Primary sclerosing cholangitis (PSC) is a chronic condition characterized by inflammation, fibrosis, and obliteration involving the intra- as well as extrahepatic bile ducts . Initially described in 1924 and once considered a rare condition, the condition can no longer be considered rare as advancements in cholangiography have led to more frequent diagnosis. While the etiology remains elusive, it is commonly classified as an autoimmune liver disease and other immune-mediated conditions, most notably inflammatory bowel disease, are frequently concurrently encountered. Genetic predisposition also appears to play a contributory role based on the finding of associated as well as protective haplotypes. Complications of PSC are both nonspecific and associated with chronic cholestatic liver disease as well as those specific to PSC. The natural history is highly variable with the potential for progression to cirrhosis, end-stage liver disease, and the need for liver transplantation. Patients with PSC are also at an increased risk for the development of cholangiocarcinoma as well as colorectal, gallbladder, and hepatocellular carcinoma. Despite the evaluations of multiple pharmacologic agents, there is currently no medical therapy that has been shown to alter the timeline to death or the need for liver transplantation. Liver transplantation is the only effective therapy for long-term survival in those who develop complications of end-stage liver disease and is associated with excellent long-term results. Variants of PSC include small-duct PSC, overlap PSC and autoimmune hepatitis, and immunoglobulin G cholangiopathy.

Evidence supporting a genetic cause includes strong familial patterns as well as a strong association with specific haplotypes, most notably B8DR3, B8DR13, and B8DR15. Conversely, haplotypes DRB1*040, DRB1*070, and MICA*002 are associated with a decreased risk of developing PSC [6–9].

An immune mechanism is supported by the findings of serum autoantibodies in a large number of those with PSC, the most common being perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) which are found in up to two-thirds of patients. Other autoantibodies occasionally encountered include antinuclear and anti-smooth muscle antibodies [10]. Additionally, hypergammaglobulinemia is common, as is the association with other autoimmune disorders, most notably inflammatory bowel disease.

Other potential etiol ogies that may play minor roles in PSC include infectious causes, toxin exposure, and vascular complications.

The association of PSC with IBD has led to the theory that damaged colonic mucosa leads to translocation of bacteria that enter the blood stream and bile ducts. The failure to identify specific organisms, the absence of portal phlebitis, failure of antibiotics or colectomy to alter the natural history and the fact that not all patients with PSC have IBD argues against an infectious etiology.

Toxin exposure as a cause of PSC is based on the theory that imbalances between hydrophilic and hydrophobic bile acids, such as lithocolic acid, can lead to biliary epithelial damage and strictures. Other toxic agents that have been evaluated include iron and copper, both of which are shown to be elevated in many patients with PSC. Elevated iron and copper levels, however, are nonspecific findings and can be associated with both hepatocellular and cholestatic disorders.

Vascular injury to the hepatic artery has long been associated with biliary strictures in liver transplant recipients; however, examination of the hepatic vasculature in PSC has failed to demonstrate damage either to the hepatic artery, portal vein, or hepatic vein.

The majority of patients with PSC will demonstrate cholestasis on hepatic biochemistries. Alkaline phosphatase values greater than 2.5-fold normal values are seen in the majority of patients. As a result, elevated alkaline phosphatase values which are confirmed to be of biliary origin should result in a thorough evaluation and consideration for PSC. Total bilirubin values are elevated in over 50 % of affected patients and 90 % demonstrate a two to threefold elevation in alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Serum iron and copper values are frequently elevated, but as previously mentioned, are nonspecific and therefore not helpful for diagnostic purposes. Despite the finding of p-ANCA autoantibodies in the majority of PSC patients, their presence is nonspecific and should not be utilized to make a diagnosis of PSC. This is in contrast to other autoimmune hepatic disorders such as autoimmune hepatitis and primary biliary cirrhosis where serum autoantibodies play a pivotal role in diagnosis.

