Dr Roger Chapman

Research Area: Genetics and Genomics
Technology Exchange: SNP typing
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Whilst working as a Lecturer on the Liver Unit at the Royal Free Hospital under the supervision of Professor Dame Sheila Sherlock, I developed two main interests. Firstly, I studied various aspects of the effects of alcohol on iron metabolism, which formed the basis of my MD Thesis (Iron Metabolism in Liver Disease).
Secondly, I became interested in investigating the aetiology, clinical features and treatment of primary sclerosing cholangitis (PSC) and its relationship to liver dysfunction in inflammatory bowel disease.

Since moving to Oxford, I have maintained my interest in sclerosing cholangitis. At present we are investigating the hypothesis that the disease is immunologically mediated, perhaps triggered, by the development of a bacterial or viral infection.

In association with Prof Erik Schrumpf in Norway, I obtained a 3 year grant in1998 worth £200,000 from the EEC to form The European Study Group of PSC in order to promote European collaboration into PSC. The first meeting was held in Oslo in 1996. The group has been very successful with nine publications arising from joint projects.

The group continued to collaborate after an initial 3 year period and then expanded to take in other European groups interested in PSC. We have investigated the issue of crossover/overlap conditions between the various autoimmune liver diseases.

I am also a founder member of the International Autoimmune Hepatitis Group formed in 1992. This group remains active in organising international collaboration between research groups with a common interest in autoimmune liver diseases. Through this group I have been involved recently (2010) in producing a position paper regarding “Overlap Syndromes in autoimmune liver disease”.

We are currently studying the putative roles of retroviruses in the pathogenesis of autoimmune liver diseases, particularly PBC and PSC in collaboration with Dr Paul Klenerman. The role of immunogenetics and T regulatory cells on the development and course of the disease has been studied.

We have recently (2008) obtained funding (500,000 euros) from the Norwegian PSC research group (No- PSC) for a British genome wide scan into PSC; this involves the collection of DNA from 1000 PSC patients. In collaboration with Cambridge University I am also involved in a large UK GWAS study of PBC. We are collaborating with a number of other international centres including the Mayo Clinic in these large studies. I am also collaborating with Norway in a study of small duct PSC. In addition, we are proposing to obtain funding for a British GWAS study into Autoimmune Liver Disease. The British PSC support group provides regular annual funding (£10,00 per annum ) for research for our unit to continue our studies.

We have completed a study evaluating the presence of PSC in patients with total colitis and normal LFT’s using MRCP scanning. This has shown a high prevalence of PSC in otherwise clinical and biochemically normal patients with UC. This study has been extended to perform MRCP in UC patients with colonic dysplasia and cancer.

In addition, over the last decade we have carried several studies into the efficacy of high dose ursodeoxycholic acid (UDCA) in PSC both in the treatment of liver disease and the prophylaxis of colonic cancer.

The role of PSC and the effect of UDCA in colonic dysplasia is also being investigated in ulcerative colitis associated PSC and Crohn’s disease associated PSC. The natural history of pouch function in PSC pts who have undergone colectomy is also being evaluated, including quality of life (QoL) assessments.

A recent and expanding area of research for our group is IgG4 associated systemic disease with particular reference to its relationship to PSC. We are carrying out a number of clinical studies into this disorder including natural history, relationship to IBD and laboratory based studies into T and B cell function.

My group is also carrying out studies into Sphincter of Oddi dysfunction with regard to natural history, response to treatment, Quality of life (Q of L) assessments and prospective psychological studies.

In addition, I have been involved in various clinical trials, including assessing the role of and testing the efficacy of different agents in the treatment of luminal GI disorders including peptic ulceration, dyspepsia, reflux oesophagitis and irritable bowel syndrome. I am also closely currently involved in two international studies examining the role of a nuclear receptor agonist in the treatment of refractory Primary Biliary Cirrhosis (PBC).

Over the last 20 years, I have supervised 5 research fellows who have written successful doctoral theses for the Universities of Oxford and London. I am currently co supervising with Dr Ellie Barnes, a research fellow studying IgG4- related systemic disease.

Name Department Institution Country
Professor Ellie (Eleanor) Barnes Experimental Medicine Division Oxford University, Peter Medawar Building United Kingdom
Selvaraj EA, Culver EL, Bungay H, Bailey A, Chapman RW, Pavlides M. 2019. Evolving role of magnetic resonance techniques in primary sclerosing cholangitis. World J Gastroenterol, 25 (6), pp. 644-658. | Show Abstract | Read more

Development of non-invasive methods to risk-stratify patients and predict clinical endpoints have been identified as one of the key research priorities in primary sclerosing cholangitis (PSC). In addition to serum and histological biomarkers, there has been much recent interest in developing imaging biomarkers that can predict disease course and clinical outcomes in PSC. Magnetic resonance imaging/magnetic resonance cholangiopancreatography (MRI/MRCP) continue to play a central role in the diagnosis and follow-up of PSC patients. Magnetic resonance (MR) techniques have undergone significant advancement over the last three decades both in MR data acquisition and interpretation. The progression from a qualitative to quantitative approach in MR acquisition techniques and data interpretation, offers the opportunity for the development of objective and reproducible imaging biomarkers that can potentially be incorporated as an additional endpoint in clinical trials. This review article will discuss how the role of MR techniques have evolved over the last three decades from emerging as an alternative diagnostic tool to endoscopic retrograde cholangiopancreatography, to being instrumental in the ongoing search for imaging biomarker of disease stage, progression and prognosis in PSC.

Goode EC, Clark AB, Mells GF, Srivastava B, Spiess K, Gelson WTH, Trivedi PJ, Lynch KD, Castren E, Vesterhus MN et al. 2019. Factors Associated With Outcomes of Patients With Primary Sclerosing Cholangitis and Development and Validation of a Risk Scoring System. Hepatology, 69 (5), pp. 2120-2135. | Show Abstract | Read more

We sought to identify factors that are predictive of liver transplantation or death in patients with primary sclerosing cholangitis (PSC), and to develop and validate a contemporaneous risk score for use in a real-world clinical setting. Analyzing data from 1,001 patients recruited to the UK-PSC research cohort, we evaluated clinical variables for their association with 2-year and 10-year outcome through Cox-proportional hazards and C-statistic analyses. We generated risk scores for short-term and long-term outcome prediction, validating their use in two independent cohorts totaling 451 patients. Thirty-six percent of the derivation cohort were transplanted or died over a cumulative follow-up of 7,904 years. Serum alkaline phosphatase of at least 2.4 × upper limit of normal at 1 year after diagnosis was predictive of 10-year outcome (hazard ratio [HR] = 3.05; C = 0.63; median transplant-free survival 63 versus 108 months; P < 0.0001), as was the presence of extrahepatic biliary disease (HR = 1.45; P = 0.01). We developed two risk scoring systems based on age, values of bilirubin, alkaline phosphatase, albumin, platelets, presence of extrahepatic biliary disease, and variceal hemorrhage, which predicted 2-year and 10-year outcomes with good discrimination (C statistic = 0.81 and 0.80, respectively). Both UK-PSC risk scores were well-validated in our external cohort and outperformed the Mayo Clinic and aspartate aminotransferase-to-platelet ratio index (APRI) scores (C statistic = 0.75 and 0.63, respectively). Although heterozygosity for the previously validated human leukocyte antigen (HLA)-DR*03:01 risk allele predicted increased risk of adverse outcome (HR = 1.33; P = 0.001), its addition did not improve the predictive accuracy of the UK-PSC risk scores. Conclusion: Our analyses, based on a detailed clinical evaluation of a large representative cohort of participants with PSC, furthers our understanding of clinical risk markers and reports the development and validation of a real-world scoring system to identify those patients most likely to die or require liver transplantation.

Muir AJ, Levy C, Janssen HLA, Montano-Loza AJ, Shiffman ML, Caldwell S, Luketic V, Ding D, Jia C, McColgan BJ et al. 2019. Simtuzumab for Primary Sclerosing Cholangitis: Phase 2 Study Results With Insights on the Natural History of the Disease. Hepatology, 69 (2), pp. 684-698. | Show Abstract | Read more

Lysyl oxidase like-2 (LOXL2) plays a central role in fibrogenesis and is elevated in the serum and liver of patients with primary sclerosing cholangitis (PSC). We evaluated the safety and efficacy of simtuzumab, a monoclonal antibody directed against LOXL2, in patients with PSC. Patients with compensated liver disease caused by PSC were randomized 1:1:1 to receive weekly subcutaneous injections of simtuzumab 75 mg, simtuzumab 125 mg, or placebo for 96 weeks. The primary efficacy endpoint was mean change in hepatic collagen content assessed by morphometry between baseline and week 96. Additional endpoints included change in Ishak fibrosis stage and the frequency of PSC-related clinical events. Overall, 234 patients were randomized and started treatment. At week 96, the mean change from baseline in hepatic collagen content was -0.5% for patients receiving simtuzumab 75 mg (P = 0.73 versus placebo), +0.5% for patients receiving simtuzumab 125 mg (P = 0.33 versus placebo), and 0.0 for patients receiving placebo. Compared with placebo, neither dose of simtuzumab led to significant reductions in Ishak fibrosis stage, progression to cirrhosis, or frequency of clinical events. Overall, 80 (34%) patients had fibrosis progression and 47 (20%) experienced PSC-related clinical events. In a multivariate model of baseline factors, PSC-related clinical events were more frequent in patients with advanced fibrosis (hazard ratio [HR], 2.03; 95% confidence interval [CI], 1.02-4.06; P = 0.045), higher alkaline phosphatase (HR per 10 U/L, 1.01; 95% CI, 1.00-1.02; P = 0.015), and higher enhanced liver fibrosis score (HR per unit, 1.26; 95% CI, 0.98-1.61; P = 0.073). Overall, rates of adverse events and laboratory abnormalities were similar between groups. Conclusion: Treatment with the LOXL2 inhibitor simtuzumab for 96 weeks did not provide clinical benefit in patients with PSC.

Chapman RW. 2018. Cost effectiveness of using ursodeoxycholic acid to treat primary biliary cholangitis. Br J Hosp Med (Lond), 79 (8), pp. 460-464. | Show Abstract | Read more

Primary biliary cholangitis is a chronic inflammatory, autoimmune cholestatic liver disease, which untreated will usually progress to end-stage biliary cirrhosis. The aims of treatment and management of primary biliary cholangitis are the amelioration of associated symptoms, particularly pruritis and fatigue, and the prevention of end-stage liver disease. The presentation, natural history and clinical course are variable. Recent published European and UK clinical guidelines have emphasized the need for risk stratification and an individualized approach to patient management in primary biliary cholangitis. The bile acid, ursodeoxycholic acid, is established as the first-line treatment of primary biliary cholangitis. Assessment of clinical response to treatment is based on specified improvements in serum liver tests including near normalization of the serum alkaline phosphatase level at 1 year. At least two thirds of patients with primary biliary cholangitis should respond to ursodeoxycholic acid after 1 year's treatment. The correct dosage of ursodeoxycholic acid is determined by body weight viz 13-15 mg/kg/day. A significant number of patients with primary biliary cholangitis in the UK are being underdosed. Over a third of ursodeoxycholic acid partial responders become responders within 2 years after increasing the ursodeoxycholic acid doses to recommended levels. While transplant rates for primary biliary cholangitis have halved over the last 20 years, it is clear that optimizing the dose of ursodeoxycholic acid in partial responders would further decrease morbidity, mortality and the need for liver transplantation.

de Graaf KL, Lapeyre G, Guilhot F, Ferlin W, Curbishley SM, Carbone M, Richardson P, Moreea S, McCune CA, Ryder SD et al. 2018. NI-0801, an anti-chemokine (C-X-C motif) ligand 10 antibody, in patients with primary biliary cholangitis and an incomplete response to ursodeoxycholic acid. Hepatol Commun, 2 (5), pp. 492-503. | Show Abstract | Read more

NI-0801 is a fully human monoclonal antibody against chemokine (C-X-C motif) ligand 10 (CXCL10), which is involved in the recruitment of inflammatory T cells into the liver. The safety and efficacy of NI-0801 was assessed in patients with primary biliary cholangitis. In this open-label phase 2a study, patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid received six consecutive intravenous administrations of NI-0801 (10 mg/kg) every 2 weeks. Patients were followed up for 3 months after the last infusion. Liver function tests, safety assessments, as well as pharmacokinetic and pharmacodynamic parameters were evaluated at different time points throughout the dosing period and the safety follow-up period. Twenty-nine patients were enrolled in the study and were treated with NI-0801. The most frequently reported adverse events included headaches (52%), pruritus (34%), fatigue (24%), and diarrhea (21%). No study drug-related serious adverse events were reported. NI-0801 administration did not lead to a significant reduction in any of the liver function tests assessed at the end of the treatment period (i.e., 2 weeks after final NI-0801 administration) compared to baseline. Conclusion: Despite clear pharmacologic responses in the blood, no therapeutic benefit of multiple administrations of NI-0801 could be demonstrated. The high production rate of CXCL10 makes it difficult to achieve drug levels that lead to sustained neutralization of the chemokine, thus limiting its targetability. (Hepatology Communications 2018;2:492-503).

Chapman RW. 2018. Editorial: vancomycin - a promising option for the treatment of primary sclerosing cholangitis? Aliment Pharmacol Ther, 47 (9), pp. 1321-1322. | Read more

Kowdley KV, Luketic V, Chapman R, Hirschfield GM, Poupon R, Schramm C, Vincent C, Rust C, Parés A, Mason A et al. 2018. A randomized trial of obeticholic acid monotherapy in patients with primary biliary cholangitis. Hepatology, 67 (5), pp. 1890-1902. | Show Abstract | Read more

Obeticholic acid (OCA), a potent farnesoid X receptor agonist, was studied as monotherapy in an international, randomized, double-blind, placebo-controlled phase 2 study in patients with primary biliary cholangitis who were then followed for up to 6 years. The goals of the study were to assess the benefit of OCA in the absence of ursodeoxycholic acid, which is relevant for patients who are intolerant of ursodeoxycholic acid and at higher risk of disease progression. Patients were randomized and dosed with placebo (n = 23), OCA 10 mg (n = 20), or OCA 50 mg (n = 16) given as monotherapy once daily for 3 months (1 randomized patient withdrew prior to dosing). The primary endpoint was the percent change in alkaline phosphatase from baseline to the end of the double-blind phase of the study. Secondary and exploratory endpoints included change from baseline to month 3/early termination in markers of cholestasis, hepatocellular injury, and farnesoid X receptor activation. Efficacy and safety continue to be monitored through an ongoing 6-year open-label extension (N = 28). Alkaline phosphatase was reduced in both OCA groups (median% [Q1, Q3], OCA 10 mg -53.9% [-62.5, -29.3], OCA 50 mg -37.2% [-54.8, -24.6]) compared to placebo (-0.8% [-6.4, 8.7]; P < 0.0001) at the end of the study, with similar reductions observed through 6 years of open-label extension treatment. OCA improved many secondary and exploratory endpoints (including γ-glutamyl transpeptidase, alanine aminotransferase, conjugated bilirubin, and immunoglobulin M). Pruritus was the most common adverse event; 15% (OCA 10 mg) and 38% (OCA 50 mg) discontinued due to pruritus. CONCLUSION: OCA monotherapy significantly improved alkaline phosphatase and other biochemical markers predictive of improved long-term clinical outcomes. Pruritus increased dose-dependently with OCA treatment. Biochemical improvements were observed through 6 years of open-label extension treatment. (Hepatology 2018;67:1890-1902).

