Primary Sclerosing Cholangitis 

Updated: Nov 21, 2019
Author: Vikas Khurana, MD, FACP, FACG; Chief Editor: Vinay Kumar Kapoor, MBBS, MS, FRCS, FAMS 

Overview

Background

Primary sclerosing cholangitis (PSC) is a chronic liver disease characterized by a progressive course of cholestasis with inflammation and fibrosis of the intrahepatic and extrahepatic bile ducts.[1, 2, 3, 4] The underlying cause of the inflammation is believed to be autoimmune. The condition may lead to cirrhosis of the liver with portal hypertension and end-stage liver disease (ESLD).[1, 5] (See Presentation.)

PSC is strongly associated with inflammatory bowel disease (IBD),[5, 6, 7] mainly ulcerative colitis, and is often complicated by the development of cholangiocarcinoma.[2, 8] A higher risk of colorectal cancer has been described among patients with ulcerative colitis and PSC; therefore, surveillance for colorectal cancer is strongly recommended in these patients.[6, 7, 9]

PSC has been reported more frequently since the advent of endoscopic retrograde cholangiopancreatography (ERCP) and magnetic resonance cholangiopancreatography (MRCP). Liver function tests, including levels of serum alkaline phosphatase, gamma glutamyl transpeptidase, and serum aminotransferase, and the presence of hypergammaglobulinemia, are the most valuable in the laboratory workup. (See Workup.)

Therapy is aimed at treating symptoms and managing complications. Immunosuppressants, chelators, and steroids are used in an attempt to control the disease process but have not shown significant benefit. Liver transplantation is the only therapy that can alter the eventual outcome. PSC is the fourth leading indication for liver transplantation in adults. (See Treatment and Medication.)

For more information, see the Medscape Drugs & Diseases articles Pediatric Primary Sclerosing Cholangitis and Primary Sclerosing Cholangitis Imaging.

It is suggested the reader also read Primary Sclerosing Cholangitis: Therapeutic Options and Surveillance Management, an overview of PSC and its management options by Kumar, Wheatley, and Puttanna.

Etiopathophysiology

The etiology of primary sclerosing cholangitis (PSC) remains unknown, but it is thought to be multifactorial, including genetic predisposition, exposure to an environmental antigen, and subsequent aberrant immunologic response to that stimulus.[1, 10, 11] There is also an increased prevalence of HLA alleles A1, B8, and DR3 in PSC.[12, 13]

An autoimmune mechanism is suggested, because approximately 70% of patients with PSC have inflammatory bowel disease (IBD).[14] However, only approximately 4% of patients with IBD have or develop PSC. A marked increase in serum autoantibody levels occurs in patients with PSC as well, with antineutrophil cytoplasmic antibodies (ANCA) in 87%, anticardiolipin (aCL) antibodies in 66%, and antinuclear antibodies (ANA) in 53%. It has been reported that PSC and IBD have overlapping yet distinct genetic architectures.[15]

In the biliary ducts, an inflammatory response to chronic or recurrent bacterial infection in the portal circulation and from exposure to toxic bile acids has been postulated.[16] A genetic predisposition has been suggested because of an increased prevalence of HLA-B8, HLA-DR3, and HLA-Drw52a. Genome-wide association studies (GWAS) performed in PSC have identified about 20 genes that are significantly associated with PSC, most of which localize within the human leukocyte antigen (HLA) complex.[14]  Subclassification of PSC patients according to their genetic predisposition may well constitute a valuable tool for future research in the subject.[17]

Ischemic damage to the biliary tree has also been postulated, as surgical trauma to the biliary tract can cause similar damage and because of the high number of patients with PSC who are ANCA–positive as observed in other vasculitides. Therefore, the most plausible concept of the pathogenesis of PSC involves the exposure of genetically predisposed individuals to an environmental antigen that subsequently elicits an aberrant immune response, leading to development of the disease.

