Secondary sclerosing cholangitis: contemporary etiologies, diagnostic pathways, and treatment strategies for clinicians: a narrative review

Introduction

Sclerosing cholangitis is a chronic cholestatic disease that can be caused by diverse etiologies leading to biliary fibrosis, stricturing, and obliteration of intra and/or extrahepatic bile ducts. Often, the specific etiology cannot be identified, and these cases are termed primary sclerosing cholangitis (PSC) (1). However, if a potential etiology can be identified, the condition is termed secondary sclerosing cholangitis (SSC). It is important to rule out other etiologies prior to labeling someone as having PSC, as etiology-directed therapy is essential to prevent disease progression to biliary cirrhosis (2,3). SSC can be driven by diverse underlying etiologies such as ischemic/critical illness, infectious, including coronavirus disease 2019 (COVID-19), human immunodeficiency virus (HIV), and parasites, autoimmune, including IgG4-related and eosinophilic, sickle cell-related, drug-induced, and malignancy-related. Recent studies further emphasize that SSC often presents late and progresses more rapidly than PSC, particularly in critically ill patients; however, prompt identification of the underlying trigger can mitigate this risk (4). This narrative review aims to consolidate current evidence on SSC and synthesize diagnostic and treatment strategies for clinicians. We present this article in accordance with the Narrative Review reporting checklist (available at https://tgh.amegroups.com/article/view/10.21037/tgh-2026-0018/rc).

Methods

We conducted a narrative review to summarize contemporary etiologies, diagnostic strategies, and treatment approaches for SSC. A structured search of the literature was performed in PubMed to identify relevant publications. The search included medical subject headings (MeSH) and free-text keywords related to SSC and its major etiologies, including “ischemic cholangiopathy”, “SSC-CIP (secondary sclerosing cholangitis in critically ill patients)”, “critical illness cholangiopathy”, “HIV cholangiopathy”, “COVID-19 cholangiopathy”, “AIDS cholangiopathy”, “IgG4-related sclerosing cholangitis”, “eosinophilic cholangitis”, “drug-induced cholangitis”, “immune checkpoint inhibitor cholangiopathy” and “malignancy-associated cholangitis”. The Boolean operators OR/AND were used within etiologic groups to connect cholangitis terms with specific etiologies.

The search was limited to English language studies involving humans, including randomized controlled trials, systematic reviews, observational studies, case series, and practice guidelines published in the last five years, with inclusion of landmark older studies where needed (Table 1). Two reviewers independently screened titles and abstracts for relevance. Eligible studies underwent full-text review, and discrepancies in study selection were resolved by consensus. The findings were synthesized into a narrative review stratified by major etiologies of SSC (Table 2) with emphasis on recent trends and advances in clinical practice.

General diagnostic approach to SSC

Given that SSC encompasses diverse etiologies with overlapping presentations, a structured, stepwise diagnostic approach is essential. The following framework, summarized in (Figure 1), can be applied across all SSC etiologies discussed in this review; etiology-specific diagnostic nuances are described within each section below.

Figure 1 Diagnostic approach for secondary sclerosing cholangitis. The figure illustrates a stepwise diagnostic framework applicable across all etiologies of secondary sclerosing cholangitis. Step 1 outlines initial laboratory evaluation, including history, risk factors, liver function tests, GGT, and calculation of the R-factor to characterize the pattern of injury. Step 2 presents first-line imaging with abdominal ultrasound to assess for biliary dilation or obstruction. Step 3 describes the indications for further imaging with MRCP to characterize biliary strictures and ductal abnormalities. Step 4 outlines the role of therapeutic and diagnostic ERCP, including brush and cytology, biopsies, and biliary stenting as indicated. Step 5 defines the role of histopathology and liver biopsy when the diagnosis remains uncertain or when immune-mediated, malignant, or indeterminate etiologies require tissue confirmation. ALP, alkaline phosphatase; ALT, alanine aminotransferase; DILI, drug-induced liver injury; EC, eosinophilic cholangitis; ERCP, endoscopic retrograde cholangiopancreatography; GGT, gamma-glutamyl transferase; IgG4-SC, IgG4-related sclerosing cholangitis; LFTs, liver function tests; MRCP, magnetic resonance cholangiopancreatography; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis; RUCAM, Roussel Uclaf causality assessment method; RUQ, right upper quadrant; SSC, secondary sclerosing cholangitis.

Initial laboratory evaluation and abdominal ultrasound (US)

All patients with unexplained cholestasis should undergo a full hepatic panel including alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), total and direct bilirubin, alanine aminotransferase (ALT), and aspartate aminotransferase (AST). The R-factor calculated as [ALT/upper limit of normal (ULN)]/(ALP/ULN) characterizes the pattern of injury: values below 2 confirm a cholestatic pattern, raising suspicion for biliary disease and prompting cholangiographic workup. Targeted serology should be obtained early to guide etiologic differentiation, including serum IgG4, antinuclear antibody (ANA), antimitochondrial antibody (AMA), complete blood count with eosinophil differential, and serum IgE when eosinophilic cholangitis or drug hypersensitivity is suspected. Abdominal US is the appropriate first-line imaging modality but has limited sensitivity (30–40%) for SSC-related biliary abnormalities (5). A normal US in the setting of persistent cholestasis should not preclude further evaluation.

