Primary sclerosing cholangitis explained

Primary sclerosing cholangitis
Field:Gastroenterology
Duration:Long term and progressive
Causes:Unknown

Primary sclerosing cholangitis (PSC) is a long-term progressive disease of the liver and gallbladder characterized by inflammation and scarring of the bile ducts, 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 yellow discoloration of the skin and eyes, itching, and abdominal pain.

The bile duct scarring that occurs in PSC narrows the ducts of the biliary tree and impedes the flow of bile to the intestines. Eventually, it can lead to cirrhosis of the liver and liver failure. PSC increases the risk of various cancers, including liver cancer, gallbladder carcinoma, colorectal cancer, and cholangiocarcinoma.[1] [2] The underlying cause of PSC is unknown. Genetic susceptibility, immune system dysfunction, and abnormal composition of the gut flora may play a role.[3] This is further suggested by the observation that around 75% of individuals with PSC also have inflammatory bowel disease (IBD), most often ulcerative colitis.[4]

No effective medical treatment for primary sclerosing cholangitis is known. Its most definitive treatment is a liver transplant,[1] but disease recurrence can occur in 25-30% of cases.[5]

PSC is a rare disease and most commonly affects people with IBD.[2] About 3.0 to 7.5% of people with ulcerative colitis have PSC, and 80% of people with PSC have some form of IBD.[6] Diagnosis usually occurs in people in their 30s or 40s.[6] Individuals of Northern European ancestry are affected more often than people of Southern European or Asian descent.[2] Men are affected more often than women.[7] 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.[7]

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;[1] however, a substantial proportion have debilitating signs and symptoms of the disease.[8] Signs and symptoms of PSC may include severe itching and nonspecific fatigue. Yellowing of the skin and white portion of the eyes may also be seen. Enlargement of the liver and spleen are seen in roughly 40% of affected individuals. Abdominal pain affects about 20% of people with PSC.

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.[9]

Cause

The exact cause of primary sclerosing cholangitis is unknown, and its pathogenesis is improperly understood.[1] 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.[11] [12]

Data have provided novel insights suggesting:

  1. an important association between the intestinal microbiota and PSC[13] [14] [15] and
  2. a process referred to as cellular senescence and the senescence-associated secretory phenotype in the pathogenesis of PSC.[16] [17]

In addition, longstanding, well-recognized associations are seen between PSC and human leukocyte antigen alleles (A1, B8, and DR3).[3]

Pathophysiology

PSC is characterized by inflammation of the bile ducts (cholangitis) with consequent stricturing (i.e., narrowing) and hardening (sclerosis) of these ducts due to scar formation, be it inside and/or outside the liver.[18] 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.[19]

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).[20]

Liver enlargement is seen due to portal hypertension caused by compression of portal veins by the proximate sclerosed intrahepatic bile ducts, and leads to right upper quadrant abdominal pain.

Diagnosis

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:

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.[21]

Most people with PSC have evidence of autoantibodies and abnormal immunoglobulin levels.[22] For example, approximately 80% of people with PSC have perinuclear 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).[3]

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,[23] and HIV-associated cholangiopathy.[24] 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.[25]

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:

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.[26] 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.[27] [28] [29]

Supportive treatment for PSC symptoms is the cornerstone of management. These therapies are aimed at relieving symptoms such as itching with antipruritics (e.g. bile acid sequestrants such as cholestyramine); antibiotics 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).[30]

ERCP and specialized techniques may also be needed to help distinguish between a benign PSC stricture and a bile-duct cancer (cholangiocarcinoma).[31]

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. 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.[32]

Prognosis

Estimated median survival from diagnosis until liver transplant or PSC-related death is 21.3 years.[33] Various models have been developed to help predict survival,[34] 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. An IgA isotype autoantibody to the pancreatic GP2 protein (anti-GP2 IgA antibody) is the first verified prognostic biomarker in PSC.[35] The role of anti-GP2 IgA in PSC was simultaneously investigated and reported by two research groups,[36] [37] and later confirmed by others.[38] [39] Association was demonstrated between anti-GP2 IgA and progressive liver fibrosis, cholangiocarcinoma development and shorter transplantation free survival in PSC patients.

