[Frontiers in Bioscience E4, 1683-1705, January 1, 2012]
Primary sclerosing cholangitis: etiopathogenesis and clinical management
Asha Gupta,1 Christopher L. Bowlus2
1
TABLE OF CONTENTS
1. ABSTRACT
Primary sclerosing cholangitis (PSC) is a chronic inflammatory liver disease characterized by the destruction of medium to large-sized bile ducts and intense, concentric fibrosis. Complications from PSC include bacterial cholangitis, cirrhosis, and cholangiocarcinoma and a therapy that might alter the natural history of the disease remains lacking. Our understanding of the pathogenesis of PSC also remains rudimentary but several theories exist, suggesting roles for genetic susceptibility, abnormal innate immune responses lymphocyte trafficking, and toxic bile formation. Medical and surgical therapies, short of liver transplantation, have been disappointing. Currently, the management of PSC is aimed largely at the endoscopic treatment of dominant biliary strictures and complications of cholestasis until the disease has progressed to cirrhosis, at which time liver transplantation is indicated. Progress in our basic understanding of PSC is desperately needed in order to rationally design new therapeutic approaches to this disease.
2. FEATURES OF PSC
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by obliterative fibrosis and inflammation of the intrahepatic and extrahepatic biliary ducts (1-5). It is an insidious but progressive disease, eventually leading to biliary cirrhosis, hepatic failure, and in 10-30% of patients, cholangiocarcinoma (1, 3, 6). Currently, liver transplantation is the only effective treatment available for end-stage liver disease secondary to PSC and as such, PSC is the fifth leading indication for transplantation in the United States (3, 6).
2.1. Epidemiology
PSC is more common in men than woman, and the majority of patients are diagnosed in the third to fourth decade. However, cases are seen in all age groups, and studies in Japan have suggested a bimodal age distribution with a second peak in the seventh decade (7). In addition to liver disease, PSC is closely associated with inflammatory bowel disease (IBD). Approximately 75% of patients with PSC have IBD, and of these, nearly 80-90% are diagnosed with ulcerative colitis (UC) (1-3, 8-10). This association with IBD has been noted to be greater in Northern European and American populations than Southern European (50%) and Asian (35%) populations with IBD (7, 11-13).
The true incidence of PSC is unknown, though studies from Oslo, Norway, Sweden, Wales, and Olmstead County, Minnesota estimate it to be between 0.9 and 1.3 cases per 100,000 person-years (6, 14-18). However, a recent study in the UK noted an incidence of 0.41 cases per 100,000 person-years (19). Our own analysis in a population of over three million members enrolled in a large health care system in Northern California found a similar annual incidence of 0.59 cases per 100,000 person-years (unpublished). This discrepancy may be explained by the ethnic diversity of the populations in these latter analyses compared to some of the earlier published studies, particularly as there appears to be a higher prevalence of PSC in Northern Europeans and Caucasians. In contrast, a lower prevalence has been noted in Southern European, Asian, and Alaskan populations, which may be due in part to a lower rate of investigation (11, 12, 20). Regardless, the true incidence of this disease may be underestimated, as it is a relatively rare condition with an insidious course that requires specialized expertise and invasive procedures for diagnosis.
2.2. Clinical features
In the early stages of PSC, most patients are asymptomatic and abnormal liver enzymes may be the only indication of disease. Once advanced, signs and symptoms of cholestasis, portal hypertension and advanced liver disease frequently develop, including fatigue, pruritus, jaundice, weight loss, hepatomegaly, ascites, and abdominal pain (Table 1). With chronic cholestasis, patients are also at risk for developing malabsorption of fat-soluble vitamins, steatorrhea, metabolic bone disease, and cholelithiasis. Bacterial cholangitis may also occur, particularly after endoscopic or surgical procedures. Cholangiocarcinoma, one of the most feared complications of PSC, has an annual incidence of 1.5% per year in PSC patients, with the highest incidence within the first year of diagnosis (14, 21, 22).
As noted, PSC is closely associated with IBD, though the colonic manifestations in these patients are different from patients with IBD alone. This suggests that PSC-IBD is a distinct phenotype. In particular, the colitis of PSC-IBD is often extensive, though clinically quiescent, regardless of whether it is classified as UC or Crohn's disease (CD) (9, 10). Additionally, it is often associated with rectal sparing and backwash ileitis, characteristics typically found in CD (9, 10). In PSC-IBD patients who have undergone proctocolectomy and ileal pouch-anal anastomosis, a higher incidence of pouchitis has been noted (10, 23). Crohn's disease associated with PSC does not typically have strictures or fistulas. Furthermore, some data suggest that PSC-IBD patients are at greater risk for developing colorectal neoplasia, and have lower survival rates than similar IBD patients without PSC (2, 9, 10). Finally, genetic testing has found that of the fifteen susceptible loci for UC, only two are associated with an increased risk of PSC, further supporting that PSC-IBD is a distinct entity (24). In addition to IBD, 24% of PSC patients will also be diagnosed with another autoimmune disease (25), notably type I diabetes (Table 2).
2.3. Biochemical features
As the majority of patients are asymptomatic in the early stages of disease, often PSC is first suspected when biochemical abnormalities are noted on routine or screening laboratories (Table 3). Typically, a cholestatic pattern is appreciated with elevated alkaline phosphatase levels as the predominant feature. Additionally, mild to moderate elevations in serum aminotransferases may be noted though normal liver tests can also be seen. Bilirubin levels are often normal, particularly early in the disease though these can fluctuate at times and often progressively increase as the disease advances (1, 16). Similar to other cholestatic liver diseases, elevated liver and urine copper levels and decreased serum ceruloplasmin may also be present (26). PSC should be considered in all patients with IBD or other autoimmune diseases who are found to have cholestatic liver tests.
2.4. Serologic features
Several autoantibodies have been detected in the serum of PSC patients, though none have been found to have sufficient specificity or sensitivity to be used for screening or diagnosis. The most prevalent autoantibody, perinuclear antineutrophil cytoplasmic autoantibodies, is seen in 65-95% of patients with PSC, 50-80% of those with UC, and 10-20% of patients with CD (8, 27-34). Other autoantibodies, such as antinuclear, anti-Saccharomyces cerevisiae, antismooth muscle, anticardiolipin, thyroperoxidase, and rheumatoid factor, are less prevalent (35). Hypergammaglobulinemia and elevated serum IgM levels are also noted in 30% and 50% of patients, respectively (1). IgG4 levels are often elevated in patients with autoimmune pancreatitis, as well as IgG4-related sclerosing cholangitis, which should be distinguished from typical PSC (36, 37). Antimitochondrial antibody is not usually detected in PSC, and can help differentiate PSC from primary biliary cirrhosis (PBC). Table 4 summarizes the prevalence of these autoantibodies in patients with PSC.
2.5. Radiographic features
Cholangiography remains the gold standard for the diagnosis of PSC. Findings of segmental strictures with proximal dilation and sacculation of the bile ducts create the "beaded" appearance that is classic for PSC (Figure 1). Traditionally, cholangiography has been performed through endoscopic retrograde cholangiography (ERC). However, a recent meta-analysis found that magnetic resonance cholangiography (MRC) is sufficiently sensitive and specific to make the diagnosis in many cases of PSC and thus may be a more appropriate first-line diagnostic tool (38, 39). However, if there is a high index of suspicion and MRC is negative or equivocal, ERC should be performed, as MRC has been found to be less sensitive in cases of early disease and cirrhosis (39). Additionally, ERC has the advantage of also being therapeutic, allowing ductal dilation and stenting, and providing further diagnostic information with brush cytology and biopsies. However, it also carries the risk for complications such as pancreatitis, abdominal pain, cholangitis, pancreatitis, bleeding, and bile duct perforation.
2.6. Histologic features
PSC affects both intrahepatic and extrahepatic bile ducts. Biopsies from these ducts show epithelial necrosis and fibrous thickening of the wall, with infiltrate of inflammatory cells. Generally, PSC affects both small and large ducts in the majority of patients though a small subset has involvement of only the small ducts (small duct PSC). Liver biopsy is not reliable alone for the diagnosis of PSC, as it is non-specific and may be normal when only large ducts are involved (40). However, when performed, characteristic findings include bile duct proliferation, periductal fibrosis with typical "onion-skinning" lesions, periductal inflammation, and bile duct obliteration. These histologic features may be classified into four stages using Ludwig criteria: (1) cholangitis or portal hepatitis; (2) periportal fibrosis or hepatitis; (3) septal fibrosis and/or bridging necrosis; (4) biliary cirrhosis (41, 42).
2.7. Diagnostic criteria
Given the heterogeneous nature of PSC and the lack of a quantifiable diagnostic test, strict criteria for establishing the diagnosis of PSC have not been established. Typically, the diagnosis is based upon the presence of a cholestatic pattern of liver biochemistries, typical cholangiographic findings, and the absence of secondary causes of sclerosing cholangitis (43) (Table 5). However, a significant percentage of PSC patients will have normal liver biochemistries, and often the cholangiographic findings are subtle and dependent upon MRC techniques and ERC operator expertise. In addition, PSC patient often have undergone biliary surgery, or may have choledocholithiasis or cholangiocarcinoma (CCA) at the time of diagnosis. Thus, the diagnosis of PSC must be based on a combination of clinical presentation, laboratory and serologic findings, histopathology, and cholangiography.
2.7.1. Small duct PSC
In a small number of patients, PSC involves only the small ducts of the liver without affecting the larger bile ducts. These patients present with typical cholestatic liver tests and liver histology, but normal cholangiograms. The incidence of small duct PSC has not been well-studied, though it is estimated to be as low as 0.15 cases per 100,000 person-years, or approximately 6-16% of the PSC population (16, 44). Most patients with small duct PSC have been noted to have slower clinical progression, with higher rates of survival and fewer cases of cholangiocarcinoma or transplantation (44, 45). However, approximately 12% of patients with small duct PSC will progress to large duct disease, placing them at similar risks to the general PSC population (44, 45).
2.7.2. PSC-AIH overlap syndrome
PSC-AIH overlap syndrome is the classification given to patients with both the cholangiographic features of PSC and the biochemical and histologic features of autoimmune hepatitis (AIH). More common in children and young adults, the prevalence of PSC-AIH overlap has been reported to be as low as 8% and as high as 49% (46, 47). Such high degree of variability is likely due to the lack of defined diagnostic criteria for this condition. This has led some practitioners, including the International Autoimmune Hepatitis Group, to suggest that these patients should be categorized by their predominant disease, namely PSC or AIH, rather than labeled as an overlap syndrome. However, many clinicians continue to use the term "PSC-AIH overlap syndrome", and define it by such clinical features as high serum aminotransferase levels, normal to high alkaline phosphatase levels, high titers of antinuclear and anti-smooth muscle antibiodies, liver pathology with periportal and periseptal lymphocytic piecemeal necrosis, and cholangiographic evidence of PSC (43, 46, 48-50). Furthermore, there has been some evidence to suggest that PSC patients with AIH features may benefit from immunosuppressive therapy, particularly corticosteroids, highlighting the need for further characterization (51).
2.8. Clinical course and prognosis
PSC has a variable clinical course, though the disease most often progresses to end-stage liver disease. The median time from diagnosis to death or liver transplantation ranges from 12 to 18 years (52-54).
Many models have been developed to provide prognostic prediction for life expectancy in PSC patients. The Mayo Clinic Revised Natural History Model for PSC is the most widely accepted model for predicting survival probability (55). This score is based on objective findings of age, bilirubin, albumin, aspartate transaminase, and history of variceal bleeding. However, the accuracy of this model remains poor, and thus cannot be applied to the individual. Recently, Ponsioen et al. have been working to validate the Amsterdam cholangiographic classification system as another prognostic model (54, 56). This system uses qualitative descriptions of the intrahepatic and extrahepatic ductal system, with scores from 0 to 4 depending on the degree of visible abnormality. A combined score has been found to have an inverse relationship to survival and, though subjective, may provide an additional predictive model in the future.
3. ETIOPATHOGENESIS
Despite a number of proposed models to explain the mechanisms involved in PSC, none of them fully explain all the features of PSC, and most lack sufficient supporting evidence. For the most part, these theories attempt to explain the link between IBD and PSC, and several features of this link must be considered. First, the IBD of PSC is a unique entity, often referred to as PSC-IBD (10). Although PSC-IBD has been classically categorized as UC because it usually involves the entire colon, other features including ileal involvement and rectal sparing are more typical of Crohn's disease. It is unclear whether the features of PSC-IBD predispose to PSC or whether they are the result of genetic and environmental factors shared with PSC. Second, PSC is not dependent on active intestinal disease and, in fact, can occur after colectomy (57). Third, immunosuppressive agents, particularly those that are effective for the treatment of IBD, have not been shown to be effective for PSC. Another important feature to be considered is the recurrence of PSC after liver transplantation, suggesting that the target organ has common or generic features that predispose to the immune attack.
Herein, we review the current understanding of the mechanistic hypotheses that have been proposed to explain the pathogenesis of PSC, namely those involving genetic susceptibility, lymphocyte homing, innate immunity and toxic bile. Barriers to the further elucidation of these hypotheses of PSC pathogenesis include: 1) the difficulty in obtaining target tissue, especially in early stages of disease, 2) phenotypic variability and the lack of consensus on classification, 3) the relative rarity of the condition requiring collaboration between multiple institutions, and 4) the absence of an animal model that adequately recapitulates the human condition.
3.1. Genetic susceptibility
Both genetic and non-genetic factors have been identified to predispose to PSC, but how they increase the risk remains largely undefined. Smoking has been repeatedly shown to be a factor that decreases the risk of PSC (58-61). However, this effect may not be directly related to PSC, since smoking also decreases the risk of UC (62). In our recent analysis of patients listed for liver transplantation, PSC was associated with a higher socioeconomic status, independent of age, race, and gender, but urban versus rural living had no effect (63). Identification of the specific variables associated with this increased risk may help us to understand the non-genetic susceptibility to PSC.
The importance of genetic susceptibility to PSC is generally accepted, but the strength of the supporting data is limited. Because PSC is a rare condition, a sufficiently powered concordance study of twins or siblings is not feasible. Nevertheless, in a study of 145 Swedish PSC patients, the prevalence of PSC among their first-degree relatives was approximately 100-times greater than the total population (64). A larger study similarly found that, among a national Swedish cohort of PSC patients (n=678), the risk of cholangitis was increased in offspring, siblings, and parents of the PSC patients, compared to relatives of a control group with hazard ratios of 11.5, 11.1, and 2.3, respectively (65). In an attempt to identify the causative genetic variants for this increased risk, a plethora of candidate gene studies have been reported, ranging from fibrosis mediators to bile acid transporters to immune related genes. In most cases, the studies are underpowered and, with the exception of the Human Leukocyte Antigen (HLA), the results have failed to be replicated in additional cohorts. For example, ICAM-1, which mediates leukocyte adhesion during immune responses and is important in transendothelial migration of neutrophils and T cell activation, has been implicated in UC, as well as a number of other inflammatory disorders including multiple sclerosis and Behcet's disease. Previous studies have demonstrated expression of ICAM on proliferating bile ductules and interlobular bile ducts in PSC patients with advanced disease. The polymorphism K469E in exon 6 leads to a change from glutamic acid to lysine in the immunoglobulin-like domain 5 of ICAM-1, which is thought to affect interactions between LFA-1 and B cells. Although the frequency of the K469E polymorphism was significantly lower in a UK PSC cohort (66), this finding was not replicated in a larger study of Scandinavian PSC cohort (67). Furthermore, most studies have not included an IBD cohort to determine whether associated genes are PSC specific or shared between IBD and PSC. Only recently have the first genome-wide association studies been performed in PSC (68, 69), with the anticipation that additional studies will be performed as soon as adequately large cohorts are collected among international collaborators.