Magnetic resonance cholangiopancreatography (MRCP) versus endoscopic retrograde cholangiopancreatography (ERCP): indications and decision criteria

MRCP is the preferred noninvasive modality for evaluation of biliary strictures, ductal irregularities, and intrahepatic involvement and should follow when US is unrevealing in the setting of ongoing cholestasis (1,2). MRCP characterizes stricture morphology, which may suggest a specific etiology—smooth tapered strictures in IgG4-SC, beading and pruning in SSC-CIP and PSC, asymmetric intrahepatic involvement in malignancy—without procedural risk. MRCP has recognized limitations in early SSC-CIP, where findings may be nonspecific, and in the presence of pneumobilia, which can generate signal voids mimicking biliary stones (6).

ERCP should be reserved for: (I) therapeutic intervention (biliary cast extraction, stricture dilation, stent placement); (II) tissue acquisition via brush cytology, transpapillary biopsy, or cholangioscopy-directed sampling; or (III) technically suboptimal or clinically inconclusive MRCP. Given its procedural risks (post-ERCP pancreatitis, cholangitis, perforation), ERCP should not be used as a primary diagnostic study when MRCP is feasible (6-8).

Role of histology: when biopsy is warranted

Liver biopsy or biliary tissue sampling should be obtained when: (I) clinical, biochemical, and cholangiographic workup does not establish a clear etiology; (II) immune-mediated cholangiopathy [IgG4-SC, eosinophilic cholangitis, immune checkpoint inhibitor (ICI)-associated cholangiopathy] is suspected and tissue confirmation would alter management; (III) malignancy cannot be excluded on imaging alone; or (IV) indeterminate biliary strictures require pathologic characterization. Etiology-specific histopathologic findings are described within each section below and summarized in (Table 3).

Secondary sclerosing cholangitis in critically ill patients (SSC-CIP)

Epidemiology

SSC occurs acutely in severely ill patients from sepsis, trauma, burns, or cardiothoracic surgery (CTS), with CTS notably conferring a higher risk of developing SSC-CIP (9,10). The incidence is estimated at 1 in 2,000 intensive care unit (ICU) admissions, but the true burden is likely higher as many patients succumb prior to diagnosis. The mean age at diagnosis is 50 years but can range between 19 and 79 years—underscoring the variability of underlying reasons for ICU admissions (5,11). There is a male predominance, as in PSC, ranging from 2:1 to 9:1 (5,7,12). Studies have shown that most patients diagnosed with SSC-CIP were placed on mechanical ventilation for more than 30 days, on average 41 days with FiO2 >0.8 and high PEEP for many hours to keep oxygenation >90% (6,13). In addition, hypotensive patients requiring vasopressors had a 60% association with developing SSC-CIP (Table 4) (6,8).

Pathophysiology

The pathophysiology of SSC-CIP is not fully understood. One thought centers around ischemic injury to the biliary tree in the setting of shock, vasopressor use, severe hypoxemia, and high PEEP or ventilatory pressures (9). Unlike hepatocytes, which receive blood from both portal veins and hepatic arteries, the biliary tree receives blood supply only from hepatic artery branches, making it more susceptible to changes in arterial blood flow. Ischemia also results in alterations to bile composition, promotes infection, and eventually leads to bile duct necrosis with biliary cast formation and acceleration of multifocal intrahepatic stricturing (13). This is a progressive and irreversible process that destroys intrahepatic bile ducts leading to SSC (14). Another consideration is the concept of toxic bile, which suggests that the factors that protect cholangiocytes from bile acids are disrupted in the setting of critical illness due to inflammation and hypotension (15).

Clinical presentation

Patients with SSC-CIP may present with jaundice, pruritus, and abdominal discomfort (4,6). The distinguishing feature of SSC-CIP versus cholestasis of sepsis is the persistence of cholestasis despite recovery from critical illness (4,6). Early clinical signs of SSC-CIP include a rapid rise in ALP and γ-glutamyl transferase; bilirubin may also be elevated, although less pronounced than ALP (13,14). ALT and AST are only mildly increased (4). These findings are nonspecific and overlap with other cholangitis conditions such as PSC and can be easily overlooked.

Diagnostic workup and endoscopic features

Evaluation of suspected SSC-CIP begins with a standard hepatic panel and abdominal US. The R-factor is typically below 2, confirming the cholestatic pattern, with ALP and GGT rising disproportionately to transaminases, which are typically only mildly elevated (4,13,14). GGT is often the first parameter to be elevated [peak 20–50 times the upper limit of normal (ULN)], typically 7–9 days after primary insult, followed by ALP (peak 5–21 times ULN) and lastly bilirubin (peak 3–39 times ULN), rising over >14 days on average (11,16). The initial diagnostic study in patients with cholestatic abnormalities is abdominal US; however, given its low sensitivity (30%) in detecting SSC-CIP, a normal abdominal US in the setting of worsening cholestasis, particularly post-ICU, should prompt further evaluation (11). MRCP is the preferred next step and characterizes the evolution of SSC-CIP with biliary cast formation in early stages, progressing to diffuse intrahepatic strictures sparing the common bile duct in later stages (4,12,13). MRCP has limitations in early disease with nonspecific findings of biliary casts and is restricted by the presence of pneumobilia manifesting as a signal void, which may be mistaken for biliary stones (13). ERCP is more useful for discrete early lesions and allows for interventions at the time of diagnosis, including biliary cast extraction and sphincterotomy (12-14). Given the invasive nature of ERCP, MRCP is preferred as the initial step. ERCP should be reserved in cases where MRCP is suboptimal, inconclusive, or therapeutic intervention is required.

