Continuing Education Activity

Primary sclerosing cholangitis (PSC) is a chronic, progressive cholestatic liver disease marked by inflammation and fibrosis of the intrahepatic and extrahepatic bile ducts, leading to multifocal strictures and eventual biliary cirrhosis. It is strongly associated with inflammatory bowel disease, especially ulcerative colitis, and carries increased risks of cholangiocarcinoma, gallbladder cancer, colorectal cancer, portal hypertension, and cirrhosis. Clinical presentation varies from asymptomatic cases with incidental cholestatic liver enzyme abnormalities to symptoms such as fatigue, pruritus, and right upper quadrant pain. This activity reviews PSC pathogenesis, diagnosis, risk stratification, and evidence-based management, emphasizing symptom control, malignancy surveillance, and complication management. Learners will enhance their ability to recognize early clinical and laboratory features, interpret imaging and serologic findings, differentiate overlap syndromes, implement cancer surveillance, and identify candidates for transplantation or clinical trials. As no medical therapy alters disease progression, liver transplantation remains the only curative option for advanced disease.

Objectives:

• Identify the epidemiology of primary sclerosing cholangitis.
• Apply current diagnostic criteria while excluding secondary causes of sclerosing cholangitis.
• Select the most appropriate management approach for a patient with primary sclerosing cholangitis.
• Collaborate on interprofessional team strategies to improve care coordination and outcomes for patients affected by primary sclerosing cholangitis.

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Introduction

Primary sclerosing cholangitis (PSC) is a chronic, progressive cholestatic liver disease of unknown etiology characterized by inflammation and fibrosis of the intrahepatic and extrahepatic bile ducts, leading to multifocal strictures and eventual biliary cirrhosis.[1] Classification includes 3 subtypes: classic or large-duct PSC involving both intrahepatic and extrahepatic ducts (approximately 90% of cases), small-duct PSC confined to the small intrahepatic ducts (approximately 5% of cases), and PSC with autoimmune hepatitis (AIH) overlap (approximately 5% of cases).

A strong association exists with inflammatory bowel disease (IBD), particularly ulcerative colitis, which occurs in 60% to 80% of PSC cases.[2] Concurrent PSC and ulcerative colitis markedly increase colorectal cancer risk, warranting surveillance colonoscopy every 1 to 2 years. PSC also carries substantial risk for hepatobiliary malignancies, especially cholangiocarcinoma, with a lifetime incidence of 10% to 20% and an annual risk of 1% to 2%, in addition to increased gallbladder cancer risk.[3]

Historically, diagnosis relied on cholangiographic findings obtained via endoscopic retrograde cholangiopancreatography (ERCP); magnetic resonance cholangiopancreatography (MRCP) is now the preferred noninvasive imaging modality. No medical therapy has demonstrated the ability to modify disease progression. Ursodeoxycholic acid (UDCA) is frequently used empirically and may improve alkaline phosphatase levels, although long-term benefits remain unproven.[4] Liver transplantation provides the only curative treatment for advanced disease, yet PSC recurs in up to one-third of transplant recipients.[4]

Etiology

PSC represents a multifactorial disease driven by the interplay between genetic susceptibility and environmental triggers, culminating in an aberrant immune-mediated attack on the bile ducts.[5] Genome-wide association studies have identified over 20 susceptibility loci, with the strongest associations located in the HLA region, along with several non-HLA risk loci involved in immune-regulatory pathways, including the IL2/IL21 cytokine gene region and FUT2.[6] A strong epidemiologic association links PSC with inflammatory bowel disease, particularly ulcerative colitis. IBD occurs in approximately 60% to 80% of patients with PSC, whereas only 2% to 8% of patients with ulcerative colitis and 1% to 2% of patients with Crohn disease develop PSC.[7]

PSC demonstrates prominent autoimmune features, including multiple autoantibodies, most notably atypical pANCA detected in the majority of patients, and strong associations with specific HLA haplotypes, further supporting an immune-mediated pathogenesis.[5] Histologically, affected livers display dense lymphocytic infiltrates. Pathogenic T cells, including gut-homing CCR9+ T cells and proinflammatory Th17 cells, localize to periductal regions and target the biliary epithelium, while cholangiocytes aberrantly express MHC class II molecules that promote direct immune cell–cholangiocyte interactions. B cells and plasma cells also contribute, with intrahepatic B-cell accumulation, clonal expansion involving overlapping gut and liver clones, and in situ autoantibody production, indicating that humoral immune mechanisms, alongside T-cell–mediated injury, drive bile duct damage and fibrosis.[8] Collectively, these findings characterize PSC as an immune-mediated cholangiopathy arising in genetically susceptible individuals exposed to environmental or microbial triggers.