3.1.1. HLA and related gene associations
An association with the HLA complex on chromosome 6p21 with PSC has been well documented from early serologic studies (70, 71). These studies and others have established a strong association in populations of northern European origin between PSC and HLA, 2 susceptibility haplotypes (B*08,DRB1*0301,DQA1*0501,DQB1*0201 and DRB1*13,DQA1*0103,DQB1*0603), and 1 protective haplotype (DRB1*04) (72, 73). More recently, a genome wide association study has established HLA as the most important risk locus by far (68). In this study, a total of 443,816 SNPs were initially genotyped in 285 Norwegian PSC patients and 298 healthy controls, with replication attempted in 3 independent case-control panels from Scandinavia (137 PSC cases and 368 controls), Belgium/The Netherlands (229 PSC cases and 735 controls), and Germany (400 cases and 1832 controls). The strongest associations were detected for HLA-B*08 and DRB*03, with odds ratios of 4.9 and 3.8, respectively. In comparison, the only PSC-specific locus identified to be significant outside the HLA complex, rs9524260 on chromosome 13, showed significant associations in only 3 out of the 4 study panels, with a combined odds ratio of 0.71.
In addition to the strength of this association, the HLA is important for its specificity to PSC relative to UC. HLA is only weakly associated with UC compared to its PSC association (68, 74, 75). In addition, the HLA class II alleles conferring susceptibility to or protection from PSC are found to be associated with PSC patients with or without IBD, and these alleles are not associated with UC (74). Furthermore, the HLA alleles associated with UC are not linked to PSC.
Despite the importance of HLA in PSC, the strong linkage disequilibrium within the HLA region has slowed progress toward identifying the gene or genes that account for the associations. One possible approach to overcome this obstacle is the assessment of HLA associations in the admixed African American population in which the HLA haplotype diversity is much greater (76). In an initial approach, we analyzed HLA allele frequencies in African Americans listed for liver transplantation for PSC or alcoholic liver disease, a condition without any documented HLA associations (63). Importantly, in these African American PSC patients, the B8 and DR13 associations in PSC were replicated, whereas DR3 was not significantly associated with PSC. On the contrary, the negative association with DR4 was detected in African Americans with PSC. Investigation of extended HLA-B and DR haplotypes in African Americans showed that the associated alleles HLA-B8, DR13 or DR4 occurred on several, separate haplotypes, suggesting that HLA-B and HLA-DR associations observed are likely to represent independent phenomena not arising by linkage disequilibrium. These findings illustrate the plausibility of identifying HLA associated susceptibility genes to PSC in African Americans.
Multiple mechanisms supporting the associations with these HLA haplotypes have been put forth, most prominent among them suggesting that these HLA alleles modulate immune responses against specific (auto-)antigens. However, the HLA complex is densely encoded with multiple immunologically important genes that have also been implicated in PSC, specifically major histocompatibility complex class I chain-related A (MICA) and tumor necrosis factor-alpha (TNF-α) (77-80). Associations between HLA-C and HLA-B allele have also been proposed to be related to their interactions with killer immunoglobulin-like receptors (KIRs) on natural killer (NK) cells and various T-lymphocytes (81). NK cell effector function is balanced by inhibitory and activating receptors, such as KIR, which bind HLA class I molecules (82). At least 14 functional KIR genes are present on chromosome 19q13.4, where they exhibit significant allelic and haplotypic variability, the latter of which is largely related to the presence or absence of activating KIR genes. Inhibitory KIRs encode immunoreceptor tyrosine-based inhibitory motifs in their cytoplasmic tails. Activating KIRs interact with DAP12 homodimers that contain immunoreceptor tyrosine-based activating motifs. Specific combinations of HLA and KIR alleles have been implicated in autoimmunity, tumor immunosurveillance and viral diseases. In a study of Scandinavian PSC patients, the frequency of HLA-Bw4 and -C2, ligands for the inhibitory KIRs 3DL1 and 2DL1, respectively, were significantly reduced compared to controls, suggesting an increase in NK cell activity by decreased inhibition (81). Replication of the decreased HLA-C2 frequency was achieved in an Italian PSC cohort, and was shown to be independent of the HLA class II association (83).
3.1.2. IBD shared loci
With the strong association between PSC and IBD, it would not be surprising if they share some common genetic basis (Figure 2). However, most IBD susceptibility genes tested to date, including those for both UC and CD, have failed to show a common genetic link to PSC (24, 68, 80, 84, 85). The few exceptions to this are loci at 2q35, 3p21, and 13q31 corresponding to candidate genes takeda G-protein coupled bile acid receptor 5 (TGR5), macrophage stimulating 1 (MST1), and glypican 5 and 6 (GPC5/6), respectively (68, 75, 86-88). This lack of a more common genetic basis between PSC and UC or Crohn's disease supports the clinical notion that PSC-IBD is a unique phenotype. What role genetic variants in these 3 shared susceptibility loci play in the PSC susceptibility is not clear. At chromosome 2q35, the bile acid receptor TGR5 gene is one of the most plausible disease genes, as it is strongly expressed in monocytes and macrophages, and inhibits the release of inflammatory cytokines from activated macrophages, including Kupffer cells (89, 90). TGR5 has also been shown to co-localized with and stimulate the activity of the cystic fibrosis transmembrane conductance regulator (CFTR) (91). Interestingly, CFTR has also been implicated in PSC susceptibility (92-95). Recently, sequencing of the TGR5 gene in 267 PSC patients and 274 controls identified 6 nonsynonymous mutations, 4 of which were found only in PSC patients, and with 3 demonstrating reduced or abolished TGR5 function when incorporated into a reporter construct (96). Fine mapping of the locus around TGR5, however, has not been able to definitely localize the region to TGR5 due to a region of linkage disequilibrium spanning several genes including IL8RA and IL8RB.
MST1 has been proposed as the most likely candidate gene at the 3p21 locus. MST1 is a circulating protein which exhibits multiple functions including the induction of apoptosis (97), inhibition of LPS-induced cyclooxygenase-2 expression by macrophages via the RON receptor (98), and lymphocyte trafficking by modulating the "inside-out" pathway for lymphocyte function-associated antigen-1 adhesion (99, 100). The PSC-, CD- and UC-associated MST1 variant has been suggested to impair the binding of MST1 to its receptor (101).
3.2. Innate immune response in PSC
The association of PSC with IBD suggests that, like the latter, PSC is not necessarily a classic autoimmune disease in the sense that there is targeted destruction of tissue directed at a specific self-antigen. Rather, IBD is the result of an abnormal innate immune response to antigens of the intestinal flora, which activates an adaptive immune response (102). Genome wide association studies and subsequent functional studies in IBD have implicated several genes such as NOD2 and ATG16L1, both involved in the intracellular processing of bacterial antigens (103-105). In the case of CD this leads to a predominantly TH-1 type of immune response and increases in IL-17 producing lymphocytes. In contrast, ulcerative colitis tends to be more of a TH-2 response. Whether PSC, which tends to be characterized by TH-1cytokines and stricturing reminiscent of CD, involves similar mechanisms has not been fully investigated.
The activation of the innate immune system as a primary inciting event of PSC has been proposed by several investigators (106). According to this theory, PSC is triggered by bacteria or, more likely, pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS), lipoteichoic acid, peptidoglycans and unmethylated bacterial dinucleotide motifs that enter the portal circulation through an inflamed, permeable intestine. PAMPs activate macrophages, dendritic cells and NK cells through pattern recognition receptors, including Toll-like receptors (TLRs) and CD14, leading to the secretion of cytokines which, in turn, activate NK cells (IL-12), and promote recruitment and activation of lymphocytes (TNF-a , IL-1b and CXCL8). NK cells may also be activated by MHC Class I chain-related gene products MICA and MICB, which are stress-induced proteins that can promote the cytotoxic function of NK, NKT and g d T cells through the NKG2D receptor.
Similar to the intestinal mucosa, TLRs are also expressed on the biliary mucosa, and their expression has been shown to be induced in a variety of liver diseases (107). Interestingly, IgG directed against biliary epithelial cells (BEC) has been found in the sera of some PSC patients. These sera induce the expression of TLR4 and TLR9 on BEC in culture, and can be found to co-localize with these same TLRs on BEC in situ (108). In fact treatment of BEC with PSC sera-containing anti-BEC antibodies induces secretion of GM-CSF, IL-1b and IL-8, which in turn may lead to the recruitment of neutrophils, macrophages and T cells. However, the target(s) of these anti-BEC antibodies remains unknown.
Macrophages, key cells in the transition from innate to adaptive immune responses, appear to accumulate in the sinusoidal and perisinusoidal spaces in PSC, but not in PBC and other biliary tract diseases. The accumulation is independent of necrosis, cholestasis, and neutrophil infiltration (109). In our previous study of 19 PSC patient liver biopsies, 84% of patients with PSC had inflammatory cells localized to the portal area, although only 4 (21%) were found to have inflammatory cells infiltrating the small bile ducts. When compared to normal subjects, PSC (P < .0001) had a significantly higher number of tissue sections with CD68- and/or MPO-positive cells in the portal areas (110).
In animal models, bacterial components can induce a biliary-based inflammation. However, in humans, lipoteichoic acid is relatively infrequent in PSC livers (111). A potential link between bacterial components and hepatobiliary inflammation was first substantiated by Chadwick et al., who demonstrated that N-formylated chemotactic peptides that are produced by several species of intestinal bacteria undergo enterohepatic circulation, and that the levels of these compounds are increased in experimentally-induced colitis (112-114). In addition, rectal administration of N-formyl L-methionine L-leucine L-tyrosine in rats with acetate-induced colitis results in a biliary-based inflammation consisting of macrophages and neutrophils in the early stages, and subsequently CD4+ and CD8+ T cells (115, 116).
In a series of experiments with surgically created self-filling jejunal blind loops leading to bacterial overgrowth, Lichtman et al. demonstrated that, in genetically susceptible rat strains, hepatobiliary injury with features similar to PSC develops, including bile duct proliferation, fibrosis, and acute or chronic periportal and focal parenchymal inflammation (117). The lack of similar findings in self-emptying blind loops that do not develop bacterial overgrowth suggested a role for bacteria, or their cell wall components. The role of bacterial peptidoglycans was supported when the effects of the blind loops were abrogated by oral metronidazole and tetracycline, or by mutanolysin, a muralytic enzyme that cleaves the beta 1-4 N-acetylmuramyl-N-acetylglucosamine linkage of peptidoglycan-polysaccharide (118, 119).
These studies, along with human studies suggesting an increase in intestinal permeability in IBD, make plausible a theory of PSC involving translocation of bacterial cell wall components via the portal circulation to the liver, with further hepatobiliary inflammation and injury, presumably through a pathway that initially involves activation of the innate immune response. However, this model does not have colitis, and there is no evidence that bacterial overgrowth in humans leads to PSC. In fact, Bjornsson et al. concluded that small intestinal bacterial overgrowth and increased intestinal permeability are not important in the pathogenesis of chronic PSC, based on their results that only 1 out of 22 PSC patients had small intestine bacterial overgrowth, and that intestinal permeability of their patients did not differ significantly from that of controls (120).
Organisms postulated to be involved in the induction of the innate immune response in PSC include Chlamydia spp. and Helicobacter pylori. Ponsioen et al. found an elevated seroprevalence of Chlamydia-LPS antibodies in PSC patients compared to a matched control group. The lack of Chlamydia spp. in cultures of bile from these patients suggested that these findings were not due to active infection (121). Amplification of 16S ribosomal RNA from explanted livers of 25 patients with PSC detected Helicobacter sequences in perihilar ductal and liver tissue of 6 of these patients. However, 3 out of 31 control livers with non-biliary tract disease also demonstrated Helicobacter rRNA sequences (122). Similarly, Boomkens et al. reported no significant difference between the incidences of Helicobacter DNA in liver tissue from PSC patients compared to controls (123). In addition, there has not been any evidence that Helicobacter affects the histology of biliary epithelium (124). Further complicating the interpretation of these studies are the high rates of gram-negative biliary isolates from patients with dominant stenosis, and determining whether these organisms and the immune responses are primary to the disease or secondary to stricturing (125).
Our gene expression profile of PBMC from PSC patients compared to age and sex matched controls using microarray technology also suggests an important role for innate immune response in PSC (126). We identified 942 genes differentially expressed in patients with PSC compared to controls, many of them related to pathways involved in macrophage differentiation by M-CSF, as well as IL-2 receptor b activation of T cells, IL-6 signaling, and MAP kinase-signaling pathways. One of the more interesting genes confirmed to be increased in PSC was TNFAIP6, a 35 kilodalton secreted protein found in many cell types and tissues in response to a variety of stimuli. In particular, TNFAIP6 is expressed in physiologic and pathophysiologic conditions of inflammation, specifically in response to TNF-a and IL-1 (127). Multiple functions have been attributed to TNFAIP6, including inhibition of neutrophil migration, regulation of the protease network, and interactions with multiple glycosaminoglycans. Studies in murine models of arthritis have revealed that TNFAIP6 has potent anti-inflammatory effects through multiple mechanisms. Systemically administered TNFAIP6 induces greater than 50% inhibition of neutrophil migration in the air pouch model of inflammation. Intravital microscopy suggests that TNFAIP6 influences many aspects of neutrophil extravasation, particularly firm adhesion. In addition, compared to wild-type mice, mice with targeted deletion of Tnfaip6 show more severe proteoglycan-induced arthritis, which is associated with earlier and more extensive neutrophil infiltration, and elevated levels of serum IL-6. Furthermore, TNFAIP6 induces cyclo-oxygenase-2 expression in macrophages with preferential synthesis of the anti-inflammatory prostaglandin D2. Notably, these studies do not show any effects of TNFAIP6 on T or B cells responses. Thus, the upregulation of TNFAIP6 in PSC patients may be a marker of intense innate immune responses with TNF-a or IL-1 stimulation, and likely has inhibitory effects on the inflammatory process.
In summary, evidence exists suggesting that the innate immune response plays a role in the pathogenesis of PSC (Figure 3). This may be an insufficient response that fails to clear pathogens leading to chronic, unresolved infection and inflammation. In contrast, the failure to develop tolerance or down-regulate an innate immune response could similarly lead to chronic inflammation.
3.3. Lymphocyte trafficking
The observation that PSC may develop after years after total colectomy, and the lack of correlation between liver disease activity of PSC and intestinal disease activity of IBD, has lead to the hypothesis that the inflammation of PSC is a result of aberrant trafficking of intestinal memory T-lymphocytes to the liver (Figure 4) (128, 129). Supporting this theory is the finding that adhesion molecules and chemokine receptors that are normally restricted to the gut are aberrantly expressed in the liver, presumably leading to the recruitment of intestinal lymphocytes through the enterohepatic circulation (130-135).
