PSC is a chronic cholestatic liver and biliary tract disease with a highly variable natural history. The pathogenesis of the disorder remains elusive. Complications of the disease are a direct result of fibrosis and strictures involving intra and extrahepatic bile ducts. PSC may be asymptomatic for long periods but may also have an aggressive course, leading to recurrent biliary tract obstruction, recurrent episodes of cholangitis, and progression to end-stage liver disease. The diagnosis is now most frequently established using magnetic resonance cholangiography (MRCP), although direct cholangiography may be more sensitive. The typical cholangiographic findings include focal stricturing and saccular dilatation of the bile ducts (“beaded”). The differential diagnosis of PSC includes several disorders that lead to biliary strictures such as bacterial cholangitis, intraarterial administration of floxuridine, prior biliary surgery, and AIDS- related cholangiopathy.
ACG Guideline Recommendation Summary:
- Differential diagnosis of primary sclerosing cholangitis
- Secondary sclerosing cholangitis
- Cholangiocarcinoma
- IgG4-associated cholangitis
- Histiocytosis X
- Autoimmune hepatitis
- HIV syndrome
- Bile duct strictures
- Cholendocholithiasis
- Primary biliary cirrhosis
- Papillary tumors
- Diagnosis
- Endoscopic retrograde cholangiopancreatography (ERCP) has been the most common procedure in diagnosing PBS. However, magnetic resonance cholangiopancreatography (MRCP) is rapidly becoming the preferred method because it is noninvasive, cheaper and has no associated risk of pancreatitis. A liver biopsy is not needed unless a patient is suspected of having small duct PSC.
- Therapy
- There is currently no established treatment for PSC. However, clinicians are using doses of ursodeoxycholic acid at 20 mg/kg per day for treating PSC.
- Endoscopic Management
- Endoscopic treatment of dominant strictures may improve prognosis, help to relieve the complications of pruritus and cholangitis, allow for early diagnosis of cholangiocarcinoma and may lead to improved survival. ERCP with balloon dilatation is recommended for relieving symptoms of dominant strictures of PSC patients. If a PSC patient undergoes ERCP, antibiotic prophylaxis should be taken to prevent post-ERCP cholangitis. Routine stenting after dilation is not recommended.
- IBD and PSC
- Up to 80% of patients with PSC have IBD. Undergoing annual colon surveillance is recommended in PSC patients with colitis at the time of PCS diagnosis. A colonoscopy with biopsies is recommended in PSC patients whether or not there are symptoms at PSC diagnosis. An exam every 3-5 years is also recommended for patients without prior evidence of colitis.
- Hepatobiliary Malignancies and Gallbladder Disease
- PSC patients are at risk for developing hepatobiliary malignancies. The risk for cholangiocarcinoma is several hundred times higher in patients with PSC vs. patients without PSC. Screening for cholangiocarcinoma with regular cross-sectional imaging with ultrasound or magnetic resonance and serial CA 19-9 is recommended every 6 to 12 months. Patients with PSC with gallbladder polyps more than 8 mm should also undergo cholecystectomy.
- Special Situations
- Every PSC patient is unique and some patients may develop autoimmune hepatitis and other infections. Testing for autoimmune hepatitis is recommended for patients with PSC under 25 years of age and for those patients with higher than expected aminotransferases. MRCP is recommended for PSC patients under 25 years of age with autoimmune hepatitis who have elevated alkaline phosphatase serum levels.
- General Management
- Patients with PSC should undergo bone mineral density screening at diagnosis using duel energy X-ray absorption repeated at 2- to 4-year intervals; patients with advanced liver disease should be checked and monitored for fat-soluble vitamin deficiencies; and patients with PSC and mild pruritus should undergo local skin treatment with antihistamines or emollients to reduce symptoms.
The ACG Guideline include 24 suggested recommendations on how to diagnose a patient, whether ursodeoxycholic acid should be used as a treatment, on endoscopic management, and how to treat patients who need a liver transplant or have inflammatory bowel disease (IBD), as well as general management issues.
DIAGNOSIS
- MRCP is preferred over endoscopic retrograde cholangiopancreatography (ERCP) to establish a diagnosis of PSC.
- Liver biopsy is not necessary to make a diagnosis in patients with suspected PSC based on diagnostic cholangiographic findings.
- Liver biopsy is recommended to make a diagnosis in patients with suspected small duct PSC or to exclude other conditions such as suspected overlap with autoimmune hepatitis.
- Antimitochondrial autoantibody testing can help exclude primary biliary cirrhosis.
- Patients with PSC should be tested at least once for elevated serum immunogloblulin G4 (IgG4) levels.
MEDICAL TREATMENT
- At this time, there is no established medical treatment for patients with PSC.
