Primary Sclerosing Cholangitis in Patients with Ulcerative Colitis

The prevalence of primary sclerosing cholangitis (PSC) in patients with ulcerative colitis (UC) attending the Depts. of Medical and Surgical Gastroenterology, Aalborg Hospital, during a 12-year period, was determined. All patients with an alkaline phosphatase (ALP) value above the normal range were investigated. Of 305 patients with UC, 24 patients had elevated ALP values, and 11 of these (3.6% of the study population), 4 males and 7 females, were found to have PSC by direct cholangiography. In five patients the disease worsened (two patients died of cholangiocarcinoma), in four it was stationary, and in two patients the disease improved during a mean observation period of 6 years. No differences in location of disease, disease activity, or duration of disease were found between patients with UC and PSC and patients with UC without PSC. The ALP values were raised to a mean of 3.7 times the upper normal limit (observed range, 1.5-5.5 times the upper normal limit). Aspartate aminotransferase was moderately elevated in most patients, but no other abnormal biochemical liver test results were observed at onset. The results of our study indicate that PSC is the major cause of raised ALP values in patients with UC; thus cholangiography should be performed in UC patients with unexplained elevated ALP levels. A prognostic indicator is needed to predict the individual prognosis and to determine the optimal timing of liver transplantation.     

Update in the Care and Management of Patients with Primary Sclerosing Cholangitis

Purpose of Review

Primary sclerosing cholangitis (PSC) is a progressive cholestatic liver disease for which specific medical therapy is not available. The goals of treatment are primarily early detection and management of complications. In this review, we discuss novel therapies under evaluation and provide the foundation for surveillance strategies.

Recent Findings

Drugs under investigation include norursodeoxycholic acid, nuclear receptor agonists, anti-fibrotics, antibiotics, and anti-inflammatory drugs. Endoscopic therapy is indicated for symptomatic dominant strictures and in the work-up of malignancies. Recently, the use of stents was associated with an increased rate of complications compared to balloon dilatation; and long-term stenting should be avoided. Malignancies currently account for most of the PSC-related mortality.

Summary

Many drugs are emerging for the treatment of PSC but liver transplantation is the only treatment modality shown to prolong survival. PSC recurrence occurs in up to 35% of transplanted allografts within a median of 5 years. Surveillance for hepatobiliary and colorectal malignancies is indicated.

     

Cholangiocarcinoma and High-Grade Dysplasia in Young Patients with Primary Sclerosing Cholangitis

Introduction

Cholangiocarcinoma (CCA) is very often an adulthood disease with primary sclerosing cholangitis (PSC) as one of the risk factors. It is rarely seen in the pediatric population, and when it is diagnosed before adulthood, it can be associated with PSC as well as HIV infection, biliary atresia, radiation therapy, and choledochal cyst. Although there have been some case reports of pediatric CCA, cases of childhood CCA associated with PSC are still relatively rare.

Aim

To describe the clinical and pathologic features of CCA in pediatric patients with previously diagnosed PSC.

Methods

Retrospective study

Results

Four patients with PSC (age range 15–18, mean 17 years) were included in this study. All patients underwent ERCP for diagnosis. Tissue samples obtained included routine cytology and FISH. ERCP was used to target sites for tissue acquisition in all patients. 3/4 of patients have inflammatory bowel disease (two Crohn’s disease and one ulcerative colitis). Alkaline phosphatase was elevated in 3/4 patients, aspartate aminotransferase/alanine aminotransferase were elevated in 2/4 patients, and total bilirubin/direct bilirubin were elevated in 2/4 patients. 4/4 patients had positive FISH studies, and 3/4 patients had brush cytology concerning for CCA. 2/4 patients received chemotherapy, one patient underwent orthotopic liver transplant, and one patient underwent Whipple procedure. Two patients died soon after being diagnosed.

Conclusions

Young patients with PSC can develop CCA. This finding has implications for both screening and surveillance for cancer in pediatric patients with PSC.     