Prognosis and treatment

Liver transplantation is the only known definitive treatment for SSC-CIP. The mortality rate is estimated to be around 50% during patients’ initial ICU stay, while most patients who survive require liver transplantation (3,6,7,11). In a 2005 Mayo Clinic review, 31 patients diagnosed with SSC, those who did not undergo liver transplantation had a median survival of 72 months compared to 89 months in those with PSC (14). Other symptom-based treatments, including endoscopic sphincterotomy, extraction of as many biliary casts as possible, and high-dose ursodeoxycholic acid (UDCA) to improve bile flow, have been described; however, these treatments are limited and cannot prevent progressive biliary destruction (13,14).

Infectious (HIV, parasitic, pyogenic, COVID-19)

Epidemiology

Several infectious etiologies can lead to cholestatic injury, including recurrent pyogenic cholangitis (RPC), parasitic infections, and COVID-19. In recurrent pyogenic infections, 90% of cases have been associated with intrahepatic duct stones (7). Parasitic infections inducing SSC are extremely rare with insufficient data to quantify prevalence.

COVID-19 has been known to cause severe acute respiratory syndrome, leading to about 7 million deaths worldwide (17). Post-COVID SSC in critically ill patients has been documented at rates more than 46 times higher than pre-pandemic data, with an incidence of 2.3 per 100 mechanically ventilated COVID-19 patients [95% confidence interval (CI): 1.5–3.4] (5,18). Patients with post-COVID cholangiopathy are predominantly male, with a median age of 50 years (9,18). In a review of 26 studies including 10,946 patients, the mean age was 50.5 years, with at least 263 ICU admissions, and approximately 16% of patients required liver transplantation (19,20).

Pathophysiology

RPC arises from recurrent gram-negative biliary infections, most often with biliary obstruction and intrahepatic pigmented stones, and is predominantly found in Southeast Asia (7,9). COVID-19 induced cholangiopathy has been increasingly reported following infection. Although the exact mechanism is unclear, ACE2, a receptor present on both vascular endothelial cells and SARS-CoV-2, leads to uncontrolled activation of the interleukin-6 (IL-6), driving hyperinflammation and ischemic injury (9).

Clinical presentation

Patients affected with RPC may present with nonspecific right hypochondrial pain, fever, and jaundice (9). In a case report describing bacterial cholangitis induced SSC, elevated bilirubin levels and ALP were reported along with classic cholangitis symptoms of jaundice, right upper quadrant pain, and fever (21). Similar to SSC-CIP, COVID-induced SSC is associated with patients requiring mechanical ventilation and prolonged-ICU stay (9). Patients typically present with jaundice and pruritus in addition to persistently elevated cholestatic liver enzymes several weeks or months after admission to the ICU (9). A significant number of patients did not have preexisting liver disease, and diabetes mellitus is the most common comorbidity associated with post-COVID cholangiopathy (9,22).

Diagnostic workup and endoscopic features

Evaluation begins with initial liver enzymes and an abdominal US, followed by cholangiography. ERCP is favored over MRCP when stone extraction or biliary drainage is needed, which is often the case in RPC (9,20,22,23). The “missing-duct sign” has been described on MRCP imaging in RPC, characterized by intrahepatic stones causing filling defects (7). In a case report describing a rare case of acute bacterial cholangitis-induced SSC, ERCP showed hilar biliary stenoses and multiple strictures of intrahepatic bile ducts associated with peripheral duct dilatation (9). In most studies, post-COVID cholangiopathy was defined as ALP greater than 1.5 times normal, bilirubin greater than 2 times normal, and GGT greater than 3 times the normal value (20). Histologically, post-COVID-19 cholangiopathy has unique features of microangiopathy, which is characterized by endothelial swelling with luminal narrowing of the hepatic artery and portal vein (7). Cholangiocytes show prominent cytoplasmic vacuolization, underscoring the necrotic process of prolonged cholangiopathy (7). Roth et al. [2021] described MRCP findings of intrahepatic bile duct beading, along with biliary strictures and dilatations (24). Portal tract biopsies showed microangiopathic changes including endothelial swelling of hepatic arteries, microthrombosis, and vessel wall necrosis in the setting of ischemia (24). Biopsy is warranted in post-COVID cholangiopathy when the diagnosis remains uncertain or when alternative etiologies require exclusion; the microangiopathic pattern is pathognomonic when present.

