Editing Primary sclerosing cholangitis

{{Short description|Inflammatory disease of the bile ducts}}
{{Infobox medical condition (new)
| name = Primary sclerosing cholangitis
| synonyms = 
| image = Cholangiogram of primary sclerosing cholangitis.jpg
| caption = [[Cholangiogram]] of primary sclerosing cholangitis
| pronounce = 
| field = [[Gastroenterology]]
| symptoms = Typically no symptoms; abdominal pain, fatigue, fever, [[jaundice]]
| complications = [[Cholangiocarcinoma]]
| onset = 
| duration = Long term and progressive
| types = 
| causes = Unknown; most likely [[Autoimmune disease|autoimmune]]
| risks = [[Inflammatory bowel disease]], pre-existing liver disease
| diagnosis = Radiological imaging
| differential = Secondary causes of sclerosing cholangitis
| prevention = 
| treatment = Symptomatic
| medication = 
| prognosis = 
| frequency = 
| deaths = 
}}
<!-- Definition and symptoms -->

'''Primary sclerosing cholangitis''' ('''PSC''') is a long-term progressive disease of the [[liver]] and [[gallbladder]] characterized by [[inflammation]] and scarring of the [[bile duct]]s, which normally allow [[bile]] to drain from the gallbladder. Affected individuals may have no symptoms or may experience signs and symptoms of liver disease, such as [[jaundice]], [[pruritus|itching]], and abdominal pain.

<!-- Cause and Pathophysiology -->
The bile duct scarring that occurs in PSC narrows the ducts of the [[Biliary tract|biliary tree]] and impedes the flow of bile to the [[duodenum]]. Eventually, it can lead to [[cirrhosis]] of the liver and [[liver failure]]. PSC increases the risk of various cancers, including [[hepatocellular carcinoma|liver cancer]], [[gallbladder carcinoma]], [[colorectal cancer]], and [[cholangiocarcinoma]].<ref name="Lazaridis2016">{{cite journal | vauthors = Lazaridis KN, LaRusso NF | title = Primary Sclerosing Cholangitis | journal = The New England Journal of Medicine | volume = 375 | issue = 12 | pages = 1161–1170 | date = September 2016 | pmid = 27653566 | pmc = 5553912 | doi = 10.1056/NEJMra1506330 | type = Review }}</ref><ref name="Folseraas2016">{{cite journal | vauthors = Folseraas T, Boberg KM | title = Cancer Risk and Surveillance in Primary Sclerosing Cholangitis | journal = Clinics in Liver Disease | volume = 20 | issue = 1 | pages = 79–98 | date = February 2016 | pmid = 26593292 | doi = 10.1016/j.cld.2015.08.014 }}</ref>  The underlying cause of PSC is unknown. Genetic susceptibility, [[autoimmunity|immune system dysfunction]], and [[dysbiosis|abnormal composition of the gut flora]] may play a role.<ref name="Kummen2013" /><ref name="Charatchar">{{cite journal | vauthors = Charatcharoenwitthaya P, Lindor KD | title = Primary sclerosing cholangitis: diagnosis and management | journal = Current Gastroenterology Reports | volume = 8 | issue = 1 | pages = 75–82 | date = February 2006 | pmid = 16510038 | doi = 10.1007/s11894-006-0067-8 | s2cid = 37474299 }}</ref> This is further suggested by the observation that around 75% of individuals with PSC also have [[inflammatory bowel disease]] (IBD), most often [[ulcerative colitis]].<ref>{{cite book| vauthors = Sleisenger MH |title=Sleisenger and Fordtran's gastrointestinal and liver disease: pathophysiology, diagnosis, management |year=2006 |publisher=Saunders |location=Philadelphia |edition=8th}}</ref>

<!-- Prevention and Treatment -->
No effective medical treatment for primary sclerosing cholangitis is known. Its most definitive treatment is a [[liver transplantation|liver transplant]],<ref name="Lazaridis2016" /> but disease recurrence can occur in 25–30% of cases.<ref name="Melb2022">{{cite journal |last1=Tan |first1=Natassia |last2=Ngu |first2=N. |last3=Lee |first3=T. |last4=Abrahams |first4=T. |last5=Pandya |first5=K. |last6=Freeman |first6=E. |last7=Hannah |first7=N. |last8=Gazelakis |first8=K. |last9=Madden |first9=R. |last10=Lynch |first10=K. |last11=Valaydon |first11=Z. |last12=Sood |first12=S. |last13=Dev |first13=A. |last14=Bell |first14=S. |last15=Thompson |first15=A. |last16=Ding |first16=J. |last17=Nicoll |first17=A. |last18=Liu |first18=K. |last19=Gow |first19=P. |last20=Lubel |first20=J. |last21=Kemp |first21=W. |last22=Roberts |first22=S. |last23=Majeed |first23=A. |title=Epidemiology and outcomes of primary sclerosing cholangitis: an Australian multicentre retrospective cohort study |journal=Hepatology International |date= June 2022 |volume=16 |issue=5 |pages=1094–1104 |doi=10.1007/s12072-022-10356-1 |pmid=35657479 |pmc=9525417 }}</ref> For patients unable or unwilling to receive a transplant, therapy primarily focuses on relieving symptoms, rather than stopping disease progression. If the sclerosing cholangitis is a ''secondary'' effect of a different disease, treatment is directed towards the underlying cause.<ref name=":2">{{Cite journal |last1=Karlsen |first1=Tom H. |last2=Folseraas |first2=Trine |last3=Thorburn |first3=Douglas |last4=Vesterhus |first4=Mette |date=December 2017 |title=Primary sclerosing cholangitis – a comprehensive review |url=https://linkinghub.elsevier.com/retrieve/pii/S0168827817321967 |journal=Journal of Hepatology |language=en |volume=67 |issue=6 |pages=1298–1323 |doi=10.1016/j.jhep.2017.07.022|pmid=28802875 |doi-access=free }}</ref>

