Primary Sclerosing Cholangitis Imaging

Primary sclerosing cholangitis (PSC) is a chronic, progressive, inflammatory disease characterized by biliary inflammation and fibrosis leading to bile duct strictures and cirrhosis. PSC carries increased risk of hepatobiliary malignancies. ^[1]  The cause is unknown, but a hypersensitivity reaction is implicated. Sclerosing cholangitis is a chronic cholestatic disease characterized by stricturing, beading, and obliterative fibrosis of bile ducts. Sclerosing cholangitis is considered primary (PSC) if no underlying etiology is identified or is considered secondary (SSC) if related to another identifiable cause such as bile duct injury, cholelithiasis, ischemia, and chemical injury. ^{[2, 3, 4, 5, 6, 7]}

When symptoms are present, they typically include fatigue, pruritus, or jaundice. Patients present with abnormalities on liver function tests and progressive intermittent obstructive jaundice, which may be associated with fever, chills, night sweats, pain, and itching. The antimitochondrial antibody is present in about 95% of cases. ^[8]

The diagnosis can be confirmed via cholangiopancreatography—magnetic resonance cholangiopancreatography (MRCP), or endoscopic retrograde cholangiopancreatography (ERCP) if the former is inconclusive. The clinical course is marked by progressive liver disease leading to cirrhosis with its attendant complications of portal hypertension, often involving recurrent episodes of cholangitis. Greater elevation in alkaline phosphatase or liver stiffness is associated with worse clinical outcomes. ^[9]

Management includes endoscopic treatment of symptomatic biliary strictures and evaluation of dominant strictures, as no adequate medical treatment is available. Multiple medical therapies are under evaluation. Ultimately, liver transplantation may be necessary for management of decompensated cirrhosis or disabling symptoms. Risk of cancer is markedly increased, notably including cholangiocarcinoma (CCA) and gallbladder and colorectal cancers (particularly in patients with colitis). Cancer screening can be done with semiannual liver imaging (MRCP or ultrasonography) and colonoscopy every 1 to 2 years for those with colitis. ^[9]

PSC is strongly associated with inflammatory bowel disease (IBD) and can overlap with other autoimmune diseases, including autoimmune hepatitis and immunoglobulin G4-related disease. ^[10]  Approximately 75% of patients with PSC have IBD, primarily ulcerative colitis. 

Prevalence of PSC is 0 to 16.2/100,000 persons; PSC usually occurs in young and middle-aged men, typically with onset at 30 to 40 years of age. ^[11]

Although diagnosis relies extensively on imaging, the role of imaging in determining prognosis is unclear. ERCP- and MRCP-based indices have short-term prognostic value in PSC. More studies are needed to validate their accuracy in predicting disease-related progression such as liver decompensation, ascending cholangitis, CCA, and liver transplantation. ^[12]

Imaging modalities

Imaging has an essential role in diagnosis, surveillance, and detection of complications. MRCP and ERCP have high specificity and sensitivity for detection of primary disease and assessment of disease progression. However, in many patients, PSC is diagnosed incidentally via ultrasonography (US) or computed tomography (CT). Novel imaging techniques such as transient elastography and magnetic resonance elastography are used to survey the grade of liver fibrosis. Annual cancer surveillance is necessary for all patients with PSC to screen for CCA and gallbladder cancer. Familiarity with PSC pathogenesis and imaging features across various classic imaging modalities and novel imaging techniques can aid in accurate diagnosis while guiding treatment management. ^[10]

For detection of dysplasia or CCA, ERCP with intraductal sampling remains compulsory. Endoscopy remains crucial in the care of these patients, although MRCP has replaced ERCP as the primary imaging modality for diagnosis. Endoscopy offers management for adverse events such as bile leaks and anastomotic strictures after liver transplantation. Finally, the special phenotype of IBD associated with PSC, as well as the frequent occurrence of portal hypertension, mandates close follow-up with colonoscopy and upper endoscopy. With emergence of novel techniques, the endoscopist remains a key member of the multidisciplinary team caring for patients with PSC. ^[13]

Both the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) have recommended MRCP as the first-line modality for imaging of bile duct abnormalities in PSC. Advantages of MRCP include that it is noninvasive and it does not require contrast media or ionizing radiation. However, MRCP may have limited accuracy in early PSC. ^[14] Therefore, ERCP remains the mainstay for accurate diagnosis of PSC through analysis of the hepatobiliary tree because of its higher sensitivity. ^[14] When clinical suspicion continues with negative or nondiagnostic findings on MRCP, ERCP should be performed. ERCP can also be used for treatment with balloon dilatation or stenting. ^{[15, 16, 17, 18, 19, 20, 21, 22, 23, 24]}  ERCP is invasive and may cause ascending cholangitis. ^[25]

(Radiologic characteristics of PSC are shown in the images below.)

