38 Hepatobiliary disorders
SUE CULLEN AND ROGER CHAPMAN
Hepatobiliary complications of inflammatory bowel diseases
The hepatobiliary system and the aHmentary tract are closely linked embryologically, physiologically, biochemically and anatomically with all mesenteric venous drainage ascending via the portal vein into the liver. It is not surprising, therefore, that the liver is especially vulnerable to the development of com- plications of many different gastrointestinal diseases, particularly inflammatory bowel disease (IBD).
The first association between colonic ulceration and liver disease was made in 1874 by Thomas, who described a young man who died of a 'much enlarged, fatty liver in the presence of ulceration of the colon' [1]. The association was confirmed by Lister in 1899, who reported a patient with ulcerative colitis (UC) and secondary diffuse hepatitis [2]. Over the next 100 years it has become well estabhshed that there is a close relationship between IBD and various hepato- biliary disorders. These disorders are listed in Table 1.
In the past 20 years a different concept of hepato- biliary disorder in IBD has emerged. It is now apparent that the major hepatobiliary diseases seen in association with both UC and Crohn's disease (CD) - namely pericholangitis, primary sclerosing cholangitis (PSC), cirrhosis, cholangiocarcinoma, and most cases of autoimmune hepatitis - represent different aspects of the same spectrum of hepato- bihary disease.
Prevalence of liver disease
The prevalence of liver disease in patients with UC and CD has varied widely in different series. The discrepancy between the series may be largely due to differences in the number of patients included with severe, active, or extensive IBD, and also in the method used to investigate liver dysfunction.
Table 1. Hepatobiliary disorders associated with inflammatory bowel disease
A Primary sclerosing cholangitis (PSC) Large duct PSC
Small duct PSC ('pericholangitis') Cirrhosis
Hepatoma Cholangiocarcinoma B Miscellaneous disorders
Fatty liver Granulomas Amyloidosis Hepatic abscess Gallstones
Autoimmune hepatitis Primary biliary cirrhosis Budd-Chiari sydrome
Associated with Ulcerative Crohn's
colitis disease
+ + + (+) + + + + + (+)
+ + +
+ + + +
(+)
(+) (+)
+ , definite association; ( + ) , possible association
Abnormal liver function tests are found in over half of patients with IBD requiring surgery, and are due to a number of factors such as malnutrition, sepsis, and blood transfusions with the subsequent risk of viral infection. However, significant liver disease is much less common. The true prevalence of hepatobiliary abnormality is difficult to determine, as it would involve obtaining liver histology and cholangiography on an unselected group of patients with IBD. Most series, therefore, have relied upon detecting persistent abnormalities on serum bio- chemical testing before proceeding to hepatic biopsy or endoscopic retrograde cholangiography. Techno- logical advances such as magnetic resonance cholangiography and spectroscopy may allow more accurate assessments of the prevalence of liver abnormality to be made.
Stephan R. Targan, Fergus Shanahan andLoren C. Karp (eds.), Inflammatory Bowel Disease: From Bench to Bedside, 2nd Edition, 731-745.
© 2003 Kluwer Academic Publishers. Printed in Great Britain
In an early study from Oxford, 5-6% of 300 unselected adult patients with UC had significant histological abnormalities on hepatic histology com- pared with 10% of 100 unselected patients with CD;
none of these patients underwent cholangiography [3, 4]. A group of 336 Norwegian patients with UC and persistently abnormal liver function tests were investigated using cholangiography [5]. The study found that more than 14% of patients had some form of hepatobiliary disease and 5% of all patients had PSC although most were asymptomatic (Table 2).
Similar results were obtained in 1500 Swedish patients with UC [6]. In this thorough study, endo- scopic cholangiography was obtained in 65 of 72 patients with elevated values of serum alkaline phosphatase. PSC was diagnosed in 3.7% of the UC group. The prevalence was 5.5% in patients with extensive colitis and only 0.5% in patients with distal disease [6]. This figure may be an underestimate, as a study from the Mayo Clinic has shown that standard liver function tests may be normal despite the presence of PSC on cholangiography [7].
PSC is also associated with CD but has only been reported in patients with extensive colonic involve- ment. A study from Norway has suggested that PSC is as common in patients with colonic CD as it is in UC [8]. Studies to date have suggested a prevalence of 1.3-13% of PSC among Crohn's patients [8-10].
The prevalence of hepatobiliary abnormalities with normal liver function tests in patients with UC has been investigated in a study from Sweden [11].
Liver biopsies were assessed from 74 patients with UC and normal liver function tests. Fifty percent had a completely normal liver biopsy. The biopsies of three patients with total colitis displayed concentric periductular fibrosis and the rest showed minimal portal inflammation or fatty filtration. The patients were then followed for a mean of 18 years. None of the three patients with concentric fibrosis developed abnormal liver function tests, although cholangio- graphy was not performed. Two other patients developed liver disease; cirrhosis in one and auto- immune chronic hepatitis and cholangiocarcinoma in the other.