- Ursodeoxycholic acid (UDCA) in doses >28 mg/kg/day should not be used for the management of patients with PSC.
- Other treatments that have been tested without any obvious proven clinical benefit or improvement of liver biochemistries include:
- Azathioprine
- Budesonide
- Docosahexaenoic acid
- Methotrexate
- Metronidazole
- Minocycline
- Mycophenolate mofetil
- Nicotine
- Pentoxifylline
- Pirfenodone
- Prednisolone
- Tacrolimus
- Vancomycin
ENDOSCOPIC MANAGEMENT
- ERCP with balloon dilatation is recommended for PSC patients with dominant stricture and pruritus, and/or cholangitis, to relieve symptoms.
- PSC with a dominant stricture seen on imaging should have an ERCP with cytology, biopsies, and fluorescence in-situ hybridization (FISH), to exclude diagnosis of cholangiocarcinoma.
- PSC patients undergoing ERCP should have antibiotic prophylaxis to prevent post-ERCP cholangitis.
- Routine stenting after dilation of a dominant stricture is not required, whereas short-term stenting may be required in patients with severe stricture.
PERCUTANEOUS MANAGEMENT
- Percutaneous cholangiography for treatment of dominant strictures can be performed in PSC patients with altered anatomy that prevents successful ERCP, such as Roux-en-Y choledo-chojejunostomy or gastric bypass, or as a rescue therapy after failed endoscopic access. Percutaneous cholangiography is generally the second line of treatment after ERCP because of the risk of complications, including hepatic arterial injury, hemobilia, and cholangitis
LIVER TRANSPLANTATION
- Liver transplantation, when possible, is recommended over medical therapy or surgical drainage in PSC patients with decompensated cirrhosis, to prolong survival.
- Patients should be referred for liver transplantation when their Model for End-Stage Liver Disease (MELD) score exceeds 14.
- In specific clinical circumstances, patients with PSC may be offered additional MELD points, to improve their priority for receiving a donor organ for liver transplantation. MELD exception points can be approved by the United Network for Organ Sharing Regional Review Board for the following indications:
- Recurrent episodes of cholangitis, with >2 episodes of bacteremia or >1 episode of sepsis.
- Cholangiocarcinoma less then 3 cm in diameter, without evidence of metastasis, undergoing treatment through an institutional review board-approved clinical trial.
- Intractable pruritus.
- Recurrence of PSC after liver transplantation is relatively common, affecting as many as 20% of patients at 5 years after transplantation.
PSC AND IBD
- The risk of colorectal dysplasia and cancer is significantly higher (approximately four- to fivefold) among patients with PSC and IBD compared with those with IBD without PSC.
- Annual colon surveillance preferably with chromoendoscopy is recommended in PSC patients with colitis beginning at the time of PSC diagnosis.
- A full colonoscopy with biopsies is recommended in patients with PSC regardless of the presence of symptoms to assess for associated colitis at time of PSC diagnosis.
- Some advocate repeating the exam every 3–5 years in those without prior evidence of colitis.
HEPATOBILIARY MALIGNANCIES AND GALLBLADDER DISEASE
- Consider screening for cholangiocarcinoma with regular cross-sectional imaging with ultrasound or MR and serial CA 19-9 every 6–12 months.
- Cholecystectomy should be performed for patients with PSC and gallbladder polyps >8 mm, to prevent the development of gallbladder adenocarcinoma.
SPECIAL SITUATIONS
- PSC and autoimmune hepatitis may co-exist in the same patient and the prevalence of autoimmune hepatitis in patients with PSC is ~10%.
- Further testing for autoimmune hepatitis is recommended for patients with PSC <25 years of age or those with higher- than-expected levels of aminotransferases usually 5× upper limit of normal.
- MRCP is recommended for patients <25 years of age with autoimmune hepatitis, who have elevated serum ALP usually greater than 2× the upper limit of normal.
PSC IN CHILDREN
- PSC appears to be much less common among children than adults, with an estimated prevalence 20% lower than in adults and is a rare indication for liver transplantation in this population. PSC in children is more often associated with higher serum aminotransferase levels and concomitant autommune hepatitis, and sclerosing cholangitis is a more common phenomenon, leading to the use of the term “autoimmune sclerosing cholangitis.” Serum ALP may be elevated in children due to bone growth; hence, suspected cholestasis should be confirmed by measurement of gamma-glutamyl transpeptidase levels. Cholangiocarcinoma appears to be rare in this population and surveillance for gallbladder cancer or cholangiocarcinoma is not recommended.
