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Primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is a rare, chronic, progressive liver disease characterized by inflammation, fibrosis, and stricturing of the intrahepatic and extrahepatic bile ducts, resulting in cholestasis, bile duct obstruction, and eventual liver damage that can lead to cirrhosis and liver failure.^[1]^[2]^[3] PSC most commonly affects men in their 30s and 40s, with a prevalence of approximately 17 to 25 cases per 100,000 people in North America and Northern Europe as of 2024, and an annual incidence of up to 1 per 100,000.^[2]^[3]^[4] It is strongly associated with inflammatory bowel disease (IBD), particularly ulcerative colitis, occurring in 60-80% of PSC patients, though the exact causal relationship remains unclear.^[1]^[3] The pathogenesis is multifactorial, involving genetic susceptibility (such as variations in the HLA complex), dysregulated immune responses targeting cholangiocytes, and potential environmental triggers like alterations in the gut microbiome.^[1]^[3] Many individuals with PSC are asymptomatic at diagnosis, often identified incidentally through elevated liver enzymes like alkaline phosphatase during IBD evaluation, while symptomatic patients may experience fatigue, pruritus (itching), jaundice, abdominal pain, or fever.^[1]^[3] Complications include recurrent bacterial cholangitis, portal hypertension, osteoporosis, fat-soluble vitamin deficiencies, and a markedly increased risk of malignancies, such as cholangiocarcinoma (10-20% lifetime risk), gallbladder cancer, and colorectal cancer in those with concurrent IBD.^[2]^[3] Diagnosis typically relies on a combination of biochemical tests showing cholestasis, imaging such as magnetic resonance cholangiopancreatography (MRCP) to visualize characteristic multifocal strictures and dilatations ("beading" appearance), and exclusion of secondary causes like IgG4-related disease.^[1]^[3] Liver biopsy is reserved for cases with atypical features. There is no curative medical therapy; management focuses on symptom relief with ursodeoxycholic acid (UDCA) for pruritus and biochemical improvement (though its long-term benefits are debated), endoscopic interventions for dominant strictures, and surveillance for cancer.^[1]^[3] Liver transplantation is the definitive treatment for end-stage disease, with excellent outcomes but a 20% risk of PSC recurrence in the allograft.^[2]^[3] Ongoing research explores novel therapies targeting immune pathways and bile acid metabolism, including promising phase 3 trial results for norucholic acid as of 2025.^[3]^[5]

Introduction

Definition and overview

Primary sclerosing cholangitis (PSC) is a rare, chronic, progressive liver disease characterized by inflammation, fibrosis, and stricturing of the intrahepatic and/or extrahepatic bile ducts, leading to cholestasis, bile duct obliteration, and eventual liver cirrhosis.^[6]^[2] The condition primarily affects the medium and large bile ducts, resulting in multifocal areas of narrowing and dilation that resemble a beaded appearance on imaging.^[1] PSC is frequently associated with inflammatory bowel disease (IBD), particularly ulcerative colitis, occurring in 60-80% of PSC patients.^[2] The disease was first described in 1924 by French surgeon Pierre Delbet as a distinct form of biliary fibrosis and stenosis, though earlier reports date back to the mid-19th century; it was recognized as a unique clinical entity in the 1960s with the advent of improved diagnostic techniques like cholangiography.^[7] Globally, PSC affects up to 1 in 10,000 individuals, with a pooled prevalence of approximately 11-14 per 100,000 persons, and higher rates observed in Northern Europe and North America where incidence can reach 1-1.6 per 100,000 person-years.^[8]^[9] PSC typically has an insidious onset, often progressing slowly from initial inflammatory changes in the bile ducts to advanced fibrosis and cirrhosis over 10-20 years in the absence of intervention.^[10] The only curative treatment is liver transplantation, which is indicated for end-stage liver disease.^[6]

Epidemiology

Primary sclerosing cholangitis (PSC) exhibits varying incidence and prevalence across populations, with annual incidence rates in Western countries ranging from 0.4 to 1.3 per 100,000 individuals and prevalence estimates between 6.3 and 16.2 per 100,000.^[11]^[8] A 2025 meta-analysis of global data reported pooled incidence of 0.65 per 100,000 and prevalence of 7.52 per 100,000, projecting a rise to 22.98 per 100,000 by 2040, primarily driven by enhanced detection through advanced imaging and diagnostic awareness.^[4] These figures underscore PSC as a rare but increasing burden in hepatobiliary disease epidemiology. Demographically, PSC disproportionately affects males, with a male-to-female ratio of approximately 2:1, and typically manifests in individuals aged 30 to 60 years at diagnosis.^[6]^[12] Although rare in pediatric populations, with incidence below 0.2 per 100,000 in children, cases of pediatric PSC have shown an upward trend in recent decades, linked to improved recognition and screening in at-risk groups such as those with inflammatory bowel disease.^[13]^[14] Geographically, PSC incidence is highest in Northern Europe, including Scandinavia where rates exceed 1 per 100,000 annually, and in North America, contrasting with lower figures in Asia (0.095–0.38 per 100,000) and Africa.^[15]^[16] This distribution points to a likely interplay of genetic predispositions, such as HLA associations more prevalent in Caucasian populations, and environmental factors like microbial exposures.^[17] Temporal trends reveal a steady increase in PSC diagnoses since the 1990s, attributed to widespread adoption of magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiopancreatography for early identification.^[18] Recent 2025 analyses confirm overall stability in incidence but highlight elevated rates within inflammatory bowel disease cohorts, where PSC prevalence reaches 2–5%.^[19]^[20]

