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Clin Liver Dis 8 (2004) 195 – 211
Primary sclerosing cholangitis
Flavia D. Mendes, MD, Keith D. Lindor, MD*
Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, 200 First Street SW,
Rochester, MN 55905, USA
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease
of unknown origin that is strongly associated with inflammatory bowel disease
(IBD). It is characterized by progressive destruction of bile ducts, which may result in the development of biliary cirrhosis. Initially thought to be a rare disorder,
PSC is currently one of the more common indications for liver transplantation.
Epidemiology, natural history, and prognosis
The true incidence and prevalence of PSC is not well determined. Only a few
population-based studies have looked at the incidence and prevalence of PSC.
In Western populations, the estimated prevalence of PSC is 6 to 8 cases per
100,000 persons [1 –3]. Unpublished data from a population-based study performed in The Mayo Clinic and Foundation looking at the incidence of PSC
in Olmsted County, Minnesota, showed a significant increase in the incidence
of PSC in the period of 1991 through 2000, compared with 1976 through 1990
(1.48 versus 0.37 per 100,000 person-years). It was thought that this change
might indicate a true increase in the incidence of this disease.
The initial diagnosis is usually made within the third and fourth decades of
life. PSC has a male predominance, with a male:female ratio of 3:1.
As many as 80% of the patients with PSC have IBD. There are data suggesting
that PSC is the most common chronic liver disease in patients with IBD [4,5].
No correlation exists between the activity of IBD and the occurrence of PSC.
Some studies have shown smoking to be a protective factor against PSC
[6– 8], although the risk factors for developing PSC aside from IBD are unknown.
At the time of diagnosis, as many as 44% of the patients are asymptomatic;
however the condition tends to progress over time [9]. There is a suggestion that
survival is better in asymptomatic patients, but this possibility is controversial. In
* Corresponding author.
E-mail address: [email protected] (K.D. Lindor).
1089-3261/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved.
doi:10.1016/S1089-3261(03)00127-2
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F.D. Mendes, K.D. Lindor / Clin Liver Dis 8 (2004) 195–211
the three larger independent studies looking at the natural history of PSC, the
median survival time was approximately 12 years [9 – 11].
Several prognostic survival models have been developed in an attempt to
determine the rate of disease progression and the optimal timing for liver
transplantation [9– 12]. Most of these models are limited because they require
liver biopsy and use somewhat subjective variables. Most recently Kim et al [13]
proposed a new model that uses patient age, levels of serum bilirubin, albumin, and
aspartate aminotransferase, and history of variceal bleeding in assessing the risk
of patients with PSC. This model has not been prospectively validated, however.
Etiology and pathogenesis
Several causative mechanisms have been proposed to explain the pathogenesis
of PSC; however it still remains poorly understood. It seems that immunologic
mechanisms as well as nonimmunologic factors (eg, infection, toxins, and ischemia) could be responsible for the development of this disease in genetically
susceptible individuals.
Genetic predisposition
The concept of genetic susceptibility to PSC is supported by reports of familial
occurrence of this disorder [14], as well as by HLA associations.
Early studies described an increased frequency of HLA B8 and DR3 in patients with PSC [15 – 17]. These antigens are known to be associated with several
autoimmune diseases. Subsequent studies also showed susceptibility to be linked
to the presence of HLA DRw52a, HLA DR2, and HLA DR4, which may be a
marker of rapid disease progression [18 –20].
More recent data suggest that genetic susceptibility to PSC may be related to
polymorphisms of the tumor necrosis factor (TNF) gene, also found in chromosome 6, near the HLA genes [21]. Non-MHC genes may also be implicated.
Further work is required to aid in the understanding of the complex mechanisms of genetic susceptibility in PSC.
Immunologic factors
Several humoral and cellular immunologic alterations have been described in
patients with PSC, suggesting that immune-mediated mechanisms play a significant role in the pathogenesis of this disorder.
A Swedish study found an increased frequency of autoimmune disorders among
PSC patients compared with IBD patients without liver disease [22]. Patients
with PSC have a decrease in total number of circulating T cells, and an increased
number of T cells in liver infiltrates; elevated circulating immune complexes [23],
and complement activation [24], but these changes have not been demonstrated
to be linked to the disease pathogenesis.