US is the initial examination modality of choice for patients presenting with jaundice and right upper quadrant pain. The liver may show nonspecific abnormalities on US, which only infrequently lead to definitive diagnosis. The primary role of US involves helping clinicians make the diagnosis of other bile duct mechanical obstructions such as gallstones and neoplasia. ^[16]  Endoscopic US may be used for diagnosing extrahepatic PSC. ^[14]

CT scans reveal nonspecific changes. Indistinguishable features may be noted with CCA and other forms of cholangitis. Intra-abdominal lymphadenopathy suggesting CCA may be detected on CT. ^[14]

Plain radiographs have a small role to play in the diagnosis of PSC. MRCP and ERCP are preferred modalities because of their high sensitivity and specificity. ERCP is considered the gold standard, with specificity of approximately 96%. Typical cholangiopancreatographic findings include multifocal annular biliary structures with dilated intrahepatic and extrahepatic bile ducts and alternating normal segments. This is known as the beaded pattern of PSC. ^[14]

(See the images below.)

Cholangiopancreatographic features of PSC include predominantly intrahepatic ductal disease with short multiple strictures associated with multifocal mild ductal dilations. Cholangiopancreatography shows a pruned-tree appearance with filling of central ducts and diffuse obstruction of peripheral smaller radicles. More advanced disease is associated with long strictures.

Bile duct dilations may result from the inflammatory process or from distal obstruction. Multifocal strictures have a predilection for bifurcations. Skip lesions in which the duct is of normal caliber may be observed.

These features give the ducts a beaded appearance. Coarse nodularity with mural irregularities may produce a cobblestone appearance. Ductal diverticula or pseudodiverticula observed as small saccular outpouchings are pathognomonic findings for PSC.

The common bile duct (CBD) is almost always involved.

The cystic duct shows strictures, mural nodularity, and dilations with formation of diverticula in 18% of patients. Gallbladder irregularity is uncommon. Pancreatic duct strictures and irregularities are observed in 8% of patients. ^[26]

Intrahepatic pigment calculi, which are easily crushable, are noted in 8% of patients and may cause mechanical obstruction. Rarely, these calculi may obstruct the CBD; however, bile duct dilation may not occur in the presence of CCA. ^[26]

Degree of confidence

The appearance of terminal bile ducts varies, particularly on ERCP, and overinterpretation is common. To address this problem, numerous views are obtained at various stages of contrast filling; these may help in resolution of equivocal changes. Radiographic distinction between CCA and sclerosing cholangitis occasionally may be impossible because the diagnostic specificity of intrahepatic bile duct changes remains controversial.

Ascending cholangitis, AIDS-related cholangiopathy, CCA, chemotherapy-induced cholangitis, eosinophilic cholangitis, recurrent pyogenic cholangitis, cholangitis secondary to parasites, and primary biliary cirrhosis can produce a similar radiographic appearance.

Although MRCP and ERCP have high specificity and sensitivity for detection of primary disease and assessment of disease progression, PSC is diagnosed incidentally by US or CT in many patients. ^[10]

Intrahepatic bile duct changes shown on CT scans reflect cholangiopancreatographic features with pruning and beading of ducts. Pruning on CT scans is defined as the presence on a single CT slice of a 4-cm or longer segment of dilated duct (excluding the main right and left ducts) that lacks the side branching expected. Beading is defined as at least 3 closely alternating regions of change in caliber within an intrahepatic duct on a single CT slice.

Skip dilations, defined as isolated dilated peripheral bile ducts with no visible connection to other dilated ducts on contiguous images, are strongly suggestive of PSC.

CT appearances of extrahepatic bile duct involvement by PSC include focal or diffuse eccentric or concentric involvement and wall thickening (>2 mm and < 5 mm), bile duct dilation, relative lack of dilation proximal to an apparent bile duct stricture, and enhanced intraluminal intramural nodules (>1 cm in diameter) seen on thin-section high-resolution images.

Contrast enhancement of the bile duct is a nonspecific finding that can be observed in normal and abnormal bile ducts.

As many as 65% of patients with PSC may have benign celiac, gastrohepatic ligament, porta hepatis, periaortic, pancreaticoduodenal, and mesenteric lymphadenopathy. ^{[27, 28, 29]}

Lymph nodes are usually homogeneous and isodense with the pancreas.

Degree of confidence

Intrahepatic bile duct changes on CT scans reflect cholangiographic features with pruning and beading of the ducts. Skip dilations, defined as isolated dilations of intrahepatic bile ducts, are strongly suggestive of PSC; however, ductal delineation and evidence of strictures can be difficult to discern at early stages on US or CT scans. CT is complementary to cholangiopancreatography; moreover, CT should not be used as a screening examination.

