Primary biliary cholangitis (PBC) previously known as “primary biliary cirrhosis” is a rare autoimmune disease characterized by chronic injury to biliary epithelial cells. Both genetic and environmental factors contribute to its development. Genetically, there is increased incidence in families with a history of the disease due to shared genetic factors, and studies show high concordance in identical twins. Environmental factors, including smoking, exposure to hair dye, pollutants, and toxic waste are believed to play a role [12]. PBC predominantly affects adult women (approximately 90%), between the ages of 40–60 [13, 14]. In North America, the incidence rate is 2.75 per 100,000 population, with a female-to-male ratio of 4-10:1 [12].

PBC can be detected incidentally in asymptomatic patients through unrelated biochemical tests. Symptoms like pruritus and fatigue are common, sometimes preceding jaundice [13, 15]. Chronically elevated serum alkaline phosphatase without known cause may raise suspicion for PBC. Diagnosis relies on serum antibodies, primarily antimitochondrial antibodies (AMA), with a high sensitivity (84.5%) and specificity (97.8%). In AMA negative patients, the presence of PBC-specific antinuclear antibodies, such as sp100 and gp210, can establish diagnosis [16]. Liver biopsy is typically unnecessary unless serology is negative or other liver conditions are suspected [17].

Histologically, PBC progresses from initial focal inflammation around bile ducts to end-stage ductopenia. Lymphocytic cholangitis and the diagnostic hallmark, the 'florid duct lesion,' characterized by granulomatous inflammation around an injured bile duct, are key identifiers. As the disease progresses, fibrosis spreads from the portal areas, with bile duct loss intensifying [18]. Subsequent stages involve increasing inflammation, fibrotic distortion and ultimately cirrhosis [19].

In the workup for cholestasis, a right upper quadrant ultrasound is often the initial step, helping distinguish between extrahepatic causes of cholestasis, where biliary dilation is typically present, from intrahepatic causes like PBC, where biliary dilation is absent. MRI may reveal a periportal halo sign which manifests as round areas of low signal intensity on T1 and T2 weighted images around the portal venous branches with no accompanying mass effect [20]. Other imaging features, like heterogeneity on T2-weighted MRI and lacelike fibrosis on contrast-enhanced MRI, are indicative of disease progression [21,22,23,24,25]. Periportal cuffing due to edema is seen as periportal hyperintensity on T2WI around the large portal vein branches and is due to a combination of inflammation, increased cellularity, and biliary ductular proliferation, although it is not specific to PBC and is less common in advanced stages of PBC (Fig. 3) [21, 22, 25,26,27]. Cross-sectional imaging may also reveal lymphadenopathy and hepatomegaly, further aiding diagnosis [23, 24].

A 67-year-old female diagnosed with Primary Biliary Cholangitis at the age of 47. Axial T2 weighted MRI shows “periportal halo sign” as tiny, rounded areas of low signal intensity (arrowheads, a) and on postcontrast T1-weighted (arrowhead, b) around small peripheral portal vein branches distributed diffusely in both hemi-livers resulting in a markedly heterogeneous appearance. T2- weighted (arrow, c) shows periportal hyperintensity or “cuffing” around the right portal vein branch. MRI done at the age of 67 (image d) shows the absence of both periportal halo sign and periportal cuffing with the development of cirrhosis

MRCP aids in differentiating PBC from PSC and obstructive cholestasis. Typically, PBC affects small intrahepatic bile ducts (< 100 µm), which explains the normal appearance of the biliary tract in MRCP images [19]. One study found mild irregularities in the intrahepatic bile duct in PBC affecting less than 2% of the cases [25].

Ursodeoxycholic acid (UDCA) is the first-line treatment for PBC. It slows down disease progression, improves transplant free survival, and is typically taken for life [17].

Primary sclerosing cholangitis (PSC) is a chronic cholestatic disorder with multiple postulated etiologies, yet considered idiopathic. Its pathogenesis involves a combination of genetic predisposition, immune dysfunction, and environmental factors. Associations with specific HLA haplotypes highlight a genetic basis that predisposes individuals to immune responses aberrantly targeting the bile ducts [28]. These immune responses may be initiated or exacerbated by environmental triggers, such as microbial exposures, leading to chronic inflammation and fibrosis in the bile ducts, which can cause strictures, cholestasis, and eventually liver failure. Additionally, the strong association of PSC with inflammatory bowel disease, likely due to shared immune dysregulation and imbalances in gut microbiota, underscores the significant role of autoimmunity and microbial factors in its pathogenesis [28, 29]. There is a male predilection and increased incidence in the United States and Northern Europe, with a mean age of diagnosis of 40 years [30].