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Angulo et al [25] reported that 97% of patients with PSC were positive for at
least one autoantibody, whereas 81% were positive for three or more. Antineutrophil cytoplasmic antibodies (ANCA) have been detected in approximately
85% of PSC patients [26]; however, this antibody is not thought to play a pathogenic role. The presence of ANCA antibodies correlates with extensive involvement of the biliary tree but not with other clinical parameters [27]. Efforts have
been made to identify whether antigenic specificities of ANCA correlate with
distinct clinical features. Antibodies to bactericidal or permeability-increasing
protein and cathepsin G were associated with the presence of cirrhosis, whereas
anti-lactoferrin antibodies were more frequent in patients with concomitant
ulcerative colitis [28]. Autoantibodies that react against a common epitope shared
by colon and biliary epithelial cells have been described [29], and more recently,
autoantibodies against biliary epithelial cells that induce expression of CD44 and
interleukin 6 have been found, suggesting that they may have a role in the
inflammatory process [30].
Other factors
A number of other potential origins for PSC have been proposed. The close
association between PSC and ulcerative colitis led to the hypothesis that intestinal
bacteria or toxic substances might transmigrate from inflamed colonic mucosa,
causing chronic inflammation and cholangitis [31]. One study showed strong
immunostaining for endotoxin in biliary epithelial cells of PSC patients [32].
Bacterial or viral infections of the biliary tree have also been implicated as a
cause of PSC; however, there is no direct evidence to support this hypothesis. A
study performed in explanted livers showed a high positivity rate for bacterial
isolates in patients with PSC, but that finding seemed to be related to recently
performed endoscopic retrograde cholangiopancreatography (ERCP) [33]. More
recently Ponsioen et al [34] found increased prevalence of chlamydial lipopolysaccharide antibodies in PSC patients.
Ischemic damage to the bile duct was proposed because of the similar findings encountered in PSC and abnormalities after intra-arterial injection of the
chemotherapeutic agent floxuridine [31]. Vascular injury could potentially be
immune-mediated, because many of the antibodies present in PSC are markers of
vascular damage in others diseases.
Clinical manifestations and complications
As mentioned previously, as many as 44% of patients may be asymptomatic at
presentation, but symptoms may develop over time. The main symptoms include
pruritus, jaundice, abdominal pain, and fatigue. Pruritus is usually treated with
bile acid – binding resins; in patients who do not respond to this treatment, other
strategies that may be helpful include rifampin, naltrexone, and ondasetron. At
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later stages of the disease, PSC presents with complications of cirrhosis and
portal hypertension.
Patients with PSC are susceptible to repeated episodes of bacterial cholangitis
and are also prone to develop pigmented biliary stones [35]. Steatorrhea and
malabsorption of fat-soluble vitamins can occur, mainly because of the decreased
availability of conjugated bile acids in the small intestine. Patients with advanced
PSC have significantly lower bone mineral density compared with controls [36].
In one study 8.6% of the PSC patients had bone mineral densities below the
fracture thresholds [37].
Cholangiocarcinoma is the most feared complication of PSC, with a reported
lifetime prevalence ranging between 10% and 30%. The study involving largest
cohort of patients with PSC found the incidence of hepatobiliary carcinoma to
be 1.5% per year after the first year following diagnosis of PSC [38]. Risk factors for the development of cholangiocarcinoma are not well defined. Older age,
IBD, smoking, and alcohol consumption have been implicated as risk factors,
but these associations are not confirmed [39,40]. The diagnosis of cholangiocarcinoma in the setting of PSC can be difficult. Methods for early detection
have been studied, using tumor markers (CA 19-9, CEA), cytologic brushings
during ERCP, and positron emission tomography, but they have not been evaluated prospectively.
In one study 2% of the 134 patients with PSC who were evaluated for liver
transplantation had hepatocellular carcinoma, suggesting that patients with
advanced PSC are at increased risk for hepatocellular carcinoma and should be
screened for it as well as for cholangiocarcinoma before liver transplantation [41].
Bergquist et al [38] found a 14-fold increase in the risk of pancreatic cancer in
PSC patients, when compared with the general Swedish population.
Most patients with PSC suffer from IBD. Chronic ulcerative colitis is most
commonly associated with PSC, but patients with Crohn’s colitis also have a
higher risk of developing PSC than the general population. Four percent of the
patients with ulcerative colitis will develop PSC at some point [4]. No correlation
exists between the activity of IBD and PSC.
