

HLA:

Human leukocyte antigen

HPCs:

Hepatic progenitor cells

HSCs:

Hepatic stellate cells

IFN:

Interferon

IL:

Interleukin

LCA:

Lithocholic acid

MAPK:

Mitogen-activated protein kinase

MMP:

Matrix metalloproteinase

NAFLD:

nonalcoholic fatty liver disease

NF-κB:

Nuclear factor κB

Nrf2:

Nuclear factor erythroid-2-like-2

NTPD2:

Nucleoside triphosphate diphosphohydrolase-2

NTPDase1:

Nucleoside triphosphate diphosphohydrolase-1

OCA:

Obeticholic acid

PAMP:

Pathogen-associated molecular pattern

PBC:

Primary biliary cholangitis

PBG:

Peribiliary gland

PDC-E2:

Pyruvate dehydrogenase complex-E2

PDGFR-β:

Platelet-derived growth factor receptor-β

PSC:

Primary sclerosing cholangitis

RDCs:

Reactive ductular cells

ROS:

Reactive oxygen species

RTE:

Real-time elastography

SR:

Secretin receptor

TE:

Transient elastography

TGF-β:

Transforming growth factor-β

Thy-1:

Thymocyte differentiation antigen-1

TLR:

Toll-like receptor

TNF-α:

Tumor necrosis factor-α

UDCA:

Ursodeoxycholic acid

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Lee HE, Churg A, Ryu JH, Bilawich AM, Larsen BT, Tazelaar HD, et al. Histopathologic findings in lung biopsies from patients with primary biliary cholangitis. Hum Pathol. 2018;82:177–86.

    Article  PubMed  Google Scholar 

  2. Fujinaga Y, Namisaki T, Moriya K, Kitade M, Kawaratani H, Shimozato N, et al. Identification of clinical risk factors for histological progression of primary biliary cholangitis. Hepatol Res. 2019;49(9):1015–25.

    Article  CAS  PubMed  Google Scholar 

  3. Warnes T, Roberts S, Smith A, Haboubi N, McMahon RF. Liver biopsy in primary biliary cholangitis: is sinusoidal fibrosis the missing key? J Clin Pathol. 2019;72(10):669–76.

    Article  PubMed  Google Scholar 

  4. Hargrove L, Kennedy L, Demieville J, Jones H, Meng F, DeMorrow S, et al. Bile duct ligation-induced biliary hyperplasia, hepatic injury, and fibrosis are reduced in mast cell-deficient kit(W-sh) mice. Hepatology. 2017;65(6):1991–2004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. •• Ronca V, Carbone M, Bernuzzi F, Malinverno F, Mousa HS, Gershwin ME, et al. From pathogenesis to novel therapies in the treatment of primary biliary cholangitis. Expert Rev Clin Immunol. 2017;13(12):1121–31 Deep insights into current understanding of the mechanisms of PBC, and new and re-purposed therapeutic agents targeting key processes in the etiopathogenesis. Several therapeutic targets were proposed which are categorized into three compartments: immune, biliary and fibrosis.

    Article  CAS  PubMed  Google Scholar 

  6. Chiang JY. Bile acid metabolism and signaling. Compr Physiol. 2013;3(3):1191–212.

    PubMed  PubMed Central  Google Scholar 

  7. Patel A, Seetharam A. Primary biliary cholangitis: disease pathogenesis and implications for established and novel therapeutics. J Clin Exp Hepatol. 2016;6(4):311–8.

    Article  PubMed  PubMed Central  Google Scholar 

  8. • Gulamhusein AF, Hirschfield GM. Pathophysiology of primary biliary cholangitis. Best Pract Res Clin Gastroenterol. 2018;34–35:17–25 A concise review of current understanding of autoimmunity and proliferative reaction of biliary epithelial cells, as well as initiation and progression of fibrosis in PBC.

    Article  PubMed  CAS  Google Scholar 

  9. Tsuneyama K, Baba H, Morimoto Y, Tsunematsu T, Ogawa H. Primary biliary cholangitis: its pathological characteristics and immunopathological mechanisms. J Med Invest. 2017;64(1.2):7–13.