Epidemiology

In the United States, the prevalence of primary sclerosing cholangitis (PSC) is not known. Inferences have been drawn on the basis of the strong relationship with inflammatory bowel disease (IBD), which has a prevalence of 60-80% in patients with PSC in western countries.[6]

The prevalence of PSC is estimated to be 6.3 cases per 100,000 population. Western Europe is thought to have approximately the same prevalence as in the United States, although Scandinavian countries report a somewhat higher rate. In many developing countries with limited access to advanced health care, the prevalence of PSC is probably underestimated, as the diagnosis cannot be confirmed without endoscopic retrograde cholangiopancreatography (ERCP). The association of PSC with IBD may vary; for example, in Japan, only 34-37% of patients with PSC have IBD.[18, 19] The disease normally starts at age 20-30 years, although it may begin in childhood. PSC may be active for a long time before it is noticed or diagnosed.

A survey of the literature has not revealed a racial bias for PSC, but studies on this aspect of the disease are rather limited. Based on the epidemiologic data available for IBD, the Jewish population might be expected to have a 2- to 4-fold higher prevalence, followed by, in descending order of frequency, white persons, black individuals, Hispanic people, and Asian populations.

Young to middle-aged males are primarily affected.[3] Approximately 70% of patients with PSC are men, with a mean age of diagnosis around 40 years. Patients with PSC but without IBD are more likely to be women and to be older at diagnosis.

PSC is also seen predominantly in nonsmokers.

Prognosis

Primary sclerosing cholangitis (PSC) is generally a progressive disease that eventually culminates in cirrhosis with complications (eg, portal hypertension, end-stage liver disease, hepatic failure). The median length of survival from diagnosis to death is approximately 12 years. Liver transplantation is the only treatment modality that appears to change the prognosis. Survival prospects are more dismal for those who are symptomatic at diagnosis.

The revised Mayo Clinic model for survival probability in patients with PSC[20, 21] includes the following:

  • Age

  • Variceal bleeding history

  • Serum bilirubin, albumin, and aspartate aminotransferase (AST) levels

The Child-Turcotte-Pugh (CTP) scale[22] for calculation of severity of disease includes the following:

  • Grade of encephalopathy

  • Presence or absence of ascites

  • Serum albumin level

  • Prothrombin time

  • Bilirubin level

A study by Rupp et al indicated that patients with PSC who reduce their alkaline phosphatase levels within the first year of having the condition have longer periods of liver transplantation-free survival, independent of the existence of dominant biliary strictures. The study involved 215 patients with PSC, some of whom were without strictures, some of whom presented with strictures, and some of whom developed strictures during the study. The amount and speed of alkaline phosphatase reduction were monitored, with previously published values for alkaline phosphatase decreases in patients with PSC also taken into account.[23]

Complications

PSC is characterized by recurrent episodes of cholangitis, with progressive biliary scarring and obstruction. Chronic cholestasis leads to steatorrhea, fat-soluble vitamin deficiency (vitamins A, D, E, and K), metabolic bone disease with osteoporosis, and calorie loss with resultant weight loss.[1] Secondary biliary cirrhosis (SBC) due to chronic cholestasis occurs in patients with PSC. Portal hypertension with variceal bleeding, ascites, and liver failure then ensue.

PSC might initiate amyloid A protein deposition in diverse tissues, giving rise to systemic amyloidosis, due to a progressive and unresolved inflammatory process, and its possible association with inflammatory bowel disease (IBD). The proper treatment of PSC complicated by systemic Amyloid A amyloidosis remains to be determined.[24]

Cholangiocarcinoma reportedly occurs in association with PSC in 6-30% of patients; on autopsy, it is found in up to 30-40% of patients with PSC. Indeed, about half of patients with PSC are diagnosed with cholangiocarcinoma within 2 years of the initial diagnosis, with an associated poor prognosis owing to advanced disease at the time of diagnosis.[8] The development of cholangiocarcinoma remains unpredictable in any given patient, and no reliable serologic tumor markers have been identified. Worsening jaundice, pruritus, or weight loss may indicate development of a stricture or cholangiocarcinoma.