The Combination of Prednisone and Colchicine in Patients with Primary Sclerosing Cholangitis

Primary sclerosing cholangitis is a cholestatic liver disease characterized by inflammation and fibrosis of the biliary tract. The cause of the disease is unknown, and no effective medical treatment exists. In this study, 12 patients received a combination of low-dose prednisone (10 mg/day) and colchicine (0.6 mg bid). Their course was compared with that of a group of concurrent historical controls. At 6 and 12 months, there was significantly more improvement in liver test results over baseline values in patients receiving prednisone and colchicine than in the untreated controls. At 24 months, however, no significant differences in biochemical tests were appreciated between treated and untreated patients. Analysis of serial liver biopsies showed no differences in histologic change in the two groups. During the 2 yr of follow-up, there were two deaths in the control group but none in the treated group. Four untreated patients developed ascites; gastrointestinal bleeding developed in three untreated patients, one of whom developed ascites. In contrast, in the treated group, ascites and bleeding developed in only one patient. We conclude that the combination of colchicine and prednisone does not retard histologic progression or progression of standard liver tests after 2 yr of therapy. There is a trend toward less clinical deterioration and improved survival after 2 yr of treatment. On the basis of these findings, we would not advocate empiric use of these drugs for patients with primary sclerosing cholangitis, but suggest that, if they are to be used at all in PSC, they be evaluated in a controlled clinical trial as treatment for this as yet incurable disease.     

Long-Term Effect of Corticosteroid Treatment in Primary Sclerosing Cholangitis Patients

Background: A beneficial effect of corticosteroids in primary sclerosing cholangitis (PSC) has been suggested, but characteristics of responding patients and long-term outcome have not been assessed. In this retrospective study, we aimed to characterize PSC patients selected for corticosteroid treatment at our centre and to identify potential factors associated with response. Methods: We first compared groups of PSC patients treated ( n &#114 = &#114 47) and not treated ( n &#114 = &#114 88) with corticosteroids. Responding ( n &#114 = &#114 20) and non-responding ( n &#114 = &#114 27) patients were subsequently compared. Complete and partial responses were defined according to criteria established for autoimmune hepatitis. A third response category included improvement of symptoms and at least 50% reduction of transaminase and/or bilirubin levels during the first 6 months. Results: At diagnosis of PSC, patients treated with corticosteroids were significantly younger, had higher serum levels of alanine transaminases, and more histological features of autoimmune hepatitis compared to the non-treated group. Complete treatment response was obtained in three patients and partial response in two, together comprising 3.7% of all PSC patients in this study. Fifteen patients fulfilled criteria of the third response category. Response to treatment was associated with higher serum levels of alanine transaminases and bilirubin and lower levels of alkaline phosphatases at treatment start. Responders had better long-term survival than non-responders (hazard ratio 6.28; 95% confidence interval 1.62 to 24.4; P &#114 = &#114 0.008). Conclusions: A subgroup of PSC patients seems to respond favourably to corticosteroid treatment and may obtain improved long-term survival.     

Lack of Concomitant Expression of ICAM-1 and HLA-DR on Bile Duct Cells from Patients with Primary Sclerosing Cholangitis and Primary Biliary Cirrhosis

In both primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) prominent infiltrates of lymphocytes surround the bile ducts, on which an abberrant expression of major histocompatibility complex class II antigens has been found, suggesting that the immune system is involved in the biliary destruction. Since the lymphocytes presumably must adhere to the bile ducts to initiate a cell-to-cell-mediated destruction, we have studied the expression of the lymphocyte function-associated antigen-1 (LFA-1) together with its ligand, the intercellular adhesion molecule-1 (ICAM-1), and the expression of HLA-DR, using immunoperoxidase staining of cryostat sections from patients with PBC (n = 10), PSC (n = 13), and normal healthy controls (n = 6). Most lymphocytes expressed LFA-1. ICAM-1 expression was found on hepatocytes from 9 of 10 PBC and 10 of 13 PSC patients but was not seen on hepatocytes from the controls. Hepatocytes expressing HLA-DR were only found in one patient with PBC. None of the septal bile ducts expressed ICAM-1, and only one PSC patient and three PBC patients expressed ICAM-1 on their interlobular bile ducts. The bile ducts in 22 of 23 patients, however, expressed HLA-DR. Proliferating bile ductules from two PBC patients and three PSC patients showed a concomitant expression of ICAM-1 and HLA-DR. None of the bile ducts from the controls expressed ICAM-1 or HLA-DR. Thus, since most bile ducts involved in the disease process of both PBC and PSC lack expression of ICAM-1, other adhesion molecules must be involved if a cell-to-cell-mediated destruction accounts for the biliary destruction in these two disease states. Furthermore, the lack of concomitant expression of HLA-DR and ICAM-1 on the bile ducts in PBC and PSC indicates that other regulatory mechanisms exist in the biliary epithelium than in most other epithelial cells.     