Other markers which may be measured and monitored are a complete blood count, serum liver enzymes, bilirubin levels (usually grossly elevated), kidney function, and electrolytes. Fecal fat measurement is occasionally ordered when symptoms of malabsorption (e.g., gross steatorrhea) are prominent.

Related diseases

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.[2] Primary sclerosing cholangitis is one of the major known risk factors for cholangiocarcinoma,[40] a cancer of the biliary tree, for which the lifetime risk among patients with PSC is 10-15%.[6] This represents a 400-fold greater risk of developing cholangiocarcinoma compared to the general population.[1] Surveillance for cholangiocarcinoma in patients with PSC is encouraged, with some experts recommending annual surveillance with a specialized imaging study and serum markers,[41] although consensus regarding the modality and interval has yet to be established. 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.[1]

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,[42] and approximately 70% of people with PSC have IBD.[19] 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.[43] Close monitoring of PSC patients is vital.

Various forms of gallbladder disease such as gallstones and gallbladder polyps are also common in those with PSC.[1] Approximately 25% of people with PSC have gallstones.[1] Ultrasound surveillance of the gallbladder every year is recommended for people with PSC.[1] Any person with PSC who is found to have a mass in the gallbladder should undergo surgical removal of the gallbladder due to the high risk of cholangiocarcinoma.[1] Osteoporosis (hepatic osteodystrophy) and hypothyroidism are also associated with PSC.

A 2–3:1 male-to-female predilection occurs in primary sclerosing cholangitis.[19] 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. 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 and 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.[44] In the United States, an estimated 29,000 individuals have PSC.[1]

Research

Although no curative treatment is known, several clinical trials are underway that aim to slow progression of this liver disease.[45] 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.[1]

Notable cases

External links

Patient support organizations:

