Historically, the term pericholangitis has referred to the entity of chronic hepatitis and cholestatic biochemical features typically occurring in patients with inflammatory bowel disease (IBD). However, the nomenclature of this disease has come into question because of the recognition that pericholangitis and classic (or large-duct) primary sclerosing cholangitis (PSC) might be parts of a disease spectrum.
In particular, studies comparing patients who have chronic IBD, cholestatic liver biochemistry, and typical cholangiographic evidence of PSC with similar patients who have normal findings on cholangiography reveal similarities in clinical features and liver biopsy findings. Furthermore, some patients with pericholangitis and initially negative findings on cholangiography have been demonstrated on long-term follow-up to develop typical cholangiographic features of PSC.
For this reason, the disease previously termed pericholangitis is now more properly referred to as small-duct PSC. For the purpose of this article, these terms are used interchangeably. Pericholangitis and large-duct PSC should be considered as part of a disease spectrum, best referred to as PSC with small-duct involvement, large-duct involvement, or both.
Pericholangitis is a chronic cholestatic liver disease characterized by inflammation and fibrosis of microscopically identifiable (interlobular and septal) bile ducts. Although changes in large cholangiographically visible bile ducts may accompany pericholangitis, this entity is more appropriately referred to as classic or large-duct PSC.
The clinical course may be characterized by progressive hepatic fibrosis, and ultimately (in the absence of liver transplantation), complications of cirrhosis, liver failure, and even death. Other organ systems remain unaffected by the primary disease process.
The etiology of pericholangitis is unknown. Proposed theories include the following:
The incidence and prevalence of pericholangitis in the United States have not been specifically studied; however, inferences can be made on the basis of PSC data.
In a Mayo Clinic study, the overall age- and sex-adjusted incidence and prevalence of classic PSC were 0.9 cases per 100,000 population and 13.6 cases per 100,000 population, respectively.[1] Given that about 10% of patients with PSC have the small-duct variant (ie, pericholangitis), the data suggest that the incidence of pericholangitis is approximately 0.9 cases per 1 million population and the prevalence is approximately 13.6 cases per 1 million population, respectively.
A strong association exists between IBD and PSC.[2, 3, 4, 5, 6] Approximately 70-80% of patients with PSC also have IBD. Most patients have ulcerative colitis (UC), but as many as 13% of PSC patients with IBD have Crohn disease. An estimated 2-7.5% of patients with UC have PSC.
The international frequency of pericholangitis has been investigated. In a population-based study from Calgary, Alberta, Canada, Kaplan et al reported an annual incidence of 0.1 cases per 100,000 population for pericholangitis, compared with an annual incidence of 0.9 cases per 100,000 population for classic PSC.[7]
The prevalence in patients with IBD is variable.[8] For example, in a Finnish study by Heikius et al of 237 unselected patients with IBD, the prevalence of PSC was 11%.[5] Of these patients, 11.5% had the small-duct variant (pericholangitis). In a Turkish study by Bayraktar et al, none of 81 patients with IBD had PSC.[6] The reason for these international differences in PSC prevalence is unknown.
In one study, the mean age at diagnosis was 38 years in the pericholangitis group versus 39 years in the classic PSC group.[9] Similar figures were reported in the Mayo Clinic study: 40 years versus 39 years, respectively.[1] Thus, pericholangitis does not seem to be an early stage of PSC in most cases; rather, it likely represents a more benign form of the disease.
The impact of sex on the prevalence of pericholangitis is unclear. Classic PSC is thought to be more common in males than in females; the male-to-female ratio is approximately 2:1. In the Bjornsson et al study, 19 (58%) of the 33 patients with pericholangitis were male, whereas 188 (72%) of the 260 patients with classic PSC were male.[9] No consistent relation to ethnicity has been reported.
Classic PSC is associated with a progression of fibrosis to cirrhosis, end-stage liver disease, and liver transplantation in a significant proportion of patients. The median duration from diagnosis to death or liver transplantation is approximately 12 years.
Patients are also at an increased risk of malignancy, including cholangiocarcinoma, hepatocellular carcinoma, and colorectal dysplasia and adenocarcinoma in the presence of IBD. For example, 7-20% of patients with classic PSC will eventually develop cholangiocarcinoma (annual incidence, 0.5-1.5%).