Tissue specific recruitment of lymphocytes to inflammation involves the coordinated recognition of "addressins" expressed by vascular endothelial cells by homing receptors on the lymphocyte along with interactions of chemokines and chemokine receptors. In addition to tissue specificity, chemokines and chemokine receptors also impart lymphocyte lineage specificity. For example, TH1 cells express CCR5 and CXCR3, TH2 cells express CCR4 and CCR8, TH17 cells express CCR4, CCR6, and CXCR3, and recently, liver derived regulatory T cells have been characterized as expressing CCR4 and CXCR3 (136). The recruitment of lymphocytes to the liver is unique in many ways, including the dual blood supply entering the liver, the constant exposure of the liver to food and bacterial antigens entering via the portal vein, the low flow state within the hepatic sinusoids, the large fenestrae of the sinusoidal endothelium, and the need for specific recruitment within the liver (i.e. portal tract, lobule or biliary epithelium). The roles played by these receptors during recruitment of lymphocytes into the inflamed liver is becoming clearer but, for the most part, does not appear to be disease specific. For a more detailed review of this process, the reader is referred to the excellent review by Oo and Adams (137).
Recruitment of lymphocytes to the intestine involves activation of lymphocytes by dendritic cells in gut associated lymphatic tissue resulting in the expression of the α4β7 integrin and the CCR9 chemokine receptor. The ligand for a 4b 7, mucosal addressin cell adhesion molecule-1 (MAdCAM-1), is specifically expressed on the intestinal endothelium and during inflammation on intestinal mucosa. The CCR9 ligand, CCL25, is also capable of activating α4β7, and is expressed preferentially in the intestine as well. The combination of MAdCAM-1 and CCL25 is critical for the specific recruitment of a 4b 7+CCR9+ lymphocytes to the intestine. MAdCAM-1 was initially thought to be confined to gut endothelium, but has since been shown to be expressed in the portal vein and sinusoidal endothelium in autoimmune mediated liver diseases (138). Grant et al. reported the presence of MAdCAM-1 staining in the portal veins of 11/16 PSC patients, 6/10 AIH patients, and 3/11 PBC patients (134). Dual-color immunofluorescence demonstrated the proximity of a 4b 7 T-cells to MAdCAM-1 positive vessels, and adhesion assays confirmed the functionality of the interaction. Somewhat surprisingly, however, the frequency of a Eb 7+, but not a 4b 7+ liver infiltrating lymphocytes (LIL) was increased relative to peripheral blood in PSC. In the only other study of the expression of MAdCAM-1 in human liver diseases, MAdCAM-1 was associated with portal tract inflammation in chronic hepatitis C and B, as well as PBC and PSC (139).
In contrast to a 4b 7+ LIL, CCR9+ LIL do appear to be specifically increased in PSC compared to PBC. Although the frequency of CCR9+ lymphocytes is not increased in peripheral blood, approximately 20% of LIL from PSC livers express CCR9 compared < 2% in normal livers or PBC (132). This is in comparison to nearly 100% of lamina propria lymphocytes expressing CCR9+ in Crohn's disease. These CCR9+ LIL include CD8+ and CD4+ T cells, the former demonstrating a memory phenotype. The intestinal origin of these a 4b 7+ CCR9+ lymphocytes is supported by the recent finding that liver dendritic cells and stellate cells were unable to imprint these homing markers on CD8+ T cells (130). The CCR9 ligand CCL25 also appears to be specifically upregulated in PSC liver. Furthermore, CCR9+ LIL preferentially migrate to CCL25 rather than to CXCL12 or CCL5, and are triggered by CCL25 to bind immobilized MAdCAM-1 via α4β7.
Integrin αVβ6 is expressed in large amounts on certain activated epithelia, both mediating attachment to fibronectin and acting as a co-receptor for the activation of latent transforming growth factor (TGF)- β1. In order to elucidate its role in liver fibrosis, Patsenker et al. studied αVβ6 function in rats after bile duct ligation and in Mdr2-/- mice. αVβ6 was expressed in large amounts on proliferating bile duct epithelia in fibrosis. In addition, EMD527040, a a Vb 6 antagonist, decreased bile ductular proliferation and peribiliary collagen deposition, and down-regulated fibrogenic genes while up-regulating fibrolytic genes. It also reduced endogenous activation of TGF-β1 (140). In human liver, a Vb 6 is absent in normal liver, but it is expressed on activated bile duct epithelia and transitional hepatocytes. In chronic hepatitis C, integrin β6 mRNA increases with stage of fibrosis. Thus, a Vb 6 does not appear to be a specific receptor targeting lymphocytes in PSC. Clearly a better understanding of the basic biology of lymphocyte homing to the liver and specificity of homing in PSC is needed. In addition, still unknown are the mechanisms leading to the aberrant expression of adhesion molecules and chemokines in the inflamed liver.
3.4. Toxic bile theory
Bile is a complex mixture of bile acids, bilirubin, cholesterol, phospholipids, and proteins, which is toxic to cells even under normal conditions, (141). Several protective mechanisms, including micelle formation and bile flow, prevent injury to biliary epithelial cells despite the high concentration of bile acids normally present. Alterations in the composition of bile, decreased bile flow, and increased biliary pressure may all disrupt the normal bile homeostasis, and lead to toxic bile formation. Bile composition is largely dependent upon excretion of its components across the hepatocyte canalicular membrane, and upon dilution/alkalinization by the cholangiocytes. Bile acids that would induce apoptosis and necrosis of cholangiocytes normally form mixed micelles with phosphotidylcholine and cholesterol to prevent bile acid toxicity. Impairment of transporters responsible for maintaining the bile acid/phospholipid ratio (MDR3 or BSEP) or bicarbonate excretion and hydration of bile (CFTR or AE2) can potentially lead to toxic bile formation. Alternatively, bile stasis, a frequent phenomenon in PSC, may lead to toxic bile formation leading to the exacerbation of bile duct injury (Figure 5).
Support for the toxic bile acid theory comes primarily from the multidrug resistance gene 2 (Mdr2) knockout mouse (142-144). Targeted disruption of Mdr2 leads to sclerosing of the biliary tree with extra- and intrahepatic biliary strictures and dilations, onion-skin type periductal fibrosis, and focal obliteration of bile ducts similar to that seen with primary and secondary sclerosing cholangitis in humans (142). Presumably, biliary phospholipids that are normally transported into bile via the canalicular phospholipids flipase Mdr2 and that form mixed phospholipid-bile acid micelles protect cholangiocytes from bile acid-induced cell injury. Biliary phospholipids are absent in Mdr2-/-, which may lead to toxic bile acid-induced damage, resulting in sclerosing cholangitis (145). In addition to toxic bile acids, the absence of phospholipids results in cholesterol supersaturated bile, which could facilitate oxidation similar to the process of atherosclerosis (146). Cholangiocytes from Mdr2-/- mice express cellular adhesion molecules such as vascular cellular adhesion molecule-1, chemokines, growth factors and cytokines similar to those typical of atherosclerosis, and support some commonality between diseases. However, unlike human PSC, the Mdr2-/- mice do not develop IBD (146). In fact, induction of colitis in the Mdr2-/- mice had little effect on the sclerosing cholangitis phenotype.
Another potential player in the toxic bile theory is CFTR, the gene responsible for cystic fibrosis. Patients with mutations in CFTR are prone to develop a biliary-based cirrhosis, but distinct from PSC. Interestingly, induction of colitis in Cftr-/- mice results in bile duct injury (93). Human genetic studies of CFTR variants in PSC have been conflicting (92, 94, 95, 147, 148).
Despite the animal models supporting the toxic bile theory, support in humans is generally lacking, particularly as a primary initiating factor. Although some rare variants of MDR3 have been associated with biliary pathology, including sclerosing cholangitis (149, 150), genetic studies of the human orthologue of Mdr2 (MDR3 or ABCB4) have not found any association of genetic variants with PSC susceptibility (151). In addition, PSC patients with normal serum bilirubin levels have been shown to have normal biliary excretion of bile acids and lipids, suggesting that the toxic bile theory may only play a role in the later stages of PSC (151-153). Further support for the toxic bile theory in disease progression rather than initiation has come from a genetic study linking polymorphisms in the steroid and xenobiotic receptor gene, a ligand-dependent transcription factor that mediates protection against bile acid-induced liver injury in cholestatic animal models, and survival in PSC (154).
The etiopathogenesis of PSC remains enigmatic, and likely involves a series of genetic, environmental, immune, and metabolic events (Figure 6). Genetic susceptibility to the disease is clearly an important factor and, as the specific genetic components are identified, better insights into the mechanisms of this disease will be understood. The paucity of data on the basic characterization of innate immune response in PSC is surprising given its vital role in IBD, particularly Crohn's disease. Although intestinal lymphocytes appear to be recruited from the gut to the liver in PSC, why chronic inflammation and fibrosis occur only in a subset of IBD patients remains to be defined. In addition, an important question remains as to whether this same process holds true for the increasing percentage of PSC patients without IBD. Growing evidence supports a role for the direct action of bile during cholangiocytes damage, but it remains to be established whether this is an early or late event in the disease.
4. CLINICAL MANAGEMENT
As the pathogenesis for PSC remains elusive, targeted medical therapy for this disease has not yet been established. At this time, there are no proven medical therapies for PSC, and the goals of treatment are primarily symptom and complication management. Liver transplantation is the only effective treatment currently available for end-stage PSC at this time.
4.1. Medical Therapy
Ursodeoxycholic acid (UDCA) is a hydrophilic bile acid that is the most widely used and studied drug in randomized control trials for PSC. It is a well-established treatment for primary biliary cirrhosis, though its efficacy in PSC appears to be much less certain. Early randomized control trials examined UDCA therapy at low doses (13-15mg/kg/day) and found that there were improvements in biochemical data such as serum bilirubin, alkaline phosphatase, ALT and albumin. However, UDCA did not affect disease progression or development of complications (155). Small cross-sectional and retrospective studies have suggested that patients who receive UDCA may have lower rates for developing colonic neoplasia. However, prospective studies remain to be performed (156, 157). Other studies have also reported improvement in liver histology and cholangiography with UDCA treatment, though the data for this is limited (158). More recent studies have looked at higher doses of UDCA, but the results have been less than promising. Olsson, et al. performed a randomized study comparing high dose UDCA (17-23mg/kg/day) with placebo in 219 patients with a 5-year follow-up. They did not note any significant benefit in survival or prevention of cholangiocarcinoma, though their study was not sufficiently powered for statistical significance (159). A more recent study by Lindor, et al. randomized 150 patients to even higher doses of UDCA (28-30mg/kg/day) or placebo, and they also noted an improvement in liver tests, but overall, patients taking UDCA had worse clinical outcomes (160). The study was terminated early due to the high rate of the primary outcome in the treatment arm, namely cirrhosis, varices, cholangiocarcinoma, liver transplantation, and death. Thus, given this conflicting data, the American Association for the Study of Liver Disease currently recommends against the use of UDCA therapy in PSC patients while the European Association For the Study of the Liver believes that there is insufficient evidence to make a clear recommendation at this time (43, 161).
As noted above, several theories have been postulated for the development of PSC including autoimmune response, infection, cytokine activation, and bile acid transporter or ion channel abnormality. As such, agents targeting these systems have been investigated in small pilot and animal studies, though they have been largely unsuccessful. In particular, immunosuppressants such as budesonide, cyclosporin, tacrolimus, methotrexate,and mycophenolate mofetil have been studied in randomized trials, though none were found to prolong survival or time to transplantation, and all have serious side effects (1, 43, 162-168). TNF-α inhibitors including pentoxyfylline and etanercept, are another class of immunsuppressants which have been studied, but have not been found to be beneficial (169, 170).
Other agents including antifibrotics such as colchicine and D-Penicillamine have also been proposed, but these have not been clinically efficacious as well (171-173). Nicotine has been studied under the premise that PSC is less common in smokers. However, studies looking at both oral and transdermal administration of nicotine did not show effectiveness (174, 175). Finally, antibiotics have also been suggested with some promising results. A recent pilot study with 16 patients found that minocycline decreased alkaline phosphatase levels and Mayo risk scores though long-term effects were not established (176). In a randomized control trial of 80 patients, those receiving metronidazole combined with UDCA in comparison to UDCA and placebo were found to have lower levels of alkaline phosphatase and Mayo risk score in the study arm, though no significant difference in disease progression (177). Thus, the use of antibiotics for the treatment of PSC remains unclear, though there may be some benefit in chronic use for prevention of bacterial cholangitis (1, 43).
4.2. Management of PSC-Associated Complications
4.2.1. Pruritus
Pruritus is one of the most common symptoms of PSC and can be severely debilitating. For most patients, resin-binding agents such as cholestyramine or colestipol hydrochloride are efficacious as first line therapy (1, 48, 178). However, the etiology of pruritus is not thought to be secondary to retention of bile acids in the skin. Rather, it has been proposed to be a central process, possibly involving increased central opioidergic neurotransmission or activation of serotonergic pathways (179, 180). This may explain why all bile-acid sequestrants are not effective treatments. For example, a recent study examining colesevelam in 35 patients found that, although it decreased bile acid levels, there was no alleviation of pruritus (181). On the other hand, opioid antagonists such as naloxone or naltrexone, and selective serotonin reuptake inhibitors such as sertaline, have been shown to have some benefit (180, 182-184). Rifampin has also been found useful to treat pruritus, though the mechanism for this is unclear (185). Other agents that can also be considered include phenobarbital, anti-histamines, S-adenosylmethionine, ondanestron, steroids, and ultraviolet light (1, 179). Refractory cases should prompt investigation for a dominant stricture.
4.2.2. Dominant strictures
Approximately 30-40% of patients develop a dominant stricture defined as a stenosis of ≤ 1.5mm in the common bile duct or ≤ 1mm in the hepatic duct (43). Found to occur in nearly half of patients with PSC, dominant strictures can lead to jaundice and cholangitis (43, 186). Additionally, the presence of strictures raises concern for possible CCA, as this is a common finding in CCA. Of note, a recent study suggested that patients who develop dominant strictures have reduced transplant free survival (187). However, patients who have undergone endoscopic treatment for these stenoses have been found to have predicted survival greater than otherwise (188, 189). Although randomized, controlled trials have not documented a benefit of endoscopic intervention; treatment of dominant strictures is warranted and should be geared towards relieving biliary obstruction and sampling the stricture to evaluate for malignancy. Endoscopic or percutaneous balloon dilation with or without stenting and biliary sphincterotomy are the most common therapies currently performed on dominant strictures. Perioperative antibiotics are often administered as cholangitis can result from instrumentation. Other possible complications include pancreatitis, biliary tract damage or perforation, and hemorrhage (43). For those who fail endoscopic or percutaneous therapy, surgical options are also available, especially for noncirrhotic patients. In particular, hilar and extrahepatic strictures may be resected or a Roux Y hepaticojejunostomy performed (190, 191). This approach should be first line for patients in whom CCA is strongly suspected or previously confirmed.
Bacterial cholangitis frequently occurs in patients who have had a previous biliary surgical procedure and who have an obstructing dominant stricture. Bacterial cholangitis should be treated with broad-spectrum i.v. antibiotics, and drainage in the case of a dominant stricture. For patients with frequent episodes of bacterial cholangitis unresponsive to dilation of dominant strictures, prophylactic or on-demand therapy with ciprofloxacin, which achieves high biliary concentrations, is often effective.
