Hepatobiliary Complications

The Gallstone Elimination Report

Gallstone Elimination Manual by David Smith

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The incidence of hepatobiliary complications ranges from 5% to 15% in IBD patients. These complications include steatosis, cholelithiasis and PSC. An Italian study reported an overall prevalence of hepatobiliary alterations, e.g. steatosis and altered liver function test results, in 12% of IBD patients. A recent study by Bargiggia et al. reported gallstones, liver steatosis and liver enlargement in about 55% of 511 IBD patients undergoing abdominal ultrasound (Fig. 3).

Cholelithiasis is reportedly more frequent in patients with IBD, and the risk of gallstones was found increased in both CD and UC patients [odds ratio (OR) 3.6 for CD and 2.5 for UC]. The risk was also greater in patients with CD localised in the distal ileum (OR 4.5) and in UC patients with pancolitis (OR 3.3) [57]. In a study on 251 patients with CD, Hutchinson et al. found a 28% prevalence of gallstones and the only independent risk factor was prior surgery [58].

The most important and specific hepatobiliary complication in IBD is PSC, reported in up to 10% of patients, and 70-90% of PSC patients have associated UC. The clinically most severe consequence of this disease is increased risk of cholangiocarcinoma, the incidence of which is around 15% [59]. PSC is a chronic progressive disease of the biliary tree that

Complications Crohn Disease
Fig. 3. Hepatobiliary abnormalities identified by ultrasonography in IBD patients. * p<0.001 vs. controls § p<0.016 vs. controls (Modified from [57])

can involve both the intra- and the extrahepatic bile ducts; it is characterised by duct strictures and dilations and concentric fibrosis of the intrahepatic bile ducts. Its clinical course does not parallel bowel disease activity, and it may progress in patients even years after proctocolectomy. The pathogenesis of PSC is still not clearly understood, but there is abundant evidence that immune dysregulation plays a crucial part in the development of this liver disease. Different studies have reported changes in tissue lymphocyte population, abnormal cytokine patterns and aberrant expression of HLA class II molecules on the bile duct epithelium. This provides indirect evidence that PSC is an immune-mediated disease, which causes immunological damage to the biliary tree. PSC also has some features of autoimmune disease, such as presence of autoantibodies, association with other autoimmune diseases and strong link with the haplotype B8-DRB1*0301-DQB1*0201. The mechanism by which immune tolerance is lost has yet to be fully understood, however [60]. Genetic susceptibility to PSC has been investigated, and a number of studies have reported that a pattern of genetic polymorphism is involved in generating the predisposition to develop this disease.

As a possible explanation for the correlation between intestinal and hepatic disease, some studies have suggested that the initial event could be passage of bacterial products through the inflamed mucosa into the portal circulation. These bacterial products could be cleared by hepatic macrophages, thus inducing an immune response that causes peribiliary duct fibrosis in a susceptible host. Another hypothesis, that is better able to justify the clinical course of the biliary disease, concerns the presence of entero-hepatic circulation of lymphocytes between gut and liver: mucosal lymphocytes produced as a result of intestinal inflammation would remain as memory cells, causing hepatic inflammation under certain circumstances. This theory is supported by the finding that certain lymphocyte homing receptors are shared by the liver and gut [61]. Moreover, nitric oxide (NO) synthase overexpression has been found in biliary cell ducts in advanced PSC. Such synthase overexpression is not induced by different proin-flammatory cytokines, and it produces a large amount of NO, resulting in production of reactive O species. These highly reactive substances damage many different cell functions and DNA repair enzymes and, in the long term, chronic inflammation may be responsible for the oncological complication of PSC [62].

Diagnosis of PSC is often incidental during follow-up of patients with IBD and, in most cases, patients are asymptomatic but have altered liver function test results. Symptoms of PSC include pruritus, fatigue, right upper quadrant pain, jaundice and often cholangitis. Only few patients present with symptoms of advanced liver disease or cholangiocarcino-ma. Laboratory tests reveal cholestasis with increased alkaline phosphatase values whereas liver function test findings may be normal or fluctuate during the course of the disease, becoming worse in its advanced stages. Autoantibodies that have the strongest association with PSC are p-ANCA, found in 33-88% of cases. PSC is diagnosed by finding strictures and dilations of the intra- or extrahepatic bile ducts on magnetic resonance (MR) cholangiopancre-atography (which has proved as sensitive as endo-scopic retrograde cholangiopancreatography) (Fig. 4). Liver biopsy is also important to determine the stage of liver disease, rule out any biliary dyspla-sia and diagnose small-duct PSC. Small duct PSC affects a subgroup of patients with altered liver function test results and histological changes typical of PSC but with negative imaging tests. Recent studies have reported a better course of this disease, with only 12% of patients progressing to classical PSC and no cases of cholangiocarcinoma. A study conducted in Oslo reported that small-duct PSC is more frequent in CD than in UC.