Prognosis and treatment

In isolated bacterial cholangitis-induced SSC, prolonged antibiotic therapy alone has been associated with remission when biliary injury follows a single episode rather than recurrent obstruction (21). In RPC, first-line treatment includes antibiotics and drainage, with adjunctive biliary decompression that should not be delayed in anticipation of resolution from antibiotics (9). In those with RPC complicated by liver failure, transplantation is the only curative therapy for these patients. For post-COVID cholangiopathy, while some improve without invasive intervention, others may progress to liver failure requiring transplantation (4). Symptomatic treatments with UDCA, cholestyramine, and even antiplatelet medications have shown some benefit (9). Ultimately, liver transplantation is the only treatment that has shown definitive benefits for infection-induced SSC.

Drug-induced SSC

SSC is an emerging phenotype of drug-induced liver injury (DILI). Based on a recent systematic review identifying 19 drugs linked to SSC, ICIs are currently the leading cause (Table 5) (25). Ketamine, both in chronic recreational use and ICU settings, is an increasingly recognized additional cause of drug-induced SSC (26).

Epidemiology

ICI-related liver injury occurs in 2–10% of patients receiving the treatment (27). ICIs such as nivolumab and pembrolizumab were most strongly associated with the small-duct cholestasis (25,26). In one retrospective study, more than half of patients with advanced malignancies treated with ICIs developed a biliary-predominant pattern of liver enzymes elevation with non-obstructive biliary dilation resistant to steroid (28). In a separate systematic review, the median onset of PD-1 inhibitor-related sclerosing cholangitis occurred after 5.5 cycles; however, it can occur as soon as two to four cycles of treatment (28,29).

Regular ketamine users presenting with a sclerosing cholangitis pattern of injury have a reported incidence of biliary abnormalities of 65–70% (27,28,30). In a study discussing recreational ketamine-induced cholangiopathy, the mean age of patients affected was 26 years with 65% men (30). Therapeutic ketamine in the ICU has also been increasingly documented to cause biliary injury (6).

Pathophysiology

The exact mechanism behind DILI and drug-induced cholangitis injuries remains unknown due to the wide variability of different drugs causing injury. ICI-induced cholangitis is driven predominantly by CD8+ and CD3+ T cells without significant eosinophilia, leading to biliary duct dilatation and progressive ductopenia (6,26). Another common drug causing cholangiopathy is ketamine, and although the exact mechanism of biliary dilation is yet to be established, one theory proposed that, as an NMDA antagonist, it can cause smooth muscle relaxation, which may apply to the biliary tree smooth muscle (31). Overall, drug-induced cholangiopathies often affect small bile ducts producing mixed patterns of hepatocellular and cholangitis injuries, which in turn if chronically affected, produces bile duct atrophy and loss resulting in ductopenia and portal fibrosis (28).

Clinical presentation

Clinically, drug-induced cholangitis is often silent, but can manifest as jaundice, a mixed hepatocellular-cholangitis pattern with elevated ALP and GGT and possible elevated serum bilirubin and transaminases, like other causes of SSC (28). Drug-induced sclerosing cholangitis typically involves large intrahepatic and extrahepatic bile ducts presenting initially as transient cholangitis, followed by features of chronic biliary disease many months later (28).In a cohort study analyzing 48 cases of ICI-induced cholangitis, almost half of the cholangitis cases occurred after 6 months of ICI treatment, with jaundice universally present and bilirubin elevation inversely correlated with treatment cycles (32). Though the presentation for drug-induced cholangitis can be variable, if patients develop mixed or cholestatic patterns with high ALP levels, SSC should be suspected.

Diagnostic workup and endoscopic features

In drug-induced SSC, a cholestatic liver enzyme pattern and a clear temporal relationship to drug exposure are the key initial clues. Serologic evaluation should exclude alternative immune-mediated etiologies (IgG4, ANA, AMA), as ICI-associated cholangiopathy can mimic PSC and IgG4-SC clinically and biochemically. Imaging findings of ICI-induced cholangiopathy usually reveal large-duct cholangitis of intrahepatic and extrahepatic ducts with non-obstructive biliary dilatation or stenosis (25). MRCP is typically first-line imaging to detect morphological changes. Similarly, in other drugs that cause sclerosing cholangitis, such as ketamine, MRCP imaging has been reported to show strictures and dilatations of intrahepatic bile ducts, with multiple biliary casts and peribiliary cysts, without obstruction (6). ERCP should be pursued when tissue acquisition is needed, particularly when cholangiocarcinoma cannot be excluded or when dominant strictures require therapeutic dilation. Liver biopsy demonstrating CD8+/CD3+ T-cell predominant infiltration without significant eosinophilia supports ICI-associated cholangiopathy and is particularly valuable when distinguishing from IgG4-SC or malignant cholangiopathy (6,23,29).