<!-- Epidemiology -->
PSC is a rare disease and most commonly affects people with IBD.<ref name="Folseraas2016"/> About 3.0 to 7.5% of people with ulcerative colitis have PSC, and 80% of people with PSC have some form of IBD.<ref name="Kummen2013">{{cite journal | vauthors = Kummen M, Schrumpf E, Boberg KM | title = Liver abnormalities in bowel diseases | journal = Best Practice & Research. Clinical Gastroenterology | volume = 27 | issue = 4 | pages = 531–542 | date = August 2013 | pmid = 24090940 | doi = 10.1016/j.bpg.2013.06.013 }}</ref> Diagnosis usually occurs in people in their 30s or 40s.<ref name="Kummen2013"/> Individuals of Northern European ancestry are affected more often than people of Southern European or Asian descent.<ref name="Folseraas2016"/> Men are affected more often than women.<ref name="Williamson2015">{{cite journal | vauthors = Williamson KD, Chapman RW | title = Primary sclerosing cholangitis: a clinical update | journal = British Medical Bulletin | volume = 114 | issue = 1 | pages = 53–64 | date = June 2015 | pmid = 25981516 | doi = 10.1093/bmb/ldv019 | doi-access = free }}</ref> The disease was initially described in the mid-1800s, but was not fully characterized until the 1970s with the advent of improved medical-imaging techniques such as [[endoscopic retrograde cholangiopancreatography]].<ref name="Williamson2015"/>

==Signs and symptoms==
Nearly half of people with PSC do not have symptoms, and are often incidentally discovered to have PSC due to abnormal [[liver function tests]];<ref name="Lazaridis2016"/> however, a substantial proportion have debilitating signs and symptoms of the disease.<ref name="ReferenceA">{{cite journal | vauthors = Tabibian JH, Lindor KD | title = Ursodeoxycholic acid in primary sclerosing cholangitis: if withdrawal is bad, then administration is good (right?) | journal = Hepatology | volume = 60 | issue = 3 | pages = 785–788 | date = September 2014 | pmid = 24752961 | doi = 10.1002/hep.27180 | s2cid = 5341568 | doi-access = free }}</ref> Signs and symptoms of PSC may include severe [[pruritus|itching]] and nonspecific fatigue. [[Jaundice]] may also be seen. Enlargement of the [[hepatomegaly|liver]] and [[splenomegaly|spleen]] are seen in roughly 40% of affected individuals. Abdominal pain affects about 20% of people with PSC.{{cn|date=March 2022}}

Multiple episodes of life-threatening acute [[cholangitis]] (infection within the bile ducts) can be seen due to impaired drainage of the bile ducts, which increases the risk of infection.<ref>{{cite journal | vauthors = Tabibian JH, Yang JD, Baron TH, Kane SV, Enders FB, Gostout CJ | title = Weekend Admission for Acute Cholangitis Does Not Adversely Impact Clinical or Endoscopic Outcomes | journal = Digestive Diseases and Sciences | volume = 61 | issue = 1 | pages = 53–61 | date = January 2016 | pmid = 26391268 | doi = 10.1007/s10620-015-3853-z | s2cid = 8266015 }} Epub 2015 Sep 21.</ref>
* Dark urine due to excess [[conjugated bilirubin]], which is water-soluble and excreted by the kidneys (i.e. choluria)
* [[Malabsorption]], especially of [[fat]], and [[steatorrhea]] (fatty stool), due to an inadequate amount of bile reaching the small intestine, leading to decreased levels of the fat-soluble [[vitamin]]s, [[vitamin A|A]], [[vitamin D|D]], [[vitamin E|E]], and [[vitamin K|K]].
* [[Portal hypertension]], a complication of [[cirrhosis]], which can manifest with [[Esophageal varices|esophageal]] and parastomal varices<ref>{{cite journal | vauthors = Tabibian JH, Abu Dayyeh BK, Gores GJ, Levy MJ | title = A novel, minimally invasive technique for management of peristomal varices | journal = Hepatology | volume = 63 | issue = 4 | pages = 1398–1400 | date = April 2016 | pmid = 26044445 | doi = 10.1002/hep.27925 | s2cid = 34965702 | doi-access = free }}</ref> as well as [[hepatic encephalopathy]] (mental status alteration/disturbance caused by liver dysfunction and shunting of blood away from the scarred liver; such that ammonia detoxification is reduced with concomitant encephalopathy) or [[ascites]].