Epidemiology

PSC constitutes a rare immune-mediated liver disease with a pooled global incidence of 0.87 per 100,000 person-years and a prevalence of 13.53 per 100,000 persons. Higher rates occur in North America and Northern Europe compared with Asia and other regions.[9][10] Peak incidence arises between ages 25 and 45, and most diagnoses occur between ages 36 and 39.[11]

A male predominance characterizes PSC, with 60% to 71% of affected individuals being men, who carry a 1.5- to 2-fold greater risk than women.[12] First-degree relatives, particularly siblings, have an increased risk compared with the general population.[13] Nonsmokers more commonly develop PSC, although the mechanism underlying the apparent protective association with smoking remains unclear.[11] Population-based studies further indicate rising incidence, especially among individuals with higher socioeconomic status.[13]

Pathophysiology

PSC is a chronic cholestatic liver disease characterized by progressive inflammation, fibrosis, and stricturing of the bile ducts, driven by a complex interplay of genetic, immune, and environmental factors. Genome-wide association studies have identified strong associations with HLA-B08:01, HLA-DRB103:01, and other loci within the HLA class I, II, and III regions, implicating adaptive immune dysregulation in disease initiation.[14] 

Environmental triggers, eg, microbial dysbiosis and gut-derived antigens, are thought to provoke immune activation in genetically susceptible individuals, resulting in persistent cholangiocyte injury. Altered bile acid metabolism further contributes to pathogenesis; PSC patients exhibit reduced levels of 12α-hydroxylated bile acids and impaired CYP8B1 activity, thereby promoting a toxic biliary environment that exacerbates epithelial damage.[15] This chronic inflammatory milieu not only leads to cholestasis and portal hypertension but also places patients at significant risk for cholangiocarcinoma, likely driven by inflammation-induced carcinogenesis.[16]

Histopathology

PSC is histologically characterized by concentric, lamellar periductal fibrosis—often referred to as “onion-skin” fibrosis. This fibrotic response disrupts the peribiliary capillary plexus and impairs cholehepatic countercurrent circulation, leading to arterial ischemia and cholangiocyte injury. Over time, this process progressively obliterates intrahepatic bile ducts, leading to the formation of biliary strictures.[17][18] 

Portal tracts typically show a mixed inflammatory infiltrate, including lymphocytes, plasma cells, and neutrophils, often forming lymphoid aggregates, with inflammation centered around bile ducts.[18] Chemokine and cytokine secretion by activated immune cells in response to bile leakage from injured cholangiocytes amplifies fibrotic signaling.[19] As PSC advances, features, eg, ductular reaction, bile duct loss, and bridging fibrosis, become apparent, and chronic cholestasis can be demonstrated by cytokeratin 7 (K7) immunostaining.[20]

History and Physical

Clinical Features

Approximately 50% of patients with PSC remain asymptomatic at diagnosis, with liver function test abnormalities often detected incidentally. Symptomatic presentation typically emerges during the third to fourth decade of life, with a male predominance of approximately 65%.[21] Fatigue represents the most frequently reported symptom, affecting up to 71% of patients, and tends to worsen as the disease progresses, peaking in the afternoon and evening. Right upper quadrant (RUQ) abdominal pain occurs in 20% to 40% of patients, while pruritus affects approximately 38%, often intensifying in the evening and during winter months. Refractory pruritus can markedly impair quality of life and, in severe cases, may indicate the need for liver transplantation.

Less common clinical manifestations include jaundice, reported in 6% of patients, unintentional weight loss, and episodes of fever with chills, which may suggest acute bacterial cholangitis. Physical examination findings include hepatomegaly in up to 44% of patients, splenomegaly in 39%, and excoriations resulting from severe pruritus.[22][23]

Evaluation

Patients with PSC often present with nonspecific symptoms, eg, pruritus, fatigue, abdominal discomfort, depression, and anxiety. Therefore, diagnostic evaluation is essential to narrow the broad differential diagnosis.

Laboratory Studies

Laboratory evaluation typically reveals a cholestatic pattern of liver enzyme abnormalities, with elevated alkaline phosphatase and gamma-glutamyl transferase (GGT). Mild to moderate elevations in transaminases (AST and ALT) are also common. However, markedly elevated levels—more than 5 times the upper limit of normal—may suggest an overlap with autoimmune hepatitis.[22] 

Serologic testing may reveal positive autoantibodies, e.g., increased serum immunoglobulin M (IgM) levels, perinuclear antineutrophil cytoplasmic antibodies (p-ANCA), ANA, and anti-smooth muscle antibody, though these findings are nonspecific. Serum IgG4 levels are elevated in approximately 10% to 15% of PSC patients; however, significantly elevated IgG4 levels (eg, more than 4 times the upper limit of normal or an IgG4:IgG1 ratio >0.24) should raise suspicion for IgG4-related sclerosing cholangitis. This distinct entity must be ruled out.[24] 