In summary, approximately 5% of adult patients with IBD will have significant hepatobiliary disease.
Although the number of patients with hepatobiliary abnormality is approximately the same for UC and CD, severe significant liver disease is m o r e commonly seen in patients with UC and when it occurs in CD it is usually associated with extensive colonic involvement.
Table 2. Prevalence of primary sclerosing cholangitis in patients with ulcerative colitis
Country of origin (ret.)
No. of patients with UC
Percentage with PSC
Oxford, UK [3]
Oslo, Norway [5]
Stockholm, Sweden [6]
681 336 1500
2.9 5 3.7 (5.5 in total colitis)
Primary sclerosing cholangitis
PSC is a chronic cholestatic liver disease character- ized by an obliterative inflammatory stricturing fibrosis which usually involves the whole biliary tree [9, 12] (Fig. 1). The changes may sometimes be localized to either the extrahepatic or intrahepatic bile ducts, and the degree of involvement varies considerably from patient to patient.
Relationship of primary sclerosing cholangitis with IBD
Association with ulcerative colitis
Approximately 70% of northern European patients with PSC have coexisting UC, and PSC is the most common form of chronic liver disease found in UC [9, 12] (Table 3). Studies from southern Europe, however, have found only 36-44% of patients with PSC have underlying UC, although not all patients in these studies underwent total colonoscopy and colonic biopsies [13, 14]. Data from Japan suggest that the relationship is even weaker, with only 20% of PSC patients having a diagnosis of UC [15]. Some authorities believe that all patients with PSC will develop IBD at some point. Many studies from different parts of the world have reviewed the clinical features of patients with UC and PSC. The findings from all studies have been remarkably consistent.
Paradoxically, the colitis is usually total but sympto- matically mild, often with no rectal bleeding, and is often characterized by prolonged remissions [16].
Interestingly, patients with UC and PSC have a male
predominance, with a male:female ratio of 2:1 which
is in contrast to the slightly female predominance of
UC in isolation [17].
Figure 1. Cholangiogram from patient with ulcerative colitis and abnormal cholestatic liver function tests showing stricturing and dilation of extrahepatic and intrahepatic bile ducts.
Smoking
Cigarette smoking has been recognized as a protec- tive factor against the development of UC. Two studies have suggested that cigarette smoking may also additionally protect against the development of PSC. Moreover, this protective effect was more marked in patients with PSC than UC and was seen in patients with and without IBD [18, 19, 20]. The mechanism of protection in both disorders remains unknown.
Onset
Although the symptoms of UC usually develop before those of sclerosing cholangitis, in some patients the onset of PSC may precede the symptoms of colitis by up to 4 years. Although large-scale studies have not been performed, there is some evidence that the prevalence of liver abnormality may be higher in children than adults with colitis.
Abnormal liver function tests were detected in 60%
of 34 children with UC; abnormalities were most commonly seen in total colitis. Cholangiography was performed in only two patients, one of whom had sclerosing cholangitis [21].
Table 3. Prevalence of inflammatory bowel disease in patients with primary sclerosing cholangitis (PSC)
Institution (country of origin) disease; ret.
Royal Free Hospital (UK) [10]
Mayo Clinic (USA) [9]
Huddinge (Sweden)
King's College London (UK, children) Okolicsanyi (Italy) [14]
Escorsell (Spain [13]
No. of patients with PSC
29 50 305 13 82 43
Percentage with
IBD 72 70 72 77 54 47
Outcome
The outcome of the hepatobiliary disease is comple- tely unrelated to the activity, severity, or clinical course of the colitis. This is borne out by the fact that colectomy makes no difference to the clinical pro- gression or to the mortality of patients with PSC.
Indeed, liver disease may develop some years after a
total colectomy has been performed [22]. Patients
with combined UC and PSC may have a worse
prognosis from liver disease than patients with PSC
alone [17]. Involvement of the extrahepatic bile ducts
alone is more frequently seen in patients who do not
have IBD [17].
Biliary and colorectal cancer in ulcerative colitis and PSC
The association between UC and colorectal carci- noma has been recognized since the 1920s [23]. In
1995 Broome et al. suggested that there was an increased risk of colorectal neoplasia in patients with concomitant PSC [24] (see Fig. 2). This hypothesis has been extensively tested since that date, with conflicting datasets published in recent years. Most experts currently agree that PSC is an independent risk factor for developing colorectal carcinoma. The possible mechanisms for the increased susceptibility to neoplasia are not clear, but genetic predisposition, alterations in the bile salt pool due to cholestasis, and folate deficiency are all possibilities [25]. Yearly colonoscopy is recommended in patients with UC and PSC.
Three recent studies have all shown that PSC patients consistently develop a more proximal color- ectal carcinoma than patients with UC alone [26-28].