Treatment for PSC is based on specific agents, such as immunosuppressants, antifibrogenic drugs and ursodeoxycholic acid. Cholestatic complications are treated with cholestyramine, ursodeoxycholic acid (UDCA) and antihistamines. End-stage liver disease requires orthotopic liver transplantation [63]. UDCA is a hydrophilic bile acid widely used in cholestatic liver disease. The positive effect of UDCA has yet to be fully explained, but it probably contrasts toxic effects of hydrophobic bile acids on hepatic cells. Therapeutic actions of UDCA are:

1. protecting cholangiocytes by displacing hydrophobic bile acid from the bile acid pool.

2. A choleretic effect that prevents retention of potentially toxic biliary products in the liver.

3. An antiapoptotic effect via activation of epidermal growth factor receptor and mitogen-activated protein kinases.

4. A potential immunomodulatory role on cytokine secretion by monocytes.

Many trials have been performed to understand the clinical efficacy of UDCA in the context of PSC, and almost all demonstrated improvement in liver function test findings while only the small trials by Stiehl et al. and Beuers et al. and the high-dose trial by Mitchel et al. have demonstrated improvement in liver histology. All trials using a standard dose of UDCA (13-15 mg/kg) failed to demonstrate any significant effect on disease progression despite the positive effect on liver function test findings [64-66]. As the biliary concentration of UDCA increases with

Ercp Primary Sclerosis Cholangitis
Fig. 4. Two ERCP images of primary sclerosing cholangitis (our experience)

increasing doses, reaching a plateau at a dose of 22-25 mg/kg, higher doses are likely to be more effective than lower doses. A small trial by the Oxford group using a high dose of UDCA demonstrated significant improvement in both the cholangiographic picture and degree of liver fibrosis but arrived at no conclusive results on how this treatment affects survival.

Steroids have been considered potentially useful for treatment of PSC because of their immunomodu-latory effect, but no positive impact on the liver disease has been seen in patients administered cycles of steroids for their concomitant UC. Steroid therapy has been evaluated in a number of small, often uncontrolled, trials. Two such studies on PSC patients treated with steroids several years ago came to different conclusions, and another study combining prednisolone and colchicine therapy failed to demonstrate any positive effect on disease progression or survival [67, 68].

Various immunosuppressants have been studied for the treatment of PSC, most of them with disappointing results. Three trials failed to show any efficacy of methotrexate, alone or in combination with UDCA [69-71]. Cyclosporine has been found to pre vent progression of histological changes in the liver in the 2-year follow-up of one randomised controlled trial involving 34 patients. In preliminary studies, tacrolimus proved capable of improving liver function test results, but further trials are needed [72]. The outcome of preliminary studies with pentoxi-fylline and etanercept revealed no clinical benefit [73, 74].

The course of colitis in patients with PSC is usually a mild pancolitis. A recent study comparing UC alone with UC associated with PSC reported a mild clinical course of colitis in the latter, characterised by fewer hospital stays and courses of steroid therapy [75].

The outcome of restorative proctocolectomy in UC complicated by PSC is not clear. A recent study compared outcome - in terms of risk of dysplasia/cancer, morbidity/mortality and long-term results - of IBD patients with and without PSC undergoing proctocolectomy. It revealed that IBD patients with PSC have higher risk of cancer in the resected colon after proctocolectomy and higher long-term mortality. Function and quality of life were similar in the two groups, but the presence of PSC was associated with worse survival [76].

The risk of colorectal cancer is reportedly higher (31%) in UC patients with PSC than in those with UC alone (5%) [77]. Since the original publication by Broome et al. [78] in 1992, about 14 studies have appeared on the risk of colorectal cancer in patients with PSC. Some of these studies are difficult to interpret because all patients with colitis are cases of pan-colitis, which is itself an independent risk factor for colorectal cancer in UC. There is nonetheless general consensus that patients with UC and associated PSC have higher risk of dysplasia and should undergo colonoscopy with multiple biopsies every year. A recent work has suggested that UDCA may have a role in preventing colorectal neoplasia because it can reduce the amount of toxic hydrophobic bile acids reaching the colon [79]. A small study on 59 PSC patients undergoing surveillance colonoscopy found a significantly lower prevalence of colonic dysplasia in patients taking UDCA. Another, larger study on 120 patients showed a small reduction in the amount of dysplasia in patients taking UDCA, but this failed to reach significance. A recent study by Wolf et al. compared 28 patients who were given UDCA for 6 months with 92 patients who were not, demonstrating that UDCA did not reduce the risk of developing cancer and dysplasia but did reduce the mortality rate [80]. Recent reports have suggested a worse course of colitis after liver transplantation despite immunosuppressant treatment, thus encouraging a more aggressive surgical approach to the management of colitis. Haagsma et al. studied 78 patients with end-stage PSC or autoimmune cirrhosis treated with liver transplantation and a median follow up of 7.2 years. They found that the cumulative risk for IBD was 3%, 12% and 20% at 1,3 and 5 years, respectively, after liver transplantation. Moreover, IBD disease-free survival was higher in patients taking aza-thioprine. Pretransplantation IBD and the use of tacrolimus were independent predictors for IBD after liver transplantation. Prevalence of IBD after liver transplantation was found to be affected by the immunosuppresion used, and azathioprine seems to have a protective effect [81].

Dealing with PSC is a real challenge, especially when associated with UC, but more information is now emerging on the effects of PSC on clinical features of UC, and this is helpful in coping with the high risk of colorectal malignancies in these patients.

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