==Cause==
The exact cause of primary sclerosing cholangitis is  unknown, and its pathogenesis is improperly understood.<ref name="Lazaridis2016"/> Although PSC is thought to be caused by [[autoimmune disease]], it does not demonstrate a clear response to immunosuppressants. Thus, many experts believe it to be a complex, multifactorial (including immune-mediated) disorder and perhaps one that encompasses several different hepatobiliary diseases.<ref name="ReferenceB">{{cite journal | vauthors = Tabibian JH, Lindor KD | title = Primary sclerosing cholangitis: a review and update on therapeutic developments | journal = Expert Review of Gastroenterology & Hepatology | volume = 7 | issue = 2 | pages = 103–114 | date = February 2013 | pmid = 23363260 | doi = 10.1586/egh.12.80 | s2cid = 207210857 }}</ref><ref>{{cite journal | vauthors = O'Hara SP, Tabibian JH, Splinter PL, LaRusso NF | title = The dynamic biliary epithelia: molecules, pathways, and disease | journal = Journal of Hepatology | volume = 58 | issue = 3 | pages = 575–582 | date = March 2013 | pmid = 23085249 | pmc = 3831345 | doi = 10.1016/j.jhep.2012.10.011 }}</ref> Alternatively, some experts have suggested that the reason immunosuppressant medications are ineffective is because PSC almost always remains undiagnosed until a very advanced stage, at which point damage may be irreversible or require more aggressive treatment than other autoimmune diseases.<ref name=":2" />

Data have provided novel insights suggesting:
# an important association between the intestinal [[microbiota]] and PSC<ref>{{cite journal | vauthors = Tabibian JH, O'Hara SP, Lindor KD | title = Primary sclerosing cholangitis and the microbiota: current knowledge and perspectives on etiopathogenesis and emerging therapies | journal = Scandinavian Journal of Gastroenterology | volume = 49 | issue = 8 | pages = 901–908 | date = August 2014 | pmid = 24990660 | pmc = 4210190 | doi = 10.3109/00365521.2014.913189 }}</ref><ref>{{cite journal | vauthors = Tabibian JH, Varghese C, O'Hara SP, LaRusso NF | title = Microbiome-Immune Interactions and Liver Disease | journal = Clinical Liver Disease | volume = 5 | issue = 4 | pages = 83–85 | date = April 2015 | pmid = 29755735 | pmc = 5944616 | doi = 10.1002/cld.453 }}</ref><ref>{{cite journal | vauthors = Tabibian JH, Varghese C, LaRusso NF, O'Hara SP | title = The enteric microbiome in hepatobiliary health and disease | journal = Liver International | volume = 36 | issue = 4 | pages = 480–487 | date = April 2016 | pmid = 26561779 | pmc = 4825184 | doi = 10.1111/liv.13009 }}</ref> and
# a process referred to as [[cellular senescence]] and the senescence-associated secretory phenotype in the pathogenesis of PSC.<ref>{{cite journal | vauthors = Tabibian JH, O'Hara SP, Splinter PL, Trussoni CE, LaRusso NF | title = Cholangiocyte senescence by way of N-ras activation is a characteristic of primary sclerosing cholangitis | journal = Hepatology | volume = 59 | issue = 6 | pages = 2263–2275 | date = June 2014 | pmid = 24390753 | pmc = 4167827 | doi = 10.1002/hep.26993 }}</ref><ref>{{cite journal | vauthors = Tabibian JH, Trussoni CE, O'Hara SP, Splinter PL, Heimbach JK, LaRusso NF | title = Characterization of cultured cholangiocytes isolated from livers of patients with primary sclerosing cholangitis | journal = Laboratory Investigation; A Journal of Technical Methods and Pathology | volume = 94 | issue = 10 | pages = 1126–1133 | date = October 2014 | pmid = 25046437 | pmc = 4184949 | doi = 10.1038/labinvest.2014.94 }}</ref>
In addition, longstanding, well-recognized associations are seen between PSC and [[human leukocyte antigen]] alleles (A1, B8, and DR3).<ref name=Charatchar/>

==Pathophysiology==
PSC is characterized by inflammation of the bile ducts (cholangitis) with consequent stricturing (i.e., narrowing) and hardening ([[sclerosis (medicine)|sclerosis]]) of these ducts due to scar formation, be it inside and/or outside the liver.<ref name=":0">{{cite journal | vauthors = Hirschfield GM, Karlsen TH, Lindor KD, Adams DH | title = Primary sclerosing cholangitis | journal = Lancet | volume = 382 | issue = 9904 | pages = 1587–1599 | date = November 2013 | pmid = 23810223 | doi = 10.1016/s0140-6736(13)60096-3 | s2cid = 13423425 }}</ref>  The resulting scarring of the bile ducts obstructs the flow of bile, which further perpetuates bile duct and liver injury.  Chronic impairment of bile flow due to blockage and dysfunctional bile transport ([[cholestasis]]) causes progressive biliary fibrosis and ultimately biliary cirrhosis and liver failure.<ref name=Robbins>{{cite book  | vauthors = Robbins SL, Kumar V, Cotran RS  | title = Robbins basic pathology  | publisher = Saunders  | location = Philadelphia  | year = 2003  | pages = [https://archive.org/details/robbinsbasicpath0000unse/page/620 620–1]  | edition = 7th  | chapter = Chapter 16  | isbn = 978-0-7216-9274-6  | chapter-url-access = registration  | chapter-url = https://archive.org/details/robbinsbasicpath0000unse/page/620 }}</ref>

The primary physiological function of bile is to assist in the breakdown and absorption of fat in the intestinal tract; a relative deficiency of bile can lead to fat malabsorption and deficiencies of [[fat-soluble vitamins]] (A, D, E, K).<ref>{{cite journal |last1=Iravani |first1=Shahrokh |last2=Dooghaie-Moghadam |first2=Arash |last3=Razavi-Khorasani |first3=Niloofar |last4=Moazzami |first4=Bobak |last5=Dowlati Beirami |first5=Amirreza |last6=Mansour-Ghanaei |first6=Alireza |last7=Majidzadeh-A |first7=Keivan |last8=Mehrvar |first8=Azim |last9=Khoshdel |first9=Alireza |last10=Nasiri Toosi |first10=Mohssen |last11=Sadeghi |first11=Amir |title=An update on treatment options for primary sclerosing cholangitis |journal=Gastroenterology and Hepatology from Bed to Bench |date=2020 |volume=13 |issue=2 |pages=115–124 |pmid=32308932 |pmc=7149806 }}</ref>