Prognosis and treatment

Prognosis is generally favorable after prompt drug withdrawal, particularly prior to advanced ductopenia or fibrosis. In persistent cases requiring adjunct therapy, corticosteroids or UDCA have been commonly used (25,33). UDCA has cytoprotective and anti-apoptotic properties, and by enriching the bile acid pool with more hydrophilic bile acids, it reduces the cytotoxicity of retained bile on cholangiocytes (26). In cases where first-line therapies are not optimal, azathioprine, mycophenolate mofetil, or tocilizumab have been used with variable effects (34). In one systematic review, responses to corticosteroids in ICI-induced SSC were significantly poorer compared to those with immune-mediated hepatitis, with only 11.5% of patients responding well to treatment (29). When pharmacotherapy is ineffective, endoscopic interventions can help reduce cholestasis and improve drainage, but do not reverse established ductal injury (28,29).

Malignancy-associated [cholangiocarcinoma, intrahepatic metastasis, lymphoma, Langerhans cell histiocytosis (LCH)]

Epidemiology

Malignancy-associated sclerosing cholangitis represents an important subset of SSC in which neoplastic processes cause progressive biliary injury, fibrosis, and stricturing (35,36). The most frequently involved malignancies include cholangiocarcinoma, diffuse intrahepatic metastases from breast cancer, colon cancer, melanoma, lymphoma with periportal tract involvement, and LCH. Cholangiocarcinoma represents 10–15% of hepatobiliary cancers, with only a subset experiencing diffuse sclerosing cholangiopathy. Secondary hepatic lymphoma is seen in up to 50% non-Hodgkin lymphoma, but significant biliary involvement is infrequent.

Pathophysiology

Malignancy can cause SSC by direct invasion, extrinsic compression, or destruction of bile ducts, leading to chronic inflammation, fibrosis, and stricturing. Most commonly, cholangiocarcinoma typically produces concentric ductal thickening with invasion and obstruction of the biliary duct (35,36). Hepatic metastases (breast, colon, or melanoma) infiltrate periportal tracts or compress intrahepatic ducts. Lymphomas can infiltrate the portal tracts or cause mass effect, while LCH causes granulomatous infiltration and destruction of small and medium bile ducts, which can progress to cirrhosis.

Clinical presentation

Patients typically present with progressive cholestatic symptoms, including jaundice, abdominal pain, pruritus, dark urine, and pale stools. Constitutional symptoms including weight loss, fatigue, and anorexia are common and reflect underlying malignancy (35,36). Systemic features including B symptoms (fever, night sweats, weight loss) may provide etiologic clues and raise concern for lymphoma, while multisystem involvement with bone lesions, rash, and diabetes insipidus may suggest LCH (35,36).

Diagnostic workup and endoscopic features

Initial laboratory evaluation demonstrates a cholestatic enzyme pattern, with ALP and GGT elevation. When cholangiocarcinoma is clinically suspected, serum CA 19-9 should be obtained, although its sensitivity and specificity are limited in the presence of cholestasis. Abdominal US may identify focal hepatic masses or biliary dilation, but is insufficient for characterization of ductal involvement. MRCP is the preferred initial cholangiographic modality and commonly reveals multifocal asymmetric or eccentric intrahepatic strictures, long irregular stenosis, or dominant strictures with mass effect (2,34). In lymphoma or metastatic disease, cross-sectional imaging may show periportal soft tissue infiltration, hepatic masses, lymphadenopathy, or diffuse infiltrative changes causing extrinsic ductal compression. In LCH, advanced cases may demonstrate coarse beading and progressive obliteration of the biliary tree. Tissue sampling is essential to differentiate malignant infiltration from inflammatory cholangiopathy and to direct oncologic management. ERCP with brush cytology, endoscopic ultrasound (EUS)-guided sampling, or cholangioscopy-directed biopsy should follow MRCP when tissue is required. Cholangiocarcinoma is confirmed by identifying adenocarcinoma on biopsy, brush cytology, or EUS-guided sampling. Lymphoma requires histology and flow cytology, while positron emission tomography/computed tomography (PET/CT) scans can aid in staging and evaluating systemic disease. LCH is confirmed with biopsy demonstrating CD1a+, S100+, and Langerin+ histiocytes. Workup must also exclude alternative causes of SSC, including ischemic, infectious, drug-related, and immune-mediated etiologies (35,36).

Prognosis and treatment

Prognosis depends heavily on the underlying malignancy and severity of biliary damage (14,35,36). Since biliary involvement typically occurs in advanced malignancies, outcomes are generally poorer than those of PSC or SSC-CIP. For patients with cholangiocarcinoma, surgical resection is the only curative option, but often not feasible at presentation. In unresectable disease, systemic chemotherapy and/or radiation therapy are initiated, whereas ERCP-guided dilation or stenting can provide effective palliation of cholestasis and cholangitis (2,5). Systemic chemotherapy is used for lymphoma and LCH, while liver transplantation may be considered for end-stage cholestatic liver disease when systemic disease is controlled (5). Irrespective of malignancy type, supportive hepatobiliary care is essential to managing symptoms and preventing complications.