Dominant biliary strictures can be identified in about 20% of patients with PSC and must be differentiated from cholangiocarcinoma. Strictures cause cholestasis with jaundice and pruritus and may also result in cholangitis.

The risk of colon cancer is increased for patients with both ulcerative colitis and PSC versus those with ulcerative colitis alone.

 

Presentation

History

Whereas primary sclerosing cholangitis (PSC) occurs in about 5% of patients with inflammatory bowel disease (IBD), approximately 70% of patients with PSC have IBD.[14] Of these, 87% have ulcerative colitis and 13% have Crohn colitis; however, the course of IBD is not related to PSC. Most patients are male and are diagnosed at a mean age of approximately 40 years.[25]

Symptoms upon initial presentation consist of fatigue, pruritus, and right upper quadrant pain. The clinical course varies a great deal. Symptoms may remit and then recur spontaneously. Occasionally, patients with PSC have an acute hepatitislike presentation. Recurrent febrile episodes of bacterial cholangitis (ie, fever with jaundice) occur in 10-15% of patients during the course of PSC. Pancreatic duct involvement in PSC is uncommon, and pancreatic exocrine insufficiency is not correlated when ductal abnormalities are noted.

Patients with asymptomatic PSC constitute 20-40% of the cohort in some large studies. This high percentage is thought to be attributable to the practices of screening patients with ulcerative colitis for elevated alkaline phosphatase levels and performing endoscopic retrograde cholangiopancreatography (ERCP). Cirrhosis, portal hypertension, and liver failure occur in progressive disease, with symptoms consistent with these entities, including variceal bleeding, ascites, and hepatic encephalopathy. As noted earlier, the risk for cholangiocarcinoma is increased significantly in patients with PSC.[26, 27]

Physical Examination

Physical examination results are significant for jaundice, weight loss and, occasionally, pruritic skin marks. Hepatomegaly is common, and splenomegaly is present in up to one third of patients with primary sclerosing cholangitis (PSC). As the disease progresses, signs of liver failure, including spider angiomata, ascites, and muscle atrophy, become apparent.

 

DDx

Diagnostic Considerations

The differential diagnosis of primary sclerosing cholangitis (PSC) includes congenital diseases (eg, Caroli disease, choledochal cysts) and secondary cholangiopathy, as observed in patients with collagen vascular diseases (eg, systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis) and in those with infiltrative diseases (eg, mediastinal fibrosis, Riedel thyroiditis, eosinophilic cholangitis, histiocytosis X). Infectious causes from parasitic, fungal, viral, or bacterial infections or from recurrent cholangitis itself, especially in patients who are immunocompromised, can cause multifocal liver abscesses that lead to a PSC-like appearance of the bile duct.

Biliary S100A9 levels may be a useful marker for PSC activity, and its implication in inflammation and carcinogenesis warrants further investigation.[28]

The most important differential diagnosis is from cholangiocarcinoma. CA 19-9 levels above 130 U/mL may suggest the diagnosis of cholangiocarcinoma, which can be established by brush cytology (endoscopic or percutaneous transhepatic).

Differential Diagnoses

 

Workup

Approach Considerations

Liver function tests (LFTs) and histology (liver biopsy) are used in the evaluation of patients with suspected primary sclerosing cholangitis (PSC).[6]

LFTs, including levels of serum alkaline phosphatase (ALP), serum aminotransferase (ALT and AST), and gamma glutamyl transpeptidase (GGTP), and the presence of hypergammaglobulinemia, are the most valuable in the laboratory workup.

The most important imaging study is magnetic resonance cholangiopancreatography (MRCP). Percutaneous transhepatic cholangiography (PTC) and endoscopic retrograde cholangiopancreatography (ERCP) may also be utilized, more for therapeutic intent than for diagnosis. The most common characteristic histologic feature is onion skin fibrosis (concentric periductal fibrosis) (see the image below). Liver biopsy is rarely used for diagnosis of PSC, although it does help determine both the stage and the prognosis of the disease.