4.2.3. Cholangiocarcinoma
CCA has been reported to occur in up to 30% of patients. More recent studies report a 10-year cumulative incidence of 7 -9% with the highest incidence within the first year of diagnosis (192-194). Risk factors for CCA include elevated serum bilirubin, variceal bleeding, proctocolectomy, duration of ulcerative colitis, and genetic variants in the NKG2D gene (22, 195). Cholangiocarcinoma carries a poor prognosis, and responds poorly to chemotherapy or radiation therapy. Most liver transplant programs consider cholangiocarcinoma associated with PSC to be an absolute or relative contraindication to liver transplantation (196). However, recent protocols involving stringent pre-transplantation screening and neoadjuvant chemotherapy have reported promising results (197, 198).
Distinguishing a benign stricture from CCA can be difficult. CA19-9 is often elevated in CCA, but it is also elevated in bacterial cholangitis. At a cut-off of 130 U/mL, the sensitivity and specificity are 79% and 98%, respectively (199). Image studies rarely detect CCA, but can be virtually diagnostic with typical features of delayed venous enhancement. Brush cytology has low sensitivity, ranging from 18-40%, but has very high specificity. The presence of polysomy by fluorescent in situ hybridization may increase the sensitivity. Positron emission tomography may have a role in the diagnosis of CCA in PSC but further studies are warranted (200-202). There is insufficient evidence to recommend routine screening but annual imaging and CA19-9 is often performed (43).
4.2.4. Metabolic diseases
Hepatic osteodystrophy should be screened for with bone density testing at diagnosis and every 2-3 years. Osteopenia can be treated with calcium (1.0-1.5 g) and vitamin D (1,000 IU), daily. Consideration must be given to administration of bisphosphonates for osteoporosis. Steatorrhea can be caused by a decrease in duodenal concentration of bile acids and thus a decrease in micellar formation, or concurrent conditions such as chronic pancreatitis and celiac disease. Fat-soluble vitamin deficiency (A, D, E, and K) can be related to steatorrhea, but levels of fat-soluble vitamins should be measured even in the absence of steatorrhea and deficiencies treated with replacement therapy.
4.2.5. Gallbladder disease
25% of PSC patients will develop gallstones, usually black pigment stones (203, 204). There is no association with disease stage or use of UDCA. PSC patients are at increased risk of gallbladder carcinoma as well as CCA, and should be screened annually with US(205). Cholecystectomy should be considered in any PSC patient with a gallbladder polyp or mass.
4.3 .Complications of cirrhosis
4.3.1. Peristomal varices
Peristomal varices are common in patients who have undergone a proctocolectomy for underlying inflammatory bowel disease and who have an ileal stoma (206). Bleeding from peristomal varices can be controlled by performing a surgical portosystemic shunt or placement of a transjugular intrahepatic portosystemic shunt. Complications of peristomal variceal bleeding can be prevented by performing an ileoanal anastomotic surgical procedure in patients with PSC who need a proctocolectomy.
4.3.2. Liver Transplantation
Liver transplantation is currently the treatment of choice for patients with end-stage PSC. Liver transplantation in patients with PSC is associated with patient survival rates of up to 90% at 1 year, and 85% at 5 years (43). Indications for liver transplantation are similar to those for other chronic liver diseases. Additional indications include intractable pruritus, recurrent cholangitis, and early cholangiocarcinoma. Recurrence of PSC occurs in up to 20-25% of patients after 5-10 years (207-213). However, the diagnosis of recurrent PSC is difficult because of lack of gold standard diagnostic criteria and potential confounding factors that can mimic PSC including chronic rejection, cytomegalovirus infection, and hepatic artery thrombosis.
5. SUMMARY AND PERSPECTIVE
PSC is an enigmatic inflammatory disease of the liver for which there is an enormous unmet medical need. Progress towards understanding the basis of the disease and new treatment approaches have been slow to emerge. However, with recent multi-institutional collaborative efforts, applications of new technologies, and trials of novel therapies, there is a glimmer of hope for acceleration of PSC discoveries. In the short term, ongoing genetic studies will conclusively identify the genetic variants responsible for known susceptibility loci and discover new PSC specific loci; immunologic studies will reveal the connection between intestinal and liver inflammation; and animal models will aid our understanding of the role of bile acid transport and the biliary epithelial cell in PSC. In the clinical arena, we should expect progress in clinical trials with increased collaboration using non-absorbable antibiotics, farnesoid X receptor agonists, and biologic immunomodulators. Additional needs include the development of a system to meaningfully classify this heterogeneous disease and biomarkers to quantify liver fibrosis and detect early stage cholangiocarcinoma.
6. REFERENCES
1. YM Lee and MM Kaplan: Management of primary sclerosing cholangitis. Am J Gastroenterol, 973, 528-34 (2002)
doi:10.1111/j.1572-0241.2002.05585.x
PMid:11922543
2. GR MacFaul and RW Chapman: Sclerosing cholangitis. Curr Opin Gastroenterol, 223, 288-93 (2006)
doi:10.1097/01.mog.0000218966.78558.67
PMid:16550044
3. P Portincasa, M Vacca, A Moschetta, M Petruzzelli, G Palasciano, KJ van Erpecum and GP van Berge-Henegouwen: Primary sclerosing cholangitis: updates in diagnosis and therapy. World J Gastroenterol, 111, 7-16 (2005)
4. J Bargen: Complications and sequelae of chronic ulcerative colitis. Ann Intern Med, 3, 335-352 (1929)
5. P Kimmelstiel, HL Large, Jr. and HD Verner: Liver damage in ulcerative colitis. Am J Pathol, 282, 259-89 (1952)
6. K Bambha, WR Kim, J Talwalkar, H Torgerson, JT Benson, TM Therneau, EV Loftus, Jr., BP Yawn, ER Dickson and LJ Melton, 3rd: Incidence, clinical spectrum, and outcomes of primary sclerosing cholangitis in a United States community. Gastroenterology, 1255, 1364-9 (2003)
doi:10.1016/j.gastro.2003.07.011
PMid:14598252
7. H Takikawa: Characteristics of primary sclerosing cholangitis in Japan. Hepatol Res, 37 Suppl 3, S470-3 (2007)
doi:10.1111/j.1872-034X.2007.00241.x
PMid:17931205
8. CA Aoki, CL Bowlus and ME Gershwin: The immunobiology of primary sclerosing cholangitis. Autoimmun Rev, 43, 137-43 (2005)
doi:10.1016/j.autrev.2004.09.003
PMid:15823499
9. U Broome and A Bergquist: Primary sclerosing cholangitis, inflammatory bowel disease, and colon cancer. Semin Liver Dis, 261, 31-41 (2006)
doi:10.1055/s-2006-933561
PMid:16496231
10. EV Loftus, Jr., GC Harewood, CG Loftus, WJ Tremaine, WS Harmsen, AR Zinsmeister, DA Jewell and WJ Sandborn: PSC-IBD: a unique form of inflammatory bowel disease associated with primary sclerosing cholangitis. Gut, 541, 91-6 (2005)
doi:10.1136/gut.2004.046615
PMid:15591511 PMCid:1774346
11. A Escorsell, A Pares, J Rodes, JA Solis-Herruzo, M Miras and E de la Morena: Epidemiology of primary sclerosing cholangitis in Spain. Spanish Association for the Study of the Liver. J Hepatol, 215, 787-91 (1994)
doi:10.1016/S0168-8278(94)80240-8
12. R Kochhar, MK Goenka, K Das, B Nagi, DK Bhasin, YK Chawla, K Vaiphei, K Singh and JB Dilawari: Primary sclerosing cholangitis: an experience from India. J Gastroenterol Hepatol, 115, 429-33 (1996)
doi:10.1111/j.1440-1746.1996.tb00286.x
PMid:8743914
13. L Okolicsanyi, L Fabris, S Viaggi, N Carulli, M Podda and G Ricci: Primary sclerosing cholangitis: clinical presentation, natural history and prognostic variables: an Italian multicentre study. The Italian PSC Study Group. Eur J Gastroenterol Hepatol, 87, 685-91 (1996)
14. CN Bernstein, JF Blanchard, P Rawsthorne and N Yu: The prevalence of extraintestinal diseases in inflammatory bowel disease: a population-based study. Am J Gastroenterol, 964, 1116-22 (2001)
doi:10.1111/j.1572-0241.2001.03756.x
PMid:11316157
15. KM Boberg, E Aadland, J Jahnsen, N Raknerud, M Stiris and H Bell: Incidence and prevalence of primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis in a Norwegian population. Scand J Gastroenterol, 331, 99-103 (1998)
16. GG Kaplan, KB Laupland, D Butzner, SJ Urbanski and SS Lee: The burden of large and small duct primary sclerosing cholangitis in adults and children: a population-based analysis. Am J Gastroenterol, 1025, 1042-9 (2007)
doi:10.1111/j.1572-0241.2007.01103.x
PMid:17313496
17. JG Kingham, N Kochar and MB Gravenor: Incidence, clinical patterns, and outcomes of primary sclerosing cholangitis in South Wales, United Kingdom. Gastroenterology, 1267, 1929-30 (2004)
doi:10.1053/j.gastro.2004.04.052
PMid:15188211
18. B Lindkvist, M Benito de Valle, B Gullberg and E Bjornsson: Incidence and prevalence of primary sclerosing cholangitis in a defined adult population in Sweden. Hepatology, 522, 571-7 (2010)
doi:10.1002/hep.23678
PMid:20683956
19. TR Card, M Solaymani-Dodaran and J West: Incidence and mortality of primary sclerosing cholangitis in the UK: a population-based cohort study. J Hepatol, 486, 939-44 (2008)
doi:10.1016/j.jhep.2008.02.017
PMid:18433916
20. KJ Hurlburt, BJ McMahon, H Deubner, B Hsu-Trawinski, JL Williams and KV Kowdley: Prevalence of autoimmune liver disease in Alaska Natives. Am J Gastroenterol, 979, 2402-7 (2002)
doi:10.1111/j.1572-0241.2002.06019.x
PMid:12358264
21. KM Boberg, A Bergquist, S Mitchell, A Pares, F Rosina, U Broome, R Chapman, O Fausa, T Egeland, G Rocca and E Schrumpf: Cholangiocarcinoma in primary sclerosing cholangitis: risk factors and clinical presentation. Scand J Gastroenterol, 3710, 1205-11 (2002)
doi:10.1080/003655202760373434
PMid:12408527
22. K Burak, P Angulo, TM Pasha, K Egan, J Petz and KD Lindor: Incidence and risk factors for cholangiocarcinoma in primary sclerosing cholangitis. Am J Gastroenterol, 993, 523-6 (2004)
doi:10.1111/j.1572-0241.2004.04067.x
PMid:15056096
23. C Penna, R Dozois, W Tremaine, W Sandborn, N LaRusso, C Schleck and D Ilstrup: Pouchitis after ileal pouch-anal anastomosis for ulcerative colitis occurs with increased frequency in patients with associated primary sclerosing cholangitis. Gut, 382, 234-9 (1996)
doi:10.1136/gut.38.2.234
PMid:8801203 PMCid:1383029
24. TH Karlsen, J Hampe, K Wiencke, E Schrumpf, E Thorsby, BA Lie, U Broome, S Schreiber and KM Boberg: Genetic polymorphisms associated with inflammatory bowel disease do not confer risk for primary sclerosing cholangitis. Am J Gastroenterol, 1021, 115-21 (2007)
doi:10.1111/j.1572-0241.2006.00928.x
PMid:17100974
25. S Saarinen, O Olerup and U Broome: Increased frequency of autoimmune diseases in patients with primary sclerosing cholangitis. Am J Gastroenterol, 9511, 3195-9 (2000)
doi:10.1111/j.1572-0241.2000.03292.x
PMid:11095341
26. JB Gross, Jr., J Ludwig, RH Wiesner, JT McCall and NF LaRusso: Abnormalities in tests of copper metabolism in primary sclerosing cholangitis. Gastroenterology, 892, 272-8 (1985)
27. HH Rasmussen, J Fallingborg, PB Mortensen, L Freund, U Tage-Jensen, V Kruse and SN Rasmussen: Primary sclerosing cholangitis in patients with ulcerative colitis. Scand J Gastroenterol, 279, 732-6 (1992)
doi:10.3109/00365529209011174
PMid:1411277
28. C Roozendaal, AW Van Milligen de Wit, EB Haagsma, G Horst, C Schwarze, HH Peter, JH Kleibeuker, JW Tervaert, PC Limburg and CG Kallenberg: Antineutrophil cytoplasmic antibodies in primary sclerosing cholangitis: defined specificities may be associated with distinct clinical features. Am J Med, 1055, 393-9 (1998)
doi:10.1016/S0002-9343(98)00294-0
29. R Tobias, JP Wright, RE Kottler, PC Bornman, SK Price, A Hatfield and IN Marks: Primary sclerosing cholangitis associated with inflammatory bowel disease in Cape Town, 1975 - 1981. S Afr Med J, 637, 229-35 (1983)
30. SK Lo, KA Fleming and RW Chapman: Prevalence of anti-neutrophil antibody in primary sclerosing cholangitis and ulcerative colitis using an alkaline phosphatase technique. Gut, 3310, 1370-5 (1992)
doi:10.1136/gut.33.10.1370
PMid:1446862 PMCid:1379606
31. S Lindgren, S Nilsson, L Nassberger, H Verbaan and J Wieslander: Anti-neutrophil cytoplasmic antibodies in patients with chronic liver diseases: prevalence, antigen specificity and predictive value for diagnosis of autoimmune liver disease. Swedish Internal Medicine Liver Club (SILK). J Gastroenterol Hepatol, 154, 437-42 (2000)
