Prospective surveillance for cholangiocarcinoma in unselected individuals with primary sclerosing cholangitis.

BACKGROUND & AIMS: The evidence for hepatobiliary tumour surveillance in patients with primary sclerosing cholangitis (PSC) is scarce. In this study, we aimed to prospectively evaluate cholangiocarcinoma (CCA) surveillance with yearly MRI with cholangiopancreatography (MRI/MRCP) in a nationwide cohort. METHODS: In total, 512 patients with PSC from 11 Swedish hospitals were recruited. The study protocol included yearly clinical follow-ups, liver function tests and contrast-enhanced MRI/MRCP and carbohydrate antigen (CA) 19-9. Patients with severe/progressive bile duct changes on MRI/MRCP were further investigated with endoscopic retrograde cholangiopancreatography. Patients were followed for 5 years or until a diagnosis of CCA, liver transplantation (LT) and/or death. Risk factors associated with CCA were analysed with Cox regression. RESULTS: Eleven patients (2%) were diagnosed with CCA, and two (0.5%) with high-grade bile duct dysplasia. Severe/progressive bile duct changes on MRI/MRCP were detected in 122 patients (24%), of whom 10% had an underlying malignancy. The primary indication for LT (n = 54) was biliary dysplasia in nine patients (17%) and end-stage liver disease in 45 patients (83%), of whom three patients (7%) had unexpected malignancy in the explants. The median survival for patients with CCA was 13 months (3-22 months). Time to diagnosis of high-grade dysplasia and/or hepatobiliary malignancy was significantly associated with severe/progressive bile duct changes on MRI/MRCP (hazard ratio 10.50; 95% CI 2.49-44.31) and increased levels of CA19-9 (hazard ratio 1.00; 95% CI 1.00-1.01). CONCLUSION: In an unselected cohort of patients with PSC, yearly CA19-9 and MRI/MRCP surveillance followed by ERCP was ineffective in detecting cancer early enough to support long-term survival. Given the low occurrence of CCA, studies on individualised strategies for follow-up and improved diagnostic methods for PSC-related CCA are warranted. IMPACT AND IMPLICATIONS: A prospective nationwide 5-year study was conducted to evaluate yearly cholangiocarcinoma surveillance using MRI and CA19-9 in patients with primary sclerosing cholangitis. Only 2% of the patients were diagnosed with cholangiocarcinoma during follow-up and their prognosis remained poor despite surveillance. This surveillance strategy failed to detect cancer early enough to support long-term survival. Therefore, individualised strategies and improved diagnostic methods will be required to improve the early detection of cholangiocarcinoma in patients with primary sclerosing cholangitis.

Mycophenolate mofetil treatment in patients with autoimmune hepatitis failing standard therapy with prednisolone and azathioprine.

BACKGROUND: Data on rescue treatment of autoimmune hepatitis in patients that fail standard treatment are sparse. AIMS: To report our long-term experience with mycophenolate mofetil. METHODS: Retrospective study in 22 patients with autoimmune hepatitis who failed azathioprine and prednisolone due to adverse events (n = 14, 64%), lack of remission (n = 5, 23%) or a combination (n = 3, 13%). RESULTS: Mycophenolate mofetil was started at a dose of 20 mg/kg/day and increased to a maximum of 3 g/day. Follow-up was 0-6 months in 7 patients; more than 12 months in 15 (68%) and more than 24 months in 10. Normal aminotransferase levels were obtained (n = 3) or maintained (n = 7) in 10 patients (45%) after three to 30 weeks. 12 patients (55%) were withdrawn during the first 6 months, due to adverse events. Three patients were switched to cyclosporine and one underwent liver transplantation. Successful treatment with mycophenolate mofetil continued in 10 patients (45%) for a median of 71 months (range 20-124). Of these, one stopped prednisolone, five have a prednisolone dose <5 mg daily and four patients 5-10 mg. CONCLUSION: Approximately one of two patients with autoimmune hepatitis that fail standard treatment benefit from long-term maintenance with mycophenolate mofetil, especially those with previous intolerance to thiopurines, where mycophenolate mofetil is effective in two thirds.

[Ascites is usually caused by an underlying liver cirrhosis. Salt restriction and diuretics is the basis for treatment]. / Ascites orsakas oftast av bakomliggande levercirros-Saltrestriktion och diuretika är grundval för behandling.

Ascites is a common complication of liver cirrhosis and is associated with a poor prognosis. The main pathophysiology is an increased portal pressure with compensatory activation of neurohumoral systems. A patient history, proper physical exam and adequate examination of ascitic fluid will reveal the aetiology in most cases. Complications such as spontaneous bacterial peritonitis and thrombosis of hepatic vessel should be excluded in cases of first episode of ascites or deterioration of ascites. A moderate salt restriction and treatment with diuretics is the mainstay of treatment. Potentially nephrotoxic drugs such as NSAID and ACE inhibitors should be avoided in patients with cirrhosis.

Hepatocellular and extrahepatic cancer in patients with autoimmune hepatitis--a long-term follow-up study in 634 Swedish patients.

