Primary sclerosing cholangitis (PSC) is characterized by inflammation, fibrosis, and stricturing of intrahepatic and/or extrahepatic bile ducts, eventually progressing to biliary cirrhosis and end-stage liver disease. Two-thirds of affected patients are males, with the median age at presentation of 40 years. Although clinical presentation varies significantly, serum alkaline phosphatase (ALP) is usually elevated at the time of diagnosis, and 60%-80% of patients have associated inflammatory bowel disease (IBD). In addition, there is a strong association with increased risk of hepatobiliary and colonic neoplasias.
The diagnosis of PSC is made by demonstration of multifocal dilatations and strictures in the intrahepatic and/or extrahepatic bile ducts on magnetic resonance cholangiopancreatography (MRCP) or endoscopic retrograde cholangiopancreatography (ERCP). MRCP has similar overall accuracy, is noninvasive, and does not use radiation. On the other hand, ERCP permits therapeutic intervention and is more sensitive in the detection of subtle changes in the peripheral bile ducts. Overall, due to better cost-effectiveness, MRCP is considered the preferred initial method of diagnosis, with a sensitivity and specificity of 86% and 94%, respectively.
Secondary causes of sclerosing cholangitis are summarized in Table 1 and must be excluded prior to making a diagnosis of PSC. One important differential diagnosis is immunoglobulin G4 (IgG4)-associated cholangitis (IAC), which can present with jaundice, weight loss, abdominal pain, steatorrhea, and new onset diabetes. Imaging can show dilatation of intrahepatic and/or extrahepatic bile ducts in addition to typical pancreatic changes. IAC usually presents in older age (60-70 years) and is associated with elevation of serum IgG4 levels. IAC seems to be responsive to corticosteroids. Another reason to check IgG4 is that there is a small subgroup of patients with PSC and high IgG4 who may have more aggressive disease and might benefit from steroids as well.
Table 1. Differential Diagnosis of PSC
Diffuse intrahepatic metastasis
Recurrent pyogenic cholangitis
Sclerosing cholangitis in critically ill
Portal hypertensive biliopathy
Surgical biliary trauma
Liver biopsy rarely adds to the diagnosis of PSC. However, it is helpful in ruling out overlapping features of autoimmune hepatitis and diagnosing small duct disease.
Ursodeoxycholic acid (UDCA) is the most studied agent in the treatment of PSC, but its use is highly controversial, as reflected in conflicting recommendations from American and European guidelines:
From the European Association for the Study of the Liver guidelines: “The available database shows that UDCA (15-20 mg/kg/day) improves serum liver tests and surrogate markers of prognosis, but does not reveal a proven benefit on survival. The limited database does not yet allow a specific recommendation for general use of UDCA in PSC.”
From the American Association for the Study of Liver Diseases guidelines: “In adult patients with PSC, we recommend against the use of UDCA as medical therapy.”
Results from the most relevant studies are summarized in Table 2; importantly, a meta-analysis failed to demonstrate improvement in symptoms, rates of death or liver transplantation, or development of cholangiocarcinoma among UDCA-treated patients.
Table 2. Major Randomized Controlled Studies of UDCA in the Treatment of PSC
Significant increase in risk of death, liver transplantation, and development of varices
Although there may be a role for UDCA in treatment of PSC, high-dose UDCA (>23 mg/kg/day) should be avoided.
Multiple antibiotics have been studied in PSC to explore the interaction between inflammation, gut microbiota, and bile acid homeostasis; these antibiotics include vancomycin, metronidazole, tetracycline, azithromycin, and minocycline.
In a recent study, 35 patients with PSC were randomized to one of four groups: vancomycin 125 mg or 250 mg four times daily or metronidazole 250 mg or 500 mg three times daily for 12 weeks. The primary end point in this study was reduction in ALP at 12 weeks. Only patients in the 2 vancomycin groups reached primary endpoint. In low-dose metronidazole group, bilirubin decreased significantly at 12 weeks. Pruritus decreased significantly in the high-dose metronidazole group. Unfortunately, the study was marked by several adverse events and study dropouts. Larger randomized studies of longer duration are required to determine safety and tolerability of antibiotics.
