Journal of Hepatology
Volume 48, Supplement 1 , Pages S38-S57, 2008

The challenges in primary sclerosing cholangitis – Aetiopathogenesis, autoimmunity, management and malignancy☆

Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl Neuberg Str. 1, 30655 Hannover, Germany

published online 13 February 2008.

Article Outline

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease, characterized by progressive inflammation and fibrosis of the bile ducts, resulting in biliary cirrhosis and is associated with a high risk of cholangiocarcinoma. The majority of patients are young, male and have coexisting inflammatory bowel disease. PSC is found with a prevalence of 10/100,000 in Northern European populations. The pathophysiology of PSC is a complex multistep process including immunological mechanisms, immunogenetic susceptibility and disorders of the biliary epithelia. The diagnosis is primarily based on endoscopic cholangiography although magnetic resonance imaging is increasingly used; biochemistry and immunoserology as well as histology play only a minor role. Due to the high risk of developing cholangiocarcinoma and also other tumours of the GI tract, surveillance strategies are essential, however they have yet to be established and evaluated. Biochemical parameters, clinical risk factors, endoscopic procedures and imaging techniques contribute to the early identification of patients at risk. Since medical therapy of PSC with ursodeoxycholic acid does not improve survival, to date, liver transplantation is the only option with a cure potential; if transplantation is accurately timed, transplanted PSC patients have an excellent rate of survival. However if cholangiocarcinoma is detected, a curative treatment is not possible in the majority of cases. The present review critically summarizes the current knowledge on the aetiopathogenesis of PSC and gives an overview of the diagnostic approaches, surveillance strategies and therapeutic options. Primary sclerosing cholangitis is a disease of unknown aetiology and without any further curative treatment options apart from liver transplantation. Therefore it may be regarded as the greatest challenge in hepatology today.

Abbreviations: PSC, primary sclerosing cholangitis, IBD, inflammatory bowel disease, UC, ulcerative colitis, MHC, major histocompatibility complex, HLA, human leukocyte antigen, MIC, MHC class I chain-like, CR5Δ32, 32-bp deletion of the chemokine receptor 5, ICAM-1, intercellular adhesion molecule-1, CFTR, cystic fibrosis transmembrane conductance regulator, ANA, antinuclear antibodies, p-ANCA, perinuclear-staining, antineutrophil cytoplasmic antibodies, AIH, autoimmune hepatitis, PBC, primary biliary cirrhosis, p-ANNA, peripheral antineutrophil nuclear antibodies, TNF-α, tumour necrosis factor-α, VAP-1, vascular adhesion protein-1, MadCAM-1, mucosal addressin cell adhesion molecule-1, BEC, biliary epithelial cells, MDR, multidrug resistance protein, UDCA, ursodeoxycholic acid, IL, interleukin, TLR, toll-like receptors, IFNγ, interferon γ, CC, cholangiocarinoma, iNOS, inducible nitric oxide synthase, ERC, endoscopic retrograde cholangiography, ERCP, endoscopic retrograde cholangiopancreatography, MRC, magnetic resonance cholangiography, MRCP, magnetic resonance cholangiopancreatography, AMA, antimitochondrial antibodies, sdPSC, small-duct PSC, IgG, immune globulin G, MELD, model for end-stage liver disease, CEA, carcinoembryonic antigen, CA19-9, carbohydrate antigen 19-9, MRI, magnetic resonance imaging, CT, computed tomography, FDG-PET, positron emission tomography with 18F-fluorodeoxyglucose, US, ultrasound, IDUS, intraductal US, IGF-I, insulin-like growth factor I, CRC, colorectal cancer, OLT, orthotopic liver transplantation, PDT, photodynamic therapy

Keywords: PSC, Primary sclerosing cholangitis, Aetiology, Pathogenesis, Immunology, Surveillance, Diagnosis, Therapy, Transplantation, Malignancy, Cholangiocarcinoma

 

Back to Article Outline

1. Introduction 

Primary sclerosing cholangitis (PSC) is a chronic and progressive cholestatic liver disease, which is characterized by inflammation and fibrosis of mainly the large bile ducts leading to biliary cirrhosis in a high percentage of patients. It is associated with inflammatory bowel disease (IBD) in the majority of cases and is associated with a high risk of hepatobiliary as well as extrahepatic malignancies.

In 1929, J.A. Bargen described a case of a biliary cirrhosis in a patient with ulcerative colitis (UC); this was the first description of this disease in English [1] and subsequently he observed further cases of hepatic lesions in UC. In a series of 93 patients with UC, Kimmelstiel et al. reported in 1950 an increased frequency of liver damage [2], including bile casts and interlobular hepatitis. The term “Primary sclerosing cholangitis” was first coined in the early 1960s, when the diagnosis of this disease was based primarily on findings at laparotomy; but it was not until retrograde cholangiography by fiber duodenoscope introduced in 1970, that this disease became easier to diagnose and later also easier to treat. During the last three decades significant progress was made regarding the diagnostic and therapeutic methods, but still we are facing important challenges: the aetiopathogenesis of PSC remains poorly understood, the medical treatment of PSC is insufficient and the early detection of malignant complications to allow timely therapy, namely, liver transplantation is difficult.

Data on the epidemiology of PSC are rare and originate from a few major tertiary referral centres in Northern Europe or North America. In addition, the studies available mostly have methodological limitations [3]. Furthermore, PSC obviously does not occur with the same frequency worldwide. In Northern Europe, Canada or Minnesota incidence rates between 0.9 and 1.3/100,000/year and prevalence between 8.5 and 13.6/100,000 have been reported [4], [5], [6], [7], while in southern Europe, Asia or Alaska this disease is seen much less frequently [8], [9], [10], [11]. Between 55% and 71% of the patients are male and the mean age at diagnosis is around 40 years; a concomitant IBD can be found in 62–73% of patients and conversely 3–4% of patients with IBD have also PSC [3], [12]. Ulcerative colitis (UC) is most common, but an association with Crohn’s disease has been described in 1–14% of all PSC patients. However, in Japan [10] and Singapore [9] patients appear to be older at diagnosis and an associated IBD is less frequent. As numerous studies demonstrated, PSC is a disease of non-smokers, since current smokers have a decreased risk with an odds-ratio of 0.13–0.17 for the development of PSC [13], [14].

The clinical course of PSC is characterized by recurrent episodes of cholangitis, during which the disease slowly progresses. While patients are initially often asymptomatic, they suffer over the years from jaundice, pruritus, fever and finally all the symptoms of end-stage liver disease can appear. Nevertheless in some patients the disease can also rapidly progress when after a period of stability septic biliary complications occur. The main causes of death are cholangiocarcinoma and liver failure. The mean time from diagnosis to death or liver transplantation ranges from 9.6 to 12 years and cholangiocarcinoma develops in 8–13.2% [15], [16], [17].

Back to Article Outline

2. Aetiology and pathogenesis 

While the cause of PSC still remains unknown, there are currently numerous approaches evolving that help us to understand the multiple mechanisms involved in aetiopathogenesis [18]. Based on an adequate immunogenetic background, immunopathogenetic mechanisms occur, which cause inflammatory changes of the bile ducts possibly triggered or intensified by infectious pathogens [19], [20]. The following review describes several aspects of the aetiopathogenesis of PSC, i.e. PSC as a genetic disease, as an autoimmune disease, as an inflammatory disease triggered by infectious agents and as a cholangiopathy (Table 1).

Table 1. Summary of the current pathogenetic concepts possibly involved in the aetiology of primary sclerosing cholangitis
Pathogenetic conceptProsCons
PSC as genetic disease– Increased prevalence of PSC among first-degree relatives [21]– Association with HLA-haplotypes is only weak and not mandatory
– Association with certain MHC- and non-MHC-alleles [23], [24], [25], [26], [27], [28], [29], [30], [31]– Studies on non-HLA polymorphisms are not reproducible or contradictory
PSC as an autoimmune disease– Increased incidence of co-existing autoimmune diseases [20]– No response on immunosuppressive treatment
– Presence of multiple autoantibodies [33]– Male predominance
– Antibodies are not specific and do not correlate with clinical parameters
PSC as inflammatory reaction on infectious agents– Co-expression of VAP-1 and MadCAM-1 in the gut and the liver of patients with PSC and IBD allows an enterohepatic lymphocyte circulation [41], [42], [44], [45]– In PSC patients without IBD enterohepatic lymphocyte circulation is not a conclusive concept
– In a rat model small intestinal bacterial overgrowth lead to biliary strictures and portal inflammation [48]– No evidence of sign. bacteraemia in UC [46]
– Helicobacter species can be found in 24–75% of PSC livers [50], [52]– No evidence of small intestinal bacterial overgrowth or disturbed intestinal permeability in PSC patients [49]
– Helicobacter species are not found more often in livers of PSC patients than in non-cholestatic liver diseases [51]
PSC as a cholangiopathy– Knockout of the Mdr2 gene which encodes a canalicular phospholipid transporter in mice, results in a sclerosing cholangitis [61], [62]– In human PSC patients a significant variation of the corresponding MDR3-gene could not be found [63]
– Sera of PSC patients contain autoantibodies against a shared peptide in biliary and colon epithelium [65]
– Biliary epithelial cells that are activated by serum-autoantibodies produce cytokines and trigger inflammation [66], [67]

2.1. PSC as a genetic disease 

First-degree relatives of PSC patients have a PSC prevalence of 0.7% and siblings have an even higher prevalence of 1.5% [21]; this approximately 100-fold increased risk of PSC between genetically related individuals illustrates the importance of a genetic predisposition for the development of the disease. However, PSC is a complex non-mendelian disorder and the susceptibility to the disease is probably based on a combination of certain alleles of the major histocompatibility complex (MHC) and other non-MHC gene-polymorphisms.

The MHC encodes among others the human leukocyte antigen (HLA) class I and HLA class II molecules, which are involved in T-cell response, as well as the MHC class I chain-like (MIC)α-molecules, which play a role for the innate immune response, especially as ligands for natural killer cells [18], [19], [22]. MHC-haplotypes with an increased risk of PSC include several risk alleles like MICA*008, DRB1*0301, DRB1*1301 or DRB1*1501; the strongest association was found for the MICA*008-homozygosity with an odds-ratio of 5.01. Other haplotypes like DRB1*0701, DRB1*0401 and MICA*002 are found in lower frequency in patients with PSC compared with controls and hence they are designated as protective haplotypes with an reduced risk of PSC development [23], [24], [25].

Genes outside the MHC-region also contribute to the susceptibility to PSC or influence the disease progression; most of them are involved in immune regulation. Unfortunately, most of the studies describing an influence of genetic alterations on PSC development are not reproducible. For instance a 32-bp deletion of the chemokine receptor 5 (CR5Δ32), which is frequently found in Northern European countries, results in a reduced receptor expression on T-cells; a recent study on a Belgian population showed a significant lower frequency of this mutation compared with healthy control subjects suggesting a protective effect [26]. However, this is in contrast to a previous study from Australia, which found a higher frequency of CR5Δ32 in PSC patients [27]. E469E-homozygosity of the intercellular adhesion molecule (ICAM)-1 was associated with protection against PSC in one study [28], but again this finding was not reproducible in a bigger subsequent study [29]. Another polymorphism with an increased PSC-susceptibility is the G to A substitution at position 308 in the TNF-α promoter [30].

The findings regarding a role of the cystic fibrosis transmembrane conductance regulator (CFTR) are also contradictory; while one study demonstrated an increased prevalence of CFTR abnormalities in PSC patients, these results were not confirmed by others [31], [32].

2.2. PSC as an autoimmune disease 

The described strong association of PSC-susceptibility and progression with certain HLA-haplotypes as well as with other immune-regulating gene-polymorphisms (e.g. ICAM-1, CR5Δ32) underlines the fundamental role of immunogenetic mechanisms in the pathogenesis of PSC. The hypothesis of PSC as an autoimmune disease is supported by the high frequency of inflammatory bowel disease in PSC patients, the increased incidence of other coexisting autoimmune diseases [20] and the presence of multiple autoantibodies [33]. Nevertheless, because of its male predominance, its non-response on immunosuppressive treatment and the missing evidence of an PSC-specific autoantigen, PSC must be regarded with caution as an autoimmune disease [18], [19].

In PSC multiple non-specific autoantibodies, which are rather an epiphenomena to chronic inflammation, can be found; these include antinuclear antibodies (ANA) in 7–77%, anticardiolipin antibodies in 4–66%, anti-smooth-muscle antibodies in 13–20%, anti-thyroid peroxidase (TPO) antibodies in 16% and rheumatoid factor in 15% [19], [33]. Atypical perinuclear-staining, antineutrophil cytoplasmic antibodies (p-ANCA) can be found in 60–93% of patients with PSC but also in patients with AIH, PBC or UC [34], [35], [36]. Terjung et al. identified a 50-kDa nuclear envelope protein as target antigen in 92% of atypical p-ANCA and proposed the more accurate term “peripheral antineutrophil nuclear antibodies” (p-ANNA) [37]; nevertheless it is still questionable, whether this target protein or p-ANNAs are involved in pathogenesis. The same group attributed a significant diagnostic role to ANCAs as the only antibodies in PSC; however, there is no clear correlation of ANCA-serum-titers and clinical parameters, so they are not helpful in clinical management.

