Primary sclerosing cholangitis
|Primary sclerosing cholangitis|
Cholangiogram of primary sclerosing cholangitis.
|Classification and external resources|
|Patient UK||Primary sclerosing cholangitis|
Primary sclerosing cholangitis (PSC) is a disease of the bile ducts that causes inflammation and obliterative fibrosis of bile ducts inside and/or outside of the liver. This pathological process impedes the flow of bile to the intestines and can ultimately lead to cirrhosis of the liver, liver failure, and other complications, including but not limited to bile duct and liver cancer. The underlying cause of the inflammation remains unknown, but elements of autoimmunity and microbial dysbiosis have been described and are suggested by the fact that approximately 75% of those with PSC also have inflammatory bowel disease (IBD), most often ulcerative colitis. The most definitive treatment for PSC is liver transplantation.
Signs and symptoms
|This section does not cite any references (sources). (October 2014)|
Many patients with PSC are asymptomatic, but a substantial proportion will have debilitating signs and symptoms of the disease. These may include:
- Intense pruritus (itching)
- Severe fatigue (a non-specific symptom often present in liver disease)
- Episodes of acute cholangitis (infection within the bile ducts)
- Dark urine due to excess conjugated bilirubin, which is water-soluble, being excreted by the kidneys (i.e. choluria)
- Malabsorption (especially of fat) and steatorrhea (fatty stool) due to biliary obstruction, leading to decreased levels of the fat-soluble vitamins, A, D, E and K.
- Hepatomegaly (enlarged liver) and right upper quadrant abdominal pain
- Portal hypertension, including esophageal and parastomal varices
- Hepatic encephalopathy (mental status alteration/disturbance caused by liver dysfunction and shunting of blood away from the scarred liver)
Primary sclerosing cholangitis is idiopathic (having no known cause). While thought to be an 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.
Recent data have provided novel insights suggesting: 1) an important association between the intestinal microbiome and PSC  and 2) a process referred to as cellular senescence and the senescence-associated secretory phenotype (SASP) in the pathogenesis of PSC. In addition, there are longstanding, well-recognized associations between PSC and Human leukocyte antigen [HLA] alleles (e.g. A1, B8, and DR3).
PSC occurs because of inflammation in the bile ducts (cholangitis), which results in hardening (sclerosis) and narrowing of the bile ducts both inside and outside of the liver. The resulting scarring of the bile ducts blocks the flow of bile, causing cholestasis. Bile stasis and back-pressure induces proliferation of epithelial cells and focal destruction of the liver parenchyma, forming bile lakes. Chronic biliary obstruction causes portal tract fibrosis and ultimately biliary cirrhosis and liver failure.
Bile assists in the intestinal breakdown and absorption of fat; the relative deficiency of bile in the intestinal tract leads to fat malabsorption and deficiencies of fat-soluble vitamins (A, D, E, K).
PSC is generally diagnosed on the basis of having at least two of three clinical: serum alkaline phosphatase (ALP) > 1.5x the upper limit of normal, cholangiography demonstrating biliary strictures or irregularity consistent with PSC, and liver histology (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 non-invasive 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.
Most people with PSC have evidence of autoantibodies and abnormal immunoglobulin levels. For example, approximately 80% of people with PSC have perinuclear anti-neutrophil cytoplasmic antibodies; 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 auotimmune hepatitis (i.e. PSC-AIH overlap syndrome).
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.
The differential diagnosis can include primary biliary cirrhosis, drug induced cholestasis, cholangiocarcinoma, IgG4-associated disease, post-liver transplantation non-anastomotic biliary strictures, and HIV-associated cholangiopathy.
There is no FDA-approved pharmacologic treatment 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 proven effective in other cholestatic liver diseases. However, UDCA has yet to be shown to clear lead to improved liver histology and adverse event-free survival.
Treatment for patients with PSC also includes therapies to relieve itching (antipruritics) (e.g. the bile acid sequestrant (cholestyramine), antibiotics to treat episodes of acute cholangitis, and vitamin supplements, as people with PSC are often deficient in fat-soluble vitamins (vitamin A, vitamin D, vitamin E, and vitamin K).
Liver transplantation is the only proven long-term treatment of PSC. Indications for transplantation include recurrent bacterial cholangitis, decompensated cirrhosis, hepatocellular carcinoma, hilar cholangiocarcinoma, and complications of portal hypertension. Unfortunately, not all patients are candidates for liver transplantation, and some will experience disease recurrence afterward.
Despite there being no curative treatment at present, it is important to note that there are several clinical trials underway that aim to slow progression of this liver disease.