Liver enlargement is seen due to portal hypertension caused by compression of [[portal vein]]s by the proximate sclerosed intrahepatic bile ducts, and leads to right upper quadrant abdominal pain.{{cn|date=March 2022}}

==Diagnosis==
[[File:CT of primary sclerosing cholangitis.jpg|thumb|[[CT scan]] findings in a case of primary sclerosing cholangitis]]
[[File:Sclerosing cholangitis 0001.jpg|thumb|Ultrasound of sclerosing cholangitis in the common bile duct]]
PSC is generally diagnosed on the basis of having at least two of three clinical criteria after secondary causes of sclerosing cholangitis have been ruled out:{{cn|date=September 2022}}
* serum [[alkaline phosphatase]] (ALP) > 1.5x the upper limit of normal for longer than 6 months
* cholangiography demonstrating biliary strictures or irregularity consistent with PSC
* liver biopsy consistent with PSC (if available)

Historically, a cholangiogram would be obtained via [[endoscopic retrograde cholangiopancreatography]] (ERCP), which typically reveals "beading" (alternating strictures and dilation) of the bile ducts inside and/or outside the liver. Currently, the preferred option for diagnostic cholangiography, given its noninvasive yet highly accurate nature, is [[magnetic resonance cholangiopancreatography]] (MRCP), a [[magnetic resonance imaging]] technique.  MRCP has unique strengths, including high spatial resolution, and can even be used to visualize the [[biliary tract]] of small animal models of PSC.<ref>{{cite journal | vauthors = Tabibian JH, Macura SI, O'Hara SP, Fidler JL, Glockner JF, Takahashi N, Lowe VJ, Kemp BJ, Mishra PK, Tietz PS, Splinter PL, Trussoni CE, LaRusso NF | display-authors = 6 | title = Micro-computed tomography and nuclear magnetic resonance imaging for noninvasive, live-mouse cholangiography | journal = Laboratory Investigation; A Journal of Technical Methods and Pathology | volume = 93 | issue = 6 | pages = 733–743 | date = June 2013 | pmid = 23588707 | pmc = 3875307 | doi = 10.1038/labinvest.2013.52 }}</ref>

Most people with PSC have evidence of [[autoantibodies]] and abnormal immunoglobulin levels.<ref>{{cite journal | vauthors = Tabibian JH, Enders F, Imam MH, Kolar G, Lindor KD, Talwalkar JA | title = Association between serum IgE level and adverse clinical endpoints in primary sclerosing cholangitis | journal = Annals of Hepatology | volume = 13 | issue = 3 | pages = 384–389 | year = 2014 | pmid = 24756015 | pmc = 4215553 | doi = 10.1016/S1665-2681(19)30869-5 }}</ref> For example, approximately 80% of people with PSC have perinuclear [[Anti-neutrophil cytoplasmic antibody#p-ANCA|antineutrophil cytoplasmic antibodies]] (P-ANCA); however, this and other immunoglobulin findings are not specific to those with PSC and are of unclear clinical significance/consequence. [[Antinuclear antibodies]] and [[anti-smooth muscle antibody]] are found in 20–50% of PSC patients, and likewise are not specific for the disease, but may identify a subgroup of PSC patients who also have autoimmune hepatitis (i.e. PSC-AIH overlap syndrome).<ref name=Charatchar/>

The differential diagnosis can include primary biliary cholangitis (formerly referred to as [[primary biliary cirrhosis]]), drug-induced [[cholestasis]], [[cholangiocarcinoma]], [[IgG4-related disease]], post-liver transplantation nonanastomotic biliary strictures,<ref>{{cite journal | vauthors = Tabibian JH, Asham EH, Goldstein L, Han SH, Saab S, Tong MJ, Busuttil RW, Durazo FA | display-authors = 6 | title = Endoscopic treatment with multiple stents for post-liver-transplantation nonanastomotic biliary strictures | journal = Gastrointestinal Endoscopy | volume = 69 | issue = 7 | pages = 1236–1243 | date = June 2009 | pmid = 19249040 | doi = 10.1016/j.gie.2008.09.057 }}</ref>  and [[HIV]]-associated cholangiopathy.<ref>{{cite journal | vauthors = Lazaridis KN, LaRusso NF | title = The Cholangiopathies | journal = Mayo Clinic Proceedings | volume = 90 | issue = 6 | pages = 791–800 | date = June 2015 | pmid = 25957621 | pmc = 4533104 | doi = 10.1016/j.mayocp.2015.03.017 }}</ref> Primary sclerosing cholangitis and primary biliary cholangitis are distinct entities and exhibit important differences, including the site of tissue damage within the liver, associations with IBD, which includes ulcerative colitis and Crohn's disease, response to treatment, and risks of disease progression.<ref>{{cite journal | vauthors = Trivedi PJ, Corpechot C, Pares A, Hirschfield GM | title = Risk stratification in autoimmune cholestatic liver diseases: Opportunities for clinicians and trialists | journal = Hepatology | volume = 63 | issue = 2 | pages = 644–659 | date = February 2016 | pmid = 26290473 | pmc = 4864755 | doi = 10.1002/hep.28128 }}</ref>

===Classification===
Primary sclerosing cholangitis is typically classified into three subgroups based on whether the small and/or large bile ducts are affected. The subgroups of PSC include:<ref name="Lazaridis2016" />
* Classic PSC
* Small-duct PSC
* PSC associated with [[autoimmune hepatitis]]