Alberts R, de Vries EMG, Goode EC, Jiang X, Sampaziotis F, Rombouts K, Böttcher K, Folseraas T, Weismüller TJ, Mason AL et al. 2018. Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis. Gut, 67 (8), pp. 1517-1524. | Show Abstract | Read more

OBJECTIVE: Primary sclerosing cholangitis (PSC) is a genetically complex, inflammatory bile duct disease of largely unknown aetiology often leading to liver transplantation or death. Little is known about the genetic contribution to the severity and progression of PSC. The aim of this study is to identify genetic variants associated with PSC disease progression and development of complications. DESIGN: We collected standardised PSC subphenotypes in a large cohort of 3402 patients with PSC. After quality control, we combined 130 422 single nucleotide polymorphisms of all patients-obtained using the Illumina immunochip-with their disease subphenotypes. Using logistic regression and Cox proportional hazards models, we identified genetic variants associated with binary and time-to-event PSC subphenotypes. RESULTS: We identified genetic variant rs853974 to be associated with liver transplant-free survival (p=6.07×10-9). Kaplan-Meier survival analysis showed a 50.9% (95% CI 41.5% to 59.5%) transplant-free survival for homozygous AA allele carriers of rs853974 compared with 72.8% (95% CI 69.6% to 75.7%) for GG carriers at 10 years after PSC diagnosis. For the candidate gene in the region, RSPO3, we demonstrated expression in key liver-resident effector cells, such as human and murine cholangiocytes and human hepatic stellate cells. CONCLUSION: We present a large international PSC cohort, and report genetic loci associated with PSC disease progression. For liver transplant-free survival, we identified a genome-wide significant signal and demonstrated expression of the candidate gene RSPO3 in key liver-resident effector cells. This warrants further assessments of the role of this potential key PSC modifier gene.

de Vries EM, Wang J, Williamson KD, Leeflang MM, Boonstra K, Weersma RK, Beuers U, Chapman RW, Geskus RB, Ponsioen CY. 2018. A novel prognostic model for transplant-free survival in primary sclerosing cholangitis. Gut, 67 (10), pp. 1864-1869. | Show Abstract | Read more

OBJECTIVE: Most prognostic models for primary sclerosing cholangitis (PSC) are based on patients referred to tertiary care and may not be applicable for the majority of patients with PSC. The aim of this study was to construct and externally validate a novel, broadly applicable prognostic model for transplant-free survival in PSC, based on a large, predominantly population-based cohort using readily available variables. DESIGN: The derivation cohort consisted of 692 patients with PSC from the Netherlands, the validation cohort of 264 patients with PSC from the UK. Retrospectively, clinical and biochemical variables were collected. We derived the prognostic index from a multivariable Cox regression model in which predictors were selected and parameters were estimated using the least absolute shrinkage and selection operator. The composite end point of PSC-related death and liver transplantation was used. To quantify the models' predictive value, we calculated the C-statistic as discrimination index and established its calibration accuracy by comparing predicted curves with Kaplan-Meier estimates. RESULTS: The final model included the variables: PSC subtype, age at PSC diagnosis, albumin, platelets, aspartate aminotransferase, alkaline phosphatase and bilirubin. The C-statistic was 0.68 (95% CI 0.51 to 0.85). Calibration was satisfactory. The model was robust in the sense that the C-statistic did not change when prediction was based on biochemical variables collected at follow-up. CONCLUSION: The Amsterdam-Oxford model for PSC showed adequate performance in estimating PSC-related death and/or liver transplant in a predominantly population-based setting. The transplant-free survival probability can be recalculated when updated biochemical values are available.

Chapman RW. 2017. Update on primary sclerosing cholangitis. Clin Liver Dis (Hoboken), 9 (5), pp. 107-110. | Read more

Fickert P, Hirschfield GM, Denk G, Marschall H-U, Altorjay I, Färkkilä M, Schramm C, Spengler U, Chapman R, Bergquist A et al. 2017. norUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitis. J Hepatol, 67 (3), pp. 549-558. | Show Abstract | Read more

BACKGROUND & AIM: Primary sclerosing cholangitis (PSC) represents a devastating bile duct disease, currently lacking effective medical therapy. 24-norursodeoxycholic acid (norUDCA) is a side chain-shortened C23 homologue of UDCA and has shown potent anti-cholestatic, anti-inflammatory and anti-fibrotic properties in a preclinical PSC mouse model. A randomized controlled trial, including 38 centers from 12 European countries, evaluated the safety and efficacy of three doses of oral norUDCA (500mg/d, 1,000mg/d or 1,500mg/d) compared with placebo in patients with PSC. METHODS: One hundred sixty-one PSC patients without concomitant UDCA therapy and with elevated serum alkaline phosphatase (ALP) levels were randomized for a 12-week treatment followed by a 4-week follow-up. The primary efficacy endpoint was the mean relative change in ALP levels between baseline and end of treatment visit. RESULTS: norUDCA reduced ALP levels by -12.3%, -17.3%, and -26.0% in the 500, 1,000, and 1,500mg/d groups (p=0.029, p=0.003, and p<0.0001 when compared to placebo), respectively, while a +1.2% increase was observed in the placebo group. Similar dose-dependent results were found for secondary endpoints, such as ALT, AST, γ-GT, or the rate of patients achieving ALP levels <1.5× ULN. Serious adverse events occurred in seven patients in the 500mg/d, five patients in the 1,000mg/d, two patients in the 1500mg/d group, and three in the placebo group. There was no difference in reported pruritus between treatment and placebo groups. CONCLUSIONS: norUDCA significantly reduced ALP values dose-dependently in all treatment arms. The safety profile of norUDCA was excellent and comparable to placebo. Consequently, these results justify a phase III trial of norUDCA in PSC patients. Lay summary: Effective medical therapy for primary sclerosing cholangitis (PSC) is urgently needed. In this phase II clinical study in PSC patients, a side chain-shortened derivative of ursodeoxycholic acid, norursodeoxycholic acid (norUDCA), significantly reduced serum alkaline phosphatase levels in a dose-dependent manner during a 12-week treatment. Importantly, norUDCA showed a favorable safety profile, which was similar to placebo. The use of norUDCA in PSC patients is promising and will be further evaluated in a phase III clinical study. ClinicalTrials.gov number: NCT01755507.

Gwela A, Siddhanathi P, Chapman RW, Travis S, Powrie F, Arancibia-Cárcamo CV, Geremia A. 2017. Th1 and Innate Lymphoid Cells Accumulate in Primary Sclerosing Cholangitis-associated Inflammatory Bowel Disease. J Crohns Colitis, 11 (9), pp. 1124-1134. | Show Abstract | Read more

Background and Aims: Primary sclerosing cholangitis [PSC] is an idiopathic chronic disorder of the hepatobiliary system associated with inflammatory bowel disease [IBD], mainly ulcerative colitis [UC]. Colitis in patients with PSC and UC [PSC-UC] exhibits characteristic features and is linked to increased colon cancer risk. Genetic studies have identified immune-related susceptibility genes that only partially overlap with those involved in IBD. These observations suggest that PSC-UC may represent a distinct form of IBD. It remains to be elucidated whether different immune mechanisms are involved in colitis in these patients. We aimed to evaluate systemic and intestinal T cell and innate lymphoid cell [ILC] responses, previously associated with IBD, in patients with PSC-UC compared with patients with UC and healthy controls. Methods: Blood samples and colorectal biopsies were collected from patients with PSC-UC, patients with UC, and healthy controls. T cell and ILC phenotypes were analysed by multicolour flow cytometry. Results: Chemokine receptor [CCR] profiling of circulating T cells showed decreased CCR6-CXCR3+ Th1 cells in PSC-UC, but increased CCR6-CCR4+ Th2 cells only in UC, whereas increased CCR6+CCR4+ Th17 cells were found in both patient groups compared with healthy controls. Increased frequencies of IFN-γ secreting T cells were found in the colon of patients with PSC-UC compared with UC. Interestingly, we observed accumulation of ILC in the colon in PSC-UC. Conclusions: Our study suggests that PSC-UC represents a different immunological disorder from UC, characterised by increased intestinal Th1 and ILC responses. These results provide further evidence that PSC-UC may represent a distinct form of IBD.

Weismüller TJ, Trivedi PJ, Bergquist A, Imam M, Lenzen H, Ponsioen CY, Holm K, Gotthardt D, Färkkilä MA, Marschall H-U et al. 2017. Patient Age, Sex, and Inflammatory Bowel Disease Phenotype Associate With Course of Primary Sclerosing Cholangitis. Gastroenterology, 152 (8), pp. 1975-1984.e8. | Show Abstract | Read more

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is an orphan hepatobiliary disorder associated with inflammatory bowel disease (IBD). We aimed to estimate the risk of disease progression based on distinct clinical phenotypes in a large international cohort of patients with PSC. METHODS: We performed a retrospective outcome analysis of patients diagnosed with PSC from 1980 through 2010 at 37 centers in Europe, North America, and Australia. For each patient, we collected data on sex, clinician-reported age at and date of PSC and IBD diagnoses, phenotypes of IBD and PSC, and date and indication of IBD-related surgeries. The primary and secondary endpoints were liver transplantation or death (LTD) and hepatopancreatobiliary malignancy, respectively. Cox proportional hazards models were applied to determine the effects of individual covariates on rates of clinical events, with time-to-event analysis ascertained through Kaplan-Meier estimates. RESULTS: Of the 7121 patients in the cohort, 2616 met the primary endpoint (median time to event of 14.5 years) and 721 developed hepatopancreatobiliary malignancy. The most common malignancy was cholangiocarcinoma (n = 594); patients of advanced age at diagnosis had an increased incidence compared with younger patients (incidence rate: 1.2 per 100 patient-years for patients younger than 20 years old, 6.0 per 100 patient-years for patients 21-30 years old, 9.0 per 100 patient-years for patients 31-40 years old, 14.0 per 100 patient-years for patients 41-50 years old, 15.2 per 100 patient-years for patients 51-60 years old, and 21.0 per 100 patient-years for patients older than 60 years). Of all patients with PSC studied, 65.5% were men, 89.8% had classical or large-duct disease, and 70.0% developed IBD at some point. Assessing the development of IBD as a time-dependent covariate, Crohn's disease and no IBD (both vs ulcerative colitis) were associated with a lower risk of LTD (unadjusted hazard ratio [HR], 0.62; P < .001 and HR, 0.90; P = .03, respectively) and malignancy (HR, 0.68; P = .008 and HR, 0.77; P = .004, respectively). Small-duct PSC was associated with a lower risk of LTD or malignancy compared with classic PSC (HR, 0.30 and HR, 0.15, respectively; both P < .001). Female sex was also associated with a lower risk of LTD or malignancy (HR, 0.88; P = .002 and HR, 0.68; P < .001, respectively). In multivariable analyses assessing the primary endpoint, small-duct PSC characterized a low-risk phenotype in both sexes (adjusted HR for men, 0.23; P < .001 and adjusted HR for women, 0.48; P = .003). Conversely, patients with ulcerative colitis had an increased risk of liver disease progression compared with patients with Crohn's disease (HR, 1.56; P < .001) or no IBD (HR, 1.15; P = .002). CONCLUSIONS: In an analysis of data from individual patients with PSC worldwide, we found significant variation in clinical course associated with age at diagnosis, sex, and ductal and IBD subtypes. The survival estimates provided might be used to estimate risk levels for patients with PSC and select patients for clinical trials.

de Vries EMG, de Krijger M, Färkkilä M, Arola J, Schirmacher P, Gotthardt D, Goeppert B, Trivedi PJ, Hirschfield GM, Ytting H et al. 2017. Validation of the prognostic value of histologic scoring systems in primary sclerosing cholangitis: An international cohort study. Hepatology, 65 (3), pp. 907-919. | Show Abstract | Read more

Histologic scoring systems specific for primary sclerosing cholangitis (PSC) are not validated. We recently determined the applicability and prognostic value of three histological scoring systems in a single PSC cohort. The aim of this study was to validate their prognostic use and reproducibility across a multicenter PSC cohort. Liver biopsies from PSC patients were collected from seven European institutions. Histologic scoring was performed using the Nakanuma, Ishak, and Ludwig scoring systems. Biopsies were independently scored by six liver pathologists for interobserver agreement. The prognostic value of clinical, biochemical, and all three histologic scoring systems on predicting composite endpoints 1 (PSC-related death and liver transplantation), 2 (liver transplantation), and 3 (liver-related events), was assessed using univariable and multivariable Cox proportional hazards modeling. A total of 119 PSC patients were identified, and the median follow-up was 142 months. During follow-up, 31 patients died (20 PSC-related deaths), 31 patients underwent liver transplantation, and 35 patients experienced one or more liver-related events. All three staging systems were independent predictors of endpoints 2 and 3 (Nakanuma system: hazard ratio [HR], 3.16 [95% confidence interval (CI), 1.49-6.68] for endpoint 2 and HR, 2.05 [95% CI, 1.17-3.57] for endpoint 3; Ishak system: HR, 1.55 [95% CI, 1.10-2.18] for endpoint 2 and HR, 1.43 [95% CI, 1.10-1.85] for endpoint 3; Ludwig system: HR, 2.62 [95% CI, 1.19-5.80] for endpoint 2 and HR, 2.06 [95% CI, 1.09-3.89] for endpoint 3). Only the Nakanuma staging system was independently associated with endpoint 1: HR, 2.14 (95% CI, 1.22-3.77). Interobserver agreement was moderate for Nakanuma stage (κ = 0.56) and substantial for Nakanuma component fibrosis (κ = 0.67), Ishak stage (κ = 0.64), and Ludwig stage (κ = 0.62). CONCLUSION: We confirm the independent prognostic value and demonstrate for the first time the reproducibility of staging disease progression in PSC using the Nakanuma, Ishak, and Ludwig staging systems. The Nakanuma staging system-incorporating features of chronic biliary disease-again showed the strongest predictive value. (Hepatology 2017;65:907-919).

Hartery K, Williamson K, Chapman R, Atkinson N, East J. 2017. Use of chromoendoscopy versus white light endoscopy for colorectal cancer surveillance in inflammatory bowel disease patients with primary sclerosing cholangitis; a six year experience JOURNAL OF CROHNS & COLITIS, 11 pp. S64-S64.

Chapman RW, Williamson KD. 2017. Are Dominant Strictures in Primary Sclerosing Cholangitis a Risk Factor for Cholangiocarcinoma? Curr Hepatol Rep, 16 (2), pp. 124-129. | Show Abstract | Read more

PURPOSE OF REVIEW: Cholangiocarcinoma is a devastating, unpredictable complication of large duct primary sclerosing cholangitis (PSC), which occurs in 5-15% of patients. The aim of this review is to discuss whether dominant strictures (DS) occurring in the larger bile ducts in PSC are a risk factor for the development of cholangiocarcinoma. RECENT FINDINGS: The development of DS is related to specific genetic polymorphisms affecting the innate immune system and the microbiome. In a recent study, the mean survival of PSC patients with DS was much worse (13.7 years) than for those without a DS (23 years). Survival difference was related to a 26% risk of cholangiocarcinoma, which developed only in those with DS. Half of the patients with cholangiocarcinoma presented within 4 months of the diagnosis of PSC. In another study, the risk of developing cholangiocarcinoma was directly related to the presence of underlying IBD, although this remains controversial. Efforts are being made towards surveying for cholangiocarcinoma including magnetic resonance imaging, endoscopic surveillance and serum tumour markers, but so far, an effective surveillance strategy has not been identified. DS should be treated endoscopically in the setting of symptoms, and there is limited evidence to suggest this may impact protectively on progression to cholangiocarcinoma. SUMMARY: It is established that the presence of symptomatic DS occurring in the larger bile ducts in PSC can be the first presentation of cholangiocarcinoma. There is an increasing body of evidence that even when proven to be benign, dominant biliary strictures predispose to the future development of cholangiocarcinoma. Regular surveillance should be targeted at this selected high-risk group of PSC patients.

Culver EL, Wang LM, Bungay H, Chapman RW, Collier J. 2017. A rare cause of colonic thickening and lymphadenopathy GUT, 66 (1), pp. 78-156. | Read more

Ji S-G, Juran BD, Mucha S, Folseraas T, Jostins L, Melum E, Kumasaka N, Atkinson EJ, Schlicht EM, Liu JZ et al. 2017. Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease. Nat Genet, 49 (2), pp. 269-273. | Show Abstract | Read more

Primary sclerosing cholangitis (PSC) is a rare progressive disorder leading to bile duct destruction; ∼75% of patients have comorbid inflammatory bowel disease (IBD). We undertook the largest genome-wide association study of PSC (4,796 cases and 19,955 population controls) and identified four new genome-wide significant loci. The most associated SNP at one locus affects splicing and expression of UBASH3A, with the protective allele (C) predicted to cause nonstop-mediated mRNA decay and lower expression of UBASH3A. Further analyses based on common variants suggested that the genome-wide genetic correlation (rG) between PSC and ulcerative colitis (UC) (rG = 0.29) was significantly greater than that between PSC and Crohn's disease (CD) (rG = 0.04) (P = 2.55 × 10-15). UC and CD were genetically more similar to each other (rG = 0.56) than either was to PSC (P < 1.0 × 10-15). Our study represents a substantial advance in understanding of the genetics of PSC.

