Primary Sclerosing Cholangitis

Disease Overview

Summary

Primary sclerosing cholangitis (PSC) is a rare progressive disorder characterized by inflammation, thickening, and abnormal formation of fibrous tissue (fibrosis) within the passages that carry bile from the liver (bile ducts). Both the bile ducts within the liver (intrahepatic) and outside the liver (extrahepatic) are affected. This often results in the obstruction or interruption of bile flow from the liver (cholestasis). Symptoms associated with PSC include fatigue and itching (pruritus), followed by yellowing of the skin, mucous membranes, and whites of the eyes (jaundice). Affected individuals may also have dark urine, light-colored stools, abdominal pain, and/or nausea. In some cases, the liver may also become abnormally enlarged (hepatomegaly). Scarring of the liver (cirrhosis) eventually develops and many individuals will ultimately require a liver transplant. According to the medical literature, approximately 60 to 80 percent of individuals with PSC also have inflammatory bowel disease (IBD), most often ulcerative colitis. The relationship between these disorders and the exact cause of PSC are not fully understood.

Introduction

PSC is a complex disorder and the cause (etiology) and underlying manner the disease develops (pathogenesis) are not fully understood. PSC was first described in the medical literature in 1867. Some researchers believe that PSC represents a group of disorders or a disorder with several distinct subtypes (e.g. PSC with IBD or without IBD). It is likely that PSC may have different underlying causes in different individuals. PSC is a rapidly evolving disease concept and information about PSC is constantly changing and emerging as researchers work to better understand this disorder.

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Synonyms

chronic obliterative cholangitis
fibrosing cholangitis
PSC
stenosing cholangitis

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Signs & Symptoms

Primary sclerosing cholangitis primarily involves the bile ducts. The formation of bile is one of the functions of the liver. Bile is a fluid that contains water, certain minerals that carry an electric charge (electrolytes), and other materials including bile salts, phospholipids, cholesterol, and an orange-yellow pigment (bilirubin) that is a byproduct of the natural breakdown of the hemoglobin of red blood cells. Bile flow accomplishes two important tasks within the body, it aids in digestion and absorption of dietary fats, vitamins, and other nutrients and helps eliminate excess cholesterol, bilirubin, waste, and toxins from the body. Therefore, a problem with normal bile flow often results in malabsorption of vital nutrients and the accumulation of toxic materials in the body.

PSC is characterized by episodes of interrupted or obstructed bile flow from the liver (cholestasis), resulting from inflammation, thickening, and/or abnormal formation of fibrous tissue (fibrosis) within the bile ducts. The specific symptoms, progression and severity of PSC can vary greatly from one individual to another. Initially, many affected individuals may not have any noticeable symptoms (asymptomatic) or only mild symptoms. Some individuals will only display mild symptoms for many years.

Common initial symptoms of PSC are fatigue, abdominal discomfort, and itching (pruritus). Itching can potentially be severe and even disabling. When the flow of bile from the liver is blocked, the bile may be absorbed into the bloodstream, resulting in yellowing of the skin, mucous membranes, and whites of the eyes (obstructive jaundice). Additional symptoms include a general feeling of ill health (malaise); abdominal pain, especially the upper right portion of the abdomen; nausea; dark urine; light-colored stools; unintended weight loss, and/or abnormal enlargement of the liver (hepatomegaly) and/or spleen (splenomegaly).

Some individuals may develop deficiency of certain vitamins, including vitamins A, D, E and K. These are fat-soluble vitamins. Bile normally helps fat to be broken down and these vitamins to be absorbed by the body.

Some individuals with chronic liver disease develop metabolic bone disease, which may be referred to as hepatic osteodystrophy. Affected individuals can eventually develop osteoporosis, a condition in which the bones become brittle and fragile. Individuals with osteoporosis are prone to repeated fractures. In severe cases, fractures may occur from even mild stresses such as coughing. Bones in the wrist, hips and spine are often affected.

