Definition

Primary sclerosing cholangitis (PSC) is defined as an idiopathic chronic inflammatory disease of the bile ducts characterized by diffuse or segmental areas of inflammation and fibrosis resulting in multifocal intrahepatic and extrahepatic biliary strictures. Localized areas of dilatation proximal to biliary strictures produces a characteristic beaded appearance on cholangiography. The disease progresses slowly in most patients over a 10 to 15 year period and usually leads to cirrhosis, the complications of portal hypertension and premature death from liver failure.

Incidence

About two thirds of patients with PSC are men with a mean age at diagnosis of 40 years. The disease typically occurs in patients with inflammatory bowel disease, but may occur alone or in association with retroperitoneal or mediastinal fibrosis. Approximately 75% of patients with PSC have inflammatory bowel disease. The incidence of PSC in patients with ulcerative colitis ranges from 1% to 4%. PSC may precede or follow the bowel disease; progression of one is unrelated to the other. Worldwide the disease prevalence appears to be on the increase. This may be due to increased awareness of the disease coupled with improved accuracy of biliary imaging.

Pathogenesis

The cause of PSC is unknown. A variety of factors have been incriminated in the disease process. These include chronic portal bacteremia, bile acid metabolites from enteric flora, toxins produced by enteric bacteria, chronic viral infections, ischemic damage, and genetic abnormalities of immunoregulation. The natural history of PSC however, does not support a major pathogenetic role for portal bacteremia or bacterial metabolites. Antibiotic treatment does not prevent progression of the disease nor is there any correlation between the severity of ulcerative colitis and that of primary sclerosing cholangitis. PSC may develop before the onset of colitis or subsequently after total colectomy.

Chronic viral infections and ischemic damage to bile ducts have been implicated as causative factors in PSC. Cholangitis caused by cytomegalovirus in patients with acquired immunodeficiency has a cholangiographic appearance similar to PSC. However, there are no data that indicate any relation in immunocompetent patients. Likewise, no pathological data support the theory that ischemic damage to bile ducts is a cause of PSC. Genetic and immunologic factors may play a role in PSC, although the disorder is not inherited in any distinct pattern. There are familial occurrences of PSC as well as an association between PSC and HLA-B8, DR3, DR2 and DR4.

Patients with PSC have signs of abnormal immunoregulation, including infiltration and destruction of bile ducts by lymphocytes, hypergammaglobulinemia with a disproportionate increase in serum IgM, perinuclear antineutrophil cytoplasmic antibodies, and anticolon epithelial autoantibodies. Circulating immune complexes, increased metabolism of complement component C3, and activation of the complement system by the classic pathway are also found. PSC is associated with other disorders of immunoregulation, including inflammatory bowel disease, thyroiditis and type 1 diabetes.

The cellular immune system appears to play a part in PSC. The total number of circulating T-cells is decreased, whereas the number of T-cells are increased in the portal tracts. The ratio of CD4 to CD8 lymphocytes in the circulation is increased, as are the number and percentage of B cells. There is inhibition of leukocyte migration in the presence of biliary antigens and enhanced autoreactivity of portal T-lymphocytes.

Diagnosis

The current criteria used to diagnose PSC are based on the clinical presentation, biochemical abnormalities, histologic features and the characteristic cholangiographic changes which affect the intrahepatic and extrahepatic bile ducts.

Before the diagnosis of PSC is established, other diseases that cause secondary sclerosing cholangitis need to be excluded. These include chronic bacterial cholangitis secondary to bile duct strictures or choledocholithiasis, previous biliary surgery, choledochal cysts, cholangiocarcinoma and infectious cholangiopathy associated with AIDS. These lesions can generally be excluded by taking a careful history, evaluating the appropriate blood results, and reviewing the cholangiographic and ultrasound findings, and bile duct cytology and biopsies.

Clinical Presentation

Some patients are asymptomatic at the time of diagnosis and may remain so for a prolonged period. In patients with clinically apparent disease there are no specific or pathognomonic symptoms or signs. The symptoms include cholestatic jaundice, pruritus and right upper quadrant abdominal discomfort. Fevers, chills and marked abdominal pain are unusual in patients who have not had previous biliary surgery. Jaundice, hepatomegaly and splenomegaly are the most common clinical signs of advanced disease.

The natural history of PSC is characterized by relapses and remissions. In some patients, the disease remains quiescent for prolonged periods of time. In most cases the disorder is progressive, with the development of secondary biliary cirrhosis and ultimately liver failure.

Some patients with PSC may present with the signs of portal hypertension, hepatosplenomegaly, bleeding oesophagogastric varices and ascites. In patients with inflammatory bowel disease, the symptoms and signs of ulcerative colitis or Crohn's disease are frequently dominant. In these patients, PSC is usually diagnosed when investigating an elevated alkaline phosphatase level. The findings of keratoconjunctivitis sicca, xerostomia, and swelling of the salivary glands are diagnostic of associated Sjögren's syndrome.