Further hints of an involvement of humoral immunity are the early observations of elevated circulating immune complexes [38] as well as the complement activation with elevated C3d and C4d in PSC compared with obstructive cholestasis [39].

The finding of a T-cell predominant portal infiltrate indicates the role of cellular immunity in PSC [19]. Indeed the function of liver derived T lymphocytes of PSC patients seems to be considerably altered by a TNF-α dependent mechanism with impaired cytokine production and reduced proliferative responses to mitogens [40].

In consideration of the strong link between PSC and IBD, the hypothesis of an enterohepatic circulation of lymphocytes generated in the gut occurred, which persist as long-lived memory cells and upon activation trigger hepatic inflammation; this concept explains why PSC sometimes develops even many years after proctocolectomy [41], [42]. The recirculation could be facilitated by the co-expression of vascular adhesion protein (VAP)-1 [43] and mucosal addressin cell adhesion molecule (MadCAM)-1 [44] in both organs in patients with PSC and IBD, while under normal conditions their expression is restricted to the gut (MadCAM-1) resp. the liver (VAP-1). Livers of patients with PSC showed strong expression of CCL25, a chemokine normally expressed only in the gut and thymus; it allows CCR9+ T-cells, which are generated during colonic inflammation, to infiltrate the liver by adhesion to MadCAM-1 [45].

2.3. PSC as an inflammatory reaction to infectious agents 

Some authors see PSC as an immune-mediated inflammatory disease rather than as an autoimmune disease. This would be consistent with a role of bacterial or viral antigens, which enter the portal circulation through the mucosa in IBD and trigger as molecular mimics an immune reaction leading to PSC. However, in a study on eight patients with UC no significant bacteraemia was verified in specimens of mesenteric and peripheral venous blood obtained during surgery for uncontrolled disease [46]; moreover in histological studies portal phlebitis in PSC was usually mild and did not differ from patients with UC without PSC [47]. Small intestinal bacterial overgrowth lead to biliary strictures and portal inflammation in a rat model [48], but it does not seem to contribute to the pathogenesis of PSC in humans; in a study on 22 PSC patients only one showed significant small intestinal bacterial overgrowth and the intestinal permeability was normal in all patients [49].

Current data concerning a possible role of helicobacter species in the pathogenesis of PSC are controversial. In a first study using PCR techniques to identify helicobacter in liver biopsies, 9 of 12 (75%) samples from PSC patients and 11 of 12 samples from PBC patients were positive, while all the normal livers and 92% of non-cholestatic cirrhotic livers were negative; furthermore PSC patients with UC were more likely to be positive [50]. Nonetheless, a subsequent study could detect helicobacter species only in 5 of 13 PSC livers as well as in 10 of 29 non-cholestatic livers and therefore disclaimed an influence of helicobacter on PSC [51]. A recent study also found helicobacter positive PCR in only 24% of PSC livers and 9.7% of non-biliary liver diseases [52].

Some authors suspected viruses like Cytomegalovirus or Reovirus type 3 played a role in PSC pathogenesis, however, more comprehensive studies did not support this hypothesis [53], [54].

Numerous studies analyzed bile obtained during ERCP and found enteric bacteria [55], [56] or even fungal infections with Candida [57]; yet these findings were more frequent in patients with previous ERCP and/or with dominant stenoses so that bile duct infections seemed to be more relevant for PSC progression rather than for aetiopathogenesis and primary manifestation of the disease.

Altogether, infectious agents probably do not directly cause PSC but could activate an immune reaction by the above mentioned enterohepatic lymphocyte circulation or could accelerate disease progression when leading to a biliary infection.

2.4. PSC as a cholangiopathy 

PSC is a disease mainly of the large bile ducts and belongs to the cholangiopathies, a group of various hereditary or acquired diseases of the biliary tree with cholestasis as a common symptom and with cholangiocytes as primary target cells of the disease process [58], [59].

The complex osmotic secretory process of bile formation depends on a number of membrane transport systems including ion transporters and organic-solute transporters. These transporters are differentially expressed on the sinusoidal and the canalicular membrane of hepatocytes and on biliary epithelial cells (BEC) [60]. Knockout of the Mdr2 gene, which encodes a canalicular transporter for phospholipids in mice, causes absence of phospholipids in bile and leads to a sclerosing cholangitis with hepatobiliary changes that resemble PSC in humans. Interestingly enough, feeding of ursodeoxycholic acid (UDCA) in these mice lowered alkaline phosphatase levels but increased alanine aminotransferase levels and led to bile infarcts, while 24-norUDCA improved liver tests and liver histology [61], [62]. Although in human PSC patients significant variations of the corresponding MDR3, the human equivalent of the mouse Mdr2 gene, have not been found [63], this mouse model directs attention to a possible role of hepatobiliary transporters and changes of bile composition and may help to understand some pathogenetic and therapeutic principals in PSC.

Das et al. looked into the issue of how BEC become the target of an immune reaction in patients with PSC and UC. They developed murine monoclonal antibodies against a colonic protein that reacts with IgG from colon specimens solely of UC patients. This antibody reacted additionally with mucosal or epidermal epithelial cells of the gall bladder, the bile duct, the hepatic ducts and the skin, but not with other organs such as synovia, eye tissue or the small intestine [64]. In contrast to patients with PBC, other liver diseases or normal controls, approximately two-thirds of the sera of patients with PSC contained autoantibodies against this epitope [65], and therefore, it might be a candidate as a target protein for immune reaction on biliary epithelia in patients with UC.

The group from the Karolinska Institute in Sweden found antibodies against isolated BEC in the sera of 63% of PSC patients which induced BEC to produce high levels of interleukin (IL) 6 and increased the expression of the adhesion molecule CD44 [66]. A recent study from the same group demonstrated that the stimulation of BEC with these antibodies induced the expression of Toll-like receptors (TLR), extracellular signal-regulated kinase and transcription factors. When further stimulated with lipopolysaccharide the TLR expressing BEC produced high levels of cytokines such as IL8, interferon γ (IFNγ) and tumour necrosis factor α (TNF-α) [67]. As previous studies from Spirli et al. showed, each combination of IL6, IL1, TNF-α or IFNγ stimulated biliary epithelia to generate NO and thus inhibited cAMP-dependent fluid secretion of isolated bile duct units [68], [69]. In summary, these findings clarify how antibody-activated BEC further stimulated by bacterial products, trigger chronic inflammation which leads to ductular cholestasis.

2.5. Aetiopathogenesis of malignancies in PSC 

Chronic inflammatory diseases such as PSC are frequently linked with an enhanced risk for cancer. A very large study compared the risk of extra- and intrahepatic malignancies during a median follow-up period of 5.7 years (0–27.8) in 604 PSC patients with that of the general Swedish population [15]. The frequency of hepatobiliary cancer in PSC patients was 13.3% and 37% of these malignancies were diagnosed less than one year after PSC was diagnosed. It has been estimated that the incidence of cholangiocarinoma (CC) in PSC patients is 1–1.5% per year. In addition to the 161-fold increased risk for hepatobiliary cancer, PSC patients showed a 10-fold risk for colorectal cancer and a 14-fold risk for pancreatic cancer compared to the general population.

CC can arise at any stage of PSC and is the leading cause of death in these patients. It develops either as a mass lesion in the liver or as a ductal carcinoma in the biliary tree with a ratio of 1:4 to 1:7 in different studies [70]. In patients with PSC, cholangiocarcinoma occurs approximately in 15% in the liver, 20% in the distal common biliary duct, and in 65% in the hilar region. The risk factors for cholangiocarcinogenesis in PSC patients are poorly defined. Smoking and alcohol consumption have been suggested as risk factors while duration of PSC or inflammatory bowel disease appears not to be associated with an increased risk for CC in PSC patients.

The pathogenesis and molecular mechanisms of CC development in PSC are poorly understood. In experimental models, bile has been shown to induce oxidative stress and to up-regulate genes involved in carcinogenesis [71]. In PSC patients, the cholangiocytes are exposed to cytokines of inflammatory pathways such as interleukin-6 which prolongs survival of malignant cholangiocytes [72]. In addition, several investigations have suggested that inflammatory cytokines cause inducible nitric oxide synthase (iNOS) expression in cholangiocytes with peroxynitrite formation, oxidative DNA damage and inhibition of DNA repair. Subsequent accumulation of mutations in tumour suppressor genes and oncogenes as well as development of genetic instability finally leads to dysplasia of biliary epithelia and CC. Little is known about a characteristic pattern or hierarchy of different molecular alterations in PSC-associated CC. There are few data regarding molecular alterations in k-ras, an important oncogene, and p53 one of the most important tumour suppressor genes. Oncogenic k-ras mutations are present in approximately 30% of the PSC-related CC, and overexpression of p53 or p53 mutations has been observed in 30–80% of these tumours [73], [74]. p53 mutations seem to occur only in malignant tissue, while k-ras mutations are also observed in dysplasia of bile duct epithelia in PSC patients, which suggest that, in contrast to p53 mutations, k-ras mutation is an early event in PSC-related cholangiocarcinogenesis. The p16INK4a is a major regulator of the cell cycle and also frequently altered in different tumour types. Several studies showed that p16INK4a inactivation by chromosome 9p21 loss, mutations within the coding gene and mutations or methylation of the p16INK4a promoter is common in PSC-associated cholangiocarcinoma [75], [76].

On the whole, PSC appears to be caused by a complex interaction between deregulated immune mechanisms in genetically predisposed persons and environmental factors such as infectious agents. However, this multitude of possible pathogenetic processes should allow the question, as to whether PSC is perhaps just a common clinical end-stage syndrome of a number of similar diseases with different aetiologies. Tumour development of the liver, CC but also HCC, and extrahepatic tissues such as pancreas and colon in PSC still is a black box. However, bringing light into this complex area may give significant clues to this overall poorly understood and mysterious disease.

Back to Article Outline

3. Diagnosis of PSC 

The clinical symptoms described in PSC as well as the laboratory tests are not specific but result in further diagnostic steps such as cholangiography, magnetic resonance imaging or liver biopsy. The definite diagnosis of PSC cannot be confirmed until secondary causes of cholangitis are ruled out.

3.1. Clinical presentation 

At the time of diagnosis, a considerable proportion of the patients (21–44%) is asymptomatic [6], [17], [77] and is identified just through incidental or selective (in case of IBD) testing of the liver enzymes. One recent study showed that in contrast to the period 1984–1998, patients in the following 6 years (1998–2004) were more often asymptomatic and older when first diagnosed or diagnosed in earlier pre-cirrhotic stages and presented less frequently with associated IBD [78].

Symptomatic patients present frequently with abdominal pain (33–37%), jaundice (27–30%) or pruritus (20–40%) and with fever (11–35%). Other common findings in clinical examinations and abdominal ultrasound are hepatomegaly (44–55%) or splenomegaly (29–30%). Only 2–4% patients have ascites and 2.6–6% have a history of variceal bleeding prior to diagnosis [16], [17], [78], [79]. The general prevalence of esophageal varices diagnosed by upper endoscopy varies from 7% to 36% [17], [80]. Fatigue was described as a common symptom in PSC. However, a sophisticated study addressing this issue demonstrated that fatigue did not differ in PSC patients and patients with IBD alone, and that its prevalence was even lower than in age- and sex-matched subjects from the general population [81].

Cholangiocarcinoma is found in 3.3% of PSC patients within the first 3 months after diagnosis, and in 5% within the first year. These patients tend to be more symptomatic on initial diagnosis; therefore, the first clinical evaluation is of particular importance [15], [17], [82].

Apart from the well-known association with IBD more than 20% of PSC patients display at least one additional extraintestinal autoimmune feature: most frequently, insulin dependent diabetes mellitus was found in 10.1%, thyroid disorders in 8.4% and psoriasis in 4.2% [20].

Another frequent finding in more advanced stages of the disease is an osteopenic bone disease with 50% of the patients having a bone mineral density below the fracture threshold [83].

3.2. Biochemistry and immunoserology 

PSC patients typically present with a cholestatic biochemical profile with 3–10 times of the upper limit increased levels of the serum alkaline phosphatase (AP). However, this finding is neither specific nor mandatory [79], [84]. Slight increases of the serum aminotransferase values are also frequently found. Serum bilirubin levels are usually normal at the beginning, but with progression of the disease they increase with fluctuations due to choledocholithiasis or dominant stenoses. Since hepatic synthesis function is initially unimpaired, parameters like albumin, cholinesterase or prothrombin time are normal at early stages.

