Primary Sclerosing Cholangitis (PSC)

Primary sclerosing cholangitis (PSC) is estimated to exist in up to 35 per 100,000 people, with a generally higher prevalence at higher latitudes (1). Although the cause is unknown, PSC is associated with inflammatory bowel disease (IBD), which is present in 60 to 90% of patients depending on region (1, 2). Approximately 2.5% of patients with ulcerative colitis and approximately 1% with Crohn disease have PSC (3). This association with IBD and the presence of several autoantibodies (eg, antinuclear antibodies [ANA] and perinuclear antineutrophilic antibodies [pANCA]) in patients with PSC suggest immune-mediated mechanisms. T cells appear to be involved in the destruction of the bile ducts, implying disordered cellular immunity. A genetic predisposition is suggested by a tendency for the disorder to develop in multiple family members and a higher frequency in people with specific human leukocyte antigen types, most prominently B8and, which is often correlated with autoimmune disorders. An unknown trigger (eg, bacterial infection, ischemic duct injury) may precipitate development of PSC in genetically predisposed people. Other etiologic factors may include gut inflammation or leakage, bile homeostasis, and the gut microbiome.

Three broad disease phenotypes are recognized (4, 5):

• Classic phenotype, involving large and small bile ducts and often associated with IBD

• Small-duct phenotype

• PSC autoimmune hepatitis overlap phenotype

The classic phenotype is associated with inflammatory bowel disease in 70-80% of patients, and carries increased risk gallbladder cancer, hepatocellular carcinoma, cholangiocarcinoma, and in patients with concomitant inflammatory bowel disease, of colon cancer. Small-duct disease has a better prognosis and lower cholangiocarcinoma risk than classic disease. The overlap phenotype is more responsive to immunotherapy.

Overview of Primary Sclerosing...

video

Onset is usually insidious, with progressive fatigue and then pruritus. In a population-based study, the majority (57%) of patients presented with asymptomatic laboratory abnormalities; the remainder presented with symptoms including abdominal pain, pruritis, diarrhea, jaundice, fatigue, and fevers (1). Steatorrhea and deficiencies of fat-soluble vitamins can develop. Persistent jaundice harbingers advanced disease. Symptomatic gallstones and choledocholithiasis tend to develop in approximately 50% of patients, and bacterial cholangitis in approximately 40% (1).

Some patients, asymptomatic until late in the course, first present with hepatosplenomegaly and/or cirrhosis.

Primary sclerosing cholangitis (PSC) tends to slowly and inexorably progress. The terminal phase involves decompensated cirrhosis, portal hypertension, ascites, and liver failure.

Despite the association between PSC and inflammatory bowel disease (IBD), the 2 diseases tend to run separate courses. Ulcerative colitis may appear years before PSC and tends to have a milder course when associated with PSC. Similarly, total colectomy does not change the course of PSC (2). The presence of both PSC and IBD increases the risk of colorectal carcinoma, regardless of whether a liver transplantation has been performed for PSC. Cholangiocarcinoma develops in 10 to 20% of patients (3, 1).

• Laboratory tests

• Abdominal ultrasound

• Magnetic resonance cholangiopancreatography (MRCP)

• Sometimes liver biopsy, for diagnosis of small-duct or autoimmune hepatitis overlap phenotypes

Primary sclerosing cholangitis (PSC) is suspected in patients with unexplained abnormalities in liver tests, particularly in those with inflammatory bowel disease (IBD). A cholestatic pattern is typical: elevated alkaline phosphatase and gamma-glutamyltransferase (GGT) rather than aminotransferases. Gamma globulin and IgM levels tend to be increased. Antinuclear antibodies and pANCA are usually positive. Antimitochondrial antibody, positive in primary biliary cholangitis, is characteristically negative. Serum IgG4 levels are performed to help exclude IgG4-related sclerosing cholangitis (1).

Imaging of the hepatobiliary system begins with ultrasound to exclude extrahepatic biliary obstruction. Although ultrasound or CT can show ductal dilation, diagnosis requires cholangiography to show multiple strictures and dilations in the intrahepatic and extrahepatic bile ducts. Cholangiography should begin with magnetic resonance cholangiopancreatography (MRCP). Endoscopic retrograde cholangiopancreatography (ERCP) is avoided for purely diagnostic purposes and only performed if biopsy or intervention is required, due the risk of complications (1).

Liver biopsy is usually not required for diagnosis, but can detect disease affecting only small bile ducts and reveal overlap with autoimmune hepatitis. When performed, biopsy shows bile duct proliferation, periductal fibrosis, inflammation, and loss of bile ducts. With disease progression, periductal fibrosis extends from the portal regions and eventually leads to secondary biliary cirrhosis.

Adults with PSC, even in the absence of cirrhosis, should undergo abdominal imaging (ultrasound, abdominal CT, or MRI/MRCP) every 6 to 12 months to screen for gallbladder cancer and cholangiocarcinoma. Serum levels of carbohydrate antigen (CA) 19-9 should be monitored regularly (2).

Colonoscopy with biopsies should be performed in patients without pre-existing IBD at the time of diagnosis of PSC and should be carried out annually in patients with PSC and IBD from the time of diagnosis of PSC due to the increased risk of colorectal adenocarcinoma.

• Bile acid sequestrants for symptom management

• Ursodeoxycholic acid can improve liver tests but has no clear survival benefitUrsodeoxycholic acid can improve liver tests but has no clear survival benefit

• Endoscopic retrograde cholangiopancreatography (ERCP) dilation for major (dominant) strictures

• Transplantation for recurrent bacterial cholangitis or complications of liver failure

Asymptomatic patients may require only monitoring (eg, physical examination and liver tests twice per year).

Bile acid sequestrants (eg, cholestyramine) are first-line therapy for pruritis refractory to antihistamines and nonpharmacologic therapy (eg, topical emollients) (Bile acid sequestrants (eg, cholestyramine) are first-line therapy for pruritis refractory to antihistamines and nonpharmacologic therapy (eg, topical emollients) (1). Ursodeoxycholic acid also reduces itching and improves biochemical markers (particularly alkaline phosphatase), but evidence for improved survival is mixed at best (). Ursodeoxycholic acid also reduces itching and improves biochemical markers (particularly alkaline phosphatase), but evidence for improved survival is mixed at best (2). Routine antibiotics are not recommended but are used in episodes of bacterial cholangitis.

Therapeutic ERCP is indicated for significant strictures and in the context of bacterial cholangitis (1, 3). If a single stricture appears to be the major cause of obstruction (a dominant stricture may develop in up to 45% of patients), ERCP dilation (with brush cytology and fluorescence in situ hybridization [FISH] to screen for cholangiocarcinoma) and stenting can relieve symptoms.

Liver transplantation improves survival and quality of life in patients with primary sclerosing cholangitis (PSC) (1). Indications include recurrent bacterial cholangitis, complications of end-stage liver disease (eg, intractable ascites, portosystemic encephalopathy, bleeding esophageal varices), or cholangiocarcinoma (in appropriately selected patients).

Patients with PSC autoimmune hepatitis overlap should undergo treatment based on guidelines for autoimmune hepatitis (1).