Several studies have demonstrated that patients with PSC and ulcerative colitis
have a higher risk of developing colorectal neoplasia than patients with ulcerative
colitis alone [42 – 44]. In a recent study, 25% of patients with PSC and ulcerative
colitis developed colorectal cancer or dysplasia, as opposed to 5.6% of patients
with isolated ulcerative colitis. Colorectal cancer associated with PSC seemed
more likely to be proximal, to be diagnosed at a more advanced stage, and to be
fatal [45]. Aggressive colonoscopic surveillance is advocated.
Diagnosis
The diagnosis of PSC is based on characteristic cholangiographic findings in
combination with clinical, biochemical, and histologic features. It is important to
exclude secondary causes of sclerosing cholangitis, such as biliary neoplasms,
F.D. Mendes, K.D. Lindor / Clin Liver Dis 8 (2004) 195–211
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previous biliary surgeries, choledocholithiasis, medication-induced bile duct damage, and chronic bacterial cholangitis.
Cholangiographic findings
ERCP is considered the standard method for diagnosis of PSC. When
ERCP is unsuccessful, transhepatic cholangiography can be used to visualize the
biliary tree.
The typical cholangiographic findings of PSC include multifocal strictures and
dilatations that have a classic beaded appearance and may form diverticular
outpouchings (Fig. 1). In most cases, these findings affect both intrahepatic and
extrahepatic bile ducts, but they can involve either alone.
Noninvasive imaging
Recent studies show that magnetic resonance cholangiopancreatography
(MRCP) is a valuable technique in the diagnosis and follow-up of patients with
PSC [46,47]. Angulo et al [46] reported a diagnostic accuracy greater than 90%
in the diagnosis of PSC. There is some suggestion that MRCP may be superior to
ERCP for intrahepatic visualization [48,49].
Other abdominal imaging studies, such as CT and ultrasonography, may suggest the diagnosis but are nonspecific.
Fig. 1. ERCP with balloon of a patient with PSC, showing features of multiple strictures and dilatations, involving mainly the intrahepatic biliary tree (9 R).
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Histologic features
Liver biopsy in this condition is more useful for staging purposes than for
diagnosis itself. The typical onionskin fibrosis may occur in only 10% of biopsies
of PSC patients.
Ludwig et al described a staging system for PSC [31]. Stage I is characterized
by portal hepatitis, in stage II fibrosis or hepatitis involves the periportal area, in
stage III septal fibrosis or bridging necrosis occur, and stage IV is characterized
by biliary cirrhosis. Angulo et al [50] evaluated the rate of histologic progression
in patients with PSC. Of the patients with stage II PSC, 42%, 66%, and 93%
progressed over 1, 2, and 5 years, respectively; 14%, 25%, and 52% of the patients
with stage III PSC progressed over 1, 2, and 5 years, respectively. Regression
of the histologic stage was noted in 15% of the total observations, suggesting
that there is significant sample variability, which may limit the use of serial liver
biopsies for follow-up of these patients [50].
Typical findings on liver biopsy, in the absence of cholangiographic evidence
of PSC characterize an entity termed small duct PSC, which accounts for less
than 5% of PSC patients.
Laboratory tests
Patients with PSC typically present with a cholestatic pattern of abnormal liver
enzymes. Alkaline phosphatase is usually three to five times above normal,
whereas aminotransferase levels are only mildly elevated. Hyperbilirubinemia
may suggest advanced disease or the development of complications such as
dominant strictures, cholangiocarcinoma, biliary stones, and bacterial cholangitis
but may also occur in the absence of any of these conditions. Hypergammaglobulinemia, autoantibodies, and abnormal copper accumulation are also common laboratory findings.
Management
Several therapeutic modalities have been investigated for the treatment of
PSC in an attempt to avoid disease progression. Unfortunately none except liver
transplantation has been proven to alter the course of the disease significantly.
Pharmacologic management
A number of drugs have been studied in PSC patients. Many of the studies
were performed in an uncontrolled fashion with a small number of patients. A
summary of the published placebo-controlled trials, using different medications
for the treatment of PSC is shown in Table 1. A list of the drugs evaluated in pilot
studies and their therapeutic benefits is presented in Table 2.