Culver EL, Chapman RW. 2016. IgG4-related hepatobiliary disease: an overview. Nat Rev Gastroenterol Hepatol, 13 (10), pp. 601-612. | Show Abstract | Read more

IgG4-related hepatobiliary diseases are part of a multiorgan fibroinflammatory condition termed IgG4-related disease, and include IgG4-related sclerosing cholangitis (IgG4-SC) and IgG4-related hepatopathy. These diseases can present with biliary strictures and/or mass lesions, making them difficult to differentiate from primary sclerosing cholangitis (PSC) or other hepatobiliary malignancies. Diagnosis is based on a combination of clinical, biochemical, radiological and histological findings. However, a gold standard diagnostic test is lacking, warranting the identification of more specific disease markers. Novel assays - such as the serum IgG4:IgG1 ratio and IgG4:IgG RNA ratio (which distinguish IgG4-SC from PSC with high serum IgG4 levels), and plasmablast expansion to recognize IgG4-SC with normal serum IgG4 levels - require further validation. Steroids and other immunosuppressive therapies can lead to clinical and radiological improvement when given in the inflammatory phase of the disease, but evidence for the efficacy of treatment regimens is limited. Progressive fibrosclerotic disease, liver cirrhosis and an increased risk of malignancy are now recognized outcomes. Insights into the genetic and immunological features of the disease have increased over the past decade, with an emphasis on HLAs, T cells, circulating memory B cells and plasmablasts, chemokine-mediated trafficking, as well as the role of the innate immune system.

Grover VPB, Southern L, Dyson JK, Kim JU, Crossey MME, Wylezinska-Arridge M, Patel N, Fitzpatrick JA, Bak-Bol A, Waldman AD et al. 2016. Early primary biliary cholangitis is characterised by brain abnormalities on cerebral magnetic resonance imaging. Aliment Pharmacol Ther, 44 (9), pp. 936-945. | Show Abstract | Read more

BACKGROUND: Brain change can occur in primary biliary cholangitis (PBC), potentially as a result of cholestatic and/or inflammatory processes. This change is linked to systemic symptoms of fatigue and cognitive impairment. AIM: To identify whether brain change occurs early in PBC. If the change develops early and is progressive, it may explain the difficulty in treating these symptoms. METHODS: Early disease brain change was explored in 13 patients with newly diagnosed biopsy-proven precirrhotic PBC using magnetisation transfer, diffusion-weighted imaging and 1 H magnetic resonance spectroscopy. Results were compared to 17 healthy volunteers. RESULTS: Cerebral magnetisation transfer ratios were reduced in early PBC, compared to healthy volunteers, in the thalamus, putamen and head of caudate with no greater reduction in patients with greater symptom severity. Mean apparent diffusion coefficients were increased in the thalamus only. No 1 H magnetic resonance spectroscopy abnormalities were seen. Serum manganese levels were elevated in all PBC patients, but no relationship was seen with imaging or symptom parameters. There were no correlations between neuroimaging data, laboratory data, symptom severity scores or age. CONCLUSIONS: This is the first study to be performed in this precirrhotic patient population, and we have highlighted that neuroimaging changes are present at a much earlier stage than previously demonstrated. The neuroimaging abnormalities suggest that the brain changes seen in PBC occur early in the pathological process, even before significant liver damage has occurred. If such changes are linked to symptom pathogenesis, this could have important implications for the timing of second-line-therapy use.

Doorenspleet ME, Hubers LM, Culver EL, Maillette de Buy Wenniger LJ, Klarenbeek PL, Chapman RW, Baas F, van de Graaf SF, Verheij J, van Gulik TM et al. 2016. Immunoglobulin G4(+) B-cell receptor clones distinguish immunoglobulin G 4-related disease from primary sclerosing cholangitis and biliary/pancreatic malignancies. Hepatology, 64 (2), pp. 501-507. | Show Abstract | Read more

UNLABELLED: Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) of the biliary tree and pancreas is difficult to distinguish from sclerosing cholangitis and biliary/pancreatic malignancies (CA). An accurate noninvasive test for diagnosis and monitoring of disease activity is lacking. We demonstrate that dominant IgG4(+) B-cell receptor (BCR) clones determined by next-generation sequencing accurately distinguish patients with IgG4-associated cholangitis/autoimmune pancreatitis (n = 34) from those with primary sclerosing cholangitis (n = 17) and CA (n = 17). A novel, more affordable, and widely applicable quantitative polymerase chain reaction (qPCR) protocol analyzing the IgG4/IgG RNA ratio in blood also achieves excellent diagnostic accuracy (n = 125). Moreover, this qPCR test performed better than serum IgG4 levels in sensitivity (94% vs. 86%) and specificity (99% vs. 73%) and correlates with treatment response (n = 20). CONCLUSIONS: IgG4(+) BCR clones and IgG4/IgG RNA ratio markedly improve delineation, early diagnosis, and monitoring of IgG4-RD of the biliary tree and pancreas. (Hepatology 2016;64:501-507).

Culver EL, Wang LM, Bungay H, Chapman RW, Collier J. 2017. A rare cause of colonic thickening and lymphadenopathy. Gut, 66 (1), pp. 78. | Read more

Jones D, Chapman R, Thorburn D, Dillon JF, Ryder SD, Hirschfield G, Mells G, Carbone M, Pencek R, Hooshmand-Rad R, Shapiro D. 2016. EFFICACY AND SAFETY OF OBETICHOLIC ACID (OCA) IN PBC PATIENTS WITH ADVANCED DISEASE AS EVIDENCED BY ABNORMAL BILIRUBIN: AN INTEGRATED ANALYSIS GUT, 65 (Suppl 1), pp. A93-A94. | Read more

Culver EL, Sadler R, Simpson D, Cargill T, Makuch M, Bateman AC, Ellis AJ, Collier J, Chapman RW, Klenerman P et al. 2016. Elevated Serum IgG4 Levels in Diagnosis, Treatment Response, Organ Involvement, and Relapse in a Prospective IgG4-Related Disease UK Cohort. Am J Gastroenterol, 111 (5), pp. 733-743. | Show Abstract | Read more

OBJECTIVES: Elevated serum immunoglobulin G4 (IgG4) levels have been associated with autoimmune pancreatitis and IgG4-related disease (IgG4-RD) for over a decade. However, an elevated serum IgG4 is not specific for the disease. There have been inconsistent reports of its use in diagnosis, as a marker of disease relapse, and its relationship to organ involvement in retrospective cohorts. The aims of this study were to ascertain conditions that are associated with an elevated serum IgG4 and to investigate the role of IgG4 in diagnosis, relapse, and organ involvement in a prospective cohort of patients with IgG4-RD. METHODS: We evaluated serum IgG4 measurements in the Oxford Immunology Laboratory over 6 years. Patients in whom serum IgG4 was requested to differentiate IgG4-RD from other diseases were recruited into a longitudinal follow-up study to determine final diagnosis. In a prospective cohort of IgG4-RD patients, organ involvement, response to therapy, and disease relapse were determined. RESULTS: Two thousand and sixty-seven samples from 1,510 patients had serum IgG4 measured. Of these, IgG4 was elevated (≥1.4 g l(-1)) in 243 (16.1%) patients. The main indication (85.6%) was to distinguish between IgG4-RD and non-IgG4-RD conditions. Only 5.1% of patients who had serum IgG4 measured for this purpose had a final diagnosis of IgG4-RD. Of those with an elevated serum IgG4, 22.4% met IgG4-RD diagnostic criteria. Serum IgG4 was elevated in 48 (82.8%) of IgG4-RD patients. An IgG4 cutoff of 1.4 g l(-1) gave a sensitivity of 82.8% and specificity of 84.7% to diagnose IgG4-RD. Increasing this to 2.8 g l(-1) increased specificity to 96.2% and negative predictive value to 97.7%, with a lower sensitivity of 56.9% and positive predictive value of 44.5%. Serum IgG4 levels fell with corticosteroid therapy, but this was not disease-specific. A serum IgG4 of ≥2.8 g l(-1) at diagnosis was associated with multi-organ involvement and risk of relapse. CONCLUSIONS: Serum IgG4 levels are elevated in multiple non-IgG4-RD inflammatory and malignant conditions, with less than one-quarter of those with an elevated IgG4 meeting IgG4-RD diagnostic criteria. A serum IgG4 of ≥2.8 g l(-1) is useful in distinguishing between IgG4-RD and non-IgG4-RD diagnoses, predicting multiple-organ involvement and risk of relapse in IgG4-RD.

Gwela A, Siddhanathi P, Chapman RW, Arancibia C, Travis SPL, Powrie F, Geremia A. 2016. Distinct inflammatory signatures in primary sclerosing cholangitis associated with inflammatory bowel disease JOURNAL OF CROHNS & COLITIS, 10 pp. S95-S95.

Smit WL, Culver EL, Chapman RW. 2016. New Thoughts on Immunoglobulin G4-Related Sclerosing Cholangitis. Clin Liver Dis, 20 (1), pp. 47-65. | Show Abstract | Read more

Immunoglobulin G4 (IgG4)-related sclerosing cholangitis (IgG4-SC) is the biliary manifestation of the multisystem IgG4-related disease. IgG4-SC presents with biliary strictures and/or masses that can bear a striking similarity to other malignant and inflammatory diseases. Diagnosis is based on a combination of clinical, biochemical, radiological, and histologic findings with careful exclusion of malignant disease. Corticosteroids are the mainstay of treatment with good clinical, biochemical, and radiological responses. This review provides a comprehensive overview of the current knowledge of the prevalence, clinical features, radiology and histology findings, diagnosis, treatment, natural history, and pathophysiology of IgG4-SC.

Williamson KD, Chapman RW. 2016. New Therapeutic Strategies for Primary Sclerosing Cholangitis. Semin Liver Dis, 36 (1), pp. 5-14. | Show Abstract | Read more

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease, which in the majority of patients progresses to liver transplantation or death. To date, no medical treatment has been proven to be of benefit, although ursodeoxycholic acid is widely used. The etiopathogenesis of PSC is unclear, although it is associated with inflammatory bowel disease. Various hypotheses have been suggested, which have led to different therapeutic strategies. Recent studies have suggested that the microbiome may play a role in PSC, raising the possibility of efficacy of antibiotics and fecal microbiota transplantation. Gut-homing T cells may be important in the pathogenesis of PSC, and several agents are in development, targeting various receptors, integrins, and ligands on this pathway, including VAP-1, MAdCAM-1, α4β7, and CCR9. Nuclear receptor agonists such as obeticholic acid and fibrates hold promise, as do other therapies that alter bile acid composition such as norUDCA. Antifibrotic agents such as Loxl2 inhibitors are also being assessed. In conclusion, it is likely that an effective drug therapy for PSC will become available over the next decade.

Chapman RW. 2015. Primary sclerosing cholangitis Medicine, 43 (11), pp. 648-652. | Show Abstract | Read more

© 2015 Elsevier Ltd. Primary sclerosing cholangitis (PSC) is a chronic, cholestatic liver disease caused by diffuse inflammation and fibrosis that can involve the entire biliary tree. The progressive pathological process obliterates intrahepatic and extrahepatic bile ducts, leading ultimately to biliary cirrhosis, portal hypertension and hepatic failure. The cause is unknown but it is closely associated with inflammatory bowel disease, particularly ulcerative colitis, which occurs in about 70% of cases. Approximately 5-10% of patients with total ulcerative colitis will have co-existing PSC. Clinical symptoms include fatigue, intermittent jaundice, weight loss, right upper-quadrant abdominal pain and pruritus. The clinical course of PSC is variable. Serum biochemical tests usually indicate cholestasis; the diagnosis is established by cholangiography. In symptomatic patients, median survival from presentation to death or liver transplantation is about 12 years. About 75% of asymptomatic patients survive 20 years or more. Median overall survival is 23 years. Overall, 37% of patients die from hepatic failure, while approximately 44% die from cancer - PSC is a premalignant condition. The commonest malignancy is hepatobiliary in origin, usually bile duct carcinoma, which is often aggressive. Patients with associated inflammatory bowel disease may die from colonic cancer or complications of colitis. PSC has no curative treatment. Medical treatment with the bile acid, ursodeoxycholic acid, may slow progression of the disease and act as a chemoprotective agent against colonic dysplasia. Liver transplantation is the only option in young patients with PSC and advanced liver disease; 5-year survival is 80-90% in most centres. The disease will recur in the donor liver in 30% of patients after 5 years.

Kalaitzakis E, Benito de Valle M, Rahman M, Lindkvist B, Björnsson E, Chapman R, Kontodimopoulos N. 2016. Mapping chronic liver disease questionnaire scores onto SF-6D utility values in patients with primary sclerosing cholangitis. Qual Life Res, 25 (4), pp. 947-957. | Show Abstract | Read more

PURPOSE: The chronic liver disease questionnaire (CLDQ) is a frequently used liver-specific quality of life instrument, but it does not provide information on preference-adjusted health status, which is essential for cost-utility analysis. We aimed to develop a mapping function deriving utilities from the CLDQ in primary sclerosing cholangitis (PSC). METHODS: Short form-6D (SF-6D) utilities were calculated from SF-36 data collected in a recent prospective study in which unselected patients with PSC also completed the CLDQ. Ordinary least squares (OLS), generalized linear, median, and kernel regression analyses were employed to devise a mapping function predicting utilities. This was validated in three random subsamples of the cohort and in a separate sample of PSC patients following liver transplantation. Adjusted R (2) and root-mean-square error (RMSE) as well as Pearson's r coefficients and mean absolute errors between predicted and observed values were used to determine model performance. RESULTS: Decompensated liver disease and fatigue, systemic symptoms, and emotional distress, assessed with the CLDQ, were related to worse SF-6D utilities. The final OLS prediction model explained 66.3 % of the variance in the derivation sample. Predicted and observed utilities were strongly correlated (r = 0.807, p < 0.001), but the mean absolute error (0.0604) and adjusted RMSE (10.6 %) were of intermediate size. Similar model characteristics were observed after employment of generalized linear and median regression models and at validation. CONCLUSIONS: A model has been constructed, showing good validity predicting SF-6D utilities from CLDQ scores at the group level in PSC. Further testing is required to externally validate the model.

Hubers L, Doorenspleet M, Klarenbeek P, Culver E, Wenniger LMDB, Chapman R, Van de Graaf S, Verheij J, Van Gulik T, Baas F et al. 2015. The IgG/IgG4 mRNA Ratio By Quantitative PCR Accurately Diagnoses IgG4-Related Disease and Predicts Treatment Response ARTHRITIS & RHEUMATOLOGY, 67

Ponsioen CY, Chapman RW, Chazouillères O, Hirschfield GM, Karlsen TH, Lohse AW, Pinzani M, Schrumpf E, Trauner M, Gores GJ. 2016. Surrogate endpoints for clinical trials in primary sclerosing cholangitis: Review and results from an International PSC Study Group consensus process. Hepatology, 63 (4), pp. 1357-1367. | Show Abstract | Read more

UNLABELLED: Primary sclerosing cholangitis (PSC) is a rare, but serious, cholestatic disease for which, to date, no effective therapy exists to halt disease progression toward end-stage liver disease. Clinical trial design to study drugs that improve prognosis is hampered by the relatively low event rate of clinically relevant endpoints. To overcome this shortcoming, there is an urgent need to identify appropriate surrogate endpoints. At present, there are no established surrogate endpoints. This article provides a critical review and describes the results of a consensus process initiated by the International PSC Study Group to delineate appropriate candidate surrogate endpoints at present for clinical trials in this frequently dismal disease. The consensus process resulted in a shortlist of five candidates as surrogate endpoints for measuring disease progression: alkaline phosphatase (ALP); transient elastography (TE); histology; combination of ALP+histology; and bilirubin. Of these, histology, ALP, and TE came out as the most promising. However, the expert panel concluded that no biomarker currently exceeds level 3 validation. Combining multiple endpoints is advisable. CONCLUSION: At present, there are insufficient data to support level 2 validation for any surrogate endpoint in PSC. Concerted efforts by all stakeholders are highly needed. Novel, promising noninvasive biomarkers are under study and should be incorporated as exploratory endpoints in clinical trials.