Periductal onion skin fibrosis seen in primary scl Periductal onion skin fibrosis seen in primary sclerosing cholangitis.

Laboratory Studies

Liver function tests

The most valuable laboratory studies in primary sclerosing cholangitis (PSC) are liver function tests. Serum alkaline phosphatase dominates the profile, which is cholestatic in nature. Levels are usually 3-5 times the reference-range values. Alkaline phosphatase can be divided into its various fractions to ascertain its origin from liver disease, as opposed to bone disease. Serum gamma-glutamyl transpeptidase levels mirror this rise and can help differentiate cholestasis from bone disease. Some patients with hypothyroidism, hypophosphatemia, or zinc or magnesium deficiency may have normal alkaline phosphatase levels.

Serum aminotransferase levels are increased in PSC but not markedly so. Serum bilirubin levels, with the conjugated component, are usually increased, but fluctuations in the level can occur. Serum albumin levels decrease later in the course of the disease, and the presence of hypoalbuminemia earlier in the disease may indicate active inflammatory bowel disease (IBD).

Hypergammaglobulinemia is present in 30% of patients, and 50% have increased immunoglobulin (IgM) levels. Perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) are present in 84% of patients; anticardiolipin (aCL) antibodies, in 66%; and antinuclear antibodies (ANA), in 53%. Multispecific ANCA with ANA and anti-smooth muscle antibody (ASMA) may be potential markers for PSC.[29]

Imaging Studies

Because it is noninvasive, magnetic resonance cholangiopancreatography (MRCP) is the preferred study to evaluate the bile ducts.[5] MRCP findings include multiple annular strictures and dilatations of the intrahepatic and extrahepatic biliary ducts giving a beaded appearance and a pruned tree appearance. MRCP combined with magnetic resonance imaging (MRI) is able to demonstrate focal biliary anomalies and subtle liver lesions.[8]

Although endoscopic retrograde cholangiopancreatography (ERCP) is the gold standard for diagnosis of cholangitis, it is used more for therapeutic intervention than for confirming the diagnosis of primary sclerosing cholangitis (PSC).[5] Percutaneous transhepatic cholangiography (PTC) is performed when ERCP is unsuccessful. If ERCP or PTC are performed, brush cytology may be obtained to rule out cholangiocarcinoma. Serum CA 19-9 levels may also be obtained.

Although ultrasonography is commonly used for the initial evaluation of patients with PSC, it is not good at detecting small tumors in the heterogeneous liver.[8] However, contrast-enhanced ultrasonography can be useful for revealing cholangiocarcinoma by demonstrating rapid and marked washout.[8]

See the related images below.

Endoscopic retrograde cholangiopancreatography per Endoscopic retrograde cholangiopancreatography performed in a patient with abnormal liver function test results shows multiple intrahepatic bile duct strictures and beading.
Double-contrast barium enema (same patient as in t Double-contrast barium enema (same patient as in the previous image) shows filiform polyps and an ahaustral colon resulting from ulcerative colitis.
Percutaneous transhepatic cholangiogram shows dila Percutaneous transhepatic cholangiogram shows dilatation, stricturing, and beading of the intrahepatic bile ducts. Note the surgical clips from a previous cholecystectomy.
This T-tube cholangiogram shows an irregularity of This T-tube cholangiogram shows an irregularity of the common bile duct, stricturing, beading, and dilatation of the intrahepatic bile ducts. Note a calculus in the termination of the left hepatic duct (arrow).
Magnetic resonance cholangiopancreatography shows Magnetic resonance cholangiopancreatography shows a normal-sized common bile duct, but strictures of both the left and right ducts are noted as well as a dilated proximal left hepatic duct.
This technetium-99m iminodiacetic acid scan shows This technetium-99m iminodiacetic acid scan shows retention of the radionuclide proximal to strictures in the distribution of the left hepatic duct. Note the lack of filling of the gallbladder because of a previous cholecystectomy. Isotope has entered the small bowel.