Beading, pruning, irregularity, and asymmetry of intrahepatic bile ducts as shown on CT scans are not specific for PSC. Similar CT changes may be found in other forms of cholangitis and CCA.

Both the AASLD and the EASL have recommended MRCP as the first-line modality for imaging of bile duct abnormalities in PSC. Advantages of MRCP include that it is noninvasive and it does not require contrast media or ionizing radiation. ^[14] Characteristic findings on MRCP include multiple segmental strictures with slightly dilated intrahepatic and extrahepatic ducts. ^[15]  However, MRCP may have limited accuracy in early PSC. Therefore, ERCP remains the mainstay for accurate diagnosis of PSC through analysis of the hepatobiliary tree because of its higher sensitivity. ^[14]

As the disease progresses, a pruned-tree appearance may become visible as small peripheral ducts become obliterated. ^[15]

Biliary tract, liver parenchymal, and pancreatic features suggestive of PSC on MRI have been reported. ^{[30, 31, 32]}

Use of T1-weighted, fat-suppressed, spin-echo pulse sequences, with or without intravenous gadolinium, facilitates visualization of the bile duct wall. Peripheral, wedge-shaped areas of high T2-weighted signal intensity in the liver parenchyma and dilation of bile ducts are characteristic MRI features of PSC observed in approximately 72% of patients.

Associated features include periportal edema (40%), lobar atrophy (8-28%), and portal hypertension (35%).

Abnormal hyperintensity of the liver parenchyma may be observed on T1-weighted images in 23% of patients. Increased enhancement of the liver parenchyma on dynamic arterial-phase gradient-echo images, predominantly in peripheral areas, may be observed in 56% of patients. Periportal inflammation may be revealed on MRI as a region of low signal intensity on T1-weighted images and intermediate signal between liver and bile on T2-weighted images.

On gadolinium-enhanced images, enhancement of inflammatory periportal tissue permits distinction from nonenhancing periportal edema.

Characteristic changes within the pancreas on MRI are suggestive of PSC. Increased signal on T2-weighted images, decreased signal on T1-weighted images, enlargement of the pancreas, and decreased contrast enhancement suggest pancreatic disease associated with PSC.

(See the image below.)

Diffusion-weighted MRI added to standard MRCP protocols is valuable for diagnosis of PSC and for evaluation of disease severity. Moreover, diffusion-weighted imaging can be used in continuation with standard MRI sequences for evaluation of liver fibrosis stage and distribution. ^[33]

Gadolinium-based contrast agents have been linked to development of nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy (NFD). NSF/NFD is a debilitating and sometimes fatal disease. Characteristics include red or dark patches on the skin; burning, itching, swelling, hardening, and tightening of the skin; yellow spots on the whites of the eyes; joint stiffness with trouble moving or straightening the arms, hands, legs, or feet; pain deep in the hip bones or ribs; and muscle weakness. For more information, see Medscape.

Degree of confidence

Patients with PSC who have been studied on MRI are few; thus, the reliability of the changes described above is uncertain. MRCP may be used, but the extent of intrahepatic disease may be estimated incorrectly because ductal distention cannot be achieved on MRCP.

Features of PSC on MRI are not specific and may be noted with CCA and other forms of cholangitis.

A comparative study concluded that MRI is superior to US for detection of early-stage CCA in patients with PSC and that identification of CCA with MRI before onset of symptoms is associated with improved outcomes. ^[34]

Diagnosis of PCA can be confirmed via cholangiopancreatography—MRCP, or ERCP if the former is inconclusive. The clinical course is marked by progressive liver disease leading to cirrhosis with its attendant complications of portal hypertension, often including recurrent episodes of cholangitis. ^[9]

PCA is associated with numerous hepatobiliary complications, including increased risk of malignancy (in particular, CCA) and biliary tract stone formation. Evaluation of biliary strictures in patients with PSC is especially challenging, with only modest sensitivity of imaging and endoscopic methods for diagnosis of CCA; treatment of biliary strictures poses a similarly significant clinical challenge. Peroral cholangioscopy has evolved technologically and has increased in popularity as an endoscopic tool that can provide direct intraductal visualization while facilitating therapeutic manipulation of the biliary tract. However, indications for and effectiveness of its use in patients with PSC remain uncertain. ^[35]

Prompt and accurate differentiation of benign and malignant strictures in PSC is crucial. ERCP with brush cytology—the most common modality to achieve this—is hindered by a low diagnostic yield. Cholangioscopy can overcome this limitation by establishing a visual diagnosis based on the characteristic morphologic features of CCA and can aid in targeted biopsies of suspicious lesions. However, its role in PSC remains unclear. Cholangioscopy allows identification of morphologic features of both malignant and benign disease in PSC in the setting of extrahepatic duct strictures and provides an opportunity to obtain adequate targeted tissue samples for histopathologic confirmation. ^[36]

Ultrasonographically, biliary abnormalities are not usually visible unless biliary dilation is associated. Intrahepatic saccular dilations may be visualized occasionally, and in long-standing disease, echogenic intraductal structures, representing sludge or calculi, are visible on US images. Bile duct wall thickening and small intraluminal protrusions have been reported in patients with PSC. In end-stage disease, US signs of portal hypertension may become evident.