==Management==
No pharmacologic treatment has been approved by the U.S. [[Food and Drug Administration]] for PSC. Some experts recommend a trial of [[ursodeoxycholic acid]] (UDCA), a bile acid occurring naturally in small quantities in humans, as it has been shown to lower elevated liver enzyme numbers in patients with PSC and has proven effective in other cholestatic liver diseases. However, UDCA has yet to be shown to clearly lead to improved liver histology and survival.<ref name="ReferenceA" /><ref name="Lindor">{{cite journal | vauthors = Lindor KD, Kowdley KV, Luketic VA, Harrison ME, McCashland T, Befeler AS, Harnois D, Jorgensen R, Petz J, Keach J, Mooney J, Sargeant C, Braaten J, Bernard T, King D, Miceli E, Schmoll J, Hoskin T, Thapa P, Enders F | display-authors = 6 | title = High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis | journal = Hepatology | volume = 50 | issue = 3 | pages = 808–814 | date = September 2009 | pmid = 19585548 | pmc = 2758780 | doi = 10.1002/hep.23082 }}</ref> Guidelines from the [[American Association for the Study of Liver Diseases]] and the [[American College of Gastroenterology]] do not support the use of UDCA but guidelines from the [[European Association for the Study of the Liver]] do endorse the use of moderate doses (13–15 milligrams per kilogram) of UDCA for PSC.<ref name="Lazaridis2016" /><ref name="Chapman2010">{{cite journal | vauthors = Chapman R, Fevery J, Kalloo A, Nagorney DM, Boberg KM, Shneider B, Gores GJ | title = Diagnosis and management of primary sclerosing cholangitis | journal = Hepatology | volume = 51 | issue = 2 | pages = 660–678 | date = February 2010 | pmid = 20101749 | doi = 10.1002/hep.23294 | s2cid = 35432726 | doi-access =  }}</ref><ref name="Lindor2015">{{cite journal | vauthors = Lindor KD, Kowdley KV, Harrison ME | title = ACG Clinical Guideline: Primary Sclerosing Cholangitis | journal = The American Journal of Gastroenterology | volume = 110 | issue = 5 | pages = 646–59; quiz 660 | date = May 2015 | pmid = 25869391 | doi = 10.1038/ajg.2015.112 | s2cid = 41646016 | doi-access = free }}</ref><ref name="EASL2009">{{cite journal | title = EASL Clinical Practice Guidelines: management of cholestatic liver diseases | journal = Journal of Hepatology | volume = 51 | issue = 2 | pages = 237–267 | date = August 2009 | pmid = 19501929 | doi = 10.1016/j.jhep.2009.04.009 | doi-access = free | author1 = European Association for the Study of the Liver }}</ref>

Supportive treatment for PSC symptoms is the cornerstone of management. These therapies are aimed at relieving symptoms such as itching with [[antipruritic]]s (e.g. [[bile acid sequestrant]]s such as [[cholestyramine]]); [[antibiotic]]s to treat episodes of [[ascending cholangitis]]; and vitamin supplements, as people with PSC are often deficient in fat-soluble vitamins (A, D, E, and K).<ref>{{cite journal | title = EASL Clinical Practice Guidelines: management of cholestatic liver diseases | journal = Journal of Hepatology | volume = 51 | issue = 2 | pages = 237–267 | date = August 2009 | pmid = 19501929 | doi = 10.1016/j.jhep.2009.04.009 | doi-access = free | author1 = European Association for the Study of the Liver }}</ref>

ERCP and specialized techniques may also be needed to help distinguish between a benign PSC stricture and a bile-duct cancer (cholangiocarcinoma).<ref>{{cite journal | vauthors = Tabibian JH, Visrodia KH, Levy MJ, Gostout CJ | title = Advanced endoscopic imaging of indeterminate biliary strictures | journal = World Journal of Gastrointestinal Endoscopy | volume = 7 | issue = 18 | pages = 1268–1278 | date = December 2015 | pmid = 26675379 | pmc = 4673389 | doi = 10.4253/wjge.v7.i18.1268 | doi-access = free }}</ref>

Liver transplantation is the only proven long-term treatment of PSC. Indications for transplantation include recurrent bacterial ascending cholangitis, decompensated cirrhosis, [[hepatocellular carcinoma]], hilar cholangiocarcinoma, and complications of portal hypertension. Not all patients are candidates for liver transplantation, and some experience disease recurrence afterward.<ref name="ReferenceB" /> The reasons why some patients develop recurrent PSC remains largely obscure, but surprisingly, those without recurrence of disease (hence protected from recurrence) are characterized by an increased presence of the potentially pathogenic '' [[Shigella]]'' species.<ref>{{cite journal | vauthors = Visseren T, Fuhler GM, Erler NS, Nossent YR, Metselaar HJ, IJzermans JN, Darwish Murad S, Peppelenbosch MP | display-authors = 6 | title = Recurrence of primary sclerosing cholangitis after liver transplantation is associated with specific changes in the gut microbiome pretransplant – a pilot study | journal = Transplant International | volume = 33 | issue = 11 | pages = 1424–1436 | date = November 2020 | pmid = 33617049 | pmc = 7689804 | doi = 10.1111/tri.13692 }}</ref>