Pericholangitis appears to represent a more benign variant of classic PSC. In a study from Oxford and Oslo, Bjornsson et al described the natural history of 33 patients with pericholangitis and 260 patients with classic PSC over a mean follow-up of nearly 9 years.[9] In this study, only 4 (12%) of the 33 patients with pericholangitis died or required liver transplantation versus 122 (47%) of the 260 patients with classic PSC.
These findings were confirmed in a smaller study from the Mayo Clinic. In this report, Angulo et al found that the median survival without liver transplantation was 29.5 years in patients with pericholangitis (n = 18) versus only 17 years in the classic PSC group (n = 36).[10] Survival in the pericholangitis group was similar to that expected in the white US population, whereas that of the classic PSC group was significantly lower.
In contrast to patients with classic PSC, an increased risk of malignancy has not been reported in patients with pericholangitis. For example, in the natural history studies of Bjornsson et al[9] and Angulo et al,[10] no patient with pericholangitis developed an intestinal or hepatobiliary malignancy.
A minority of patients with pericholangitis ultimately develop cholangiographic evidence of large-duct PSC. In the Bjornsson et al study, cholangiography was repeated in 19 (58%) of the 33 patients with pericholangitis.[9] Only 4 patients (12%) developed large-duct PSC, with typical intrahepatic and/or extrahepatic changes on cholangiography.
In the Mayo Clinic study, 5 of the 18 patients with pericholangitis underwent repeat cholangiography because of worsening liver biochemistry.[10] Of these patients, 3 (17% of the total) developed typical cholangiographic features of large-duct PSC.
Medical or surgical therapy for associated IBD does not appear to affect the prognosis of pericholangitis.
Complications of pericholangitis may include the following:
Warn patients of the potential for pericholangitis to progress to end-stage liver disease and to necessitate consideration of liver transplantation.
Patients should watch for symptoms suggestive of hepatic decompensation, including ascites, edema, gastrointestinal (GI) bleeding, jaundice, encephalopathy, and malnutrition, which may warrant referral for transplantation assessment.
Symptoms of patients with pericholangitis vary considerably, depending on the reported series. Frequently, the diagnosis is made in asymptomatic patients with inflammatory bowel disease (IBD) when routine liver biochemistry studies reveal a cholestatic liver profile.
Other patients present with cholestatic features, including jaundice and pruritus. Jaundice may develop insidiously or occur as abrupt intermittent episodes of icterus. Finally, some patients may present with typical features of acute cholangitis—namely, fever, jaundice, and abdominal pain.
In a minority of patients, pericholangitis progresses to severe fibrosis and cirrhosis. In these patients, features of hepatic decompensation (eg, the development of ascites, edema, bleeding related to portal hypertension, or hepatic encephalopathy) may predominate.
The physical examination findings in patients with pericholangitis are usually unremarkable. Abnormal physical findings include the following:
Liver enzymes (alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, and gamma-glutamyl transpeptidase) should be assessed. Patients typically have a cholestatic liver profile with predominant elevations of alkaline phosphatase and gamma-glutamyl transpeptidase. Aminotransferase levels may be within the reference range or be moderately elevated.
Serum bilirubin levels may range from within the reference range to displaying marked elevation. The bilirubin level may rise insidiously in association with gradual progression of the disease or rise abruptly with intermittent episodes of fever and abdominal pain suggesting acute cholangitis.
In the early stages of the disease, the prothrombin time (PT) and the albumin level typically are within the reference ranges, although the albumin level may be decreased as a consequence of coexisting inflammatory bowel disease (IBD). As the disease progresses to later stages, the PT may rise and the albumin may fall.
Patients may have coexistent risk factors for the acquisition of viral hepatitis, including the blood transfusions that are often necessary for the management of anemia in patients with IBD. Rule out chronic hepatitis B and C with hepatitis B surface antigen (HBsAg) and antihepatitis C (anti-HCV) antibody tests. Hypergammaglobulinemia and hypercholesterolemia have been reported in some patients.
