Primary sclerosing cholangitis pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dima Nimri, M.D. [2]
Overview
The pathophysiology of primary sclerosing cholangitis is not fully understood, although it is thought to be the result of a combination of genetic as well as environmental factors. The risk of primary sclerosing cholangitis among siblings is estimated to be 9-39 times higher than the general population. The HLA locus on chromosome 6p21 and genes of the IL-2 pathway are associated with increased susceptibility to the development of primary sclerosing cholangitis. Environmental factors associated with increased risk of primary sclerosing cholangitis include exposure to farm animals during childhood and other dietary habits, such as less consumption of coffee and fish than controls. Smoking seems to be a protective factor against the development of primary sclerosing cholangitis.
Pathophysiology
Pathogenesis
The pathophysiology of primary sclerosing cholangitis is not fully understood, although it is thought to be the result of a combination of genetic as well as environmental factors.[1]
Environmental Factors
The following environmental factors may be protective or associated with an increased risk of developing primary sclerosing cholangitis:[1]
- Smoking:
- Smoking seems to be protective against primary scelrosing cholangitis, independent of its protective risk of ulcerative colitis.[2]
- Dietary habits:
- Exposure to farm animals:
- Patients with primary sclerosing cholangitis were more likely to be exposed to farm animals, but not domestic animals, during their childhood.[2]
- Use of contraceptive hormones in female patients:
- Female patients with primary sclerosing cholangitis were less likely to have used contraceptive hormones when compared to female controls.[2]
Genetics
- Primary sclerosing cholangitis is associated with environmental as well as genetic factors.
- The risk of primary sclerosing cholangitis among siblings is estimated to be 9-39 times higher than the general population.[5]
- The HLA-A1, B8, and DR3 locus on chromosome 6p21[6] and genes of the IL-2 pathway[7][8] are associated with increased susceptibility to the development of primary sclerosing cholangitis.
- In addition, the following 16 gene loci are associated with increased risk of primary sclerosing cholangitis.[6][7][8]
| Locus | Gene |
|---|---|
| 1p36 | MMEL1 |
| 2q13 | BCL2L11 |
| 2q33 | CD28 |
| 2q37 | GPR35 |
| 3p21 | MST1 |
| 4q27 | IL2 / IL21 |
| 6p21 | HLA B |
| 6q15 | BACH2 |
| 10p15 | IL2RA |
| 11q23 | SIK2 |
| 12q13 | HDAC7 |
| 12q24 | SH2B3 |
| 18q21 | TCF4 |
| 18q22 | CD226 |
| 19q13 | PRKD2 |
| 21q22 | PSMG1 / ETS2 |
Associated Conditions
Some of the conditions associated with primary sclerosing cholangitis include:[1][9]
- Inflammatory bowel disease (IBD): Approximately 70-80% of patients with primary sclerosing cholangitis have IBD (Crohn's disease and ulcerative colitis).[10]
- Autoimmune hepatitis: Approximately 35% of children with primary sclerosing cholangitis have associated autoimmune hepatitis[11], while only 5% of adults have combined primary sclerosing cholangitis with associated autoimmune hepatitis.[12]
- Gallbladder disease: This includes gallbladder stones and cholecystitis, polyps and cancer.[13][14]
- Sjogren syndrome
- Retroperitoneal fibrosis
- Mediastinal fibrosis
- Riedel thyroiditis
- Orbital pseudo tumour
Microscopic Pathology
References
- ↑ 1.0 1.1 1.2 Lazaridis KN, LaRusso NF (2016). "Primary Sclerosing Cholangitis". N. Engl. J. Med. 375 (12): 1161–70. doi:10.1056/NEJMra1506330. PMID 27653566.
- ↑ 2.0 2.1 2.2 2.3 Andersen IM, Tengesdal G, Lie BA, Boberg KM, Karlsen TH, Hov JR (2014). "Effects of coffee consumption, smoking, and hormones on risk for primary sclerosing cholangitis". Clin. Gastroenterol. Hepatol. 12 (6): 1019–28. doi:10.1016/j.cgh.2013.09.024. PMID 24076415.
- ↑ Lammert C, Juran BD, Schlicht E, Xie X, Atkinson EJ, de Andrade M, Lazaridis KN (2014). "Reduced coffee consumption among individuals with primary sclerosing cholangitis but not primary biliary cirrhosis". Clin. Gastroenterol. Hepatol. 12 (9): 1562–8. doi:10.1016/j.cgh.2013.12.036. PMC 4101072. PMID 24440215.
- ↑ Eaton JE, Juran BD, Atkinson EJ, Schlicht EM, Xie X, de Andrade M, Lammert CS, Luketic VA, Odin JA, Koteish AA, Kowdley KV, Chopra KB, Hirschfield GM, Chalasani NP, Lazaridis KN (2015). "A comprehensive assessment of environmental exposures among 1000 North American patients with primary sclerosing cholangitis, with and without inflammatory bowel disease". Aliment. Pharmacol. Ther. 41 (10): 980–90. doi:10.1111/apt.13154. PMC 4402146. PMID 25783671.
- ↑ Bergquist A, Montgomery SM, Bahmanyar S, Olsson R, Danielsson A, Lindgren S, Prytz H, Hultcrantz R, Lööf LA, Sandberg-Gertzén H, Almer S, Askling J, Ehlin A, Ekbom A (2008). "Increased risk of primary sclerosing cholangitis and ulcerative colitis in first-degree relatives of patients with primary sclerosing cholangitis". Clin. Gastroenterol. Hepatol. 6 (8): 939–43. doi:10.1016/j.cgh.2008.03.016. PMID 18674735.