Clinical presentation

Signs and symptoms

Primary sclerosing cholangitis (PSC) often presents asymptomatically, with up to 50% of cases diagnosed incidentally through abnormal liver function tests during evaluation for associated conditions or routine screening.^[1]^[6] In the early symptomatic phase, fatigue is the most common manifestation, affecting 60-70% of patients and significantly impacting quality of life.^[21] Pruritus, or intense itching due to bile acid accumulation in the skin, occurs in 40-60% of individuals and may be particularly bothersome at night or in warm conditions.^[22] Mild right upper quadrant abdominal pain is also frequent, reported in about 20% of cases, often related to biliary obstruction.^[6] As the disease advances, symptoms become more pronounced and include jaundice, characterized by yellowing of the skin and eyes, along with dark urine and pale stools from cholestasis.^[23] Weight loss and steatorrhea, resulting from fat malabsorption due to reduced bile flow, may develop, leading to nutritional deficiencies.^[23] Fever and chills can emerge if bacterial cholangitis complicates the strictures.^[24] Symptoms of PSC are typically intermittent and fluctuate over time, often worsening during pregnancy in about 30% of affected women or with concurrent infections.00282-3/fulltext)^[24] While no dedicated scoring system exists for symptom severity, tools like the Mayo risk score provide context for disease progression and potential symptom escalation.^[25] Symptoms may overlap with those of associated inflammatory bowel disease, such as abdominal pain or diarrhea, complicating the clinical picture.^[21]

Associated conditions

Primary sclerosing cholangitis (PSC) is strongly associated with inflammatory bowel disease (IBD), with 70-80% of PSC patients concurrently diagnosed with IBD.^[26] Among these cases, ulcerative colitis (UC) predominates, accounting for 70-85% of PSC-IBD occurrences, while Crohn's disease is less common at 10-20%.^[26] The PSC-IBD phenotype often exhibits distinct colonic features, including predominant right-sided involvement in UC, backwash ileitis, and rectal sparing in up to 52% of cases, contrasting with typical IBD patterns.^[26] An important overlap syndrome involves PSC and autoimmune hepatitis (AIH), occurring in 2-10% of PSC patients.^[27] This condition is characterized by elevated transaminase levels indicating hepatocellular injury, alongside interface hepatitis observed on liver biopsy, which helps differentiate it from isolated PSC.^[27] PSC is also linked to other autoimmune disorders, including celiac disease (prevalence 2-3%), type 1 diabetes mellitus (approximately 2%), and autoimmune thyroiditis (around 3%).^[28]^[29] These associations reflect shared immune dysregulation, though no strong viral etiologic links have been established.^[6] Clinically, these comorbidities necessitate routine IBD screening via colonoscopy at PSC diagnosis to detect colorectal neoplasia, given the elevated cancer risk in PSC-IBD (up to 10% in some variants).^[6] Additionally, in patients with UC-PSC, prior colectomy has been associated with reduced risk of liver transplantation or death compared to post-diagnosis procedures, influencing overall transplant outcomes.^[30]

Pathogenesis

Causes

The etiology of primary sclerosing cholangitis (PSC) remains unknown, with no single cause identified; it is widely regarded as a multifactorial, immune-mediated disorder influenced by genetic, environmental, and microbial factors.^[31]^[32] Genetic factors play a significant role in PSC susceptibility, with strong associations observed in the human leukocyte antigen (HLA) complex, particularly HLA-B8 and DRB1*03:01 alleles in individuals of Caucasian descent.^[33] Genome-wide association studies (GWAS) have identified over 30 non-HLA susceptibility loci, including variants in genes such as FUT2 and IL2RA, which are involved in immune regulation and bile homeostasis.^[34]^[35]^[36] Heritability estimates for PSC include an SNP-heritability of approximately 23%, with relative sibling risk ratios around 10, underscoring a polygenic architecture similar to other immune-mediated diseases.^[35]^[37] Environmental triggers are hypothesized to interact with genetic predisposition in PSC pathogenesis, with evidence suggesting a role for gut microbiome dysbiosis, potential toxins, or infections that may initiate immune responses against bile ducts.^[38] Smoking appears protective, with meta-analyses reporting an odds ratio of approximately 0.5 for developing PSC among smokers compared to non-smokers, possibly due to immunomodulatory effects on the gut microbiota.^[39] In contrast, alcohol consumption is not considered causal in PSC onset, though it may exacerbate liver damage in affected individuals.^[40] PSC involves immune dysregulation characterized by an autoimmune-like attack on biliary epithelium, yet it lacks classic autoantibodies typical of other autoimmune liver diseases; instead, T-cell mediated inflammation and fibrosis predominate, driven by innate and adaptive immune activation potentially triggered by microbial antigens from the gut.^[32] This process is strongly linked to inflammatory bowel disease, present in up to 80% of PSC cases, highlighting shared immune pathways.^[41]