PSC carries an estimated median liver transplant-free survival time (from diagnosis) of approximately 15 years. Various models have been developed to help predict survival, but their use is generally best suited for research and not clinical purposes. Recently, normalization of serum alkaline phosphatase has been shown to be an accurate and non-invasive predictor of favorable long-term outcomes.
Primary sclerosing cholangitis is associated with cholangiocarcinoma, a cancer of the biliary tree, for which the lifetime risk among patients with PSC is 10-15%. This represents a 160-fold greater risk of developing cholangiocarcinoma compared to the general population. Surveillance for cholangiocarcinoma in patients with PSC is encouraged, with some experts recommending annual surveillance, but there is no official consensus on the modality and interval of choice. Colon cancer is also associated with PSC.
PSC has a significant association with ulcerative colitis, an inflammatory bowel disease primarily affecting the large intestine. As many as 5% of patients with inflammatory bowel disease (IBD), especially ulcerative colitis (UC), may be co-diagnosed with PSC and approximately 70% of people with primary sclerosing cholangitis have ulcerative colitis. Those with PSC and IBD are at approximately 30-fold increased risk of developing colorectal cancer; therefore, regular surveillance is recommended. The presence of colitis is associated with a greater risk of liver disease progression and bile duct cancer (cholangiocarcinoma). Close monitoring of PSC patients is vital.
Other diseases with which PSC is associated include osteoporosis (hepatic osteodystrophy) and hypothyroidism.
There is a 2-3:1 male-to-female predilection in primary sclerosing cholangitis. 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 inflammatory bowel disease (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. There is relatively little data on the prevalence and incidence of primary sclerosing cholangitis, 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, it is likely that the risk is higher in populations where UC is more common. In the United States, an estimated 25,000 individuals have PSC.
- Chris Klug - professional snowboarder with PSC who had liver transplant
- 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 - died of complications of PSC.
- Charatcharoenwitthaya P, Lindor KD (Feb 2006). "Primary sclerosing cholangitis: diagnosis and management". Current Gastroenterology Reports 8 (1): 75–82. doi:10.1007/s11894-006-0067-8. PMID 16510038.
- Sleisenger, MH (2006). Sleisenger and Fordtran's gastrointestinal and liver disease: pathophysiology, diagnosis, management (8th ed.). Philadelphia: Saunders.
- Tabibian JH, Lindor KD. Ursodeoxycholic acid in primary sclerosing cholangitis: If withdrawal is bad, then administration is good (right?). Hepatology. 2014 Sep;60(3):785-8.
- Tabibian JH, Abu Dayyeh BK, Gores GJ, Levy MJ. A novel, minimally-invasive technique for management of peristomal varices. Hepatology. 2015 Jun 4. doi: 10.1002/hep.27925.
- Tabiban JH, Lindor KD. Primary sclerosing cholangitis: a review and update on therapeutic developments. Expert Rev. Gastroenterol Hepatol. 2013 Feb;7(2):103-14.
- O'Hara SP, Tabibian JH, Splinter PL, LaRusso NF. The dynamic biliary epithelia: Molecules, pathways, and disease. J Hepatol. 2013 Mar;58(3):575-82.
- Tabibian JH, O'Hara SP, Trussoni CE, Tietz PS, Splinter PL, Mounajjed T, Hagey LR, Larusso NF. Absence of the intestinal microbiota exacerbates hepatobiliary disease in a murine model of primary sclerosing cholangitis. Hepatology. 2015 Jun 4. doi: 10.1002/hep.27927.
- Tabibian JH, O'Hara SP, Lindor KD. Primary sclerosing cholangitis and the microbiota: current knowledge and perspectives on etiopathogenesis and emerging therapies. Scand J Gastroenterol. 2014 Aug;49(8):901-8.
- Tabibian JH, Varghese C, O'Hara SP, LaRusso NF. Microbiome-immune interactions and liver disease. Clin Liver Dis. 2014. Apr 2015;5(4):83-85.
- Tabibian JH, O'Hara SP, Splinter PL, Trussoni CE, Larusso NF. Cholangiocyte senescence via N-Ras activation is a characteristic of primary sclerosing cholangitis. Hepatology. 2014 Jun;59(6):2263-75.
- 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. Lab Invest. 2014 Oct;94(10):1126-33.
- Hirschfield, Gideon M; Karlsen, Tom H; Lindor, Keith D; Adams, David H. "Primary sclerosing cholangitis". The Lancet 382 (9904): 1587–1599. doi:10.1016/s0140-6736(13)60096-3.