IgG4-related sclerosing cholangitis and eosinophilic cholangitis

Epidemiology

Immunoglobulin G4-sclerosing cholangitis (IgG4-SC) is one of the most common extra pancreatic manifestations of IgG4-related disease and may account for up to 10% of benign biliary strictures and approximately 3–15% of all sclerosing cholangitis cases seen in tertiary centers (37-40). IgG4-SC is found in 30–60% of patients with type 1 autoimmune pancreatitis and about 90% of those with IgG4-SC have concomitant autoimmune pancreatitis. It predominantly affects middle-aged to older men, consistent with the demographic pattern of IgG4-related diseases (37,41). Eosinophilic cholangitis is an exceedingly rare immune-mediated biliary disorder, typically presenting in middle and older age with eosinophilia, with fewer than 50 cases described in the published literature (42,43). Its true prevalence is likely unknown, as many cases resolve with corticosteroid therapy before biopsy confirmation.

Pathophysiology

Immunoglobulin G4-related disease (IgG4-RD) is a systemic immune-mediated fibroinflammatory condition characterized by infiltration with IgG4-positive plasma cells and lymphocytes, which most commonly involve the pancreas, biliary tract, lacrimal glands, salivary glands, and retroperitoneum (44). The pathogenesis involves immune dysregulation with T helper cell and regulatory T cell (Treg) activation, which in turn drives the production of IgG4 antibodies. Tregs are thought to function abnormally in IgG4-RD, failing to control the inflammatory cascade and, in turn, leading to B cell activation and differentiation into IgG4-producing plasma cells (44,45). Typically, IgG4 levels are elevated in over 80% of patients (46).

The pathophysiology of eosinophilic cholangitis, while incompletely understood, is thought to involve aberrant eosinophil recruitment and degranulation within the bile duct wall, mediated by eotaxin and IL-5 signaling (47). Release of eosinophil granule proteins, including major basic protein and eosinophil cationic protein, causes direct cytotoxic injury to cholangiocytes and periductal stroma, resulting in edema, fibrosis, and progressive biliary obstruction. The condition may arise as primary immune dysregulation or secondarily in the context of drug hypersensitivity, parasitic infection, particularly Clonorchis or Ascaris, or hypereosinophilic syndrome. The histopathologic hallmark is tissue eosinophilia exceeding 20 eosinophils per high-power field with absent or minimal IgG4 positive plasma cell infiltration (42,43,47).

Clinical presentation

Both IgG4-SC and eosinophilic cholangitis typically present with progressive cholestatic symptoms. IgG4-SC may present with systemic symptoms, given its involvement of other organs, including the pancreas, salivary glands, retroperitoneum, and kidneys (38-40). Weight loss is particularly common in IgG4-SC given its strong association with autoimmune pancreatitis. Eosinophilic cholangitis can be associated with features of atopy including asthma, eczema, and elevated IgE (42,43).Peripheral eosinophilia, when present, provides a valuable diagnostic clue; however, its absence does not exclude the diagnosis, as tissue eosinophilia may occur without peripheral elevation in a subset of cases (47).

Diagnostic workup and endoscopic features

In IgG4 and eosinophilic cholangitis, serologic evaluation is particularly high yield. Serum IgG4 >135 mg/dL and IgG4/IgG1 ratio >0.24 support IgG4-SC and should be obtained whenever immune-mediated cholangiopathy is suspected. A complete blood count with eosinophil differential and serum IgE should be obtained to evaluate for eosinophilic cholangitis. When US is unrevealing, MRCP or ERCP is essential for stricture extent and morphology characterization, while CT/MRI may reveal extrahepatic organ involvement.

In IgG4-SC, MRCP and ERCP typically demonstrate long, smooth, tapered strictures with minimal upstream dilation, unlike the typical beading and irregularity seen in PSC (38-40). IgG4-SC is classified into 4 types by cholangiographic location of stricture (41). Histologically, IgG4-SC is characterized by lymphoplasmacytic infiltrate with IgG4-positive plasma cells, and storiform fibrosis (38,48). Diagnosis of IgG4-SC relies on the HISORt criteria, involving histopathology, imaging, serology, other organ involvement, and response to therapy. In addition, the revised Japanese clinical diagnostic criteria in 2020 consist of six diagnostic items, including narrowing of the intrahepatic and/or extrahepatic bile duct, thickening of the bile duct wall, serological findings, pathological findings, other organ involvement, and effectiveness of steroid therapy (41). Based on these diagnostic items, a definite, probable, or possible diagnosis of IgG4-SC can be made.

In eosinophilic cholangitis, the workup should include a differential blood count, with elevated peripheral eosinophilia in the majority of cases. Imaging with CT or MRI can show uniform thickening of intra and extrahepatic bile duct walls with stenosis presenting as rat-tail sign with upstream dilation. However, endoscopic histology is considered the gold standard. Histology typically demonstrates dense eosinophilic infiltrates, edema, and periductal fibrosis without IgG4 predominance (38,43). Histological confirmation of eosinophilic cholangitis is necessary to exclude cancer, given its similar presentation on imaging. Secondary causes of eosinophilia including drug hypersensitivity reactions, parasitic infection, and hypereosinophilic syndrome must be excluded before a primary diagnosis is established (42,47). ERCP is indicated when malignancy cannot be excluded on noninvasive workup, tissue confirmation is required for diagnosis, or dominant strictures require therapeutic intervention. Biopsy is confirmatory in IgG4-SC and mandatory in eosinophilic cholangitis, as there are no validated serum biomarkers for the latter.

