Henk R. van Buuren

High lifetime risk of cancer in primary sclerosing cholangitis

BACKGROUND/AIMS Primary sclerosing cholangitis (PSC) patients are at risk for developing cholangiocarcinoma (CCA) and colorectal carcinoma (CRC). Our aim was to assess the risk of malignancies and their influence on survival. METHODS Data from PSC patients diagnosed between 1980 and 2006 in two university hospitals were retrieved. The Kaplan-Meier method and a time-dependent Cox regression model were used to calculate risks of malignancies and their influence on survival. RESULTS Two hundred and eleven patients were included, 143 (68%) were male and 126 (60%) had inflammatory bowel disease (IBD). Median transplantation-free survival was 14 years. The risk of CCA after 10 and 20 years was 9% and 9%, respectively. In patients with concomitant IBD the 10-year and 20-year risks for CRC were 14% and 31%, which was significantly higher than for patients without IBD (2% and 2% (P=0.008)). CCA, cholangitis, and age at entry were independent risk factors for the combined endpoint death or liver transplantation. Risk factors for the endpoint death were CCA, CRC, age, and symptomatic presentation. CONCLUSIONS Patients with PSC and IBD have a high long-term risk of developing CRC and this risk is about threefold higher than the risk for CCA. Both malignancies are associated with decreased survival.

Improved Prognosis of Patients With Primary Biliary Cirrhosis That Have a Biochemical Response to Ursodeoxycholic Acid

BACKGROUND & AIMS Ursodeoxycholic acid (UDCA) improves laboratory liver test results in patients with primary biliary cirrhosis (PBC). Few studies have assessed the prognostic significance of biochemical data collected following UDCA treatment. We performed a prospective multicenter study of patients with PBC treated with UDCA to compare prognosis with biochemical response. METHODS PBC was classified as early (pretreatment bilirubin and albumin levels normal), moderately advanced (one level abnormal), or advanced (both levels abnormal). Biochemical response was defined as proposed by Pares (decrease in alkaline phosphatase [ALP] level>40% of baseline level or normal level), Corpechot (ALP level<3-fold the upper limit of normal [ULN], aspartate aminotransferase level<2-fold the ULN, bilirubin level<1-fold the ULN), and our group (Rotterdam; normalization of abnormal bilirubin and/or albumin levels). RESULTS The study included 375 patients, and median follow-up time was 9.7 (range, 1.0-17.3) years. The prognosis for early PBC was comparable with that of the Dutch population and better than predicted by the Mayo risk score. Survival of responders was better than that of nonresponders, according to Corpechot and Rotterdam criteria (P<.001). Prognosis of early PBC was comparable for responders and nonresponders; prognosis of responders was significantly better in those with (moderately) advanced disease. CONCLUSIONS Prognosis for UDCA-treated patients with early PBC is comparable to that of the general population. Survival of those with advanced PBC with biochemical response to UDCA is significantly better than for nonresponders. Thus, UDCA may be of benefit irrespective of the stage of disease. Prognostic information, based on bilirubin and albumin levels, is superior to that provided by ALP levels.

Lysophosphatidic Acid Is a Potential Mediator of Cholestatic Pruritus

BACKGROUND & AIMS Pruritus is a common and disabling symptom in cholestatic disorders. However, its causes remain unknown. We hypothesized that potential pruritogens accumulate in the circulation of cholestatic patients and activate sensory neurons. METHODS Cytosolic free calcium ([Ca(2+)](i)) was measured in neuronal cell lines by ratiometric fluorometry upon exposure to serum samples from pruritic patients with intrahepatic cholestasis of pregnancy (ICP), primary biliary cirrhosis (PBC), other cholestatic disorders, and pregnant, healthy, and nonpruritic disease controls. Putative [Ca(2+)](i)-inducing factors in pruritic serum were explored by analytical techniques, including quantification by high-performance liquid chromatography/mass spectroscopy. In mice, scratch activity after intradermal pruritogen injection was quantified using a magnetic device. RESULTS Transient increases in neuronal [Ca(2+)](i) induced by pruritic PBC and ICP sera were higher than corresponding controls. Lysophosphatidic acid (LPA) could be identified as a major [Ca(2+)](i) agonist in pruritic sera, and LPA concentrations were increased in cholestatic patients with pruritus. LPA injected intradermally into mice induced scratch responses. Autotaxin, the serum enzyme converting lysophosphatidylcholine into LPA, was markedly increased in patients with ICP versus pregnant controls (P < .0001) and cholestatic patients with versus without pruritus (P < .0001). Autotaxin activity correlated with intensity of pruritus (P < .0001), which was not the case for serum bile salts, histamine, tryptase, substance P, or mu-opioids. In patients with PBC who underwent temporary nasobiliary drainage, both itch intensity and autotaxin activity markedly decreased during drainage and returned to preexistent levels after drain removal. CONCLUSIONS We suggest that LPA and autotaxin play a critical role in cholestatic pruritus and may serve as potential targets for future therapeutic interventions.