As mentioned above, multiple autoantibodies can be detected in PSC [33] however, as Terjung et al. [36] stated, only p-ANCA might play some diagnostic role and there is no correlation with clinical parameters or the clinical spectrum of the disease.

3.3. Endoscopy 

The most important diagnostic tool in the establishment of PSC are the cholangiographic features of the biliary tract. So far, endoscopic retrograde cholangiography (ERC) remains the current gold standard for imaging of the biliary tract in patients with PSC. The intra- and/or extrahepatic bile ducts show localized or multifocal strictures and intervening segments of normal or dilated ducts. The cholangiographic appearance of PSC includes a broad spectrum of features. While some patients may have primarily extrahepatic bile duct alterations, others might represent with normal common bile duct but significant intrahepatic changes. Li-Yeng and Goldberg proposed a classification of biliary tract alterations in PSC. This classification has been slightly modified by Majoie et al. and amended by Rajaram et al. (Table 2) [85], [86]. The classification separately grades extra- and intrahepatic affections of the bile ducts. Alterations range from strictures with minimal dilatations to basically complete loss of peripheral ducts. Examples of radiographic PSC-associated alterations are shown in Fig. 1. Endoscopically detectable alterations of the bile ducts and biliary tree are limited to patients with large bile duct PSC. Patients with small bile duct PSC present with similar biochemical and histological features as PSC, but with a normal cholangiogram [87]. Therefore, a normal cholangiogram in a patient with cholestasis cannot rule out PSC and requires additional diagnostic tests, such as a liver biopsy. Vice versa, other cholestatic liver diseases present with ERC features similar to PSC [88]. Especially ischemic lesions and secondary biliary cholangitis may present with similar bile duct lesion in the cholangiogram. Over recent years, various groups reported an ischemic-like cholangiopathy with secondary sclerosing cholangitis and biliary cast formation in patients who had survived prolonged intensive care treatment (Fig. 2) [89], [90], [91]. Therefore, in addition to ERC the patient’s history, laboratory tests and histology have to be taken into account before the diagnosis of PSC can be established. The risk of post ERCP pancreatitis is not increased in PSC patients if compared to non-PSC patients [92], [93]. While various studies found the incidence of ERC-induced cholangitis to be approximately 1% in unselected patient cohorts, van Milligen et al. reported a 10% incidence of cholangitis in PSC patients [94], [95], [96], [97]. The increased risk of cholangitis supports the concept of antibiotic prophylaxis and addition of antibiotics to the contrast agent. Stiehl et al. for example, reported an ERC-related cholangitis in only 3.3% in their cohort of PSC patients, however, they consequently administered peri-interventional i.v. antibiotics and added antibiotics to the contrast agent [93]. Unfortunately, prospective and comparative data have not been reported so far concerning this specific issue.

Table 2. Cholangiographic classification system for primary sclerosing cholangitis (modified from [112], [146])
Intrahepatic
Type 0No abnormalities
Type IMultiple strictures with normal caliber of the bile ducts or minimal dilatations
Type IIMultiple short, bandlike strictures, saccular dilatations, decreased arborisation
Type IIIDespite adequate filling pressure only central branches filled; severe pruning, one or more outpouchings
Extrahepatic
Type 0No abnormalities
Type IIrregularities of extrahepatic duct contour, without distant narrowing
Type IISegmental stenosis of extrahepatic duct, with smooth or irregular margin
Type IIIIrregular stenosis and beading of almost entire length of the common duct
Type IVExtremely irregular margin of the extrahepatic duct, diverticulumlike outpoutchings
  • View full-size image.
  • Fig. 2. 

    Secondary biliary sclerosis can mimick cholangiographic features of PSC. (A) The cholangiogram of a patient with ischemic-like cholangiopathy and biliary cast formation after prolonged anamnestic polytrauma with sepsis and mechanical ventilation. (B) A biliary cast that had been removed from the hepatic duct in this patient.

3.4. Magnetic resonance cholangiography (MRC) 

Considering the inevitable risks of ERC for serious complications such as cholangitis, pancreatitis, perforation or bleeding, alternative imaging procedures for diagnosing PSC have become more desirable. Hence, in recent years, magnetic resonance cholangiography (MRC) as a non-invasive technique has increasingly been used in the diagnosis of PSC.

A number of studies comparing both procedures found that MRC showed a sensitivity of 80–91%, a specificity of 85–99% and an accuracy between 83% and 93% [98], [99], [100], [101], [102], [103]. These results were only a little inferior to those obtained with ERC-techniques with a sensitivity 89–96%, specificity 8–100% and accuracy 85–97% [100], [102].

Despite similar accuracy, the findings leading to the diagnosis of PSC differ for both modalities. ERC depicts more bile duct stenoses and pruning while MRC finds more skip dilatations together with bile duct occlusions [103] (Fig. 3).

  • View full-size image.
  • Fig. 3. 

    ERC with the corresponding MRC of two patients with PSC. Patient A presents with multifocal strictures of the intrahepatic bile ducts and with a high-grade stenosis at the cystic duct junction. Patient B features a long-segment filiform stenosis of the common bile duct; the intrahepatic ducts seem to be profoundly narrowed in ERC while MRC accentuates the dilated bile ducts in intervening segments.

MRC has the advantage of visualizing bile ducts proximal to a complete bile duct obstruction and of providing additional diagnostic information on the liver parenchyma [100]. With the exception of some contraindications such as claustrophobia or the existence of metallic implants, diagnostic quality images can be obtained by MRC in nearly all patients, particularly in those individuals with biliary-enteric anastomosis or gastric bypass as well.

However, because of inferior spatial resolution, severe stenoses may appear as complete occlusions in MRC and mild wall irregularities can be easily overestimated [103]. Furthermore, in cirrhotic patients and if PSC is limited to peripheral ducts, the disease appears to be more difficult to detect with MRC [99]. Naturally, one considerable limitation of MRC is the fact that further diagnostic (i.e. brush cytology) or therapeutic (i.e. dilatation) interventions are not possible, but very necessary in the majority of cases according to one study [100].

Altogether, MRC seems to be a good initial approach in the diagnosis of PSC in asymptomatic patients without cholestasis or with only moderate cholestasis. It should be considered for follow-up studies or when a complete visualization of the biliary tract is necessary. However, ERC remains the gold standard at least for initial diagnosis and PSC management including exclusion of malignancy of stenotic bile ducts; in particular when diagnostic or therapeutic interventions are expected, then ERC is the procedure of choice [100], [101], [103].

3.5. Histology 

The main histopathological findings in PSC are less specific and include portal fibrosis (60–80%) and portal lymphocyte infiltration (69%), even cirrhosis is present in 9–33%. The more specific periductal fibrosis with the typical “onion skin”-pattern resulting in ductopenia as well as bile duct proliferation is found in 8–55% and cholestasis can be observed in 7–50% [47], [104].

Ludwig et al. classified histological features in PSC in four stages [47]: At stage I, changes such as cholangitis or portal hepatitis are confined to the portal tracts, at stage II fibrosis or hepatitis are also periportally found, septal fibrosis and/or bridging necrosis indicate stage III, while biliary cirrhosis defines stage IV.

However, because of the merely non-specific changes percutaneous liver biopsy is rarely diagnostic in PSC and is used primarily to exclude other coexisting diseases or to support the diagnosis in doubtful cases. A retrospective study revealed that liver biopsy in patients with a known PSC (assured by ERC) added new information and affected clinical management in only 1.3% [105]. Moreover, serial liver biopsies demonstrated a high degree of sampling variability [104], since PSC is a focal disease, so the usefulness of liver biopsy for staging, as some authors proposed, has to be questioned. Therefore, histology is no longer included in current survival models for PSC [17], [106].

3.6. Differential diagnosis and variant syndromes 

Other cholestatic liver diseases that feature similar cholangiographic findings as PSC have already been mentioned. In case of an AMA-negative cholestatic disease with a normal cholangiogram, liver biopsy is recommended as the next diagnostic step, to rule out, among others, an AMA-negative PBC, an autoimmune cholangitis and sarcoidosis or cholestatic hepatitis [107]. If the histology is compatible with PSC and IBD is present, small-duct PSC (sdPSC) can be assumed.

Ludwig et al. [47] coined the phrase small-duct PSC instead of the obsolete term “pericholangitis” as designation for a chronic hepatitis associated with IBD, a normal cholangiogram and with biochemical and histological features compatible with PSC. The question of whether IBD presence is mandatory for the diagnosis has not yet been definitively resolved. According to current studies, only 3–17% of patients with sdPSC die or undergo liver transplantation compared with 42–47% in the group of patients with large-duct involvement. In addition, up to the present time cholangiocarcinoma (CC) has not been reported in patients with sdPSC [108], [109], [110], [111]. Approximately 12–16% of patients develop features of large-duct PSC during follow-up. UDCA therapy appears to improve liver biochemistry, however does not delay disease progression [111].

An overlap syndrome of PSC and autoimmune hepatitis (AIH) is presumed in patients with PSC, who also fulfil the diagnostic criteria for AIH. Based on the revised AIH scoring system [112], overlap was found in 1.4–8% of PSC patients [17], [113], [114]. Paediatric AIH patients showed an overlap with primary sclerosing cholangitis in 49% [115]. Patients with overlap syndrome exhibited higher serum levels of aminotransferases, IgG, total globulins and higher titers of autoantibodies. These patients were younger at presentation, association with IBD was less common [116] and their median histological score was higher than in patients with PSC alone [114]. Immunosuppressive therapy appears to be beneficial with a significant reduction of aminotransferases and the transplant-free survival appears to be higher than in PSC alone [113], [116].

Patients with IgG4-related autoimmune pancreatitis (sclerosing pancreatitis) often feature sclerosing cholangitis as an extrapancreatic manifestation. This type of sclerosing cholangitis resembles PSC in the cholangiogram but responds well to steroid therapy. It is characterized histologically by a marked lymphoplasmacytic infiltration with IgG4-positive plasma cells and CD4+/CD25+ regulatory T-cells [117], [118], [119]. On the other hand, a recent study from the Mayo clinic found elevated IgG4-levels in 9% of PSC patients [120]. These patients had in addition significantly higher levels of total bilirubin and of alkaline phosphatase, a lower frequency of IBD and a shorter time to liver transplantation. There were no differences in age, gender or in history of pancreatitis. The authors speculated that this special subset of PSC patients may behave similar to patients with autoimmune pancreatitis and that treatment of these patients with corticosteroids should be considered.

Back to Article Outline

4. Surveillance 

One of the major challenges for clinicians, with regard to the limited long-term prognosis of PSC, is an effective surveillance strategy in the medical care of these patients in order to select the optimum time for liver transplantation and to identify biliary tract malignancies as early as possible. Thus a number of studies attempted to figure out clinical, biochemical, endoscopic or imaging parameters which may help physicians to identify the patients with reduced long-term prognosis due to hepatic decompensation or cholangiocarcinoma (CC). However, all the surveillance strategies described are neither prospective nor are they based on patients of differing ethnicity enrolled by multiple centres from various parts of the world.

4.1. Biochemical and clinical parameters for surveillance 

Due to the fact that the prognostic scores for cirrhotic diseases such as the model for end-stage liver disease (MELD) or the Child–Pugh score do not assess survival in PSC well, to date a couple of prognostic scores which estimate survival of PSC patients have been developed, e.g. the well known Mayo survival model [106]. Age and bilirubin were identified as independent predictive parameters in all of these scores [16], [17], [106], [121], whereas the histological stage was only included in older scores. Low albumin proved to be of prognostic relevance in the two current scores [17], [106], while aspartate aminotransferase could be identified as an independent prognostic parameter only from the Mayo group. Other clinical parameters which evolved as independent prognostic factors in one or two of the scores were splenomegaly, hepatomegaly or variceal bleeding. Another recently published study identified an aspartate to alanine aminotransferase ratio ⩾1 as predictor of liver-related death with an almost 4-fold higher risk [122].

Multiple studies looked for risk factors or predictive parameters for CC; however the fact that most of the results of these studies were not reproducible, and in some cases even contradictory, demonstrates the enormous difficulty of predicting hepatobiliary malignancy in PSC. Parameters found to be predictive only in single studies which could not be verified in other studies were: history of variceal bleeding and history of proctocolectomy (mostly due to refractory UC) [123], smoking [82], [124], alcohol consumption [125], higher bilirubin levels on admission, previous colorectal cancer, and no UDCA treatment [126]. Three studies identified a longer duration of IBD as a risk factor [124], [126], [127] and several studies identified a recent diagnosis of PSC as a predictor of malignancy [124], [126], [127], [128]. At the time of cancer diagnosis, patients with hepatobiliary carcinoma present more often with abdominal pain according to three studies [82], [124], [127]. Hence a patient with a recently diagnosed PSC with severe symptoms and a long history of IBD should be examined very carefully in order to rule out the possibility of CC.