Magnetic resonance elastography (MRE) measurement of liver stiffness appears to show promise as a potential biomarker in chronic liver disease.[30] In a retrospective review of 266 patients with PSC, MRE not only showed a 100% sensitivity and 94% specificity for detecting cirrhosis, but it was also predictive of the development of decompensated liver disease. The investigators noted that advanced liver stiffness was unlikely in the presence of a serum alkaline phosphatase level less than 1.5 times the upper limit of normal.[30]

Histologic Findings

Liver biopsy is not required for the diagnosis of primary sclerosing cholangitis (PSC) if magnetic resonance cholangiopancreatography (MRCP) findings are suggestive.

A variety of histopathologic liver changes are noted in patients with PSC. The most common characteristic feature is onion skin fibrosis (see the image below), which describes the appearance of periductal concentric fibrosis around the interlobular and septal bile ducts. This is present in only half of all biopsy specimens from patients with otherwise typical PSC, whereas concentric fibrosis with obliteration of the small ducts (obliterative fibrous cholangitis)—a virtually diagnostic histopathologic lesion—is found in less than 10% of biopsy specimens. Periductal fibrosis may be accompanied by infiltrates of inflammatory cells. Piecemeal necrosis, as occurs in patients with chronic hepatitis, may be observed as well.

Periductal onion skin fibrosis seen in primary scl Periductal onion skin fibrosis seen in primary sclerosing cholangitis.

Staging

Ludwig and associates described 4 stages of PSC,[31] as follows:

  • Stage 1: Portal hepatitis, degeneration of bile ducts with inflammatory cell infiltrate

  • Stage 2: Extension of disease to periportal area with prominent bile ductopenia

  • Stage 3: Septal fibrosis and necrosis

  • Stage 4: Frank cirrhosis

 

Treatment

Approach Considerations

No approved or proven therapy exists for primary sclerosing cholangitis (PSC).[1, 3, 32] Pharmacotherapy is aimed at treating symptoms and managing complications. Immunosuppressants, bile salts, chelators (eg, cholestyramine for pruritus), and steroids are used in an attempt to control the disease process but have not shown significant benefit.

Further care is dictated by the stage and degree of progression of the disease. It involves care by a gastroenterologist, who must monitor the patient's condition with frequent laboratory tests and maintain vigilance for the many complications of PSC.

Liver transplantation is the only therapy that can alter the eventual outcome, with reported posttransplant survival rates of 85% at 5 years and 70% at 10 years.[6] Suitability for liver transplantation should be determined expeditiously and, if appropriate, offered to the patient. Risk for development of inflammatory bowel disease (IBD) persists even after transplantation.

Endoscopic or percutaneous transhepatic dilation of dominant strictures, with or without stenting, has been shown to alleviate cholestasis and to improve laboratory test results; however, it is not currently believed to affect disease progression. Ruling out malignancy in these strictures is difficult.

Ursodeoxycholic acid studies

Use of ursodeoxycholic acid (UDCA) is debatable and controversial. The American Association for the Study of Liver Diseases (AASLD) does not recommend UDCA for as a routine chemopreventive agent to reduce the risk of colorectal dysplasia in patients with PSC and ulcerative colitis[33] ; the European Association for the Study of the Liver (EASL) recommends oral UDCA (13-15 mg/kg/day) as first-line pharmacotherapy in all patients with PSC, often continued for life. The dosing regimen for UDCA is also under debate, including whether a low dose (15-20 mg/kg/day) or high dose (30 mg/kg/day) is optimal.

UDCA has been shown to improve the liver function profile in some patients and, in conjunction with endoscopic dilation, has shown a survival benefit in some studies.