Secondary biliary cirrhosis occurs as a part of the disease complex of PSC. Most patients with secondary biliary cirrhosis have no ultrasonographic abnormalities, but occasionally irregular segmental duct dilation is observed.

Patients with advanced disease may show an increase in periportal echogenicity.

Cirrhotic changes such as nodularity, increased liver attenuation, and splenomegaly may be apparent.

Degree of confidence

US appearances of PSC are nonspecific; seldom can a confident diagnosis of PSC be made on the basis of US alone. The primary role of US involves diagnosis of other causes of obstructive jaundice.

The differential diagnosis includes CCA and other causes of ascending cholangitis and primary biliary cirrhosis. In addition to PSC, bile duct wall thickening is associated with hepatic clonorchiasis, recurrent pyogenic cholangitis (Oriental cholangiohepatitis), biliary ascariasis, peribiliary cysts, and AIDS-related cholangiopathy.

Prolonged isotope transit time may be noted with some causes of hepatic dysfunction; similarly, nonvisualization of the gallbladder may occur with cystic duct obstruction and chronic gallbladder disease.

Radionuclide scanning using technetium-99m (^99mTc) iminodiacetic acid compounds shows multiple focal areas of persistent activity distributed within the liver parenchyma. The clearance rate of the isotope through the liver is markedly prolonged, and gallbladder visualization is achieved in 70% of patients. ^{[26, 37]} The specificity of ^99mTc iminodiacetic acid scanning is low, but this technique is valuable for quantifying biliary kinetics.

(See the image below.)

Prolonged isotope transit time may occur with other causes of hepatic dysfunction; similarly, nonvisualization of the gallbladder may be reported with cystic duct obstruction and chronic gallbladder disease.

About 30-50% of patients with primary sclerosing cholangitis (PSC) develop dominant strictures in the biliary tree that are the cause of jaundice and bacterial cholangitis and serve as predilection spots for neoplastic development. Cancer is the most common cause of death in PSC. A central concern is the need to distinguish malignant from benign strictures; this is done eventually by invasive methods performed to obtain a brush cytology or biopsy sample, in most cases via endoscopic retrograde cholangiopancreatography (ERCP). Given that medical therapies such as ursodesoxycholic acid and immunosuppressive drugs have no proven effect, therapeutic ERCP has become the primary management strategy for improving symptoms and in some patients may slow disease progression. ^[38]

Cholangioscopy is useful in establishing a visual diagnosis of cholangiocarcinoma (CCA), but this is harder to achieve in PSC because of the stricture-forming nature of the disease. Furthermore, it can be harder to differentiate malignant from benign features of underlying inflammation. Cholangioscopic features of benign disease in PSC are varied. Knowledge of these features is essential in differentiating benign and malignant findings. Awareness of these features, combined with findings of biopsy and cytologic evaluation, can help in tailoring management for patients with benign PSC. ^[39]

Early detection of perihilar CCA among patients with PSC is important in identifying people eligible for curative therapy. Although many recommend CCA screening, there are divergent opinions and limited data regarding the use of ultrasonography (US) or magnetic resonance imaging (MRI) for early CCA detection, and it is unknown whether benefit is derived from testing asymptomatic individuals. ^[34]

Development of noninvasive methods to risk-stratify patients and to predict clinical endpoints has been identified as one of the key research priorities in PSC. In addition to serum and histologic biomarkers, much interest has been expressed in developing imaging biomarkers that can predict disease course and clinical outcomes in PSC. MRI and magnetic resonance cholangiopancreatography (MRCP) continue to play a central role in diagnosis and follow-up of patients with PSC. MR techniques have undergone significant advancement over past decades in both MR data acquisition and interpretation. Progression from a qualitative to a quantitative approach in MR acquisition techniques and data interpretation offers the opportunity for development of objective and reproducible imaging biomarkers that can potentially be incorporated as an additional endpoint in clinical trials. ^[40]

In a 2020 meta-analysis, Satiya and associates reported that diagnosis of CCA in patients with PSC remains challenging, and that the accuracy of MRI/MRCP has not been completely established. They stated that MRI/MRCP followed by ERCP is a sensitive and specific tool for diagnosing CCA among patients with PSC and that further research should estimate the accuracy of MRI/MRCP for CCA diagnosis using prospective methods and longer-term outcomes. ^[41]