Pathophysiology

Primary sclerosing cholangitis (PSC) is characterized by chronic inflammation and progressive fibrosis of the intrahepatic and extrahepatic bile ducts, leading to periductal fibrosis that manifests as an "onion-skin" pattern of concentric collagen deposition around the ducts.^[6] This fibrotic process displaces the peribiliary capillary plexus, inducing ischemia and further exacerbating bile duct injury, which results in multifocal strictures interspersed with areas of dilatation, producing the classic "beading" appearance observable on cholangiography.^[42] The inflammation involves a mixed infiltrate of lymphocytes, plasma cells, and neutrophils surrounding the bile ducts, with biliary epithelial cells (cholangiocytes) overexpressing adhesion molecules such as ICAM-1 and chemokines that perpetuate the inflammatory cascade.^[42] The resulting obstruction of bile flow causes cholestasis, a central mechanism in PSC progression, wherein accumulated toxic bile acids directly damage hepatocytes and cholangiocytes, promoting additional inflammation and fibrosis.^[6] This cholestatic injury triggers portal hypertension through vascular remodeling and eventual biliary cirrhosis, as sustained bile stasis leads to parenchymal distortion and nodular regeneration.^[3] Bile acid toxicity further amplifies the fibrogenic response by activating stellate cells and myofibroblasts in the periductal region, creating a vicious cycle of inflammation and scarring.^[42] Immune dysregulation plays a pivotal role, with both innate and adaptive arms contributing to the disease process; innate immunity involves aberrant Toll-like receptor (TLR) signaling and NF-κB activation in cholangiocytes, leading to excessive cytokine production, while adaptive immunity features T-cell infiltration and autoantibody targeting of biliary epithelium.^[3] Key proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-17 (IL-17) are elevated, driving endothelial dysfunction in the biliary microvasculature and enhancing leukocyte recruitment to the ducts.^[42] Genetic factors, including associations with HLA class I and II alleles like HLA-B08 and HLA-DRB103:01, influence immune susceptibility but do not directly dictate the fibrotic progression.^[6] The disease typically progresses from involvement of small intrahepatic ducts to obliteration of larger ducts, culminating in end-stage liver disease over a median of about 10-18 years without intervention.^[3] This model is modulated by the gut-liver axis, where alterations in gut microbiota facilitate bacterial translocation through the portal vein, priming hepatic T cells and amplifying periductal inflammation via increased expression of mucosal addressin cell adhesion molecule-1 (MAdCAM-1) on sinusoidal endothelium.^[42]

Diagnosis

The diagnosis of primary sclerosing cholangitis (PSC) follows the 2024 criteria established by the Japanese Biliary Association, which emphasize non-invasive imaging and exclusion of secondary causes. These criteria include characteristic cholangiographic findings on magnetic resonance cholangiography (MRC), cholestatic liver enzyme elevation (alkaline phosphatase in adults or gamma-glutamyl transferase in children), concurrent inflammatory bowel disease (IBD), and supportive histology for atypical cases such as small-duct PSC or overlap syndromes.^[43]