The detection of serum tumour markers such as carcinoembryonic antigen (CEA) or carbohydrate antigen 19-9 (CA19-9) was regarded initially as a helpful diagnostic tool in diagnosing CC in PSC. Preliminary retrospective studies found sufficient accuracy for a combined score of CA19-9 and CEA [129] respectively significantly higher levels of CA19-9 in PSC patients with CC [82]. Also, three current retrospective studies which used higher cut-off values between 100U/ml and 200U/ml [124], [125], [130] found significant correlations with CC. However, the results of two prospective studies in which serial tests of tumour markers were performed were disappointing in predicting CC [125], [131]. The main disadvantage of tumour markers is their unspecific increase in case of acute cholangitis or dominant stenoses [132]. Furthermore, only advanced cases seem to be detectable by CA19-9 which makes it inappropriate for surveillance [130]. Serum trypsinogen-2 was recently found to be superior to CA19-9 in differentiating patients with PSC and CC from patients with PSC alone [133]; further studies are needed to support these promising results.

4.2. Imaging techniques for surveillance 

Imaging techniques too are of restricted value in the early detection of CC in PSC due to the fact that they are unable to detect CC at a stage which allows for curative resection or liver transplantation. Indeed, in a retrospective study on 30 PSC patients with biliary tract carcinoma, CT and MRI were able to detect CC in about 85% [134], however this non-blinded retrospective study had several limitations and did not provide information on the patients’ outcome. In another study on 48 patients with PSC and CC, the diagnosis of CC was suspected in only 63% by CT and in 46% by ultrasound (US) [127] and the majority of cases were too far advanced for curative treatment.

Dynamic positron emission tomography with 18F-fluorodeoxyglucose (FDG-PET) was found to be useful for screening of CC in PSC patients, since in a study on 24 patients it detected (in contrast to CT) correctly 3 of 4 CC/high-grade-dysplasia and was false positive in only 1 of 20 patients [135]. However, other studies did not confirm these results [70], so that the value of FDG-PET as a surveillance method in PSC should be evaluated in prospective studies.

The sensitivity of ultrasound in detecting CC in PSC is low; nonetheless, it might be useful to assess cirrhotic complications of advanced disease. Furthermore, US allows to detect gallbladder polyps, which are in about 50% of cases malignant in PSC [136] which would indicate a cholecystectomy. Furthermore, due to the fact that the risk of pancreatic carcinoma appears to be increased more than 10-fold in PSC [15], ultrasound might be useful for screening in this high-risk population.

4.3. Endoscopic methods for surveillance 

Unfortunately, ERC alone has a low sensitivity and specificity to discriminate between benign and malignant bile duct stenoses [82], [137]. Therefore, routine surveillance ERCs have not been shown to be of significant benefit for the patients. Increase in cholestasis however, should trigger endoscopic examinations [124]. In addition to radiographic delineation of the biliary tree, ERC can be complemented by brush cytology, forceps biopsy, intraductal ultrasound and direct visualization of the biliary tree using ‘through the scope‘ cholangioscopy (Fig. 4). Depending on the various studies, the published sensitivity of ERC guided biliary brush cytology can be very low [138], [139], [140]. However, brush cytology has a high specificity for CC [138], [139], [140]. The low sensitivity requires repeat examinations, if cytology is negative while the cholangiogram is suspect of CC. ERC can be performed to advance forceps in the bile duct and obtaining histological samples. Advancing of rigid biopsy forceps in the common bile duct can induce perforations in particular in the hand of the unskilled physician. Unfortunately, to date no wire guided biopsy forceps has been introduced, so that performing a biopsy in the hepatic ducts remains difficult. However, the combination of forceps biopsy and brush cytology increases sensitivity [141]. Cholangioscopy enables direct visualization of the biliary epithelium. In a recent study from our department, Tischendorff et al. demonstrated that cholangioscopy is superior to ERC alone in discriminating between malignant and benign strictures (Fig. 5) [142]. With the development of a 4-way deflecting cholangioscope and cholangioscopy guided biopsies further improvement in the diagnosis of early CC may be achieved [143].

Intraductal ultrasound may be another important technical addition for differential diagnosis of dominant strictures. In addition to cholangioscopy, Tischendorff et al. studied the role of intraductal ultrasound to discriminate between benign and malignant strictures. In comparison to solely ERC, intraductal ultrasound (IDUS) significantly increased sensitivity from 62.5% to 87.5% and specificity from 53.1% to 90.6% [144]. In addition to the above mentioned methods, ERC can be used to aspirate bile fluid. Kubicka and colleagues measured mutations in the K-ras oncogene in epithelia derived from bile fluid of PSC patients [145]. While k-ras mutations can be detected in the bile of PSC patients without CC, however, patients that were positive for k-ras mutations were at a significantly higher risk to develop CC. Biliary insulin-like growth factor I (IGF-I) is significantly increased in patients with CC and can distinguish between carcinoma and benign strictures [146]. Whether these promising data can be applied for PSC patients, still needs to be investigated.

Approximately 60–80% of patients with PSC suffer from IBD [17], [147]. UC constitutes the biggest group with nearly 80% [17], [147]. Chronic intestinal inflammation increases the risk of colonic neoplasms. A subsequent increase in colorectal cancer incidence has been reported in association with ulcerative colitis. A cancer incidence of approximately 9% and 30% after 20 and 30 years of disease has been reported [148]. Several studies have indicated that patients with UC and coexisting PSC may be at an even higher risk for the development of CRC [149], [150], [151], [152], [153], [154]. Broome et al. reported an almost 5-fold increase in the absolute cumulative risks of developing colorectal cancer or dysplasia for UC patients with PSC after 20 years of colitis [154]. If possible, surveillance colonoscopy should be performed during remission in order to allow differentiation between reactive changes from dysplasia. Chromoendoscopy and zoom colonoscopy might be helpful to unmask intraepithelial neoplasia and guide biopsy [155], [156].

Back to Article Outline

5. Treatment 

5.1. Medical therapy 

Present day data and clinical experience do not suggest that PSC represents a disease which is curable by medical therapy [157]. A cure would include the improvement or normalization of abnormal cholestatic biochemical features but more importantly the improvement of sclerosing changes to the intra- and extrahepatic biliary tree, which ultimately lead to biliary cirrhosis, to episodes of cholangitis, and which carry the risk of cholangiocellular carcinoma. The only available drug that combines a favourable toxicity profile and can lead to a reduction of cholestatic serum parameters is currently ursodeoxycholic acid (UDCA). Predictive scores which have been developed to assess the progress of PSC in view of the clinical experiences of high interindividual variability and unpredictable acceleration episodes almost always contain serum bilirubin as a parameter [16], [77], [106], [121], [158], [159]. Between 1998 and 2000 four such scores have been reported that employ bilirubin in addition to age, histology, variceal bleeding, hepatomegaly, inflammatory bowel disease, albumin, AST, and haemoglobin [16], [77], [106], [121]. From this perspective, an improvement of the parameter bilirubin, common to these four scores, would be a plausible indicator of an improved prognosis. However, a number of controversies surround the use of UDCA. In two studies by Mitchell et al. and Harnois et al. published in 2001, an improvement was documented using 20mg/kg body weight, and 25–30mg/kg body weight, respectively [160], [161]. Both use UDCA doses which are considerably higher than those common in the therapy of primary biliary cirrhosis (PBC) (15mg/kg body weight). From these data a higher dose appeared to be more beneficial in PSC. However, a study analyzing UDCA in bile as a function of oral UDCA dose found that doses exceeding 25mg/kg body weight are not likely to be useful since the maximum transport of UDCA into the bile levelled off at this dose with no further increase [162]. After these and other initial reports, a meta-analysis was published in 2002 [162] which concluded that UDCA therapy improved biochemical parameters but that the overall beneficial effect in patients with PSC, in particular survival benefit, was uncertain. In 2005 a large study was reported that appeared to confirm this view. Olsson et al. studied 219 PSC patients in a placebo-controlled trial [163]. Treatment was carried out with 17–23mg/kg body weight of UDCA and a trend towards a better survival and less need for transplantation was seen which did not reach statistical significance. A difference in the incidence of CC was not observed. However, statistical analyses reported in this study concluded that 346 patients would have been required to reach statistical significance. Based on the body of the literature available, a positive effect of UDCA at present cannot be excluded and clearly larger placebo-controlled studies are required. This will only be possible in multi-centre approaches.

An additional effect of UDCA has been seen in two reports which observed a decrease of the dysplasia in colon polyps associated with UDCA doses as low as 10–15mg/kg body weight [164], [165]. Although this requires confirmation in larger studies, the association of PSC with ulcerative colitis in 75% of affected individuals would make this an interesting ancillary effect of UDCA therapy.

The issue of immunosuppression in PSC is controversial and the majority of centres and publications do not recommend the routine administration of corticosteroids and other immunosuppressants [157], [166]. In PSC one of the most feared and unpredictable complicating factors is bacterial cholangitis and cholangiosepsis. Immunosuppression would be expected to aggravate this complication. In rare instances such as overlapping features of PSC and autoimmune hepatitis (AIH), immunosuppression may be of benefit but this requires rigorous documentation of AIH which includes biopsies, autoimmune serology and suggestive biochemistry [167], [168].

5.2. Endoscopic therapy 

Inflammatory alterations in PSC can lead to almost complete stenosis of the extrahepatic biliary tree and can cause acute deterioration of liver function and more rapid progression to biliary cirrhosis (Fig. 4). Such lesions are termed as dominant biliary strictures. Endoscopic treatment of strictures can improve cholestasis and pruritus [91], [169], [170], [171]. Several modes of endoscopic treatment have been developed and applied successfully in PSC patients. Endoscopic treatment is especially aimed at strictures located in the common bile duct and main hepatic ducts. Current endoscopic therapy consists of either bougienage or balloon dilation of strictures with or without concomitant placement of endoprotheses [92], [93], [171], [172], [173], [174], [175]. Nasobiliary catheter drainage and lavage with or without instillation of corticosteroids have been successfully applied as well [176], [177]. These endoscopic treatment modalities are all aimed at maintaining biliary patency and at inducing sustained improvement of clinical and biochemical variables. Baluyut et al. showed that endoscopic treatment has a beneficial effect on survival in PSC patients when applying the Mayo clinic survival model [175]. Cholangioscopy, as an additional diagnostic tool revealed biliary stones in 56% of PSC patients [178]. 30% were missed on cholangiography and detected only by cholangioscopy. Clinical improvement after removal of stones was achieved in 63% of patients. Unfortunately, no randomised trials have been published which compare the various endoscopic treatment options for their efficacy in maintaining biliary patency. The limited number of patients and the very heterogenous patient population hinders the realization of randomised endoscopic trials. Therefore, so far, no general recommendation can be given concerning the best endoscopic approach to dominant strictures. When dominant strictures are treated endoscopically, it is most important not to overlook the presence of CC. Therefore, repeated brush cytologies and/or forceps biopsies of suspicious areas should be obtained.

5.3. Liver transplantation (OLT) 

In PSC patients, survival has been shown to be reduced both in symptomatic and in asymptomatic patients [106], [157], which is in part attributable to the inherent risk of CC affecting 10–20% of these patients and renders decision making for liver transplantation a formidable challenge. In addition, PSC patients with advanced destructive cholangiopathy frequently exhibit only mild signs of liver failure based upon coagulation abnormalities, hypoalbuminemia, or complications of portal hypertension [17]. The course of deterioration leading to liver failure is often observed after long periods of clinical stability and frequently proceeds rapidly following septic biliary complications. This is not well predicted by the aforementioned PSC scores and this is also true for the model of end-stage liver disease (MELD) which is used for organ allocation in the USA and as of 2006 in the Eurotransplant member countries.

Two major problems define the challenges involved in the indication for liver transplantation in PSC. Firstly, timing is difficult [179]. PSC patients are young and preemptive liver transplantation carries a higher short-term risk of OLT itself than the most likely short-term natural course of the disease. On the other hand, patients who urgently require OLT because of advanced biliary destruction frequently do not meet priority criteria calculated by the MELD system. Secondly, the 161-fold increase of CC risk [15] is an eventuality which may eliminate the option of liver transplantation altogether if evidence of CC is detected by diagnostic imaging procedures. The diagnosis of early CC is difficult and presently there is no single diagnostic procedure characterized by high sensitivity and specificity available [124]. Moreover, those patients at risk cannot be reliably identified.