Drug (dosage)
Study
Number
in study
Period
Biochemical
response
Histologic
response
Radiologic
response
Symptoms
response
Mayo risk score
or survival
UDCA (13 – 15 mg/kg/day)
UDCA (750 mg/day)
UDCA (600 mg/day)
UDCA (13 – 15 mg/kg/day)
UDCA (25 – 30 mg/kg/day)
UDCA (20 mg/kg/day)
Penicillamine (750 mg/day)
Methotrexate (15 mg/wk)
Colchicine (1 mg/day)
Nicotine (15 mg/day)
Beuers et al, 1992 [53]
Stiehl et al, 1994 [95]
De Maria et al, 1996 [96]
Lindor et al, 1997 [54]
Harnois et al, 2001 [55]
Mitchell et al, 2001 [56]
LaRusso et al, 1988 [65]
Knox et al, 1994 [59]
Olsson et al, 1995 [64]
Vleggaar et al, 2001 [67]
14
20
59
105
30
26
70
24
84
12
1 year
1 year
2 years
2.2 years
1 year
2 years
3 years
2 years
3 years
8 weeks
Yes
Yes
No
Yes
Yes
Yes
No
No
No
No
Yes
Yes
No
No
NA
Yes
No
No
No
NA
NA
NA
No
NA
NA
Yes
No
No
NA
NA
No
Trend
No
No
NA
No
No
No
No
No
NA
NA
NA
Not improved
Improved
NA
No
NA
No
NA
F.D. Mendes, K.D. Lindor / Clin Liver Dis 8 (2004) 195–211
Table 1
Placebo-controlled trials for the treatment of primary sclerosing cholangitis
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Table 2
Drugs evaluated in pilot studies for the treatment of primary sclerosing cholangitis
Drug
No of patients
Therapeutic benefit
Study
Tacrolimus
Nicotine
Cladibrine
Pentoxifylline
Budesonide
Pirfenidone
Prednisone + colchicine
UDCA + methotrexate
UDCA + prednisolone +
azathioprine
UDCA + budesonide
or prednisone
10
8
4
20
21
24
12
19
15
Biochemical
None
Histological
None
Biochemical
None
None
None
Biochemical
and histologic
Symptomatica
Van Thiel et al, 1995 [60]
Angulo et al, 1999 [68]
Duchini et al, 2000 [61]
Bharucha et al 2000 [62]
Angulo et al, 2000 [63]
Angulo et al, 2002 [66]
Lindor et al, 1991 [69]
Lindor et al, 1996 [70]
Schramm et al, 1999 [71]
a
18
van Hoogstraten et al 2000 [72]
minor benefits with prednisone.
Ursodeoxycholic acid
There is evidence suggesting that ursodeoxycholic acid (UDCA) has several
beneficial effects in cholestatic disorders. It is cytoprotective, by inhibiting bile
acid –induced cytolysis and apoptosis, and it has antioxidant and immunomodulatory effects as well. This drug has been the most extensively studied in patients with PSC.
Uncontrolled studies have observed improvement of liver enzymes in PSC
patients treated with UDCA [51,52]. Beuers et al [53] performed the first doubleblind, placebo-controlled trial in 14 patients with PSC and documented significant biochemical and histologic improvements. There was no beneficial effect on
symptoms or impact in the Mayo risk score, however.
In contrast to these promising results, Lindor [54], in a larger multicenter
prospective trial that included 105 patients randomly assigned to receive treatment
with 13 to 15 mg/kg per day of UDCA or placebo for a median follow-up of
2.2 years, found no clinical benefit with respect to time to treatment failure or
histologic findings in the treatment arm, even though there was significant biochemical improvement [54].
Because of discouraging results with standard doses of UDCA, two groups
have evaluated the use of high-dose UDCA to treat PSC [55,56]. Mitchell et al
[56], in a preliminary study, treated 26 patients with either UDCA, 20 mg/kg, or
placebo for 2 years and demonstrated significant biochemical, histologic, and
cholangiographic improvements without significant side effects. No impact on
symptoms was noted, however. Harnois et al [55] reported similar results in an
open study of 30 patients treated with high-dose (25 – 30 mg/kg) UDCA for
1 year. When Mayo risk scores of these patients were compared with those
observed in a previous study, the projected 4-year mortality was significantly
greater in patients treated with placebo than in those receiving high-dose UDCA.