In a study of adult patients with PSC who were given 28-30 mg/kg/day of UDCA versus placebo, Lindor et al reported that the patients treated with UDCA had a greater decrease in serum liver test results but a higher risk of serious adverse events (ie, varices, cholangiocarcinoma, liver transplantation, and death). The risk of a primary endpoint was 2.3-fold greater for the UDCA-treated group than those in the placebo group and 2.1-fold greater risk for death, transplantation, or minimal listing criteria.[34]

Shi et al performed a meta-analysis of randomized, controlled trials comparing UDCA with placebo or no treatment and found that UDCA improved liver biochemistry study results and that there were trends in histologic and cholangiographic improvement.[35] However, the study also showed no improvement for pruritus and fatigue, liver transplantation, or incidence of death.[35]

Liver Transplantation

Indications for liver transplantation in patients with primary sclerosing cholangitis (PSC) include variceal bleeding or portal gastropathy, intractable ascites, recurrent cholangitis, progressive muscle wasting, hepatic encephalopathy, and poor quality of life. Survival rates have been shown to be 93.7% at 1 year, 92.2% at 2 years, 86.4% at 5 years, and 69.8% at 10 years. However, PSC recurs in 15-20% of patients after liver transplantation.[10, 36]

In addition to liver transplantation, procedures include restorative proctocolectomy (RPC) with ileal pouch anal anastomosis (IPAA) for patients with ulcerative colitis and biliary reconstructive procedures.[37] Note that proctocolectomy in patients with both PSC and ulcerative colitis has no effect on the course of PSC.

Posttransplantation complications include recurrence of PSC, worsening of inflammatory bowel disease (IBD) activity, and de novo IBD occurrence.[6]

Diet and Activity

Patients with steatorrhea are encouraged to include medium-chain triglycerides in their diet. Fat-soluble vitamin deficiency correction should be attempted by supplementation. Oral supplementation is necessary if associated pancreatic enzyme deficiency is present. Calcium supplementation for bone disease may also be needed.

Physical activity should not be restricted; however, in patients with osteoporosis, the possibility of fractures should temper the type of activity allowed.

Consultations

A gastroenterologist must be consulted. When needed, surgical consultation should be initiated by the gastroenterologist and when liver transplantation is offered. An endocrinologist may be consulted for management of bone disease.

Long-Term Monitoring

Nearly 50% of deaths in patients with primary sclerosing cholangitis (PSC) are due to cancer.[38] All patients with PSC should undergo surveillance for malignancy. Such monitoring includes the following:

  • Colonoscopy and biopsy to rule out inflammatory bowel disease (IBD)
  • Annual or biannual colonoscopy to rule out colorectal carcinoma in patients with PSC and IBD, even after liver transplantation
  • Serum CA 19-9 levels every 6-12 months for surveillance of cholangiocarcinoma
  • Annual ultrasonography to monitor for gall bladder cancer
 

Guidelines

Guidelines Summary

In August 2019, the British Society of Gastroenterology (BSG) and UK-PSC published guidelines for the prevention and treatment of primary sclerosing cholangitis.[39] These guidelines are summarized below.

Primary Sclerosing Cholangitis

Cholestatic liver biochemistry with typical cholangiographic features in the absence of other identifiable causes of secondary sclerosing cholangitis is usually sufficient for a diagnosis of primary sclerosing cholangitis (PSC).

Magnetic resonance cholangiopancreatography (MRCP) is recommended as the principal imaging modality for investigating suspected PSC.

Liver biopsy should be reserved for possible small duct PSC, assessment of suspected possible overlap variants, or when the diagnosis is unclear.

Risk stratification based on non-invasive assessment is recommended.

Do not use ursodeoxycholic acid (UDCA) for the prevention of colorectal cancer or cholangiocarcinoma.

Corticosteroids and immunosuppressants are not recommended for the treatment of classic PSC; however, corticosteroids may be indicated in patients with additional features of autoimmune hepatitis (AIH) or IgG4-related sclerosing cholangitis (IgG4-SC).

Perform endoscopic screening for esophageal varices in line with international guidelines where there is evidence of cirrhosis and/or portal hypertension.