Patients with PSC may be asymptomatic or present with symptoms ranging from right upper quadrant pain and fever due to active cholangitis, to pruritus, jaundice, and fatigue from biliary obstruction or signs of cirrhosis such as abdominal distension from ascites if the diagnosis is delayed [29]. Diagnosis is made in the setting of chronic cholestatic laboratory abnormalities such as elevated alkaline phosphatase, gamma glutamyl transferase, moderate transaminitis plus multifocal bile duct stricturing seen on MRCP or ERCP, in the absence of another causative etiology of sclerosing cholangitis [9, 31]. PSC is therefore a diagnosis of exclusion.

PSC is often challenging to characterize histologically; thus, when diagnostic imaging (i.e., large-duct PSC) is conclusive, a biopsy is usually neither indicated nor helpful due to the liver’s patchy and variable physiologic manifestation. Biopsy findings often range from normal to nonspecific signs of extrahepatic biliary obstruction such as portal-based edema and mild ductular reaction. While concentric periductal fibrosis ('onion skin') is a classic diagnostic finding but may not always be present. Other features may include lymphocytic inflammation of the bile duct epithelium. As the disease progresses, bile ducts may atrophy or 'wither,' leading to their obliteration and loss, as hepatic fibrosis advances [32].

Imaging features of PSC include multifocal bile duct stricturing with a beaded appearance from intervening mildly dilated segments that can be intrahepatic, extrahepatic, or most commonly both. With chronicity, visualization of peripheral bile ducts is lost as they become fibrosed and the liver takes on a cirrhotic morphology with areas of confluent fibrosis. Sites of active cholangitis, hepatolithiasis, and hepatic abscesses can occur with obstruction causing upstream stasis and inflammation. Patients with PSC have an increased risk for cholangiocarcinoma, that may present as a high-grade stricture, polypoid luminal mass, or an intrahepatic focal lesion [31].

As cholestasis from PSC progresses, obliteration of peripheral ducts leads to a “pruned” appearance of the biliary tree on cholangiography which is reflected pathologically by progressive periductal fibrosis, chronic inflammation, and ischemic atrophy of biliary epithelia results in stricturing and ductopenia (Fig. 4). Thus, PSC is a potential etiology of VBDS and biliary cirrhosis [9, 33]. The majority of adult patients with ductopenia have either primary biliary cirrhosis, PSC, or a PSC-PBC overlap syndrome. A key differentiating feature of PSC is multifocal strictures resulting in upstream multifocal dilatation of the smaller and peripheral bile ducts. Multifocal biliary dilation is often the first imaging sign, particularly if a CT is obtained first [34].

A 29-year-old female with Ulcerative colitis since the age of 14 years old presents with cholestasis. Magnetic resonance cholangiopancreatography (MRCP) maximum intensity projection and axial T1-weighted post-contrast images at the time of diagnosis (image a); at 4 years (image b) and at 12 years (image c) are shown. The MRCP demonstrates classic stricture-dilatation of the intrahepatic bile ducts (arrowhead, a). With disease progression, there is progressive obliteration of the bile ducts (arrowheads, b–c). The liver also shows progressive decrease in volume (yellow arrows, b–c), worsening of fibrosis (white arrow, b–c) and development of cirrhosis

UDCA act by inducing hepatobiliary secretion, inhibiting apoptosis, and protecting cholangiocytes against the toxic effects of hydrophobic bile acids. It is used for PSC in combination with endoscopic interrogation and dilation of high-grade and relevant strictures [34]. The only curative treatment for PSC is liver transplantation.

The bile ducts are prone to ischemic injury due to their reliance on primarily arterial blood supply, in contrast to the liver, which has a dual blood supply from the portal vein and hepatic artery. The peribiliary vascular plexus is supplied by the right hepatic artery from above, the retroduodenal and retroportal arteries from below, and has a rich supply of transcapsular collaterals [35]. As a consequence, occlusion of the hepatic artery is generally has limited clinical significance except in liver transplantation, where collateral pathways are severed [36]. Outside of liver transplantation, where ischemic cholangiopathy most commonly occurs in the setting of a patent hepatic artery due to an ischemic event such as shock or cardiac arrest, toxic/ischemic injury to the small vessels of the peribiliary plexus (e.g., intraarterial chemotherapy), or vasculitis with obliteration of the peribiliary arterioles [31].

Ischemic cholangiopathy presents clinically with laboratory evidence of cholestasis and is often a leading diagnostic consideration in a critically ill patient with persistent liver chemistry abnormalities despite recovery from the original inciting event. The pathologic findings are similar to other forms of VBDS, though additional findings may include fibrous thickening, thrombosis, or obliteration of the peribiliary arterioles [1]. More specifically, the presence of bile duct epithelial cell necrosis and sloughing with biliary cast formation, when present, is the histopathologic finding most diagnostic of ischemic cholangiopathy in an appropriate clinical context.