In terms of practical management, the first point can only be addressed by careful clinical monitoring of PSC patients in transplant centres with an experienced hepatology team, where the likelihood of early complication diagnosis and management, as well as the individualized timing of listing for OLT is higher [17]. The second point has been addressed in two centres by establishing specific protocols for the management of hilar CC and OLT [180], [181]. Rea et al. reported a rigorous algorithm for non-resectable hilar CC patients who were carefully selected and capable of surviving chemotherapy, radiation therapy and surgery. A multimodal approach including neoadjuvant chemo-/radiation therapy, brachytherapy, chemotherapy, laparotomy and OLT was employed resulting in a 5-year survival of 82%, which did not differ from results in PSC patients without CC [180]. However, although attractive, these interdisciplinary strategies are best limited to studies and experienced liver transplant and hepatology centres.

Overall, the results of liver transplantation in PSC are good (Fig. 6), leading to 10-year survival rates of approximately 70% [182]. In our centre, the median survival of PSC patients with CC was 12.7 months and all PSC patients irrespective of OLT had a mean survival of 112 months [124]. Recurrence after OLT is difficult to diagnose but appears to occur in up to 25% of patients [183]. Liver transplantation continues to represent the only curative option in PSC. Future developments will have to address the missing sensitivity and specificity of early CC detection, as well as the clinical prediction of the disease course and consequently, specific OLT allocation criteria for this group of patients.

  • View full-size image.
  • Fig. 6. 

    Kaplan–Meier analysis of cumulative survival after liver transplantation from 01/2003 to 08/2007 at Hannover Medical School comparing 55 patients with PSC (incl. five patients with CC) and 318 patients with other chronic liver diseases (hepatitis B and C, alcoholic liver disease, hepatocellular carcinoma and others). The log-rank-test shows a significant better survival of patients with PSC (p<0.01).

5.4. Treatment of cholangiocarcinoma in PSC 

Surgical resection or liver transplantation is the only curative option for patients with PSC-associated CC. However, the prognosis of patients with CC is poor, even after surgical resection. A large population-based study recently showed that survival after surgery for extrahepatic CC has dramatically improved since 1973. However, patients with intrahepatic CC have achieved an improvement in survival largely confined to more recent years. This may be explained by innovative developments in imaging technology, improvements in patient selection and advances in surgical techniques [184]. In the therapy of hilar CC, the most favourable results with 5-year survival rates of 61% are achieved by no-touch-technique, en-bloc-resection and wide tumour-free margins [185].

Compared to patients with non-malignant diseases, patients with PSC-associated CC have a worse prognosis after liver transplantation. Due to the shortage of donor organs, liver transplantation for patients with CC has therefore been abandoned by most liver centres. The above mentioned non-randomised pilot study with neoadjuvant radiochemotherapy reported excellent 5-year survival rates of 80%, at least in a subset of patients with PSC-associated CC. In one study liver transplantation with neoadjuvant chemoradiation achieved an even better survival with less recurrence than conventional resection [180]. There are presently no randomised controlled studies using this neoadjuvant strategy and, therefore, the value of neoadjuvant radiochemotherapy and liver transplantation for patients with PSC-associated CC is still unclear. Obvious limitations of this strategy are a substantial drop out rate during the neoadjuvant therapy due to tumour progression and treatment-related complications, such as vascular complications after liver transplantation [186].

Palliative therapy of PSC-associated CC includes endoscopic management of biliary stenosis (dilatation, stenting), treatment of bacterial cholangitis and systemic chemotherapy. A randomised study with photodynamic therapy of CC resulted in prolongation of survival (493 days versus 98 days; p<0.0001), improved biliary drainage and better quality of life for the patients compared with endoscopic stenting alone [187]. Although a randomised study investigating the combination of chemotherapy and PDT is still not available, there is evidence of synergistic antitumoural activity of local PDT and systemic chemotherapy in cell culture experiments and early clinical studies [188].

There is only a limited number of studies regarding the systemic treatment options for biliary cancers. To date, the best response rates have been achieved with combination chemotherapies containing platinum analogues and gemcitabine. In the absence of larger clinical phase III trials, a standard chemotherapy for biliary cancers does not exist today [189].

Back to Article Outline

6. Conclusion 

Primary sclerosing cholangitis represents in many ways one of the most intriguing challenges of current hepatology. Its aetiology is still mysterious though a number of promising experimental approaches enlighten the different aspects of pathophysiology. PSC is not a classical autoimmune disease but the increasing understanding of underlying immunological mechanisms stimulates further investigations; the interaction between biliary epithelial cells and cellular and humoral immunity and the search for triggers of a deregulated immunity is of particular interest in this context. At present, there is no effective pharmacotherapy available, thus new insights into pathophysiological mechanisms will hopefully lead to new therapeutic innovations. Advances of endoscopic techniques promise additional possibilities in diagnosis and treatment. Even though the clinical course of the disease is rather variable, the mean survival of PSC patients is markedly shortened. Cholangiocarcinoma is a frequent outcome of PSC with a very poor prognosis. Therefore clinical management is exceptionally demanding. Advances in new imaging techniques expand the diagnostic options and allow new views on the disease. Considering the high risk of malignancy effective and evidence-based surveillance strategies based on a combination of endoscopic, imaging and biochemical techniques are urgently required. These will be beneficial for the timing of liver transplantation, the only curative treatment at present, and the current allocation systems should account for the special features of this disease.

Finally, significant progress in the management of PSC will depend on breakthroughs in the pathophysiological understanding of this mysterious disease. These studies will need to look at the site of action which is the biliary tree. Thus endoscopic management will go hand in hand with studies on aetiology and pathogenesis that rely on the investigation of biological materials obtained endoscopically from the site of action, e.g. the biliary tree with its pathological changes, in particular bile duct epithelium and the pathognomonic dominant biliary strictures. Hopefully, the years ahead will be interesting for the sake of our patients.