This observation may be explained by the higher
40 H
30 J
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o
2010 H
exposure of the right side of the colon to the carcino- genic properties of the secondary bile acids produced in cholestasis, although this hypothesis remains unproven. The increased risk of carcinoma of the bile ducts, including gallbladder carcinoma, in patients with UC is also well established and now appears to occur almost exclusively in the context of pre-exist- ing PSC. Furthermore, one study has suggested that cholangiocarcinoma develops significantly more often in patients with colonic dysplasia or carci- noma, thus suggesting that these patients may constitute a high-risk subgroup requiring increased colonic and biliary surveillance [29]. However, further prospective studies are needed to confirm these findings.
Orthotopic liver transplantation is the only effec- tive treatment for PSC. The presence of IBD does not affect the outcome, but is associated with a higher rate of severe acute graft rejection [30, 31]. Surpris- ingly, there is some evidence that the clinical course of IBD worsens post-transplant despite the immuno-
UC + PSC
UC
/ 10
Duration (y)
I
—1~
20
I 30
Figure 2. The cumulative risk of developing colonic or biliary dysplasia in 40 patients with primary sclerosing cholangitis (PSC) and ulcerative colitis (UC) compared with 80 matched controls with UC alone. (Reproduced with permission from ref. 23)
suppression given to protect the graft from rejection.
A series published by the Royal Free Hospital found an increase in the clinical activity of the associated colitis in eight of 16 patients transplanted for PSC [31]. Similar data have been published from Birming- ham, with nine of 26 (35%) of patients noticing a worsening of their symptoms of IBD [30]. In con- trast, Gavaler et al. and Shaked et al. found no worsening of IBD symptoms post-transplant in 23 and 24 patients respectively [32, 33]. These conflict- ing data may in part be explained by the differences in immunosuppressive regimens used post-trans- plantation. The Royal Free and Birmingham centers usually withdraw steroids early, and maintain immunosuppression with cyclosporine or tacrolimus with or without azathioprine. The Gavaler and Shaked reports are from units where steroids are used as maintenance immunosuppression.
The risk of colon cancer in PSC increases after transplantation, occurring most commonly in the early post-transplant period, and is probably associated with high-level immunosuppression accelerating the growth of malignant cells. Colono- scopy with extensive mucosal biopsies is therefore recommended prior to transplantation, and annually thereafter in this particularly high-risk group [34, 35].
Pouchitis
Patients with UC treated by colectomy with an ileal reservoir (pouch) are sometimes affected by a non- specific inflammation of the pouch (pouchitis). This complication is much more common in patients with PSC and UC (64% of patients affected) than in those with UC alone (32%o of patients affected) [36], and is the major comphcation of this operation. Prior to the development of pouch operations the Brooke ileo- stomy was the most commonly performed operation for UC. In patients with coexistent PSC, however, peristomal varices occur in approximately 25% of cases, and bleeding from these varices can be difficult to manage [37]. Although the intraoperative and postoperative complication rate and mortality is comparable in the two operations, pouchitis tends to present a less difficult management problem than recurrent peristomal variceal bleeds; therefore ileal pouch-anal anastomosis is usually the operation of choice in these patients.
Association with Crohn's disease
PSC is associated with CD although the prevalence is lower than for UC and the prevalence of bile-duct carcinoma is less in CD. The explanation for these apparent differences in prevalence between the two IBD is unclear, but may be related to the less frequent occurrence of total colonic involvement in patients with CD.
Epidemiology
The prevalence of PSC is unknown. As previously stated, there is a 2.4-7.5%) prevalence of PSC in patients with UC. The prevalence of PSC in the United States has been estimated to be two to seven cases per 100 000 population, based on a prevalence of UC of 40-225 cases per 100 000. This estimate has been confirmed by the results from Olsson et al. [6], who noted the prevalence of UC and PSC to be 171 and 6.3 cases per 100000 population respectively.
The most recent data from Norway found a preva- lence of 8.5 cases of PSC per 100 000 population [38].
These results, however, probably underestimate the actual prevalence of PSC, as the disease can occur in patients with normal serum levels of alkaline phosphatase, and 20-30% of patients with PSC have no associated IBD. PSC is more common than previously suspected, and may have a frequency similar to primary biliary cirrhosis.
Aetiology
The cause of PSC is unknown, but any proposed etiologic mechanism must incorporate the close association with UC. A number of hypotheses have been proposed to explain the association between colonic disease and biliary tract inflammation and fibrosis (Table 4). Recent studies have suggested that genetic and immunologic factors are important in
Table 4. Possible causes of primary sclerosing cholangitis Portal bacteremia
Abnormal bile acids Absorbed colonic toxins Viral infections Copper toxicity
Immunologic mechanisms Genetic predisposition Ischemic arteriolar injury
the pathogenesis of PSC. Three sets of sibhngs from three famihes have been described with PSC and UC [39-41]. Furthermore the frequency of HLA-B8, DR3 and DR52A is much higher in PSC patients than in controls [40-42]. More recently HLA- DR52A, which is closely associated with the HLA- B8 DR3 haplotype by linkage disequilibrium, has been shown to be the most closely associated HLA allele in PSC, as the HLA-B8 and DR3 haplotype is associated with a number of autoimmune diseases such as autoimmune chronic active hepatitis, myasthenia gravis and thyrotoxicosis [43]. Although the prevalence of HLA-B8 and DR3 is not increased in patients with UC, a patient with UC who is unfortunate enough to possess the HLA-B8 and DR3 haplotype, has a 10-fold increase in the relative risk of developing PSC.