IMMUNOGLOBULIN G4-AASSOCIATED CHOLANGITIS
- IgG4-associated pancreatitis and cholangitis is being increasingly recognized in patients who present with sclerosing cholangitis. IgG4-associated autoimmune pancreatitis is a clearly described entity characterized by strictures in the pancreatic duct, elevated IgG4 levels and response to immunosuppressive therapy. This condition may be associated with biliary strictures and elevated plasma IgG4 levels, and liver biopsy may reveal a lymphoplasmacytic infiltrate . In some cases, the biliary disease is predominant and features of autoimmune pancreatitis may or may not be present.
- Measurement of IgG4 levels is reasonable in patients with PSC and consideration should be given to imaging for autoimmune pancreatitis and the presence of IgG4-associated cholangitis among those with markedly elevated IgG4 levels.
- Liver biopsy should be considered to identify the classical lymphoplasmacytic infiltrate and consideration of immunosuppression therapy may be useful in such patients, especially if they have higher-than- expected elevations of serum aminotransferase levels.
GENERAL MANAGEMENT
- Local skin treatment should be performed with emollients and/or antihistamines in patients with PSC and mild pruritus, to reduce symptoms.
- Bile acid sequestrants such as cholestyramine should be taken (prescribed) in patients with PSC and moderate pruritus to reduce symptoms. Second-line treatment such as rifampin and naltrexone can be considered if cholestyramine is ineffective or poorly tolerated.
- Recommend screening for varices in patients with signs of advanced disease with platelet counts <150×103/dl.
- Patients with PSC should undergo bone mineral density (BMD) screening at diagnosis with dual energy X-ray absorption at diagnosis and repeated at 2- to 4-year intervals.
- Patients with advanced liver disease should be screened and monitored for fat-soluble vitamin deficiencies.
SUMMARY OF RECOMMENDATIONS
- MRCP is preferred over ERCP to establish a diagnosis of PSC.
- Liver biopsy is not necessary to make a diagnosis in patients with suspected PSC based on diagnostic cholangiographics findings.
- Liver biopsy is recommended to make a diagnosis in patients with suspected small duct PSC or to exclude other conditions such as suspected overlap with autoimmune hepatitis.
- Antimitochondrial autoantibody testing can help exclude primary biliary cirrhosis.
- Patients with PSC should be tested at least once for elevated serum IgG4 levels.
- UDCA in doses >28 mg/kg/day should not be used for management of patients with PSC
- ERCP with balloon dilatation is recommended for PSC patients with dominant stricture and pruritus, and/or cholangitis, to relieve symptoms.
- PSC with a dominant stricture seen on imaging should have an ERCP with cytology, biopsies and FISH to exclude diagnosis of cholangiocarcinoma.
- PSC patients undergoing ERCP should have antibiotic prophylaxis to prevent post-ERCP cholangitis.
- Routine stenting after dilation of a dominant stricture is not required, whereas short-term stenting may be required in patients with severe stricture.
- Liver transplantation, when possible, is recommended over medical therapy or surgical drainage in PSC patients with decompensated cirrhosis, to prolong survival
- Patients should be referred for liver transplantation when their MELD score exceeds 14.
- Annual colon surveillance preferably with chromoendoscopy is recommended in PSC patients with colitis beginning at the time of PSC diagnosis.
- A full colonoscopy with biopsies is recommended in patients with PSC regardless of the presence of symptoms to assess for associated colitis at the time of PSC diagnosis.
- Some advocate repeating the exam every 3–5 years in those without prior evidence of colitis.
- Consider screening for cholangiocarcinoma with regular cross-sectional imaging with ultrasound or MR and serial CA 19-9 every 6–12 months.
- Cholecystectomy should be performed for patients with PSC and gallbladder polyps >8 mm, to prevent the development of gallbladder adenocarcinoma.
- Further testing for autoimmune hepatitis is recommended for patients <25 years of age with PSC or those with higher- than-expected levels of aminotransferases usually 5× upper limit of normal.
- MRCP is recommended for patients <25 years of age with autoimmune hepatitis, who have elevated serum ALP usually >2× the upper limit of normal.
- Local skin treatment should be performed with emollients and/or antihistamines in patients with PSC and mild pruritus, to reduce symptoms.
- Bile acid sequestrants such as cholestyramine should be taken (prescribed) in patients with PSC and moderate pruritus, to reduce symptoms. Second-line treatment such as rifampin and naltrexone can be considered if cholestyramine is ineffective or poorly tolerated.
- Recommend screening for varices in patients with signs of advanced disease with platelet counts <150×103/dl.
- Patients with PSC should undergo BMD screening at diagnosis with dual energy X-ray absorption at diagnosis and repeated at 2- to 4-year intervals.
- Patients with advanced liver disease should be screened and monitored for fat-soluble vitamin deficiencies.
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