Primary Sclerosing Cholangitis


Article Author:
Prashanth Rawla


Article Editor:
Hrishikesh Samant


Editors In Chief:
Hela Kchir
Joseph Lee
Savio John


Managing Editors:
Avais Raja
Orawan Chaigasame
Khalid Alsayouri
Kyle Blair
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Abbey Smiley
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beenish Sohail
Hajira Basit
Phillip Hynes
Sandeep Sekhon


Updated:
6/26/2019 1:20:42 PM

Introduction

Primary sclerosing cholangitis (PSC) is a chronic and progressive cholestatic liver disorder of unknown etiology. Inflammation, fibrosis, and stricturing of intrahepatic and/or extrahepatic biliary ducts characterize PSC.[1] PSC is usually a progressive disorder that leads to complications of cholestasis and liver failure. Median survival from time of diagnosis to death without liver transplantation is around 10 years.[2]

Established subtypes of PSC are[3]:

  1. Classic: Affects small and large bile ducts
  2. Small-duct: Affects only small bile ducts
  3. Associated with autoimmune hepatitis: Affects small and large bile ducts

Etiology

Healthcare professionals do not fully understand the etiology of PSC; however, they attribute genetic and environmental factors to its development.[3] Inflammatory bowel disease (IBD) is considered to be a significant risk factor for the development of PSC.[4] About 60% to 80% of patients with PSC have IBD (predominantly Ulcerative colitis in about 80% and Crohn disease in 20%), and about 5% to 10% of patients with ulcerative colitis have coexisting PSC.[5]

Epidemiology

The incidence rates for PSC range from 0 to 1.3 per 100,000 inhabitants/year and prevalence rates are 0 to 16.2 per 100,000 inhabitants.[6] Incidence and prevalence of PSC are high in North America and Northern Europe when compared to Asia. Patients are diagnosed between the ages of 30 and 40 years. The median age at the diagnosis of PSC was 41 years. PSC is more common in men (65% to 70%), and males have a 2-fold increased risk of developing PSC when compared to females.[7] The relative risk of PSC among siblings with the disease is 9 to 39 times higher when compared as the risk in the general population.

Pathophysiology

PSC is characterized by inflammation, fibrosis, and cholestasis. Hereditary and environmental factors play a role in the pathogenesis of primary sclerosing cholangitis. Healthcare researchers hypothesize that after exposure to an unidentified environmental source, persistent injury of the cells lining the bile ducts (cholangiocytes) occurs via several genetically predisposed pathways.[8] A large cohort genome-wide association study showed a strong association with human leukocyte antigen (HLA).[9] PSC is strongly associated with HLA class I, II, and III regions (i.e., HLA-B*08, HLA-DRB1 alleles, and a locus near NOTCH4, respectively).[8] Inflammation and fibrosis lead to cholestasis and parenchymal injury. Biliary obstruction might facilitate cholangitis.[10] Biliary scarring leads to portal hypertension which causes venous compression in the portal triads.

PSC is a premalignant disease as 10% to 20% of patients with PSC develop cholangiocarcinoma. PSC induced cholangiocarcinoma is thought to be inflammation-induced cancer contributed by the toxic environment of bile which acts as a cofactor in accelerating the carcinogenesis. Genetic and immune factors may play an important role.

Histopathology

Progressive fibrosis around intrahepatic bile ducts leads to concentric and circumferential laminations called as "onion skin" fibrosis. This leads to the displacement of the pre-biliary capillary plexi and creates a barrier to oxygenation and maintenance of cholehepatic countercurrent circulation between the artery and the bile duct. Arterial or capillary ischemia is involved in the pathogenesis of stricturing and circumferential pre-biliary fibrosis. Secretion of chemokines and cytokines by innate immune cells and inflammatory and fibrotic response to toxic bile leaking between inured cholangiocytes leads to periductal fibrosis.[11]

History and Physical

About 50% of the patients with PSC are asymptomatic on presentation, and they are diagnosed after abnormal liver function tests are found when tested for other reasons. Most patients complain of right upper quadrant abdominal pain (in 20%), pruritus (in 10%) (which might be episodic), fatigue and jaundice (in 6%). Pruritus can be extremely disabling, leading to severe excoriations, and a decreased quality of life. Weight loss may also be reported at presentation. Late symptoms or symptoms of advanced liver disease include jaundice, gastrointestinal (GI) bleeding, ascites, and confusion.

Physical examination may reveal hepatomegaly (in 44% of patients), splenomegaly (in 39%), jaundice, and excoriations from pruritus.