== Complications ==
[[Cholangiocarcinoma]] (CCA) represents a major complication and the leading cause of death in patients with primary sclerosing cholangitis (PSC), with a lifetime prevalence ranging from 6-13%. Patients with PSC have a 400-600 fold higher risk of developing CCA compared to the general population, with an annual risk between 0.5-1.5%. Notably, 30-50% of PSC-associated CCAs are diagnosed within the first year after PSC diagnosis, and up to 80% of patients die within one year of CCA detection. Risk factors include advanced age, male sex, concomitant inflammatory bowel disease, and high-grade biliary strictures. The development of CCA follows a multistep [[carcinogenesis]] model involving chronic inflammation, which progresses from damaged biliary epithelium to dysplasia and eventually invasive cancer, with molecular mechanisms including inflammatory pathways, oxidative stress, genetic alterations (commonly affecting [[p53]]), and [[Epigenetics|epigenetic]] changes that create an aberrant phenotype in [[Cholangiocyte|cholangiocytes]].<ref name=":3">{{Cite journal |last1=Catanzaro |first1=Elisa |last2=Gringeri |first2=Enrico |last3=Burra |first3=Patrizia |last4=Gambato |first4=Martina |date=2023-10-11 |title=Primary Sclerosing Cholangitis-Associated Cholangiocarcinoma: From Pathogenesis to Diagnostic and Surveillance Strategies |journal=Cancers |language=en |volume=15 |issue=20 |pages=4947 |doi=10.3390/cancers15204947 |doi-access=free |issn=2072-6694 |pmc=10604939 |pmid=37894314}}</ref>

==Prognosis==
There are no reliable prognostic models for PSC, owing to the highly variable disease course. Patients who are asymptomatic at the time of diagnosis are known to have better outcomes than those who have symptoms. However, many asymptomatic patients will develop symptoms later in time. Laboratory tests such as [[liver function tests]] are surprisingly unreliable when used as prognostic indicators for PSC.<ref name=":2" />

Estimated median survival from diagnosis until liver transplant or PSC-related death is 21.3 years.<ref>{{cite journal | vauthors = Boonstra K, Weersma RK, van Erpecum KJ, Rauws EA, Spanier BW, Poen AC, van Nieuwkerk KM, Drenth JP, Witteman BJ, Tuynman HA, Naber AH, Kingma PJ, van Buuren HR, van Hoek B, Vleggaar FP, van Geloven N, Beuers U, Ponsioen CY | display-authors = 6 | title = Population-based epidemiology, malignancy risk, and outcome of primary sclerosing cholangitis | journal = Hepatology | volume = 58 | issue = 6 | pages = 2045–2055 | date = December 2013 | pmid = 23775876 | doi = 10.1002/hep.26565 | hdl-access = free | s2cid = 205889681 | hdl = 1887/117347 }}</ref> Various models have been developed to help predict survival,<ref>{{cite journal | vauthors = Tornai D, Ven PL, Lakatos PL, Papp M | title = Serological biomarkers for management of primary sclerosing cholangitis | journal = World Journal of Gastroenterology | volume = 28 | issue = 21 | pages = 2291–2301 | date = June 2022 | pmid = 35800183 | pmc = 9185217 | doi = 10.3748/wjg.v28.i21.2291 | doi-access = free }}</ref> but their use is generally best suited for research and not clinical purposes. A serum [[alkaline phosphatase]] less than 1.5 times the upper limit of normal has been associated with better outcomes, but its use in predicting long-term outcomes is unclear.<ref name="Lazaridis2016" /> An [[Immunoglobulin A|IgA]] isotype [[autoantibody]] to the pancreatic [[GP2 (gene)|GP2]] protein (anti-GP2 IgA antibody) is the first verified prognostic biomarker in PSC.<ref name=":1">{{cite journal | vauthors = Tornai D, Papp M | title = Editorial: serologic antibodies in primary sclerosing cholangitis – a tell-tale sign of compromised gut-liver immunity? | journal = Alimentary Pharmacology & Therapeutics | volume = 53 | issue = 2 | pages = 350–351 | date = January 2021 | pmid = 33368511 | doi = 10.1111/apt.16201 | s2cid = 229379767 | doi-access = free }}</ref> The role of anti-GP2 IgA in PSC was simultaneously investigated and reported by two research groups,<ref>{{cite journal | vauthors = Jendrek ST, Gotthardt D, Nitzsche T, Widmann L, Korf T, Michaels MA, Weiss KH, Liaskou E, Vesterhus M, Karlsen TH, Mindorf S, Schemmer P, Bär F, Teegen B, Schröder T, Ehlers M, Hammers CM, Komorowski L, Lehnert H, Fellermann K, Derer S, Hov JR, Sina C | display-authors = 6 | title = Anti-GP2 IgA autoantibodies are associated with poor survival and cholangiocarcinoma in primary sclerosing cholangitis | journal = Gut | volume = 66 | issue = 1 | pages = 137–144 | date = January 2017 | pmid = 27406039 | doi = 10.1136/gutjnl-2016-311739 | s2cid = 3479797 | hdl = 10852/62341 | hdl-access = free }}</ref><ref>{{cite journal | vauthors = Tornai T, Tornai D, Sipeki N, Tornai I, Alsulaimani R, Fechner K, Roggenbuck D, Norman GL, Veres G, Par G, Par A, Szalay F, Lakatos PL, Antal-Szalmas P, Papp M | display-authors = 6 | title = Loss of tolerance to gut immunity protein, glycoprotein 2 (GP2) is associated with progressive disease course in primary sclerosing cholangitis | journal = Scientific Reports | volume = 8 | issue = 1 | pages = 399 | date = January 2018 | pmid = 29321484 | pmc = 5762861 | doi = 10.1038/s41598-017-18622-1 | bibcode = 2018NatSR...8..399T }}</ref> and later confirmed by others.<ref>{{cite journal | vauthors = Sowa M, Kolenda R, Baumgart DC, Pratschke J, Papp M, Tornai T, Suchanski J, Bogdanos DP, Mytilinaiou MG, Hammermann J, Laass MW, Conrad K, Schramm C, Franke A, Roggenbuck D, Schierack P | display-authors = 6 | title = Mucosal Autoimmunity to Cell-Bound GP2 Isoforms Is a Sensitive Marker in PSC and Associated With the Clinical Phenotype | language = English | journal = Frontiers in Immunology | volume = 9 | pages = 1959 | date = 2018 | pmid = 30233574 | pmc = 6127632 | doi = 10.3389/fimmu.2018.01959 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Wunsch E, Norman GL, Milkiewicz M, Krawczyk M, Bentow C, Shums Z, Mahler M, Lopens S, Reinhold D, Franke A, Schramm C, Roggenbuck D, Milkiewicz P | display-authors = 6 | title = Anti-glycoprotein 2 (anti-GP2) IgA and anti-neutrophil cytoplasmic antibodies to serine proteinase 3 (PR3-ANCA): antibodies to predict severe disease, poor survival and cholangiocarcinoma in primary sclerosing cholangitis | journal = Alimentary Pharmacology & Therapeutics | volume = 53 | issue = 2 | pages = 302–313 | date = January 2021 | pmid = 33159471 | pmc = 7821312 | doi = 10.1111/apt.16153 }}</ref> Association was demonstrated between anti-GP2 IgA and progressive liver fibrosis, [[cholangiocarcinoma]] development and shorter transplantation free survival in PSC patients.<ref name=":1" />