In some cases, affected individuals may experience episodes of fever, chills, and night sweats resulting from infection of the bile ducts (bacterial cholangitis). In addition, PSC may progress to cause scarring and damage to the liver (cirrhosis) and increased blood pressure in the veins carrying blood from the gastrointestinal (GI) tract back to the heart through the liver (portal hypertension). Portal hypertension can result in serious complications including fluid accumulation in the stomach (ascites), bleeding from blood vessels within the esophagus, stomach and rectum, and hepatic encephalopathy, a brain disorder that ranges from a subtle condition with no outward signs or symptoms to a severe condition that can cause severe complications, such as confusion and coma.

As individuals with PSC age, they often eventually develop life-threatening complications such as liver (hepatic) failure. Individuals with PSC are at a greater risk than the general population of developing a form of cancer that affects the bile ducts (cholangiocarcinoma). Approximately 8-15% of affected individuals eventually develop cholangiocarcinoma. Affected individuals are also at risk of developing gallbladder cancer.

In approximately 60 to 80 percent of cases, individuals with PSC also have ulcerative colitis, an inflammatory bowel disease (IBD) of unknown cause that is characterized by chronic inflammation and ulceration of the lining of the major portion of the large intestine (colon). PSC is also associated with Crohn’s disease, another form of IBD. These conditions can be mild or even “silent” causing no apparent symptoms (asymptomatic). Individuals with PSC and IBD (and particularly ulcerative colitis) or Crohn’s disease are at a greater risk of developing colon cancer compared to individuals with only one of these conditions or to the general population.

In addition to IBD, numerous autoimmune or immune-mediated disorders have been reported to occur in association with PSC. Such disorders include sarcoidosis, thyroid disease, Peyronie’s disease, retroperitoneal fibrosis, psoriasis, rheumatoid arthritis, Celiac disease, Sjogren’s syndrome, chronic pancreatitis, lupus, diabetes mellitus, Wegener’s granulomatosis, pyoderma gangrenosum, Grave’s disease, Langerhans cell histiocytosis and certain immunodeficiency disorders. The exact relationship between these disorders and PSC is unknown. It is possible that PSC develops as a secondary condition to some of these disorders. (For more information on these disorders, choose exact disorder name as your search term in the Rare Disease Database.)

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Causes

Primary sclerosing cholangitis is a multifactorial disorder, which means that several different factors such as genetic, environmental and immunologic ones occurring in combination are necessary for the development of the disorder. The specific factors involved in the development of PSC have not been conclusively identified.

Researchers believe that the disorder results due to a nonspecific triggering event that causes an abnormal immune system response, specifically an abnormal allergic or inflammatory reaction (immune-mediated disorder) or because of the immune system mistakenly attacking healthy tissue (autoimmunity) in people who are genetically susceptible to such a reaction. This abnormal response ultimately causes progressive damage to the bile ducts. The triggering event is most likely an infectious or toxic agent.

Genetics plays an important role in the development of PSC and the incidence of the disorder among first-degree relatives, especially siblings, is higher than otherwise would be expected. Researchers have discovered sixteen different genetic regions that are associated with the disorder. Certain genes in these genetic areas may predispose affected individuals to developing PSC. A genetic predisposition means that a person carries a gene or gene(s) for a disease, but it may not be expressed unless something in the environment triggers the disease. Some, but not all, of these gene regions involve a genetically determined human leukocyte antigen or HLA. HLAs are proteins that play an important role in the body’s immune system. Several of the genetic areas associated with PSC are also associated with inflammatory bowel disease (IBD).

There are several theories as to the underlying cause and pathogenesis of PSC including the leaky gut syndrome for individuals with PSC and IBD or the toxic bile theory, which has been established in mouse models of the disease, but has not been established in studies on people with PSC. No theory explains all cases of PSC, which further suggests that PSC has distinct subtypes or represents a group of similar disorders. More research is necessary to understand the underlying cause and various mechanisms that ultimately result in the development of PSC, and to create a classification system defining specific subtypes of the disorder.

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Affected populations

Primary sclerosing cholangitis is a rare disorder that affects males twice as often as females. Although it may affect individuals of any age, the disorder most often occurs in middle-aged adults. The exact incidence and prevalence of the disorder is unknown. One estimate places the incidence at approximately 1 person per each 100,000 in the general population in the United States or Europe. Some studies suggest that the incidence of PSC is increasing. PSC is one of the leading reasons people require a liver transplant in the United States. In Nordic countries, PSC is the number one cause for a liver transplant.

