Primary sclerosing cholangitis: One disease or several?
Christopher L. Bowlus M.D.
Division of Gastroenterology and Hepatology, University of California Davis School of Medicine, Sacramento, CA
Christopher L. Bowlus, M.D., Division of Gastroenterology and Hepatology, University of California Davis School of Medicine, 4150 V Street, PSSB 3500, Sacramento, CA 95817. E-mail: firstname.lastname@example.org.
Primary sclerosing cholangitis (PSC) is a heterogeneous, idiopathic, inflammatory disorder of the bile ducts frequently associated with inflammatory bowel diseases (IBD) of the colon. The first descriptions of PSC in the 1920s described an “obliterative cholangitis” of the extrahepatic biliary tree with diffuse thickening of the wall and narrowing of the lumen. In the 1960s, radiographic cholangiograms revealed the diffuse involvement of the intrahepatic and extrahepatic biliary tree in many cases, and histologic studies noted the wide range of findings on liver biopsy, from normal to the classic concentric biliary fibrosis. The diagnosis of PSC then and now relies upon these cholangiographic features of focal biliary strictures and dilations in the absence of a secondary cause of sclerosing cholangitis. Early descriptions of PSC noted the predominance of men in the third and fourth decade of life and association with ulcerative colitis. However, the features of PSC are seen increasingly in a variety of clinical settings, which raises the question of whether PSC as we describe it is a single disease or a syndrome arising from several different underlying pathologic processes (Table 1 and Fig. 1).
Table 1. Subclassification of PSC
Sex Ratio (M:F)
Large duct PSC
All ages; median age at diagnosis ∼45 years
All ages; median age at diagnosis ∼60 years
Small duct PSC
Median age at diagnosis ∼30 years
Median age ∼45 years
Median age 11 years
Corticosteroids, vancomycin, ursodeoxycholic acid
Median age ∼60 years
African American PSC
Median age for listing for liver transplantation ∼40 years
Classic Large Duct PSC
PSC as originally described occurs predominantly in men (male:female ratio 3:2) in the setting of IBD with cholestasis. Interestingly, the IBD typically is a pan-colitis, which often shares features of both ulcerative colitis and Crohn's colitis with frequent ileitis and rectal sparing. In addition, the IBD is commonly asymptomatic, thus all newly diagnosed PSC patients without a diagnosis of IBD must undergo colonoscopy. The association between PSC and IBD appears to be greater in northern latitudes—although even there, the frequency of non-IBD PSC is increasing.
The natural history of large duct PSC ranges from rapidly progressive to indolent. The mean transplant-free survival has been reported to be from 12 to more than 20 years, with the latter including more recent population-based estimates. Currently, there are no medical therapies that have been shown to improve clinical outcomes in PSC. Recently, large genome-wide association studies have begun to add to our understanding of the genetic risk alleles of PSC beyond the well-established HLA-DR3 and HLA-B8.2
IBD is concomitant in 60%-80% of PSC cases and is thought to be an important underlying pathogenic mechanism. Cases of PSC in the absence of IBD tend to be equally distributed among men and women and are diagnosed at a much older age. The absence of IBD may be associated with a better prognosis. Although the rarity of PSC without IBD limits the power of genetic analysis, this group of PSC patients appears to have the similar HLA risk alleles compared with PSC with IBD.
Small Duct PSC
A small group of PSC patients present with clinical and histologic features compatible with PSC, except for the lack of typical cholangiographic findings and have been defined as small duct PSC. In some series, IBD was required for the diagnosis, but not in others. In addition, these patients may have been labeled in the past as antimitochondrial antibody–negative primary biliary cirrhosis or autoimmune cholangiopathy. In most cohorts, small duct PSC comprises ∼10% of the total PSC population, rarely progresses to large duct PSC, and has a generally favorable outcome.
Overlap of PSC and Autoimmune Hepatitis
Some patients with PSC also have features of autoimmune hepatitis (AIH). They may present with significant elevations of liver aminotransferases and histologic findings consistent with AIH, or they may initially present as a typical case of AIH that subsequently becomes cholestatic with the development of sclerosing cholangitis. In some cases, PSC-AIH may respond to immunosuppression. Unfortunately, there are no agreed-upon diagnostic criteria for PSC-AIH overlap, which is likely why the reported frequency of PSC-AIH varies from 1.4% to 17% of the PSC population. Importantly, autoantibodies such as antinuclear antibodies and anti–smooth muscle antibodies are frequent in PSC without evidence of AIH.
PSC in children appears to have many of the same features as PSC in adults, namely a male predominance and strong association with IBD. However, in children, PSC appears to be much more responsive to therapies and has a higher frequency of overlap with AIH. Autoimmune sclerosing cholangitis is a term used to designate a group of patients with PSC-AIH features with the exceptional reversal of cholangiographic findings with immunosuppression. Recent case series have also reported marked clinical improvement with oral vancomycin in children with PSC. Notably, neither of these therapies has shown similar effects in adults.
Immunoglobulin G4–Related Sclerosing Cholangitis
The recent recognition of immunoglobulin G4 (IgG4)-related sclerosing cholangitis found in association with autoimmune pancreatitis as one of many diseases associated with elevated IgG4 serum levels and tissue infiltration of IgG4-plasma cell has led to the recognition that some previously diagnosed cases of PSC were in fact IgG4-related. To add confusion to this issue, recent findings show that serum IgG4 levels are often elevated in PSC, and IgG4 plasma cells are frequent in PSC liver explants, but the two features do not necessarily correlate. In addition, IgG4-related diseases are typically responsive to corticosteroids, which is not seen in PSC. Nevertheless, several cohort studies have identified IgG4 levels that are significantly associated with decreased transplant-free survival among PSC patients, thus making it a useful prognostic marker.[9, 10]
PSC in Non-Caucasian Populations
Most studies of PSC have been performed in northern European populations or populations that descended from northern Europe, leading some to conclude that PSC is a disease of Caucasians. However, PSC is a “modern” disease, and given its association with IBD, it is likely that as the geo-epidemiology of IBD changes, the frequency of PSC in non-Caucasian populations is likely to change. To date, there are few data from Asia, but apart from the autoimmune pancreatitis sclerosing cholangitis described in Japan, PSC appears to be extremely rare.
In contrast, studies of a large health care organization and US transplantation data suggest that the incidence and prevalence rates of PSC among African Americans is at least as great as that in Caucasians.[11, 12] In African Americans, there is a less striking male predominance and a lower IBD rate. Interestingly, HLA-DR3, which is strongly associated with PSC in European populations, is rare among African Americans and is not associated with PSC in African American patients (Fig. 2). However, the HLA-B8 association is shared between both Caucasian and African American PSC patients.
PSC is a heterogeneous disorder that varies in clinical presentation, natural history, and, potentially, treatment response. In most cases, PSC is in fact secondary to IBD and is therefore likely to be the same disease modified by a number of genetic and nongenetic influences. As larger numbers of patients are studied in more detail, subphenotypes will be further refined and correlated with genetic data to begin to reveal the mechanisms responsible for this heterogeneity.