Back to Article Outline

References 

  1. Bargen J. Complications and sequelae of chronic ulcerative colitis. Ann Intern Med. 1929;3:335–352
  2. Kimmelstiel P, Large HL, Verner HD. Liver damage in ulcerative colitis. Am J Pathol. 1952;28:259–289
  3. Schrumpf E, Boberg KM. Epidemiology of primary sclerosing cholangitis. Best Pract Res Clin Gastroenterol. 2001;15:553–562
  4. Boberg KM, Aadland E, Jahnsen J, Raknerud N, Stiris M, Bell H. Incidence and prevalence of primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis in a Norwegian population. Scand J Gastroenterol. 1998;33:99–103
  5. Kaplan GG, Laupland KB, Butzner D, Urbanski SJ, Lee SS. The burden of large and small duct primary sclerosing cholangitis in adults and children: a population-based analysis. Am J Gastroenterol. 2007;102:1042–1049
  6. Bambha K, Kim WR, Talwalkar J, Torgerson H, Benson JT, Therneau TM, et al. Incidence, clinical spectrum, and outcomes of primary sclerosing cholangitis in a United States community. Gastroenterology. 2003;125:1364–1369
  7. Kingham JG, Kochar N, Gravenor MB. Incidence, clinical patterns, and outcomes of primary sclerosing cholangitis in South Wales, United Kingdom. Gastroenterology. 2004;126:1929–1930
  8. Escorsell A, Pares A, Rodes J, Solis-Herruzo JA, Miras M, de la Morena E. Epidemiology of primary sclerosing cholangitis in Spain. Spanish Association for the Study of the Liver. J Hepatol. 1994;21:787–791
  9. Ang TL, Fock KM, Ng TM, Teo EK, Chua TS, Tan JY. Clinical profile of primary sclerosing cholangitis in Singapore. J Gastroenterol Hepatol. 2002;17:908–913
  10. Takikawa H, Takamori Y, Tanaka A, Kurihara H, Nakanuma Y. Analysis of 388 cases of primary sclerosing cholangitis in Japan; presence of a subgroup without pancreatic involvement in older patients. Hepatol Res. 2004;29:153–159
  11. Hurlburt KJ, McMahon BJ, Deubner H, Hsu-Trawinski B, Williams JL, Kowdley KV. Prevalence of autoimmune liver disease in Alaska Natives. Am J Gastroenterol. 2002;97:2402–2407
  12. Olsson R, Danielsson A, Jarnerot G, Lindstrom E, Loof L, Rolny P, et al. Prevalence of primary sclerosing cholangitis in patients with ulcerative colitis. Gastroenterology. 1991;100:1319–1323
  13. Mitchell SA, Thyssen M, Orchard TR, Jewell DP, Fleming KA, Chapman RW. Cigarette smoking, appendectomy, and tonsillectomy as risk factors for the development of primary sclerosing cholangitis: a case control study. Gut. 2002;51:567–573
  14. Loftus EV, Sandborn WJ, Tremaine WJ, Mahoney DW, Zinsmeister AR, Offord KP, et al. Primary sclerosing cholangitis is associated with nonsmoking: a case-control study. Gastroenterology. 1996;110:1496–1502
  15. Bergquist A, Ekbom A, Olsson R, Kornfeldt D, Loof L, Danielsson A, et al. Hepatic and extrahepatic malignancies in primary sclerosing cholangitis. J Hepatol. 2002;36:321–327
  16. Broome U, Olsson R, Loof L, Bodemar G, Hultcrantz R, Danielsson A, et al. Natural history and prognostic factors in 305 Swedish patients with primary sclerosing cholangitis. Gut. 1996;38:610–615
  17. Tischendorf JJ, Hecker H, Kruger M, Manns MP, Meier PN. Characterization, outcome, and prognosis in 273 patients with primary sclerosing cholangitis: a single center study. Am J Gastroenterol. 2007;102:107–114
  18. O’Mahony CA, Vierling JM. Etiopathogenesis of primary sclerosing cholangitis. Semin Liver Dis. 2006;26:3–21
  19. Worthington J, Cullen S, Chapman R. Immunopathogenesis of primary sclerosing cholangitis. Clin Rev Allergy Immunol. 2005;28:93–103
  20. Saarinen S, Olerup O, Broome U. Increased frequency of autoimmune diseases in patients with primary sclerosing cholangitis. Am J Gastroenterol. 2000;95:3195–3199
  21. Bergquist A, Lindberg G, Saarinen S, Broome U. Increased prevalence of primary sclerosing cholangitis among first-degree relatives. J Hepatol. 2005;42:252–256
  22. Donaldson PT. Genetics of liver disease: immunogenetics and disease pathogenesis. Gut. 2004;53:599–608
  23. Norris S, Kondeatis E, Collins R, Satsangi J, Clare M, Chapman R, et al. Mapping MHC-encoded susceptibility and resistance in primary sclerosing cholangitis: the role of MICA polymorphism. Gastroenterology. 2001;120:1475–1482
  24. Donaldson PT, Norris S. Evaluation of the role of MHC class II alleles, haplotypes and selected amino acid sequences in primary sclerosing cholangitis. Autoimmunity. 2002;35:555–564
  25. Spurkland A, Saarinen S, Boberg KM, Mitchell S, Broome U, Caballeria L, et al. HLA class II haplotypes in primary sclerosing cholangitis patients from five European populations. Tissue Antigens. 1999;53:459–469
  26. Henckaerts L, Fevery J, Van Steenbergen W, Verslype C, Yap P, Nevens F, et al. CC-type chemokine receptor 5-Delta32 mutation protects against primary sclerosing cholangitis. Inflamm Bowel Dis. 2006;12:272–277
  27. Eri R, Jonsson JR, Pandeya N, Purdie DM, Clouston AD, Martin N, et al. CCR5-Delta32 mutation is strongly associated with primary sclerosing cholangitis. Genes Immun. 2004;5:444–450
  28. Yang X, Cullen SN, Li JH, Chapman RW, Jewell DP. Susceptibility to primary sclerosing cholangitis is associated with polymorphisms of intercellular adhesion molecule-1. J Hepatol. 2004;40:375–379
  29. Bowlus CL, Karlsen TH, Broome U, Thorsby E, Vatn M, Schrumpf E, et al. Analysis of MAdCAM-1 and ICAM-1 polymorphisms in 365 Scandinavian patients with primary sclerosing cholangitis. J Hepatol. 2006;45:704–710
  30. Mitchell SA, Grove J, Spurkland A, Boberg KM, Fleming KA, Day CP, et al. Association of the tumour necrosis factor alpha-308 but not the interleukin 10-627 promoter polymorphism with genetic susceptibility to primary sclerosing cholangitis. Gut. 2001;49:288–294
  31. Gallegos-Orozco JF, Yurk CE, Wang N, Rakela J, Charlton MR, Cutting GR, et al. Lack of association of common cystic fibrosis transmembrane conductance regulator gene mutations with primary sclerosing cholangitis. Am J Gastroenterol. 2005;100:874–878
  32. Sheth S, Shea JC, Bishop MD, Chopra S, Regan MM, Malmberg E, et al. Increased prevalence of CFTR mutations and variants and decreased chloride secretion in primary sclerosing cholangitis. Hum Genet. 2003;113:286–292
  33. Angulo P, Peter JB, Gershwin ME, DeSotel CK, Shoenfeld Y, Ahmed AE, et al. Serum autoantibodies in patients with primary sclerosing cholangitis. J Hepatol. 2000;32:182–187
  34. Mulder AH, Horst G, Haagsma EB, Limburg PC, Kleibeuker JH, Kallenberg CG. Prevalence and characterization of neutrophil cytoplasmic antibodies in autoimmune liver diseases. Hepatology. 1993;17:411–417
  35. Bansi DS, Fleming KA, Chapman RW. Importance of antineutrophil cytoplasmic antibodies in primary sclerosing cholangitis and ulcerative colitis: prevalence, titre, and IgG subclass. Gut. 1996;38:384–389
  36. Terjung B, Spengler U. Role of auto-antibodies for the diagnosis of chronic cholestatic liver diseases. Clin Rev Allergy Immunol. 2005;28:115–133
  37. Terjung B, Spengler U, Sauerbruch T, Worman HJ. “Atypical p-ANCA” in IBD and hepatobiliary disorders react with a 50-kilodalton nuclear envelope protein of neutrophils and myeloid cell lines. Gastroenterology. 2000;119:310–322
  38. Bodenheimer HC, LaRusso NF, Thayer WR, Charland C, Staples PJ, Ludwig J. Elevated circulating immune complexes in primary sclerosing cholangitis. Hepatology. 1983;3:150–154
  39. Senaldi G, Donaldson PT, Magrin S, Farrant JM, Alexander GJ, Vergani D, et al. Activation of the complement system in primary sclerosing cholangitis. Gastroenterology. 1989;97:1430–1434
  40. Bo X, Broome U, Remberger M, Sumitran-Holgersson S. Tumour necrosis factor alpha impairs function of liver derived T lymphocytes and natural killer cells in patients with primary sclerosing cholangitis. Gut. 2001;49:131–141
  41. Grant AJ, Lalor PF, Salmi M, Jalkanen S, Adams DH. Homing of mucosal lymphocytes to the liver in the pathogenesis of hepatic complications of inflammatory bowel disease. Lancet. 2002;359:150–157
  42. Eksteen B, Miles AE, Grant AJ, Adams DH. Lymphocyte homing in the pathogenesis of extra-intestinal manifestations of inflammatory bowel disease. Clin Med. 2004;4:173–180
  43. Salmi M, Jalkanen S. Endothelial ligands and homing of mucosal leukocytes in extraintestinal manifestations of IBD. Inflamm Bowel Dis. 1998;4:149–156
  44. Grant AJ, Lalor PF, Hubscher SG, Briskin M, Adams DH. MAdCAM-1 expressed in chronic inflammatory liver disease supports mucosal lymphocyte adhesion to hepatic endothelium (MAdCAM-1 in chronic inflammatory liver disease). Hepatology. 2001;33:1065–1072
  45. Eksteen B, Grant AJ, Miles A, Curbishley SM, Lalor PF, Hubscher SG, et al. Hepatic endothelial CCL25 mediates the recruitment of CCR9+ gut-homing lymphocytes to the liver in primary sclerosing cholangitis. J Exp Med. 2004;200:1511–1517
  46. Palmer KR, Duerden BI, Holdsworth CD. Bacteriological and endotoxin studies in cases of ulcerative colitis submitted to surgery. Gut. 1980;21:851–854
  47. Ludwig J, Barham SS, LaRusso NF, Elveback LR, Wiesner RH, McCall JT. Morphologic features of chronic hepatitis associated with primary sclerosing cholangitis and chronic ulcerative colitis. Hepatology. 1981;1:632–640
  48. Lichtman SN, Sartor RB, Keku J, Schwab JH. Hepatic inflammation in rats with experimental small intestinal bacterial overgrowth. Gastroenterology. 1990;98:414–423
  49. Bjornsson E, Cederborg A, Akvist A, Simren M, Stotzer PO, Bjarnason I. Intestinal permeability and bacterial growth of the small bowel in patients with primary sclerosing cholangitis. Scand J Gastroenterol. 2005;40:1090–1094
  50. Nilsson HO, Taneera J, Castedal M, Glatz E, Olsson R, Wadstrom T. Identification of Helicobacter pylori and other Helicobacter species by PCR, hybridization, and partial DNA sequencing in human liver samples from patients with primary sclerosing cholangitis or primary biliary cirrhosis. J Clin Microbiol. 2000;38:1072–1076
  51. Boomkens SY, de Rave S, Pot RG, Egberink HF, Penning LC, Rothuizen J, et al. The role of Helicobacter spp. in the pathogenesis of primary biliary cirrhosis and primary sclerosing cholangitis. FEMS Immunol Med Microbiol. 2005;44:221–225
  52. Krasinskas AM, Yao Y, Randhawa P, Dore MP, Sepulveda AR. Helicobacter pylori may play a contributory role in the pathogenesis of primary sclerosing cholangitis. Dig Dis Sci. 2007;52:2265–2270
  53. Mehal WZ, Hattersley AT, Chapman RW, Fleming KA. A survey of cytomegalovirus (CMV) DNA in primary sclerosing cholangitis (PSC) liver tissues using a sensitive polymerase chain reaction (PCR) based assay. J Hepatol. 1992;15:396–399
  54. Minuk GY, Rascanin N, Paul RW, Lee PW, Buchan K, Kelly JK. Reovirus type 3 infection in patients with primary biliary cirrhosis and primary sclerosing cholangitis. J Hepatol. 1987;5:8–13
  55. Pohl J, Ring A, Stremmel W, Stiehl A. The role of dominant stenoses in bacterial infections of bile ducts in primary sclerosing cholangitis. Eur J Gastroenterol Hepatol. 2006;18:69–74
  56. Bjornsson ES, Kilander AF, Olsson RG. Bile duct bacterial isolates in primary sclerosing cholangitis and certain other forms of cholestasis – a study of bile cultures from ERCP. Hepatogastroenterology. 2000;47:1504–1508
  57. Kulaksiz H, Rudolph G, Kloeters-Plachky P, Sauer P, Geiss H, Stiehl A. Biliary Candida infections in primary sclerosing cholangitis. J Hepatol. 2006;45:711–716
  58. Tietz PS, Larusso NF. Cholangiocyte biology. Curr Opin Gastroenterol. 2006;22:279–287
  59. Lazaridis KN, Strazzabosco M, Larusso NF. The cholangiopathies: disorders of biliary epithelia. Gastroenterology. 2004;127:1565–1577
  60. Trauner M, Meier PJ, Boyer JL. Molecular pathogenesis of cholestasis. N Engl J Med. 1998;339:1217–1227
  61. Fickert P, Wagner M, Marschall HU, Fuchsbichler A, Zollner G, Tsybrovskyy O, et al. 24-norUrsodeoxycholic acid is superior to ursodeoxycholic acid in the treatment of sclerosing cholangitis in Mdr2 (Abcb4) knockout mice. Gastroenterology. 2006;130:465–481
  62. Fickert P, Zollner G, Fuchsbichler A, Stumptner C, Weiglein AH, Lammert F, et al. Ursodeoxycholic acid aggravates bile infarcts in bile duct-ligated and Mdr2 knockout mice via disruption of cholangioles. Gastroenterology. 2002;123:1238–1251
  63. Pauli-Magnus C, Kerb R, Fattinger K, Lang T, Anwald B, Kullak-Ublick GA, et al. BSEP and MDR3 haplotype structure in healthy Caucasians, primary biliary cirrhosis and primary sclerosing cholangitis. Hepatology. 2004;39:779–791
  64. Das KM, Vecchi M, Sakamaki S. A shared and unique epitope(s) on human colon, skin, and biliary epithelium detected by a monoclonal antibody. Gastroenterology. 1990;98:464–469
  65. Mandal A, Dasgupta A, Jeffers L, Squillante L, Hyder S, Reddy R, et al. Autoantibodies in sclerosing cholangitis against a shared peptide in biliary and colon epithelium. Gastroenterology. 1994;106:185–192
  66. Xu B, Broome U, Ericzon BG, Sumitran-Holgersson S. High frequency of autoantibodies in patients with primary sclerosing cholangitis that bind biliary epithelial cells and induce expression of CD44 and production of interleukin 6. Gut. 2002;51:120–127