Colling R, Verrill C, Fryer E, Kartsonaki C, Wang LM, Chapman R, Rajabally N, Fleming K. 2016. Bile duct basement membrane thickening in primary sclerosing cholangitis. Histopathology, 68 (6), pp. 819-824. | Show Abstract | Read more

AIMS: Primary sclerosing cholangitis (PSC) is characterized histologically by portal inflammation, bile duct injury and regeneration and concentric periductal fibrosis. Although seen commonly in our experience, the significance of histological thickening of the bile duct basement membrane on periodic acid Schiff (PAS)-positive, diastase-resistant (DPAS) staining has never been analysed formally. In this paper we provide an evidence-based assessment of basement membrane thickening (BMT) reproducibility and diagnostic accuracy. METHODS AND RESULTS: A total of 128 archived medical liver core biopsies were retrieved and blinded for review by two independent histopathologists. BMT was assessed and designated as absent or present with a grade (G) of G1-G3. The sensitivity of any BMT for PSC was good at 77%, with moderate specificity at 61%. When only G3 BMT was considered positive, the specificity was high at 95% but the sensitivity was poor at 16%. The interobserver agreement (0.69) and consistency (0.72) were good. CONCLUSIONS: Basement membrane thickening is a reproducible predictor for PSC with good sensitivity and specificity. The presence of G2 and especially G3 BMT showed high specificity and could be regarded as highly predictive of PSC. The presence of more than G1 BMT should be reported and the possibility of PSC should be raised in the differential diagnosis.

Williamson KD, Chapman RW. 2015. Primary sclerosing cholangitis: a clinical update. Br Med Bull, 114 (1), pp. 53-64. | Show Abstract | Read more

INTRODUCTION: Primary sclerosing cholangitis (PSC) is a progressive cholestatic disorder that ultimately can lead to cirrhosis, liver failure, malignancy and death. It is strongly associated with inflammatory bowel disease (IBD), and though a rare disease, its incidence is increasing. There are no proven medical therapies for PSC. SOURCES OF DATA: Ovid Medline was utilised to search for articles with keywords 'sclerosing cholangitis' and 'cholangiocarcinoma' and containing titles 'primary sclerosing cholangitis', and references of these papers were cross-referenced for further relevant manuscripts. AREAS OF AGREEMENT: PSC is a rare disease, and there is a strong association with risk loci within the major histocompatibility complex and other genes common to other autoimmune diseases. PSC is a premalignant condition, associated with higher rates of hepatobiliary and colorectal cancer in patients with ulcerative colitis (UC). AREAS OF CONTROVERSY: The pathogenesis is unclear, and competing theories exist surrounding toxic bile acids, enhanced homing of particular T cells from the gut to the liver and increased passage of toxins to the liver through a permeable bowel wall. It is unclear whether the higher rate of colonic cancer in PSC/UC occurs in PSC/Crohn's disease. Ursodeoxycholic acid therapy reduces liver enzymes but has not been shown to improve survival. It may reduce the prevalence of bowel cancer. GROWING POINTS: Recent genetic studies have revealed new risk loci, pointing to the importance of the immune system and its interaction with the biome. AREAS TIMELY FOR DEVELOPING RESEARCH: On the basis of the genetic studies discussed earlier, novel agents are being developed and trialled in the treatment of PSC.

Williamson KD, Chapman RW. 2015. Editorial: further evidence for the role of serum alkaline phosphatase as a useful surrogate marker of prognosis in PSC. Aliment Pharmacol Ther, 41 (1), pp. 149-151. | Read more

Naess S, Björnsson E, Anmarkrud JA, Al Mamari S, Juran BD, Lazaridis KN, Chapman R, Bergquist A, Melum E, Marsh SGE et al. 2014. Small duct primary sclerosing cholangitis without inflammatory bowel disease is genetically different from large duct disease. Liver Int, 34 (10), pp. 1488-1495. | Show Abstract | Read more

BACKGROUND & AIMS: Small duct primary sclerosing cholangitis (PSC) is phenotypically a mild version of large duct PSC, but it is unknown whether these phenotypes share aetiology. We aimed to characterize their relationship by investigating genetic associations in the human leucocyte antigen (HLA) complex, which represent the strongest genetic risk factors in large duct PSC. METHODS: Four classical HLA loci (HLA-A, HLA-B, HLA-C and HLA-DRB1) were genotyped in 87 small duct PSC patients, 485 large duct PSC patients and 1117 controls across three geographical regions. RESULTS: HLA-DRB1*13:01 (OR = 2.0, 95% CI 1.2-3.4, P = 0.01) and HLA-B*08 (OR = 1.6, 95% CI 1.1-2.4, P = 0.02) were significantly associated with small duct PSC compared with healthy controls. Based on the observed frequency of HLA-B*08 in small duct PSC, the strongest risk factor in large duct PSC, an estimated 32% (95% CI 4-65%) of this population can be hypothesized to represent early stages or mild variants of large duct PSC. This subgroup may be constituted by small duct PSC patients with inflammatory bowel disease (IBD), which greatly resembled large duct PSC in its HLA association. In contrast, small duct PSC without IBD was only associated with HLA-DRB1*13:01(P = 0.03) and was otherwise distinctly dissimilar from large duct PSC. CONCLUSIONS: Small duct PSC with IBD resembles large duct PSC in its HLA association and may represent early stages or mild variants of large duct disease. Different HLA associations in small duct PSC without IBD could indicate that this subgroup is a different entity. HLA-DRB1*13:01 may represent a specific risk factor for inflammatory bile duct disease.

Næss S, Björnsson E, Anmarkrud JA, Mamari SA, Juran BD, Lazaridis KN, Chapman R, Bergquist A, Melum E, Marsh SGE et al. 2014. Small duct primary sclerosing cholangitis without inflammatory bowel disease is genetically different from large duct disease Liver International, 34 (10), pp. 1488-1495. | Show Abstract | Read more

© 2014 John Wiley & Sons A/S. Background & Aims: Small duct primary sclerosing cholangitis (PSC) is phenotypically a mild version of large duct PSC, but it is unknown whether these phenotypes share aetiology. We aimed to characterize their relationship by investigating genetic associations in the human leucocyte antigen (HLA) complex, which represent the strongest genetic risk factors in large duct PSC. Methods: Four classical HLA loci (HLA-A, HLA-B*, HLA-C and HLA-DRB1) were genotyped in 87 small duct PSC patients, 485 large duct PSC patients and 1117 controls across three geographical regions. Results: HLA-DRB1*13:01 (OR = 2.0, 95% CI 1.2-3.4, P = 0.01) and HLA-B*08 (OR = 1.6, 95% CI 1.1-2.4, P = 0.02) were significantly associated with small duct PSC compared with healthy controls. Based on the observed frequency of HLA-B*08 in small duct PSC, the strongest risk factor in large duct PSC, an estimated 32% (95% CI 4-65%) of this population can be hypothesized to represent early stages or mild variants of large duct PSC. This subgroup may be constituted by small duct PSC patients with inflammatory bowel disease (IBD), which greatly resembled large duct PSC in its HLA association. In contrast, small duct PSC without IBD was only associated with HLA-DRB1*13:01(P = 0.03) and was otherwise distinctly dissimilar from large duct PSC. Conclusions: Small duct PSC with IBD resembles large duct PSC in its HLA association and may represent early stages or mild variants of large duct disease. Different HLA associations in small duct PSC without IBD could indicate that this subgroup is a different entity. HLA-DRB1*13:01 may represent a specific risk factor for inflammatory bile duct disease.

Cited:

95

Scopus

Huggett MT, Culver EL, Kumar M, Hurst JM, Rodriguez-Justo M, Chapman MH, Johnson GJ, Pereira SP, Chapman RW, Webster GJM, Barnes E. 2014. Type 1 autoimmune pancreatitis and IgG4-related sclerosing cholangitis is associated with extrapancreatic organ failure, malignancy, and mortality in a prospective UK cohort The American journal of gastroenterology, 109 (10), pp. 1675-1683. | Show Abstract | Read more

OBJECTIVES: Type I autoimmune pancreatitis (AIP) and IgG4-related sclerosing cholangitis (IgG4-related SC) are now recognized as components of a multisystem IgG4-related disease (IgG4-RD). We aimed to define the clinical course and long-term outcomes in patients with AIP/IgG4-SC recruited from two large UK tertiary referral centers.METHODS: Data were collected from 115 patients identified between 2004 and 2013, and all were followed up prospectively from diagnosis for a median of 33 months (range 1-107), and evaluated for response to therapy, the development of multiorgan involvement, and malignancy. Comparisons were made with national UK statistics.RESULTS: Although there was an initial response to steroids in 97%, relapse occurred in 50% of patients. IgG4-SC was an important predictor of relapse (P<0.01). Malignancy occurred in 11% shortly before or after the diagnosis of IgG4-RD, including three hepatopancreaticobiliary cancers. The risk of any cancer at diagnosis or during follow-up when compared with matched national statistics was increased (odds ratio=2.25, CI=1.12-3.94, P=0.02). Organ dysfunction occurred within the pancreas, liver, kidney, lung, and brain. Mortality occurred in 10% of patients during follow-up. The risk of death was increased compared with matched national statistics (odds ratio=2.07, CI=1.07-3.55, P=0.02).CONCLUSIONS: Our findings suggest that AIP and IgG4-SC are associated with significant morbidity and mortality owing to extrapancreatic organ failure and malignancy. Detailed clinical evaluation for evidence of organ dysfunction and associated malignancy is required both at first presentation and during long-term follow-up.

Pavlides M, Barnabas A, Fernandopulle N, Bailey AA, Collier J, Phillips-Hughes J, Ellis A, Chapman R, Braden B. 2014. Repeat endoscopic retrograde cholangiopancreaticography after failed initial precut sphincterotomy for biliary cannulation. World J Gastroenterol, 20 (36), pp. 13153-13158. | Show Abstract | Read more

AIM: To investigate the outcome of repeating endoscopic retrograde cholangiopancreaticography (ERCP) after initially failed precut sphincterotomy to achieve biliary cannulation. METHODS: In this retrospective study, consecutive ERCPs performed between January 2009 and September 2012 were included. Data from our endoscopy and radiology reporting databases were analysed for use of precut sphincterotomy, biliary access rate, repeat ERCP rate and complications. Patients with initially failed precut sphincterotomy were identified. RESULTS: From 1839 consecutive ERCPs, 187 (10%) patients underwent a precut sphincterotomy during the initial ERCP in attempts to cannulate a native papilla. The initial precut was successful in 79/187 (42%). ERCP was repeated in 89/108 (82%) of patients with failed initial precut sphincterotomy after a median interval of 4 d, leading to successful biliary cannulation in 69/89 (78%). In 5 patients a third ERCP was attempted (successful in 4 cases). Overall, repeat ERCP after failed precut at the index ERCP was successful in 73/89 patients (82%). Complications after precut-sphincterotomy were observed in 32/187 (17%) patients including pancreatitis (13%), retroperitoneal perforations (1%), biliary sepsis (0.5%) and haemorrhage (3%). CONCLUSION: The high success rate of biliary cannulation in a second attempt ERCP justifies repeating ERCP within 2-7 d after unsuccessful precut sphincterotomy before more invasive approaches should be considered.

Huggett MT, Culver EL, Kumar M, Hurst JM, Rodriguez-Justo M, Chapman MH, Johnson GJ, Pereira SP, Chapman RW, Webster GJM, Barnes E. 2014. Type 1 autoimmune pancreatitis and IgG4-related sclerosing cholangitis is associated with extrapancreatic organ failure, malignancy, and mortality in a prospective UK cohort. Am J Gastroenterol, 109 (10), pp. 1675-1683. | Show Abstract | Read more

OBJECTIVES: Type I autoimmune pancreatitis (AIP) and IgG4-related sclerosing cholangitis (IgG4-related SC) are now recognized as components of a multisystem IgG4-related disease (IgG4-RD). We aimed to define the clinical course and long-term outcomes in patients with AIP/IgG4-SC recruited from two large UK tertiary referral centers. METHODS: Data were collected from 115 patients identified between 2004 and 2013, and all were followed up prospectively from diagnosis for a median of 33 months (range 1-107), and evaluated for response to therapy, the development of multiorgan involvement, and malignancy. Comparisons were made with national UK statistics. RESULTS: Although there was an initial response to steroids in 97%, relapse occurred in 50% of patients. IgG4-SC was an important predictor of relapse (P<0.01). Malignancy occurred in 11% shortly before or after the diagnosis of IgG4-RD, including three hepatopancreaticobiliary cancers. The risk of any cancer at diagnosis or during follow-up when compared with matched national statistics was increased (odds ratio=2.25, CI=1.12-3.94, P=0.02). Organ dysfunction occurred within the pancreas, liver, kidney, lung, and brain. Mortality occurred in 10% of patients during follow-up. The risk of death was increased compared with matched national statistics (odds ratio=2.07, CI=1.07-3.55, P=0.02). CONCLUSIONS: Our findings suggest that AIP and IgG4-SC are associated with significant morbidity and mortality owing to extrapancreatic organ failure and malignancy. Detailed clinical evaluation for evidence of organ dysfunction and associated malignancy is required both at first presentation and during long-term follow-up.

Pavlides M, Cleland J, Rahman M, Christian A, Doyle J, Gaunt R, Travis S, Mortensen N, Chapman R. 2014. Outcomes after ileal pouch anal anastomosis in patients with primary sclerosing cholangitis Journal of Crohn's and Colitis, 8 (7), pp. 662-670. | Show Abstract | Read more

Background and aims: Outcomes after ileal pouch anal anastomosis (IPAA) are not well established in patients with primary sclerosing cholangitis (PSC). We conducted a comprehensive outcomes assessment in these patients. Methods: A retrospective case note review of complications in all PSC-IPAA (n=21) and matched ulcerative colitis patients with IPAA (UC-IPAA; n=79) after surgery in Oxford (1983-2012) was conducted, and functional outcomes (Öresland score) were evaluated (2012). Quality of life [Cleveland Global Quality of Life Questionnaire, Short Form-36 (SF-36)], and sexual function were also assessed (2012) including patients with PSC-associated UC without IPAA (PSC-UC; n=19). Sub-group analysis of patients with large duct (ld) PSC-IPAA (n=17) was also performed. Results: The 1-, 5-, 10- and 20-year risk of acute pouchitis for PSC-IPAA was 10%, 19%, 31% and 65% respectively, compared to 3%, 10%, 14% and 28% in UC-IPAA (p=0.03). More PSC-IPAA (36%) had poor nocturnal pouch function (vs 2% in UC-IPAA; p=0.0016). There were no differences in surgical complications, quality of life or sexual function between the 3 main groups. LdPSC-IPAA had poorer pouch function (Öresland score: 7.7 vs 5.4 in UC-IPAA; p=0.02), and worse quality of life [SF-36 Physical: 42 vs 50.5 in UC-IPAA; 47.7 in PSC-UC; p=0.03 and Mental Health summary scores: 41.6 vs 51.2 in UC-IPAA; 42.3 in PSC-UC; p=0.04]. Conclusions: PSC-IPAA suffer more acute pouchitis and have worse functional outcomes than UC-IPAA. LdPSC-IPAA also have poorer quality of life. © 2013 European Crohn's and Colitis Organisation.