Prognosis and treatment

Autoimmune cholangitis typically has a favorable prognosis if diagnosed early. First-line therapy is systemic corticosteroids (prednisone or prednisolone at 0.6 mg/kg/day), which induce remission in most cases. IgG4-SC generally responds rapidly and dramatically to corticosteroids, with more than 90% of patients experiencing symptomatic and radiologic improvement (38-40). However, relapse is not uncommon, occurring in approximately half of cases, necessitating maintenance therapy with immunomodulators such as azathioprine, mycophenolate mofetil, or B cell depletion treatment with rituximab. Long-term outcomes are typically favorable, particularly when treatment is initiated early; however, progressive fibrosis and, less commonly, cirrhosis can occur without treatment. In a Mayo Clinic cohort of 89 IgG4-SC patients matched to PSC controls, long-term outcomes in IgG4-SC were favorable compared to PSC, with a significantly lower 10-year probability of cirrhosis or cholangiocarcinoma (11% vs. 45%, P=0.0001) and no patients requiring liver transplantation; 10-year overall survival trended higher (79% vs. 68%) (49). Relapse should prompt evaluation for alternative causes, including cholangiocarcinoma (49,50). Eosinophilic cholangitis similarly responds well to corticosteroids, with most patients experiencing complete resolution of strictures and associated symptoms (42,43). Treatment of identifiable secondary causes, including parasitic infection or drug hypersensitivity, is essential. Recurrence is uncommon, and long-term outcomes are favorable. However, some cases require biliary stenting or surgical intervention for refractory biliary strictures (43,51,52).

Transcatheter arterial chemoembolization (TACE) related cholangitis

Epidemiology

TACE is generally recognized as a safe and effective treatment for recurrent hepatocellular carcinoma (HCC) post-resection with preserved liver function as well as liver metastases from neuroendocrine tumors (NETs). The incidence of TACE-induced ischemic cholangitis has not been studied; however, several retrospective studies have documented the incidence of adverse effects in their respective patient populations. Nakada et al. reported that among 156 patients reviewed, 5.1% developed ischemic cholangitis, with a median time to diagnosis of 2.2 months after the TACE (53). In a separate study analyzing complication rates between doxorubicin and drug-eluting beads TACE (debTACE) for HCC and NETs, at least one liver or biliary injury occurred after 35.7% of debTACE sessions (54). In the same study, dilated biliary ducts were the most frequent injury along with biliomas, which were only found in debTACE for NETs, not HCC (54). In the same study utilizing multivariate analysis, the only factor that independently predicted liver/biliary injury was deb-TACE. There has been a reported incidence of conventional TACE (cTACE) ranging between 0.5–4% (54). Prior reports correlated the higher number of TACE sessions with a higher number of biliary injuries (55).

Pathophysiology

TACE is performed by inserting an angiographic catheter through the femoral artery, followed by the common hepatic artery, with subsequent visualization of the hepatic artery and portal vein. The mechanism of biliary injury in TACE is closely linked to the terminal hepatic arterial supply to the peribiliary capillary plexus (55). Bile duct epithelium exclusively requires arterial perfusion; thus, selective arterial occlusion by embolic material produces ischemic injury preferentially to cholangiocytes. Risk factors include a higher cumulative number of TACE sessions, use of drug-eluting bead (DEB) formulations compared with conventional lipiodol-based emulsions, selective catheterization of distal arterial segments, pre-existing biliary anatomic variations or dilatation, and the presence of portal vein thrombosis. Notably, the absence of cirrhosis has been paradoxically identified as a risk factor, possibly due to loss of protective hepatic arterial flow redistribution seen in cirrhotic livers with established collateral vasculature (56). Distinguishing TACE-induced cholangitis from superimposed infective cholangitis or hepatic abscess requires careful integration of clinical, biochemical, and imaging data.

Clinical presentation

The general pattern of TACE-induced cholangitis is similar to that of other secondary causes of cholangitis, presenting with elevated ALP and GGT as the predominant biochemical finding. In one study, ALP and GGT were elevated in patients with bile duct injuries after TACE more than those without bile duct injuries, and subsequent multivariate analysis suggested elevated ALP was an independent predictor for TACE-induced cholangitis (56). In the same study, elevation of platelets was found in patients with bile duct injury, and further analysis suggested that patients with a history of cirrhosis provide a protective factor against bile duct injury (56).

Diagnostic workup and endoscopic features

Post-TACE, a rise in ALP and GGT beyond baseline on the standard hepatic panel is the principal laboratory trigger for dedicated biliary imaging. CT or MRI is the preferred initial imaging modality, providing detailed characterization of bilioma formation, periductal edema, and hepatic parenchymal changes (53,57). It also allows crucial exclusion of hepatic abscess, an important differential diagnosis that may require alternative management. MRCP may follow when stricture morphology and intrahepatic ductal involvement require characterization. ERCP findings have reportedly demonstrated dilatation of the common bile duct with focal narrowing, consistent with other secondary causes of cholangitis (57). CT/MRI findings show biliary duct dilation accompanied by congestion and edema or biliomas, described as isolated circular low-density areas distributed along the Gleason’s sheath, which communicated with the bile duct (3,53). ERCP is indicated for therapeutic purposes, including biliary drainage, balloon dilation, or stent placement for persistent strictures rather than a primary diagnostic tool (58). Liver biopsy is not routinely required to diagnose TACE-related cholangitis; when performed, an ischemic cholangiopathy pattern may be observed (55).