Other markers which may be measured and monitored are a [[complete blood count]], serum [[liver enzyme]]s, [[bilirubin]] levels (usually grossly elevated), [[kidney function]], and [[electrolyte]]s. However, none of these tests are reliable indicators of prognosis, as they are either specific to certain disease [[Complication (medicine)|complications]] or have a tendency to fluctuate over time, irrespective of the actual disease progression.<ref name=":2" /> [[Fecal fat]] measurement is occasionally ordered when symptoms of malabsorption (e.g., gross [[steatorrhea]]) are prominent.{{cn|date=September 2022}}

=== Cancer ===
[[Cholangiocarcinoma]], a major complication of PSC, is associated with a very poor prognosis. Approximately 80% of patients diagnosed with PSC-associated cholangiocarcinoma die within 1 year.<ref name=":3" />

The development of any of the cancers associated with PSC predicts a poor prognosis. Complications from PSC-associated cancers account for 40% of deaths from PSC.<ref name="Folseraas2016" /> Primary sclerosing cholangitis is one of the major known risk factors for cholangiocarcinoma,<ref name="Tsaitas2014">{{cite journal | vauthors = Tsaitas C, Semertzidou A, Sinakos E | title = Update on inflammatory bowel disease in patients with primary sclerosing cholangitis | journal = World Journal of Hepatology | volume = 6 | issue = 4 | pages = 178–187 | date = April 2014 | pmid = 24799986 | pmc = 4009473 | doi = 10.4254/wjh.v6.i4.178 | doi-access = free }}</ref> a cancer of the biliary tree, for which the lifetime risk among patients with PSC is 10-15%.<ref name="Kummen2013" /> This represents a 400-fold greater risk of developing cholangiocarcinoma compared to the general population.<ref name="Lazaridis2016" />  Surveillance for cholangiocarcinoma in patients with PSC is encouraged, with some experts recommending annual surveillance with a specialized imaging study and serum markers,<ref>Tabibian JH, Lindor KD. Challenges of Cholangiocarcinoma Detection in Patients with Primary Sclerosing Cholangitis. J Analytical Oncology. 2012;1(1):50–55.</ref> although consensus regarding the modality and interval has yet to be established.{{citation needed|date=October 2013}} Similarly, a screening [[colonoscopy]] is recommended in people who receive a new diagnosis of primary sclerosing cholangitis since their risk of colorectal cancer is 10 times higher than that of the general population.<ref name="Lazaridis2016" />

=== Related diseases ===
PSC is strongly associated with IBD, in particular [[ulcerative colitis]] (UC) and to a lesser extent [[Crohn's disease]]. As many as 5% of patients with IBD are co-diagnosed with PSC,<ref>{{cite journal | vauthors = Olsson R, Danielsson A, Järnerot G, Lindström E, Lööf L, Rolny P, Rydén BO, Tysk C, Wallerstedt S | display-authors = 6 | title = Prevalence of primary sclerosing cholangitis in patients with ulcerative colitis | journal = Gastroenterology | volume = 100 | issue = 5 Pt 1 | pages = 1319–1323 | date = May 1991 | pmid = 2013375 | doi = 10.1016/0016-5085(91)90784-I }}</ref> and approximately 70% of people with PSC have IBD.<ref name=Robbins/> Of note, the presence of colitis appears to be associated with a greater risk of liver disease progression and bile duct cancer (cholangiocarcinoma) development, although this relationship remains poorly understood.<ref>{{cite journal | vauthors = Boonstra K, Weersma RK, van Erpecum KJ, Rauws EA, Spanier BW, Poen AC, van Nieuwkerk KM, Drenth JP, Witteman BJ, Tuynman HA, Naber AH, Kingma PJ, van Buuren HR, van Hoek B, Vleggaar FP, van Geloven N, Beuers U, Ponsioen CY | display-authors = 6 | title = Population-based epidemiology, malignancy risk, and outcome of primary sclerosing cholangitis | journal = Hepatology | volume = 58 | issue = 6 | pages = 2045–2055 | date = December 2013 | pmid = 23775876 | doi = 10.1002/hep.26565 | hdl-access = free | s2cid = 205889681 | hdl = 1887/117347 }}</ref> Close monitoring of PSC patients is vital.