    Article  PubMed  Google Scholar 

  10. Huang W, Kachapati K, Adams D, Wu Y, Leung PS, Yang GX, et al. Murine autoimmune cholangitis requires two hits: cytotoxic KLRG1(+) CD8 effector cells and defective T regulatory cells. J Autoimmun. 2014;50:123–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Yang CY, Ma X, Tsuneyama K, Huang S, Takahashi T, Chalasani NP, et al. IL-12/Th1 and IL-23/Th17 biliary microenvironment in primary biliary cirrhosis: implications for therapy. Hepatology. 2014;59(5):1944–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Tan Z, Qian X, Jiang R, Liu Q, Wang Y, Chen C, et al. IL-17A plays a critical role in the pathogenesis of liver fibrosis through hepatic stellate cell activation. J Immunol. 2013;191(4):1835–44.

    Article  CAS  PubMed  Google Scholar 

  13. Liberal R, Grant CR, Ma Y, Csizmadia E, Jiang ZG, Heneghan MA, et al. CD39 mediated regulation of Th17-cell effector function is impaired in juvenile autoimmune liver disease. J Autoimmun. 2016;72:102–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Feldbrugge L, Jiang ZG, Csizmadia E, Mitsuhashi S, Tran S, Yee EU, et al. Distinct roles of ecto-nucleoside triphosphate diphosphohydrolase-2 (NTPDase2) in liver regeneration and fibrosis. Purinergic Signal. 2018;14(1):37–46.

    Article  PubMed  CAS  Google Scholar 

  15. Guo J, Luo Y, Yin F, Huo X, Niu G, Song M, et al. Overexpression of tumor necrosis factor-like ligand 1A in myeloid cells aggravates liver fibrosis in mice. J Immunol Res. 2019;2019:7657294.

    PubMed  PubMed Central  Google Scholar 

  16. Calmus Y, Poupon R. Shaping macrophages function and innate immunity by bile acids: mechanisms and implication in cholestatic liver diseases. Clin Res Hepatol Gastroenterol. 2014;38(5):550–6.

    Article  CAS  PubMed  Google Scholar 

  17. Lages CS, Simmons J, Maddox A, Jones K, Karns R, Sheridan R, et al. The dendritic cell-T helper 17-macrophage axis controls cholangiocyte injury and disease progression in murine and human biliary atresia. Hepatology. 2017;65(1):174–88.

    Article  CAS  PubMed  Google Scholar 

  18. Krenkel O, Tacke F. Liver macrophages in tissue homeostasis and disease. Nat Rev Immunol. 2017;17(5):306–21.

    Article  CAS  PubMed  Google Scholar 

  19. •• Elssner C, Goeppert B, Longerich T, Scherr AL, Stindt J, Nanduri LK, et al. Nuclear translocation of RELB is increased in diseased human liver and promotes ductular reaction and biliary fibrosis in mice. Gastroenterology. 2019;156(4):1190–205 e14 This is an extensive study of reactive bile ducts in patients with chronic liver diseases, focusing on nuclear translocation of RELB in the mediation of BEC proliferation in cholestatic liver fibrosis.

    Article  PubMed  Google Scholar 

  20. Shearn CT, Fennimore B, Orlicky DJ, Gao YR, Saba LM, Battista KD, et al. Cholestatic liver disease results increased production of reactive aldehydes and an atypical periportal hepatic antioxidant response oxidative response. Free Radic Biol Med. 2019;143:101–14.

    Article  CAS  PubMed  Google Scholar 

  21. Wu N, Meng F, Zhou T, Venter J, Giang TK, Kyritsi K, et al. The secretin/secretin receptor axis modulates ductular reaction and liver fibrosis through changes in transforming growth factor-beta1-mediated biliary senescence. Am J Pathol. 2018;188(10):2264–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Sato K, Meng F, Giang T, Glaser S, Alpini G. Mechanisms of cholangiocyte responses to injury. Biochim Biophys Acta Mol Basis Dis. 2018;1864(4 Pt B):1262–9.