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Disorders with Similar Symptoms

Symptoms of the following disorders can be similar to primary sclerosing cholangitis. Comparisons may be useful for a differential diagnosis:

Primary biliary cholangitis (PBC) is a rare liver disorder that primarily affects females and typically becomes apparent during middle age. It is characterized by yellow discoloration of the skin (jaundice) associated with obstruction and inflammation of the bile ducts (cholestasis). Additional symptoms include fatigue, pain in the upper right portion of the abdomen, diarrhea, itching (pruritus), dry eyes, dry mouth, swelling of the feet and ankles, and the formation of small fatty deposits (xanthomas) on the skin around the eyes or in the skin creases of the palms, soles, elbows or knees. In some cases, serious complications can develop including cirrhosis, portal hypertension, osteoporosis, and vitamin deficiencies. Affected individuals are at risk of developing liver cancer. Although the exact cause of PBC is unknown, various factors including immunologic, genetic, and environmental ones are believed to play a role in the development of the disorder. (For more information on this disorder, choose “primary biliary cholangitis” as your search term in the Rare Disease Database.)

Autoimmune hepatitis is a liver disease that occurs when the body’s immune system mistakenly attacks liver tissue. The reason why the body attacks healthy tissue is unknown. Symptoms can include those commonly associated with liver disease including fatigue, nausea, vomiting, itching, abdominal pain, jaundice, loss of appetite, dark urine, skin rashes, and an abnormally enlarged liver. Autoimmune hepatitis may be mild or severe and can develop slowly over time or rapidly. Untreated, the disorder can eventually progress to cirrhosis and liver failure. In many cases, if treated early enough, immunosuppressive drugs can manage the disorder. Although the exact cause of autoimmune hepatitis is unknown, multiple factors including environmental, immunologic and genetic ones are suspected to play a role.

When features of autoimmune hepatitis occur with either PSC or PBC, this is defined as overlap. Some researchers believe that, despite overlapping symptoms, a primary diagnosis of one of the disorders should be made in almost every case.

Small duct primary sclerosing cholangitis is a variant of PSC in which affected individuals have abnormal blood tests and a liver biopsy that reveals features that are consistent with a diagnosis of PSC. However, these individuals have normal findings on more sensitive tests such as magnetic resonance cholangiopancreatography. This form of PSC is associated with fewer, milder symptoms than individuals with classic PSC. Individuals with small duct PSC often have IBD as well. Small duct PSC accounts for approximately 6%-16% of all cases of PSC. Some individuals will eventually develop classic PSC and end stage liver disease.

Secondary sclerosing cholangitis (SSC) is a general term for a group of disorders characterized by sclerosing cholangitis, but that are caused by a known pathological process. The clinical features of SSC are extremely similar to those seen in PSC. Conditions that can cause SSC include those that result in obstruction of the bile ducts such as a tumor, gallstones or various congenital abnormalities. SSC can also develop as a consequence of surgery or injury due to lack of blood flow (ischemia) to the liver and bile ducts as may be associated with systemic vasculitis, radiation injury, or critically-ill patients. Infections can also cause SSC including cytomegalovirus, parasitic infections (e.g. liver flukes), or bacterial infections such as recurrent pyogenic cholangitis.

IgG4-associated sclerosing cholangitis is a disorder characterized signs and symptoms that are extremely similar to classic PSC. However, these individuals have elevated levels of immunoglobulin G4 in blood serum. An immunoglobulin is a specialized protein of the immune system that functions as an antibody to protect the body from foreign substances such as bacteria. Unlike individuals with classic PSC, individuals with IgG4-associated sclerosing cholangitis respond to treatment with corticosteroids. In addition, IgG4-associated sclerosing cholangitis is rarely associated with IBD and is commonly associated with inflammation of the pancreas (pancreatitis). Some individuals with classic PSC also have elevated levels of immunoglobulin G4. Consequently, some physicians consider this disorder to be a variant of PSC, while others consider it a different and distinct disorder. Although IgG4-associated sclerosing cholangitis responds to treatment with corticosteroids, relapse is common.