Various forms of gallbladder disease such as [[gallstone]]s and gallbladder [[Polyp (medicine)|polyp]]s are also common in those with PSC.<ref name="Lazaridis2016"/> Approximately 25% of people with PSC have gallstones.<ref name="Lazaridis2016"/> Ultrasound surveillance of the gallbladder every year is recommended for people with PSC.<ref name="Lazaridis2016"/> Any person with PSC who is found to have a mass in the gallbladder should undergo [[cholecystectomy|surgical removal of the gallbladder]] due to the high risk of cholangiocarcinoma.<ref name="Lazaridis2016"/> [[Osteoporosis]] (hepatic osteodystrophy) and [[hypothyroidism]] are also associated with PSC.{{cn|date=September 2022}}

A 2–3:1 male-to-female predilection occurs in primary sclerosing cholangitis.<ref name=Robbins/>  PSC can affect men and women at any age, although it is commonly diagnosed in the fourth decade of life, most often in the presence of IBD.<ref name=":0" />  PSC progresses slowly and is often asymptomatic, so it can be present for years before it is diagnosed and before it causes clinically significant consequences.  Relatively few data are available on the [[Prevalence (epidemiology)|prevalence]] and [[Incidence (epidemiology)|incidence]] of PSC, with studies in different countries showing annual incidence of 0.068–1.3 per 100,000 people and prevalence 0.22–8.5 per 100,000; given that PSC is closely linked with ulcerative colitis, the risk is likely higher in populations where UC is more common.<ref>{{cite journal | vauthors=Feld JJ, Heathcote EJ |title=Epidemiology of autoimmune liver disease |journal= Journal of Gastroenterology and Hepatology|volume=18 |issue=10 |pages=1118–28 |date=October 2003 |pmid=12974897 |doi=10.1046/j.1440-1746.2003.03165.x |s2cid=24075827 |doi-access= }}</ref>  In the United States, an estimated 29,000 individuals have PSC.<ref name="Lazaridis2016"/>

==Research==
Although no curative treatment is known, several clinical trials are underway that aim to slow progression of this liver disease.<ref>{{cite journal | vauthors = Trivedi PJ, Hirschfield GM | title = Treatment of autoimmune liver disease: current and future therapeutic options | journal = Therapeutic Advances in Chronic Disease | volume = 4 | issue = 3 | pages = 119–141 | date = May 2013 | pmid = 23634279 | pmc = 3629750 | doi = 10.1177/2040622313478646 }}</ref> [[Obeticholic acid]] is being investigated as a possible treatment for PSC due to its antifibrotic effects. [[Simtuzumab]] is a [[monoclonal antibody]] against the profibrotic enzyme [[LOXL2]] that is being developed as a possible therapy for PSC.<ref name="Lazaridis2016"/>

==Notable cases==
* [[Chris Klug]] – professional snowboarder with PSC who had liver transplant <ref name="SportsRef">{{cite Sports-Reference |url=https://www.sports-reference.com/olympics/athletes/kl/chris-klug-1.html |archive-url=https://web.archive.org/web/20200417224750/https://www.sports-reference.com/olympics/athletes/kl/chris-klug-1.html |url-status=dead |archive-date=April 17, 2020 |title=Chris Klug Olympic Results |accessdate=April 8, 2020}}</ref> 
* [[Chris LeDoux]] – professional rodeo rider and country musician with PSC who died of cholangiocarcinoma
* [[Elena Baltacha]] – British professional tennis player, diagnosed with PSC at age 19 and died five months after being diagnosed with PSC-associated liver cancer (specifically cholangiocarcinoma) at the age of 30
* [[Walter Payton]] – professional American Football player and humanitarian, died of complications of PSC
* [[Kieron Dyer]] – professional footballer
* [[James Redford (filmmaker)|James Redford]] – director and son of [[Robert Redford]] who underwent two liver transplants due to PSC<ref>{{Cite news |last=Genzlinger |first=Neil |date=October 22, 2020 |title=James Redford, Documentarian and Environmentalist, Dies at 58 |language=en-US |work=The New York Times |url=https://www.nytimes.com/2020/10/22/movies/james-redford-dead.html |access-date=September 15, 2022 |issn=0362-4331}}</ref>
* [[Lars-Göran Petrov]] – Swedish death metal vocalist best known for his work with [[Entombed (band)|Entombed]]

== References ==
{{Reflist}}

== External links ==
Patient support organizations:
* [http://www.pscpartners.org www.pscpartners.org]—based in the US
* [http://www.pscpartners.ca www.pscpartners.ca]—based in Canada
* [http://www.pscsupport.org.au www.pscsupport.org.au]—based in Australia
* [http://www.pscsupport.org.uk www.pscsupport.org.uk]—based in the UK

{{Medical resources
|  DiseasesDB      = 10643
|  ICD10           = {{ICD10|K|83|0|k|80}}
|  ICD9            = {{ICD9|576.1}}
|  OMIM            = 613806
|  MedlinePlus     = 000285
|  eMedicineSubj   = med
|  eMedicineTopic  = 3556
|  MeshID          = D015209
}}
{{Gastroenterology}}

[[Category:Articles containing video clips]]
[[Category:Autoimmune diseases]]
[[Category:Biliary tract disorders]]
[[Category:Hepatology]]
[[Category:Inflammations]]