Use colonoscopy and colonic biopsies to seek colitis in all patients with PSC.

Patients with suspected PSC undergoing endoscopic retrograde cholangiopancreatography (ERCP) should receive prophylactic antibiotics.

Non-invasive investigations such as MRCP, dynamic liver MRI, and/or contrast CT should be performed in patients who have new or changing symptoms or evolving abnormalities.

Patients with PSC should not undergo ERCP until there has been expert multidisciplinary assessment to justify endoscopic intervention.

In patients undergoing ERCP for dominant strictures, pathological sampling of suspicious strictures is mandatory.

Biliary dilatation is preferred to the insertion of biliary stents in patients undergoing ERCP for dominant strictures.

Assess eligibility and referral for liver transplantation in patients with PSC.

Assess all patients with PSC for osteoporosis.

When cholangiocarcinoma is suspected, use contrast-enhanced, cross-sectional imaging for diagnosis and staging.

Encourage patients with PSC to participate in support groups.

IgG4-related Sclerosing Cholangitis

Do not rely on elevated serum IgG4 levels to make a definitive diagnosis of IgG4-related disease (IgG4-RD) or distinguish it from PSC.

Obtain a confirmatory histological diagnosis in patients with suspected IgG4-related sclerosing cholangitis (IgG4-SC).

Recognize that other organ involvement (in particular, pancreatic manifestations of IgG4-RD) may provide important information to distinguish IgG4-SC from PSC.

Diagnose IgG4-SC according to recommendations of international consensus guidelines.

Corticosteroids should be given as first-line treatment.

Consider all patients with IgG4-SC, including those with multiorgan involvement in IgG4-RD, for continued immunosuppressive therapy.

Refer patients with complex IgG4-SC and those with suspected malignancy to a specialist.

Resources

For more information, please see the following:

For more Clinical Practice guidelines go to Guidelines.

 

Medication

Medication Summary

No pharmacologic therapy has been proven effective for primary sclerosing cholangitis (PSC). Drug therapy is aimed at treating symptoms and managing complications. Immunosuppressants, chelators, and steroids are used in an attempt to control the disease process but have not shown significant benefit. Ursodeoxycholic acid (UDCA) improves the liver function profile in some patients and, in conjunction with endoscopic dilation, has shown a survival benefit in some studies. Trials using UDCA in higher doses and earlier in the disease course are ongoing.

Biologics (eg, anti-TNF-α) may benefit PSC when used to treat concomitant IBD.[40]

Phase II and III clinical trials are investigating new drugs designed to target specific disease mechanisms for precision medicine treatment of PSC.[14]

Immunosuppressant agents

Class Summary

With the possibility of an autoimmune pathogenesis for PSC, immunosuppressive therapy has been used in treatment of PSC. Results of therapeutic trials, however, have been disappointing.

Azathioprine (Imuran, Azasan)

Azathioprine antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. It may decrease proliferation of immune cells, which results in lower autoimmune activity.

Cyclosporine (Sandimmune, Neoral)

Cyclosporine is a cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions, such as delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft versus host disease for a variety of organs. For both children and adults, dosing is based on ideal body weight.

Prednisone

Prednisone is an immunosuppressant for the treatment of autoimmune disorders. It may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear activity. It stabilizes lysosomal membranes and suppresses lymphocyte and antibody production.

Methotrexate (Trexall, Rheumatrex)

Methotrexate is an antimetabolite used in the treatment of certain neoplastic diseases, severe psoriasis, and adult rheumatoid arthritis. It inhibits dihydrofolic acid reductase. Dihydrofolates must be reduced to tetrahydrofolates by this enzyme before they can be used as carriers of single-carbon groups in the synthesis of purine nucleotides and thymidylate. Methotrexate therefore interferes with DNA synthesis, repair, and cellular replication.

Chelators

Class Summary

Observation of increased serum, urinary, and hepatic copper concentrations in patients with primary sclerosing cholangitis has prompted the use of penicillamine, which is a chelator.