doi:10.1046/j.1440-1746.2000.02078.x
PMid:10824890
32. AH Mulder, G Horst, EB Haagsma, PC Limburg, JH Kleibeuker and CG Kallenberg: Prevalence and characterization of neutrophil cytoplasmic antibodies in autoimmune liver diseases. Hepatology, 173, 411-7 (1993)
doi:10.1002/hep.1840170310
PMid:8444414
33. F Seibold, D Slametschka, M Gregor and P Weber: Neutrophil autoantibodies: a genetic marker in primary sclerosing cholangitis and ulcerative colitis. Gastroenterology, 1072, 532-6 (1994)
34. P Angulo, JB Peter, ME Gershwin, CK DeSotel, Y Shoenfeld, AE Ahmed and KD Lindor: Serum autoantibodies in patients with primary sclerosing cholangitis. J Hepatol, 322, 182-7 (2000)
doi:10.1016/S0168-8278(00)80061-6
35. S Cullen and R Chapman: Primary sclerosing cholangitis. Autoimmun Rev, 26, 305-12 (2003)
doi:10.1016/S1568-9972(03)00030-2
36. L Zhang, JT Lewis, SC Abraham, TC Smyrk, S Leung, ST Chari, JJ Poterucha, CB Rosen, CM Lohse, JA Katzmann and TT Wu: IgG4+ plasma cell infiltrates in liver explants with primary sclerosing cholangitis. Am J Surg Pathol, 341, 88-94 (2010)
doi:10.1097/PAS.0b013e3181c6c09a
PMid:20035148
37. E Bjornsson, S Chari, M Silveira, A Gossard, N Takahashi, T Smyrk and K Lindor: Primary Sclerosing Cholangitis Associated with Elevated ImmunoglobulinG4: Clinical Characteristics and Response to Therapy. Am J Ther (2010)
38. M Dave, BJ Elmunzer, BA Dwamena and PD Higgins: Primary sclerosing cholangitis: meta-analysis of diagnostic performance of MR cholangiopancreatography. Radiology, 2562, 387-96 (2010)
doi:10.1148/radiol.10091953
PMid:20656832
39. C Weber, R Kuhlencordt, R Grotelueschen, U Wedegaertner, TL Ang, G Adam, N Soehendra and U Seitz: Magnetic resonance cholangiopancreatography in the diagnosis of primary sclerosing cholangitis. Endoscopy, 409, 739-45 (2008)
doi:10.1055/s-2008-1077509
PMid:18698533
40. KW Burak, P Angulo and KD Lindor: Is there a role for liver biopsy in primary sclerosing cholangitis? Am J Gastroenterol, 985, 1155-8 (2003)
doi:10.1111/j.1572-0241.2003.07401.x
PMid:12809842
41. J Ludwig, SS Barham, NF LaRusso, LR Elveback, RH Wiesner and JT McCall: Morphologic features of chronic hepatitis associated with primary sclerosing cholangitis and chronic ulcerative colitis. Hepatology, 16, 632-40 (1981)
doi:10.1002/hep.1840010612
PMid:7308996
42. J Ludwig, ER Dickson and GS McDonald: Staging of chronic nonsuppurative destructive cholangitis (syndrome of primary biliary cirrhosis). Virchows Arch A Pathol Anat Histol, 3792, 103-12 (1978)
doi:10.1007/BF00432479
43. R Chapman, J Fevery, A Kalloo, DM Nagorney, KM Boberg, B Shneider and GJ Gores: Diagnosis and management of primary sclerosing cholangitis. Hepatology, 512, 660-78 (2010)
44. P Angulo, Y Maor-Kendler and KD Lindor: Small-duct primary sclerosing cholangitis: a long-term follow-up study. Hepatology, 356, 1494-500 (2002)
doi:10.1053/jhep.2002.33202
PMid:12029635
45. E Bjornsson, R Olsson, A Bergquist, S Lindgren, B Braden, RW Chapman, KM Boberg and P Angulo: The natural history of small-duct primary sclerosing cholangitis. Gastroenterology, 1344, 975-80 (2008)
doi:10.1053/j.gastro.2008.01.042
PMid:18395078
46. GV Gregorio, B Portmann, J Karani, P Harrison, PT Donaldson, D Vergani and G Mieli-Vergani: Autoimmune hepatitis/sclerosing cholangitis overlap syndrome in childhood: a 16-year prospective study. Hepatology, 333, 544-53 (2001)
doi:10.1053/jhep.2001.22131
PMid:11230733
47. HR van Buuren, HJE van Hoogstraten, T Terkivatan, SW Schalm and FP Vleggaar: High prevalence of autoimmune hepatitis among patients with primary sclerosing cholangitis. J Hepatol, 334, 543-8 (2000)
doi:10.1034/j.1600-0641.2000.033004543.x
PMid:11059858
48. NF LaRusso, BL Shneider, D Black, GJ Gores, SP James, E Doo and JH Hoofnagle: Primary sclerosing cholangitis: summary of a workshop. Hepatology, 443, 746-64 (2006)
doi:10.1002/hep.21337
PMid:16941705
49. N Chandok, MG Silveira and KD Lindor: Comparing the simplified and international autoimmune hepatitis group criteria in primary sclerosing cholangitis. Gastroenterol Hepatol (N Y), 62, 108-12 (2010)
50. R Olsson, H Glaumann, S Almer, U Broome, B Lebrun, A Bergquist, E Bjornsson, H Prytz, A Danielsson and S Lindgren: High prevalence of small duct primary sclerosing cholangitis among patients with overlapping autoimmune hepatitis and primary sclerosing cholangitis. Eur J Intern Med, 202, 190-6 (2009)
doi:10.1016/j.ejim.2008.06.004
PMid:19327611
51. KM Boberg, T Egeland and E Schrumpf: Long-term effect of corticosteroid treatment in primary sclerosing cholangitis patients. Scand J Gastroenterol, 389, 991-5 (2003)
52. U Broome, R Olsson, L Loof, G Bodemar, R Hultcrantz, A Danielsson, H Prytz, H Sandberg-Gertzen, S Wallerstedt and G Lindberg: Natural history and prognostic factors in 305 Swedish patients with primary sclerosing cholangitis. Gut, 384, 610-5 (1996)
doi:10.1136/gut.38.4.610
PMid:8707097 PMCid:1383124
53. JM Farrant, KM Hayllar, ML Wilkinson, J Karani, BC Portmann, D Westaby and R Williams: Natural history and prognostic variables in primary sclerosing cholangitis. Gastroenterology, 1006, 1710-7 (1991)
54. CY Ponsioen, SM Vrouenraets, W Prawirodirdjo, R Rajaram, EA Rauws, CJ Mulder, JB Reitsma, SH Heisterkamp and GN Tytgat: Natural history of primary sclerosing cholangitis and prognostic value of cholangiography in a Dutch population. Gut, 514, 562-6 (2002)
doi:10.1136/gut.51.4.562
PMid:12235081 PMCid:1773389
55. WR Kim, TM Therneau, RH Wiesner, JJ Poterucha, JT Benson, M Malinchoc, NF LaRusso, KD Lindor and ER Dickson: A revised natural history model for primary sclerosing cholangitis. Mayo Clin Proc, 757, 688-94 (2000)
doi:10.4065/75.7.688
PMid:10907383
56. CY Ponsioen, JB Reitsma, KM Boberg, L Aabakken, EA Rauws and E Schrumpf: Validation of a cholangiographic prognostic model in primary sclerosing cholangitis. Endoscopy, 429, 742-7 (2010)
doi:10.1055/s-0030-1255527
PMid:20623444
57. JR Cangemi, RH Wiesner, SJ Beaver, J Ludwig, RL MacCarty, RR Dozois, AR Zinsmeister and NF LaRusso: Effect of proctocolectomy for chronic ulcerative colitis on the natural history of primary sclerosing cholangitis. Gastroenterology, 963, 790-4 (1989)
58. TH Florin, N Pandeya and GL Radford-Smith: Epidemiology of appendicectomy in primary sclerosing cholangitis and ulcerative colitis: its influence on the clinical behaviour of these diseases. Gut, 537, 973-9 (2004)
doi:10.1136/gut.2003.036483
PMid:15194646 PMCid:1774125
59. SA Mitchell, M Thyssen, TR Orchard, DP Jewell, KA Fleming and RW Chapman: Cigarette smoking, appendectomy, and tonsillectomy as risk factors for the development of primary sclerosing cholangitis: a case control study. Gut, 514, 567-73 (2002)
doi:10.1136/gut.51.4.567
PMid:12235082 PMCid:1773401
60. KJ van Erpecum, SJ Smits, PC van de Meeberg, FH Linn, FH Wolfhagen, GP vanBerge-Henegouwen and A Algra: Risk of primary sclerosing cholangitis is associated with nonsmoking behavior. Gastroenterology, 1105, 1503-6 (1996)
doi:10.1053/gast.1996.v110.pm8613056
PMid:8613056
61. EV Loftus, Jr., WJ Sandborn, WJ Tremaine, DW Mahoney, AR Zinsmeister, KP Offord and LJ Melton, 3rd: Primary sclerosing cholangitis is associated with nonsmoking: a case-control study. Gastroenterology, 1105, 1496-502 (1996)
doi:10.1053/gast.1996.v110.pm8613055
PMid:8613055
62. RD Cohen and SB Hanauer: Protection from primary sclerosing cholangitis: smoke trails of just coattails? Gastroenterology, 1105, 1658-62 (1996)
doi:10.1053/gast.1996.v110.agast961658
PMid:8613079
63. CL Bowlus, CS Li, TH Karlsen, BA Lie and C Selmi: Primary sclerosing cholangitis in genetically diverse populations listed for liver transplantation: unique clinical and human leukocyte antigen associations. Liver Transpl, 1611, 1324-30 (2010)
doi:10.1002/lt.22161
PMid:21031548
64. A Bergquist, G Lindberg, S Saarinen and U Broome: Increased prevalence of primary sclerosing cholangitis among first-degree relatives. J Hepatol, 422, 252-6 (2005)
doi:10.1016/j.jhep.2004.10.011
PMid:15664252
65. A Bergquist, SM Montgomery, S Bahmanyar, R Olsson, A Danielsson, S Lindgren, H Prytz, R Hultcrantz, LA Loof, H Sandberg-Gertzen, S Almer, J Askling, A Ehlin and A Ekbom: Increased risk of primary sclerosing cholangitis and ulcerative colitis in first-degree relatives of patients with primary sclerosing cholangitis. Clin Gastroenterol Hepatol, 68, 939-43 (2008)
doi:10.1016/j.cgh.2008.03.016
PMid:18674735
66. X Yang, SN Cullen, JH Li, RW Chapman and DP Jewell: Susceptibility to primary sclerosing cholangitis is associated with polymorphisms of intercellular adhesion molecule-1. J Hepatol, 403, 375-9 (2004)
doi:10.1016/j.jhep.2003.11.009
PMid:15123348
67. CL Bowlus, TH Karlsen, U Broome, E Thorsby, M Vatn, E Schrumpf, BA Lie and KM Boberg: Analysis of MAdCAM-1 and ICAM-1 polymorphisms in 365 Scandinavian patients with primary sclerosing cholangitis. J Hepatol, 455, 704-10 (2006)
doi:10.1016/j.jhep.2006.03.012
PMid:16750586
68. TH Karlsen, A Franke, E Melum, A Kaser, JR Hov, T Balschun, BA Lie, A Bergquist, C Schramm, TJ Weismuller, D Gotthardt, C Rust, EE Philipp, T Fritz, L Henckaerts, RK Weersma, P Stokkers, CY Ponsioen, C Wijmenga, M Sterneck, M Nothnagel, J Hampe, A Teufel, H Runz, P Rosenstiel, A Stiehl, S Vermeire, U Beuers, MP Manns, E Schrumpf, KM Boberg and S Schreiber: Genome-wide association analysis in primary sclerosing cholangitis. Gastroenterology, 1383, 1102-11 (2010)
doi:10.1053/j.gastro.2009.11.046
PMid:19944697
69. E Melum, A Franke, C Schramm, TJ Weismuller, DN Gotthardt, FA Offner, BD Juran, JK Laerdahl, V Labi, E Bjornsson, RK Weersma, L Henckaerts, A Teufel, C Rust, E Ellinghaus, T Balschun, KM Boberg, D Ellinghaus, A Bergquist, P Sauer, E Ryu, JR Hov, J Wedemeyer, B Lindkvist, M Wittig, RJ Porte, K Holm, C Gieger, HE Wichmann, P Stokkers, CY Ponsioen, H Runz, A Stiehl, C Wijmenga, M Sterneck, S Vermeire, U Beuers, A Villunger, E Schrumpf, KN Lazaridis, MP Manns, S Schreiber and TH Karlsen: Genome-wide association analysis in primary sclerosing cholangitis identifies two non-HLA susceptibility loci. Nat Genet, 431, 17-9 (2011)
doi:10.1038/ng.728
PMid:21151127
70. E Schrumpf, O Fausa, O Forre, JH Dobloug, S Ritland and E Thorsby: HLA antigens and immunoregulatory T cells in ulcerative colitis associated with hepatobiliary disease. Scand J Gastroenterol, 172, 187-91 (1982)
doi:10.3109/00365528209182038
PMid:6982501
71. RW Chapman, Z Varghese, R Gaul, G Patel, N Kokinon and S Sherlock: Association of primary sclerosing cholangitis with HLA-B8. Gut, 241, 38-41 (1983)
doi:10.1136/gut.24.1.38
PMid:6600227 PMCid:1419910
72. JM Farrant, DG Doherty, PT Donaldson, RW Vaughan, KM Hayllar, KI Welsh, AL Eddleston and R Williams: Amino acid substitutions at position 38 of the DR beta polypeptide confer susceptibility to and protection from primary sclerosing cholangitis. Hepatology, 162, 390-5 (1992)
doi:10.1002/hep.1840160217
PMid:1639348
73. A Spurkland, S Saarinen, KM Boberg, S Mitchell, U Broome, L Caballeria, E Ciusani, R Chapman, G Ercilla, O Fausa, I Knutsen, A Pares, F Rosina, O Olerup, E Thorsby and E Schrumpf: HLA class II haplotypes in primary sclerosing cholangitis patients from five European populations. Tissue Antigens, 535, 459-69 (1999)
doi:10.1034/j.1399-0039.1999.530502.x
PMid:10372541
74. TH Karlsen, KM Boberg, M Vatn, A Bergquist, J Hampe, E Schrumpf, E Thorsby, S Schreiber and BA Lie: Different HLA class II associations in ulcerative colitis patients with and without primary sclerosing cholangitis. Genes Immun, 83, 275-8 (2007)
doi:10.1038/sj.gene.6364377
PMid:17301827
75. A Franke, T Balschun, TH Karlsen, J Sventoraityte, S Nikolaus, G Mayr, FS Domingues, M Albrecht, M Nothnagel, D Ellinghaus, C Sina, CM Onnie, RK Weersma, PC Stokkers, C Wijmenga, M Gazouli, D Strachan, WL McArdle, S Vermeire, P Rutgeerts, P Rosenstiel, M Krawczak, MH Vatn, CG Mathew and S Schreiber: Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility. Nat Genet, 4011, 1319-23 (2008)
doi:10.1038/ng.221
PMid:18836448
76. JR Oksenberg, LF Barcellos, BA Cree, SE Baranzini, TL Bugawan, O Khan, RR Lincoln, A Swerdlin, E Mignot, L Lin, D Goodin, HA Erlich, S Schmidt, G Thomson, DE Reich, MA Pericak-Vance, JL Haines and SL Hauser: Mapping multiple sclerosis susceptibility to the HLA-DR locus in African Americans. Am J Hum Genet, 741, 160-7 (2004)
doi:10.1086/380997
PMid:14669136
77. K Wiencke, A Spurkland, E Schrumpf and KM Boberg: Primary sclerosing cholangitis is associated to an extended B8-DR3 haplotype including particular MICA and MICB alleles. Hepatology, 344 Pt 1, 625-30 (2001)