Recent studies have suggested that the use of UDCA reduces the risk for
developing colorectal cancer in patients with ulcerative colitis and PSC [57,58].
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Immunosuppressants
Given the immunologic basis for the pathogenesis of PSC, a few trials have
looked into immunosuppressive and anti-inflammatory agents as a form of therapy for this condition.
In the one prospective, controlled trial that studied the use of methotrexate
in PSC, 12 patients were treated with methotrexate and were compared with
12 patients treated with placebo. No differences in outcome or in biochemical,
histologic, or cholangiographic findings were observed [59].
In a small pilot study, tacrolimus (FK-506) improved liver enzymes, but this
improvement was not associated with improvement in ERCP finding, hepatic
volume, or histologic features [60].
Cladibrine, which has antilymphocytic activity, was studied in four patients,
treated for 6 months and followed for 2 years. There was a significant decrease
in portal inflammation and T-lymphocyte CD4 infiltrate, but no improvement
in symptoms, liver enzymes, or degree of biliary stenosis was documented
[61]. Randomized, controlled trials with larger follow-up are required to confirm
these results.
Pentoxifylline, which inhibits TNF-a, has been shown to prevent and reverse hepatobiliary lesions similar to PSC in rats with experimental small bowel
bacterial overgrowth. In a pilot study of 20 patients with PSC treated for up to
1 year, no biochemical or symptomatic improvement was seen with pentoxifylline therapy [62].
Corticosteroids
No long-term controlled studies have investigated corticosteroids in the
treatment of PSC. Most of the small, uncontrolled trials showed no significant
benefit with the use of oral steroids. This lack of demonstrated benefit in conjunction with the systemic side effects, especially bone loss, has limited their use
in treating these patients. Most recently Angulo et al [63] have investigated the use
of budesonide in 21 patients treated for 1 year; only minimal improvement was
noted in alkaline phosphatase and aspartate aminotransferase levels and in
the degree of portal inflammation. No significant changes in the Mayo risk
score, degree of fibrosis, or histologic staging were reported. There was, however,
marked bone loss compared with matched controls [63].
Antifibrogenic and other agents
Colchicine was studied in a multicenter trial motivated by its antifibrogenic
property and promising effects on survival in primary biliary cirrhosis. Over a
3-year period, 44 patients were treated with colchicine and compared with
40 patients treated with placebo, in a randomized, double-blind fashion. The
treatment group did not show any difference in mortality or liver transplantation
rates, symptoms, or biochemical or histologic findings [64].
In patients with PSC, as in other cholestatic liver diseases, there is an increase
in hepatic copper concentration. Penicillamine has cupruretic antifibrogenic, and
immunosuppressive effects. La Russo et al [65] have tested it in a double-blind,
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placebo-controlled trial with 70 patients, showing no clinical benefit and significant toxicity. A study using pirfenidone, a new antifibrotic agent, led to disappointing results as well [66].
Nicotine was evaluated as a potential treatment for PSC, based on the reported
association of PSC with nonsmoking status and on positive effects of nicotine
in treatment of ulcerative colitis. No benefit was seen with oral or transdermal
nicotine [67,68].
Combination therapy
The combination of prednisone and colchicine was evaluated in an open-label
study performed in 12 patients with PSC compared with historical controls. No
significant difference in biochemical tests or liver biopsies were noted, but there
was a trend toward less clinical deterioration and improved survival [69]. UDCA
in combination with methotrexate showed no benefits [70]. A German study
assessed UDCA in combination with prednisolone and azathioprine in 15 patients
with PSC. This study showed promising results, with significant decrease in liver
enzymes and histologic improvement in 6 of 10 patients who had repeat liver
biopsies. In 7 patients who were initially treated with UDCA alone, liver enzymes
improved only after addition of immunotherapy [71]. No randomized trial has
been performed using this combination. UDCA plus budesonide or prednisone
did not significantly improve symptoms or liver enzymes in a short-term trial
[72]. A study using UDCA and endoscopic dilatation of major stenosis suggested
improvement in survival rates compared with the Mayo model [73].