Penicillamine (Cuprimine, Depen)

Penicillamine is a chelating agent that is recommended for the removal of excess copper in patients with Wilson disease. It depresses circulating IgM rheumatoid factor and T-cell activity but not B-cell activity.

Gallstone Solubilizing Agents

Class Summary

Ursodiol is thought to remove toxic bile acids from the enterohepatic circulation and to offer protection to the bile duct from injury.

Ursodiol (Actigall)

Ursodiol suppresses hepatic synthesis and secretion of cholesterol and inhibits intestinal absorption of cholesterol. It may displace natural, toxic, and endogenous bile acids from the enterohepatic circulation and provide a cytoprotective effect, which may lead to decreased cholestasis and improved liver functions.

Lipid-Lowering Agents, Other

Class Summary

Cholestyramine is thought to decrease pruritus by combining with bile acids in the intestine and by causing them to be excreted because of nonreabsorption.

Cholestyramine (Prevalite, Questran)

Cholestyramine forms a nonabsorbable complex with bile acids in the intestine, which, in turn, inhibits enterohepatic reuptake of intestinal bile salts. In patients with partial biliary obstruction, the reduction of serum bile acid levels by cholestyramine reduces excess bile acids deposited in dermal tissue, which decreases pruritus.

 

Questions & Answers

Overview

What is primary sclerosing cholangitis (PSC)?

What is the pathogenesis of primary sclerosing cholangitis (PSC)?

What is the prevalence of primary sclerosing cholangitis (PSC) and which patient groups are at highest risk?

What is the prognosis of primary sclerosing cholangitis (PSC)?

What is the revised Mayo Clinic model for survival probability in primary sclerosing cholangitis (PSC)?

What is the Child-Turcotte-Pugh scale for primary sclerosing cholangitis (PSC)?

How does alkaline phosphatase levels affect the prognosis of primary sclerosing cholangitis (PSC)?

What are the complications of primary sclerosing cholangitis (PSC)?

Presentation

How frequently is inflammatory bowel disease (IBD) comorbid with primary sclerosing cholangitis (PSC)?

What are the signs and symptoms of primary sclerosing cholangitis (PSC)?

Which physical findings are characteristic of primary sclerosing cholangitis (PSC)?

DDX

Which conditions should be included in the differential diagnoses of primary sclerosing cholangitis (PSC)?

What are the differential diagnoses for Primary Sclerosing Cholangitis?

Workup

Which tests are performed in the evaluation for primary sclerosing cholangitis (PSC)?

What is the role of lab studies in the workup of primary sclerosing cholangitis (PSC)?

What is the role of imaging studies in the workup of primary sclerosing cholangitis (PSC)?

Which histologic findings are characteristic of primary sclerosing cholangitis (PSC)?

What are the stages of primary sclerosing cholangitis (PSC)?

Treatment

What are the treatment options for primary sclerosing cholangitis (PSC)?

What is the role of ursodeoxycholic acid (UDCA) in the treatment of primary sclerosing cholangitis (PSC)?

What is the role of liver transplantation in the treatment of primary sclerosing cholangitis (PSC)?

What is the role of dietary and activity modifications in the treatment of primary sclerosing cholangitis (PSC)?

Which specialist consultations are beneficial in the management of primary sclerosing cholangitis (PSC)?

What is included in the long-term monitoring of patients with primary sclerosing cholangitis (PSC)?

Medications

What is the role of pharmacologic therapy for primary sclerosing cholangitis (PSC)?

Which medications in the drug class Lipid-Lowering Agents, Other are used in the treatment of Primary Sclerosing Cholangitis?

Which medications in the drug class Gallstone Solubilizing Agents are used in the treatment of Primary Sclerosing Cholangitis?

Which medications in the drug class Chelators are used in the treatment of Primary Sclerosing Cholangitis?

Which medications in the drug class Immunosuppressant agents are used in the treatment of Primary Sclerosing Cholangitis?