Details of Disease

General Information of Disease (ID: DISTH5WJ)

Disease Name	Primary sclerosing cholangitis
Synonyms	cholangitis, primary sclerosing; PSC
Disease Class	DB96: Autoimmune liver disease
Definition	Primary sclerosing cholangitis (PSC) is a rare, slowly progressive liver disease characterized by inflammation and destruction of the intra- and/or extra-hepatic bile ducts that lead to cholestasis, liver fibrosis, liver cirrhosis and ultimately liver failure.
Disease Hierarchy	DIS7GZNB: Sclerosing cholangitis DISTH5WJ: Primary sclerosing cholangitis
ICD Code	ICD-11 ICD-11: DB96.2 ICD-10 ICD-10: K83.0 Expand ICD-11 'DB96.2 Expand ICD-10 'K83.0
Disease Identifiers	MONDO ID MONDO_0013433 UMLS CUI C0566602 OMIM ID 613806 MedGen ID 107565 Orphanet ID 171 SNOMED CT ID 197441003

Drug-Interaction Atlas (DIA) of This Disease

Drug-Interaction Atlas (DIA)

This Disease is Treated as An Indication in 5 Clinical Trial Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
GS-9674	DM936V7	Phase 3	Small molecular drug	[1]
HTD1801	DM2F620	Phase 2	NA	[2]
LUM001	DMQZXDW	Phase 2	NA	[3]
PLN-74809	DMQDN46	Phase 2	Small molecule	[4]
Simtuzumab	DM5SFWW	Phase 2	Monoclonal antibody	[3]
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Molecular Interaction Atlas (MIA) of This Disease

Molecular Interaction Atlas (MIA)

This Disease Is Related to 30 DTT Molecule(s)

Gene Name	DTT ID	Evidence Level	Mode of Inheritance	REF
DDR2	TTU98HG	Limited	Biomarker	[5]
ARSA	TTYQANR	moderate	Biomarker	[6]
DEFB4A	TTIVY12	moderate	Altered Expression	[7]
LOXL2	TTFSUHX	moderate	Biomarker	[8]
SLC17A5	TTFSUIA	moderate	Biomarker	[9]
CD28	TTQ13FT	Strong	Genetic Variation	[10]
CFTR	TTRLZHP	Strong	Biomarker	[11]
FGF19	TTGCH11	Strong	Biomarker	[12]
FUT3	TTUPAD7	Strong	Genetic Variation	[13]
GCLM	TTNFESW	Strong	Altered Expression	[14]
GPBAR1	TTSDVTR	Strong	Biomarker	[15]
GPR35	TT254XD	Strong	Genetic Variation	[16]
HDAC7	TTMUEK1	Strong	Genetic Variation	[17]
HIF1A	TTSN6QU	Strong	Biomarker	[18]
IL2RA	TT10Y9E	Strong	Genetic Variation	[19]
LSS	TT7O8ZA	Strong	Biomarker	[20]
MADCAM1	TTBD6I7	Strong	Genetic Variation	[21]
NOS2	TTF10I9	Strong	Biomarker	[22]
NR1H4	TTS4UGC	Strong	Biomarker	[23]
PDZK1	TTDTBLM	Strong	Biomarker	[24]
PNPLA3	TTEUAEH	Strong	Genetic Variation	[25]
RIC8B	TT26BHC	Strong	Genetic Variation	[17]
RSPO3	TT7HJTF	Strong	Genetic Variation	[26]
SH2B3	TT36N7Z	Strong	Biomarker	[27]
SIK2	TTCUGZR	Strong	Genetic Variation	[17]
SLC10A2	TTPI1M5	Strong	Biomarker	[23]
SPTBN1	TTS9BDA	Strong	Genetic Variation	[28]
TM6SF2	TTE1OHM	Strong	Genetic Variation	[25]
TNFRSF25	TTDV6BQ	Strong	Genetic Variation	[29]
POLR2G	TTD4YFP	Definitive	Genetic Variation	[30]
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⏷ Show the Full List of 30 DTT(s)

This Disease Is Related to 1 DTP Molecule(s)

Gene Name	DTP ID	Evidence Level	Mode of Inheritance	REF
SLC26A3	DTN1FMD	Strong	Genetic Variation	[31]
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This Disease Is Related to 1 DME Molecule(s)

Gene Name	DME ID	Evidence Level	Mode of Inheritance	REF
MMEL1	DEYCUQ2	Strong	Genetic Variation	[17]
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This Disease Is Related to 39 DOT Molecule(s)