Laboratory tests

Laboratory tests play a crucial role in supporting the diagnosis of primary sclerosing cholangitis (PSC) and monitoring disease progression, primarily through blood-based assessments that reveal a cholestatic pattern of liver injury. Liver function tests typically demonstrate markedly elevated levels of alkaline phosphatase (ALP), often exceeding 1.5 times the upper limit of normal in the majority of patients, reflecting biliary obstruction and cholestasis.^[6] Mild elevations in transaminases, such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT), are common but usually limited to 2-3 times the upper limit of normal, while total bilirubin remains normal in early stages and rises only in advanced disease or with complications like strictures.^[6] These findings are not specific to PSC but, when persistent for more than 6 months, prompt further diagnostic evaluation.^[6] Autoantibody testing reveals perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) in 65-85% of PSC patients, often displaying an atypical immunofluorescence pattern that targets nuclear antigens rather than typical cytoplasmic granules.^[44] Antinuclear antibodies (ANA) and smooth muscle antibodies (SMA) are detected in 20-50% of cases, though these are nonspecific and more frequently associated with overlap syndromes involving autoimmune hepatitis.^[6] Such serological markers aid in differential diagnosis but lack sufficient specificity for confirming PSC alone. Other serological markers include elevated serum immunoglobulin M (IgM) levels in approximately 50% of patients, contributing to a polyclonal hypergammaglobulinemia that underscores the immune-mediated aspects of the disease.^[6] Serum bile acid concentrations are also increased, with total bile acids often markedly higher than in healthy individuals, correlating with cholestatic severity and pruritus.^[45] For prognostic assessment, the Mayo Risk Score incorporates laboratory components such as age, serum bilirubin, albumin, and AST levels, along with a history of variceal bleeding, to estimate transplant-free survival.^[46] Ongoing monitoring involves serial measurements of ALP to track disease progression and response to interventions, as persistently high levels are linked to worse outcomes and increased risk of cholangiocarcinoma.^[47] Additionally, assessment of fat-soluble vitamin levels (A, D, E, and K) is recommended to detect malabsorption secondary to cholestasis, with deficiencies potentially leading to complications like osteoporosis or coagulopathy.^[24]

Imaging modalities

Imaging in primary sclerosing cholangitis (PSC) primarily aims to visualize characteristic bile duct abnormalities, such as multifocal strictures, segmental dilatations, and a "beaded" appearance, which are essential for diagnosis and surveillance.^[48] Non-invasive modalities are preferred initially, with invasive techniques reserved for cases requiring tissue sampling or intervention.^[49] Magnetic resonance cholangiopancreatography (MRCP) serves as the first-line imaging modality for diagnosing PSC due to its non-invasive nature and high diagnostic accuracy.^[50] It effectively depicts intra- and extrahepatic bile duct irregularities, including strictures and dilatations, with a pooled sensitivity of 86% and specificity of 94%.^[49] MRCP is recommended for initial evaluation and annual surveillance to monitor disease progression and detect complications like cholangiocarcinoma, often incorporating diffusion-weighted imaging to enhance lesion detection.^[50] Optimal protocols include coronal and axial T2-weighted imaging, 3D MRCP for spatial resolution, and hepatobiliary contrast agents when needed.^[50] Endoscopic retrograde cholangiopancreatography (ERCP) provides direct visualization of the biliary tree and allows for brush cytology or biopsy, making it valuable for confirming PSC in equivocal cases and surveilling for malignancy.^[48] Although historically the reference standard, ERCP is now secondary to MRCP for routine diagnosis due to its invasiveness and risks, including post-procedure pancreatitis in up to 5-10% of cases.^[50] It is particularly useful when MRCP findings are inconclusive or when therapeutic interventions, such as stent placement for dominant strictures, are indicated.^[51] Ultrasound is often employed as an initial screening tool to assess liver parenchymal changes, such as heterogeneity or nodularity, and to detect gross biliary dilatation or masses, though it lacks specificity for intrahepatic duct abnormalities in PSC.^[48] Computed tomography (CT), typically multiphasic contrast-enhanced, evaluates for liver texture alterations, vascular involvement, or tumors but performs poorly in delineating fine biliary strictures compared to MRCP.^[48] Both modalities are adjunctive rather than diagnostic for PSC duct pathology.^[48] Advanced imaging techniques, such as MR elastography, complement standard modalities by non-invasively staging hepatic fibrosis through liver stiffness measurement, with a cutoff of 4.93 kPa showing 100% sensitivity and 94% specificity for detecting cirrhosis in PSC patients.^[48] This approach aids in prognostic assessment but does not directly visualize biliary changes.^[48]