Development of fever, chills and right upper quadrant pain with or without jaundice indicates the development of bacterial cholangitis, which may occur sporadically.

Evaluation

Liver biochemical tests usually demonstrate a cholestatic pattern, with an elevation of the serum alkaline phosphatase being characteristic finding. Elevation of transaminases (aspartate transaminase and alanine transaminase) is modest (2 to 3 times the upper limit of normal). Bilirubin and albumin levels may be normal at the time of diagnosis but become increasingly abnormal as the disease progresses. Elevated serum bilirubin levels suggest the possibility of more advanced disease, dominant biliary strictures or cirrhosis.

Atypical perinuclear antineutrophil cytoplasmic antibodies are positive in about 26% to 94% of patients with PSC, although they are not specific for the disease. Elevated concentrations of total immunoglobulins (IgM in 50%) may be seen. Positive antinuclear antibodies, smooth muscle antibodies should alert clinicians to the possibility of autoimmune hepatitis related PSC or overlap syndromes. Immunoglobulin subsets elevation (IgG4 in 10%) may also be seen. Serum IgG4 elevations are not specific to IgG4-related disease. Serum IgG4 levels of more than four times the upper limit of normal and/or IgG4:IgG1 ratio of more than 0·24 strongly suggests IgG4-associated PSC.[10]

Imaging, usually with ultrasound or computed tomography, may be performed in the patient with persistent cholestatic liver tests to exclude biliary obstruction. The diagnosis of PSC is typically made with the demonstration of characteristic multiple and focal areas of stricturing and dilation of intrahepatic and/or extrahepatic bile ducts on cholangiography. A cholangiogram may be obtained using magnetic resonance cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography (ERCP), or percutaneous transhepatic cholangiography (PTC). MRCP is usually the first test of choice. Because ERCP is an invasive procedure and the diagnostic accuracy of MRCP is comparable to ERCP, MRCP is preferred over ERCP. PTC is reserved for patients who are not able to undergo MRCP, for example, those with implanted metal devices) or ERCP.

A liver biopsy is usually not needed for diagnosis unless overlap with autoimmune hepatitis or a small-duct PSC is suspected. Noninvasive diagnostic tools that assess fibrosis, like magnetic resonance elastography and transient elastography of the liver are promising, but their specific role in evaluating the degree of liver fibrosis in patients with PSC is unclear.[8]

Diagnostic criteria for the diagnosis of PSC include:

  1. An increased serum alkaline phosphatase level that persists for more than 6 months
  2. Cholangiographic findings of bile-duct strictures detected using either MRCP or ERCP
  3. Exclusion of causes of secondary sclerosing cholangitis

Treatment / Management

Treatment of PSC is challenging and complex. There is no established treatment of PSC yet. Ursodeoxycholic acid (UDCA) has been widely studied as a therapy for PSC patients. Treatment guidelines for PSC are conflicting. American College of Gastroenterology and the American Association for the Study of Liver Diseases do not support the use of ursodeoxycholic acid. Use of moderate doses of ursodeoxycholic acid has been approved by the European Association for the Study of the Liver. Nonetheless, at moderate doses of 15 to 20 mg/kg daily, remains widely used.[10][12]

Other treatments which have been tested and are not proven to be beneficial are prednisolone, budesonide, colchicine, penicillamine, azathioprine, tacrolimus, methotrexate, mycophenolate mofetil, and antitumor necrosis factor antibodies.

In PSC patients with dominant stricture (defined as stenoses measuring less than 1.5 mm in the common bile duct or less than 1.0 mm in the hepatic ducts) and pruritus, and/or cholangitis, ERCP with balloon dilatation is recommended to relieve symptoms.

Surgical options for PSC include biliary reconstructive procedures like choledochoduodenostomy in with the surgeon attaches the common bile duct to the duodenum, choledochojejunostomy in which the surgeon attaches the common bile duct to the jejunum, and liver transplantation. Liver transplantation is the definitive treatment for patients with decompensated cirrhosis. Patients whose model for end-stage liver disease (MELD) score exceeds 14 should be referred for liver transplantation. Orthotopic liver transplantation has 5-year survival rates of up to 80% in patients with PSC.[12]

Differential Diagnosis

  • Secondary sclerosing cholangitis: Secondary causes of PSC include chronic bacterial cholangitis, cholangiocarcinoma, choledocholithiasis, recurrent pancreatitis, and surgical biliary trauma.
  • IgG4-associated cholangitis
  • PSC-autoimmune hepatitis overlap syndrome is typically seen in children and young adults.
  • Histiocytosis X
  • HIV syndrome
  • Bile duct strictures
  • Primary biliary cirrhosis
  • Papillary tumors