Gene Name	DOT ID	Evidence Level	Mode of Inheritance	REF
CCBE1	OTO4UIDB	Limited	Genetic Variation	[32]
NEUROG3	OT6DIPWC	Limited	Altered Expression	[33]
SARNP	OTE0OVK5	Limited	Biomarker	[34]
TCF4	OTB9ASTK	moderate	Genetic Variation	[35]
ACAD8	OT3JI5GB	Strong	Biomarker	[36]
AGA	OTNWT1WB	Strong	Biomarker	[37]
BCL2L11	OTNQQWFJ	Strong	Biomarker	[38]
BSN	OTZ72VIB	Strong	Genetic Variation	[17]
CCL25	OTLWJ8CJ	Strong	Altered Expression	[39]
CD226	OT4UG0KB	Strong	Genetic Variation	[17]
CUZD1	OTDQJVZ8	Strong	Biomarker	[40]
DCT	OTYVNTBG	Strong	Biomarker	[41]
DEFB104A	OTLQZR6K	Strong	Genetic Variation	[7]
DLAT	OT9LBJVN	Strong	Biomarker	[42]
DLG5	OTU9Z17K	Strong	Genetic Variation	[43]
FBL	OTRODIE5	Strong	Biomarker	[44]
FBN2	OT3KYJQL	Strong	Biomarker	[45]
FUT2	OTLXM6WI	Strong	Genetic Variation	[46]
HLA-DRB3	OT5PM9N7	Strong	Genetic Variation	[47]
HLA-DRB5	OTUX5TWM	Strong	Genetic Variation	[48]
KCNH4	OTHJ8WTU	Strong	Altered Expression	[49]
KCNH8	OT3I5FLB	Strong	Altered Expression	[49]
KIF12	OTTALNDD	Strong	Genetic Variation	[50]
MICA	OTPEIEAR	Strong	Genetic Variation	[47]
MICB	OTS2DVDW	Strong	Biomarker	[51]
MST1	OTOC4UNG	Strong	Genetic Variation	[52]
NANOS2	OTFM2IDJ	Strong	Biomarker	[22]
NEIL1	OTHBU5DJ	Strong	Genetic Variation	[53]
ORM2	OTRJGZP8	Strong	Biomarker	[54]
PDZD2	OTPPVRGY	Strong	Biomarker	[55]
PHLDB1	OTIRCB6I	Strong	Genetic Variation	[17]
PRKD2	OTIFSVI8	Strong	Genetic Variation	[17]
PUS10	OTFFJWZX	Strong	Genetic Variation	[17]
RLN2	OTY3OG71	Strong	Biomarker	[56]
RMI2	OTA0HP4S	Strong	Genetic Variation	[17]
ADGRB3	OT1EWGRW	Definitive	Genetic Variation	[30]
AGBL2	OTCX9987	Definitive	Biomarker	[57]
JAM3	OTX0F9QL	Definitive	Biomarker	[58]
NOL3	OT1K0L0D	Definitive	Biomarker	[59]
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⏷ Show the Full List of 39 DOT(s)