Population-based epidemiology, malignancy risk, and outcome of primary sclerosing cholangitis.

Extensive population‐based studies are much needed to accurately establish epidemiology and disease course in patients with primary sclerosing cholangitis (PSC). We aimed to obtain population‐based prevalence and incidence figures, insight in disease course with regard to survival, liver transplantation (LT), and occurrence of malignancies, as well as risk factors thereof. Four independent hospital databases were searched in 44 hospitals in a large geographically defined area of the Netherlands, comprising 50% of the population. In addition, all PSC patients in the three Dutch liver transplant centers and all inflammatory bowel disease (IBD) patients in the adherence area of a large district hospital were identified. All medical records were reviewed on‐site, verifying diagnosis. Five hundred and ninety PSC patients were identified, resulting in an incidence of 0.5 and a point prevalence of 6.0 per 100,000. Median follow up was 92 months. Estimated median survival from diagnosis until LT or PSC‐related death in the entire cohort was 21.3 years, as opposed to 13.2 years in the combined transplant centers cohort (n = 422; P < 0.0001). Colorectal carcinoma (CRC) risk was 10‐fold increased, as compared to ulcerative colitis controls, and developed at a much younger age (39 years; range, 26‐64), compared to IBD controls (59 years; range, 34‐73; P = 0.019). Colonoscopic surveillance was associated with significantly better outcome. Conclusion: This study exemplifies that, for relatively rare diseases, it is paramount to collect observational data from large, population‐based cohorts, because incidence and prevalence rates of PSC are markedly lower and survival much longer than previously reported. The selection of a bias‐free, population‐based cohort showed a significantly longer survival, compared to the tertiary referral cohort. CRC can develop at an early age, warranting surveillance from time of PSC diagnosis. (Hepatology 2013; 58:2045–2055)

Serum autotaxin is increased in pruritus of cholestasis, but not of other origin, and responds to therapeutic interventions†‡

Pruritus is a seriously disabling symptom accompanying many cholestatic liver disorders. Recent experimental evidence implicated the lysophospholipase, autotaxin (ATX), and its product, lysophosphatidic acid (LPA), as potential mediators of cholestatic pruritus. In this study, we highlight that increased serum ATX levels are specific for pruritus of cholestasis, but not pruritus of uremia, Hodgkins disease, or atopic dermatitis. Treatment of patients with cholestasis with the bile salt sequestrant, colesevelam, but not placebo, effectively reduced total serum bile salts and fibroblast growth factor 19 levels, but only marginally altered pruritus intensity and ATX activity. Rifampicin (RMP) significantly reduced itch intensity and ATX activity in patients with pruritus not responding to bile salt sequestrants. In vitro, RMP inhibited ATX expression in human HepG2 hepatoma cells and hepatoma cells overexpressing the pregnane X receptor (PXR), but not in hepatoma cells in which PXR was knocked down. Treatment of severe, refractory pruritus by the molecular adsorbents recirculation system or nasobiliary drainage improved itch intensity, which, again, correlated with the reduction of ATX levels. Upon reoccurrence of pruritus, ATX activity returned to pretreatment values. Conclusion: Serum ATX activity is specifically increased in patients with cholestatic, but not other forms of, systemic pruritus and closely correlates with the effectiveness of therapeutic interventions. The beneficial antipruritic action of RMP may be explained, at least partly, by the PXR‐dependent transcriptional inhibition of ATX expression. Thus, ATX likely represents a novel therapeutic target for pruritus of cholestasis. (HEPATOLOGY 2012)