There is some debate about which are the most important HLA associations. Studies from Scanda- navia have suggested that DRB1*0301 and DRB1*1301 are the primary susceptibility alleles.
More recent work has identified very strong associa- tions with the tumor necrosis factor-a (TNF-a) promotor (TNF*2) allele and MICA*008 allele [44 47].
Non-MHC genes are also likely to contribute to the susceptibility to and progression of PSC. Unpub- lished data from Sweden have suggested an associa- tion with polymorphisms in genes encoding cyto- toxic lymphocyte antigen-4 (CTLA-4 chromosone 2q32) and preliminary studies from Oxford have implicated a polymorphism in the matrix metallo- proteinase 3 [48]. Both these findings, however, await confirmation.
The possible importance of immunologic factors has been emphasized by the number of recent reports which have shown humoral and cellular abnormal- ities in PSC.
Perinuclear antineutrophil cytoplasmic antibodies (ANCA) have been detected in the sera of 26-85% of patients with PSC with or without UC and up to 68%
with UC only [49-51]. Current data suggest that the ANCA reactive antigens are similar, and may be indicative of a common immunopathologic mechan- ism. As for UC no correlation exists between disease activity and ANCA in PSC. Unfortunately the anti- gen(s) which is specific to mature neutrophils has not been isolated, although one group have recently suggested that a nuclear envelope protein may be the target antigen [52]. It remains unclear whether ANCA have pathogenic diagnostic or prognostic significance, or merely represent an epiphenomenon.
Current evidence would suggest that PSC is an immunologically mediated disease which requires exposure to bacterial products in the portal venous blood to trigger its expression. Vierling et al.
hypothesized that bacteria might gain access to the portal venous blood in the setting of acute or chronic colitis. Hepatic macrophages would then secrete interleukins and TNF-a into the peribiliary space of the portal tracts stimulating secretion of chemokines and cytokines from the biliary epithelial cells, pro- moting regurgitation of bile into the peribiliary space and interfering with cholehepatic circulation.
Neutrophils, monocytes, macrophages, T cells and fibroblasts would be attracted to the area and, together with platelet-derived growth factor (PDGF), could promote enzymatic digestion of extracellular matrix, and collagen synthesis resulting in peribiliary fibrosis and progressive inflammation and biliary obstruction [53]. This hypothesis does not, however, explain the pancreatic duct abnorm- ality observed in 10-50% of PSC patients.
Clinical features
PSC is mainly a disease of young males, with a male:female ratio of 2:1. The majority of patients present between the ages of 25 and 40 years, although the disease has been diagnosed at any age between 1 and 90 years! The clinical presentation of PSC is variable but commonly includes fatigue, intermittent jaundice, weight loss, right upper quadrant abdom-
inal pain and pruritus [9, 13]. Despite the name of the disease, only a minority of patients suffer attacks of acute c h o l a n g i t i s , and these usually follow reconstructive biliary surgery or some form of endo- scopic interventional therapy.
Some patients with PSC may present with an
established cirrhosis and portal hypertension with-
out any previous symptoms of cholangitis or choles-
tasis. These patients may be diagnosed and treated as
cryptogenic cirrhosis for many years before the
diagnosis is established. Physical examination is
abnormal in about half the symptomatic patients at
presentation. C o m m o n abnormalities include
hepatosplenomegaly and jaundice, although jaun-
dice often appears only late in the course of the
disease. The stigmata of liver disease - including
spider naevi, palmar erythema and clubbing - are
not usually found. An increasing number of asymp-
tomatic patients with PSC are being diagnosed in
whom physical examination is normal. The diagno-
sis is usually made incidentally when a persistently raised serum alkaline phosphatase is discovered in a patient with UC [6].
Laboratory investigations
Serum biochemical tests usually indicate cholestasis.
However, the levels of alkaline phosphatase and bilirubin may vary widely in an individual patient during the course of the disease; increasing, for example, during periods of acute cholangitis and falling after appropriate therapy. Sometimes the levels may fluctuate for no apparent reason. Modest elevations in serum transaminases are usually found, while hypoalbuminemia and clotting abnormalities are found only at a late stage [9, 12].
The diagnostic role of antineutrophil cytoplasmic antibodies (ANCA) in PSC has been discussed ear- lier. Low titers of serum antinuclear and smooth- muscle antibodies have been found in patients with PSC but they have no diagnostic significance; serum mitochondrial antibody is invariably absent [9].