References

1	ClinicalTrials.gov (NCT03890120) Safety, Tolerability, and Efficacy of Cilofexor in Non-Cirrhotic Adults With Primary Sclerosing Cholangitis (PRIMIS). U.S. National Institutes of Health.
2	ClinicalTrials.gov (NCT03333928) A Proof-of-Concept and Dose-Ranging Study Investigating the Efficacy and Safety of HTD1801 in Adult Subjects With Primary Sclerosing Cholangitis (PSC). U.S.National Institutes of Health.
3	Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
4	ClinicalTrials.gov (NCT04480840) A Randomized, Double-blind, Dose-ranging, Placebo-controlled, Phase 2a Evaluation of the Safety, Tolerability, and Pharmacokinetics of PLN-74809 in Participants With Primary Sclerosing Cholangitis (PSC) and Suspected Liver Fibrosis (INTEGRIS-PSC). U.S.National Institutes of Health.
5	Elevated expression of tyrosine kinase DDR2 in primary biliary cirrhosis.Autoimmunity. 2002 Dec;35(8):521-9. doi: 10.1080/0891693021000057784.
6	Primary Sclerosing Cholangitis in Children With Inflammatory Bowel Diseases Is Associated With Milder Clinical Activity But More Frequent Subclinical Inflammation and Growth Impairment.Clin Gastroenterol Hepatol. 2020 Jun;18(7):1509-1517.e7. doi: 10.1016/j.cgh.2019.08.048. Epub 2019 Sep 4.
7	Human -Defensin 2 in Primary Sclerosing Cholangitis.Clin Transl Gastroenterol. 2017 Mar 16;8(3):e80. doi: 10.1038/ctg.2017.8.
8	Simtuzumab for Primary Sclerosing Cholangitis: Phase 2 Study Results With Insights on the Natural History of the Disease.Hepatology. 2019 Feb;69(2):684-698. doi: 10.1002/hep.30237. Epub 2019 Jan 11.
9	Assessing the Validity of Adult-derived Prognostic Models for Primary Sclerosing Cholangitis Outcomes in Children.J Pediatr Gastroenterol Nutr. 2020 Jan;70(1):e12-e17. doi: 10.1097/MPG.0000000000002522.
10	Genetic variation at the CD28 locus and its impact on expansion of pro-inflammatory CD28 negative T cells in healthy individuals.Sci Rep. 2017 Aug 9;7(1):7652. doi: 10.1038/s41598-017-07967-2.
11	Pathobiology of inherited biliary diseases: a roadmap to understand acquired liver diseases.Nat Rev Gastroenterol Hepatol. 2019 Aug;16(8):497-511. doi: 10.1038/s41575-019-0156-4.
12	Effect of NGM282, an FGF19 analogue, in primary sclerosing cholangitis: A multicenter, randomized, double-blind, placebo-controlled phase II trial.J Hepatol. 2019 Mar;70(3):483-493. doi: 10.1016/j.jhep.2018.10.035. Epub 2018 Nov 9.
13	FUT2 and FUT3 genotype determines CA19-9 cut-off values for detection of cholangiocarcinoma in patients with primary sclerosing cholangitis.J Hepatol. 2013 Dec;59(6):1278-84. doi: 10.1016/j.jhep.2013.08.005. Epub 2013 Aug 16.
14	Aberrant expression of redox regulatory proteins in patients with concomitant primary Sclerosing cholangitis/inflammatory bowel disease.Exp Mol Pathol. 2018 Aug;105(1):32-36. doi: 10.1016/j.yexmp.2018.05.012. Epub 2018 May 29.
15	Bile acid receptors in the biliary tree: TGR5 in physiology and disease.Biochim Biophys Acta Mol Basis Dis. 2018 Apr;1864(4 Pt B):1319-1325. doi: 10.1016/j.bbadis.2017.08.021. Epub 2017 Aug 25.
16	Genome-wide association analysis in primary sclerosing cholangitis and ulcerative colitis identifies risk loci at GPR35 and TCF4.Hepatology. 2013 Sep;58(3):1074-83. doi: 10.1002/hep.25977. Epub 2013 Jan 17.
17	Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis.Nat Genet. 2013 Jun;45(6):670-5. doi: 10.1038/ng.2616. Epub 2013 Apr 21.
18	Hypoxia-inducible factor activation in myeloid cells contributes to the development of liver fibrosis in cholestatic mice.J Pharmacol Exp Ther. 2012 May;341(2):307-16. doi: 10.1124/jpet.111.189340. Epub 2012 Jan 23.
19	Reduced FOXP3(+) regulatory T cells in patients with primary sclerosing cholangitis are associated with IL2RA gene polymorphisms.J Hepatol. 2014 May;60(5):1010-6. doi: 10.1016/j.jhep.2013.12.027. Epub 2014 Jan 8.
20	Tumor suppressor gene, cell surface adhesion molecule, and multidrug resistance in Mllerian serous carcinomas: clinical divergence without immunophenotypic differences.Gynecol Oncol. 2000 Dec;79(3):430-7. doi: 10.1006/gyno.2000.6000.