Biochemical abnormalities

Laboratory tests in patients with PSC usually show a cholestatic pattern, but biochemical abnormalities alone are never diagnostic. The serum alkaline phosphatase level is usually elevated, and most patients have mild to moderate increases in serum aminotransferase levels, usually less than three times the upper limit of normal. Serum bilirubin levels are abnormal in most patients, and albumin levels and prothrombin time are abnormal in a smaller percentage. Autoantibodies are present in less than 10% of patients and a small number of patients with PSC have positive results for antimitochondrial antibodies. Hypergammaglobulinemia occurs in one third, and IgM levels are increased in one half of patients. Hepatic copper levels are increased in nearly 90% of patients with PSC.

Cholangiography

Cholangiographic demonstration of the bile ducts is necessary to confirm the diagnosis and is best done by ERCP. Typical cholangiographic findings are multifocal strictures usually involving both the intrahepatic and extrahepatic biliary systems, although only one of these systems may be involved.

Typically, the strictures are diffusely distributed and are short and annular. Intervening segments of normal or slightly dilated bile ducts produce the classic beaded appearance. Markedly dilated bile ducts, polypoid masses within the bile ducts, or progressive stricture formation on serial cholangiograms are suggestive of a complicating bile duct carcinoma. Pancreatic duct abnormalities, found in 15% of patients with PSC, resemble changes seen in chronic pancreatitis, although patients with these abnormalities seldom have symptoms of pancreatitis.

Pathology

The gross pathologic findings in PSC depend on the duration, extent, and location of the disease. In early cases, the liver may appear grossly normal, whereas in established PSC, biliary cirrhosis may be present with associated portal hypertension, ascites, and splenomegaly. Grossly, the extrahepatic biliary tree appears thickened, with degrees of dense fibrosis and inflammation. The bifurcation of the hepatic duct is macroscopically involved in most cases. Enlarged lymph nodes may be present in the porta hepatis.

Although histologic changes are present on the liver biopsy in most patients with PSC, these changes are often non-specific. The most consistent abnormality is the absence of interlobular bile ducts in the portal tracts. An infiltrate of plasma cells, neutrophils and occasionally, eosinophils in these tracts is characteristic. Bile salts and copper accumulate in the periportal tissue. Liver biopsy is recommended not only for diagnostic purposes but also for staging the liver disease to determine the prognosis.

PSC is staged histologically according to the system proposed by Ludwig

Stage 1 periductal fibrosis and inflammation confined to the portal tracts

Stage 2 portal and periportal fibrosis and inflammation

Stage 3 fibrosis and inflammation bridging portal tracts

Stage 4 cirrhosis

Medical therapy

A variety of immunosuppressive, anti-inflammatory, and antifibrotic agents including D-penicillamine, cyclosporine, methotrexate, corticosteroids, azathioprine, colchicine, cholestyramine, ursodeoxycholic acid and antibiotics have been used to treat PSC.

However, no drug has been shown to improve the natural history of the disease. The accurate evaluation of treatment has been limited by the indolent course of PSC in many patients and the spontaneous exacerbation's and remissions in others. Hence, it takes years before any treatment can be shown to alter the natural history. Of the various drugs used to treat primary sclerosing cholangitis, only a few have been evaluated in randomized, controlled trials.

Endoscopic treatment

ERCP with balloon dilatation and temporary stenting where technically possible is preferred to percutaneous transhepatic cholangiographic intervention in the management of symptomatic dominant extrahepatic strictures. Several authors have reported favorable short-term results with endoscopic dilation. Approximately 50% of patients with PSC who have balloon dilatation of dominant biliary strictures are improved for up to 2 years. Recurrent stricture formation however is common. Some endoscopists prefer to insert a biliary stent after dilatation, which is left in place for several months. Stent placement has a risk of cholangitis if the stent blocks which requires removal and insertion of a new stent.

Surgical treatment

Surgical treatment of extrahepatic strictures is now used infrequently because of concern that operations in the vicinity of the porta hepatis may hamper future liver transplantation. Although PSC involves both intrahepatic and extrahepatic bile ducts in most patients, the hepatic duct bifurcation is often the most severely involved region. The surgical approach which is used in some centers involves resection of the hepatic duct bifurcation, intraoperative dilation of the intrahepatic biliary tree, reconstruction with a hepaticojejunostomy and insertion of long-term transhepatic stents to prevent restricturing of the intrahepatic bile ducts. This approach is reported to improve jaundice and overall transplant-free survival in a select group of patients without cirrhosis. However the absence of prospective controlled data makes it difficult to accurately assess the beneficial effects that operative biliary drainage may have on the natural history of PSC. Because PSC is progressive in most patients, operative biliary drainage is still regarded as a palliative procedure used to relieve obstructive jaundice, infective cholangitis and intractable pruritus. There is general consensus that operative biliary drainage provides no benefit in patients with PSC who have cirrhosis or advanced diffuse intrahepatic biliary disease.