Notes and References

  1. Lazaridis KN, LaRusso NF . Primary Sclerosing Cholangitis . The New England Journal of Medicine . 375 . 12 . 1161–1170 . September 2016 . 27653566 . 5553912 . 10.1056/NEJMra1506330 . Review .
  2. Folseraas T, Boberg KM . Cancer Risk and Surveillance in Primary Sclerosing Cholangitis . Clinics in Liver Disease . 20 . 1 . 79–98 . February 2016 . 26593292 . 10.1016/j.cld.2015.08.014 .
  3. Charatcharoenwitthaya P, Lindor KD . Primary sclerosing cholangitis: diagnosis and management . Current Gastroenterology Reports . 8 . 1 . 75–82 . February 2006 . 16510038 . 10.1007/s11894-006-0067-8 . 37474299 .
  4. Book: Sleisenger MH . Sleisenger and Fordtran's gastrointestinal and liver disease: pathophysiology, diagnosis, management . 2006 . Saunders . Philadelphia . 8th.
  5. Tan . Natassia . Ngu . N. . Lee . T. . Abrahams . T. . Pandya . K. . Freeman . E. . Hannah . N. . Gazelakis . K. . Madden . R. . Lynch . K. . Valaydon . Z. . Sood . S. . Dev . A. . Bell . S. . Thompson . A. . Ding . J. . Nicoll . A. . Liu . K. . Gow . P. . Lubel . J. . Kemp . W. . Roberts . S. . Majeed . A. . Epidemiology and outcomes of primary sclerosing cholangitis: an Australian multicentre retrospective cohort study . Hepatology International . June 2022 . 16 . 5 . 1094–1104 . 10.1007/s12072-022-10356-1 . 35657479 . 9525417 .
  6. Kummen M, Schrumpf E, Boberg KM . Liver abnormalities in bowel diseases . Best Practice & Research. Clinical Gastroenterology . 27 . 4 . 531–542 . August 2013 . 24090940 . 10.1016/j.bpg.2013.06.013 .
  7. Williamson KD, Chapman RW . Primary sclerosing cholangitis: a clinical update . British Medical Bulletin . 114 . 1 . 53–64 . June 2015 . 25981516 . 10.1093/bmb/ldv019 . free .
  8. Tabibian JH, Lindor KD . Ursodeoxycholic acid in primary sclerosing cholangitis: if withdrawal is bad, then administration is good (right?) . Hepatology . 60 . 3 . 785–788 . September 2014 . 24752961 . 10.1002/hep.27180 . 5341568 . free .
  9. Tabibian JH, Yang JD, Baron TH, Kane SV, Enders FB, Gostout CJ . Weekend Admission for Acute Cholangitis Does Not Adversely Impact Clinical or Endoscopic Outcomes . Digestive Diseases and Sciences . 61 . 1 . 53–61 . January 2016 . 26391268 . 10.1007/s10620-015-3853-z . 8266015 . Epub 2015 Sep 21.
  10. Tabibian JH, Abu Dayyeh BK, Gores GJ, Levy MJ . A novel, minimally invasive technique for management of peristomal varices . Hepatology . 63 . 4 . 1398–1400 . April 2016 . 26044445 . 10.1002/hep.27925 . 34965702 . free .
  11. Tabibian JH, Lindor KD . Primary sclerosing cholangitis: a review and update on therapeutic developments . Expert Review of Gastroenterology & Hepatology . 7 . 2 . 103–114 . February 2013 . 23363260 . 10.1586/egh.12.80 . 207210857 .
  12. O'Hara SP, Tabibian JH, Splinter PL, LaRusso NF . The dynamic biliary epithelia: molecules, pathways, and disease . Journal of Hepatology . 58 . 3 . 575–582 . March 2013 . 23085249 . 3831345 . 10.1016/j.jhep.2012.10.011 .
  13. Tabibian JH, O'Hara SP, Lindor KD . Primary sclerosing cholangitis and the microbiota: current knowledge and perspectives on etiopathogenesis and emerging therapies . Scandinavian Journal of Gastroenterology . 49 . 8 . 901–908 . August 2014 . 24990660 . 4210190 . 10.3109/00365521.2014.913189 .
  14. Tabibian JH, Varghese C, O'Hara SP, LaRusso NF . Microbiome-Immune Interactions and Liver Disease . Clinical Liver Disease . 5 . 4 . 83–85 . April 2015 . 29755735 . 5944616 . 10.1002/cld.453 .
  15. Tabibian JH, Varghese C, LaRusso NF, O'Hara SP . The enteric microbiome in hepatobiliary health and disease . Liver International . 36 . 4 . 480–487 . April 2016 . 26561779 . 4825184 . 10.1111/liv.13009 .
  16. Tabibian JH, O'Hara SP, Splinter PL, Trussoni CE, LaRusso NF . Cholangiocyte senescence by way of N-ras activation is a characteristic of primary sclerosing cholangitis . Hepatology . 59 . 6 . 2263–2275 . June 2014 . 24390753 . 4167827 . 10.1002/hep.26993 .