Classification and variants

Primary sclerosing cholangitis (PSC) is primarily classified into large-duct PSC and small-duct PSC based on the involvement of the biliary tree. Large-duct PSC, the classic form, accounts for approximately 70-80% of cases and is characterized by multifocal strictures and dilatations visible on cholangiography, affecting both intrahepatic and extrahepatic bile ducts greater than 100 micrometers in diameter.^[52] In contrast, small-duct PSC involves only the intrahepatic bile ducts smaller than 100 micrometers and represents 5-20% of PSC cases, with normal cholangiographic findings requiring liver biopsy for diagnosis, showing periductal fibrosis and onion-skinning on histology.^[52] Several variants of PSC exist, including perihilar PSC, which features a dominant stricture at the hepatic hilum, often complicating diagnosis due to overlap with cholangiocarcinoma.^[53] Another variant is the overlap syndrome with autoimmune hepatitis (AIH), diagnosed using modified Paris criteria that include an alkaline phosphatase (ALP)/alanine aminotransferase (ALT) ratio less than 1.5, elevated immunoglobulin G levels, histological interface hepatitis, and positive autoantibodies such as antinuclear or smooth muscle antibodies.^[54] Pediatric PSC, typically diagnosed around age 12 with a male predominance, often presents with inflammatory bowel disease in up to 76% of cases and exhibits a more aggressive course, including higher rates of autoimmune sclerosing cholangitis overlap (up to 33%) and small-duct involvement (13-42%).^[55] IgG4-related sclerosing cholangitis serves as an important mimic of PSC, presenting with similar biliary strictures but differing in demographics (older onset around age 66, predominantly male) and associations (frequent comorbid autoimmune pancreatitis in 88%, rare inflammatory bowel disease).^[56] Unlike PSC, IgG4-related disease responds robustly to corticosteroid therapy and has a lower risk of cholangiocarcinoma (0.8% vs. higher in PSC).^[56] Differential diagnosis includes secondary sclerosing cholangitis, which must be excluded before confirming PSC, as it arises from identifiable causes such as ischemic injury (e.g., hepatic artery thrombosis), recurrent pyogenic cholangitis due to stones or parasites, or toxic exposures like intra-arterial chemotherapy.^[57] Although no formal clinical staging system exists for PSC, histological assessment using the Ludwig classification evaluates disease progression through four stages: stage 1 (portal tract inflammation and periductal fibrosis), stage 2 (periportal fibrosis), stage 3 (septal fibrosis bridging portal tracts), and stage 4 (cirrhosis).^[7]

Management

Symptomatic treatment

Symptomatic treatment for primary sclerosing cholangitis (PSC) focuses on alleviating common symptoms such as pruritus, fatigue, and pain, while addressing nutritional deficiencies and preventing infections, without targeting the underlying disease progression. Endoscopic interventions are used to manage biliary strictures contributing to symptoms and complications.^[58] Pruritus, a frequent and distressing symptom in PSC due to cholestasis, is managed stepwise beginning with nonpharmacologic measures like avoiding hot environments, using emollients to hydrate skin, and antihistamines for mild cases.^[58] First-line pharmacologic therapy involves bile acid sequestrants such as cholestyramine at 4–16 g/day, administered 20 minutes before meals to bind bile acids in the intestine and reduce circulating pruritogens.^[58] For refractory pruritus, second-line options include rifampin (150–300 mg twice daily), which may improve itch through unclear mechanisms possibly involving bile acid metabolism, or naltrexone (50–100 mg/day), an opioid antagonist that blocks central itch signaling pathways; both require monitoring for hepatotoxicity and opioid effects, respectively.^[58]^[59] Fatigue, reported by up to 50% of PSC patients and unrelated to disease severity, lacks targeted therapies but benefits from supportive strategies including evaluation for contributing factors like hypothyroidism or depression, regular aerobic exercise, and sleep hygiene optimization.^[58] A 12-week home-based exercise program has been shown to significantly reduce fatigue severity in PSC patients.^[60] Abdominal pain, often linked to biliary strictures, is managed supportively with exercise and, if needed, antidepressants for associated mood symptoms, while avoiding opioids due to risks of hepatic encephalopathy and respiratory depression in liver disease.^[61]^[62] Nutritional support is essential given cholestasis-induced malabsorption of fat-soluble vitamins, with routine screening recommended at diagnosis and annually; deficiencies in vitamins A, D, and E occur in approximately 40% of early-stage PSC patients.^[58] Supplementation includes vitamin A (5,000–10,000 IU/day for repletion, 1,500–5,000 IU/day maintenance), vitamin D (4,000–8,000 IU/day for repletion, 400–2,000 IU/day maintenance), and vitamin E (100–200 mg/day for repletion, 15–25 mg/day maintenance), alongside medium-chain triglycerides to aid fat absorption when needed.^[58] Vitamin K supplementation is advised if prothrombin time is prolonged.^[59] Acute bacterial cholangitis, a complication of biliary strictures, requires prompt intravenous antibiotics such as ciprofloxacin plus metronidazole to cover gram-negative and anaerobic organisms, with hospitalization for severe cases.^[59] For patients with recurrent cholangitis, prophylactic oral antibiotics like trimethoprim-sulfamethoxazole may be considered to reduce episode frequency.

