Pericholangitis

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) are 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. ^[1]

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 bile ducts visible on cholangiography 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:

• Autoimmunity

• Portal bacteremia

• Absorption of colonic toxins

• Ischemic injury to the biliary tree

• Viral infections

• Toxic bile acids in a genetically predisposed individual

United States statistics

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. ^[2] 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. ^{[3, 4, 5, 6, 7]} 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.

International statistics

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. ^[8]

The prevalence in patients with IBD is variable. ^[9] For example, in a Finnish study by Heikius et al of 237 unselected patients with IBD, the prevalence of PSC was 11%. ^[6] 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. ^[7] The reason for these international differences in PSC prevalence is unknown.

Age-, sex-, and race-related demographics

In one study, the mean age at diagnosis was 38 years in the pericholangitis group versus 39 years in the classic PSC group. ^[10] Similar figures were reported in the Mayo Clinic study: 40 years versus 39 years, respectively. ^[2] 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. ^[10] 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. ^[11]

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%). ^[12]

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. ^[10] 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). ^[13] 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 ^[10] and Angulo et al, ^[13] 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. ^[10] 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. ^[13] 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

Complications of pericholangitis may include the following:

• End-stage liver disease – Portal hypertensive bleeding (esophageal and gastric varices, portal hypertensive gastropathy), ascites and edema, jaundice, and malnutrition

• Classic large-duct primary sclerosing cholangitis (PSC)

• Cholangiocarcinoma (very rarely)

• Deficiencies of fat-soluble vitamins (ie, A, D, E, or K)

• Osteopenia and osteoporosis

• Colonic dysplasia and adenocarcinoma in patients with IBD - Patients with PSC and IBD are reported to have an increased risk of colonic dysplasia and adenocarcinoma; the exact risk in pericholangitis is unknown but is presumed to be similar to that in classic PSC

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.