The role of fenofibrate (a peroxisome proliferator-activated receptor-alpha agonist) in the treatment of PSC has been evaluated in two pilot studies. In total, 21 patients were treated for 6-12 months with 200 mg/day (n = 13) or 160 mg/day (n = 8). Both studies showed significant reduction in serum ALP levels. Side effects associated with the use of fenofibrate in these two studies included myalgia, nausea, and heartburn.[8, 9] Larger randomized studies are warranted since there are reports of hepatitis associated with the use of fibrates.
Exploring the association between cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction in PSC and fatty acid abnormalities seen in CFTR knockout models, Martin et al. studied the effect of docosahexaenoic acid supplementation in patients with PSC. This was a 12-month, open-label pilot study during which 23 patients with PSC were given docosahexaenoic acid at 800 mg twice daily orally. A significant drop in serum ALP was noticed at months 9 and 12, and ∼20% of patients had a >50% drop in the enzyme. In addition, the fatty acid abnormalities were corrected. In animal models, correction of fatty acid abnormalities correlated with histological improvement of bile duct injury. No adverse events were observed.
Several other drugs are currently under investigation, including rifaximin, nor-UDCA, retinoic acid, simtuzumab (LOXL-2 antibodies), and an apical sodium-dependent bile salt transporter blocker.
An increased risk of colorectal cancer is well described in patients with PSC and IBD (cumulative 5- and 10-year incidence of 7% and 11%, respectively). The American Association for the Study of Liver Diseases and European Association for the Study of the Liver guidelines recommend colonoscopy with biopsies at the time of diagnosis. If the patient has evidence of IBD, colonoscopy should be repeated every 1 to 2 years thereafter; however, if the patient does not have IBD, the time of repeat colonoscopy is not clearly defined. A recent study suggested 5 years later, or sooner if clinically indicated.
The cumulative 5- and 10- year incidence of hepatobiliary malignancies is 8% and 14%, respectively, which is 177 times higher than that for the general population.
The risk of gallbladder cancer is increased 10-fold. Gallbladder cancer is more frequent in males, and 70% of these patients are under the age of 60 years. Figure 1 illustrates a surveillance strategy for gallbladder cancer in patients who have PSC.
The lifetime risk of cholangiocarcinoma in patients who have PSC is 15%-20%, with an annual incidence of 0.6%. More than half of these patients are diagnosed within the first year after diagnosis of PSC. Different modalities can be used for surveillance; Figure 2 summarizes a suggested strategy for surveillance of cholangiocarcinoma in patients with PSC.
A dominant stricture should be evaluated for cholangiocarcinoma by brushing for cytology with and without fluorescence in situ hybridization and/or biopsy. If clinically indicated, it is appropriate to treat such a stricture with endoscopic dilation with or without stenting initially.
In recent studies, normalization of serum ALP has been shown to correlate with improved prognosis in patients with PSC. In a study by Al Mamari et al., improvement in serum ALP to below 1.5 times the upper limit of normal was associated with decreased risk of cholangiocarcinoma and better overall outcomes. In another study revisiting the results of Olsson's landmark trial using 17-23 mg/kg/day of UDCA, patients with reduced or normal ALP had significantly higher survival rates, regardless of whether or not patients received UDCA treatment.
Aside from serum ALP, prognostic indexes such as the Mayo risk score have been used in research studies, albeit of unclear value for the individual patient.
Overall, PSC is a progressive disease with 10-year survival free of liver transplantation between 65% and 75%. There is no proven medical therapy available for this disease. Although UDCA has been studied widely, its role in disease progression and chemoprophylaxis is not well established. Novel therapies are currently being investigated for disease management, but most studies are small. Table 3 summarizes our recommendations for diagnosis, treatment and surveillance in patients with PSC.
Table 3. PSC Management and Surveillance
Abbreviations: CA, carbohydrate antigen; MRI, magnetic resonance imaging; US, ultrasound.
MRCP is preferred initial method
UDCA is controversial; avoid high-dose UDCA
Colonoscopy at time of diagnosis
If high suspicion and MRCP-negative, proceed to ERCP
Steroids if associated features of autoimmune hepatitis or high IgG4
• IBD: repeat every 1–2 years
• No evidence of IBD: repeat every 5 years or sooner if clinically indicated
Liver biopsy if needed
Endoscopic dilatation of dominant stricture if clinically indicated