Increased serum IgM concentrations are seen in about half of symptomatic patients, and the levels of IgM are similar to those observed in patients with primary biliary cirrhosis. Elevation of IgG is found in about one-third of adult patients tested and 60- 80% of children with PSC.
Radiographic features
Endoscopic cholangiography is the best method of demonstrating the biliary system in patients with sclerosing cholangitis. Although in skilled hands the bile ducts can be visualized by percutaneous trans- hepatic cholangiography, this technique is difiicult in sclerosing cholangitis and has a higher morbidity rate. The cholangiographic appearances are diagnos- tic and consist of multiple stricturing and dilation (beading) of the intrahepatic and extrahepatic bile ducts [9, 12] (Fig. 1).
Occasionally involvement may be limited to the intrahepatic ducts alone, or more rarely in patients with concurrent UC only the extrahepatic bile ducts may be abnormal. Small diverticuli along the com- mon bile duct are diagnostic, and found in about 25% of patients [54]. Magnetic resonance cholangio- pancreatography (MRCP) provides a non-invasive method of imaging the biliary tree and characteristic appearances of PSC on MRCP are being defined.
Recent studies have reported 85-88% sensitivities
and 92-97% specificities for the detection of PSC using M R C P [55]. The technique is still being assessed, but will probably become the diagnostic method of choice for PSC in the future.
Pathological features
Extrahepatic bile ducts appear macroscopically as thickened cords, although the overall diameter is not usually increased. In cross-section the lumen is narrow and the wall may be up to eight times the usual thickness. The inflammation and dense concentric fibrosis usually affect the submucosa and outer layers of the bile ducts, leaving the mucosa largely unaffected.
The histologic appearances of the liver biopsy are not usually diagnostic, although some form of biliary disease can usually be identified, indicating the need for cholangiography. The classical histologic feature of PSC, viz. 'onion-skin' concentric fibrosis, is seen in about one-third of patients (Figure 3).
Natural history
In the majority of patients PSC is a progressive disease. The median time of survival from the time of diagnosis of PSC is approximately 12 years [9, 13]
in symptomatic patients. However, 75% of patients with asymptomatic disease are alive after 15 years of follow-up. The majority of patients die in hepatic failure following deepening cholestatic jaundice.
However, approximately 10-20% of patients with long-standing PSC develop bile duct carcinoma, which often follows a very aggressive course [12, 56].
Up to 21% of patients will have an incidental biliary carcinoma found at the time of transplantation [34].
Mean survival after the diagnosis of cholangiocarci-
noma is 9 months. Prognostic models have been
developed to try to predict the clinical course of the
hepatobiliary disease and the development of
cholangiocarcinoma [57-60]. However, no model
has been shown to be of any use in the individual
patient, although most studies have shown that an
elevated serum bilirubin level at presentation is
associated with a poor prognosis. Further models
are being developed to facilitate the timing of liver
transplantation, and to evaluate the usefulness of
monitoring the effect of experimental therapy on
disease progression.
Figure 3. Bile duct surrounded by layers of concentric 'onion-skin' fibrosis.
Treatment
There is no curative treatment for PSC, but a plethora of medical, endoscopic and surgical approaches have been advocated. The treatment of PSC can be divided into the management of choles- tasis, the management of the complications, and lastly, specific treatments of the disease process.
Management of cholestasis
Symptomatic patients are frequently troubled by pruritus. This is best managed initially by cholestyr- amine, and the dose should be increased until relief of pruritus is obtained. Both rifampicin and naltrexone are also sometimes effective. In addition, fat-soluble vitamin replacement is necessary for the jaundiced patient and this should be replaced by monthly intramuscular injections. Metabolic bone disease (usually osteoporosis) is a frequent complication of advanced PSC. No proven effective treatment is available for the prevention or management of osteopenia, although bisphosphates with calcium and vitamin D supplements should be considered in patients with osteoporosis, and in patients with advanced cholestasis.
Management of complications
Broad-spectrum antibiotics such as ciprofloxacin should be given for acute attacks of cholangitis but they have no proven prophylactic value and should not be used routinely on a long-term basis except in patients with recurrent cholangitis. If cholangiogra- phy shows well-defined obstruction to the main extrahepatic bile ducts, mechanical relief must be considered. In many patients the best therapeutic approach is by introducing a prosthesis (stent) through the obstruction. This may be placed non- operatively by the percutaneous transhepatic route or at endoscopic retrograde cholangiopancreatogra- phy (ERCP). Balloon dilation of the strictures prior to stenting may be useful in those few patients with well-defined localized strictures, and can lead to a striking improvement in symptoms and serum biochemistry [61]. The development of small biliary stones and sludge can lead to sudden clinical or biochemical deterioration. In these patients endo- scopic sphincterotomy with extraction of the biliary debris is beneficial. Some authors have advocated nasobiliary drainage, but no long-term controlled results have been reported.