    Article  CAS  PubMed  Google Scholar 

  23. Carpino G, Nevi L, Overi D, Cardinale V, Lu WY, Di Matteo S, et al. Peribiliary gland niche participates in biliary tree regeneration in mouse and in human primary sclerosing cholangitis. Hepatology. 2019. https://doi.org/10.1002/hep.30871.

    Article  CAS  PubMed  Google Scholar 

  24. Kaneko K, Kamimoto K, Miyajima A, Itoh T. Adaptive remodeling of the biliary architecture underlies liver homeostasis. Hepatology. 2015;61(6):2056–66.

    Article  CAS  PubMed  Google Scholar 

  25. Pozniak KN, Pearen MA, Pereira TN, Kramer CSM, Kalita-De Croft P, Nawaratna SK, et al. Taurocholate induces biliary differentiation of liver progenitor cells causing hepatic stellate cell chemotaxis in the ductular reaction: role in pediatric cystic fibrosis liver disease. Am J Pathol. 2017;187(12):2744–57.

    Article  CAS  PubMed  Google Scholar 

  26. Okabe H, Yang J, Sylakowski K, Yovchev M, Miyagawa Y, Nagarajan S, et al. Wnt signaling regulates hepatobiliary repair following cholestatic liver injury in mice. Hepatology. 2016;64(5):1652–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Gieseck RL 3rd, Ramalingam TR, Hart KM, Vannella KM, Cantu DA, Lu WY, et al. Interleukin-13 activates distinct cellular pathways leading to ductular reaction, steatosis, and fibrosis. Immunity. 2016;45(1):145–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Erice O, Munoz-Garrido P, Vaquero J, Perugorria MJ, Fernandez-Barrena MG, Saez E, et al. MicroRNA-506 promotes primary biliary cholangitis-like features in cholangiocytes and immune activation. Hepatology. 2018;67(4):1420–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kim YC, Jung H, Seok S, Zhang Y, Ma J, Li T, et al. MicroRNA-210 promotes bile acid-induced cholestatic liver injury by targeting mixed-lineage leukemia-4 methyltransferase in mice. Hepatology. 2019. https://doi.org/10.1002/hep.30966.

  30. Wells RG. The portal fibroblast: not just a poor man's stellate cell. Gastroenterology. 2014;147(1):41–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Banales JM, Huebert RC, Karlsen T, Strazzabosco M, LaRusso NF, Gores GJ. Cholangiocyte pathobiology. Nat Rev Gastroenterol Hepatol. 2019;16(5):269–81.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Koyama Y, Wang P, Liang S, Iwaisako K, Liu X, Xu J, et al. Mesothelin/mucin 16 signaling in activated portal fibroblasts regulates cholestatic liver fibrosis. J Clin Invest. 2017;127(4):1254–70.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Fausther M, Lavoie EG, Dranoff JA. Liver myofibroblasts of murine origins express mesothelin: Identification of novel rat mesothelin splice variants. PLoS One. 2017;12(9):e0184499.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Kisseleva T. The origin of fibrogenic myofibroblasts in fibrotic liver. Hepatology. 2017;65(3):1039–43.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Iwaisako K, Jiang C, Zhang M, Cong M, Moore-Morris TJ, Park TJ, et al. Origin of myofibroblasts in the fibrotic liver in mice. Proc Natl Acad Sci U S A. 2014;111(32):E3297–305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Dranoff JA, Wells RG. Portal fibroblasts: underappreciated mediators of biliary fibrosis. Hepatology. 2010;51(4):1438–44.

    Article  PubMed  PubMed Central  Google Scholar 

  37. •• Nishio T, Hu R, Koyama Y, Liang S, Rosenthal SB, Yamamoto G, et al. Activated hepatic stellate cells and portal fibroblasts contribute to cholestatic liver fibrosis in MDR2 knockout mice. J Hepatol. 2019;71(3):573–85 This is an elegant study defining the role of portal fibroblasts and hepatic stellate cells in the initiation and progression of fibrosis in PBC.