Liver transplantation

Liver transplantation is now the treatment of choice for patients with end-stage PSC and advanced liver disease. Indications for liver transplantation include bleeding due to esophageal varices or portal gastropathy, intractable ascites (with or without spontaneous bacterial peritonitis), recurrent episodes of bacterial cholangitis, progressive muscle wasting, and hepatic encephalopathy. Three-year survival after liver transplantation is 85% at most centers. The timing of transplantation in patients with PSC can be a difficult clinical decision. With recent improvements in survival after liver transplantation for PSC, some authors have advocated performing a liver transplant earlier in the course of the disease. Several studies have demonstrated a significant improvement in long-term survival after transplantation when compared to the predicted survival in high-risk cirrhotic PSC patients who are not transplanted. However, caution should be exercised in extrapolating these results to noncirrhotic patients, who have a more favorable prognosis and longer predicted survival. The operative mortality for liver transplants continues to be relatively high when compared to the mortality for both operative and non-operative biliary drainage procedures in noncirrhotic patients. Strictures in the transplanted bile ducts are a post-transplant problem in patients with PSC. Possible causes of the strictures are the recurrence of PSC, bile duct ischemia, chronic rejection, infectious cholangitis related to the Roux-en-Y biliary anastomosis and chronic immunosuppression. Current data point to infection as the predominant cause. Creation of a longer jejunal loop in the Roux-en-Y anastomosis and treatment with appropriate antibiotics are usually effective in preventing or treating this complication.

Conclusion

Primary sclerosing cholangitis is a chronic progressive disease which occurs most commonly in young men and is characterized by diffuse bile duct strictures, chronic cholestasis and a frequent association with chronic ulcerative colitis. The diagnosis is confirmed on cholangiography. The natural history of PSC suggests the disease is slowly progressive over a 10–15 year period. PSC is complicated by cirrhosis and portal hypertension. The disease has an increased incidence of bile duct cancer and symptoms of pruritus and cholangitis are frequently related to the development of a dominant stricture. There currently is no medical therapy that is effective in the treatment of PSC. Endoscopic dilatation and stenting is the optimal treatment of symptomatic dominant biliary strictures while operative biliary drainage may alleviate symptoms, it appears to have no effect on the natural history of the disease and should be avoided, if possible, because it may interfere with subsequent liver transplantation, which is the only effective life-saving procedure for patients with advanced PSC.

References

1.

Ahrendt S A, Pitt H A, Kalloo A N, Venbrux A C, Klein A S. et al. Primary sclerosing cholangitis. Resect, dilate or transplant? Ann Surg. (1998);227:412–423. [PMC free article: PMC1191280] [PubMed: 9527065]

2.

Kaplan M M. Toward better treatment of primary sclerosing cholangitis. N Engl J Med. (1997);336:717–721. [PubMed: 9041105]

3.

Klompmaker I J, Haagsma E B, Verwer R, Jansen P L M, Slooff M J H. Primary sclerosing cholangitis and liver transplantation. Scand J Gastroenterol. (1996);31 (suppl 218):98–102. [PubMed: 8865458]

4.

Lee Y -M, Kaplan M M. Primary sclerosing cholangitis. N Engl J Med. (1995);332:924–933. [PubMed: 7877651]

5.

Lemmer E R, Bornman P C, Krige J E J. Primary sclerosing cholangitis-requiem for biliary drainage operations? Arch Surg. (1994);129:723–728. [PubMed: 8024452]

6.

Lindor K D. Ursodial for primary sclerosing cholangitis. N Engl J Med. (1997);336:691–695. [PubMed: 9041099]

7.

Ponsioen, CIJ, Tytgat N J. Primary sclerosing cholangitis: a clinical review. Am J Gastroenterol. (1998);93:515–523. [PubMed: 9576440]

8.

Van den Berg A, Jansen P L M. Pathogenesis and medical therapy of primary sclerosing cholangitis. Eur J Gastroenterol Hepatol. (1999);11:121–124. [PubMed: 10102221]

9.

Van Hoogstraten H J F, Wolfhagen F H J, van de Meeberg P C, Kuiper H, Nix G A J J. et al. Ursodeoxycholic acid therapy for primary sclerosing cholangitis: results of a 2-year randomized controlled trial to evaluate single versus multiple daily doses. J Hepatol. (1998);29:417–423. [PubMed: 9764988]

10.

Wagner S, Gebel M, Meier P, Trautwein C, Bleck J. et al. Endoscopic dilatation of dominant strictures in primary sclerosing cholangitis. Endoscopy. (1996);28:546–551. [PubMed: 8911801]