Ischemic cholangiopathy after liver transplantation can manifest in four distinct patterns. The most severe, “Diffuse Necrosis”, involves widespread abnormalities and narrowing of the intrahepatic bile ducts within two months after transplant. “Multifocal Progressive” shows initial mild stenosis of the second-order and peripheral ducts that progressively worsens. The “Confluence Dominant” pattern is characterized by strictures localized at the biliary confluence, whereas the “Minor Form” presents mild early-stage abnormalities that do not progress to extensive strictures [37]. Commonly it manifests on imaging as multifocal stricturing of the intrahepatic and extrahepatic bile ducts [38]. Less commonly, it may present as biliary necrosis with the development of multiple peribiliary collections or bilomas that communicate with the biliary tree. Rarely, it may present as ductopenia in which ischemic biliary injury results in bile duct loss and VBDS [2]. As in other causes of ductopenia, the imaging findings are nonspecific, but a relative paucity of intrahepatic bile ducts may be evident on MRCP (Fig. 5). Prior imaging studies demonstrating vascular complications such as arterial thrombosis or stenosis can also be helpful in arriving at this diagnosis. Liver transplantation is frequently necessary and is considered curative [39].

A 53-year-old female with orthotopic liver transplant approximately 7 years ago with hepatic artery stenosis and ischemia induced chronic biliary anastomotic stricture requiring internalized PTC drain and repeat biliary stenting. The hepatic artery stenosis was treated with angioplasty. The patient had persistent chronic cholestasis, elevated alkaline phosphatase and transaminase. The Endoscopic retrograde cholangiopancreatography (ERCP) images demonstrate progressive decrease in the number and caliber of bile ducts over the years. (arrowheads, a–c) due to ischemic damage to the bile ducts. ERCP at baseline (image a); at 6 years (image b) and at 7 years (image c) are shown. The Magnetic resonance cholangiopancreatography maximum intensity projection images demonstrate comparable findings to the ERCP, showing progressive decrease in the number and caliber of the bile ducts (arrows, d–f) and development of biloma (arrowhead, f) over time

Chronic rejection occurs in 3–17% of patients after liver transplantation [40]. Bile duct loss is a typical pathologic finding of chronic rejection, often attributed to a combination of T-cell mediated cytotoxic injury to the bile ducts and obliterative arteriopathy resulting in ischemic biliary injury [41].

Histologically, acute T-cell mediated allograft rejection manifests as a portal-based inflammatory infiltrates, particularly within the bile duct epithelium, causing epithelial damage. This inflammation is usually rich in lymphocytes, sometimes with eosinophils. Chronic T-cell mediated rejection shows a spectrum of changes: early signs include senescence-related bile duct epithelial changes and bile duct loss in less than 50% of portal areas. This may progress to hepatocyte necrosis extending into lobular parenchyma. More advanced chronic rejection is marked by frank ductopenia (loss of bile ducts in ≥ 50% of portal areas), loss of hepatic arterioles, fibrosis, and overt histopathologic features of cholestasis [42].

Clinically, patients with chronic rejection or VBDS present with elevations in serum liver enzymes with a cholestatic liver injury pattern i.e., elevated alkaline phosphatase and gamma-glutamyl transferase [43]. Secondary signs such as liver fibrosis and cirrhosis in the setting of increasing jaundice and cholestatic markers in a patient with a history of acute rejection may be the only imaging clues to the correct diagnosis [44]. On MRCP, chronic rejection or ductopenia may manifest as a relative paucity of small intrahepatic bile ducts (Fig. 6) [45]. As with other forms of cholestatic liver injury, excretion of hepatobiliary contrast is often diminished or absent. In a patient with prior transplantation and laboratory evidence of cholestasis, the primary role of imaging is to exclude biliary stricturing or obstruction.

A 24-year-old male with orthotopic liver transplant for autoimmune hepatitis, after two previously failed transplants due to chronic rejection and complications from hepatic arterial thrombosis, presents with increased bilirubin levels of 30 mg/dL. MRI with Magnetic resonance cholangiopancreatography performed two months post-transplantation shows no dilation in the central bile ducts (arrowheads, a). The peripheral bile ducts are poorly visualized, raising concerns for ductopenia. A follow-up imaging six months later demonstrates multiple levels of bile duct obliteration (arrowheads, b) and non-visualization of the peripheral ducts. The persistent hyperbilirubinemia and bile duct loss, in the absence of hepatic arterial abnormalities, raised concerns for chronic rejection, which was confirmed by liver biopsy

Chronic rejection may be reversible with optimized immunosuppression; however, the association of ductopenia carries a poor prognosis [46]. In patients with chronic rejection and irreversible allograft dysfunction, repeat transplantation is generally required [47].