doi:10.1053/jhep.2001.27543
PMid:11584356
78. S Norris, E Kondeatis, R Collins, J Satsangi, M Clare, R Chapman, H Stephens, P Harrison, R Vaughan and P Donaldson: Mapping MHC-encoded susceptibility and resistance in primary sclerosing cholangitis: the role of MICA polymorphism. Gastroenterology, 1206, 1475-82 (2001)
doi:10.1053/gast.2001.24041
PMid:11313318
79. W Bernal, M Moloney, J Underhill and PT Donaldson: Association of tumor necrosis factor polymorphism with primary sclerosing cholangitis. J Hepatol, 302, 237-41 (1999)
doi:10.1016/S0168-8278(99)80068-3
80. SA Mitchell, J Grove, A Spurkland, KM Boberg, KA Fleming, CP Day, E Schrumpf and RW Chapman: Association of the tumour necrosis factor alpha -308 but not the interleukin 10 -627 promoter polymorphism with genetic susceptibility to primary sclerosing cholangitis. Gut, 492, 288-94 (2001)
doi:10.1136/gut.49.2.288
PMid:11454808 PMCid:1728404
81. TH Karlsen, KM Boberg, M Olsson, JY Sun, D Senitzer, A Bergquist, E Schrumpf, E Thorsby and BA Lie: Particular genetic variants of ligands for natural killer cell receptors may contribute to the HLA associated risk of primary sclerosing cholangitis. J Hepatol, 465, 899-906 (2007)
doi:10.1016/j.jhep.2007.01.032
PMid:17383044
82. SI Khakoo and M Carrington: KIR and disease: a model system or system of models? Immunol Rev, 214, 186-201 (2006)
doi:10.1111/j.1600-065X.2006.00459.x
PMid:17100885
83. JR Hov, A Lleo, C Selmi, B Woldseth, L Fabris, M Strazzabosco, TH Karlsen and P Invernizzi: Genetic associations in Italian primary sclerosing cholangitis: heterogeneity across Europe defines a critical role for HLA-C. J Hepatol, 525, 712-7 (2010)
doi:10.1016/j.jhep.2009.11.029
PMid:20347497
84. P Gaj, A Habior, M Mikula and J Ostrowski: Lack of evidence for association of primary sclerosing cholangitis and primary biliary cirrhosis with risk alleles for Crohn's disease in Polish patients. BMC Med Genet, 9, 81 (2008)
doi:10.1186/1471-2350-9-81
PMid:18715515 PMCid:2535589
85. MC Eike, GB Nordang, TH Karlsen, KM Boberg, MH Vatn, K Dahl-Jorgensen, KS Ronningen, G Joner, B Flato, A Bergquist, E Thorsby, O Forre, TK Kvien, DE Undlien and BA Lie: The FCRL3 -169T>C polymorphism is associated with rheumatoid arthritis and shows suggestive evidence of involvement with juvenile idiopathic arthritis in a Scandinavian panel of autoimmune diseases. Ann Rheum Dis, 679, 1287-91 (2008)
86. A Franke, T Balschun, TH Karlsen, J Hedderich, S May, T Lu, D Schuldt, S Nikolaus, P Rosenstiel, M Krawczak and S Schreiber: Replication of signals from recent studies of Crohn's disease identifies previously unknown disease loci for ulcerative colitis. Nat Genet, 406, 713-5 (2008)
doi:10.1038/ng.148
PMid:18438405
87. SA Fisher, M Tremelling, CA Anderson, R Gwilliam, S Bumpstead, NJ Prescott, ER Nimmo, D Massey, C Berzuini, C Johnson, JC Barrett, FR Cummings, H Drummond, CW Lees, CM Onnie, CE Hanson, K Blaszczyk, M Inouye, P Ewels, R Ravindrarajah, A Keniry, S Hunt, M Carter, N Watkins, W Ouwehand, CM Lewis, L Cardon, A Lobo, A Forbes, J Sanderson, DP Jewell, JC Mansfield, P Deloukas, CG Mathew, M Parkes and J Satsangi: Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn's disease. Nat Genet, 406, 710-2 (2008)
doi:10.1038/ng.145
PMid:18438406 PMCid:2719289
88. RK Weersma, PC Stokkers, I Cleynen, SC Wolfkamp, L Henckaerts, S Schreiber, G Dijkstra, A Franke, IM Nolte, P Rutgeerts, C Wijmenga and S Vermeire: Confirmation of multiple Crohn's disease susceptibility loci in a large Dutch-Belgian cohort. Am J Gastroenterol, 1043, 630-8 (2009)
doi:10.1038/ajg.2008.112
PMid:19174780
89. V Keitel, M Donner, S Winandy, R Kubitz and D Haussinger: Expression and function of the bile acid receptor TGR5 in Kupffer cells. Biochem Biophys Res Commun, 3721, 78-84 (2008)
doi:10.1016/j.bbrc.2008.04.171
PMid:18468513
90. Y Kawamata, R Fujii, M Hosoya, M Harada, H Yoshida, M Miwa, S Fukusumi, Y Habata, T Itoh, Y Shintani, S Hinuma, Y Fujisawa and M Fujino: A G protein-coupled receptor responsive to bile acids. J Biol Chem, 27811, 9435-40 (2003)
doi:10.1074/jbc.M209706200
PMid:12524422
91. V Keitel, K Cupisti, C Ullmer, WT Knoefel, R Kubitz and D Haussinger: The membrane-bound bile acid receptor TGR5 is localized in the epithelium of human gallbladders. Hepatology, 503, 861-70 (2009)
doi:10.1002/hep.23032
PMid:19582812
92. L Henckaerts, M Jaspers, W Van Steenbergen, L Vliegen, J Fevery, H Nuytten, T Roskams, P Rutgeerts, JJ Cassiman, S Vermeire and H Cuppens: Cystic fibrosis transmembrane conductance regulator gene polymorphisms in patients with primary sclerosing cholangitis. J Hepatol, 501, 150-7 (2009)
doi:10.1016/j.jhep.2008.07.033
PMid:18992954
93. PG Blanco, MM Zaman, O Junaidi, S Sheth, RK Yantiss, IA Nasser and SD Freedman: Induction of colitis in cftr-/- mice results in bile duct injury. Am J Physiol Gastrointest Liver Physiol, 2872, G491-6 (2004)
doi:10.1152/ajpgi.00452.2003
PMid:15064232
94. S Sheth, JC Shea, MD Bishop, S Chopra, MM Regan, E Malmberg, C Walker, R Ricci, LC Tsui, PR Durie, J Zielenski and SD Freedman: Increased prevalence of CFTR mutations and variants and decreased chloride secretion in primary sclerosing cholangitis. Hum Genet, 1133, 286-92 (2003)
95. E Girodon, D Sternberg, O Chazouilleres, C Cazeneuve, D Huot, Y Calmus, R Poupon, M Goossens and C Housset: Cystic fibrosis transmembrane conductance regulator (CFTR) gene defects in patients with primary sclerosing cholangitis. J Hepatol, 372, 192-7 (2002)
doi:10.1016/S0168-8278(02)00161-7
96. JR Hov, V Keitel, JK Laerdahl, L Spomer, E Ellinghaus, A ElSharawy, E Melum, KM Boberg, T Manke, T Balschun, C Schramm, A Bergquist, T Weismuller, D Gotthardt, C Rust, L Henckaerts, CM Onnie, RK Weersma, M Sterneck, A Teufel, H Runz, A Stiehl, CY Ponsioen, C Wijmenga, MH Vatn, PC Stokkers, S Vermeire, CG Mathew, BA Lie, U Beuers, MP Manns, S Schreiber, E Schrumpf, D Haussinger, A Franke and TH Karlsen: Mutational characterization of the bile acid receptor TGR5 in primary sclerosing cholangitis. PLoS One, 58, e12403 (2010)
doi:10.1371/journal.pone.0012403
PMid:20811628 PMCid:2928275
97. SW Chan, CJ Lim, L Chen, YF Chong, C Huang, H Song and W Hong: The hippo pathway in biological control and cancer development. J Cell Physiol (2010)
98. YQ Zhou, YQ Chen, JH Fisher and MH Wang: Activation of the RON receptor tyrosine kinase by macrophage-stimulating protein inhibits inducible cyclooxygenase-2 expression in murine macrophages. J Biol Chem, 27741, 38104-10 (2002)
doi:10.1074/jbc.M206167200
PMid:12177064
99. M Raab, H Wang, Y Lu, X Smith, Z Wu, K Strebhardt, JE Ladbury and CE Rudd: T cell receptor "inside-out" pathway via signaling module SKAP1-RapL regulates T cell motility and interactions in lymph nodes. Immunity, 324, 541-56 (2010)
doi:10.1016/j.immuni.2010.03.007
PMid:20346707
100. K Katagiri, T Katakai, Y Ebisuno, Y Ueda, T Okada and T Kinashi: Mst1 controls lymphocyte trafficking and interstitial motility within lymph nodes. EMBO J, 289, 1319-31 (2009)
doi:10.1038/emboj.2009.82
PMid:19339990 PMCid:2683056
101. P Goyette, C Lefebvre, A Ng, SR Brant, JH Cho, RH Duerr, MS Silverberg, KD Taylor, A Latiano, G Aumais, C Deslandres, G Jobin, V Annese, MJ Daly, RJ Xavier and JD Rioux: Gene-centric association mapping of chromosome 3p implicates MST1 in IBD pathogenesis. Mucosal Immunol, 12, 131-8 (2008)
doi:10.1038/mi.2007.15
PMid:19079170
102. ME Himmel, G Hardenberg, CA Piccirillo, TS Steiner and MK Levings: The role of T-regulatory cells and Toll-like receptors in the pathogenesis of human inflammatory bowel disease. Immunology, 1252, 145-53 (2008)
doi:10.1111/j.1365-2567.2008.02939.x
PMid:18798918 PMCid:2561137
103. J Hampe, A Franke, P Rosenstiel, A Till, M Teuber, K Huse, M Albrecht, G Mayr, FM De La Vega, J Briggs, S Gunther, NJ Prescott, CM Onnie, R Hasler, B Sipos, UR Folsch, T Lengauer, M Platzer, CG Mathew, M Krawczak and S Schreiber: A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet, 392, 207-11 (2007)
doi:10.1038/ng1954
PMid:17200669
104. Y Ogura, DK Bonen, N Inohara, DL Nicolae, FF Chen, R Ramos, H Britton, T Moran, R Karaliuskas, RH Duerr, JP Achkar, SR Brant, TM Bayless, BS Kirschner, SB Hanauer, G Nunez and JH Cho: A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature, 4116837, 603-6 (2001)
doi:10.1038/35079114
PMid:11385577
105. JP Hugot, M Chamaillard, H Zouali, S Lesage, JP Cezard, J Belaiche, S Almer, C Tysk, CA O'Morain, M Gassull, V Binder, Y Finkel, A Cortot, R Modigliani, P Laurent-Puig, C Gower-Rousseau, J Macry, JF Colombel, M Sahbatou and G Thomas: Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature, 4116837, 599-603 (2001)
doi:10.1038/35079107
PMid:11385576
106. CA O'Mahony and JM Vierling: Etiopathogenesis of primary sclerosing cholangitis. Semin Liver Dis, 261, 3-21 (2006)
doi:10.1055/s-2006-933559
PMid:16496229
107. E Seki and DA Brenner: Toll-like receptors and adaptor molecules in liver disease: update. Hepatology, 481, 322-35 (2008)
doi:10.1002/hep.22306
PMid:18506843
108. A Karrar, U Broome, T Sodergren, M Jaksch, A Bergquist, M Bjornstedt and S Sumitran-Holgersson: Biliary epithelial cell antibodies link adaptive and innate immune responses in primary sclerosing cholangitis. Gastroenterology, 1324, 1504-14 (2007)
doi:10.1053/j.gastro.2007.01.039
PMid:17408653
109. RG Cameron, LM Blendis and MG Neuman: Accumulation of macrophages in primary sclerosing cholangitis. Clin Biochem, 343, 195-201 (2001)
doi:10.1016/S0009-9120(01)00215-6
110. CT Wu, JP Eiserich, AA Ansari, RL Coppel, S Balasubramanian, CL Bowlus, ME Gershwin and J Van De Water: Myeloperoxidase-positive inflammatory cells participate in bile duct damage in primary biliary cirrhosis through nitric oxide-mediated reactions. Hepatology, 384, 1018-25 (2003)
111. K Tsuneyama, K Harada, N Kono, K Hiramatsu, Y Zen, Y Sudo, ME Gershwin, M Ikemoto, H Arai and Y Nakanuma: Scavenger cells with gram-positive bacterial lipoteichoic acid infiltrate around the damaged interlobular bile ducts of primary biliary cirrhosis. J Hepatol, 352, 156-63 (2001)
doi:10.1016/S0168-8278(01)00084-8
112. CH Hobson, TJ Butt, DM Ferry, J Hunter, VS Chadwick and MF Broom: Enterohepatic circulation of bacterial chemotactic peptide in rats with experimental colitis. Gastroenterology, 944, 1006-13 (1988)
113. RP Anderson, TJ Butt and VS Chadwick: Hepatobiliary excretion of bacterial formyl-methionyl peptides in rat. Structure activity studies. Dig Dis Sci, 372, 248-56 (1992)
doi:10.1007/BF01308179
PMid:1735343
114. CH Hobson, EC Roberts, MF Broom, DM Mellor, RM Sherriff and VS Chadwick: Radio-immunoassay for formyl methionyl leucyl phenylalanine. I. Development and application to assessment of chemotactic peptide production by enteric bacteria. J Gastroenterol Hepatol, 51, 32-7 (1990)
doi:10.1111/j.1440-1746.1990.tb01765.x
PMid:2129421
115. S Yamada, M Ishii, N Kisara, R Nagatomi and T Toyota: Macrophages are essential for lymphocyte infiltration in formyl peptide-induced cholangitis in rat liver. Liver, 193, 253-8 (1999)
doi:10.1111/j.1478-3231.1999.tb00043.x
116. S Yamada, M Ishii, LS Liang, T Yamamoto and T Toyota: Small duct cholangitis induced by N-formyl L-methionine L-leucine L-tyrosine in rats. J Gastroenterol, 295, 631-6 (1994)
doi:10.1007/BF02365447
PMid:8000512
117. SN Lichtman, RB Sartor, J Keku and JH Schwab: Hepatic inflammation in rats with experimental small intestinal bacterial overgrowth. Gastroenterology, 982, 414-23 (1990)
118. SN Lichtman, J Keku, JH Schwab and RB Sartor: Hepatic injury associated with small bowel bacterial overgrowth in rats is prevented by metronidazole and tetracycline. Gastroenterology, 1002, 513-9 (1991)
119. SN Lichtman, EE Okoruwa, J Keku, JH Schwab and RB Sartor: Degradation of endogenous bacterial cell wall polymers by the muralytic enzyme mutanolysin prevents hepatobiliary injury in genetically susceptible rats with experimental intestinal bacterial overgrowth. J Clin Invest, 904, 1313-22 (1992)
doi:10.1172/JCI115996
PMid:1401067 PMCid:443175
120. E Bjornsson, A Cederborg, A Akvist, M Simren, PO Stotzer and I Bjarnason: Intestinal permeability and bacterial growth of the small bowel in patients with primary sclerosing cholangitis. Scand J Gastroenterol, 409, 1090-4 (2005)
doi:10.1080/00365520510023288
121. CY Ponsioen, J Defoer, FJ Ten Kate, GJ Weverling, GN Tytgat, Y Pannekoek and PM Wertheim-Dillen: A survey of infectious agents as risk factors for primary sclerosing cholangitis: are Chlamydia species involved? Eur J Gastroenterol Hepatol, 146, 641-8 (2002)