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74

WOS

Boonstra K, Culver EL, Wenniger LMDB, van Heerde MJ, van Erpecum KJ, Poen AC, van Nieuwkerk KMJ, Spanier BWM, Witteman BJM, Tuynman HARE et al. 2014. Serum Immunoglobulin G4 and Immunoglobulin G1 for Distinguishing Immunoglobulin G4-Associated Cholangitis From Primary Sclerosing Cholangitis HEPATOLOGY, 59 (5), pp. 1954-1963. | Show Abstract | Read more

The recent addition of immunoglobulin (Ig)G4-associated cholangitis (IAC), also called IgG4-related sclerosing cholangitis (IRSC), to the spectrum of chronic cholangiopathies has created the clinical need for reliable methods to discriminate between IAC and the more common cholestatic entities, primary (PSC) and secondary sclerosing cholangitis. The current American Association for the Study of Liver Diseases practice guidelines for PSC advise on the measurement of specific Ig (sIg)G4 in PSC patients, but interpretation of elevated sIgG4 levels remains unclear. We aimed to provide an algorithm to distinguish IAC from PSC using sIgG analyses. We measured total IgG and IgG subclasses in serum samples of IAC (n=73) and PSC (n=310) patients, as well as in serum samples of disease controls (primary biliary cirrhosis; n=22). sIgG4 levels were elevated above the upper limit of normal (ULN=>1.4 g/L) in 45 PSC patients (15%; 95% confidence interval [CI]: 11-19). The highest specificity and positive predictive value (PPV; 100%) for IAC were reached when applying the 4× ULN (sIgG4>5.6 g/L) cutoff with a sensitivity of 42% (95% CI: 31-55). However, in patients with a sIgG4 between 1× and 2× ULN (n=38/45), the PPV of sIgG4 for IAC was only 28%. In this subgroup, the sIgG4/sIgG1 ratio cutoff of 0.24 yielded a sensitivity of 80% (95% CI: 51-95), a specificity of 74% (95% CI: 57-86), a PPV of 55% (95% CI: 33-75), and a negative predictive value of 90% (95% CI: 73-97). Conclusion: Elevated sIgG4 (>1.4 g/L) occurred in 15% of patients with PSC. In patients with a sIgG4 >1.4 and <2.8 g/L, incorporating the IgG4/IgG1 ratio with a cutoff at 0.24 in the diagnostic algorithm significantly improved PPV and specificity. We propose a new diagnostic algorithm based on IgG4/IgG1 ratio that may be used in clinical practice to distinguish PSC from IAC. © 2014 by the American Association for the Study of Liver Diseases.

Boonstra K, Culver EL, de Buy Wenniger LM, van Heerde MJ, van Erpecum KJ, Poen AC, van Nieuwkerk KMJ, Spanier BWM, Witteman BJM, Tuynman HARE et al. 2014. Serum immunoglobulin G4 and immunoglobulin G1 for distinguishing immunoglobulin G4-associated cholangitis from primary sclerosing cholangitis. Hepatology, 59 (5), pp. 1954-1963. | Show Abstract | Read more

UNLABELLED: The recent addition of immunoglobulin (Ig)G4-associated cholangitis (IAC), also called IgG4-related sclerosing cholangitis (IRSC), to the spectrum of chronic cholangiopathies has created the clinical need for reliable methods to discriminate between IAC and the more common cholestatic entities, primary (PSC) and secondary sclerosing cholangitis. The current American Association for the Study of Liver Diseases practice guidelines for PSC advise on the measurement of specific Ig (sIg)G4 in PSC patients, but interpretation of elevated sIgG4 levels remains unclear. We aimed to provide an algorithm to distinguish IAC from PSC using sIgG analyses. We measured total IgG and IgG subclasses in serum samples of IAC (n = 73) and PSC (n = 310) patients, as well as in serum samples of disease controls (primary biliary cirrhosis; n = 22). sIgG4 levels were elevated above the upper limit of normal (ULN = >1.4 g/L) in 45 PSC patients (15%; 95% confidence interval [CI]: 11-19). The highest specificity and positive predictive value (PPV; 100%) for IAC were reached when applying the 4 × ULN (sIgG4 > 5.6 g/L) cutoff with a sensitivity of 42% (95% CI: 31-55). However, in patients with a sIgG4 between 1 × and 2 × ULN (n = 38/45), the PPV of sIgG4 for IAC was only 28%. In this subgroup, the sIgG4/sIgG1 ratio cutoff of 0.24 yielded a sensitivity of 80% (95% CI: 51-95), a specificity of 74% (95% CI: 57-86), a PPV of 55% (95% CI: 33-75), and a negative predictive value of 90% (95% CI: 73-97). CONCLUSION: Elevated sIgG4 (>1.4 g/L) occurred in 15% of patients with PSC. In patients with a sIgG4 >1.4 and <2.8 g/L, incorporating the IgG4/IgG1 ratio with a cutoff at 0.24 in the diagnostic algorithm significantly improved PPV and specificity. We propose a new diagnostic algorithm based on IgG4/IgG1 ratio that may be used in clinical practice to distinguish PSC from IAC.

Chapman RW. 2014. Malignancy in primary sclerosing cholangitis: Bile duct, liver, and colon. Clin Liver Dis (Hoboken), 3 (4), pp. 83-85. | Show Abstract | Read more

Watch a video presentation of this article Watch the interview with the author Answer questions and earn CME. © 2014 by the American Association for the Study of Liver Diseases.

Geremia A, Arancibia C, Gwela A, Chapman RW, Travis SPL, Powrie F. 2014. Innate lymphoid cells accumulate in IBD JOURNAL OF CROHNS & COLITIS, 8 pp. S1-S1. | Read more

Pavlides M, Cleland J, Rahman M, Christian A, Doyle J, Gaunt R, Travis S, Mortensen N, Chapman R. 2014. Outcomes after ileal pouch anal anastomosis in patients with primary sclerosing cholangitis. J Crohns Colitis, 8 (7), pp. 662-670. | Show Abstract | Read more

BACKGROUND AND AIMS: Outcomes after ileal pouch anal anastomosis (IPAA) are not well established in patients with primary sclerosing cholangitis (PSC). We conducted a comprehensive outcomes assessment in these patients. METHODS: A retrospective case note review of complications in all PSC-IPAA (n=21) and matched ulcerative colitis patients with IPAA (UC-IPAA; n=79) after surgery in Oxford (1983-2012) was conducted, and functional outcomes (Öresland score) were evaluated (2012). Quality of life [Cleveland Global Quality of Life Questionnaire, Short Form-36 (SF-36)], and sexual function were also assessed (2012) including patients with PSC-associated UC without IPAA (PSC-UC; n=19). Sub-group analysis of patients with large duct (ld) PSC-IPAA (n=17) was also performed. RESULTS: The 1-, 5-, 10- and 20-year risk of acute pouchitis for PSC-IPAA was 10%, 19%, 31% and 65% respectively, compared to 3%, 10%, 14% and 28% in UC-IPAA (p=0.03). More PSC-IPAA (36%) had poor nocturnal pouch function (vs 2% in UC-IPAA; p=0.0016). There were no differences in surgical complications, quality of life or sexual function between the 3 main groups. LdPSC-IPAA had poorer pouch function (Öresland score: 7.7 vs 5.4 in UC-IPAA; p=0.02), and worse quality of life [SF-36 Physical: 42 vs 50.5 in UC-IPAA; 47.7 in PSC-UC; p=0.03 and Mental Health summary scores: 41.6 vs 51.2 in UC-IPAA; 42.3 in PSC-UC; p=0.04]. CONCLUSIONS: PSC-IPAA suffer more acute pouchitis and have worse functional outcomes than UC-IPAA. LdPSC-IPAA also have poorer quality of life.

Chapman RW, Stanghellini V, Geraint M, Halphen M. 2014. Response to Drs Shearer and Ford. Am J Gastroenterol, 109 (1), pp. 136. | Read more

Williamson KD, Chapman RW. 2014. Primary sclerosing cholangitis. Dig Dis, 32 (4), pp. 438-445. | Show Abstract | Read more

Primary sclerosing cholangitis (PSC) is a chronic, cholestatic liver disease caused by diffuse inflammation and fibrosis that can involve the entire biliary tree. It is a progressive disorder which can ultimately lead to biliary cirrhosis, portal hypertension and hepatic failure. PSC is a complex genetic disorder with male predominance. Environmental predisposing factors include non-smoking. It is closely associated with inflammatory bowel disease (IBD), particularly ulcerative colitis, which occurs in about two thirds of PSC cases. Recent studies have suggested that PSC-IBD is a separate disease entity from IBD alone with distinctive genetic and phenotypic characteristics. Most PSC patients are asymptomatic at presentation; clinical symptoms include fatigue, jaundice, weight loss, right upper quadrant pain and pruritis. Serum biochemical tests indicate cholestasis, and diagnosis is usually established by cholangiography. In symptomatic patients, median survival from presentation to death or liver transplantation is about 12 years. It is a premalignant condition, and the majority of deaths are from malignancy, particularly cholangiocarcinoma or colonic cancer. PSC has no curative treatment. Medical treatment with ursodeoxycholic acid may slow progression of the disease and reduce colonic dysplasia, though trials lack statistical significance. Liver transplantation is the only option in young patients with PSC and advanced liver disease.

Wenniger LMDB, Culver EL, Chapman RW, Barnes E, Beuers U. 2013. Chronic antigenic stimulation may predispose to the development of IgG4-related disease of bile ducts and pancreas HEPATOLOGY, 58 pp. 252A-252A.

Chapman RW, Stanghellini V, Geraint M, Halphen M. 2013. Randomized clinical trial: macrogol/PEG 3350 plus electrolytes for treatment of patients with constipation associated with irritable bowel syndrome. Am J Gastroenterol, 108 (9), pp. 1508-1515. | Show Abstract | Read more

OBJECTIVES: Polyethylene glycol (PEG) 3350 plus electrolytes (PEG 3350+E) is an established treatment for constipation and has been proposed as a treatment option for constipation associated with irritable bowel syndrome (IBS-C). This study aimed to compare the efficacy and safety of PEG 3350+E vs. placebo in adult patients with IBS-C. METHODS: Following a 14-day run-in period without study medication, patients with confirmed IBS-C were randomized to receive PEG 3350+E (N=68) or placebo (N=71) for 28 days. The primary endpoint was the mean number of spontaneous bowel movements (SBMs) per day in the last treatment week. RESULTS: In both groups, mean weekly number of SBMs (±s.d.) increased from run-in. The difference between the groups in week 4 (PEG 3350+E, 4.40±2.581; placebo, 3.11±1.937) was statistically significant (95% confidence interval: 1.17, 1.95; P<0.0001). Although mean severity score for abdominal discomfort/pain was significantly reduced compared with run-in with PEG 3350+E, there was no difference vs. placebo. Spontaneous complete bowel movements, responder rates, stool consistency, and severity of straining also showed superior improvement in the PEG 3350+E group over placebo in week 4. The most common drug related treatment-emergent adverse events were abdominal pain (PEG 3350+E, 4.5%; placebo, 0%) and diarrhoea (PEG 3350+E, 4.5%; placebo, 4.3%). CONCLUSIONS: In IBS-C, PEG 3350+E was superior to placebo for relief of constipation, and although a statistically significant improvement in abdominal discomfort/pain was observed compared with baseline, there was no associated improvement compared with placebo. PEG 3350+E is a well-established and effective treatment that should be considered suitable for use in IBS-C.

Talwalkar JA, Chapman RW. 2013. The resurgence of serum alkaline phosphatase as a surrogate biomarker for prognosis in primary sclerosing cholangitis. Clin Gastroenterol Hepatol, 11 (7), pp. 847-849. | Read more

Liu JZ, Hov JR, Folseraas T, Ellinghaus E, Rushbrook SM, Doncheva NT, Andreassen OA, Weersma RK, Weismüller TJ, Eksteen B et al. 2013. Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis. Nat Genet, 45 (6), pp. 670-675. | Show Abstract | Read more

Primary sclerosing cholangitis (PSC) is a severe liver disease of unknown etiology leading to fibrotic destruction of the bile ducts and ultimately to the need for liver transplantation. We compared 3,789 PSC cases of European ancestry to 25,079 population controls across 130,422 SNPs genotyped using the Immunochip. We identified 12 genome-wide significant associations outside the human leukocyte antigen (HLA) complex, 9 of which were new, increasing the number of known PSC risk loci to 16. Despite comorbidity with inflammatory bowel disease (IBD) in 72% of the cases, 6 of the 12 loci showed significantly stronger association with PSC than with IBD, suggesting overlapping yet distinct genetic architectures for these two diseases. We incorporated association statistics from 7 diseases clinically occurring with PSC in the analysis and found suggestive evidence for 33 additional pleiotropic PSC risk loci. Together with network analyses, these findings add to the genetic risk map of PSC and expand on the relationship between PSC and other immune-mediated diseases.

Hirschfield GM, Chapman RW, Karlsen TH, Lammert F, Lazaridis KN, Mason AL. 2013. The genetics of complex cholestatic disorders. Gastroenterology, 144 (7), pp. 1357-1374. | Show Abstract | Read more

Cholestatic liver diseases are caused by a range of hepatobiliary insults and involve complex interactions among environmental and genetic factors. Little is known about the pathogenic mechanisms of specific cholestatic diseases, which has limited our ability to manage patients with these disorders. However, recent genome-wide studies have provided insight into the pathogenesis of gallstones, primary biliary cirrhosis, and primary sclerosing cholangitis. A lithogenic variant in the gene that encodes the hepatobiliary transporter ABCG8 has been identified as a risk factor for gallstone disease; this variant has been associated with altered cholesterol excretion and metabolism. Other variants of genes encoding transporters that affect the composition of bile have been associated with cholestasis, namely ABCB11, which encodes the bile salt export pump, and ABCB4, which encodes hepatocanalicular phosphatidylcholine floppase. In contrast, studies have associated primary biliary cirrhosis and primary sclerosing cholangitis with genes encoding major histocompatibility complex proteins and identified loci associated with microbial sensing and immune regulatory pathways outside this region, such as genes encoding IL12, STAT4, IRF5, IL2 and its receptor (IL2R), CD28, and CD80. These discoveries have raised interest in the development of reagents that target these gene products. We review recent findings from genetic studies of patients with cholestatic liver disease. Future characterization of genetic variants in animal models, stratification of risk alleles by clinical course, and identification of interacting environmental factors will increase our understanding of these complex cholestatic diseases.

Cited:

93

Scopus

Al Mamari S, Djordjevic J, Halliday JS, Chapman RW. 2013. Improvement of serum alkaline phosphatase to &lt;1.5 upper limit of normal predicts better outcome and reduced risk of cholangiocarcinoma in primary sclerosing cholangitis Journal of Hepatology, 58 (2), pp. 329-334. | Show Abstract | Read more

Background & Aims: Normalization of serum alkaline phosphatase (SAP) was recently shown to correlate with better prognosis in Primary Sclerosing Cholangitis (PSC). We aimed at evaluating the impact of SAP improvement to below 1.5 the upper limit of normal (ULN) on the prognosis of this cholestatic liver disease. Methods: Oxford PSC database was screened for cases diagnosed between 1980 and 2004. Cases which met the inclusion criteria were retrospectively examined for clinical parameters, laboratory values, and clinical end points (liver decompensation, liver transplantation, and liver-related deaths including cholangiocarcinoma). Cases were followed-up to 31/12/2010. Results: 139 patients were included, (87 males). Improvement of SAP to below 1.5 ULN was achieved by 55 (40%) patients in a median time of 2 years, compared to 84 (60%) who did not. 3/55 (6%) patients with SAP improvement reached an end point compared to 32/84 (38%) patients with no SAP improvement (p <0.0001). 13/84 (15%) patients with no SAP improvement developed cholangiocarcinoma compared to no cholangiocarcinoma in the group with SAP improvement (p = 0.002). The end point free survival was significantly longer in patients with SAP improvement (p <0.0001). The significance of SAP improvement as a predictor of prognosis persisted after controlling for other clinical and laboratory variables. Improvement of SAP to below 1.5 ULN was comparable to complete normalization of SAP in terms of prognosis. Conclusions: Improvement in SAP to below 1.5 ULN is associated with better outcome and reduced risk of CCA in PSC. This was comparable to the achievement of complete normalization of SAP. © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Al Mamari S, Djordjevic J, Halliday JS, Chapman RW. 2013. Improvement of serum alkaline phosphatase to <1.5 upper limit of normal predicts better outcome and reduced risk of cholangiocarcinoma in primary sclerosing cholangitis. J Hepatol, 58 (2), pp. 329-334. | Show Abstract | Read more

BACKGROUND & AIMS: Normalization of serum alkaline phosphatase (SAP) was recently shown to correlate with better prognosis in Primary Sclerosing Cholangitis (PSC). We aimed at evaluating the impact of SAP improvement to below 1.5 the upper limit of normal (ULN) on the prognosis of this cholestatic liver disease. METHODS: Oxford PSC database was screened for cases diagnosed between 1980 and 2004. Cases which met the inclusion criteria were retrospectively examined for clinical parameters, laboratory values, and clinical end points (liver decompensation, liver transplantation, and liver-related deaths including cholangiocarcinoma). Cases were followed-up to 31/12/2010. RESULTS: 139 patients were included, (87 males). Improvement of SAP to below 1.5 ULN was achieved by 55 (40%) patients in a median time of 2 years, compared to 84 (60%) who did not. 3/55 (6%) patients with SAP improvement reached an end point compared to 32/84 (38%) patients with no SAP improvement (p <0.0001). 13/84 (15%) patients with no SAP improvement developed cholangiocarcinoma compared to no cholangiocarcinoma in the group with SAP improvement (p = 0.002). The end point free survival was significantly longer in patients with SAP improvement (p <0.0001). The significance of SAP improvement as a predictor of prognosis persisted after controlling for other clinical and laboratory variables. Improvement of SAP to below 1.5 ULN was comparable to complete normalization of SAP in terms of prognosis. CONCLUSIONS: Improvement in SAP to below 1.5 ULN is associated with better outcome and reduced risk of CCA in PSC. This was comparable to the achievement of complete normalization of SAP.