Drug-induced ductopenia is an idiosyncratic reaction linked to various pharmaceuticals, including antibiotics (e.g., amoxicillin-clavulanate), antiepileptics (e.g., phenytoin), antiretrovirals, interleukins, and immune checkpoint inhibitors [48, 49]. Drug-induced injury can present as isolated cholestasis or commonly as a mixed form (cholestasis with hepatitis) [50]. Ductopenia typically manifests 1–6 months post-acute liver injury, where inflammatory responses primarily target cholangiocytes, potentially leading to bile duct degeneration and loss.

The symptoms can range from fatigue and abdominal discomfort to dark urine and pale stools. In acute cholangitis presentation, fever, shivering, and abdominal pain may precede jaundice [50]. Signs of bile duct damage are frequent in the acute hepatitis phase, while bile duct loss indicates a more chronic stage [51]. Diagnostic workup includes autoimmune markers, viral hepatitis serologies, and immunoglobulin levels to rule out alternative cholestasis causes in a patient with persistent elevations in serum alkaline phosphatase and bilirubin following onset of the drug. Drug levels and metabolites may be evaluated in specific cases [52].

Histopathologic findings in drug-induced liver injury vary widely, ranging from acute to chronic changes. Acute injury may resolve by itself or evolve into chronic phases if the offending agent continues. This typically presents as mixed portal-based inflammation with bile duct injury and degenerative changes in the biliary epithelium. While lobular parenchyma often shows mild inflammatory changes, cholestasis within hepatocytes and canaliculi is usually more pronounced than the degree of lobular or portal-based inflammation, a condition known as 'bland cholestasis'. Over time, chronicity may lead to progressive loss of intrahepatic bile ducts and fibrosis [52, 53].

Imaging findings, though non-specific, can include bile duct dilation, irregularities resembling sclerosing cholangitis (Fig. 7), or hepatic inflammatory changes in acute phases. These manifestations may progress to more severe conditions such as ductopenia, portal tract inflammation, and fibrosis with continued drug exposure.

52-year-old female with metastatic clear cell RCC, treated with Ipilimumab + Nivoluman presented with acute rise in liver function test. Axial T2W MRI image demonstrates beaded appearance of the bile ducts (arrowheads, a). Post contrast venous phase T1W MRI shows heterogeneous enhancement of the liver parenchyma (image b). Magnetic resonance cholangiopancreatography maximum intensity projection shows beaded dilation of the bile ducts (arrowheads, c). Liver biopsy findings included acute cholestasis with bile duct injury and ductular reaction. The findings were consistent with a diagnosis of drug induced cholangiopathy after excluding other etiologies. The diagnosis was concordant with the clinical diagnosis of immunotherapy induced cholangitis

MRI with MRCP is supportive in diagnosis, with MRCP being particularly useful for detecting intrahepatic bile duct irregularities or dilation and for sequential monitoring of drug-induced injury progression or treatment response over time, although these may not be apparent in early disease stages (Fig. 8). Additionally, MRI provides information regarding any associated liver damage or parenchymal changes including periportal edema and heterogeneous parenchymal enhancement during arterial phase [54, 55].

45-year-old female with cholestatic hepatitis with biopsy proven vanishing duct syndrome due to weight loss drug, Zantrex 3. The initial Magnetic resonance cholangiopancreatography (MRCP) imaging shows non-dilated bile ducts with paucity of peripheral duct (arrowheads, a). Improvement in the cholestatic liver enzyme pattern and symptoms were observed on two months follow-up, following withdrawal of the drug. The MRCP maximum intensity projection image shows better delineation of the peripheral ducts (arrowheads, b) due to ductal regeneration. MRCP maximum intensity projection image at three years follow-up shows worsening of the disease, with progressive obliteration of central and peripheral ducts due to reuse of the drug (arrowheads, c–d)

Treatment prioritizes resolving the underlying cause and withdrawing the implicated drug. UDCA may be beneficial for cholestasis. Corticosteroids are considered for immune-mediated cases, with plasmapheresis as an option in refractory situations. In cases of progressive liver failure, liver transplantation remains the definitive treatment.

Viral and bacterial cholangitis are inflammatory conditions of the bile duct system, caused by different pathogens. Bacterial or viral infectious cholangitis very uncommonly progresses to ductopenia. However, persistently elevated abnormal laboratory results should indicate the possibility of developing ductopenia. CMV is the most common virus associated with ductopenia occurring in neonates or immunocompromised hosts [48, 56].

Viral cholangitis is often a result of hepatitis viruses, leading to symptoms like jaundice, abdominal pain, and fever. Whereas, bacterial cholangitis is typically caused by bacteria ascending from the intestine, often associated with bile duct obstructions such as gallstones. Its symptoms include severe abdominal pain, jaundice, fever, and chills, and it may lead to sepsis if untreated. Diagnosis relies on clinical symptoms, elevated liver enzymes, and infection markers.

Histopathologically, sepsis in the liver often presents with cholestasis, visualized as inspissated bile in dilated ductules, terme