doi:10.1097/00042737-200206000-00009
122. AM Krasinskas, Y Yao, P Randhawa, MP Dore and AR Sepulveda: Helicobacter pylori may play a contributory role in the pathogenesis of primary sclerosing cholangitis. Dig Dis Sci, 529, 2265-70 (2007)
doi:10.1007/s10620-007-9803-7
PMid:17393314
123. SY Boomkens, S de Rave, RG Pot, HF Egberink, LC Penning, J Rothuizen, PE Zondervan and JG Kusters: The role of Helicobacter spp. in the pathogenesis of primary biliary cirrhosis and primary sclerosing cholangitis. FEMS Immunol Med Microbiol, 442, 221-5 (2005)
doi:10.1016/j.femsim.2004.11.002
124. RW Leong and JJ Sung: Review article: Helicobacter species and hepatobiliary diseases. Aliment Pharmacol Ther, 166, 1037-45 (2002)
doi:10.1046/j.1365-2036.2002.01282.x
125. J Pohl, A Ring, W Stremmel and A Stiehl: The role of dominant stenoses in bacterial infections of bile ducts in primary sclerosing cholangitis. Eur J Gastroenterol Hepatol, 181, 69-74 (2006)
doi:10.1097/00042737-200601000-00012
126. CA Aoki, K Dawson, TP Kenny, ME Gershwin and CL Bowlus: Gene expression by PBMC in primary sclerosing cholangitis: evidence for dysregulation of immune mediated genes. Clin Dev Immunol, 132-4, 265-71 (2006)
doi:10.1080/17402520600800085
PMid:17162367 PMCid:2270783
127. CM Milner, VA Higman and AJ Day: TSG-6: a pluripotent inflammatory mediator? Biochem Soc Trans, 34Pt 3, 446-50 (2006)
128. R Chapman and S Cullen: Etiopathogenesis of primary sclerosing cholangitis. World J Gastroenterol, 1421, 3350-9 (2008)
doi:10.3748/wjg.14.3350
PMid:18528932 PMCid:2716589
129. AJ Grant, PF Lalor, M Salmi, S Jalkanen and DH Adams: Homing of mucosal lymphocytes to the liver in the pathogenesis of hepatic complications of inflammatory bowel disease. Lancet, 3599301, 150-7 (2002)
doi:10.1016/S0140-6736(02)07374-9
130. B Eksteen, JR Mora, EL Haughton, NC Henderson, L Lee-Turner, EJ Villablanca, SM Curbishley, AI Aspinall, UH von Andrian and DH Adams: Gut homing receptors on CD8 T-cells ARE retinoic acid dependent and not maintained by Liver dendritic or stellate cells. Gastroenterology (2009)
131. B Eksteen, A Miles, SM Curbishley, C Tselepis, AJ Grant, LS Walker and DH Adams: Epithelial inflammation is associated with CCL28 production and the recruitment of regulatory T cells expressing CCR10. J Immunol, 1771, 593-603 (2006)
132. B Eksteen, AJ Grant, A Miles, SM Curbishley, PF Lalor, SG Hubscher, M Briskin, M Salmon and DH Adams: Hepatic endothelial CCL25 mediates the recruitment of CCR9+ gut-homing lymphocytes to the liver in primary sclerosing cholangitis. J Exp Med, 20011, 1511-7 (2004)
doi:10.1084/jem.20041035
PMid:15557349 PMCid:2211943
133. AJ Grant, S Goddard, J Ahmed-Choudhury, G Reynolds, DG Jackson, M Briskin, L Wu, SG Hubscher and DH Adams: Hepatic expression of secondary lymphoid chemokine (CCL21) promotes the development of portal-associated lymphoid tissue in chronic inflammatory liver disease. Am J Pathol, 1604, 1445-55 (2002)
doi:10.1016/S0002-9440(10)62570-9
134. AJ Grant, PF Lalor, SG Hubscher, M Briskin and DH Adams: MAdCAM-1 expressed in chronic inflammatory liver disease supports mucosal lymphocyte adhesion to hepatic endothelium (MAdCAM-1 in chronic inflammatory liver disease). Hepatology, 335, 1065-72 (2001)
doi:10.1053/jhep.2001.24231
PMid:11343233
135. R Kurkijarvi, DH Adams, R Leino, T Mottonen, S Jalkanen and M Salmi: Circulating form of human vascular adhesion protein-1 (VAP-1): increased serum levels in inflammatory liver diseases. J Immunol, 1613, 1549-57 (1998)
136. YH Oo, CJ Weston, PF Lalor, SM Curbishley, DR Withers, GM Reynolds, S Shetty, J Harki, JC Shaw, B Eksteen, SG Hubscher, LS Walker and DH Adams: Distinct roles for CCR4 and CXCR3 in the recruitment and positioning of regulatory T cells in the inflamed human liver. J Immunol, 1846, 2886-98 (2010)
doi:10.4049/jimmunol.0901216
PMid:20164417
137. YH Oo and DH Adams: The role of chemokines in the recruitment of lymphocytes to the liver. J Autoimmun, 341, 45-54 (2010)
doi:10.1016/j.jaut.2009.07.011
PMid:19744827
138. AT Borchers, S Shimoda, C Bowlus, CL Keen and ME Gershwin: Lymphocyte recruitment and homing to the liver in primary biliary cirrhosis and primary sclerosing cholangitis. Semin Immunopathol, 313, 309-22 (2009)
doi:10.1007/s00281-009-0167-2
PMid:19533132 PMCid:2758172
139. KJ Hillan, KE Hagler, RN MacSween, AM Ryan, ME Renz, HH Chiu, RK Ferrier, GL Bird, AP Dhillon, LD Ferrell and S Fong: Expression of the mucosal vascular addressin, MAdCAM-1, in inflammatory liver disease. Liver, 196, 509-18 (1999)
doi:10.1111/j.1478-3231.1999.tb00084.x
140. E Patsenker, Y Popov, F Stickel, A Jonczyk, SL Goodman and D Schuppan: Inhibition of integrin alphavbeta6 on cholangiocytes blocks transforming growth factor-beta activation and retards biliary fibrosis progression. Gastroenterology, 1352, 660-70 (2008)
doi:10.1053/j.gastro.2008.04.009
PMid:18538673
141. M Trauner, P Fickert, E Halilbasic and T Moustafa: Lessons from the toxic bile concept for the pathogenesis and treatment of cholestatic liver diseases. Wien Med Wochenschr, 15819-20, 542-8 (2008)
doi:10.1007/s10354-008-0592-1
PMid:18998069
142. P Fickert, G Zollner, A Fuchsbichler, C Stumptner, AH Weiglein, F Lammert, HU Marschall, O Tsybrovskyy, K Zatloukal, H Denk and M Trauner: Ursodeoxycholic acid aggravates bile infarcts in bile duct-ligated and Mdr2 knockout mice via disruption of cholangioles. Gastroenterology, 1234, 1238-51 (2002)
doi:10.1053/gast.2002.35948
PMid:12360485
143. Y Popov, E Patsenker, P Fickert, M Trauner and D Schuppan: Mdr2 (Abcb4)-/- mice spontaneously develop severe biliary fibrosis via massive dysregulation of pro- and antifibrogenic genes. J Hepatol, 436, 1045-54 (2005)
doi:10.1016/j.jhep.2005.06.025
PMid:16223543
144. J Jahnel, P Fickert, C Langner, C Hogenauer, D Silbert, J Gumhold, A Fuchsbichler and M Trauner: Impact of experimental colitis on hepatobiliary transporter expression and bile duct injury in mice. Liver Int, 299, 1316-25 (2009)
doi:10.1111/j.1478-3231.2009.02044.x
PMid:19558576
145. P Fickert, A Fuchsbichler, M Wagner, G Zollner, A Kaser, H Tilg, R Krause, F Lammert, C Langner, K Zatloukal, HU Marschall, H Denk and M Trauner: Regurgitation of bile acids from leaky bile ducts causes sclerosing cholangitis in Mdr2 (Abcb4) knockout mice. Gastroenterology, 1271, 261-74 (2004)
doi:10.1053/j.gastro.2004.04.009
PMid:15236191
146. P Fickert, T Moustafa and M Trauner: Primary sclerosing cholangitis--the arteriosclerosis of the bile duct? Lipids Health Dis, 6, 3 (2007)
doi:10.1186/1476-511X-6-3
PMid:17254334 PMCid:1796546
147. JF Gallegos-Orozco, EY C, N Wang, J Rakela, MR Charlton, GR Cutting and V Balan: Lack of association of common cystic fibrosis transmembrane conductance regulator gene mutations with primary sclerosing cholangitis. Am J Gastroenterol, 1004, 874-8 (2005)
doi:10.1111/j.1572-0241.2005.41072.x
PMid:15784035
148. JM McGill, DM Williams and CM Hunt: Survey of cystic fibrosis transmembrane conductance regulator genotypes in primary sclerosing cholangitis. Dig Dis Sci, 413, 540-2 (1996)
doi:10.1007/BF02282335
PMid:8617131
149. GU Denk, H Bikker, RH Lekanne Dit Deprez, V Terpstra, C van der Loos, U Beuers, C Rust and T Pusl: ABCB4 deficiency: A family saga of early onset cholelithiasis, sclerosing cholangitis and cirrhosis and a novel mutation in the ABCB4 gene. Hepatol Res, 409, 937-41 (2010)
doi:10.1111/j.1872-034X.2010.00698.x
PMid:20887599
150. R Poupon, L Arrive and O Rosmorduc: The cholangiographic features of severe forms of ABCB4/MDR3 deficiency-associated cholangiopathy in adults. Gastroenterol Clin Biol, 346-7, 380-7 (2010)
doi:10.1016/j.gcb.2010.04.011
PMid:20537830
151. C Pauli-Magnus, R Kerb, K Fattinger, T Lang, B Anwald, GA Kullak-Ublick, U Beuers and PJ Meier: BSEP and MDR3 haplotype structure in healthy Caucasians, primary biliary cirrhosis and primary sclerosing cholangitis. Hepatology, 393, 779-91 (2004)
doi:10.1002/hep.20159
PMid:14999697
152. O Rosmorduc, B Hermelin, PY Boelle, RE Poupon, R Poupon and O Chazouilleres: ABCB4 gene mutations and primary sclerosing cholangitis. Gastroenterology, 1264, 1220-2; author reply 1222-3 (2004)
doi:10.1053/j.gastro.2004.02.042
PMid:15057773
153. A Stiehl, G Rudolph, P Sauer and L Theilmann: Biliary secretion of bile acids and lipids in primary sclerosing cholangitis. Influence of cholestasis and effect of ursodeoxycholic acid treatment. J Hepatol, 233, 283-9 (1995)
154. TH Karlsen, BA Lie, K Frey Froslie, E Thorsby, U Broome, E Schrumpf and KM Boberg: Polymorphisms in the steroid and xenobiotic receptor gene influence survival in primary sclerosing cholangitis. Gastroenterology, 1313, 781-7 (2006)
doi:10.1053/j.gastro.2006.05.057
PMid:16952547
155. KD Lindor: Ursodiol for primary sclerosing cholangitis. Mayo Primary Sclerosing Cholangitis-Ursodeoxycholic Acid Study Group. N Engl J Med, 33610, 691-5 (1997)
doi:10.1056/NEJM199703063361003
PMid:9041099
156. DS Pardi, EV Loftus, Jr., WK Kremers, J Keach and KD Lindor: Ursodeoxycholic acid as a chemopreventive agent in patients with ulcerative colitis and primary sclerosing cholangitis. Gastroenterology, 1244, 889-93 (2003)
doi:10.1053/gast.2003.50156
PMid:12671884
157. BY Tung, MJ Emond, RC Haggitt, MP Bronner, MB Kimmey, KV Kowdley and TA Brentnall: Ursodiol use is associated with lower prevalence of colonic neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis. Ann Intern Med, 1342, 89-95 (2001)
158. J Shi, Z Li, X Zeng, Y Lin and WF Xie: Ursodeoxycholic acid in primary sclerosing cholangitis: meta-analysis of randomized controlled trials. Hepatol Res, 399, 865-73 (2009)
doi:10.1111/j.1872-034X.2009.00527.x
PMid:19467021
159. R Olsson, KM Boberg, OS de Muckadell, S Lindgren, R Hultcrantz, G Folvik, H Bell, M Gangsoy-Kristiansen, J Matre, A Rydning, O Wikman, A Danielsson, H Sandberg-Gertzen, KA Ung, A Eriksson, L Loof, H Prytz, HU Marschall and U Broome: High-dose ursodeoxycholic acid in primary sclerosing cholangitis: a 5-year multicenter, randomized, controlled study. Gastroenterology, 1295, 1464-72 (2005)
doi:10.1053/j.gastro.2005.08.017
PMid:16285948
160. KD Lindor, KV Kowdley, VA Luketic, ME Harrison, T McCashland, AS Befeler, D Harnois, R Jorgensen, J Petz, J Keach, J Mooney, C Sargeant, J Braaten, T Bernard, D King, E Miceli, J Schmoll, T Hoskin, P Thapa and F Enders: High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. Hepatology, 503, 808-14 (2009)
doi:10.1002/hep.23082
PMid:19585548 PMCid:2758780
161. EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol, 512, 237-67 (2009)
162. P Angulo, KP Batts, RA Jorgensen, NA LaRusso and KD Lindor: Oral budesonide in the treatment of primary sclerosing cholangitis. Am J Gastroenterol, 959, 2333-7 (2000)
doi:10.1111/j.1572-0241.2000.02323.x
PMid:11007238
163. TA Knox and MM Kaplan: A double-blind controlled trial of oral-pulse methotrexate therapy in the treatment of primary sclerosing cholangitis. Gastroenterology, 1062, 494-9 (1994)
164. KD Lindor, RA Jorgensen, ML Anderson, GJ Gores, AF Hofmann and NF LaRusso: Ursodeoxycholic acid and methotrexate for primary sclerosing cholangitis: a pilot study. Am J Gastroenterol, 913, 511-5 (1996)
165. RK Sterling, JJ Salvatori, VA Luketic, AJ Sanyal, AS Fulcher, RT Stravitz, MJ Contos, AS Mills and ML Shiffman: A prospective, randomized-controlled pilot study of ursodeoxycholic acid combined with mycophenolate mofetil in the treatment of primary sclerosing cholangitis. Aliment Pharmacol Ther, 209, 943-9 (2004)
doi:10.1111/j.1365-2036.2004.02214.x
166. JA Talwalkar, P Angulo, JC Keach, JL Petz, RA Jorgensen and KD Lindor: Mycophenolate mofetil for the treatment of primary sclerosing cholangitis. Am J Gastroenterol, 1002, 308-12 (2005)
doi:10.1111/j.1572-0241.2005.40484.x
PMid:15667487
167. JA Talwalkar, AA Gossard, JC Keach, RA Jorgensen, JL Petz and RN Lindor: Tacrolimus for the treatment of primary sclerosing cholangitis. Liver Int, 274, 451-3 (2007)
doi:10.1111/j.1478-3231.2007.01441.x
PMid:17403184
168. DH Van Thiel, P Carroll, K Abu-Elmagd, H Rodriguez-Rilo, W Irish, J McMichael and TE Starzl: Tacrolimus (FK 506), a treatment for primary sclerosing cholangitis: results of an open-label preliminary trial. Am J Gastroenterol, 903, 455-9 (1995)
169. AE Bharucha, R Jorgensen, SN Lichtman, NF LaRusso and KD Lindor: A pilot study of pentoxifylline for the treatment of primary sclerosing cholangitis. Am J Gastroenterol, 959, 2338-42 (2000)