- Robbins SL, Kumar V, Cotran RS (2003). "Chapter 16". Robbins basic pathology (7th ed.). Philadelphia: Saunders. pp. 620–1. ISBN 0-7216-9274-5.
- 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. Micro-computed tomography and nuclear magnetic resonance imaging for noninvasive, live-mouse cholangiography. Lab Invest. 2013 Jun;93(6):733-43.
- 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. Ann Hepatol. 2014 May-Jun;13(3):384-9.
- Tabibian JH, Asham EH, Goldstein L, Han S, Saab S, Tong MJ, Busuttil R, Durazo FA. Endoscopic Treatment with Multiple Stents for Post-Liver Transplantation Nonanastomotic Biliary Strictures. Gastrointest Endosc. 2009 June;69(7):1236-1243.
- Lazaridis KN, LaRusso NF. The Cholangiopathies. Mayo Clin Proc. 2015 Jun;90(6):791-800. doi: 10.1016/j.mayocp.2015.03.017.
- 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 (Sep 2009). "High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis". Hepatology 50 (3): 671–3. doi:10.1002/hep.23082. PMC 2758780. PMID 19585548.
- Trivedi, Palak J.; Hirschfield, Gideon M. (2013-05-01). "Treatment of autoimmune liver disease: current and future therapeutic options". Therapeutic Advances in Chronic Disease 4 (3): 119–141. doi:10.1177/2040622313478646. ISSN 2040-6223. PMC 3629750. PMID 23634279.
- Wiesner RH, Grambsch PM, Dickson ER, Ludwig J, MacCarty RL, Hunter EB, Fleming TR, et al. Primary sclerosing cholangitis: natural history, prognostic factors and survival analysis. Hepatology 1989; 10: 430-6.
- Tischendorf, J.; Hecker, H.; Krüger, M.; Manns, M.; Meier, P. (2007). "Characterization, outcome, and prognosis in 273 patients with primary sclerosing cholangitis: A single center study". The American journal of gastroenterology 102 (1): 107–114. doi:10.1111/j.1572-0241.2006.00872.x. PMID 17037993. Giving survival time: 306 months
- Al Mamari S, Djordjevic J, Halliday JS, Chapman RW. Improvement of serum alkaline phosphatase to <1.5 upper limit of normal predicts better outcome and reduced risk of cholangiocarcinoma in primary sclerosing cholangitis. J Hepatol. 2013 Feb;58(2):329-34.
- Tsaitas C, Semertzidou A, Sinakos E (April 2014). "Update on inflammatory bowel disease in patients with primary sclerosing cholangitis". World J Hepatol 6 (4): 178–87. doi:10.4254/wjh.v6.i4.178. PMC 4009473. PMID 24799986.
- Kummen M, Schrumpf E, Boberg KM (August 2013). "Liver abnormalities in bowel diseases". Best Pract Res Clin Gastroenterol 27 (4): 531–42. doi:10.1016/j.bpg.2013.06.013. PMID 24090940.
- Tabibian JH, Lindor KD. Challenges of Cholangiocarcinoma Detection in Patients with Primary Sclerosing Cholangitis. J Analytical Oncology. 2012;1(1):50-55.
- Olsson R, Danielsson A, Järnerot G, et al. (1991). "Prevalence of primary sclerosing cholangitis in patients with ulcerative colitis". Gastroenterology 100 (5 Pt 1): 1319–23. PMID 2013375.
- Tabibian JH, Moradkhani A, Topazian MD. Colorectal cancer surveillance in primary sclerosing cholangitis and inflammatory bowel disease. Ann Hepatol. 2015;14(4):564-566.
- Boonstra, Kirsten; Weersma, Rinse K.; van Erpecum, Karel J.; Rauws, Erik A.; Spanier, B.W. Marcel; Poen, Alexander C.; van Nieuwkerk, Karin M.; Drenth, Joost P.; Witteman, Ben J. (2013-12-01). "Population-based epidemiology, malignancy risk, and outcome of primary sclerosing cholangitis". Hepatology 58 (6): 2045–2055. doi:10.1002/hep.26565. ISSN 1527-3350.
- Feld JJ, Heathcote EJ (October 2003). "Epidemiology of autoimmune liver disease". J. Gastroenterol. Hepatol. 18 (10): 1118–28. doi:10.1046/j.1440-1746.2003.03165.x. PMID 12974897.
- PSC Partners: Patient organization with additional information
- PSC Support: Charity with additional information, discussion forum and support tools for those affected by PSC
- Additional Literature about PSC
- Information from The Morgan Foundation for the Study of PSC
- SAVE JON: Patient-Led Research Organization with additional information