  17. Tabibian JH, Trussoni CE, O'Hara SP, Splinter PL, Heimbach JK, LaRusso NF . Characterization of cultured cholangiocytes isolated from livers of patients with primary sclerosing cholangitis . Laboratory Investigation; A Journal of Technical Methods and Pathology . 94 . 10 . 1126–1133 . October 2014 . 25046437 . 4184949 . 10.1038/labinvest.2014.94 .
  18. Hirschfield GM, Karlsen TH, Lindor KD, Adams DH . Primary sclerosing cholangitis . Lancet . 382 . 9904 . 1587–1599 . November 2013 . 23810223 . 10.1016/s0140-6736(13)60096-3 . 13423425 .
  19. Book: Robbins SL, Kumar V, Cotran RS . Robbins basic pathology . Saunders . Philadelphia . 2003 . 620–1 . 7th . Chapter 16 . 978-0-7216-9274-6 . registration . https://archive.org/details/robbinsbasicpath0000unse/page/620 .
  20. Iravani . Shahrokh . Dooghaie-Moghadam . Arash . Razavi-Khorasani . Niloofar . Moazzami . Bobak . Dowlati Beirami . Amirreza . Mansour-Ghanaei . Alireza . Majidzadeh-A . Keivan . Mehrvar . Azim . Khoshdel . Alireza . Nasiri Toosi . Mohssen . Sadeghi . Amir . An update on treatment options for primary sclerosing cholangitis . Gastroenterology and Hepatology from Bed to Bench . 2020 . 13 . 2 . 115–124 . 32308932 . 7149806 .
  21. 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 . 6 . Micro-computed tomography and nuclear magnetic resonance imaging for noninvasive, live-mouse cholangiography . Laboratory Investigation; A Journal of Technical Methods and Pathology . 93 . 6 . 733–743 . June 2013 . 23588707 . 3875307 . 10.1038/labinvest.2013.52 .
  22. Tabibian JH, Enders F, Imam MH, Kolar G, Lindor KD, Talwalkar JA . Association between serum IgE level and adverse clinical endpoints in primary sclerosing cholangitis . Annals of Hepatology . 13 . 3 . 384–389 . 2014 . 24756015 . 4215553 . 10.1016/S1665-2681(19)30869-5 .
  23. Tabibian JH, Asham EH, Goldstein L, Han SH, Saab S, Tong MJ, Busuttil RW, Durazo FA . 6 . Endoscopic treatment with multiple stents for post-liver-transplantation nonanastomotic biliary strictures . Gastrointestinal Endoscopy . 69 . 7 . 1236–1243 . June 2009 . 19249040 . 10.1016/j.gie.2008.09.057 .
  24. Lazaridis KN, LaRusso NF . The Cholangiopathies . Mayo Clinic Proceedings . 90 . 6 . 791–800 . June 2015 . 25957621 . 4533104 . 10.1016/j.mayocp.2015.03.017 .
  25. Trivedi PJ, Corpechot C, Pares A, Hirschfield GM . Risk stratification in autoimmune cholestatic liver diseases: Opportunities for clinicians and trialists . Hepatology . 63 . 2 . 644–659 . February 2016 . 26290473 . 4864755 . 10.1002/hep.28128 .
  26. 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 . 6 . High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis . Hepatology . 50 . 3 . 808–814 . September 2009 . 19585548 . 2758780 . 10.1002/hep.23082 .
  27. Chapman R, Fevery J, Kalloo A, Nagorney DM, Boberg KM, Shneider B, Gores GJ . Diagnosis and management of primary sclerosing cholangitis . Hepatology . 51 . 2 . 660–678 . February 2010 . 20101749 . 10.1002/hep.23294 . 35432726 .
  28. Lindor KD, Kowdley KV, Harrison ME . ACG Clinical Guideline: Primary Sclerosing Cholangitis . The American Journal of Gastroenterology . 110 . 5 . 646–59; quiz 660 . May 2015 . 25869391 . 10.1038/ajg.2015.112 . 41646016 . free .
  29. EASL Clinical Practice Guidelines: management of cholestatic liver diseases . Journal of Hepatology . 51 . 2 . 237–267 . August 2009 . 19501929 . 10.1016/j.jhep.2009.04.009 . free . European Association for the Study of the Liver .
  30. EASL Clinical Practice Guidelines: management of cholestatic liver diseases . Journal of Hepatology . 51 . 2 . 237–267 . August 2009 . 19501929 . 10.1016/j.jhep.2009.04.009 . free . European Association for the Study of the Liver .
  31. Tabibian JH, Visrodia KH, Levy MJ, Gostout CJ . Advanced endoscopic imaging of indeterminate biliary strictures . World Journal of Gastrointestinal Endoscopy . 7 . 18 . 1268–1278 . December 2015 . 26675379 . 4673389 . 10.4253/wjge.v7.i18.1268 . free .
  32. Visseren T, Fuhler GM, Erler NS, Nossent YR, Metselaar HJ, IJzermans JN, Darwish Murad S, Peppelenbosch MP . 6 . Recurrence of primary sclerosing cholangitis after liver transplantation is associated with specific changes in the gut microbiome pretransplant - a pilot study . Transplant International . 33 . 11 . 1424–1436 . November 2020 . 33617049 . 7689804 . 10.1111/tri.13692 .