  67. Karrar A, Broome U, Sodergren T, Jaksch M, Bergquist A, Bjornstedt M, et al. Biliary epithelial cell antibodies link adaptive and innate immune responses in primary sclerosing cholangitis. Gastroenterology. 2007;132:1504–1514
  68. Spirli C, Nathanson MH, Fiorotto R, Duner E, Denson LA, Sanz JM, et al. Proinflammatory cytokines inhibit secretion in rat bile duct epithelium. Gastroenterology. 2001;121:156–169
  69. Spirli C, Fabris L, Duner E, Fiorotto R, Ballardini G, Roskams T, et al. Cytokine-stimulated nitric oxide production inhibits adenylyl cyclase and cAMP-dependent secretion in cholangiocytes. Gastroenterology. 2003;124:737–753
  70. Fevery J, Verslype C, Lai G, Aerts R, Van Steenbergen W. Incidence, diagnosis, and therapy of cholangiocarcinoma in patients with primary sclerosing cholangitis. Dig Dis Sci. 2007;52:3123–3135
  71. Komichi D, Tazuma S, Nishioka T, Hyogo H, Chayama K. Glycochenodeoxycholate plays a carcinogenic role in immortalized mouse cholangiocytes via oxidative DNA damage. Free Radic Biol Med. 2005;39:1418–1427
  72. Meng F, Yamagiwa Y, Ueno Y, Patel T. Over-expression of interleukin-6 enhances cell survival and transformed cell growth in human malignant cholangiocytes. J Hepatol. 2006;44:1055–1065
  73. Ahrendt SA, Rashid A, Chow JT, Eisenberger CF, Pitt HA, Sidransky D. p53 overexpression and K-ras gene mutations in primary sclerosing cholangitis-associated biliary tract cancer. J Hepatobiliary Pancreat Surg. 2000;7:426–431
  74. Boberg KM, Schrumpf E, Bergquist A, Broome U, Pares A, Remotti H, et al. Cholangiocarcinoma in primary sclerosing cholangitis: K-ras mutations and Tp53 dysfunction are implicated in the neoplastic development. J Hepatol. 2000;32:374–380
  75. Taniai M, Higuchi H, Burgart LJ, Gores GJ. p16INK4a promoter mutations are frequent in primary sclerosing cholangitis (PSC) and PSC-associated cholangiocarcinoma. Gastroenterology. 2002;123:1090–1098
  76. Ahrendt SA, Eisenberger CF, Yip L, Rashid A, Chow JT, Pitt HA, et al. Chromosome 9p21 loss and p16 inactivation in primary sclerosing cholangitis-associated cholangiocarcinoma. J Surg Res. 1999;84:88–93
  77. Wiesner RH, Grambsch PM, Dickson ER, Ludwig J, MacCarty RL, Hunter EB, et al. Primary sclerosing cholangitis: natural history, prognostic factors and survival analysis. Hepatology. 1989;10:430–436
  78. Bergquist A, Said K, Broome U. Changes over a 20-year period in the clinical presentation of primary sclerosing cholangitis in Sweden. Scand J Gastroenterol. 2007;42:88–93
  79. Talwalkar JA, Lindor KD. Primary sclerosing cholangitis. Inflamm Bowel Dis. 2005;11:62–72
  80. Zein CO, Lindor KD, Angulo P. Prevalence and predictors of esophageal varices in patients with primary sclerosing cholangitis. Hepatology. 2004;39:204–210
  81. Bjornsson E, Simren M, Olsson R, Chapman RW. Fatigue in patients with primary sclerosing cholangitis. Scand J Gastroenterol. 2004;39:961–968
  82. Bergquist A, Glaumann H, Persson B, Broome U. Risk factors and clinical presentation of hepatobiliary carcinoma in patients with primary sclerosing cholangitis: a case-control study. Hepatology. 1998;27:311–316
  83. Hay JE, Lindor KD, Wiesner RH, Dickson ER, Krom RA, LaRusso NF. The metabolic bone disease of primary sclerosing cholangitis. Hepatology. 1991;14:257–261
  84. Lee YM, Kaplan MM. Primary sclerosing cholangitis. N Engl J Med. 1995;332:924–933
  85. Majoie CB, Reeders JW, Sanders JB, Huibregtse K, Jansen PL. Primary sclerosing cholangitis: a modified classification of cholangiographic findings. AJR Am J Roentgenol. 1991;157:495–497
  86. Rajaram R, Ponsioen CY, Majoie CB, Reeders JW, Lameris JS. Evaluation of a modified cholangiographic classification system for primary sclerosing cholangitis. Abdom Imaging. 2001;26:43–47
  87. Wee A, Ludwig J. Pericholangitis in chronic ulcerative colitis: primary sclerosing cholangitis of the small bile ducts?. Ann Intern Med. 1985;102:581–587
  88. Trauner M, Boyer JL. Cholestatic syndromes. Curr Opin Gastroenterol. 2004;20:220–230
  89. Engler S, Elsing C, Flechtenmacher C, Theilmann L, Stremmel W, Stiehl A. Progressive sclerosing cholangitis after septic shock: a new variant of vanishing bile duct disorders. Gut. 2003;52:688–693
  90. Gelbmann CM, Rummele P, Wimmer M, Hofstadter F, Gohlmann B, Endlicher E, et al. Ischemic-like cholangiopathy with secondary sclerosing cholangitis in critically ill patients. Am J Gastroenterol. 2007;102:1221–1229
  91. Byrne MF, Chong HI, O’Donovan D, Sheehan KM, Leader MB, Kay E, et al. Idiopathic cholangiopathy in a biliary cast syndrome necessitating liver transplantation following head trauma. Eur J Gastroenterol Hepatol. 2003;15:415–417
  92. van Milligen de Wit AW, van Bracht J, Rauws EA, Jones EA, Tytgat GN, Huibregtse K. Endoscopic stent therapy for dominant extrahepatic bile duct strictures in primary sclerosing cholangitis. Gastrointest Endosc. 1996;44:293–299
  93. Stiehl A, Rudolph G, Kloeters-Plachky P, Sauer P, Walker S. Development of dominant bile duct stenoses in patients with primary sclerosing cholangitis treated with ursodeoxycholic acid: outcome after endoscopic treatment. J Hepatol. 2002;36:151–156
  94. van Milligen de Wit AW, Rauws EA, van Bracht J, Mulder CJ, Jones EA, Tytgat GN, et al. Lack of complications following short-term stent therapy for extrahepatic bile duct strictures in primary sclerosing cholangitis. Gastrointest Endosc. 1997;46:344–347
  95. Freeman ML, Nelson DB, Sherman S, Haber GB, Herman ME, Dorsher PJ, et al. Complications of endoscopic biliary sphincterotomy. N Engl J Med. 1996;335:909–918
  96. Loperfido S, Angelini G, Benedetti G, Chilovi F, Costan F, De Berardinis F, et al. Major early complications from diagnostic and therapeutic ERCP: a prospective multicenter study. Gastrointest Endosc. 1998;48:1–10
  97. Masci E, Toti G, Mariani A, Curioni S, Lomazzi A, Dinelli M, et al. Complications of diagnostic and therapeutic ERCP: a prospective multicenter study. Am J Gastroenterol. 2001;96:417–423
  98. Ernst O, Asselah T, Sergent G, Calvo M, Talbodec N, Paris JC, et al. MR cholangiography in primary sclerosing cholangitis. AJR Am J Roentgenol. 1998;171:1027–1030
  99. Fulcher AS, Turner MA, Franklin KJ, Shiffman ML, Sterling RK, Luketic VA, et al. Primary sclerosing cholangitis: evaluation with MR cholangiography – a case-control study. Radiology. 2000;215:71–80
  100. Angulo P, Pearce DH, Johnson CD, Henry JJ, LaRusso NF, Petersen BT, et al. Magnetic resonance cholangiography in patients with biliary disease: its role in primary sclerosing cholangitis. J Hepatol. 2000;33:520–527
  101. Moff SL, Kamel IR, Eustace J, Lawler LP, Kantsevoy S, Kalloo AN, et al. Diagnosis of primary sclerosing cholangitis: a blinded comparative study using magnetic resonance cholangiography and endoscopic retrograde cholangiography. Gastrointest Endosc. 2006;64:219–223
  102. Berstad AE, Aabakken L, Smith HJ, Aasen S, Boberg KM, Schrumpf E. Diagnostic accuracy of magnetic resonance and endoscopic retrograde cholangiography in primary sclerosing cholangitis. Clin Gastroenterol Hepatol. 2006;4:514–520
  103. Textor HJ, Flacke S, Pauleit D, Keller E, Neubrand M, Terjung B, et al. Three-dimensional magnetic resonance cholangiopancreatography with respiratory triggering in the diagnosis of primary sclerosing cholangitis: comparison with endoscopic retrograde cholangiography. Endoscopy. 2002;34:984–990
  104. Olsson R, Hagerstrand I, Broome U, Danielsson A, Jarnerot G, Loof L, et al. Sampling variability of percutaneous liver biopsy in primary sclerosing cholangitis. J Clin Pathol. 1995;48:933–935
  105. Burak KW, Angulo P, Lindor KD. Is there a role for liver biopsy in primary sclerosing cholangitis?. Am J Gastroenterol. 2003;98:1155–1158
  106. Kim WR, Therneau TM, Wiesner RH, Poterucha JJ, Benson JT, Malinchoc M, et al. A revised natural history model for primary sclerosing cholangitis. Mayo Clin Proc. 2000;75:688–694
  107. Kim WR, Ludwig J, Lindor KD. Variant forms of cholestatic diseases involving small bile ducts in adults. Am J Gastroenterol. 2000;95:1130–1138
  108. Bjornsson E, Boberg KM, Cullen S, Fleming K, Clausen OP, Fausa O, et al. Patients with small duct primary sclerosing cholangitis have a favourable long term prognosis. Gut. 2002;51:731–735
  109. Broome U, Glaumann H, Lindstom E, Loof L, Almer S, Prytz H, et al. Natural history and outcome in 32 Swedish patients with small duct primary sclerosing cholangitis (PSC). J Hepatol. 2002;36:586–589
  110. Angulo P, Maor-Kendler Y, Lindor KD. Small-duct primary sclerosing cholangitis: a long-term follow-up study. Hepatology. 2002;35:1494–1500
  111. Charatcharoenwitthaya P, Angulo P, Enders FB, Lindor KD. Impact of inflammatory bowel disease and ursodeoxycholic acid therapy on small-duct primary sclerosing cholangitis. Hepatology. 2008;47:133–142
  112. Alvarez F, Berg PA, Bianchi FB, Bianchi L, Burroughs AK, Cancado EL, et al. International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol. 1999;31:929–938
  113. van Buuren HR, van Hoogstraten HJE, Terkivatan T, Schalm SW, Vleggaar FP. High prevalence of autoimmune hepatitis among patients with primary sclerosing cholangitis. J Hepatol. 2000;33:543–548
  114. Kaya M, Angulo P, Lindor KD. Overlap of autoimmune hepatitis and primary sclerosing cholangitis: an evaluation of a modified scoring system. J Hepatol. 2000;33:537–542
  115. Gregorio GV, Portmann B, Karani J, Harrison P, Donaldson PT, Vergani D, et al. Autoimmune hepatitis/sclerosing cholangitis overlap syndrome in childhood: a 16-year prospective study. Hepatology. 2001;33:544–553
  116. Floreani A, Rizzotto ER, Ferrara F, Carderi I, Caroli D, Blasone L, et al. Clinical course and outcome of autoimmune hepatitis/primary sclerosing cholangitis overlap syndrome. Am J Gastroenterol. 2005;100:1516–1522
  117. Kawa S, Hamano H, Umemura T, Kiyosawa K, Uehara T. Sclerosing cholangitis associated with autoimmune pancreatitis. Hepatol Res. 2007;37:S487–S495
  118. Nakanuma Y, Zen Y. Pathology and immunopathology of immunoglobulin G4-related sclerosing cholangitis: the latest addition to the sclerosing cholangitis family. Hepatol Res. 2007;37:S478–S486
  119. Zen Y, Harada K, Sasaki M, Sato Y, Tsuneyama K, Haratake J, et al. IgG4-related sclerosing cholangitis with and without hepatic inflammatory pseudotumor, and sclerosing pancreatitis-associated sclerosing cholangitis: do they belong to a spectrum of sclerosing pancreatitis?. Am J Surg Pathol. 2004;28:1193–1203
  120. Mendes FD, Jorgensen R, Keach J, Katzmann JA, Smyrk T, Donlinger J, et al. Elevated serum IgG4 concentration in patients with primary sclerosing cholangitis. Am J Gastroenterol. 2006;101:2070–2075
  121. Dickson ER, Murtaugh PA, Wiesner RH, Grambsch PM, Fleming TR, Ludwig J, et al. Primary sclerosing cholangitis: refinement and validation of survival models. Gastroenterology. 1992;103:1893–1901
  122. Nyblom H, Nordlinder H, Olsson R. High aspartate to alanine aminotransferase ratio is an indicator of cirrhosis and poor outcome in patients with primary sclerosing cholangitis. Liver Int. 2007;27:694–699
  123. Burak K, Angulo P, Pasha TM, Egan K, Petz J, Lindor KD. Incidence and risk factors for cholangiocarcinoma in primary sclerosing cholangitis. Am J Gastroenterol. 2004;99:523–526
  124. Tischendorf JJ, Meier PN, Strassburg CP, Klempnauer J, Hecker H, Manns MP, et al. Characterization and clinical course of hepatobiliary carcinoma in patients with primary sclerosing cholangitis. Scand J Gastroenterol. 2006;41:1227–1234
  125. Chalasani N, Baluyut A, Ismail A, Zaman A, Sood G, Ghalib R, et al. Cholangiocarcinoma in patients with primary sclerosing cholangitis: a multicenter case-control study. Hepatology. 2000;31:7–11
  126. Brandsaeter B, Isoniemi H, Broome U, Olausson M, Backman L, Hansen B, et al. Liver transplantation for primary sclerosing cholangitis; predictors and consequences of hepatobiliary malignancy. J Hepatol. 2004;40:815–822
  127. Boberg KM, Bergquist A, Mitchell S, Pares A, Rosina F, Broome U, et al. Cholangiocarcinoma in primary sclerosing cholangitis: risk factors and clinical presentation. Scand J Gastroenterol. 2002;37:1205–1211
  128. Leidenius M, Hockersted K, Broome U, Ericzon BG, Friman S, Olausson M, et al. Hepatobiliary carcinoma in primary sclerosing cholangitis: a case control study. J Hepatol. 2001;34:792–798
  129. Ramage JK, Donaghy A, Farrant JM, Iorns R, Williams R. Serum tumor markers for the diagnosis of cholangiocarcinoma in primary sclerosing cholangitis. Gastroenterology. 1995;108:865–869
  130. Levy C, Lymp J, Angulo P, Gores GJ, Larusso N, Lindor KD. The value of serum CA 19-9 in predicting cholangiocarcinomas in patients with primary sclerosing cholangitis. Dig Dis Sci. 2005;50:1734–1740
  131. Bjornsson E, Kilander A, Olsson R. CA 19-9 and CEA are unreliable markers for cholangiocarcinoma in patients with primary sclerosing cholangitis. Liver. 1999;19:501–508