The diagnosis of PSC is m ade based on the classic cholangiographic findings of diffuse strictures with intervening areas of normal appearing bile ducts leading to the so-called “beading.” Seventy-five percent of strictures involve both the intra and extrahepatic bile ducts, with 15 % having strictures limited to the extrahepatic system. The cystic duct and gallbladder are involved in approximately 15 % of patients and a smaller number have pancreatic duct involvement [11–13]. Dominant strictures, defined as a diameter less than 1.5 mm in the common bile duct and less than 1.0 mm in the hepatic duct, are present in approximately half of PSC patients. Pseudodiverticula, particularly in the common bile duct are occasionally seen. While initially used as exclusionary criteria in PSC patients, the presence of biliary stones are now well-recognized as a common finding and frequent cause of cholangitis. There are three current modalities that can be used to image the biliary system. Endoscopic retrograde cholangiography (ERC) allows direct biliary visualization as well as also providing the opportunity to perform cytologic analysis, stricture dilation, removal of stones, and biliary stenting. Potential complications of ERC include bleeding, cholangitis, and pancreatitis [14]. Percutaneous hepatic cholangiography (PTC) also allows direct access to the biliary system but has similar complications to ERC and requires experienced radiologists as intrahepatic bile ducts are generally not dilated in PSC. The test of choice when attempting to make a diagnosis of PSC is the magnetic resonance cholangiography (MRC). The noninvasive nature of MRC limits complications and is more cost-effective than ERC or PTC. These advantages must be weighed against the fact that MRC unlike ERC and PTC does not offer the opportunity to perform biliary brushings for cytology nor intervene therapeutically. Magnetic resonance cholangiography also lacks sensitivity compared to ERC when assessing for peripheral bile duct changes. Once a diagnosis of PSC is established, there is no indication for further instrumentation of the biliary system unless there is a change in the p atient’s clinical status.

Liver biopsy at the present is not felt to be necessary to establish a diagnosis of PSC, nor to determine disease severity. Liver biopsy should be considered in all patients suspected of having small-duct PSC or overlap syndrome with autoimmune hepatitis. The classic finding when a liver biopsy is performed in PSC patients is the concentric fibrosis (onion-skinning ) involving the periductal region. This lesion, however, is observed in only a minority of patients [12]. Additionally, biopsy sampling variation may fail to detect these lesions in patients who otherwise have classic cholangiographic findings.

Small-duct PSC is chara cterized by cholestatic biochemistries with a normal cholangiogram. Liver biopsy is essential in this group for diagnostic purposes and may demonstrate the periductal damage and onion-skinning previously described. Small-duct PSC represents approximately 10 % of all PSC cases. Small-duct PSC patients may have symptoms but a greater percentage are asymptomatic when compared to large-duct PSC. Approximately 10–15 % of those with small-duct PSC will progress to large-duct PSC, typically over 5–10 years. Patients with small-duct PSC have a better long-term prognosis with fewer complications when compared to their large-duct counterparts [18, 19].

Between 1 and 17 % of patients with PSC will also have an overlap syndrome with autoimmune hepatitis [20–22]. These patients will present with a hepatocellular injury as well as cholestasis and have detectable antinuclear antibodies and anti-smooth muscle antibodies. Immunoglobulin G elevations, as in classical autoimmune hepatitis, are typically seen. Liver biopsy should therefore be performed in all patients with PSC who have aminotransferase values greater than five times the upper limit of normal or IgG values greater than two times the upper limit of normal. Liver biopsy demonstrates histologic findings of both conditions; the periductal “onion-skinning” damage seen in PSC and the interface hepatitis and prominent plasma cell infiltration which is classically described in autoimmune hepatitis. The autoimmune hepatitis component unlike the PSC component is responsive to immunosuppression, with the most common agents utilized being corticosteroids and azathioprine. Patients with overlap PSC and autoimmune hepatitis may progress more rapidly than those affected by PSC alone due to the combination of the hepatocellular and cholestatic components.

Autoimmune pancreatitis is a manifestation of a systemic disorder affecting multiple organs and is associated with an elevated serum immunoglobulin G4 (IgG4). Histology of the pancreas shows a predominantly lymphocyte and plasma cell infiltrate. Pancreatic abnormalities include lesions that are frequently difficult to differentiate from malignancy as well as pancreatic duct strictures. A subset of these patients will have biliary strictures similar to those seen in PSC occasionally in the absence of pancreatic abnormalities, a condition occasionally referred to as IgG4 cholangiopathy . Those with IgG4 cholangiopathy tend to have a more aggressive disease course compared to those with PSC and normal IgG4 values [23, 24]. Primary sclerosing cholangitis associated with elevated IgG4 levels are frequently responsive to corticosteroid therapy and it is recommended to measure IgG4 levels in all newly diagnosed PSC patients [25].