Patients with PSC and chronic UC treated by total
colectomy and ileostomy may develop peristomal
varices which can bleed profusely [22]. No effective
measures are available once they have developed,
although local measures such as injection of
sclerosants have been tried.
Specific treatment
Medical treatment
Medical treatment of PSC has included uncontrolled trials of corticosteroids, immunosuppressive drugs, cholecystogogues and antibiotics, either alone or in combination. The results have been universally disappointing, although assessment of treatment in this uncommon disease is difficult because the clinical course fluctuates, survival is variable and some patients may remain asymptomatic for long periods of time.
The role of corticosteroid therapy in PSC is unclear. There have been no controlled trials of steroid therapy, but many patients with sclerosing cholangitis, particularly those who also have UC, will have received corticosteroids. Corticosteroids have been used both topically and systemically in small and generally uncontrolled trials in sclerosing cholangitis. A controlled trial of nasobiliary lavage with corticosteroids or placebo did not produce any significant benefit [62].
Good results with oral prednisolone have been reported in pilot studies. However, no benefit was seen in patients treated with prednisolone and colchicine for 2 years at the Mayo Clinic [63]. Con- trolled trials with bone-sparing agents such as bispho- sphonates would be needed before this treatment could be widely recommended, in view of the dangers of bone disease being accentuated by steroid therapy.
A number of immunosuppressive agents have been tried, either alone or in combination, including penicillamine, methotrexate and cyclosporine. No benefit has been demonstrated.
Treatment with ursodeoxycholic acid is being assessed in clinical trials. A study from the Mayo Clinic has shown that ursodeoxycholic acid in stan- dard doses (10-15 mg/kg per day) produces an improvement in biochemistry but has no effect on symptoms, histology or survival [64]. However, a recent pilot study has demonstrated that higher daily doses of ursodeoxychoHc acid (20-25 mg/kg) may be efficacious [65].
Orthotopic liver transplantation
This is the only option available in young patients with PSC and advanced liver disease. Decisions regarding the optimum timing for transplantation are, however, made difficult by the variable clinical course of PSC and the potential risk of cholangio- carcinoma. Indications for transplantation are sum- marized in Table 5 [34].
Tabie 5. Indications for liver transplantation in PSC [27]
Accepted indications for transplantation Cirrhosis complicated by:
Intractable ascites Recurrent cholangitis
Variceal hemorrhage not controlled by banding or sclerotherapy IVIuscle wasting
Recurrent bacterial peritonitis Encephalopathy
Consideration for transplantation
Non-cirrhotic patients with intractable itching or fatigue Biliary dysplasia (debatable)
Survival rates for patients transplanted for PSC without evidence of cholangiocarcinoma are excel- lent, with most series publishing 5-year survival rates of 85-90%. Recent data from the Mayo Clinic have demonstrated that post-transplant survival rates are clearly related to the pre-transplant Child-Pugh stage [66]. Survival rates in Child-Pugh A over 1, 2 and 5 years were: 98.1%, 97.0% and 91.0%: Child- Pugh B: 89.1%, 81.0%, and 55% and in Child-Pugh C: 73.0%, 53.0% and 16.0%, respectively. For this reason patients with PSC should be referred for transplantation earlier than other patients with chronic liver disease. Where cholangiocarcinoma is found incidentally in the explanted liver with no spread to regional lymph nodes the prognosis is c o m p a r a b l e to p a t i e n t s with no evidence of cholangiocarcinoma [67]. Clinically a p p a r e n t cholangiocarcinoma is, however, a contraindication to transplantation as the tumor rapidly recurs post- transplantation with immunosuppression [67].
PSC recurs in the liver graft in around 20%) of cases [68]. Post-transplantation PSC appears have a survi- val rate similar to patients without evidence of recurrence. Several patients have required re-trans- plantation for advanced recurrent disease [69].
Small-duct primary sclerosing cholangitis 'pericholangitis'
Pericholangitis is a histological diagnostic term that
has been used to describe inflammatory reactions in
the portal zones of the liver which are characterized
by periductular inflammation and fibrosis. For many
years term 'pericholangitis' was synonymous
with invc ^ent of the liver in IBD [70, 71]. Some
patients with pericholangitis have been shown to progress to cirrhosis of the Hver and cholangio- carcinoma [72]. However, it has become clear that the majority of patients with histologic pericholangi- tis and persistently abnormal liver function tests will have cholangiographic appearances diagnostic of PSC at ERCP [73, 74]. A minority of patients with UC will have persistently abnormal liver function tests, together with histologic appearances such as concentric fibrosis, but have normal bile ducts at cholangiography. The term 'small-duct primary sclerosing cholangitis' has been proposed to replace the term 'pericholangitis' in this group of patients as the evidence suggests that these conditions are all part of the same disease spectrum [75]. Wee and Ludwig have described two patients who progressed from small-duct PSC to develop extrahepatic biliary involvement diagnostic of sclerosing cholangitis [75].