Halliday J, Travis S, Chapman R. 2012. Has primary sclerosing cholangitis associated with Crohn's disease a better outcome? Reply JOURNAL OF CROHNS & COLITIS, 6 (9), pp. 957-957. | Read more

Srivastava B, Mells GF, Cordell HJ, Muriithi A, Brown M, Ellinghaus E, Franke A, UK-PSC Consortium, Karlsen TH, Sandford RN et al. 2012. Fine mapping and replication of genetic risk loci in primary sclerosing cholangitis. Scand J Gastroenterol, 47 (7), pp. 820-826. | Show Abstract | Read more

BACKGROUND AND AIMS: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by progressive inflammation and fibrosis of the bile ducts eventually leading to biliary cirrhosis. Recent genetic studies in PSC have identified associations at 2q13, 2q35, 3p21, 4q27, 13q31 and suggestive association at 10p15. The aim of this study was to further characterize and refine the genetic architecture of PSC. METHODS: We analyzed previously reported associated SNPs at four of these non-HLA loci and 59 SNPs tagging the IL-2/IL-21 (4q27) and IL2RA (10p15) loci in 992 UK PSC cases and 5162 healthy UK controls. RESULTS: The most associated SNPs identified were rs3197999 (3p21 (MST1), p = 1.9 × 10⁻⁶, OR(A vs G) = 1.28, 95% CI (1.16-1.42)); rs4147359 (10p15 (IL2RA), p = 2.6 × 10⁻⁴, OR(A vs G) = 1.20, 95% CI (1.09-1.33)) and rs12511287 (4q27 (IL-2/IL-21), p = 3.0 × 10⁻⁴, OR(A vs T) = 1.21, 95% CI (1.09-1.35)). In addition, we performed a meta-analysis for selected SNPs using published summary statistics from recent studies. We observed genome-wide significance for rs3197999 (3p21 (MST1), P (combined) = 3.8 × 10⁻¹²) and rs4147359 (10p15 (IL2RA), P (combined) = 1.5 × 10⁻⁸). CONCLUSION: We have for the first time confirmed the association of PSC with genetic variants at 10p15 (IL2RA) locus at genome-wide significance and replicated the associations at MST1 and IL-2/IL-21 loci in a large homogeneous UK population. These results strongly implicate the role of IL-2/IL2RA pathway in PSC and provide further confirmation of MST1 association.

Srivastava B, Mells GF, Cordell HJ, Muriithi A, Brown M, Ellinghaus E, Franke A, Karlsen TH, Sandford RN, Alexander GJ et al. 2012. FINE MAPPING OF THE IL-2/IL-21 AND IL2RA LOCI IN PRIMARY SCLEROSING CHOLANGITIS GUT, 61 (Suppl 2), pp. A212-A213. | Read more

Rahman M, Chapel H, Chapman RW, Collier JD. 2012. Cholangiocarcinoma complicating secondary sclerosing cholangitis from cryptosporidiosis in an adult patient with CD40 ligand deficiency: case report and review of the literature. Int Arch Allergy Immunol, 159 (2), pp. 204-208. | Show Abstract | Read more

A 43-year-old man with a hyper-immunoglobulin M syndrome due to CD40 ligand deficiency presented with insidious onset of recurrent diarrhoea and deranged liver function tests. Standard stool microscopy was repeatedly negative for cryptosporidia but immunofluorescent testing and polymerase chain reaction demonstrated the presence of infection eventually. Despite both paromomycin and nitazoxanide, he developed sclerosing cholangitis secondary to cryptosporidial infection. Whilst being considered for dual bone marrow and liver transplantation, he was found to have cholangiocarcinoma on imaging after three biopsies of a suspicious lesion. This is a rare complication of this combined immune deficiency predominantly in children that has not been reported previously in a long-term survivor with this condition.

Cited:

30

European Pubmed Central

Halliday JS, Djordjevic J, Lust M, Culver EL, Braden B, Travis SPL, Chapman RWG. 2012. A unique clinical phenotype of primary sclerosing cholangitis associated with Crohn's disease. J Crohns Colitis, 6 (2), pp. 174-181. | Show Abstract | Read more

BACKGROUND AND AIMS: A distinct clinical phenotype has been demonstrated for ulcerative colitis with concomitant primary sclerosing cholangitis (PSC). The course and behaviour of Crohn's disease (CD) with PSC has, in contrast, never been defined. We aimed to define the characteristics of patients with concomitant PSC and CD. METHODS: The Oxford PSC and IBD databases were abstracted for: PSC subtype, date of diagnosis, symptom onset, smoking history, Mayo Clinic PSC score and outcomes (hepatic failure, liver transplantation, Montréal CD classification, treatment, cancer and death). Patients with PSC/CD were matched 1:2 to two control groups: one with PSC/UC and one with isolated CD. RESULTS: 240 patients with PSC were identified; 32 (13%) with CD, 129 (54%) with co-existing UC, and 79 had PSC without IBD. For PSC/CD vs. CD controls, isolated ileal CD was less common (6% vs. 31%, p=0.03). Smoking was less common in PSC/CD (13% vs. 34%, p=0.045). No difference in the distribution of CD, or treatment required was observed. For PSC/CD vs. PSC/UC controls, more patients with PSC/CD were female (50% vs. 28%, p=0.021). 22% of PSC/CD patients had small duct PSC compared with 6% with PSC/UC, (p=0.038). Major event-free survival was prolonged in the PSC/CD group compared with PSC/UC, (Cox regression p=0.04). CONCLUSION: Unlike PSC/UC, patients with PSC/CD were as likely to be female as male, more commonly had small duct PSC and less commonly progressed to cancer, liver transplantation, or death. Compared to patients with isolated CD, patients with PSC/CD were less likely to smoke or have ileal disease.

Trivedi PJ, Chapman RW. 2012. PSC, AIH and overlap syndrome in inflammatory bowel disease. Clin Res Hepatol Gastroenterol, 36 (5), pp. 420-436. | Show Abstract | Read more

Primary sclerosing cholangitis (PSC) is a progressive, cholestatic disorder characterised by chronic inflammation and stricture formation of the biliary tree. Symptoms include pruritus, fatigue and in advanced cases ascending cholangitis, cirrhosis and end-stage hepatic failure. Patients are at an increased risk of malignancy arising from the bile ducts, gallbladder, liver and colon. The majority (>80%) of Northern European patients with PSC also have inflammatory bowel disease (IBD), usually ulcerative colitis (UC). IBD commonly presents before the onset of PSC, although the opposite can occur and the onset of both conditions can be separated by many years. The colitis associated with PSC is characteristically mild although frequently involves the whole colon. Despite the majority of patients having relatively inactive colonic disease, paradoxically the risk of colorectal malignancy is substantially increased. Patients may also develop dominant, stenotic lesions of the biliary tree which may be difficult to differentiate from cholangiocarcinoma and the coexistence of IBD may influence the development of this complication. Ursodeoxycholic acid may offer a chemoprotective effect against colorectal malignancy and improve liver biochemical indices. Evidence of any beneficial effect on histological progression of hepatobiliary disease is less clear. High doses (∼25-30 mg/kg/d) may be harmful and should be avoided. Autoimmune hepatitis (AIH) is less common in patients with IBD than PSC, however, an association has been observed. A small subgroup may have an overlap syndrome between AIH and PSC and management should be individualised dependant on liver histology, serum immunoglobulin levels, autoantibodies, degree of biochemical cholestasis and cholangiography.

de Valle MB, Rahman M, Lindkvist B, Bjornsson E, Chapman R, Kalaitzakis E. 2012. Factors That Reduce Health-Related Quality of Life in Patients With Primary Sclerosing Cholangitis CLINICAL GASTROENTEROLOGY AND HEPATOLOGY, 10 (7), pp. 769-775.e2. | Read more

Halliday J, Travis S, Chapman R. 2012. Reply to Dr. Ngu et al.'s letter Journal of Crohn's and Colitis,

Barnabas A, Chapman RW. 2012. Primary sclerosing cholangitis: is any treatment worthwhile? Curr Gastroenterol Rep, 14 (1), pp. 17-24. | Show Abstract | Read more

While many therapeutic agents have been evaluated in Primary Sclerosing Cholangitis (PSC), none have been shown in controlled trials to modify the course of disease. The bile acid ursodeoxycholic acid (UDCA) has been widely used in the treatment of PSC but its use remains controversial. It may have a role in providing chemoprotection against the development of colonic dysplasia/cancer in patients with associated inflammatory bowel disease. The exclusion of IgG4-associated cholangitis, which generally responds to immunosuppressant agents, is essential prior to deciding on an appropriate therapeutic strategy in PSC. In the absence of proven therapeutic agents, treatment strategies are usually aimed at minimizing the complications of the biliary disease. Endoscopic management of dominant strictures may improve long-term outcomes. Orthotopic liver transplantation has a good outcome in patients with end stage PSC.

Braden B, Halliday J, Aryasingha S, Sharifi Y, Checchin D, Warren BF, Kitiyakara T, Travis SPL, Chapman RW. 2012. Risk for colorectal neoplasia in patients with colonic Crohn's disease and concomitant primary sclerosing cholangitis. Clin Gastroenterol Hepatol, 10 (3), pp. 303-308. | Show Abstract | Read more

BACKGROUND & AIMS: Patients with ulcerative colitis and concomitant primary sclerosing cholangitis (PSC) have a greater risk of developing colorectal dysplasia or invasive cancer than patients with only ulcerative colitis. Therefore, annual surveillance colonoscopies are recommended. We investigated whether primary sclerosing cholangitis is also a risk factor for colorectal dysplasia or cancer in patients with Crohn's disease of the colon. METHODS: We performed a retrospective review of data from a tertiary care hospital on 166 patients with PSC and inflammatory bowel disease; 120 had concomitant ulcerative colitis, 35 had Crohn's disease, and 11 had indeterminate colitis. The controls comprised 114 patients with colonic involvement of Crohn's disease and 102 patients with ulcerative colitis. The main outcome parameter was the development of colorectal cancer or intraepithelial neoplasia. RESULTS: Only 1 patient with colonic Crohn's disease and concomitant PSC developed dysplasia in an adenomatous polyp during a median follow-up of 10 years (range, 7-16 years). In contrast, 2 cancers and 8 cases of colorectal dysplasia were diagnosed in patients with ulcerative colitis and PSC during a median follow up of 11 years (range, 8-16 years); the crude annual incidence of dysplasia or colorectal cancer was 1 in 150 patients with ulcerative colitis. Among patients with colonic Crohn's disease without PSC, 2 developed colorectal cancer during follow-up. The presence of PSC did not increase the risk of developing colorectal dysplasia in patients with Crohn's disease (P = 1.00). CONCLUSIONS: PSC does not seem to increase the risk for dysplasia of the colon in patients with colonic Crohn's disease.

Culver EL, Barnes E, Delaney D, Ellis AJ, George B, Chapman RW. 2012. A rare cause of an ileocaecal mass and lymphadenopathy. Gut, 61 (6), pp. 819-917. | Read more

Srivastava B, Muriithi A, Brown M, Alexander G, Karlsen TH, Rushbrook S, Chapman RW, Consortium PSC-UK. 2011. PHENOTYPIC DESCRIPTION OF A LARGE COHORT OF PSC PATIENTS IN THE UK GUT, 60 (Suppl 2), pp. A53-A53. | Read more

Jones D, Kowdley K, Chapman R, Burroughs A, Hirschfield G, Schramm C, Poupon R, ParEs A, Shapiro D, Pruzanski M, Grp OCAPBCS. 2011. THE FIRST NEW MONOTHERAPY THERAPEUTIC PBC STUDY IN A DECADE? AN INTERNATIONAL STUDY EVALUATING THE FARNESOID X RECEPTOR AGONIST OBETICHOLIC ACID IN PBC GUT, 60 (Suppl 2), pp. A50-A50. | Read more

Halliday JS, Chapman RW. 2011. No more pilots, a phase III trial of fibrates in primary biliary cirrhosis is long overdue! J Gastroenterol Hepatol, 26 (9), pp. 1345-1346. | Read more

Culver EL, Chapman RW. 2011. Systematic review: management options for primary sclerosing cholangitis and its variant forms - IgG4-associated cholangitis and overlap with autoimmune hepatitis. Aliment Pharmacol Ther, 33 (12), pp. 1273-1291. | Show Abstract | Read more

BACKGROUND: Primary sclerosing cholangitis (PSC) remains a challenging disease to manage. The main goals are prevention of disease progression and reduction of the increased cancer risk. AIMS: To review the management strategies for PSC and its variant forms based on published studies. METHODS: Publications were identified using Pubmed, Medline and Ovid search engines. RESULTS: Distinguishing PSC from variants, such as IgG4-associated cholangitis, and overlap with autoimmune hepatitis is essential to guide treatment decisions. There is no proven efficacious medical treatment for PSC. Ursodeoxycholic acid has been disappointing in low and moderate doses, and potentially dangerous in higher doses, although its role and optimal dose in chemoprevention requires investigation. The novel bile acid, 24-norursodeoxycholic acid, has shown promise in mouse models; human trials are in progress. Dominant strictures are optimally managed by dilatation and stenting to relieve obstructive complications, although exclusion of biliary malignancy is essential. Liver transplantation is the only proven therapy for those with advanced disease. Cholangiocarcinoma remains the most unpredictable and feared complication. In highly selected groups, neo-adjuvant chemoradiation with liver transplantation seems promising, but requires further validation. Screening for inflammatory bowel disease and surveillance for colorectal carcinoma should not be overlooked. CONCLUSIONS: The effective management of PSC and its variants is hindered by uncertainties regarding pathogenesis of disease and factors responsible for its progression. Genome studies may help to identify further targets for drug therapy and factors leading to malignant transformation.

Chapman R. 2011. Genome-wide association studies in primary sclerosing cholangitis: still more questions than answers? Hepatology, 53 (6), pp. 2133-2135. | Show Abstract | Read more

Primary sclerosing cholangitis (PSC) is a chronic bile duct disease affecting 2.4-7.5% of individuals with inflammatory bowel disease. We performed a genome-wide association analysis of 2,466,182 SNPs in 715 individuals with PSC and 2962 controls,followed by replication in 1025 PSC cases and 2174 controls. We detected non-HLA associations at rs3197999 in MST1 and rs6720394 near BCL2L11 (combined P = 1.1 x (10(-16) and P = 4.1 x 10(-8) respectively).