21	Analysis of MAdCAM-1 and ICAM-1 polymorphisms in 365 Scandinavian patients with primary sclerosing cholangitis.J Hepatol. 2006 Nov;45(5):704-10. doi: 10.1016/j.jhep.2006.03.012. Epub 2006 Apr 25.
22	Cytokine-stimulated nitric oxide production inhibits adenylyl cyclase and cAMP-dependent secretion in cholangiocytes.Gastroenterology. 2003 Mar;124(3):737-53. doi: 10.1053/gast.2003.50100.
23	New therapies target the toxic consequences of cholestatic liver disease.Expert Rev Gastroenterol Hepatol. 2018 Mar;12(3):277-285. doi: 10.1080/17474124.2018.1424538. Epub 2018 Jan 10.
24	Identification of a novel staining pattern of bile duct epithelial cells in primary sclerosing cholangitis.Inflamm Bowel Dis. 2010 Feb;16(2):305-11. doi: 10.1002/ibd.21050.
25	PNPLA3 p.I148M and TM6SF2 p.E167K variants do not predispose to liver injury in cholestatic liver diseases: A prospective analysis of 178 patients with PSC.PLoS One. 2018 Aug 30;13(8):e0202942. doi: 10.1371/journal.pone.0202942. eCollection 2018.
26	Search for Genetic Modifiers of PSC: Time to Increase the Number of Needles in the Haystack.Ann Hepatol. 2017 November-December,;16(6):830-831. doi: 10.5604/01.3001.0010.5271.
27	Using GWAS to identify genetic predisposition in hepatic autoimmunity.J Autoimmun. 2016 Jan;66:25-39. doi: 10.1016/j.jaut.2015.08.016. Epub 2015 Sep 4.
28	Efficacy and safety of curcumin in primary sclerosing cholangitis: an open label pilot study.Scand J Gastroenterol. 2019 May;54(5):633-639. doi: 10.1080/00365521.2019.1611917. Epub 2019 May 26.
29	Autoantibody and human leukocyte antigen profiles in children with autoimmune liver disease and their first-degree relatives.J Pediatr Gastroenterol Nutr. 2014 Apr;58(4):457-62. doi: 10.1097/MPG.0000000000000245.
30	A novel approach to genome-wide association analysis identifies genetic associations with primary biliary cholangitis and primary sclerosing cholangitis in Polish patients.BMC Med Genomics. 2017 Jan 6;10(1):2. doi: 10.1186/s12920-016-0239-9.
31	ABCB4 mutations in adult patients with cholestatic liver disease: impact and phenotypic expression.J Gastroenterol. 2016 Mar;51(3):271-80. doi: 10.1007/s00535-015-1110-z. Epub 2015 Sep 1.
32	CCBE1 mutation causing sclerosing cholangitis: Expanding the spectrum of lymphedema-cholestasis syndrome.Hepatology. 2017 Jul;66(1):286-288. doi: 10.1002/hep.29037. Epub 2017 May 9.
33	Activation of the developmental pathway neurogenin-3/microRNA-7a regulates cholangiocyte proliferation in response to injury.Hepatology. 2014 Oct;60(4):1324-35. doi: 10.1002/hep.27262. Epub 2014 Aug 25.
34	The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients.Medicine (Baltimore). 2003 Nov;82(6):373-84. doi: 10.1097/01.md.0000100046.06009.b0.
35	The emerging roles of TCF4 in disease and development.Trends Mol Med. 2014 Jun;20(6):322-31. doi: 10.1016/j.molmed.2014.01.010. Epub 2014 Mar 1.
36	Fungi participate in the dysbiosis of gut microbiota in patients with primary sclerosing cholangitis.Gut. 2020 Jan;69(1):92-102. doi: 10.1136/gutjnl-2018-317791. Epub 2019 Apr 19.
37	AGA Clinical Practice Update on Surveillance for Hepatobiliary Cancers in Patients With Primary Sclerosing Cholangitis: Expert Review.Clin Gastroenterol Hepatol. 2019 Nov;17(12):2416-2422. doi: 10.1016/j.cgh.2019.07.011. Epub 2019 Jul 12.
38	CD4+ T cells from patients with primary sclerosing cholangitis exhibit reduced apoptosis and down-regulation of proapoptotic Bim in peripheral blood.J Leukoc Biol. 2017 Feb;101(2):589-597. doi: 10.1189/jlb.5A1015-469R. Epub 2016 Sep 14.
39	Intestinal CCL25 expression is increased in colitis and correlates with inflammatory activity.J Autoimmun. 2016 Apr;68:98-104. doi: 10.1016/j.jaut.2016.01.001. Epub 2016 Feb 9.
40	Significance of serological markers in the disease course of ulcerative colitis in a prospective clinical cohort of patients.PLoS One. 2018 Mar 28;13(3):e0194166. doi: 10.1371/journal.pone.0194166. eCollection 2018.