  33. 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 . 6 . Population-based epidemiology, malignancy risk, and outcome of primary sclerosing cholangitis . Hepatology . 58 . 6 . 2045–2055 . December 2013 . 23775876 . 10.1002/hep.26565 . free . 205889681 . 1887/117347 .
  34. Tornai D, Ven PL, Lakatos PL, Papp M . Serological biomarkers for management of primary sclerosing cholangitis . World Journal of Gastroenterology . 28 . 21 . 2291–2301 . June 2022 . 35800183 . 9185217 . 10.3748/wjg.v28.i21.2291 . free .
  35. Tornai D, Papp M . Editorial: serologic antibodies in primary sclerosing cholangitis - a tell-tale sign of compromised gut-liver immunity? . Alimentary Pharmacology & Therapeutics . 53 . 2 . 350–351 . January 2021 . 33368511 . 10.1111/apt.16201 . 229379767 . free .
  36. 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 . 6 . Anti-GP2 IgA autoantibodies are associated with poor survival and cholangiocarcinoma in primary sclerosing cholangitis . Gut . 66 . 1 . 137–144 . January 2017 . 27406039 . 10.1136/gutjnl-2016-311739 . 3479797 . 10852/62341 . free .
  37. 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 . 6 . Loss of tolerance to gut immunity protein, glycoprotein 2 (GP2) is associated with progressive disease course in primary sclerosing cholangitis . Scientific Reports . 8 . 1 . 399 . January 2018 . 29321484 . 5762861 . 10.1038/s41598-017-18622-1 . 2018NatSR...8..399T .
  38. 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 . 6 . Mucosal Autoimmunity to Cell-Bound GP2 Isoforms Is a Sensitive Marker in PSC and Associated With the Clinical Phenotype . English . Frontiers in Immunology . 9 . 1959 . 2018 . 30233574 . 6127632 . 10.3389/fimmu.2018.01959 . free .
  39. 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 . 6 . 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 . Alimentary Pharmacology & Therapeutics . 53 . 2 . 302–313 . January 2021 . 33159471 . 7821312 . 10.1111/apt.16153 .
  40. Tsaitas C, Semertzidou A, Sinakos E . Update on inflammatory bowel disease in patients with primary sclerosing cholangitis . World Journal of Hepatology . 6 . 4 . 178–187 . April 2014 . 24799986 . 4009473 . 10.4254/wjh.v6.i4.178 . free .
  41. Tabibian JH, Lindor KD. Challenges of Cholangiocarcinoma Detection in Patients with Primary Sclerosing Cholangitis. J Analytical Oncology. 2012;1(1):50-55.
  42. Olsson R, Danielsson A, Järnerot G, Lindström E, Lööf L, Rolny P, Rydén BO, Tysk C, Wallerstedt S . 6 . Prevalence of primary sclerosing cholangitis in patients with ulcerative colitis . Gastroenterology . 100 . 5 Pt 1 . 1319–1323 . May 1991 . 2013375 . 10.1016/0016-5085(91)90784-I .
  43. 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 . 6 . Population-based epidemiology, malignancy risk, and outcome of primary sclerosing cholangitis . Hepatology . 58 . 6 . 2045–2055 . December 2013 . 23775876 . 10.1002/hep.26565 . free . 205889681 . 1887/117347 .
  44. Feld JJ, Heathcote EJ . Epidemiology of autoimmune liver disease . Journal of Gastroenterology and Hepatology. 18 . 10 . 1118–28 . October 2003 . 12974897 . 10.1046/j.1440-1746.2003.03165.x . 24075827 .
  45. Trivedi PJ, Hirschfield GM . Treatment of autoimmune liver disease: current and future therapeutic options . Therapeutic Advances in Chronic Disease . 4 . 3 . 119–141 . May 2013 . 23634279 . 3629750 . 10.1177/2040622313478646 .
  46. Chris Klug Olympic Results . https://web.archive.org/web/20200417224750/https://www.sports-reference.com/olympics/athletes/kl/chris-klug-1.html . dead . April 17, 2020 . April 8, 2020.
  47. News: Genzlinger . Neil . October 22, 2020 . James Redford, Documentarian and Environmentalist, Dies at 58 . en-US . The New York Times . September 15, 2022 . 0362-4331.

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Primary sclerosing cholangitis".

Except where otherwise indicated, Everything.Explained.Today is © Copyright 2009-2024, A B Cryer, All Rights Reserved. Cookie policy.