Imaging Studies

The diagnosis of PSC is primarily based on imaging findings that demonstrate characteristic multifocal strictures of the intrahepatic and extrahepatic bile ducts with intervening normal or dilated segments, which result in the characteristic “beaded” appearance. MRCP is the preferred diagnostic modality due to its noninvasive nature and comparable sensitivity and specificity to ERCP. In contrast, ultrasound and computed tomography (CT) lack diagnostic utility for PSC.[25] 

Liver biopsy is generally not necessary when typical imaging findings are present, but biopsy may be advantageous in cases where small-duct PSC or an overlap syndrome is suspected. For noninvasive assessment of fibrosis, transient elastography and magnetic resonance elastography are increasingly used for risk stratification and longitudinal monitoring, particularly given the limitations of liver biopsy in PSC due to its patchy fibrotic distribution.[26]

Diagnostic Criteria

Current diagnostic criteria include persistent cholestatic liver enzyme elevation, characteristic biliary strictures or segmental dilations on cholangiography, and exclusion of secondary causes of sclerosing cholangitis.[27]

Treatment / Management

Management of PSC remains challenging due to the absence of any proven disease-modifying therapy. Current treatment strategies focus on symptom relief, management of complications, and timely referral for liver transplantation, which remains the only definitive cure.[23][28][29] 

Ursodeoxycholic Acid

Ursodeoxycholic acid (UDCA) has been widely studied; standard doses (approximately 13–15 mg/kg/day) may improve cholestatic liver enzymes, eg, alkaline phosphatase, but do not alter disease progression or improve transplant-free survival. High-dose UDCA (28–30 mg/kg/day) has been linked to worse outcomes, including an increased risk of colorectal neoplasia in patients with concomitant ulcerative colitis, and is therefore contraindicated. As such, major society guidelines do not recommend routine use of UDCA, though standard-dose therapy may be considered selectively for biochemical improvement in patients not eligible for clinical trials, with the understanding that it does not affect long-term outcomes.[30][31] 

Endoscopic Intervention

Management of biliary complications often involves endoscopic intervention. Dominant strictures may require dilation and stenting via ERCP to relieve obstruction or cholangitis. Liver transplantation is indicated for patients with decompensated cirrhosis or complications, eg, recurrent bacterial cholangitis. Patients with PSC who develop cholangiocarcinoma may also be considered for a liver transplant if they fit certain well-defined criteria.[29] 

Supportive Therapies

Supportive care remains a key component of PSC management. Cholestatic pruritus can be treated with cholestyramine (first-line) or second-line agents, eg, rifampicin, naltrexone, or sertraline. Fat-soluble vitamin deficiencies (A, D, E, K) should be monitored and corrected, and patients should receive calcium and vitamin D supplementation along with periodic bone density screening to mitigate the risk of osteoporosis from chronic cholestasis.[32]

Investigational Therapies

Several investigational therapies are under evaluation. Nor-ursodeoxycholic acid (norUDCA) has shown promising reductions in ALP in phase 2 trials and is currently undergoing phase 3 testing.[33] Farnesoid X receptor (FXR) agonists (eg, obeticholic acid) and PPAR agonists (eg, fenofibrate) have demonstrated biochemical improvements, though long-term benefits remain unclear.[34][35] Oral vancomycin has also shown potential in small studies and pediatric cohorts, but is not currently recommended outside of clinical trials pending further evidence.[36][37]

Differential Diagnosis

The differential diagnosis of PSC encompasses conditions that may present with similar cholestatic, inflammatory, or cholangiographic findings, including:

• Secondary sclerosing cholangitis, including causes such as recurrent bacterial cholangitis, choledocholithiasis, recurrent pancreatitis, surgical or ischemic biliary injury, and cholangiocarcinoma
• IgG4-related sclerosing cholangitis
• PSC–autoimmune hepatitis overlap syndrome, particularly in children and young adults
• Primary biliary cholangitis
• Biliary strictures (benign or malignant)
• Cholangiocarcinoma and other biliary tract neoplasms (eg, papillary tumors)
• Langerhans cell histiocytosis (Histiocytosis X)
• AIDS cholangiopathy (HIV-associated cholangiopathy)