  132. Petersen-Benz C, Stiehl A. Impact of dominant stenoses on the serum level of the tumor marker CA19-9 in patients with primary sclerosing cholangitis. Z Gastroenterol. 2005;43:587–590
  133. Lempinen M, Isoniemi H, Makisalo H, Nordin A, Halme L, Arola J, et al. Enhanced detection of cholangiocarcinoma with serum trypsinogen-2 in patients with severe bile duct strictures. J Hepatol. 2007;47:677–683
  134. Campbell WL, Ferris JV, Holbert BL, Thaete FL, Baron RL. Biliary tract carcinoma complicating primary sclerosing cholangitis: evaluation with CT, cholangiography, US, and MR imaging. Radiology. 1998;207:41–50
  135. Prytz H, Keiding S, Bjornsson E, Broome U, Almer S, Castedal M, et al. Dynamic FDG-PET is useful for detection of cholangiocarcinoma in patients with PSC listed for liver transplantation. Hepatology. 2006;44:1572–1580
  136. Buckles DC, Lindor KD, Larusso NF, Petrovic LM, Gores GJ. In primary sclerosing cholangitis, gallbladder polyps are frequently malignant. Am J Gastroenterol. 2002;97:1138–1142
  137. Bergquist A, Broome U. Hepatobiliary and extra-hepatic malignancies in primary sclerosing cholangitis. Best Pract Res Clin Gastroenterol. 2001;15:643–656
  138. Boberg KM, Jebsen P, Clausen OP, Foss A, Aabakken L, Schrumpf E. Diagnostic benefit of biliary brush cytology in cholangiocarcinoma in primary sclerosing cholangitis. J Hepatol. 2006;45:568–574
  139. Ponsioen CY, Vrouenraets SM, van Milligen de Wit AW, Sturm P, Tascilar M, Offerhaus GJ, et al. Value of brush cytology for dominant strictures in primary sclerosing cholangitis. Endoscopy. 1999;31:305–309
  140. Lindberg B, Arnelo U, Bergquist A, Thorne A, Hjerpe A, Granqvist S, et al. Diagnosis of biliary strictures in conjunction with endoscopic retrograde cholangiopancreaticography, with special reference to patients with primary sclerosing cholangitis. Endoscopy. 2002;34:909–916
  141. Ponchon T, Gagnon P, Berger F, Labadie M, Liaras A, Chavaillon A, et al. Value of endobiliary brush cytology and biopsies for the diagnosis of malignant bile duct stenosis: results of a prospective study. Gastrointest Endosc. 1995;42:565–572
  142. Tischendorf JJ, Kruger M, Trautwein C, Duckstein N, Schneider A, Manns MP, et al. Cholangioscopic characterization of dominant bile duct stenoses in patients with primary sclerosing cholangitis. Endoscopy. 2006;38:665–669
  143. Chen YK, Pleskow DK. SpyGlass single-operator peroral cholangiopancreatoscopy system for the diagnosis and therapy of bile-duct disorders: a clinical feasibility study (with video). Gastrointest Endosc. 2007;65:832–841
  144. Tischendorf JJ, Meier PN, Schneider A, Manns MP, Kruger M. Transpapillary intraductal ultrasound in the evaluation of dominant bile duct stenoses in patients with primary sclerosing cholangitis. Scand J Gastroenterol. 2007;42:1011–1017
  145. Kubicka S, Kuhnel F, Flemming P, Hain B, Kezmic N, Rudolph KL, et al. K-ras mutations in the bile of patients with primary sclerosing cholangitis. Gut. 2001;48:403–408
  146. Alvaro D, Macarri G, Mancino MG, Marzioni M, Bragazzi M, Onori P, et al. Serum and biliary insulin-like growth factor I and vascular endothelial growth factor in determining the cause of obstructive cholestasis. Ann Intern Med. 2007;147:451–459
  147. Ponsioen CY, Vrouenraets SM, Prawirodirdjo W, Rajaram R, Rauws EA, Mulder CJ, et al. Natural history of primary sclerosing cholangitis and prognostic value of cholangiography in a Dutch population. Gut. 2002;51:562–566
  148. Ekbom A, Helmick C, Zack M, Adami HO. Ulcerative colitis and colorectal cancer. A population-based study. N Engl J Med. 1990;323:1228–1233
  149. Aadland E, Schrumpf E, Fausa O, Elgjo K, Heilo A, Aakhus T, et al. Primary sclerosing cholangitis: a long-term follow-up study. Scand J Gastroenterol. 1987;22:655–664
  150. Brentnall TA, Haggitt RC, Rabinovitch PS, Kimmey MB, Bronner MP, Levine DS, et al. Risk and natural history of colonic neoplasia in patients with primary sclerosing cholangitis and ulcerative colitis. Gastroenterology. 1996;110:331–338
  151. Broome U, Lindberg G, Lofberg R. Primary sclerosing cholangitis in ulcerative colitis – a risk factor for the development of dysplasia and DNA aneuploidy?. Gastroenterology. 1992;102:1877–1880
  152. Kornfeld D, Ekbom A, Ihre T. Is there an excess risk for colorectal cancer in patients with ulcerative colitis and concomitant primary sclerosing cholangitis? A population based study. Gut. 1997;41:522–525
  153. Shetty K, Rybicki L, Brzezinski A, Carey WD, Lashner BA. The risk for cancer or dysplasia in ulcerative colitis patients with primary sclerosing cholangitis. Am J Gastroenterol. 1999;94:1643–1649
  154. Broome U, Lofberg R, Veress B, Eriksson LS. Primary sclerosing cholangitis and ulcerative colitis: evidence for increased neoplastic potential. Hepatology. 1995;22:1404–1408
  155. Kiesslich R, Fritsch J, Holtmann M, Koehler HH, Stolte M, Kanzler S, et al. Methylene blue-aided chromoendoscopy for the detection of intraepithelial neoplasia and colon cancer in ulcerative colitis. Gastroenterology. 2003;124:880–888
  156. Hurlstone DP, McAlindon ME, Sanders DS, Koegh R, Lobo AJ, Cross SS. Further validation of high-magnification chromoscopic-colonoscopy for the detection of intraepithelial neoplasia and colon cancer in ulcerative colitis. Gastroenterology. 2004;126:376–378
  157. LaRusso NF, Shneider BL, Black D, Gores GJ, James SP, Doo E, et al. Primary sclerosing cholangitis: summary of a workshop. Hepatology. 2006;44:746–764
  158. Okolicsanyi L, Fabris L, Viaggi S, Carulli N, Podda M, Ricci G. Primary sclerosing cholangitis: clinical presentation, natural history and prognostic variables: an Italian multicentre study. The Italian PSC Study Group. Eur J Gastroenterol Hepatol. 1996;8:685–691
  159. Farrant JM, Hayllar KM, Wilkinson ML, Karani J, Portmann BC, Westaby D, et al. Natural history and prognostic variables in primary sclerosing cholangitis. Gastroenterology. 1991;100:1710–1717
  160. Mitchell SA, Bansi DS, Hunt N, Von Bergmann K, Fleming KA, Chapman RW. A preliminary trial of high-dose ursodeoxycholic acid in primary sclerosing cholangitis. Gastroenterology. 2001;121:900–907
  161. Harnois DM, Angulo P, Jorgensen RA, Larusso NF, Lindor KD. High-dose ursodeoxycholic acid as a therapy for patients with primary sclerosing cholangitis. Am J Gastroenterol. 2001;96:1558–1562
  162. Rost D, Rudolph G, Kloeters-Plachky P, Stiehl A. Effect of high-dose ursodeoxycholic acid on its biliary enrichment in primary sclerosing cholangitis. Hepatology. 2004;40:693–698
  163. Olsson R, Boberg KM, de Muckadell OS, Lindgren S, Hultcrantz R, Folvik G, et al. High-dose ursodeoxycholic acid in primary sclerosing cholangitis: a 5-year multicenter, randomized, controlled study. Gastroenterology. 2005;129:1464–1472
  164. Pardi DS, Loftus EV, Kremers WK, Keach J, Lindor KD. Ursodeoxycholic acid as a chemopreventive agent in patients with ulcerative colitis and primary sclerosing cholangitis. Gastroenterology. 2003;124:889–893
  165. Tung BY, Emond MJ, Haggitt RC, Bronner MP, Kimmey MB, Kowdley KV, et al. Ursodiol use is associated with lower prevalence of colonic neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis. Ann Intern Med. 2001;134:89–95
  166. van Hoogstraten HJ, Vleggaar FP, Boland GJ, van Steenbergen W, Griffioen P, Hop WC, et al. Budesonide or prednisone in combination with ursodeoxycholic acid in primary sclerosing cholangitis: a randomized double-blind pilot study. Belgian-Dutch PSC Study Group. Am J Gastroenterol. 2000;95:2015–2022
  167. Boberg KM, Fausa O, Haaland T, Holter E, Mellbye OJ, Spurkland A, et al. Features of autoimmune hepatitis in primary sclerosing cholangitis: an evaluation of 114 primary sclerosing cholangitis patients according to a scoring system for the diagnosis of autoimmune hepatitis. Hepatology. 1996;23:1369–1376
  168. Beuers U, Rust C. Overlap syndromes. Semin Liver Dis. 2005;25:311–320
  169. Stiehl A. Primary sclerosing cholangitis: the role of endoscopic therapy. Semin Liver Dis. 2006;26:62–68
  170. Stiehl A, Rost D. Endoscopic treatment of dominant stenoses in patients with primary sclerosing cholangitis. Clin Rev Allergy Immunol. 2005;28:159–165
  171. Bjornsson E, Lindqvist-Ottosson J, Asztely M, Olsson R. Dominant strictures in patients with primary sclerosing cholangitis. Am J Gastroenterol. 2004;99:502–508
  172. Johnson GK, Geenen JE, Venu RP, Schmalz MJ, Hogan WJ. Endoscopic treatment of biliary tract strictures in sclerosing cholangitis: a larger series and recommendations for treatment. Gastrointest Endosc. 1991;37:38–43
  173. Lombard M, Farrant M, Karani J, Westaby D, Williams R. Improving biliary-enteric drainage in primary sclerosing cholangitis: experience with endoscopic methods. Gut. 1991;32:1364–1368
  174. Linder S, Soderlund C. Endoscopic therapy in primary sclerosing cholangitis: outcome of treatment and risk of cancer. Hepatogastroenterology. 2001;48:387–392
  175. Baluyut AR, Sherman S, Lehman GA, Hoen H, Chalasani N. Impact of endoscopic therapy on the survival of patients with primary sclerosing cholangitis. Gastrointest Endosc. 2001;53:308–312
  176. Wagner S, Gebel M, Meier P, Trautwein C, Bleck J, Nashan B, et al. Endoscopic management of biliary tract strictures in primary sclerosing cholangitis. Endoscopy. 1996;28:546–551
  177. Allison MC, Burroughs AK, Noone P, Summerfield JA. Biliary lavage with corticosteroids in primary sclerosing cholangitis. A clinical, cholangiographic and bacteriological study. J Hepatol. 1986;3:118–122
  178. Awadallah NS, Chen YK, Piraka C, Antillon MR, Shah RJ. Is there a role for cholangioscopy in patients with primary sclerosing cholangitis?. Am J Gastroenterol. 2006;101:284–291
  179. Wiesner RH, Porayko MK, Dickson ER, Gores GJ, LaRusso NF, Hay JE, et al. Selection and timing of liver transplantation in primary biliary cirrhosis and primary sclerosing cholangitis. Hepatology. 1992;16:1290–1299
  180. Rea DJ, Heimbach JK, Rosen CB, Haddock MG, Alberts SR, Kremers WK, et al. Liver transplantation with neoadjuvant chemoradiation is more effective than resection for hilar cholangiocarcinoma. Ann Surg. 2005;242:451–458
  181. Sudan D, DeRoover A, Chinnakotla S, Fox I, Shaw B, McCashland T, et al. Radiochemotherapy and transplantation allow long-term survival for nonresectable hilar cholangiocarcinoma. Am J Transplant. 2002;2:774–779
  182. Graziadei IW, Wiesner RH, Marotta PJ, Porayko MK, Hay JE, Charlton MR, et al. Long-term results of patients undergoing liver transplantation for primary sclerosing cholangitis. Hepatology. 1999;30:1121–1127
  183. Graziadei IW, Wiesner RH, Batts KP, Marotta PJ, LaRusso NF, Porayko MK, et al. Recurrence of primary sclerosing cholangitis following liver transplantation. Hepatology. 1999;29:1050–1056
  184. Nathan H, Pawlik TM, Wolfgang CL, Choti MA, Cameron JL, Schulick RD. Trends in survival after surgery for cholangiocarcinoma: a 30-year population-based SEER database analysis. J Gastrointest Surg. 2007;11:1488–1496
  185. Jonas S, Benckert C, Thelen A, Lopez-Hanninen E, Rosch T, Neuhaus P. Radical surgery for hilar cholangiocarcinoma. Eur J Surg Oncol. 2007;23
  186. Mantel HT, Rosen CB, Heimbach JK, Nyberg SL, Ishitani MB, Andrews JC, et al. Vascular complications after orthotopic liver transplantation after neoadjuvant therapy for hilar cholangiocarcinoma. Liver Transpl. 2007;13:1372–1381
  187. Ortner ME, Caca K, Berr F, Liebetruth J, Mansmann U, Huster D, et al. Successful photodynamic therapy for nonresectable cholangiocarcinoma: a randomized prospective study. Gastroenterology. 2003;125:1355–1363
  188. Crescenzi E, Chiaviello A, Canti G, Reddi E, Veneziani BM, Palumbo G. Low doses of cisplatin or gemcitabine plus photofrin/photodynamic therapy: disjointed cell cycle phase-related activity accounts for synergistic outcome in metastatic non-small cell lung cancer cells (H1299). Mol Cancer Ther. 2006;5:776–785
  189. Malek NP, Greten T, Kubicka S. Systemic treatment of liver and biliary tumors. Internist (Berl). 2007;48:46–49

☆ The Authors T.J. Weismüller, J. Wedemeyer, C.P. Strassburg and S. Kubicka state that they have nothing to declare regarding conflict of interest and funding with respect to this manuscript. M.P. Manns is an investigator/consultant/speaker at Novartis, Roche, Schering-Plough, Gilead Sciences Inc., Tibotec, Vertex, GlaxoSmithKline, Boehringer Ingelheim, Bristol-Myers Squibb, Idenix and Merck. M.P. Manns received meeting support and lecture fees from the Falk Foundation, Freiburg, Germany. M.P. Manns received funding from Deutsche Forschungsgemeinschaft (KF0119, SFB 621, SFB738), DFG Cluster of Excellence “Rebirth” and Transplantation centre.

PII: S0168-8278(08)00059-7

doi:10.1016/j.jhep.2008.01.020

Journal of Hepatology
Volume 48, Supplement 1 , Pages S38-S57, 2008

Article Tools

* Image Usage & Resolution