Primary Sclerosing Cholangitis

Description

Primary Sclerosing Cholangitis (PSC) is a chronic liver disease characterised by progressive inflammation and fibrosis of the bile ducts, leading to the formation of multifocal bile duct strictures, biliary obstruction, cholestasis, and ultimately cirrhosis and liver failure.

Pathogenesis

PSC involves immune-mediated damage to the bile ducts, leading to chronic inflammation and fibrosis. The bile duct fibrosis results in multifocal strictures and subsequent cholestasis. Cholestasis causes bile acid accumulation in the liver, promoting further hepatocellular injury and fibrosis. The continuous cycle of injury and repair eventually leads to biliary cirrhosis and liver failure. PSC is associated with several immunological abnormalities, including the presence of various autoantibodies, but a definitive autoimmune mechanism has not been established.

Subtypes

• Large Duct PSC: Involves the larger, extrahepatic bile ducts. More common and easier to diagnose using imaging techniques.
• Small Duct PSC: Involves the smaller, intrahepatic bile ducts. More challenging to diagnose; liver biopsy often required. Generally has a better prognosis compared to large duct PSC.
• Overlap Syndrome: Features of both PSC and autoimmune hepatitis (AIH). Characterised by biochemical and histological features of AIH along with typical PSC bile duct changes.

Epidemiology, Risk Factors & Associations

• PSC is rare, with an incidence of approximately 1 per 100,000 people per year.
• More common in men (2:1 ratio)
• Most commonly diagnosed between the ages of 30 and 50.
• PSC is strongly associated with inflammatory bowel disease (IBD), particularly ulcerative colitis (UC), with approximately 70-80% of PSC patients having concurrent IBD.
  • The association with Crohn’s disease is less strong, seen in about 3-5% of PSC patients.
• Family history increases risk.
• Possible link to chronic infections, although not well established.
• Associated with autoimmune diseases such as retroperitoneal fibrosis, mediastinal fibrosis and Sjögren syndrome.

Clinical Features

Early disease

• Often asymptomatic in early stages.
• Fatigue and pruritus.
• Jaundice due to cholestasis.
• Right upper quadrant abdominal pain.

Late disease

• Cirrhosis
• Hepatomegaly and splenomegaly

Complications

• Increased lifetime risk of cancer:
  • Cholangiocarcinoma: Especially in patients with long-standing disease (10-15% lifetime risk).
  • Gallbladder Cancer
  • Colorectal Cancer
• Liver failure due to progressive cirrhosis.
• Portal hypertension leading to variceal bleeding, ascites, and hypersplenism.
• Biliary strictures and calculi leading to recurrent cholangitis (fever, chills, abdominal pain).
• Complications of cirrhosis such as ascites, variceal bleeding, and hepatic encephalopathy.

Pathological Features

Histopathology

• Macroscopic: Thickened, fibrotic bile ducts with a beaded appearance; intrahepatic and extrahepatic bile duct strictures.
• Microscopic: Concentric onion skin fibrosis around bile ducts, bile ductular proliferation, cholestasis, periportal fibrosis. Chronic inflammation and ductopenia (decrease in the number of bile ducts) are also often present.

Immunology

• Positive anti-smooth muscle antibody (ASMA)
• Positive antinuclear antibody (ANA): Seen in up to 75% cases
• Positive p-ANCA (up to 80%): Non-specific
• Antimitochondrial Antibodies (AMA): Typically negative in PSC.

Biochemistry

• Liver Function Tests: Elevated ALP (marker of cholestasis), GGT (reflects bile duct injury), and bilirubin.
• Cholesterol: Often elevated due to cholestasis.

Immunohistochemistry

• IgG4: May be elevated in some cases, differentiating from IgG4-related sclerosing cholangitis.

Genetics

• Associated with certain HLA haplotypes, suggesting a genetic predisposition.