Rahman M, Desmond P, Mortensen N, Chapman RW. 2011. The clinical impact of primary sclerosing cholangitis in patients with an ileal pouch-anal anastomosis for ulcerative colitis. Int J Colorectal Dis, 26 (5), pp. 553-559. | Show Abstract | Read more

INTRODUCTION: Primary sclerosing cholangitis (PSC), a chronic inflammatory disease affecting the liver, is associated with ulcerative colitis (UC) in up to 75% of Northern European patients. These patients are at increased risk for the development of colorectal cancer, and the operation of choice is restorative proctocolectomy with an ileal pouch-anal anastomosis. However, complications such as pouchitis can occur, and studies have suggested that PSC is an independent risk factor for the development of pouchitis. AIM: The aim of this study is to review and discuss the available literature on the effect of PSC on clinical outcomes of patients who undergo pouch surgery for UC. The outcomes reviewed comprise the incidence of pouchitis and pouch dysplasia/cancer and quality of life, including sexual function in UC patients with or without PSC. METHODS: Pubmed/Medline and Embase searches were undertaken to obtain papers in English between 1966 and 2008. The keywords used were primary sclerosing cholangitis, ulcerative colitis, ileal pouch-anal anastomosis, quality of life, sexual function, dysplasia or cancer, pouchitis and orthotopic liver transplantation. RESULTS: The incidence of pouchitis, pouch mucosal atrophy and risk of dysplasia appear to be greater in patients with associated PSC than in UC patients without PSC. Quality of life does not appear to be worse than in patients without PSC. Sexual function has not been studied in this subgroup of patients. CONCLUSION: Pouchitis appears to be more common in the subset of UC patients with PSC, although there is clearly a need for further well-designed studies.

Culver EL, Chapman RW. 2011. Systematic review: Management options for primary sclerosing cholangitis and its variant forms - IgG4-associated cholangitis and overlap with autoimmune hepatitis Alimentary Pharmacology and Therapeutics, | Show Abstract | Read more

Background Primary sclerosing cholangitis (PSC) remains a challenging disease to manage. The main goals are prevention of disease progression and reduction of the increased cancer risk. Aims To review the management strategies for PSC and its variant forms based on published studies. Methods Publications were identified using Pubmed, Medline and Ovid search engines. Results Distinguishing PSC from variants, such as IgG4-associated cholangitis, and overlap with autoimmune hepatitis is essential to guide treatment decisions. There is no proven efficacious medical treatment for PSC. Ursodeoxycholic acid has been disappointing in low and moderate doses, and potentially dangerous in higher doses, although its role and optimal dose in chemoprevention requires investigation. The novel bile acid, 24-norursodeoxycholic acid, has shown promise in mouse models; human trials are in progress. Dominant strictures are optimally managed by dilatation and stenting to relieve obstructive complications, although exclusion of biliary malignancy is essential. Liver transplantation is the only proven therapy for those with advanced disease. Cholangiocarcinoma remains the most unpredictable and feared complication. In highly selected groups, neo-adjuvant chemoradiation with liver transplantation seems promising, but requires further validation. Screening for inflammatory bowel disease and surveillance for colorectal carcinoma should not be overlooked. Conclusion The effective management of PSC and its variants is hindered by uncertainties regarding pathogenesis of disease and factors responsible for its progression. Genome studies may help to identify further targets for drug therapy and factors leading to malignant transformation. © 2011 Blackwell Publishing Ltd.

Sadler R, Chapman RW, Simpson D, Soonawalla ZF, Waldegrave EL, Burden JM, Misbah SA, Ferry BL. 2011. The diagnostic significance of serum IgG4 levels in patients with autoimmune pancreatitis: a UK study. Eur J Gastroenterol Hepatol, 23 (2), pp. 139-145. | Show Abstract | Read more

BACKGROUND: Autoimmune pancreatitis (AIP) is recognised as an end organ manifestation of the systemic condition known as IgG4-sclerosing disease. One major characteristic of this disease, regardless of its location in the body, is the presence of high levels of circulating serum IgG, in particular IgG4 antibody. In the case of AIP, differential diagnosis from other conditions of the pancreas and biliary system, particularly cancers, can be difficult, but could result in avoiding invasive procedures and surgery. Earlier studies have evaluated the use of checking IgG4 levels in AIP diagnosis; these have produced variable results. OBJECTIVE: To further assess the diagnostic significance of serum IgG4 levels in AIP and investigate its value in differentiating from cancer of the gastroenterological system. METHODS: A retrospective study of 196 IgG4-requested samples from a 24-month period was examined. Samples were sorted into confirmed AIP, cancer or other pancreatic conditions including primary sclerosing cholangitis. RESULTS: Patients with AIP possessed a mean serum IgG level that was significantly higher compared with all other groups (mean serum IgG level=19.0 g/l+/-2.5, P<0.001). The mean serum IgG4 level of AIP patients was also significantly higher compared with all other conditions including cancer patients (mean IgG4 level=3.7 g/l+/-0.5, P<0.001). CONCLUSION: This data lends support to circulating IgG4 levels only being used as an accompanying diagnostic marker to imaging, histology and clinical presentation. In particular, this may help in differentiating between AIP and pancreatic carcinoma.

Boberg KM, Chapman RW, Hirschfield GM, Lohse AW, Manns MP, Schrumpf E, International Autoimmune Hepatitis Group. 2011. Overlap syndromes: the International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue. J Hepatol, 54 (2), pp. 374-385. | Show Abstract | Read more

Some patients present with overlapping features between disorders within the spectrum of autoimmune liver diseases (i.e. autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC)) and are commonly classified as having an "overlap syndrome". Standardized definitions of "overlap syndromes" are lacking. The aim of this report by the International Autoimmune Hepatitis Group (IAIHG) is to evaluate if there are important reasons to classify conditions with overlapping features between autoimmune liver diseases as separate diagnostic entities. Definition of diagnostic criteria for overlap conditions can only be arbitrary. The IAIHG scoring system for diagnosis of AIH has been widely used to diagnose "overlap syndromes", but was not intended for such use and has not proven to be an efficient tool for this purpose. Some patients with overlapping features between a cholestatic and hepatitic disorder appear to benefit from treatment with a combination of ursodeoxycholic acid and immunosuppressants, but this strategy is not evidence-based, and it seems unjustified to define new diagnostic groups in this regard. The IAIHG suggests that patients with autoimmune liver disease should be categorized according to the predominating feature(s) as AIH, PBC, and PSC/small duct PSC, respectively, and that those with overlapping features are not considered as being distinct diagnostic entities. The IAIHG scoring system should not be used to establish subgroups of patients. Patients with PBC and PSC with features of AIH should be considered for immunosuppressive treatment. Due to the low prevalence of such "overlap syndromes", prospective interventional therapeutic trials cannot be expected in the foreseeable future.

Culver EL, Barnes E, Delaney D, Ellis AJ, George B, Chapman RW. 2011. A rare cause of an ileocaecal mass and lymphadenopathy Gut,

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Halliday JS, Djordjevic J, Lust M, Culver EL, Braden B, Travis SPL, Chapman RWG. 2012. A unique clinical phenotype of primary sclerosing cholangitis associated with Crohn's disease JOURNAL OF CROHNS & COLITIS, 6 (2), pp. 174-181. | Read more

Ellis AJ, Chapman RW. 2010. Biliary tract: microbiological analysis of bile during cholangiography. Nat Rev Gastroenterol Hepatol, 7 (12), pp. 655-656. | Read more

Kalaitzakis E, Ambrose T, Phillips-Hughes J, Collier J, Chapman RW. 2010. Management of patients with biliary sphincter of Oddi disorder without sphincter of Oddi manometry. BMC Gastroenterol, 10 (1), pp. 124. | Show Abstract | Read more

BACKGROUND: The paucity of controlled data for the treatment of most biliary sphincter of Oddi disorder (SOD) types and the incomplete response to therapy seen in clinical practice and several trials has generated controversy as to the best course of management of these patients. In this observational study we aimed to assess the outcome of patients with biliary SOD managed without sphincter of Oddi manometry. METHODS: Fifty-nine patients with biliary SOD (14% type I, 51% type II, 35% type III) were prospectively enrolled. All patients with a dilated common bile duct were offered endoscopic retrograde cholangiopancreatography (ERCP) and sphincterotomy whereas all others were offered medical treatment alone. Patients were followed up for a median of 15 months and were assessed clinically for response to treatment. RESULTS: At follow-up 15.3% of patients reported complete symptom resolution, 59.3% improvement, 22% unchanged symptoms, and 3.4% deterioration. Fifty-one percent experienced symptom resolution/improvement on medical treatment only, 12% after sphincterotomy, and 10% after both medical treatment/sphincterotomy. Twenty percent experienced at least one recurrence of symptoms after initial response to medical and/or endoscopic treatment. Fifty ERCP procedures were performed in 24 patients with an 18% complication rate (16% post-ERCP pancreatitis). The majority of complications occurred in the first ERCP these patients had. Most complications were mild and treated conservatively. Age, gender, comorbidity, SOD type, dilated common bile duct, presence of intact gallbladder, or opiate use were not related to the effect of treatment at the end of follow-up (p > 0.05 for all). CONCLUSIONS: Patients with biliary SOD may be managed with a combination of endoscopic sphincterotomy (performed in those with dilated common bile duct) and medical therapy without manometry. The results of this approach with regards to symptomatic relief and ERCP complication rate are comparable to those previously published in the literature in cohorts of patients assessed by manometry.

Chapman R, Fevery J, Kalloo A, Nagorney DM, Boberg KM, Shneider B, Gores GJ, American Association for the Study of Liver Diseases. 2010. Diagnosis and management of primary sclerosing cholangitis. Hepatology, 51 (2), pp. 660-678. | Read more

Björnsson E, Kalaitzakis E, Neuhauser M, Enders F, Maetzel H, Chapman RW, Talwalkar J, Lindor K, Jorgensen R. 2010. Fatigue measurements in patients with primary biliary cirrhosis and the risk of mortality during follow-up. Liver Int, 30 (2), pp. 251-258. | Show Abstract | Read more

BACKGROUND: Fatigue was recently suggested to predict an increased risk of mortality in a primary biliary cirrhosis (PBC) cohort during follow-up. AIMS: To analyse the impact of fatigue on prognosis in PBC. METHODS: Patients with PBC who had earlier completed the fatigue impact scale (FIS) were identified. Prognosis in terms of death and liver transplantation (Tx) was determined. RESULTS: FIS values at baseline were analysed from 208 patients (192 females; median age 59 years (interquartile range 51-67), median follow-up of 5 years. Overall, 181 patients were alive at follow-up, 22 (12%) died and five (2.4%) underwent transplantation. FIS at baseline was 28 (12-47) and FIS at follow-up was 25 (8-64) (P<0.001; r=0.69). Among survivors, FIS at baseline was 27 (12-43), 36 (12-72) in those who died (P=0.059) and 99 (41-102) in those who underwent transplantation (P=0.0008). FIS at baseline was 44 (12-88) in patients with death and/or Tx vs. 27 (12-43) in survivors (P=0.003). Age [hazard ratio (HR) 1.1 (confidence interval (CI) 1.0-1.2)] and aspartate aminotransferase [HR 2.0 (CI 1.3-3.0)] were independently associated with decreased survival on multivariate analysis. FIS scores over 40 [HR 9.6 (CI 2.3-39.7)] and bilirubin [HR 4.8 (CI 2.8-8.2)] were independently associated with a poor outcome in patients who underwent Tx or had a liver-related death. CONCLUSIONS: Fatigue seems to change little over time in PBC. Fatigue levels were higher at baseline in those who died or underwent Tx. High fatigue levels seem to be a predictor of risk of liver-related mortality and need for transplantation over time but not a predictor of non-liver-related mortality.

Chapman RW. 2010. Primary sclerosing cholangitis: what is the role of ursodeoxycholic acid in therapy for PSC? Nat Rev Gastroenterol Hepatol, 7 (2), pp. 74-75. | Read more

Chapman RW. 2009. High-dose ursodeoxycholic acid in the treatment of primary sclerosing cholangitis: throwing the urso out with the bathwater? Hepatology, 50 (3), pp. 671-673. | Read more

Webster GJM, Pereira SP, Chapman RW. 2009. Autoimmune pancreatitis/IgG4-associated cholangitis and primary sclerosing cholangitis--overlapping or separate diseases? J Hepatol, 51 (2), pp. 398-402. | Show Abstract | Read more

Autoimmune pancreatitis is a recently described fibroinflammatory disease which is characterised by raised serum levels of IgG4 (in >70% of cases), and an IgG4-positive lymphoplasmacytic tissue infiltrate. A favourable and rapid clinical response to oral steroid therapy is often seen. Biliary involvement is common, and the term IgG4-associated cholangitis has recently been coined. The cholangiographic appearances of IgG4-associated cholangitis and primary sclerosing cholangitis can be difficult to differentiate. Moreover, raised levels of serum IgG4 have been recently found in 9% of patients with primary sclerosing cholangitis (a much higher frequency than for other gastrointestinal diseases), and those with raised levels appear to progress more rapidly to liver failure. Here we review the similarities and differences between the biliary disease in autoimmune pancreatitis and primary sclerosing cholangitis, and address the issue of disease overlap. Improvements in understanding the relationship between these conditions might lead to an enhanced understanding of the aetiopathogenesis, and improved treatment of both conditions.

Albasri A, Seth R, Jackson D, Benhasouna A, Crook S, Nateri AS, Chapman R, Ilyas M. 2009. C-terminal Tensin-like (CTEN) is an oncogene which alters cell motility possibly through repression of E-cadherin in colorectal cancer. J Pathol, 218 (1), pp. 57-65. | Show Abstract | Read more

The Tensin gene family encodes proteins thought to modulate integrin function. C-terminal Tensin-like (CTEN) is a member of the Tensin gene family which lacks the N-terminus actin-binding domain. Cten is reported to have both oncogenic and tumour-suppressor functions. We investigated the role that Cten may play in colorectal cancer (CRC). By quantitative RT-PCR CTEN is up-regulated (i.e. > two-fold increase) in 62% of cell lines and 69% of tumours compared with normal mucosa, consistent with CTEN being a possible oncogene. Stable transfection of HCT116 and SW480 (CRC cell lines with low endogenous Cten expression) with a Cten expression vector gave identical results in both cell lines. Forced Cten expression did not cause change in cell numbers, although it did confer resistance to staurosporine-induced apoptosis (p < 0.005). Cten also induced epithelial-mesenchymal transition (EMT) in tumour cells accompanied by a significant increase in both cell migration (transwell migration and cell wounding assays, p < 0.001 and p < 0.05, respectively) and cell invasion (invasion through Matrigel, p < 0.001). Given the observed EMT, we investigated the levels of E-cadherin. Cten induction was associated with a reduction in E-cadherin protein expression but not levels of E-cadherin mRNA. These data suggest that CTEN is an oncogene in CRC which stimulates EMT, cell migration and invasion and may therefore have a role in tumour invasion/spread. Furthermore, Cten induction is associated with post-transcriptional repression of E-cadherin.

Vradelis S, Kalaitzakis E, Sharifi Y, Buchel O, Keshav S, Chapman RW, Braden B. 2009. Addition of senna improves quality of colonoscopy preparation with magnesium citrate. World J Gastroenterol, 15 (14), pp. 1759-1763. | Show Abstract | Read more

AIM: To prospectively investigate the effectiveness and patient's tolerance of two low-cost bowel cleansing preparation protocols based on magnesium citrate only or the combination of magnesium citrate and senna. METHODS: A total of 342 patients who were referred for colonoscopy underwent a colon cleansing protocol with magnesium citrate alone (n = 160) or magnesium citrate and senna granules (n = 182). The colonoscopist rated the overall efficacy of colon cleansing using an established score on a 4-point scale. Patients were questioned before undergoing colonoscopy for side effects and symptoms during bowel preparation. RESULTS: The percentage of procedures rescheduled because of insufficient colon cleansing was 7% in the magnesium citrate group and 4% in the magnesium citrate/senna group (P = 0.44). Adequate visualization of the colonic mucosa was rated superior under the citramag/senna regimen (P = 0.004). Both regimens were well tolerated, and did not significantly differ in the occurrence of nausea, bloating or headache. However, abdominal cramps were observed more often under the senna protocol (29.2%) compared to the magnesium citrate only protocol (9.9%, P < 0.0003). CONCLUSION: The addition of senna to the bowel preparation protocol with magnesium citrate significantly improves the cleansing outcome.