Prognosis and treatment

There is no set treatment for TACE-induced cholangitis. In one study comparing complications between debTACE for NETs and HCC, all biliomas were treated with intravenous antibiotics successfully (54). Other reports have treated cholangitis and biliomas symptomatically, similar to other secondary cholangitis presentations such as biliary drainage, balloon dilation, and stent placement for strictures (58). Although there is no official reported survival rate for TACE-induced cholangitis, Kim HK et al. [2001] reported 70–80% recovery rate after prompt administration of conservative and drainage therapy (59). Prevention remains the cornerstone of management, given the absence of curative pharmacological therapy. Careful procedural planning, including assessment of biliary anatomy before TACE, avoidance of non-target embolization, and limiting embolic material per session, can substantially reduce the incidence of biliary injury. In patients requiring repeat TACE, surveillance imaging between sessions is advisable (55,57).

Comparative synthesis across SSC etiologies

Although each etiology of SSC shares features of biliary inflammation, fibrosis, and progressive stricturing, clinically meaningful differences in disease trajectory, treatment responsiveness, and transplant likelihood distinguish them in practice. SSC-CIP and post-COVID cholangiopathy follow the most aggressive clinical courses, with rapid progression to biliary cirrhosis, and liver transplantation is required in 15–50% of published cases (6,11,18). Early transplant evaluation is therefore warranted when biliary casts and multifocal intrahepatic strictures are identified. In contrast, IgG4-SC and eosinophilic cholangitis carry a favorable prognosis when recognized early and treated with corticosteroids, with remission rates exceeding 90%; however, relapse occurs in approximately half of IgG4-SC patients, necessitating long-term maintenance immunosuppression (38-40,49).

Drug-induced SSC presents a heterogeneous clinical picture depending on the offending agent. ICI-associated cholangiopathy is notable for its markedly poor corticosteroid response; only approximately 11.5% of patients respond well in systematic reviews, distinguishing it from other immune-mediated etiologies and emphasizing the importance of early drug cessation (29). Ketamine-associated cholangiopathy may stabilize after drug discontinuation, although advanced ductopenia may preclude full recovery. Malignancy-associated SSC carries the poorest overall prognosis given its occurrence in the context of advanced neoplastic disease. Endoscopic palliation and oncologic therapy may improve symptoms but rarely reverse established ductal injury. TACE-related cholangitis resolves with conservative management in the majority of cases with a 70–80% recovery rate, and prevention through careful procedural selection and technique is the most effective strategy (59). These distinctions are summarized in Table 6.

Strengths and limitations

This narrative review synthesizes emerging literature on SSC and highlights evolving etiologies. By organizing SSC by etiologic categories and integrating diagnostic management considerations, this review provides a practical framework for clinicians encountering cholestatic liver injury in complex clinical settings. However, limitations should be acknowledged. As a narrative review, the study selection may not be exhaustive, and some relevant studies may not be included. Furthermore, this synthesis does not include a formal quality assessment, risk of bias framework, or systematic grading of evidence levels. Given the rarity and heterogeneity of the disease, much available evidence regarding SSC is derived from observational studies, case series, and retrospective analyses. Further prospective and longitudinal studies are needed to better define optimal diagnostic pathways and treatment strategies. Where possible, we have distinguished between statements supported by multicenter cohort data and those based primarily on case-level evidence. The depth of discussion for each etiology reflects the available literature, with emerging entities such as post-COVID cholangiopathy and ICI-associated SSC generating more rapidly growing literature than rarer entities such as eosinophilic cholangitis and TACE-related cholangitis.

Conclusions

SSC encompasses a diverse group of cholangiopathies characterized by progressive bile duct injury from identifiable etiologic factors. Compared with PSC, SSC often follows a more aggressive clinical course, particularly in ischemic and post-infectious etiologies. Early recognition of the underlying etiology is therefore critical as many causes require targeted therapy, including antimicrobial treatment, immunosuppression, drug withdrawal, endoscopic interventions, or oncological management. A structured diagnostic approach integrating exposure history, laboratory testing, advanced cholangiographic imaging, and histopathology is essential to distinguish between etiologies. While the above measures can help slow down the disease course, many patients ultimately progress to advanced biliary fibrosis and cirrhosis, in which case timely referral for liver transplantation remains the definitive option. Future research should focus on prospective, multicenter studies aimed at better characterizing the course of newly recognized entities, including post-COVID cholangiopathy and ICI-associated SSC. Advancements in imaging, molecular biomarkers, and cholangiocyte-specific injury pathways may also provide new opportunities for earlier diagnosis and targeted therapy.

Acknowledgments

None.

Footnote

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