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Diagnosis

A diagnosis of primary sclerosing cholangitis is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic findings, and a variety of specialized tests.

Clinical Testing and Work-Up
Blood tests called liver function tests may be performed to measure the activity and levels of certain chemicals produced by the liver. Certain liver enzymes may be elevated including alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and gamma-glutamyltranspeptidase. Elevation of these enzymes is indicative of liver disease, but is nonspecific to PSC.

Additional blood tests to detect other substances (e.g. autoantibodies) may also be performed to aid in diagnosing PSC or to rule out other conditions.
Specialized imaging tests may also be used to help obtain a diagnosis of PSC. A magnetic resonance cholangiopancreatography or MRCP is a noninvasive test used to evaluate both the intrahepatic and extrahepatic bile ducts. This exam employs MRI, an imaging technique that uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues.

In the past an exam called endoscopic retrograde cholangiopancreatography or ERCP was used to help diagnose PSC. This exam involves inserting a thin flexible tube (endoscope) into the mouth and down through the esophagus and stomach eventually reaching the bile ducts. A contrast dye is injected into the bile ducts and an x-ray is taken to evaluate the health and function of the bile ducts.

A liver biopsy, which involves the surgical removal and microscopic examination, of a small sample of liver tissue, may be performed to evaluate the liver and determine how far PSC has progressed.

Some physicians recommended a colonoscopy to evaluate the health and function of the bowels because of the high association of PSC with inflammatory bowel disease and colon cancer. Cross sectional imaging of the liver is recommended by some providers at 6 – 12 month intervals because of the high risk of hepatobiliary cancers.

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Standard Therapies

Treatment

There is no specific, universal treatment for individuals with PSC. Treatment is directed toward the specific symptoms that are apparent in each individual and at slowing the progression of the disorder.

Endoscopic surgery to remove blockages and enlarge narrowed bile ducts may be of benefit to help prevent liver deterioration in certain cases. Lost vitamins should be replaced when required to prevent complications related to these deficiencies. Antibiotics may be useful in controlling inflammation or infection. Individuals with PSC are encouraged to follow a normal healthy diet and to avoid alcohol or only have alcohol in small amounts.

The drug cholestyramine may be effective in controlling itching. Cholestyramine may be given with or without antihistamines. If cholestyramine is ineffective, other medications may be recommended. Bisphosphonates, which are drugs that prevent the loss of bone mass, may be used to treat osteoporosis.

Ultimately, individuals with PSC may require a liver transplant. Liver transplantation has proven effective at treating individuals with PSC. Generally, this procedure is reserved for individuals with advanced symptoms of PSC (e.g. intractable pruritus, recurrent bacterial cholangitis, end-stage liver disease). In some cases, the disorder has recurred after liver transplantation.

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Clinical Trials and Studies

The drug ursodiol also known as ursodeoxycholic acid or UDCA has been studied as a treatment for individuals with PSC and has been recommended by some physicians as a treatment option. Some affected individuals have demonstrated a temporary improvement in symptoms and improved liver function after the administration of ursodiol. However, the drug does not usually slow the overall progression of the disorder and its long-term benefit is unknown. Additionally, some studies have shown that high doses of this drug can increase the risk of adverse effects. The use of ursodiol in PSC is controversial and opinions on whether to use the drug vary. Further research is necessary to determine the long-term safety and effectiveness of this treatment for individuals with PSC.

Additional treatments being tested include drainage of blocked bile through tubes inserted in ducts and enlarging abnormally narrowed bile ducts (at least temporarily) by inserting a tiny balloon inside the duct and inflating it (endoscopic balloon dilation). Effectiveness and side effects of these procedures and devices have not been fully documented and more extensive research is being pursued before their therapeutic value for primary sclerosing cholangitis can be evaluated.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/

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References

JOURNAL ARTICLES
Ali AH, Tabibian J, Nasser-Ghodsi N, Lennon RJ, Hilscher M, Silveira MG, Carey EJ, Lindor KD. Cancer surveillance in PSC. Submitted to Hepatology.