Endoscopic management

Endoscopic retrograde cholangiopancreatography (ERCP) is recommended for the management of dominant strictures in PSC, defined as tight stenoses with upstream dilation causing symptoms or biochemical worsening. Per AASLD and EASL guidelines, ERCP with balloon dilation is preferred over stenting to improve biliary drainage, reduce cholangitis risk, and alleviate symptoms like pain and jaundice (LoE 2–3). Short-term stenting may be used if dilation fails, but routine stenting is discouraged due to higher complication rates. Surveillance ERCP is not routinely recommended without clinical indication.^[58]^[49]

Disease-modifying therapies

Ursodeoxycholic acid (UDCA) is the most commonly used pharmacological agent in primary sclerosing cholangitis (PSC), administered at doses of 13–15 mg/kg/day to improve liver biochemistry, such as reductions in alkaline phosphatase (ALP) levels, though it has not demonstrated a survival benefit or delay in disease progression.^[63] Higher doses of 15–20 mg/kg/day may be considered per European Association for the Study of the Liver (EASL) guidelines to enhance surrogate markers of prognosis, but routine use remains variable due to inconsistent evidence from meta-analyses of multiple trials showing no overall impact on fibrosis or transplant-free survival.^[49] As of 2025, clinical guidelines, including those from EASL, describe UDCA's role as supportive rather than definitively disease-modifying, with recommendations emphasizing individualized assessment.^[63] Obeticholic acid, a farnesoid X receptor (FXR) agonist, has been investigated for its potential to reduce cholestasis in PSC. In a phase II trial involving daily doses of 5–10 mg over 24 weeks, obeticholic acid significantly lowered serum ALP levels compared to placebo, but it was associated with pruritus as a common adverse effect.^[63] As of 2025, it has not received regulatory approval for PSC treatment, with ongoing evaluations focusing on its biochemical effects rather than long-term outcomes.^[63] Nor-ursodeoxycholic acid (nor-UDCA), a side-chain shortened derivative of UDCA, showed promising results in a phase III double-blind, placebo-controlled trial (NUC-5) completed in May 2025. In this study of 301 patients receiving 1,500 mg daily for 96 weeks, nor-UDCA achieved the primary endpoint of partial ALP normalization (<1.5× upper limit of normal) without worsening of liver histology (Ludwig stage) in 15.1% of participants versus 4.2% on placebo (p=0.0048), alongside significant ALP reductions and histological improvements in 25.2% of treated patients.^[5] Safety profiles were comparable to placebo, with no increased adverse events, though regulatory approval for PSC remains pending as of November 2025.^[5] Elafibranor, a dual peroxisome proliferator-activated receptor (PPAR) α/δ agonist, demonstrated efficacy in a phase IIb randomized controlled trial (ELMWOOD) reported in April 2025. Over 12 weeks, doses of 80 mg and 120 mg daily led to dose-dependent biochemical improvements, including greater reductions in ALP compared to placebo, in 68 patients with non-cirrhotic PSC.^[64] The drug was well tolerated, with a favorable safety profile, supporting its advancement to further studies for disease modification.^[64] In patients with PSC overlap syndromes, such as PSC-autoimmune hepatitis (AIH), immunosuppressants like corticosteroids (e.g., prednisolone) and azathioprine are used in combination with UDCA to target the inflammatory component. EASL guidelines recommend this approach for cases with elevated alanine aminotransferase (>5× upper limit of normal), immunoglobulin G (>1.5× upper limit of normal), and compatible histology, as it may improve biochemical responses and long-term survival, though evidence is limited to observational data (level of evidence 3–4).^[49] These agents are not indicated for classic PSC without overlap features.^[49] Oral vancomycin, targeting gut microbiome dysbiosis, has been explored in trials for its potential to modulate bacterial composition in PSC, particularly in those with inflammatory bowel disease. In randomized controlled trials, doses of 125 mg four times daily over 12 weeks reduced ALP by 40–46% and improved Mayo Risk Scores, with microbiome shifts including increased Blautia and decreased Bacteroides, though effects were not sustained post-treatment.^[65] As of 2025, it remains investigational, with phase II/III studies confirming biochemical benefits but no proven impact on disease progression.^[63]

Liver transplantation

Liver transplantation serves as the definitive treatment for patients with primary sclerosing cholangitis (PSC) who progress to end-stage liver disease, offering the potential for long-term survival despite challenges such as disease recurrence. Indications for transplantation primarily include decompensated cirrhosis, recurrent cholangitis, and complications of portal hypertension, such as variceal bleeding or refractory ascites.^[66] Additionally, transplantation may be considered for intractable cholestatic pruritus or persistent jaundice that severely impairs quality of life, even in the absence of full decompensation. Prioritization for transplant is determined using the Model for End-Stage Liver Disease (MELD) score, which allocates organs based on disease severity and urgency, although exceptions may apply for PSC patients with suspected cholangiocarcinoma.^[67] The standard procedure is orthotopic liver transplantation, involving the surgical removal of the diseased liver and replacement with a donor graft, often from deceased donors, though living donor transplantation is also feasible in select cases.^[68] Post-operative outcomes are generally favorable, with 5-year patient survival rates ranging from 85% to 90%, and 10-year survival exceeding 80% when performed early in the disease course.^[69] However, PSC recurs in approximately 20% to 25% of grafts, typically within the first 5 years, which can necessitate retransplantation in a subset of patients.^[70] Post-transplant management focuses on immunosuppression to prevent graft rejection, commonly utilizing a regimen based on calcineurin inhibitors such as tacrolimus, often combined with mycophenolate mofetil and corticosteroids initially.^[71] For patients with concomitant inflammatory bowel disease (IBD), which affects up to 80% of PSC cases, vigilant management is essential, as IBD activity frequently worsens post-transplant due to the immunomodulatory effects of therapy; this includes optimizing IBD treatments like anti-tumor necrosis factor agents while monitoring for infections.^[72] Special considerations in PSC patients with ulcerative colitis (UC) include intensified surveillance for colorectal cancer, given the elevated risk post-transplant, with annual or biennial colonoscopies recommended starting from the time of listing or earlier if dysplasia is present pre-transplant.^[73] Recent 2025 analyses indicate that early transplantation further enhances long-term survival, with 10-year rates approaching 85% in well-selected cohorts.^[67]