The perinuclear antineutrophil cytoplasmic antibody (pANCA) test reveals a reported prevalence of 26-85% in classic primary sclerosing cholangitis (PSC). In one study, the sensitivity and specificity of pANCA testing with the immunofluorescence technique were 51% and 73%, respectively. The usefulness of the pANCA test in pericholangitis is not clear.
Antimitochondrial antibody testing should be ordered to rule out primary biliary cirrhosis (PBC), a common cause of cholestatic liver disease. Patients with pericholangitis characteristically lack this antibody.
Antinuclear antibodies (ANA), smooth muscle antibodies (SMA), or both have been reported in 28% of patients with pericholangitis. Tests for these antibodies should be ordered to rule out autoimmune hepatitis as a cause of liver biochemical abnormalities, although this condition typically presents with elevated levels of aminotransferases rather than a cholestatic liver profile.
Autoantigen testing may prove useful in this setting. A study by Ardesjo et al reported the identification of a novel staining pattern of bile duct epithelial cells in patients with PSC, which appeared to have potential utility as an early diagnostic marker.[11]
The investigators used immunostaining on normal human bile duct with sera from affected patients and control patients, then constructed a cDNA library from normal human bile duct and immunoscreened patient sera to identify an autoantigen.[11] Finally, using in vitro transcription and translation and immunoprecipitation, they assessed immunoreactivity against PDZ domain containing 1 (PDZK1) in patients with PSC (n = 35), control patients (n = 198), and healthy control subjects (n = 94).
The PSC sera stained cytoplasmic granules and apical cell membranes of biliary epithelial cells in a novel staining pattern.[11] Strong immunoreactivity to these structures were found in 12 of 35 (34%) PSC sera but not in sera from the healthy control subjects.[11] When the cDNA library was screened, PDZK1 was identified as a potential new autoantigen. Strong immunoreactivity to PDZK1 was detected in 1% of healthy controls, 2% of IBD patients, 8% of autoimmune pancreatitis patients, 9% of PSC patients, and 18% of Graves disease patients.
One study suggests that U2 small nuclear RNA fragments in the bile fluid may be a potential diagnostic marker for cholangiocarcinoma. Baraniskin et al reported that significantly higher bile levels of U2 RNA fragments in those with cholangiocarcinoma allowed differentiation from PSC, as measured by real-time PCR normalized to cel-54 (67% sensitivity, 91% specificity).[12]
No specific ultrasonographic findings exist for the diagnosis of pericholangitis. Perform abdominal ultrasonography to screen for other causes of hepatic pathology, including fatty liver and cholelithiasis, which also may affect patients with IBD. Although ultrasonography is insensitive, it may detect findings suggestive of cirrhosis such as a nodular, shrunken liver, or portal hypertensive changes, including splenomegaly, altered portal venous blood flow, or the formation of venous collaterals.
Perform endoscopic retrograde cholangiopancreatography (ERCP) to rule out large-duct PSC, a much more common cause of cholestasis in patients with IBD. Findings include stricturing and beading of the intrahepatic or extrahepatic bile ducts. By definition, ERCP findings are normal in patients with pericholangitis. However, some patients with large-duct PSC may have histologic evidence of pericholangitis or small-duct disease.
The role of magnetic resonance cholangiopancreatography (MRCP) in pericholangitis is unclear. Preliminary studies suggest that MRCP may be as useful as ERCP in detecting the typical cholangiographic features of PSC. MRCP findings are normal in patients with pericholangitis.
Performing a liver biopsy is essential for the diagnosis and staging of pericholangitis and to rule out other causes of liver disease.
Bleeding is the predominant risk associated with liver biopsy. Fatal and nonfatal hemorrhages have been reported in 0.04% and 0.16% of patients, respectively. Ultrasound guidance may reduce the risk of complications.
Pericholangitis may be classified into 4 stages on the basis of histologic findings. The histologic stage is an important predictor of survival in PSC and likely bears the same importance in pericholangitis.