It is clear that patients with small-duct PSC have a more favorable outlook than those with 'classical' disease in terms of risk for developing liver cirrhosis and cholangiocarcinoma [76, 77].
A number of other portal tract lesions such as chronic periportal inflammation and/or increased cellularity of portal tracts have also been described as 'pericholangitis' in patients with UC [70, 71],
In view of the confusing use of the term pericho- langitis, which has been applied to a heterogeneous mixture of hepatobiliary disorders by different authors, it has been proposed that the term and concept of pericholangitis should be abandoned [78].
Autoimmune hepatitis
Autoimmune hepatitis has been reported to occur in association with UC [79]. However, interface hepati- tis (piecemeal necrosis) on liver histology can accom- pany the classic bile-duct changes of PSC on cholan- giography [12] and it seems likely that the majority of patients with autoimmune hepatitis and IBD will have either large- or small-duct PSC. The diagnosis of autoimmune hepatitis should not be made in patients with IBD unless cholangiography is normal.
The diagnostic difficulties are compounded by the presence of circulating serum autoantibodies such as antinuclear antibodies, smooth muscle antibodies, antineutrophil cytoplasmic antibodies, and elevated serum immunoglobulins in some patients with PSC [80]. Moreover, both autoimmune hepatitis and PSC are associated with an increased prevalence of the tissue antigens HLA-B8 and HLA-DR3 [32] and
overlap syndromes exist [81]. It is unclear from current evidence whether the prevalence of auto- immune hepatitis without underlying sclerosing cholangitis is increased in patients with IBD.
Cirrliosis
The incidence of cirrhosis associated with IBD has varied in different series between 1% and 5% [82-85].
Most patients in these reports are classified as having biliary cirrhosis and, since patients with PSC can present with portal hypertension and established cirrhosis with no preceding symptoms, it seems likely that the majority of these patients will have under- lying end-stage PSC. However, not all patients with cirrhosis and IBD will have PSC, and it is possible that some cases may be due to chronic hepatitis C infection [86] associated with previous blood transfu- sions. Patients with cirrhosis may present with the typical symptoms of liver failure including jaundice, ascites, and variceal hemorrhage. Although the variceal bleeding usually occurs from veins in the esophagus, patients with concomitant IBD who have undergone total proctocolectomy may bleed from peristomal varices some 6-13 years after formation of the ileostomy stoma [22].
Ciiolangiocarcinoma
Cholangiocarcinoma in UC usually occurs in the context of pre-existing PSC and is therefore associated with long-standing total colitis. A large study from the Cleveland Clinic has reported a prevalence rate of 0.5% [87]. Bile duct carcinoma has been reported in association with CD but it occurs much more rarely [88, 89].
The clinical presentation of bile duct cancer is usually that of a progressive cholestatic jaundice.
Diagnosis of cholangiocarcinoma in the context of PSC can be extremely difficult. Cholangiography usually reveals a particularly narrow bile duct stric- ture. Brush cytology obtained endoscopically may be useful in confirming malignancy but suffers from low sensitivity. Computerized tomography (CT) scan- ning showing intrahepatic bile duct dilation is sug- gestive but not diagnostic of malignant change.
Positron emission tomography (PET) scanning has
been used with some success in the early diagnosis of
small cholangiocarcinomas, and may become a use-
ful tool in differentiating benign and malignant
strictures [90].
The tumor usually pursues a progressive course and the prognosis is very poor, with a median survival of 9 months [91]. Liver transplantation for isolated cholangiocarcinoma occurring in PSC as previously discussed, has been disappointing, with rapid recurrence of tumor [92].
There has been considerable interest in developing a laboratory test to detect early cholangiocarcinoma in patients with PSC. A combination of the serum tumor markers CEA and CA 19-9 was thought to be promising, but appears to lack specificity and sensi- tivity in detecting small tumors [93]. There is currently no evidence that this test identifies patients with localized cholangiocarcinoma or biliary dyspla- sia who would benefit from surgery [94].
New techniques are currently being evaluated for the detection and characterization of biliary dyspla- sia. If vulnerable dysplastic tissue can be reliably identified on liver biopsy specimens, liver transplan- tation should be possible to prevent the subsequent development of neoplastic change. Unfortunately the current cytobrush specimen usually taken from suspicious areas at ERCP is usually inadequate for definitive diagnosis of dysplasia, and much less for distinguishing which subjects with dysplasia are most likely to progress quickly. Serial collection of material from the suspicious area and genetic analysis may in the future allow the likelihood of progression to cholangiocarcinoma to be predicted [95].
Hepatocellular carcinoma
Two case reports have described the development of fibrolamellar hepatocellular cancer in male patients with UC and PSC. Neither patient was cirrhotic [96, 97]. In the single patient who received a transplant the tumor recurred in the donor liver [96]. In common with most causes of chronic liver disease, patients with PSC and estabhshed cirrhosis have an increased risk of developing primary liver cell cancer [98].