    Article  PubMed  Google Scholar 

  38. Tsuchida T, Friedman SL. Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol. 2017;14(7):397–411.

    Article  CAS  PubMed  Google Scholar 

  39. Zhou Y, Hagood JS, Lu B, Merryman WD, Murphy-Ullrich JE. Thy-1-integrin alphav beta5 interactions inhibit lung fibroblast contraction-induced latent transforming growth factor-beta1 activation and myofibroblast differentiation. J Biol Chem. 2010;285(29):22382–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Karin D, Koyama Y, Brenner D, Kisseleva T. The characteristics of activated portal fibroblasts/myofibroblasts in liver fibrosis. Differentiation. 2016;92(3):84–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Younossi ZM, Bernstein D, Shiffman ML, Kwo P, Kim WR, Kowdley KV, et al. Diagnosis and management of primary biliary cholangitis. Am J Gastroenterol. 2019;114(1):48–63.

    Article  PubMed  Google Scholar 

  42. Bowlus CL, Gershwin ME. The diagnosis of primary biliary cirrhosis. Autoimmun Rev. 2014;13(4–5):441–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Scheuer PJ. Ludwig symposium on biliary disorders--part II. Pathologic features and evolution of primary biliary cirrhosis and primary sclerosing cholangitis. Mayo Clin Proc. 1998;73(2):179–83.

    Article  CAS  PubMed  Google Scholar 

  44. Di Giorgio A, D'Adda A, Marseglia A, Sonzogni A, Licini L, Nicastro E, et al. Biliary features in liver histology of children with autoimmune liver disease. Hepatol Int. 2019;13(4):510–8.

    Article  PubMed  Google Scholar 

  45. Lackner C, Tiniakos D. Fibrosis and alcohol-related liver disease. J Hepatol. 2019;70(2):294–304.

    Article  PubMed  Google Scholar 

  46. Mani H, Kleiner DE. Liver biopsy findings in chronic hepatitis B. Hepatology. 2009;49(5 Suppl):S61–71.

    Article  PubMed  Google Scholar 

  47. Murillo Perez CF, Hirschfield GM, Corpechot C, Floreani A, Mayo MJ, van der Meer A, et al. Fibrosis stage is an independent predictor of outcome in primary biliary cholangitis despite biochemical treatment response. Aliment Pharmacol Ther. 2019;50(10):1127–36.

    Article  CAS  PubMed  Google Scholar 

  48. Agbim U, Asrani SK. Non-invasive assessment of liver fibrosis and prognosis: an update on serum and elastography markers. Expert Rev Gastroenterol Hepatol. 2019;13(4):361–74.

    Article  CAS  PubMed  Google Scholar 

  49. Stasi C, Leoncini L, Biagini MR, Arena U, Madiai S, Laffi G, et al. Assessment of liver fibrosis in primary biliary cholangitis: comparison between indirect serum markers and fibrosis morphometry. Dig Liver Dis. 2016;48(3):298–301.

    Article  CAS  PubMed  Google Scholar 

  50. Younossi ZM, Loomba R, Anstee QM, Rinella ME, Bugianesi E, Marchesini G, et al. Diagnostic modalities for nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and associated fibrosis. Hepatology. 2018;68(1):349–60.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Poupon R. Non-invasive assessment of liver fibrosis progression and prognosis in primary biliary cholangitis. Dig Dis. 2015;33(Suppl 2):115–7.

    Article  PubMed  Google Scholar 

  52. Corpechot C, Carrat F, Poujol-Robert A, Gaouar F, Wendum D, Chazouilleres O, et al. Noninvasive elastography-based assessment of liver fibrosis progression and prognosis in primary biliary cirrhosis. Hepatology. 2012;56(1):198–208.

    Article  PubMed  Google Scholar 

  53. Ferraioli G, Filice C, Castera L, Choi BI, Sporea I, Wilson SR, et al. WFUMB guidelines and recommendations for clinical use of ultrasound elastography: part 3: liver. Ultrasound Med Biol. 2015;41(5):1161–79.