Prognosis

The common history of PSC is highly variable and unpredictable. A persistently low serum alkaline phosphatase levels less than 1.5 times the upper limit of normal confers a good prognosis.[13] Patients with small duct PSC have a good prognosis, with no reports of bile duct malignancy in this group, and progression to advanced liver disease is uncommon. The Mayo risk score which includes age, serum bilirubin, serum albumin, serum AST, and a history of variceal bleeding is helpful in predicting survival in PSC patients.[14]

Complications

  1. Fat-soluble A, D, E, and K vitamin deficiencies
  2. Metabolic bone disease (osteoporosis)
  3. Cholangiocarcinoma
  4. Gallbladder cancer 
  5. Dominant biliary strictures
  6. Cholangitis
  7. Hepatocellular carcinoma in patients with cirrhosis.[15] Hepatic fibrosis progressively develops in these patients leading to cirrhosis and hepatocellular carcinoma.
  8. Colon cancer in patients with concomitant ulcerative colitis. Surveillance with colonoscopy should be performed annually in these patients who have concomitant PSC and IBD.[16]
  9. Cholelithiasis
  10. Portal hypertension

Consultations

  • Gastroenterology
  • Surgery
  • Hepatologists
  • Transplant Team

Deterrence and Patient Education

There is no definite cure for PSC at the time of this writing. There have been significant advances in the early diagnosis of PSC. Diagnosing PSC early is essential as treatment can be started early before the development of liver failure.

Pearls and Other Issues

General Measures

In patients with PSC and moderate pruritus, bile acid sequestrants such as cholestyramine should be taken to reduce symptoms. Rifampin and naltrexone are second-line treatment agents which can be considered if cholestyramine is ineffective or poorly tolerated.

Patients with PSC should undergo bone mineral density testing at the time of diagnosis and then every 2 to 4 years.

Fat-soluble vitamin deficiencies are common in patients with advanced liver disease, and clinicians should screen for and monitor patients for these.

Enhancing Healthcare Team Outcomes

The treatment of PSC requires an interprofessional approach. Gastroenterology consultation is useful. Surgery consult and referral to a tertiary center is needed in patients undergoing liver transplantation. Patients with osteoporosis might need to be referred to an endocrinologist. Besides the physicians, nurses, dieticians, psychiatric counselors, pharmacists, and physical therapists play a critical role in the management of these patients. Pharmacists should encourage patients to take appropriate medications and educate patients about their side effects. Patients will need to be evaluated by a dietician for appropriate diet recommendations. Physical therapy is encouraged except in patients with advanced osteoporosis. Some patients might benefit from psychiatric counseling.


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Primary Sclerosing Cholangitis - Questions

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A patient presents with jaundice, fatigue, and severe itching. She has ulcerative colitis and recently underwent total colectomy with ileorectal anastomosis and a J pouch creation. What is the most likely diagnosis?



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Which of the following is associated with sclerosing cholangitis?



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Primary sclerosing cholangitis (PSC) occurs in the absence of concomitant inflammatory bowel disease (Crohn and ulcerative colitis) in approximately what percentage of PSC cases?



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A 28-year-old female presents with a several month history of abdominal pain, diarrhea, and itching and severe fatigue. She has lost about 12 pounds over the past 3 months. She denies any trauma but has not been feeling well for many years. The physical exam reveals scleral icterus, excoriations, and hepatosplenomegaly. The liver functions and enzymes are all elevated. She undergoes percutaneous transhepatic cholangiography and a biopsy reveals "onion skin" fibrosis. For what order should she be evaluated?



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A 28-year-old female presented with cholestatic jaundice for three weeks. Her past surgical history was significant for total colectomy and ileoanal anastomosis with a J-pouch for ulcerative colitis four years ago. What is the most likely cause of her jaundice?



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A 48-year-old male presents to an outpatient clinic for his annual wellness checkup. He has a history of ulcerative colitis and is on maintenance therapy with mesalamine. His laboratory testing shows elevated liver enzymes and elevated alkaline phosphatase. Additionally, his total bilirubin, conjugated bilirubin, and IgM levels were also elevated. He denies any diarrhea, constipation, abdominal pain, fevers, chills, weight loss. He reports having a soft, formed, non-bloody 1-2 bowel movements daily. MRCP was performed, which showed hepatomegaly. Anti-mitochondrial antibody was negative. Liver biopsy was performed, but the results are pending. Which of the following conditions is the patient at increased risk of developing?