Laparoscopic Findings in Primary Sclerosing Cholangitis

Abstract: The laparoscopic appearance of the liver surface in patients with primary sclerosing cholangitis (PSC) has not been fully delineated. We examined 5 patients with PSC and reviewed 35 previously reported cases. Intense white markings in a mesh-like pattern were characteristic of PSC. The findings varied depending on the histologic stage and affected site. Red patches which have also been seen in primary biliary cirrhosis (PBC), green patches indicating cholestasis, and dilatation of the terminal bile ducts were also observed. The red patches were wider than those in PBC. The white markings were less well defined in the red patches than in other areas. The severity of the fibrosis and histologic damage was judged to be mild at the red sites. The green patches were caused by localized cholestasis. This indicated that PSC unevenly affects the liver. Severe obstruction may be present between the interlobular bile ducts and the septal bile ducts in anicteric stages. (Dig Endosc 1999; 10: 37–41)     

Outcome of Patients Undergoing Liver Transplantation for Primary Sclerosing Cholangitis

PURPOSE: The purpose of this study was to determine the outcome of patients with inflammatory bowel disease who underwent liver transplantation for primary sclerosing cholangitis. METHODS: All patients who underwent liver transplantation for primary sclerosing cholangitis at our institution were identified. A review of patients hospital and office charts was performed; all patients were then contacted, and a detailed survey was administered by telephone. RESULTS: Sixty-nine patients were identified. There were 53 males (76.8 percent) and 16 females, with a mean age of 45.3 (± 13.3) years. Fifty-two (75.4 percent) of the 69 patients had documented inflammatory bowel disease; of these, 40 had ulcerative colitis (76.9 percent), 11 had Crohns disease, and 1 had indeterminate colitis. Thirty-one patients (60 percent) were diagnosed with inflammatory bowel disease before primary sclerosing cholangitis, with a mean interval to diagnosis of primary sclerosing cholangitis of 10.8 (± 10.3) years. Seven patients had both diagnoses made at roughly the same time, and 14 patients initially were diagnosed with primary sclerosing cholangitis and subsequently were found to have inflammatory bowel disease, with a mean interval of 5.2 (± 4.4) years; 5 (35.7 percent) of those 14 patients were only diagnosed with inflammatory bowel disease after their liver transplant. The mean time from diagnosis of primary sclerosing cholangitis to liver transplantation was 6.1 (± 4.9) years. Since their transplant, 30.8 percent of patients rated their colitis as worse, 38.5 percent felt it was unchanged, and 30.8 percent felt that their colitis was better controlled. Eight (15.4 percent) of the 52 patients with inflammatory bowel disease denied having any knowledge of an increased risk of colorectal neoplasia. Four patients have required colectomy for colorectal neoplasia after liver transplantation, at a mean of 4.7 years after transplantation. Of the patients with inflammatory bowel disease, 42 (80.1 percent) had at least 1 posttransplant surveillance colonoscopy. Eight of the remaining ten patients had a colectomy, leaving only two patients (3.8 percent) who had not been surveyed. However, only 32 (61.5 percent) of the patients with inflammatory bowel disease have been on a surveillance regimen that would approximately conform to current screening recommendations. CONCLUSIONS: The activity of inflammatory bowel disease after transplantation is highly variable. Patients appeared to lack knowledge of their increased risk for colorectal neoplasia. Colorectal cancer is an uncommon but important complication in patients after liver transplantation for primary sclerosing cholangitis, and ongoing surveillance is required. Patients may require education to increase their awareness of the cancer risk and compliance with surveillance.     

Incidence, Diagnosis, and Therapy of Cholangiocarcinoma in Patients with Primary Sclerosing Cholangitis

Primary sclerosing cholangitis (PSC) can lead to the development of cholangiocarcinoma (CCA). The tumor may present as an intrahepatic focal cholangiocellular carcinoma but more often as a ductal infiltrating desmoplastic lesion. CCA is found synchronously with the diagnosis of PSC in 20–30% and within 1 year in 50%. During later follow-up, the yearly developmental rate of CCA is 0.5–1.5%. Most patients with PSC and CCA do not yet have cirrhosis but present with a severe stenosis at the hilum of the liver. This type of tumor is difficult to diagnose by imaging techniques.¹⁸F-FDG-PET scanning and CEA or CA 19-9 are not early diagnostic tools. Regular MRI, multislice CT, and repeated endoscopically obtained brush cytology of stenotic lesions are recommended. The recent use of more extensive surgical resection techniques in patients with CCA results in 5-year survival rates of ≥50%. If tumors are small or incidental findings, liver transplantation leads to a 3- to 5-year survival rate of 35%. Pretransplant radiotherapy with 5-FU chemosensitization followed by endoscopic brachytherapy with iridium-192 seems to greatly improve the outcome of transplantation. Treatment with ursodeoxycholic acid may prevent development of CCA.     