    Article  PubMed  Google Scholar 

  54. Yokoda RT, Carey EJ. Primary biliary cholangitis and primary Sclerosing cholangitis. Am J Gastroenterol. 2019;114(10):1593–605.

    Article  PubMed  Google Scholar 

  55. • Manne V, Kowdley KV. Obeticholic acid in primary biliary cholangitis: where we stand. Curr Opin Gastroenterol. 2019;35(3):191–6 A concise update with newly approved obeticholic acid as a 2ndline medication for PBC.

    Article  CAS  PubMed  Google Scholar 

  56. Bowlus CL, Pockros PJ, Kremer AE, Parés A, Forman LM, Drenth JPH, et al. Long-term obeticholic acid therapy improves histological endpoints in patients with primary biliary cholangitis. Clin Gastroenterol Hepatol. 2019. https://doi.org/10.1016/j.cgh.2019.09.050.

    Article  PubMed  CAS  Google Scholar 

  57. Reig A, Sese P, Pares A. Effects of bezafibrate on outcome and pruritus in primary biliary cholangitis with suboptimal ursodeoxycholic acid response. Am J Gastroenterol. 2018;113(1):49–55.

    Article  CAS  PubMed  Google Scholar 

  58. Chen JL, Yang X, Zhang Q, Sun L, Liu Y, Zhu BB, et al. Effect of ursodeoxycholic acid with traditional Chinese medicine on biochemical response in patients with primary biliary cholangitis: a real-world cohort study. Chin J Hepatol. 2018;26(12):909–15.

    CAS  Google Scholar 

Download references

Funding

This work is supported by the Ministry of Science & Technology of China (#2016YFE0107400 to J.W.); the National Natural Science Foundation of China (NSFC #81272436, 81572356, 81871997 to J.W., #81470857 to X-P. L. and #81702982 to J.D.); Shanghai Commission of Sciences and Technologies (#16140903700 to J.W.); Natural Science Foundation of Shanghai (#17ZR1424800 to J.D.); the National Natural Science Foundation of China (NSFC #81270007, 81670513 to F.L.); Shanghai Talent Development Funds (#201304 to F.L.); Shanghai Rising-Star Program (#13QA1400700 to F.L.); and Shanghai Outstanding Young Talent Training Plan in Health System (#13YO56 to F.L.).

Author information

Authors and Affiliations

  1. Department of Gastroenterology & Hepatology, Zhongshan Hospital of Fudan University, 180 Fengling Road, Shanghai, 200032, China

    Ling Wu, Ning-Ping Zhang, Feng Li & Jian Wu

  2. Department of Gastroenterology, Jing-an District Central Hospital, Shanghai, 200040, China

    Jia Ding

  3. Shanghai Institute of Liver Diseases, Fudan University Shanghai Medical College, Shanghai, 200032, China

    Ning-Ping Zhang, Feng Li & Jian Wu

  4. Department of Medical Microbiology & Parasitology, Fudan University Shanghai Medical College, Shanghai, 200032, China

    Jian Wu

  5. Department of Pathology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, 138 Yixue Yuan Road, Shanghai, 200032, China

    Xiu-Ping Liu

  6. School of Basic Medical Sciences, Fudan University Shanghai Medical College, 138 Yixue Yuan Road, P. O. Box 228, Shanghai, 200032, China

    Jian Wu

Authors
  1. Ling Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jia Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ning-Ping Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Feng Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiu-Ping Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jian Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Feng Li, Xiu-Ping Liu or Jian Wu.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s Note

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

This article is part of the Topical Collection on Autoimmune, Cholestatic, and Biliary Diseases

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wu, L., Ding, J., Zhang, NP. et al. Mechanisms of Fibrosis in Primary Biliary Cholangitis. Curr Hepatology Rep 19, 96–105 (2020). https://doi.org/10.1007/s11901-020-00512-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11901-020-00512-2

Keywords

Search

Navigation