OBJECTIVES: Cirrhosis is a well-known risk factor for hepatocellular cancer, but the true risk in autoimmune hepatitis (AIH) is scarcely studied. Other cancers may arise after prolonged use of immune-modulating drugs. The aim of this study was to investigate the cancer risk in a large cohort of AIH patients. MATERIAL AND METHODS: Six hundred and thirty-four Swedish patients in a well-defined cohort were matched to the Cause of Death Registry and the Cancer Registry. Standard incidence ratios were calculated by relating the incidences in the cohort to an age-matched material from the Swedish background population. RESULTS: A higher overall incidence of malignancies than the background population was found, counting from the date of diagnosis (standard incidence ratio (SIR) 2.08, 95% CI 1.68-2.55). The highest risk was found for hepatocellular carcinoma (HCC). We found 10 cases (4.0%) in 248 patients with cirrhosis, which gives an incidence rate of 0.3%. Standard incidence ratio for developing hepatobiliary cancer was 54.55 (95% CI 19.92-99.99). HCC only occurred in cirrhotic patients. There was also an increased risk for non-melanoma skin cancer (SIR 9.87, 95% CI 6.26-14.81). CONCLUSION: A slightly enhanced risk for malignancies in general compared to the background population was found. The risk of hepatobiliary cancer was increased, but the annual risk over the observational period was well under the postulated 1.5% when surveillance in cirrhotic patients is considered to be cost-effective.

Increased thrombin generation in splanchnic vein thrombosis is related to the presence of liver cirrhosis and not to the thrombotic event.

INTRODUCTION: In recent years there have been increasing evidence associating liver disease with hypercoagulability, rather than bleeding. The aim of the study was to evaluate the haemostatic potential in patients with liver disease. PATIENTS AND METHODS: We measured thrombin generation in the presence and absence of thrombomodulin in patients with portal vein thrombosis (PVT, n=47), Budd-Chiari syndrome (BCS, n=15) and cirrhosis (n=24) and compared the results to those obtained from healthy controls (n=21). Fifteen patients with PVT and 10 patients with BCS were treated with warfarin and were compared to an equal number of patients with atrial fibrillation matched for prothrombin time-international normalized ratio. We assessed resistance to thrombomodulin by using ratios [marker measured in the presence/absence of thrombomodulin]. RESULTS: There were no differences in thrombin generation between patients on warfarin treatment and their controls. Cirrhotic patients generated more thrombin in the presence of thrombomodulin and exhibited thrombomodulin resistance compared to controls [p=0.006 for endogenous thrombin potential (ETP) and p<0.001 for peak thrombin and both ratios ETP and peak] and patients with non-cirrhotic PVT (p=0.001, p=0.006, p<0.001, p<0.001 for ETP, peak, ratio ETP, ratio peak, respectively). The patients with cirrhotic PVT exhibited higher ETP (p=0.044) and peak (p=0.02) in the presence of thrombomodulin than controls, as well as thrombomodulin resistance (ETP and peak ratios: p=0.001). CONCLUSIONS: Hypercoagulability and thrombomodulin resistance in patients with cirrhosis were independent of the presence of splanchnic vein thrombosis. The hypercoagulability in patients with cirrhotic PVT could have implications for considering longer or more intensive treatment with anticoagulants in this group.

Association between reduced levels of alkaline phosphatase and survival times of patients with primary sclerosing cholangitis.

BACKGROUND & AIMS: Ursodeoxycholic acid (UDCA) has not been shown to stop progression of primary sclerosing cholangitis (PSC). However, patients with primary biliary cirrhosis treated with UDCA whose levels of alkaline phosphatase (ALP) decrease have longer survival times than patients whose levels do not decrease. We compared survival times between patients with PSC treated with UDCA or placebo, with and without decreased levels of ALP. METHODS: We collected data from patients enrolled in the Scandinavian PSC UDCA trial. Patients were randomly assigned to groups given UDCA (17-23 mg/kg/day, n = 97) or placebo (n = 101) from 1996-2001 and were followed until 2010. End points were death, liver transplantation, or cholangiocarcinoma. They were considered to be biochemical responders if they had serum levels of ALP that were normal or reduced by ≥40% after 1 year in the trial (regardless of whether they received UDCA or placebo). Numbers of patients surviving until the study end point were compared by using the Kaplan-Meier method. RESULTS: There were no differences in survival at the end of the study between patients given UDCA or placebo (P = .774, log-rank); 26 patients in the UDCA group and 29 in the placebo group reached an end point. On the basis of ALP levels, there were 79 responders and 116 nonresponders overall. Of patients given UDCA, significantly more biochemical responders survived for 10 years than nonresponders (P = .03, log-rank). However, differences remained significant regardless of group assignment; overall, patients with reductions in ALP level survived longer than patients without reductions in ALP (P = .0001, log-rank). CONCLUSIONS: There is no significant difference in long-term survival between patients with PSC given UDCA (17-23 mg/kg/day) or placebo for 5 years. However, patients who have reduced or normal levels of ALP have longer survival times, regardless of whether they receive UDCA or placebo.