- ↑ 6.0 6.1 Karlsen TH, Franke A, Melum E, Kaser A, Hov JR, Balschun T, Lie BA, Bergquist A, Schramm C, Weismüller TJ, Gotthardt D, Rust C, Philipp EE, Fritz T, Henckaerts L, Weersma RK, Stokkers P, Ponsioen CY, Wijmenga C, Sterneck M, Nothnagel M, Hampe J, Teufel A, Runz H, Rosenstiel P, Stiehl A, Vermeire S, Beuers U, Manns MP, Schrumpf E, Boberg KM, Schreiber S (2010). "Genome-wide association analysis in primary sclerosing cholangitis". Gastroenterology. 138 (3): 1102–11. doi:10.1053/j.gastro.2009.11.046. PMID 19944697.
- ↑ 7.0 7.1 Melum E, Franke A, Schramm C, Weismüller TJ, Gotthardt DN, Offner FA, Juran BD, Laerdahl JK, Labi V, Björnsson E, Weersma RK, Henckaerts L, Teufel A, Rust C, Ellinghaus E, Balschun T, Boberg KM, Ellinghaus D, Bergquist A, Sauer P, Ryu E, Hov JR, Wedemeyer J, Lindkvist B, Wittig M, Porte RJ, Holm K, Gieger C, Wichmann HE, Stokkers P, Ponsioen CY, Runz H, Stiehl A, Wijmenga C, Sterneck M, Vermeire S, Beuers U, Villunger A, Schrumpf E, Lazaridis KN, Manns MP, Schreiber S, Karlsen TH (2011). "Genome-wide association analysis in primary sclerosing cholangitis identifies two non-HLA susceptibility loci". Nat. Genet. 43 (1): 17–9. doi:10.1038/ng.728. PMC 4354850. PMID 21151127.
- ↑ 8.0 8.1 Liu JZ, Hov JR, Folseraas T, Ellinghaus E, Rushbrook SM, Doncheva NT, Andreassen OA, Weersma RK, Weismüller TJ, Eksteen B, Invernizzi P, Hirschfield GM, Gotthardt DN, Pares A, Ellinghaus D, Shah T, Juran BD, Milkiewicz P, Rust C, Schramm C, Müller T, Srivastava B, Dalekos G, Nöthen MM, Herms S, Winkelmann J, Mitrovic M, Braun F, Ponsioen CY, Croucher PJ, Sterneck M, Teufel A, Mason AL, Saarela J, Leppa V, Dorfman R, Alvaro D, Floreani A, Onengut-Gumuscu S, Rich SS, Thompson WK, Schork AJ, Næss S, Thomsen I, Mayr G, König IR, Hveem K, Cleynen I, Gutierrez-Achury J, Ricaño-Ponce I, van Heel D, Björnsson E, Sandford RN, Durie PR, Melum E, Vatn MH, Silverberg MS, Duerr RH, Padyukov L, Brand S, Sans M, Annese V, Achkar JP, Boberg KM, Marschall HU, Chazouillères O, Bowlus CL, Wijmenga C, Schrumpf E, Vermeire S, Albrecht M, Rioux JD, Alexander G, Bergquist A, Cho J, Schreiber S, Manns MP, Färkkilä M, Dale AM, Chapman RW, Lazaridis KN, Franke A, Anderson CA, Karlsen TH (2013). "Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis". Nat. Genet. 45 (6): 670–5. doi:10.1038/ng.2616. PMC 3667736. PMID 23603763.
- ↑ Vitellas KM, Keogan MT, Freed KS, Enns RA, Spritzer CE, Baillie JM, Nelson RC (2000). "Radiologic manifestations of sclerosing cholangitis with emphasis on MR cholangiopancreatography". Radiographics. 20 (4): 959–75, quiz 1108–9, 1112. doi:10.1148/radiographics.20.4.g00jl04959. PMID 10903686.
- ↑ Molodecky NA, Kareemi H, Parab R, Barkema HW, Quan H, Myers RP, Kaplan GG (2011). "Incidence of primary sclerosing cholangitis: a systematic review and meta-analysis". Hepatology. 53 (5): 1590–9. doi:10.1002/hep.24247. PMID 21351115.
- ↑ Feldstein AE, Perrault J, El-Youssif M, Lindor KD, Freese DK, Angulo P (2003). "Primary sclerosing cholangitis in children: a long-term follow-up study". Hepatology. 38 (1): 210–7. doi:10.1053/jhep.2003.50289. PMID 12830004.
- ↑ Kaya M, Angulo P, Lindor KD (2000). "Overlap of autoimmune hepatitis and primary sclerosing cholangitis: an evaluation of a modified scoring system". J. Hepatol. 33 (4): 537–42. PMID 11059857.
- ↑ Buckles DC, Lindor KD, Larusso NF, Petrovic LM, Gores GJ (2002). "In primary sclerosing cholangitis, gallbladder polyps are frequently malignant". Am. J. Gastroenterol. 97 (5): 1138–42. doi:10.1111/j.1572-0241.2002.05677.x. PMID 12014717.
- ↑ Said K, Glaumann H, Bergquist A (2008). "Gallbladder disease in patients with primary sclerosing cholangitis". J. Hepatol. 48 (4): 598–605. doi:10.1016/j.jhep.2007.11.019. PMID 18222013.