High prevalence of autoimmune hepatitis among patients with primary sclerosing cholangitis

BACKGROUND/AIMS Traditionally, autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC) are regarded as separate disease entities. We report on a group of patients that suggests the existence of an overlap syndrome of the two conditions and on the prevalence of this syndrome among patients with PSC. Furthermore, the impact of the recently revised AIH scoring system for diagnosing AIH in this context was assessed. METHODS Retrospective analysis of consecutive patients of a tertiary referral centre for liver disease with a diagnosis of PSC. RESULTS Diagnosis of the overlap syndrome was established for nine patients (8%) of a total group of 113 PSC patients. Four patients initially presented with features of AIH and in five cases PSC was diagnosed first. All patients responded to immunosuppressive therapy; in three cases long-term remission was achieved. Three patients underwent liver transplantation after 4 months and 7 and 9 years, respectively. The original and revised versions of the AIH scoring system gave essentially the same results in the patients with the PSC-AIH overlap syndrome. CONCLUSIONS Patients with overlapping features of AIH and PSC may be more common than is currently assumed. Recognition of this syndrome is of clinical significance, considering the important therapeutical consequences.

Prognosis of Ursodeoxycholic Acid-Treated Patients with Primary Biliary Cirrhosis. Results of a 10-Yr Cohort Study Involving 297 Patients

BACKGROUND AND AIMS:The therapeutic potential of ursodeoxycholic acid (UDCA) treatment in primary biliary cirrhosis (PBC) remains controversial. In addition, relatively few data have been reported on the outcome of patients who have been treated long term. The aim of the present study was to document long-term survival of a prospectively followed large cohort of UDCA treated patients in comparison to that predicted by the Mayo model and of a matched control cohort of the Dutch population.METHODS:Two hundred ninety-seven patients were included and followed during a median period of 68 (range 3–126) months until death or the end of the study.RESULTS:Survival free of transplantation (1 yr 99.7%, 5 yr 87%, and 10 yr 71%) was significantly better than predicted by the Mayo model (p = 0.01). However, for patients with abnormal serum bilirubin and/or albumin concentrations at entry, observed and predicted survival did not significantly differ. Compared with survival for a standardized cohort of the Dutch population, observed survival for the total group was significantly decreased (p = 0.0003); for noncirrhotic patients and patients with normal entry bilirubin and albumin concentrations survival was comparable. Serum bilirubin and albumin concentrations were the prognostic factors most consistently associated with survival.CONCLUSIONS:A 10-year prognosis for most UDCA-treated patients with PBC, i.e., those with a normal bilirubin and albumin concentration, is comparable to that of a matched general population. Our finding that observed survival was significantly better than predicted by the Mayo model may suggest that this model did not accurately predict prognosis in our cohort. Alternatively, this finding indicates an important therapeutic effect of long-term UDCA treatment in PBC, particularly in patients with noncirrhotic, nonadvanced disease.

Genome-Wide Association Study Identifies Variants Associated With Autoimmune Hepatitis Type 1

BACKGROUND & AIMS Autoimmune hepatitis (AIH) is an uncommon autoimmune liver disease of unknown etiology. We used a genome-wide approach to identify genetic variants that predispose individuals to AIH. METHODS We performed a genome-wide association study of 649 adults in The Netherlands with AIH type 1 and 13,436 controls. Initial associations were further analyzed in an independent replication panel comprising 451 patients with AIH type 1 in Germany and 4103 controls. We also performed an association analysis in the discovery cohort using imputed genotypes of the major histocompatibility complex region. RESULTS We associated AIH with a variant in the major histocompatibility complex region at rs2187668 (P = 1.5 × 10(-78)). Analysis of this variant in the discovery cohort identified HLA-DRB1*0301 (P = 5.3 × 10(-49)) as a primary susceptibility genotype and HLA-DRB1*0401 (P = 2.8 × 10(-18)) as a secondary susceptibility genotype. We also associated AIH with variants of SH2B3 (rs3184504, 12q24; P = 7.7 × 10(-8)) and CARD10 (rs6000782, 22q13.1; P = 3.0 × 10(-6)). In addition, strong inflation of association signal was found with single-nucleotide polymorphisms associated with other immune-mediated diseases, including primary sclerosing cholangitis and primary biliary cirrhosis, but not with single-nucleotide polymorphisms associated with other genetic traits. CONCLUSIONS In a genome-wide association study, we associated AIH type 1 with variants in the major histocompatibility complex region, and identified variants of SH2B3and CARD10 as likely risk factors. These findings support a complex genetic basis for AIH pathogenesis and indicate that part of the genetic susceptibility overlaps with that for other immune-mediated liver diseases.