Infliximab or cyclosporine as rescue therapy in hospitalized patients with steroid-refractory ulcerative colitis: a retrospective observational study.

BACKGROUND: Cyclosporine (CsA) or infliximab (IFX) are used as rescue therapies in steroid-refractory, severe attacks of ulcerative colitis (UC). There are no data comparing the efficacy of these two alternatives. METHODS: Outcome of rescue therapy was retrospectively studied in two cohorts of patients hospitalized due to steroid-refractory moderate to severe UC: 1) a Swedish-Danish cohort (n = 49) treated with a single infusion of IFX; 2) an Austrian cohort (n = 43) treated with intravenous CsA. After successful rescue therapy, maintenance immunomodulator treatment was given to 27/33 (82%) of IFX patients and to 31/40 (78%) of CsA patients. Endpoints were colectomy-free survival at 3 and 12 months. Kaplan-Meier and Cox regression models were used to evaluate the association between treatment groups and colectomy. RESULTS: At 15 days, colectomy-free survival in the IFX cohort was 36/49 (73%) versus 41/43 (95%) in the CsA cohort (P = 0.005), at 3 months 33/49 (67%) versus 40/43 (93%) (P = 0.002), and at 12 months 28/49 (57%) versus 33/43 (77%) (P = 0.034). After adjusting for potential confounding factors, Cox regression analysis yielded adjusted hazard ratios for risk of colectomy in IFX-treated patients of 11.2 (95% confidence interval [CI] 2.4-53.1, P = 0.002) at 3 months and of 3.0 (95% CI 1.1-8.2, P = 0.030) at 12 months in comparison with CsA-treated patients. There were no opportunistic infections or mortality. CONCLUSIONS: Colectomy frequencies were significantly lower after rescue therapy with CsA than with a single infusion of IFX both at 3 and 12 months' follow-up. The superiority of CsA was seen principally during the first 15 days.

Resource use and societal costs for Crohn's disease in Sweden.

BACKGROUND: The usual onset of Crohn's disease (CD) is between 15 and 30 years of age, thus affecting people during their most economically productive period in life. METHODS: This study intended to estimate societal costs and health-related quality of life (HRQoL) in Swedish patients in different stages of CD. Cross-sectional data on disease activity (measured with the Harvey-Bradshaw Index [HBI]), direct medical resource use, work productivity, and HRQoL (assessed using the 15D instrument) were collected for 420 patients by questionnaires to patients, to the treating physician, and from medical records. Based on HBI, current treatment, and response to treatment, patients were classified into the following disease states: Remission, Response, Active, Refractory, and Surgery. RESULTS: The average 4-week cost per patient in 2007 was estimated at €721 (USD 988), of which 64% was due to lost productivity. The total 4-week cost of care was €255 (USD 349) in Remission, €831 (USD 1138) in Response, €891 (USD 1220) in Active, €1360 (USD 1864) in Refractory, and €16984 (USD 23269) in Surgery. HBI was the most important predictor of costs of care--a 1-point increase in HBI increased total costs by 25% (P < 0.001). HRQoL differed between the disease states: 0.92 in Remission, 0.90 in Response, 0.82 in Active, 0.81 in Refractory, and 0.77 in Surgery. CONCLUSIONS: Patients in remission have the lowest costs and the highest HRQoL. Patients responding to treatment have lower costs of care than patients with high disease activity who are not treated or do not respond to treatment. Thus, total costs of care might be reduced by efficient treatment.

Infliximab as rescue therapy in severe to moderately severe ulcerative colitis: a randomized, placebo-controlled study.

BACKGROUND & AIMS: Despite treatment with corticosteroids, severe to moderately severe attacks of ulcerative colitis have a high colectomy rate. We intended to find a rescue therapy other than cyclosporin A, which imposes a high risk of side effects and cyclosporine-related mortality. METHODS: This was a randomized double-blind trial of infliximab or placebo in severe to moderately severe ulcerative colitis not responding to conventional treatment. Patients were randomized to infliximab/placebo either on day 4 after the initiation of corticosteroid treatment if they fulfilled the index criteria for fulminant ulcerative colitis on day 3 or on day 6-8 if they fulfilled index criteria on day 5-7 for a severe or moderately severe acute attack of ulcerative colitis. Results were analyzed according to the intention-to-treat principle. The primary end point was colectomy or death 3 months after randomization. Secondary end points were clinical and endoscopic remission at that time in patients who did not undergo operation. RESULTS: Forty-five patients were included (24 infliximab and 21 placebo). No patient died. Seven patients in the infliximab group and 14 in the placebo group had a colectomy (P = .017; odds ratio, 4.9; 95% confidence interval, 1.4-17) within 3 months after randomization. No serious side effects occurred. Three patients in the placebo group required operation for septic complications. CONCLUSIONS: Infliximab 4-5 mg/kg is an effective and safe rescue therapy in patients experiencing an acute severe or moderately severe attack of ulcerative colitis not responding to conventional treatment.