Ali AH, Tabibian JH, Nasser‐Ghodsi N, Lennon RJ, DeLeon T, Borad MJ, Hilscher M, Silveira MG, Carey EJ and Lindor KD. Surveillance for hepatobiliary cancers in patients with primary sclerosing cholangitis. Hepatology 2018; 67: 2338-2351. doi:10.1002/hep.29730

Deneau MR, El-matary W, Valentino PL, et al. The natural history of primary sclerosing cholangitis in 781 children: A multicenter, international collaboration. Hepatology. 2017;66(2): 518-527.

Ficket P, Hirschfield GM, Denk G, et al. norUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitis. Journal of Hepatology. 2017 Sep;67(3):549-558. doi: 10.1016/j.jhep.2017.05.009. Epub 2017 May 18.

Weismüller TJ, Trivedi PJ, Bergquist A, et al. Patient Age, Sex, and Inflammatory Bowel Disease Phenotype Associate With Course of Primary Sclerosing Cholangitis. Gastroenterology. 2017;152(8):1975-1984.e8.

Hilscher M, Enders FB, Carey EJ, Lindor KD, Tabibian JH. Alkaline phosphatase normalization is a biomarker of improved survival in primary sclerosing cholangitis. Annals of Hepatology. 2016;15(2):246-253.

Weersma RK, Lindor KD. Editorial – Shifting Paradigms: What is the True Prevalence & Clinical Course of Primary Sclerosing Cholangitis?. Gastroenterology. 2016 Oct;151(4):590-593.

Lunder AK, Hov JR, Borthne A, et al. Prevalence of Sclerosing Cholangitis Detected by Magnetic Resonance Cholangiography, in Patients with Long-term Inflammatory Bowel Disease. Gatroenterology. 2016. doi: 10.1053/j.gastro.2016.06.021

Mizuno S, Hirano K, Isayama H, et al. Prospective study of bezafibrate for the treatment of primary sclerosing cholangitis. J Hepatobiliary Pancreat Sci. 2015;22(10):766-70.

Corpechot C, Gaouar F. Naggar AE, et al. Baseline Values and Changes in Liver Stiffness Measured by Transient Elastography Are Associated With Severity of Fibrosis and Outcomes of

Patients With Primary Sclerosing Cholangitis. Gastroenterology. 2014;146(4):970-979.

Karlsen TH, Boberg KM. Update on primary sclerosing cholangitis. J Hepatol. 2013;[Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/23603668

Boonstra K, Weersma RK, van Erpecum KJ, et al. Population-based epidemiology, malignancy risk and outcome of primary sclerosing cholangitis. Hepatology. 2013; [Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/23775876

Liu JZ, Hoy JR, Folseraas T. et al. Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis. Nat Genet. 2013;45:670-675. https://www.ncbi.nlm.nih.gov/pubmed/23603763

Carey EJ, Lindor KD. Current pharmacotherapy for cholestatic liver disease. Expert Opin Pharmacother. 2012;13:2473-2484. https://www.ncbi.nlm.nih.gov/pubmed/23094715

Imam MH, Lindor KD. Primary sclerosing cholangitis: providing a safe and effective treatment. Expert Rev Gastroenterol Hepatol. 2012;6:255-257. https://www.ncbi.nlm.nih.gov/pubmed/22646247

Boberg KM, Chapman RW, Hirschfield GM, et al. Overlap syndromes: the International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue. J Hepatol. 2011;54:374-385. https://www.ncbi.nlm.nih.gov/pubmed/21067838

Lindor KD, Kowdley KV, Luketic VA, et al. High dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. Hepatology. 2009;50:808-814. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2758780/

Tischendorf JJ, Geier A, Trautwein C. Current diagnosis and management of primary sclerosing cholangitis. Liver Transpl. 2008;14:735-746. https://www.ncbi.nlm.nih.gov/pubmed/18508363

Angulo P, Maor-Kendler Y, Lindor KD. Small-duct primary sclerosing cholangitis: a long-term follow-up study. Hepatology. 2002;35:1494-1500. https://www.ncbi.nlm.nih.gov/pubmed/12029635

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