Outcomes

Complications

Primary sclerosing cholangitis (PSC) is associated with several serious complications arising from progressive biliary strictures, chronic cholestasis, and advanced liver dysfunction. One of the most significant is cholangiocarcinoma, a malignancy of the bile ducts, with a lifetime risk estimated at 10-20% in affected patients.^[3] This risk is heightened in the presence of dominant strictures, which necessitate vigilant surveillance to detect early malignant changes.^[74] Cholangiocarcinoma in PSC carries a poor prognosis, with 5-year survival rates typically ranging from 5-10%, often requiring liver transplantation for any chance of long-term survival.^[75] Bacterial cholangitis, resulting from ascending infections due to biliary obstruction, represents another frequent complication, particularly in advanced disease.^[6] Episodes are characterized by fever, jaundice, and abdominal pain, and are managed acutely with broad-spectrum antibiotics; endoscopic interventions such as stenting or balloon dilation may be required to relieve dominant strictures and prevent recurrence.^[74] Additional complications include metabolic bone disease, manifesting as osteoporosis, which affects approximately 50% of patients due to chronic cholestasis-induced vitamin D deficiency and malabsorption of fat-soluble vitamins.^[76] Portal hypertension develops in advanced cases, leading to esophageal varices, ascites, and potential gastrointestinal bleeding.^[6] In patients with concomitant ulcerative colitis (UC-PSC overlap), the risk of colorectal cancer is elevated 2-5 times compared to UC alone, underscoring the need for regular colonoscopic surveillance.^[77] Management of metabolic bone disease involves routine screening with dual-energy X-ray absorptiometry (DEXA) scans at diagnosis and periodically thereafter, alongside supplementation of vitamin D and calcium; bisphosphonates are recommended for those with confirmed osteoporosis to reduce fracture risk.^[78] Cancer surveillance for cholangiocarcinoma often incorporates endoscopic retrograde cholangiopancreatography (ERCP) in cases of dominant strictures.^[49]

Prognosis

Primary sclerosing cholangitis (PSC) is a progressive disease with a variable natural history, typically leading to end-stage liver disease over time. The median survival from diagnosis is approximately 10-20 years in large-duct PSC, with patients often succumbing to liver failure, cholangiocarcinoma, or complications of cirrhosis. In contrast, small-duct PSC is associated with a more favorable prognosis, with median survival estimated at 17-20 years compared to about 12 years for large-duct variants. These estimates are derived from large cohort studies tracking untreated or conservatively managed patients, highlighting the indolent but inexorable progression of biliary fibrosis and stricturing. Several prognostic models have been developed to estimate individual risk and guide clinical decision-making in PSC. The Revised Mayo Risk Score, a widely used tool, incorporates variables such as age, total bilirubin, serum albumin, aspartate aminotransferase (AST), and the presence of varices to predict survival free of liver transplantation. More recently, the UK-PSC Risk Score has emerged as an alternative, utilizing age, bilirubin, and alkaline phosphatase (ALP) levels to forecast 5-, 10-, and 15-year transplant-free survival with improved calibration for diverse populations. Persistent elevation of ALP correlates with worse outcomes and higher risk of progression to cirrhosis. Prognosis in PSC is influenced by several clinical factors at diagnosis and during follow-up. Older age at diagnosis is associated with poorer transplant-free survival. The presence of inflammatory bowel disease (IBD), particularly ulcerative colitis, does not significantly alter overall survival but may complicate management.^[79] Liver transplantation markedly extends survival in advanced cases, with 5-year post-transplant survival rates exceeding 80%, though PSC recurs in up to 20-30% of recipients. Quality of life in PSC patients is substantially impacted by chronic symptoms, particularly fatigue, which affects daily functioning and employment in a majority of cases. Multidisciplinary care, including psychological support and symptom-targeted interventions, can improve health-related quality of life.