Increased Serum Levels of Carbohydrate Antigen 19-9 and Outcomes in Primary Sclerosing Cholangitis Patients Without Cholangiocarcinoma

Background

Carbohydrate antigen 19-9 (CA 19-9) is the serum marker used to diagnose cholangiocarcinoma (CCA) in patients with primary sclerosing cholangitis (PSC).

Aim

We investigated long-term outcomes in patients with PSC and elevated CA 19-9 levels without CCA.

Methods

A total of 166 PSC patients with serum levels of CA 19-9 without CCA followed at a single center from 1998 to 2011 were included. Patients with and without elevated CA 19-9 levels (greater than 129 U/ml) were compared.

Results

Fifty-two (31.3 %) of the 166 patients with PSC without CCA had elevated serum CA-19-9. Patients with elevated CA-19-9 were followed for a mean of 4 years and 12 (23.1 %) died. They were more likely to have higher PSC risk score (1.67 ± 1.30 vs. 0.91 ± 1.53, p = 0.003) and dominant strictures (31 (59.6 %) vs. 21 (18.4 %), p < 0.001). In 17/52 (32.7 %) of patients with elevated CA-19-9, no etiology was identified; cholestasis and cholangitis were associated with elevated levels in 24/52 (48.1 %) and 11/52 (21.2 %), respectively. There were 32 of 52 (62.5 %) that underwent orthotopic liver transplantation (OLT) in elevated CA 19-9 group compared to 66/114 (56.9 %) without (p = 0.66). The median OLT-free survival with elevated CA 19-9 was 9 years from PSC diagnosis compared to 14 years without. Although there was a trend, there was no significant difference in the OLT-free survival on Kaplan–Meier analysis (log rank p = 0.12).

Conclusions

Thirty-two percent of patients with PSC had elevated serum CA 19-9 in the absence of CCA. There was a trend towards shorter OLT-free survival in PSC patients with elevated CA-19-9.     

Treatment of Primary Sclerosing Cholangitis with Oral Methotrexate

Ten patients with well-documented primary sclerosing cholangitis who had no signs of portal hypertension or liver failure were treated with oral pulse methotrexate for at least 1 yr. The methotrexate dose averaged 15 mg/wk (0.2 mg/kg/wk). All six patients who were symptomatic became asymptomatic within 1-5 months of starting methotrexate. Biochemical tests of liver function improved in all patients. The alkaline phosphatase value decreased from a mean (+/-SD) of 373 +/- 210 IU to 140 +/- 77 IU (p = 0.0008), the mean alanine aminotransferase (ALT) from 115 +/- 74 to 76 +/- 79 U/L (p = 0.005), and the mean aspartate aminotransferase (AST) value from 88 +/- 37 to 57 +/- 40 U/L (p = 0.007). The improvement in mean bilirubin (1.19 +/- 1.41 to 0.67 +/- 0.25 mg/dl) was not statistically significant. Serum albumin remained normal (3.97 +/- 0.46 to 4.22 +/- 0.36 g/dl). Nine patients had a repeat liver biopsy after 1 yr of methotrexate therapy. Six of the nine showed histologic improvement with a reduction in inflammation. The other three liver biopsies were unchanged. Repeat cholangiograms were done in six patients. Two showed improvement. In one of the two, who had early disease, the cholangiogram became normal, and the liver biopsy was markedly improved. The other four cholangiograms showed no progression of disease. No toxicity was detected in these 10 patients. These results suggest that low-dose oral methotrexate therapy is effective in primary sclerosing cholangitis if treatment is begun before signs of portal hypertension or liver failure occur.     

Pirfenidone in the Treatment of Primary Sclerosing Cholangitis

Our aim was to evaluate the safety and assess the efficacy of pirfenidone, an antifibrotic drug, in patients with primary sclerosing cholangitis (PSC). Twenty-four patients with PSC were enrolled in this pilot study. Oral pirfenidone, 2400 mg daily, was given for one year. Liver biochemistries were determined at three-month intervals. The Mayo risk score was calculated, and liver biopsy and endoscopic cholangiography were performed at entry and at one year of treatment. No significant changes in liver biochemistries were noted at the end of the treatment period or at any of the three-month intervals. The Mayo risk score did not change significantly, and no significant changes were noted in the degree of inflammation, fibrosis, histologic stage of disease, or cholangiographic findings at the end of the treatment period. Adverse events occurred in 20/24 (83%) patients, but disappeared shortly after pirfenidone was discontinued. Pirfenidone did not benefit patients with PSC, and it was frequently associated with adverse events. The results of this pilot study discourage further trials of pirfenidone in patients with PSC.