Endoscopic management
Several attempts have been made to change the progressive course of PSC
by endoscopic methods, including endoscopic sphincterotomy, nasobiliary lavage, stent placement, and balloon dilatation. Endoscopic therapy seems most
advantageous for patients with dominant strictures. Biliary lavage with steroids
was evaluated in a randomized, placebo-controlled trial and proved not to be
effective [74]. Several reports have shown beneficial effects of balloon dilatation
or temporary stenting on clinical, biochemical, and cholangiographic findings in
patients with PSC [75 –79]. A retrospective study comparing balloon dilatation
with stenting of dominant stricture showed no obvious benefit from stenting,
and stenting was associated with more complications than seen with dilatation
alone [80].
Some reports suggest that survival is positively influenced by endoscopic
therapy. Stiehl et al [81], for example, prospectively studied 106 patients treated
for up to 13 years with UDCA. Fifty-two of these patients were treated endoscopically for dominant stenosis. The actuarial survival free of orthotopic liver
transplantation at 3, 5, and 7 years was significantly better than predicted with the
Mayo multicenter survival model [81]. Similar results were observed by Baluyut
et al [82], who demonstrated a significantly higher 5-year survival rate in
63 patients undergoing endoscopic therapy when compared with the estimated
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205
rate using the Mayo Clinic survival model (83% versus 65%) [82]. One criticism
of this study is that the bilirubin values used in the calculation of the Mayo
risk score were determined before dilatation and may have overestimated the
underlying liver disease.
Endoscopic intervention is usually preferred to percutaneous biliary drainage
because it seems to be safer and is technically easier to perform.
Surgical management
Surgical resection of dominant biliary strictures with choledocojejunostomy or
hepaticojejunostomy was favored by some centers. Ahrendt et al [83] found that
the 5-year survival and survival free of liver transplantation rates were significantly higher in noncirrhotic patients treated with biliary resection than in those
treated with nonoperative dilatation (85% versus 59% and 82% versus 46%,
respectively) [83]. Surgical treatment is now less commonly performed because
of the advances in endoscopic techniques and the possibility that it may adversely
affect outcome after liver transplantation.
Liver transplantation
As discussed previously, medical, endoscopic, and surgical therapies do not
convincingly alter disease progression in PSC patients. Liver transplantation remains the only form of therapy that positively affects survival [84], and it also
seems to improve quality of life in up to 80% of the patients [85,86].
Graziadei et al [87] reported excellent long-term results in 150 patients with
PSC, who underwent liver transplantation. In this study the 1-, 2-, 5-, and 10-year
actuarial survival was 93.7%, 92.2%, 86.4%, and 69.8%, respectively, and graft
survival was 83.4%, 83.4%, 79%, and 60.5%, respectively [87]. These findings
were in accordance with previous observations [88,89].
The optimal timing for liver transplantation in patients with PSC is still uncertain. The presence of cholangiocarcinoma seems to be one of the most important factors adversely impacting outcome after transplant. Nashan et al [90]
tried to apply the original Mayo survival model to assess the ideal timing for liver
transplantation. In patients with Mayo model risk scores greater than 4.4, the
incidence of biliary malignancy was markedly increased, whereas no tumors
were found in patients with scores less than 4. They suggested that early timing of
liver transplantation should be considered at scores greater than 4 to prevent
formation of biliary malignancies.
Other predictive factors reportedly associated with poor outcome after transplantation in cholestatic liver diseases include age, renal failure, Child’s classification, and United Network for Organ Sharing (UNOS) status [91]. Whether
previous biliary tract surgery adversely affects survival is still controversial. IBD
does not seem to have an impact on liver transplantation in patients with PSC.
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Recurrent PSC after liver transplantation has been reported to develop in approximately 4% of patients per year [92]. Risk factors for recurrence are not
well defined. One retrospective study found that an intact colon before liver transplantation and male gender were significantly associated with recurrence; however, the sample size was small, and the confidence intervals were broad [93].
Apparently the risk of colorectal malignancy increases after liver transplantation and immunosuppression, but this increased risk is yet to be proven. A
recent study in 303 patients undergoing liver transplantation for PSC observed
accelerated progression of IBD but found no significant increase in the risk of
colorectal cancer [94].
Summary
Primary sclerosing cholangitis is a cholestatic liver disease strongly associated
with IBD. Considerable advances in the understanding of its pathogenesis have
been made. The idea of autoimmunity affecting genetically susceptible individuals is largely accepted; however, much remains to be explained about the origin
of this disease. Despite active investigation of different therapeutic modalities
with the goal of modifying disease progression, liver transplantation continues to
be the only option to provide survival benefit in these patients.
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