Research

Ongoing clinical trials

As of late 2025, several phase 2 and 3 clinical trials are advancing potential therapies for primary sclerosing cholangitis (PSC), focusing on biochemical improvements, symptom relief, and disease modification. The norursodeoxycholic acid (nor-UDCA) phase 3 trial (NCT03872921), a randomized, double-blind, placebo-controlled study involving approximately 300 patients, reported positive top-line results in May 2025, demonstrating superiority over placebo in the primary composite endpoint of partial normalization of alkaline phosphatase (ALP) levels and no worsening of liver imaging or symptoms.^[5]^[80] The trial showed significant ALP reductions across treatment arms, with a favorable safety profile comparable to placebo and minimal side effects, positioning nor-UDCA for potential regulatory approval pending further review.^[81] Elafibranor, a dual FXR/PPAR agonist, completed its phase 2b ELMWOOD trial (NCT05627362) in April 2025, enrolling patients with PSC to assess 12-week dosing at 80 mg and 120 mg versus placebo. The study met its primary endpoint with dose-dependent reductions in ALP levels, alongside improvements in pruritus (itch) scores and other biochemical markers, and a well-tolerated profile with no new safety signals.^[82]^[83] Phase 3 development is planned based on these results.^[84] Among other notable trials, nebokitug (CM-101), a monoclonal antibody targeting CCL24, showed positive phase 2 SPRING trial (NCT04595825) data in June 2025, confirming safety and tolerability over 48 weeks in an open-label extension, with reductions in fibrotic and inflammatory biomarkers.^[85]^[86] The cilofexor phase 3 PRIMIS trial (NCT03890120), an FXR agonist study in non-cirrhotic PSC patients, was terminated early in October 2025 following an interim futility analysis, though prior phase 2 data had indicated biochemical benefits.^[87] Additionally, microbiome-targeted approaches are under evaluation, including a phase 2 trial of oral vancomycin (NCT05876182) in Italy assessing safety and efficacy in patients with PSC and associated IBD.^[88] PSC Partners Seeking a Cure awarded five research grants in 2025 totaling over $400,000, including support for projects exploring the gut-liver axis, such as the investigation of propionate's role in modulating hepatic macrophage function to reduce fibrosis in PSC models and patient samples.^[89] These efforts also fund biomarker development for fibrosis progression, aiming to inform future trial designs.^[89]

Emerging therapeutic targets

Research into the gut microbiome has identified dysbiosis as a key contributor to the pathogenesis of primary sclerosing cholangitis (PSC), with altered bacterial composition promoting bile acid dysregulation and immune activation in the gut-liver axis.^[90] Preclinical studies demonstrate that fecal microbiota transplantation (FMT) can restore microbial diversity and reduce hepatic inflammation in PSC mouse models, supporting its potential as an early-stage intervention.^[91] In 2025, Esperion nominated ESP-2001, a highly specific allosteric ATP citrate lyase inhibitor, as a preclinical candidate for PSC; it targets lipid metabolism pathways linked to bile acid synthesis, showing reductions in markers of bile duct injury, inflammation, and fibrosis in preclinical models.^[92] Fibrosis pathways in PSC represent promising targets for anti-fibrotic agents, as periductal scarring drives disease progression. Integrin inhibitors like bexotegrast (an αvβ6/αvβ1 antagonist) block transforming growth factor-β signaling, which activates hepatic stellate cells; preclinical data and early phase II results indicate stabilization of fibrosis biomarkers such as enhanced liver fibrosis scores and pro-collagen III in PSC patients.^[93] In PSC-derived organoid models, IL-17A stimulation upregulates pro-fibrotic genes, suggesting cytokine inhibition as a viable strategy; a phase 2 trial of brodalumab, an IL-17 receptor blocker, is ongoing to assess efficacy in PSC patients.^[94]^[95] Genetic targets in PSC research focus on editing disease-associated loci to mitigate immune dysregulation and promote biliary repair. CRISPR-Cas9 editing of HLA genes in induced pluripotent stem cells (iPSCs) from PSC patients enhances immune compatibility and reduces allo-reactivity, offering a foundation for personalized regenerative therapies.^[96] Bile duct regeneration via stem cell-derived organoids, generated from PSC patient bile, recapitulates inflammatory profiles and supports testing of regenerative approaches to restore cholangiocyte function in preclinical models.^[97] As of 2025, AASLD guidance continues to emphasize microbiome modulation and farnesoid X receptor (FXR) agonism as priority areas, with agents like cilofexor targeting bile acid homeostasis to curb cholestasis in preclinical and early trials.^[63] Integrative multi-omics modeling studies predict a need for combination therapies targeting fibrosis and cancer risk by 2040, highlighting genes like COL7A1 as co-targets for antifibrotic and anti-tumor effects in PSC complicated by inflammatory bowel disease.^[98]

References

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