41	Development and characterization of naive single-type tumor antigen-specific CD8(+) T lymphocytes from murine pluripotent stem cells.Oncoimmunology. 2017 May 30;6(7):e1334027. doi: 10.1080/2162402X.2017.1334027. eCollection 2017.
42	Gene-disease associations identify a connectome with shared molecular pathways in human cholangiopathies.Hepatology. 2018 Feb;67(2):676-689. doi: 10.1002/hep.29504. Epub 2018 Jan 2.
43	Genetic polymorphisms associated with inflammatory bowel disease do not confer risk for primary sclerosing cholangitis.Am J Gastroenterol. 2007 Jan;102(1):115-21. doi: 10.1111/j.1572-0241.2006.00928.x. Epub 2006 Nov 13.
44	Primary sclerosing cholangitis: diagnostic performance of MRI compared to blood tests and clinical scoring systems for the evaluation of histopathological severity of disease.Abdom Radiol (NY). 2020 Feb;45(2):354-364. doi: 10.1007/s00261-019-02366-9.
45	Serum Metabolites as Diagnostic Biomarkers for Cholangiocarcinoma, Hepatocellular Carcinoma, and Primary Sclerosing Cholangitis.Hepatology. 2019 Aug;70(2):547-562. doi: 10.1002/hep.30319. Epub 2019 Feb 14.
46	Knockout of the primary sclerosing cholangitis-risk gene Fut2 causes liver disease in mice.Hepatology. 2017 Aug;66(2):542-554. doi: 10.1002/hep.29029. Epub 2017 Jun 19.
47	Refinement of the MHC risk map in a scandinavian primary sclerosing cholangitis population.PLoS One. 2014 Dec 18;9(12):e114486. doi: 10.1371/journal.pone.0114486. eCollection 2014.
48	HLA DR4 is a marker for rapid disease progression in primary sclerosing cholangitis.Gastroenterology. 1994 Jan;106(1):160-7. doi: 10.1016/s0016-5085(94)95085-7.
49	Biliary epithelial cell antibodies link adaptive and innate immune responses in primary sclerosing cholangitis.Gastroenterology. 2007 Apr;132(4):1504-14. doi: 10.1053/j.gastro.2007.01.039. Epub 2007 Jan 25.
50	Identification of novel loci for pediatric cholestatic liver disease defined by KIF12, PPM1F, USP53, LSR, and WDR83OS pathogenic variants. Genet Med. 2019 May;21(5):1164-1172. doi: 10.1038/s41436-018-0288-x. Epub 2018 Sep 25.
51	Primary sclerosing cholangitis is associated to an extended B8-DR3 haplotype including particular MICA and MICB alleles.Hepatology. 2001 Oct;34(4 Pt 1):625-30. doi: 10.1053/jhep.2001.27543.
52	Macrophage stimulating protein variation enhances the risk of sporadic extrahepatic cholangiocarcinoma.Dig Liver Dis. 2013 Jul;45(7):612-5. doi: 10.1016/j.dld.2012.12.017. Epub 2013 Feb 16.
53	Catalytically impaired hMYH and NEIL1 mutant proteins identified in patients with primary sclerosing cholangitis and cholangiocarcinoma.Carcinogenesis. 2009 Jul;30(7):1147-54. doi: 10.1093/carcin/bgp118. Epub 2009 May 14.
54	Mucosal Autoimmunity to Cell-Bound GP2 Isoforms Is a Sensitive Marker in PSC and Associated With the Clinical Phenotype.Front Immunol. 2018 Aug 28;9:1959. doi: 10.3389/fimmu.2018.01959. eCollection 2018.
55	Th2 and regulatory immune reactions are increased in immunoglobin G4-related sclerosing pancreatitis and cholangitis.Hepatology. 2007 Jun;45(6):1538-46. doi: 10.1002/hep.21697.
56	Nano-targeted relaxin impairs fibrosis and tumor growth in pancreatic cancer and improves the efficacy of gemcitabine in vivo.J Control Release. 2018 Nov 28;290:1-10. doi: 10.1016/j.jconrel.2018.09.031. Epub 2018 Oct 2.
57	Prevalence of autoimmune diseases and clinical significance of autoantibody profile: Data from National Institute of Hygiene in Rabat, Morocco.Hum Immunol. 2019 Jul;80(7):523-532. doi: 10.1016/j.humimm.2019.02.012. Epub 2019 Feb 23.
58	Junctional adhesion molecules JAM-B and JAM-C promote autoimmune-mediated liver fibrosis in mice.J Autoimmun. 2018 Jul;91:83-96. doi: 10.1016/j.jaut.2018.05.001. Epub 2018 May 9.
59	Phenotyping and auto-antibody production by liver-infiltrating B cells in primary sclerosing cholangitis and primary biliary cholangitis.J Autoimmun. 2017 Feb;77:45-54. doi: 10.1016/j.jaut.2016.10.003. Epub 2016 Oct 24.