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A 35-year-old female patient presents to the hospital complaining of progressive itching and yellowish discoloration of his skin. The patient is known to have ulcerative colitis since the age of 25. The patient states that her stool started floating in the toilet about two months ago. Physical examination is unremarkable except for jaundice and scratch marks. Which of the following is least likely to be found on further evaluation of this patient?



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Primary Sclerosing Cholangitis - References

References

Angulo P,Lindor KD, Primary sclerosing cholangitis. Hepatology (Baltimore, Md.). 1999 Jul     [PubMed]
Tischendorf JJ,Hecker H,Krüger M,Manns MP,Meier PN, Characterization, outcome, and prognosis in 273 patients with primary sclerosing cholangitis: A single center study. The American journal of gastroenterology. 2007 Jan     [PubMed]
Lazaridis KN,LaRusso NF, The Cholangiopathies. Mayo Clinic proceedings. 2015 Jun     [PubMed]
Boonstra K,Beuers U,Ponsioen CY, Epidemiology of primary sclerosing cholangitis and primary biliary cirrhosis: a systematic review. Journal of hepatology. 2012 May     [PubMed]
Molodecky NA,Kareemi H,Parab R,Barkema HW,Quan H,Myers RP,Kaplan GG, Incidence of primary sclerosing cholangitis: a systematic review and meta-analysis. Hepatology (Baltimore, Md.). 2011 May     [PubMed]
Chapman R,Fevery J,Kalloo A,Nagorney DM,Boberg KM,Shneider B,Gores GJ, Diagnosis and management of primary sclerosing cholangitis. Hepatology (Baltimore, Md.). 2010 Feb     [PubMed]
Lazaridis KN,LaRusso NF, Primary Sclerosing Cholangitis. The New England journal of medicine. 2016 Sep 22     [PubMed]
Dyson JK,Beuers U,Jones DEJ,Lohse AW,Hudson M, Primary sclerosing cholangitis. Lancet (London, England). 2018 Jun 23     [PubMed]
Karlsen TH,Franke A,Melum E,Kaser A,Hov JR,Balschun T,Lie BA,Bergquist A,Schramm C,Weismüller TJ,Gotthardt D,Rust C,Philipp EE,Fritz T,Henckaerts L,Weersma RK,Stokkers P,Ponsioen CY,Wijmenga C,Sterneck M,Nothnagel M,Hampe J,Teufel A,Runz H,Rosenstiel P,Stiehl A,Vermeire S,Beuers U,Manns MP,Schrumpf E,Boberg KM,Schreiber S, Genome-wide association analysis in primary sclerosing cholangitis. Gastroenterology. 2010 Mar     [PubMed]
Fickert P,Pollheimer MJ,Beuers U,Lackner C,Hirschfield G,Housset C,Keitel V,Schramm C,Marschall HU,Karlsen TH,Melum E,Kaser A,Eksteen B,Strazzabosco M,Manns M,Trauner M, Characterization of animal models for primary sclerosing cholangitis (PSC). Journal of hepatology. 2014 Jun     [PubMed]
Lindor KD,Kowdley KV,Harrison ME, ACG Clinical Guideline: Primary Sclerosing Cholangitis. The American journal of gastroenterology. 2015 May     [PubMed]
Williamson KD,Chapman RW, Primary sclerosing cholangitis: a clinical update. British medical bulletin. 2015 Jun     [PubMed]
Kim WR,Therneau TM,Wiesner RH,Poterucha JJ,Benson JT,Malinchoc M,LaRusso NF,Lindor KD,Dickson ER, A revised natural history model for primary sclerosing cholangitis. Mayo Clinic proceedings. 2000 Jul     [PubMed]
Rawla P,Sunkara T,Raj JP, Role of biologics and biosimilars in inflammatory bowel disease: current trends and future perspectives. Journal of inflammation research. 2018;     [PubMed]
Rawla P,Sunkara T,Muralidharan P,Raj JP, Update in global trends and aetiology of hepatocellular carcinoma. Contemporary oncology (Poznan, Poland). 2018;     [PubMed]
Mowat C,Cole A,Windsor A,Ahmad T,Arnott I,Driscoll R,Mitton S,Orchard T,Rutter M,Younge L,Lees C,Ho GT,Satsangi J,Bloom S, Guidelines for the management of inflammatory bowel disease in adults. Gut. 2011 May;     [PubMed]

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