Cyclical etidronate in the prevention of bone loss in corticosteroid-treated primary biliary cirrhosis: A prospective, controlled pilot study

BACKGROUND Recently, promising disease modifying effects of low dose corticosteroid treatment in primary biliary cirrhosis have been reported. However, steroid-induced bone loss constitutes a potential drawback of this treatment option. AIM To assess whether etidronate can reduce bone loss during corticosteroid treatment. METHODS Twelve primary biliary cirrhosis patients (all Child-Pugh Class A), treated with prednisone in the context of a 1-year placebo-controlled pilot study with prednisone (maintenance dose 10 mg daily), and azathioprine (50 mg daily), were randomized to receive either cyclical etidronate (400 mg daily, during 2 weeks) alternated with calcium 500 mg daily during 11 weeks or calcium alone. All patients had been receiving ursodeoxycholic acid during at least 1 year and this treatment was continued. Bone mass was measured in the lumbar spine and the femoral neck by dual energy X-ray absorptiometry before and after 3 and 12 months of treatment. Markers of bone formation (serum osteocalcin, procollagen-I-propeptide) and bone resorption (urinary deoxypyridinoline and calcium) were also monitored. RESULTS The mean lumbar bone mineral density did not significantly change in the patients taking etidronate + calcium, in contrast to patients treated with calcium alone (+0.4 vs. -3.0%; p = 0.01). Changes in femoral bone mineral density and markers of bone turnover did not significantly differ between both groups. No adverse effects of etidronate were noted. CONCLUSIONS Cyclical etidronate appears to prevent bone loss associated with prednisone treatment in patients with primary biliary cirrhosis. These preliminary results encourage the further evaluation of long term prednisone treatment and concurrent bisphosphonate therapy in primary biliary cirrhosis.

Prognostic indicators of risk for first variceal bleeding in cirrhosis: a multicenter study in 711 patients to validate and improve the North Italian Endoscopic Club (NIEC) index

OBJECTIVE:The best known indicator of risk for first bleeding in patients with cirrhosis without previous bleeding is the index devised by the North Italian Endoscopic Club for the Study and Treatment of Esophageal Varices (NIEC index), which results from the combination of size of esophageal varices, severity of red wale marks, and Child-Pugh class. Its efficiency is far from optimal, and validation studies have reported sensitivities and specificities markedly lower than those reported in the original study. In the present study we analyzed the efficiency of NIEC index in a large series of cirrhotic patients with varices without previous bleeding. In addition, we tried to improve the effectiveness of the index by modifying it, and to validate the modifications in an independent group of patients.METHODS:A total of 627 patients were enrolled and followed until either a variceal bleeding or for a maximum of 2 yr. During this time, 117 experienced a first variceal bleeding.RESULTS:Using Coxs regression analysis, size of varices, severity of red wale marks, and Child-Pugh score were significant and independent predictors of first bleeding, as already noted in the original report of the NIEC group. However, coefficients and standard errors were markedly different, and the importance of size of esophageal varices in the regression was much larger, whereas that of Child-Pugh score was much lower. According to these data, a revised index was developed (Rev-NIEC). Using receiver operating characteristic (ROC) curve analysis, the revised index showed a larger efficiency, and the area under the curve was significantly larger (0.80 ± 0.02 vs 0.74 ± 0.02; p < 0.01). In particular, the curve showed that for a specificity of 75%, the new index had a sensitivity of 72% compared to that of 55% of the NIEC index. Validation in an independent sample of 84 patients showed good agreement between predicted and observed risk for bleeding. Validation with the bootstrap technique also showed adequate stability of the results.CONCLUSIONS:The revised index seems to be superior to the traditional index, and may turn out to be more useful in the selection of patients for different therapeutic procedures and in the stratification of patients in clinical trials.