Prognosis

The clinical course of PSC exhibits significant variability, with some patients remaining stable for decades while others progress rapidly to end-stage liver disease. Large cohort studies report median transplant-free survival ranging from 10 to 15 years, reflecting the heterogeneity of the disease.[38] Prognosis differs by subtype: small-duct PSC generally follows a more indolent course, offering longer transplant-free survival and a substantially lower risk of cholangiocarcinoma than classic large-duct PSC.[39] Laboratory markers, eg, elevated alkaline phosphatase and bilirubin, correlate with more advanced disease and poorer outcomes, whereas normalization or reduction of ALP to less than 1.5 times the upper limit of normal is associated with improved survival and decreased cancer risk.[40]

Several prognostic models assist in predicting outcomes. The Mayo PSC Risk Score incorporates age, bilirubin, albumin, AST, and history of variceal bleeding to estimate 4-year mortality risk. Newer tools, including the Primary Sclerosing Cholangitis Risk Estimate Tool (PREsTo), employ machine learning to predict hepatic decompensation. The Amsterdam–Oxford PSC score provides individualized estimates of long-term transplant-free survival. Imaging-based scoring systems, e.g., ANALI MRI scores, offer additional prognostic insight by correlating biliary abnormalities and hepatic morphology with disease progression.[41][42][43][44]

Complications

The following are some significant complications associated with PSC:

• Fat-soluble A, D, E, and K vitamin deficiencies
• Metabolic bone disease (osteoporosis)
• Cholangiocarcinoma
• Gallbladder cancer 
• Dominant biliary strictures
• Cholangitis
• Hepatocellular carcinoma in patients with cirrhosis (hepatic fibrosis progressively develops in these patients, leading to cirrhosis and hepatocellular carcinoma)
• Colon cancer in patients with concomitant IBD (surveillance with colonoscopy should be performed every 1 to 2 years in these patients who have concomitant PSC and IBD)
• Cholelithiasis
• Portal hypertension

Consultations

Management of PSC typically involves consultation with specialists in gastroenterology and transplant hepatology.

Deterrence and Patient Education

PSC is a chronic liver condition with no definitive cure. Early detection and regular medical follow-up are crucial for reducing the risk of complications, eg, cholangiocarcinoma and liver failure. Ongoing surveillance with liver function tests, imaging (eg, MRCP), and cancer screening is recommended. Lifestyle changes, such as not drinking alcohol, eating a balanced diet, getting regular exercise, and fixing vitamin deficiencies, can help keep the liver healthy. Vaccination against hepatitis A and B is also advised. In cases of advanced disease with decompensated cirrhosis or significant symptoms, liver transplantation may be required. Coordinated, interprofessional care and adherence to surveillance protocols are key to optimizing patient outcomes.

Enhancing Healthcare Team Outcomes

PSC is a chronic, progressive cholestatic liver disease characterized by inflammation and fibrosis of the intrahepatic and extrahepatic bile ducts, leading to multifocal strictures, cirrhosis, and increased risk of cholangiocarcinoma and colorectal cancer in patients with concomitant inflammatory bowel disease. Diagnosis relies on cholestatic liver enzyme abnormalities and characteristic findings on MRCP, with exclusion of secondary causes. No proven disease-modifying therapy exists, and management focuses on symptom control, surveillance for malignancy, treatment of dominant strictures, and timely referral for liver transplantation.

PSC requires a coordinated interprofessional approach to optimize patient-centered care and safety. Gastroenterologists and hepatologists lead diagnostic evaluation, endoscopic management, cancer surveillance, and transplant referral, while general and advanced practitioners support longitudinal monitoring and early recognition of complications.[28][29][23] Radiologists, transplant teams, hepatobiliary surgeons, and oncologists contribute to procedural care and the management of malignancies. Transplant teams, including transplant surgeons, transplant coordinators, and social workers, should be involved early for patients with decompensated cirrhosis, intractable pruritus, or recurrent cholangitis.[45][28] Nurses coordinate care, reinforce education, and assess transplant readiness.

Additional supportive roles that help to manage comorbidities and quality-of-life concerns include infectious disease specialists for recurrent cholangitis and periprocedural prophylaxis, dermatologists for refractory pruritus, and oncologists for malignancy management during tumor board conferences. Endocrinologists manage osteoporosis, while dietitians address nutritional deficiencies and pharmacists educate on medication safety and adherence. Physical therapists support mobility, with caution in patients with advanced osteoporosis. Clear communication, shared decision-making, and structured care coordination enhance outcomes, reduce complications, and improve team performance. Effective communication among these professionals is essential to optimize outcomes and quality of life for patients with PSC.[23]

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Disclosure: Sheza Malik declares no relevant financial relationships with ineligible companies.

Disclosure: Nader Dbouk declares no relevant financial relationships with ineligible companies.

Disclosure: Lafaine Grant declares no relevant financial relationships with ineligible companies.

Disclosure: Hrishikesh Samant declares no relevant financial relationships with ineligible companies.