Stage 1 (portal stage) is characterized as follows:
Stage 2 (periportal stage) is characterized as follows:
Stage 3 (septal stage) is characterized as follows:
Stage 4 (cirrhotic stage) is characterized as follows:
No effective medical treatment exists for pericholangitis; liver transplantation is the only effective treatment. No effective preventive therapy exists for pericholangitis. Neither colectomy in patients with ulcerative colitis (UC) nor medical management of associated inflammatory bowel disease (IBD) prevents the development of pericholangitis.[13, 14, 15]
Patients with complications of end-stage pericholangitis, such as ascites, spontaneous bacterial peritonitis, portal hypertensive bleeding, and hepatic encephalopathy, should be treated like patients with other causes of chronic liver disease. Transfer patients with end-stage pericholangitis to a center specializing in liver transplantation. Failure to do so is a potential medicolegal pitfall.
A gastroenterologist should be consulted for the management of associated IBD, including screening for colorectal dysplasia and cancer. An endocrinologist and a metabolism specialist should be consulted for the management of associated osteopenia or osteoporosis.
Several medications, including penicillamine, colchicine, corticosteroids, azathioprine, methotrexate, nicotine, and pentoxifylline, have been tried for primary sclerosing cholangitis (PSC) and have proved ineffective, though they have not been specifically tested in patients with pericholangitis.[16, 17, 18] Ursodeoxycholic acid may have a role in this disorder.
For patients with documented deficiencies of fat-soluble vitamins (ie, A, D, E, or K), initiate vitamin replacement. For patients who are osteopenic, prescribe calcium (>1000 mg/day) and vitamin D (800 IU/day).
Patients who are osteoporotic should receive bisphosphonate therapy. These agents can cause esophageal irritation when taken orally, which raises concerns about their safety in patients with esophageal varices. Patients with documented esophageal varices probably should receive intermittent intravenous (IV) infusions of bisphosphonates such as pamidronate.
Liver transplantation is the only proven effective treatment for PSC. Preliminary evidence suggests that patients with late pericholangitis also do well with liver transplantation. Most series have reported a dismal prognosis for liver transplantation if cholangiocarcinoma is present, and these results discourage transplantation in this situation.
Compared with patients who undergo liver transplantation for other indications, patients with PSC seem to have a higher incidence of chronic ductopenic rejection after transplant surgery. Large-duct PSC recurs in approximately 20% of liver allografts. Recurrence of pericholangitis has yet to be reported.
Those with long-standing IBD should undergo surveillance colonoscopy every 1-2 years. Patients with IBD who have received a liver transplant for pericholangitis may be at increased risk as a consequence of the effects of immunosuppression. They require more intense colonoscopic surveillance.
The goals of pharmacotherapy are to reduce morbidity and prevent complications. However, no effective medical treatment exists for pericholangitis.
Clinical Context: UDCA (ursodiol), a naturally occurring hydrophilic bile acid, is an effective therapy for primary biliary cirrhosis (PBC), another chronic cholestatic liver disease. Several large trials have shown improvements in liver biochemistry and reductions in mortality and need for liver transplantation in patients with PBC.
Although UDCA's exact mechanism of action is unknown, the beneficial effect probably is related to its ability to reduce the concentration of hydrophobic bile acids in the bile acid pool. These bile acids have detergent actions on cholangiocellular and hepatocellular membranes, which likely contribute to hepatotoxicity in this disorder.
The evidence for UDCA's potential role in treating primary sclerosing cholangitis (PSC) is less convincing. The largest trial of UDCA for PSC to date randomly assigned 105 patients at the Mayo Clinic to receive either UDCA 13-15 mg/kg/day or placebo. Because the inclusion criteria of this trial required cholangiographic evidence of PSC, the results are not directly applicable to patients with pericholangitis.
Despite biochemical improvement in some patients treated with UDCA, there was no significant difference in clinical outcomes after follow-up periods as long as 6 years. Despite the lack of long-term benefit observed in this study, many continue to prescribe UDCA to patients with PSC because of the improvements in liver biochemistry that it brings about. The role of higher doses of UDCA (as high as 30 mg/kg/day) is currently being evaluated in large controlled trials.
Although not a proven effective treatment for pericholangitis, the gallstone dissolution agent ursodeoxycholic acid (UDCA) might have a role to play in the management of this disorder.