Fatty change
Fatty liver or steatosis is the most common type of hepatobiliary lesion found in patients who have IBD.
It has been recorded as occurring in 45% of patients with UC who undergo colectomy [99] and in 40% of patients with CD who undergo similar surgery [100].
The presence of fatty liver is related to the general state of health of these patients and the severity of the
underlying colitis rather than any other specific factor. This is reflected by the fact that, in an unselected series, fatty liver was found in only 6.3%o and 4%) of patients with UC and CD, respectively [3, 4]. Moreover, the incidence of fatty change in patients with UC at autopsy is similar to that of other debilitated patients. The pathogenesis of fatty liver in IBD is unknown. It is probably multifactorial, sec- ondary to causes such as poor nutrition, drugs, bacterial and chemical toxins, and unsuspected alcohol abuse. The steatosis is usually of the macro- vesicular type and all types of distribution, including diff'use, periportal and centrilobular, have been described in patients with IBD.
There are no symptoms associated with fatty liver, although on abdominal examination hepatomegaly may be detected. Treatment of the underlying bowel disorder and improvement in the general health of the patient will normally result in a resolution of the fatty change. There is no evidence that the lesion progresses to chronic liver disease. In view of improvements in the management of IBD the incidence of fatty change has probably fallen.
Gallstones
Patients with CD of the small bowel have an
increased incidence of gallstones. The reported
incidence in patients with Crohn's ileitis, ileal resec-
tion, or intestinal bypass ranges from 13%o to 34%)
[101-105]. However, the incidence of gallstones in
patients with UC and those with CD confined to the
colon is about 5%, and does not differ from that of
the general population. Total colectomy with ileo-
anal anastomosis does not predispose to the forma-
tion of cholesterol gallstones [105]. The increased
rate of formation of gallstones in patients with
inflammation or absence of the terminal ileum is
due to a reduction in bile-salt absorption, leading to
depletion of the bile-salt pool. As a result the con-
centration of biliary bile salts falls, and there is a
relative increase in the concentration of biliary
cholesterol. Thus, bile may become supersaturated
with cholesterol, which in turn increases cholesterol
precipitation in the gallbladder and predisposes to
the formation of cholesterol gallstones. There may be
additional factors predisposing to gallstones in these
patients. One study has demonstrated impaired gall-
bladder contractability, most marked in patients who
have undergone bowel resection or have both large
and small bowel disease [106].
Amyloidosis
Hepatic amyloidosis is a rare complication, occur- ring in less than 1% of patients with IBD; it is much more commonly associated with CD than UC. The development of amyloid can occur in association with CD involving either the small or large bowel.
The amyloid deposition in the liver is found in the media of portal blood vessels and in the sinusoidal wall, and eventually leads to atrophy and disappear- ance of hepatocytes. In addition to IBD, most patients who develop amyloidosis have either extra- intestinal foci of suppuration or arthropathy. In addition most CD patients who develop amyloid have chronically active disease. Aggressive anti- inflammatory treatment of the intestinal lesions probably reduces the chance of developing systemic amyloid. More effective recent treatment probably accounts for the reduced prevalence of amyloid.
Although regression of amyloidosis has been reported after colectomy, in the majority of patients the prognosis is poor [107].
Granulomas
Granulomas are occasionally seen in the liver biopsy specimens of patients with CD, some of whom may show a moderate elevation of serum alkaline phosphatase [108]. The granulomas can be present in portal tracts as well as in the parenchyma. The presence of hepatic granulomas in patients with CD often reflects granulomas in the bowel [109]. There have been a few isolated reports of hepatic granulo- mas occurring in association with UC but the relationship remains unproven. Granulomas are found in 3-4% of liver biopsies from patients with PSC[109].
Liver abscess
Intra-abdominal abscess is a frequent complication of CD. However, the development of hepatic abscess in association with IBD is very uncommon. The abscesses are often multiple and are associated with a high mortality [110]. Streptococci, especially Strep- tococcus milleri, are the most frequent organisms isolated from the abscesses [111].
Primary biliary cirrhosis
Thirteen patients have been described with concomi- tant UC and primary biliary cirrhosis [112]. Preva- lence of primary biliary cirrhosis in UC appears to be significantly higher than in the general population and there may be a true immunologic link between the two diseases.
Budd-Chiari syndrome
At least five patients with active UC have now been reported who have developed hepatic vein thrombo- sis and the clinical symptoms and signs of Budd- Chiari syndrome. Four of the five had no known risk factors for venous thrombosis [113-115]. The most recent patient reported was found to have positive anti-cardiolipin antibodies [116]. There has also been one report of Budd-Chiari syndrome in association with CD [117].
Drug-induced hepatitis
There have been a few case reports of drug- induced hepatitis in patients with IBD with mesala- zine, sulfasalazine and azathioprine all having been implicated [118-121], In practical terms, however, drug toxicity is a rare cause of hepatic injury in the context of IBD.
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