Radiological Features

General Features

• Magnetic Resonance Cholangiopancreatography (MRCP) is the gold standard for non-invasive imaging.
• Multifocal bile duct strictures with intervening segments of normal or mildly dilated intrahepatic and/or extrahepatic ducts, leading to a beaded appearance.
• Pruned tree appearance: Loss of peripheral bile ducts due to progressive fibrosis.
• Chronic appearance characterised by central regenerative hypertrophy and peripheral atrophy
• Associated complications of cirrhosis, portal hypertension, and potential cholangiocarcinoma.

XR

• Limited utility in diagnosing PSC; may show hepatomegaly or calcifications in advanced disease.

CT

• Non-contrast: Initial assessment; may show liver abnormalities, but not specific for bile ducts.
• C+ Arterial/Venous: Can assess liver parenchyma, detect masses suggestive of cholangiocarcinoma, and delineate biliary anatomy.

MRI

• T1: May show areas of fibrosis and decreased signal in the liver.
• T2: Increased signal intensity in areas of bile duct inflammation and fibrosis.
• MRCP: Non-invasive and highly effective
  • Diffuse or segmental saccular dilatations and strictures of intrahepatic and extrahepatic bile ducts.
  • Pruned-tree appearance due to loss of peripheral small duct branches.

US

• B-mode: Initial screening; may show bile duct thickening and liver texture changes.
• Colour Doppler: Can assess blood flow in the portal and hepatic veins, useful for detecting complications like portal hypertension.

NM

• HIDA Scan: Can assess bile flow but not typically used for diagnosing PSC.

Grading and Staging

• Ludwig Classification: Histological grading system based on the degree of fibrosis and inflammation.
• Mayo Risk Score: Predictive model for survival based on age, bilirubin, albumin, AST, and variceal bleeding.

Diagnosis

• Clinical Presentation and History: Symptoms and associated conditions (e.g., IBD).
• Biochemical Markers: Elevated ALP and GGT levels.
• Imaging: MRCP is the gold standard for diagnosing bile duct abnormalities.
• Liver Biopsy: May be necessary to diagnose small duct PSC or assess the stage of liver disease.

Differential Diagnosis

Image-based

• Primary Biliary Cholangitis (PBC): Positive AMA (vs. negative), intrahepatic bile duct involvement (usually small ducts) without beading on imaging. Mainly affects middle-aged females (vs. males).
• IgG4-Related Sclerosing Cholangitis: Elevated serum IgG4 levels, responds to steroids, distinctive imaging features.
• Cholangiocarcinoma: Focal mass, irregular ductal stricture, enhancing lesion on imaging.

Clinically-based

• Autoimmune Hepatitis: Elevated transaminases, positive autoimmune markers, interface hepatitis on biopsy.
• Choledocholithiasis: Gallstones in the bile duct causing obstruction, typically seen on imaging.
• Viral Hepatitis: Elevated transaminases, positive viral serologies.

Management

• Managed by gastroenterology or hepatology specialist.
• There is no curative treatment for PSC as of now, and management is largely supportive, focusing on alleviating symptoms and managing complications.
• Regular follow-up with liver function tests and imaging to monitor disease progression.
• Regular imaging and CA 19-9 levels to monitor for cholangiocarcinoma.
• Ursodeoxycholic acid (UDCA) to improve bile flow, immunosuppressants for overlap syndrome.
• ERCP with balloon dilatation or stenting for dominant strictures.
• Liver transplantation in end-stage liver disease or recurrent cholangitis unresponsive to other treatments.

References

1. Chapman, R., Fevery, J., Kalloo, A., et al. (2010). “Diagnosis and management of primary sclerosing cholangitis.” Hepatology, 51(2), 660-678.
2. Karlsen, T.H., et al. (2017). “Primary sclerosing cholangitis – a comprehensive review.” J Hepatol, 67(6), 1298-1323.
3. Lazaridis, K.N., and LaRusso, N.F. (2016). “Primary sclerosing cholangitis.” N Engl J Med, 375(12), 1161-1170.