doi:10.1111/j.1572-0241.2000.02324.x
PMid:11007239
170. MP Epstein and MM Kaplan: A pilot study of etanercept in the treatment of primary sclerosing cholangitis. Dig Dis Sci, 491, 1-4 (2004)
doi:10.1023/B:DDAS.0000011827.87103.2e
PMid:14992426
171. NF LaRusso, RH Wiesner, J Ludwig, RL MacCarty, SJ Beaver and AR Zinsmeister: Prospective trial of penicillamine in primary sclerosing cholangitis. Gastroenterology, 954, 1036-42 (1988)
172. KD Lindor, RH Wiesner, LJ Colwell, B Steiner, S Beaver and NF LaRusso: The combination of prednisone and colchicine in patients with primary sclerosing cholangitis. Am J Gastroenterol, 861, 57-61 (1991)
173. R Olsson, U Broome, A Danielsson, I Hagerstrand, G Jarnerot, L Loof, H Prytz, BO Ryden and S Wallerstedt: Colchicine treatment of primary sclerosing cholangitis. Gastroenterology, 1084, 1199-203 (1995)
doi:10.1016/0016-5085(95)90220-1
174. P Angulo, AE Bharucha, RA Jorgensen, CK DeSotel, WJ Sandborn, NF Larusso and KD Lindor: Oral nicotine in treatment of primary sclerosing cholangitis: a pilot study. Dig Dis Sci, 443, 602-7 (1999)
doi:10.1023/A:1026673811278
PMid:10080157
175. FP Vleggaar, NA Van Ooteghem, HR Van Buuren and GP Van Berge Henegouwen: Cholestatic liver diseases: slow progress in understanding and treating slowly progressive disorders. Scand J Gastroenterol Suppl232, 86-92 (2000)
PMid:11232499
176. MG Silveira, NJ Torok, AA Gossard, JC Keach, RA Jorgensen, JL Petz and KD Lindor: Minocycline in the treatment of patients with primary sclerosing cholangitis: results of a pilot study. Am J Gastroenterol, 1041, 83-8 (2009)
doi:10.1038/ajg.2008.14
PMid:19098854
177. M Farkkila, AL Karvonen, H Nurmi, H Nuutinen, M Taavitsainen, P Pikkarainen and P Karkkainen: Metronidazole and ursodeoxycholic acid for primary sclerosing cholangitis: a randomized placebo-controlled trial. Hepatology, 406, 1379-86 (2004)
doi:10.1002/hep.20457
PMid:15565569
178. MG Silveira and KD Lindor: Primary sclerosing cholangitis. Can J Gastroenterol, 228, 689-98 (2008)
179. NV Bergasa and EA Jones: The pruritus of cholestasis: evolving pathogenic concepts suggest new therapeutic options. Clin Liver Dis, 22, 391-405, x (1998)
180. J Browning, B Combes and MJ Mayo: Long-term efficacy of sertraline as a treatment for cholestatic pruritus in patients with primary biliary cirrhosis. Am J Gastroenterol, 9812, 2736-41 (2003)
doi:10.1111/j.1572-0241.2003.08662.x
PMid:14687826
181. EM Kuiper, KJ van Erpecum, U Beuers, BE Hansen, HB Thio, RA de Man, HL Janssen and HR van Buuren: The potent bile acid sequestrant colesevelam is not effective in cholestatic pruritus: Results of a double-blind, randomized, placebo-controlled trial. Hepatology (2010)
182. NV Bergasa, DW Alling, TL Talbot, MG Swain, C Yurdaydin, ML Turner, JM Schmitt, EC Walker and EA Jones: Effects of naloxone infusions in patients with the pruritus of cholestasis. A double-blind, randomized, controlled trial. Ann Intern Med, 1233, 161-7 (1995)
183. NV Bergasa, JM Schmitt, TL Talbot, DW Alling, MG Swain, ML Turner, JB Jenkins and EA Jones: Open-label trial of oral nalmefene therapy for the pruritus of cholestasis. Hepatology, 273, 679-84 (1998)
doi:10.1002/hep.510270307
PMid:9500694
184. MJ Mayo, I Handem, S Saldana, H Jacobe, Y Getachew and AJ Rush: Sertraline as a first-line treatment for cholestatic pruritus. Hepatology, 453, 666-74 (2007)
doi:10.1002/hep.21553
PMid:17326161
185. S Khurana and P Singh: Rifampin is safe for treatment of pruritus due to chronic cholestasis: a meta-analysis of prospective randomized-controlled trials. Liver Int, 268, 943-8 (2006)
doi:10.1111/j.1478-3231.2006.01326.x
PMid:16953834
186. E Bjornsson, J Lindqvist-Ottosson, M Asztely and R Olsson: Dominant strictures in patients with primary sclerosing cholangitis. Am J Gastroenterol, 993, 502-8 (2004)
doi:10.1111/j.1572-0241.2004.04106.x
PMid:15056092
187. G Rudolph, D Gotthardt, P Kloters-Plachky, H Kulaksiz, D Rost and A Stiehl: Influence of dominant bile duct stenoses and biliary infections on outcome in primary sclerosing cholangitis. J Hepatol, 511, 149-55 (2009)
doi:10.1016/j.jhep.2009.01.023
PMid:19410324
188. AR Baluyut, S Sherman, GA Lehman, H Hoen and N Chalasani: Impact of endoscopic therapy on the survival of patients with primary sclerosing cholangitis. Gastrointest Endosc, 533, 308-12 (2001)
189. M Gluck, NR Cantone, JJ Brandabur, DJ Patterson, JE Bredfeldt and RA Kozarek: A twenty-year experience with endoscopic therapy for symptomatic primary sclerosing cholangitis. J Clin Gastroenterol, 429, 1032-9 (2008)
doi:10.1097/MCG.0b013e3181646713
PMid:18580600
190. SA Ahrendt: Surgical approaches to strictures in primary sclerosing cholangitis. J Gastrointest Surg, 123, 423-5 (2008)
doi:10.1007/s11605-007-0342-5
PMid:17952519
191. S Tsai and TM Pawlik: Primary sclerosing cholangitis: the role of extrahepatic biliary resection. Adv Surg, 43, 175-88 (2009)
doi:10.1016/j.yasu.2009.02.015
PMid:19845177
192. MM Claessen, FP Vleggaar, KM Tytgat, PD Siersema and HR van Buuren: High lifetime risk of cancer in primary sclerosing cholangitis. J Hepatol, 501, 158-64 (2009)
doi:10.1016/j.jhep.2008.08.013
PMid:19012991
193. G Morris-Stiff, C Bhati, S Olliff, S Hubscher, B Gunson, D Mayer, D Mirza, J Buckels and SR Bramhall: Cholangiocarcinoma complicating primary sclerosing cholangitis: a 24-year experience. Dig Surg, 252, 126-32 (2008)
doi:10.1159/000128169
PMid:18446034
194. J Fevery, C Verslype, G Lai, R Aerts and W Van Steenbergen: Incidence, diagnosis, and therapy of cholangiocarcinoma in patients with primary sclerosing cholangitis. Dig Dis Sci, 5211, 3123-35 (2007)
doi:10.1007/s10620-006-9681-4
PMid:17431781
195. E Melum, TH Karlsen, E Schrumpf, A Bergquist, E Thorsby, KM Boberg and BA Lie: Cholangiocarcinoma in primary sclerosing cholangitis is associated with NKG2D polymorphisms. Hepatology, 471, 90-6 (2008)
196. NS Becker, JA Rodriguez, NR Barshes, CA O'Mahony, JA Goss and TA Aloia: Outcomes analysis for 280 patients with cholangiocarcinoma treated with liver transplantation over an 18-year period. J Gastrointest Surg, 121, 117-22 (2008)
doi:10.1007/s11605-007-0335-4
PMid:17963015
197. DJ Rea, JK Heimbach, CB Rosen, MG Haddock, SR Alberts, WK Kremers, GJ Gores and DM Nagorney: Liver transplantation with neoadjuvant chemoradiation is more effective than resection for hilar cholangiocarcinoma. Ann Surg, 2423, 451-8; discussion 458-61 (2005)
198. CB Rosen, JK Heimbach and GJ Gores: Liver transplantation for cholangiocarcinoma. Transpl Int, 237, 692-7 (2010)
doi:10.1111/j.1432-2277.2010.01108.x
PMid:20497401
199. P Charatcharoenwitthaya, FB Enders, KC Halling and KD Lindor: Utility of serum tumor markers, imaging, and biliary cytology for detecting cholangiocarcinoma in primary sclerosing cholangitis. Hepatology, 484, 1106-17 (2008)
doi:10.1002/hep.22441
PMid:18785620
200. J Fevery, O Buchel, F Nevens, C Verslype, S Stroobants and W Van Steenbergen: Positron emission tomography is not a reliable method for the early diagnosis of cholangiocarcinoma in patients with primary sclerosing cholangitis. J Hepatol, 432, 358-60 (2005)
doi:10.1016/j.jhep.2005.03.016
PMid:15975687
201. CD Anderson, MH Rice, CW Pinson, WC Chapman, RS Chari and D Delbeke: Fluorodeoxyglucose PET imaging in the evaluation of gallbladder carcinoma and cholangiocarcinoma. J Gastrointest Surg, 81, 90-7 (2004)
doi:10.1016/j.gassur.2003.10.003
PMid:14746840
202. H Prytz, S Keiding, E Bjornsson, U Broome, S Almer, M Castedal and OL Munk: Dynamic FDG-PET is useful for detection of cholangiocarcinoma in patients with PSC listed for liver transplantation. Hepatology, 446, 1572-80 (2006)
doi:10.1002/hep.21433
PMid:17133469
203. G Vazquez-Elizondo, J Mucino-Bermejo and N Mendez-Sanchez: Gallbladder disease in patients with primary sclerosing cholangitis. Ann Hepatol, 72, 182-3 (2008)
204. K Said, H Glaumann and A Bergquist: Gallbladder disease in patients with primary sclerosing cholangitis. J Hepatol, 484, 598-605 (2008)
205. DC Buckles, KD Lindor, NF Larusso, LM Petrovic and GJ Gores: In primary sclerosing cholangitis, gallbladder polyps are frequently malignant. Am J Gastroenterol, 975, 1138-42 (2002)
doi:10.1111/j.1572-0241.2002.05677.x
PMid:12014717
206. AH Kartheuser, RR Dozois, NF LaRusso, RH Wiesner, DM Ilstrup and CD Schleck: Comparison of surgical treatment of ulcerative colitis associated with primary sclerosing cholangitis: ileal pouch-anal anastomosis versus Brooke ileostomy. Mayo Clin Proc, 718, 748-56 (1996)
doi:10.4065/71.8.748
PMid:8691895
207. E Cholongitas, V Shusang, GV Papatheodoridis, L Marelli, P Manousou, N Rolando, D Patch, K Rolles, B Davidson and AK Burroughs: Risk factors for recurrence of primary sclerosing cholangitis after liver transplantation. Liver Transpl, 142, 138-43 (2008)
doi:10.1002/lt.21260
PMid:18236447
208. J Campsen, MA Zimmerman, JF Trotter, M Wachs, T Bak, T Steinberg and I Kam: Clinically recurrent primary sclerosing cholangitis following liver transplantation: a time course. Liver Transpl, 142, 181-5 (2008)
doi:10.1002/lt.21313
PMid:18236392
209. J Alexander, JD Lord, MM Yeh, C Cuevas, R Bakthavatsalam and KV Kowdley: Risk factors for recurrence of primary sclerosing cholangitis after liver transplantation. Liver Transpl, 142, 245-51 (2008)
doi:10.1002/lt.21394
PMid:18236405
210. S Tamura, Y Sugawara, J Kaneko, Y Matsui, J Togashi and M Makuuchi: Recurrence of primary sclerosing cholangitis after living donor liver transplantation. Liver Int, 271, 86-94 (2007)
211. U Oldakowska-Jedynak, M Nowak, K Mucha, B Foroncewicz, P Nyckowski, K Zieniewicz, B Ziarkiewicz-Wroblewska, W Patkowski, B Gornicka, A Paczkowska, B Michalowicz, T Pilecki, J Pawlak, M Krawczyk and L Paczek: Recurrence of primary sclerosing cholangitis in patients after liver transplantation. Transplant Proc, 381, 240-3 (2006)
doi:10.1016/j.transproceed.2005.12.026
PMid:16504713
212. B Brandsaeter, E Schrumpf, O Bentdal, K Brabrand, HJ Smith, A Abildgaard, OP Clausen and K Bjoro: Recurrent primary sclerosing cholangitis after liver transplantation: a magnetic resonance cholangiography study with analyses of predictive factors. Liver Transpl, 1111, 1361-9 (2005)
doi:10.1002/lt.20444
PMid:16184522
213. IW Graziadei: Recurrence of primary sclerosing cholangitis after liver transplantation. Liver Transpl, 87, 575-81 (2002)
doi:10.1053/jlts.2002.33952
PMid:12089708
214. A Bergquist and U Broome: Clinical features in primary sclerosing cholangitis. Clin Liver Dis, 22, 283-301, viii (1998)
215. JH Helzberg, JM Petersen and JL Boyer: Improved survival with primary sclerosing cholangitis. A review of clinicopathologic features and comparison of symptomatic and asymptomatic patients. Gastroenterology, 926, 1869-75 (1987)
216. MG Silveira and KD Lindor: Clinical features and management of primary sclerosing cholangitis. World J Gastroenterol, 1421, 3338-49 (2008)
doi:10.3748/wjg.14.3338
PMid:18528931 PMCid:2716588
217. JR Hov, KM Boberg and TH Karlsen: Autoantibodies in primary sclerosing cholangitis. World J Gastroenterol, 1424, 3781-91 (2008)
doi:10.3748/wjg.14.3781
PMid:18609700 PMCid:2721433
218. D Zauli, E Schrumpf, C Crespi, F Cassani, O Fausa and E Aadland: An autoantibody profile in primary sclerosing cholangitis. J Hepatol, 51, 14-8 (1987)
doi:10.1016/S0168-8278(87)80055-7
Abbreviations: PSC, primary sclerosing cholangitis; IBD, inflammatory bowel disease; UC, ulcerative colitis; CD, Crohn's disease; PBC, primary biliary cirrhosis; ERC, endoscopic retrograde cholangiography; MRC, magnetic resonance cholangiography; AIH, autoimmune hepatitis; HLA, human leukocyte antigen; TNF, tumor necrosis factor; KIR, killer immunoglobulin-like receptor; NK, natural killer; TGR5, takeda G-protein coupled bile acid receptor 5; GPC 5/6, glypican 5/6; CFTR, cystic fibrosis transmembrane conductance regulator; PAMPs, pathogen-associated molecular patterns; LPS, lipopolysaccharide; TLR, Toll-like receptor; BEC, biliary epithelial cells; MAdCAM-1, mucosal addressin cell adhesion molecule-1; LIL, liver infiltrating lymphocytes; TGF, transforming growth factor; Mdr2, multidrug resistance gene 2; UDCA, ursodeoxycholic acid; CCA, cholangiocarcinoma
Key Words: Primary Sclerosing Cholangitis, Inflammatory Bowel Disease, Genetics, Immunology, Treatment, Review
Send correspondence to: Christopher L. Bowlus, 4150 V Street, PSSB 3500, Sacramento, CA 95817, Tel: 916-734-3751, Fax: 916-734-7908, E-mail:clbowlus@ucdavis.edu