Kalaitzakis E, Braden B, Trivedi P, Sharifi Y, Chapman R. 2009. Intraductal papillary mucinous neoplasm in chronic calcifying pancreatitis: egg or hen? World J Gastroenterol, 15 (10), pp. 1273-1275. | Show Abstract | Read more

Intraductal papillary mucinous neoplasm (IPMN) is an increasingly reported entity. Extensive pancreatic calcification is generally thought to be a sign of chronic pancreatitis, but it may occur simultaneously with IPMN leading to diagnostic difficulties. We report a case of a patient initially diagnosed with chronic calcifying pancreatitis who was later shown to have a malignant IPMN. This case illustrates potential pitfalls in the diagnosis of IPMN in the case of extensive pancreatic calcification as well as clues that may lead the clinician to suspecting the diagnosis. The possible mechanisms of the relation between pancreatic calcification and IPMN are also reviewed.

Brain O, Brown LHW, Suvarna S, Chapman R. 2009. Markedly elevated CA19-9 associated with benign ovarian cyst and ascites. BMJ Case Rep, 2009 (mar19 1), pp. bcr1120081219-bcr1120081219. | Show Abstract | Read more

A 60-year-old woman presented after a fall and was noted to have ascites. She had a history of ulcerative colitis. History and physical examination did not reveal the likely aetiology of the ascites, but a sample showed it to be a blood-stained exudate. A malignant cause appeared likely, cross-sectional imaging was arranged and tumour markers sent. CA125 was 34 IU/ml (0-30); α-fetoprotein (AFP) and carcinoembryonic antigen (CEA) were normal. However, CA19-9 was 2880 U/ml (0-31). Pancreatic carcinoma or cholangiocarcinoma were of prime concern, but a CT scan and MRI imaging were normal. At laparoscopy a benign ruptured ovarian cyst was detected, and ascites drained. CA19-9 returned to normal and the patient remains well 9 months later. This case demonstrates how tumour markers may be misleading in the context of diagnostics, and is the highest reported example of CA19-9 rise in the context of benign ascites and benign ovarian pathology.

Dinesen L, Caspary WF, Chapman RW, Dietrich CF, Sarrazin C, Braden B. 2008. 13C-methacetin-breath test compared to also noninvasive biochemical blood tests in predicting hepatic fibrosis and cirrhosis in chronic hepatitis C. Dig Liver Dis, 40 (9), pp. 743-748. | Show Abstract | Read more

BACKGROUND: The (13)C-methacetin-breath test and also several noninvasive blood tests comprising routine laboratory parameters have been proposed to predict fibrosis and cirrhosis in chronic hepatitis C. The aim of the study was to compare the diagnostic accuracy between these tests referring to hepatic histology as gold standard. METHODS: 96 patients with chronic hepatitis C virus infection underwent percutaneous liver biopsy and the (13)C-methacetin-breath test. The Fibroindex, the aspartate aminotransferase to platelet ratio index , and the aspartate aminotransferase to alanine aminotransferase ratio were used as parameters for the staging of fibrosis. The main endpoint was the area under the characteristic curves for the diagnosis of advanced fibrosis (F3-F4) and cirrhosis (F4) according to the Batts Ludwig criteria. RESULTS: ROC analysis revealed a cut-off <14.6 per thousand best with 92.6% sensitivity and 84.1% specificity for the (13)C-methacetin-breath test, for the Fibroindex >1.82 70.4% sensitivity and 91.3% specificity, for the aspartate aminotransferase to platelet ratio >1.0 a 66.7% sensitivity and 75.4% specificity, and for the aspartate aminotransferase to alanine aminotransferase ratio >1.0 63.0% sensitivity and 59.4% specificity in predicting liver cirrhosis. The areas under the curve for the breath test, the Fibroindex, aspartate aminotransferase to platelet ratio and the aspartate aminotransferase to alanine aminotransferase ratio were 0.958, 0.845, 0.799, and 0.688, respectively, when predicting cirrhosis. For identifying patients with advanced fibrosis, the areas under the curve were 0.827, 0.804, 0.779, and 0.561, respectively. Discordances between Fibroindex (21%), aspartate aminotransferase to platelet ratio (29%) or aspartate aminotransferase to alanine aminotransferase ratio (37.6%) and liver biopsy were significantly more frequent than between (13)C-breath test (11.6%) and liver biopsy (P<0.05). CONCLUSION: The (13)C-methacetin-breath test is more reliable in predicting advanced fibrosis and cirrhosis than simple biochemical parameters (aspartate aminotransferase to platelet ratio; aspartate aminotransferase to alanine aminotransferase ratio).

Chapman R, Cullen S. 2008. Etiopathogenesis of primary sclerosing cholangitis. World J Gastroenterol, 14 (21), pp. 3350-3359. | Show Abstract | Read more

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown etiology but lymphocytic portal tract infiltration is suggestive of an immune-mediated basis for this disease. Associations with inflammatory bowel disease (IBD) especially ulcerative colitis (UC), and with particular autoimmune diseases, as well as the genetic associations further suggest PSC may be an immune-mediated disease. The immunogenetics of PSC have been the subject of active research and several HLA and non-HLA associated genes have been implicated in the development of the disease. Lymphocytes derived from the inflamed gut may enter the liver via the enterohepatic circulation to cause hepatic disease. PSC may be triggered in genetically susceptible individuals by infections or toxins entering the portal circulation through a permeable colon and hence evoking an abnormal immune response.

Cullen SN, Rust C, Fleming K, Edwards C, Beuers U, Chapman RW. 2008. High dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis is safe and effective. J Hepatol, 48 (5), pp. 792-800. | Show Abstract | Read more

BACKGROUND/AIMS: Ursodeoxycholic acid (UDCA) has been shown to improve serum liver tests in primary sclerosing cholangitis (PSC), but controlled trials have shown inconsistent effects on liver histology, and did not reveal a survival benefit. This pilot, randomised dose-ranging trial attempted to determine whether further enrichment of the bile acid pool with UDCA would lead to an improvement in outcome for PSC patients. METHODS: Thirty-one patients with PSC were randomised to treatment with either 10 mg/kg (low dose), 20 mg/kg (standard dose) or 30 mg/kg (high dose) daily of UDCA for 2 years. Patients were assessed every 12 weeks and underwent liver biopsy at the beginning and end of the trial. RESULTS: Serum liver tests improved in all groups taking UDCA. Survival probability at 1-4 years as evaluated by the Mayo risk score tended to improve for all patients and significantly improved for the high dose group (p<0.02). Only 3 (10%) of all patients had a Ludwig score showing histological deterioration over the trial period. CONCLUSIONS: High dose UDCA is well-tolerated and is associated with an improvement in survival probability. A trend towards stability/improvement in histological stage was also observed. This treatment appears to be effective for PSC and deserves further evaluation.

Kitiyakara T, Chapman RW. 2008. Chemoprevention and screening in primary sclerosing cholangitis. Postgrad Med J, 84 (991), pp. 228-237. | Show Abstract | Read more

Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease that causes fibrosis of the biliary tree. Life expectancy of patients is reduced by liver failure and a high incidence of malignancy. It is closely associated with inflammatory bowel disease, particularly ulcerative colitis, which coexists in approximately three-quarters of northern European patients. Cancers include cholangiocarcinoma, gallbladder cancer, hepatocellular carcinoma, pancreatic cancer and colorectal cancer. Ursodeoxycholic acid appears to reduce the incidence of colorectal neoplasia in patients with PSC, and there is some suggestion that it may also reduce the incidence of cholangiocarcinoma. A chemoprotective benefit of 5-aminosalicylates has not been confirmed in patients with PSC with associated inflammatory bowel disease. There is no accepted screening programme for cholangiocarcinoma, but methods for detecting early disease using biochemical markers, scanning using positron emission tomography or MRI, and endoscopic procedures such as endosonography and endoscopic retrograde cholangiopancreatography are discussed. A combination of techniques is often used in an attempt to diagnose early cholangiocarcinoma. Cholecystectomy should be performed for gallbladder polyps, as many are malignant, and ultrasonography and alpha-fetoprotein testing are suggested for screening for hepatocellular carcinoma. Colorectal carcinoma screening should be performed after the diagnosis of PSC, and surveillance colonoscopy should be performed annually if there is concomitant colitis.

Maggs JR, Chapman RW. 2008. An update on primary sclerosing cholangitis. Curr Opin Gastroenterol, 24 (3), pp. 377-383. | Show Abstract | Read more

PURPOSE OF REVIEW: Primary sclerosing cholangitis is a chronic cholestatic liver disease characterized by strictures of the biliary tree complicated by cirrhosis and cholangiocarcinoma. It is immune mediated, although the precise aetiology remains unknown. RECENT FINDINGS: The research into aetiology, genetic associations, pathogenesis, epidemiology, diagnosis of cholangiocarcinoma and medical treatments are discussed. SUMMARY: Multiple gene polymorphisms and human leucocyte antigen haplotype associations with primary sclerosing cholangitis have been investigated. Common inflammatory bowel disease associated polymorphisms and ulcerative colitis associated human leucocyte antigen haplotypes are not associated with primary sclerosing cholangitis. Biliary epithelial cells may mediate their own destruction by exaggerating innate and adaptive immune responses to bacterial products in the liver. The natural history of large and small duct primary sclerosing cholangitis has been reviewed. Positron emission tomography may be a useful adjunct to current imaging modalities in the pretransplant assessment of patients to exclude cholangiocarcinoma. Ursodeoxycholic acid remains the most studied medical treatment for primary sclerosing cholangitis; pilot studies suggest a possible role for tacrolimus and silymarin, however further studies are required.

Björnsson E, Olsson R, Bergquist A, Lindgren S, Braden B, Chapman RW, Boberg KM, Angulo P. 2008. The natural history of small-duct primary sclerosing cholangitis. Gastroenterology, 134 (4), pp. 975-980. | Show Abstract | Read more

BACKGROUND & AIMS: The long-term prognosis of patients with small-duct primary sclerosing cholangitis (PSC) remains incompletely characterized. We aimed at determining the natural history and long-term outcomes of a large number of patients with small-duct PSC. METHODS: Data from 83 patients with well-characterized small-duct PSC from several medical institutions in Europe and the United States were combined. Each patient with small-duct PSC was randomly matched to 2 patients with large-duct PSC by age, gender, calendar year of diagnosis, and institution. RESULTS: The median age at diagnosis in both groups was 38 years (61% males). Nineteen (22.9%) of the 83 patients with small-duct PSC progressed to large-duct PSC in a median of 7.4 (interquartile range [IQR], 5.1-14) years. One patient with small-duct PSC who progressed to large-duct PSC was diagnosed with cholangiocarcinoma but after progression to large-duct PSC; 20 patients with large-duct PSC developed cholangiocarcinoma. Patients with small-duct PSC had a significantly longer transplantation-free survival compared with large-duct PSC patients (13 years [IQR, 10-17] vs 10 years [IQR, 6-14], respectively; hazard ratio, 3.04; 95% confidence interval: 1.82-5.06; P < .0001). Two patients with small-duct PSC who underwent liver transplantation had recurrence of small-duct PSC in the graft 9 and 13 years, respectively, after transplantation. CONCLUSIONS: Small-duct PSC is a disease of progressive potential but associated with a better long-term prognosis as compared with large-duct PSC. Small-duct PSC may recur after liver transplantation. Cholangiocarcinoma does not seem to occur in patients with small-duct PSC, unless the disease has progressed to large-duct PSC.

Worthington J, Thyssen M, Chapman G, Chapman R, Geraint M. 2008. A randomised controlled trial of a new 2 litre polyethylene glycol solution versus sodium picosulphate + magnesium citrate solution for bowel cleansing prior to colonoscopy. Curr Med Res Opin, 24 (2), pp. 481-488. | Show Abstract | Read more

BACKGROUND: A new 2 L polyethylene glycol (PEG) solution containing ascorbic acid (Asc) and electrolytes (Moviprep) has been developed for bowel cleansing. OBJECTIVES: To compare the efficacy, safety and acceptability of PEG + Asc versus sodium picosulphate + magnesium citrate in patients scheduled to undergo colonoscopy. DESIGN AND METHODS: This single blind, parallel group pilot study included 65 adult male and female patients. A blinded assessment of cleansing was made for each bowel segment by the colonoscopist and the scores determined an overall grading of bowel cleansing. Patients completed a questionnaire on the acceptability of the preparation. RESULTS: Successful bowel preparation was reported in 84.4% of patients who received PEG + Asc and 72.7% of patients who received sodium picosulphate + magnesium citrate (treatment difference +11.6, 95% CI -11.2, +34.5; p = 0.367). Patients were more likely to have a higher overall quality of bowel cleansing with PEG + Asc (p = 0.018), with specifically better cleansing in the ascending colon (p = 0.024) and caecum (p = 0.003) compared with patients who received sodium picosulphate + magnesium citrate. The adverse event profile of the two treatments was similar, with headache and gastrointestinal effects being the most commonly reported. Some patient acceptability results favoured sodium picosulphate + magnesium citrate for those patients who had experience of previous bowel preparation, but were similar for those patients who had not had a previous bowel preparation. CONCLUSIONS: PEG + Asc provided effective bowel cleansing, which was equivalent to that of sodium picosulphate + magnesium citrate in terms of grading cleansing as overall success or failure. In the proximal colon (ascending colon and caecum) PEG + Asc provided significantly better cleansing to that achieved with sodium picosulphate + magnesium citrate.

Saich R, Chapman R. 2008. Primary sclerosing cholangitis, autoimmune hepatitis and overlap syndromes in inflammatory bowel disease. World J Gastroenterol, 14 (3), pp. 331-337. | Show Abstract | Read more

Primary sclerosing cholangitis (PSC) is a chronic progressive disorder of unknown aetiology characterised by chronic inflammation and stricture formation of the biliary tree. Symptoms include itch and lethargy and in advanced cases cholangitis and end-stage liver disease, however increasing numbers of asymptomatic individuals are being identified. The disease is rare in the general population but is strongly associated with inflammatory bowel disease (IBD) affecting up to 5% of patients with ulcerative colitis, with a slightly lower prevalence (up to 3.6%) in Crohn's disease. The strength of this association means that the vast majority (> 90%) of patients with PSC also have IBD, although many may have only mild gastro-intestinal symptoms. Usually IBD presents before PSC, although vice-versa can occur and the onset of both conditions can be separated in some cases by many years. Mean age of diagnosis of PSC is in the fifth decade of life with a strong male predominance. Risk is increased in those with a family history of PSC, suggesting a genetic predisposition and the disease is almost exclusive to non-smokers. The ulcerative colitis associated with PSC is characteristically mild, runs a quiescent course, is associated with rectal sparing, more severe right sided disease, backwash ileitis and has a high risk of pouchitis post-colectomy. Most worrisome is the high risk of colorectal malignancy which necessitates routine colonoscopic surveillance. Cholangiocarcinoma is also a frequent complication of PSC with a 10%-15% lifetime risk of developing this condition. Treatment with high dose ursodeoxycholic acid offers some chemoprotective effects against colorectal malignancy and may decrease symptoms, biochemical and histological progression of liver disease. Small duct PSC patients characteristically have normal cholangiography, and liver biopsy is required for diagnosis, it appears to have a more favourable prognosis. Autoimmune Hepatitis (AIH) is also more prevalent in patients with IBD, with up to 16% of patients with AIH also having ulcerative colitis. A small subgroup of patients have a AIH-PSC overlap syndrome and the management of these patients depends on liver histology, serum IgM levels, autoantibodies, degree of biochemical cholestasis and cholangiography as some of these patients may respond to immunosuppression.

Granito A, Muratori P, Muratori L, Pappas G, Cassani F, Worthington J, Ferri S, Quarneti C, Cipriano V, de Molo C et al. 2007. Antibodies to SS-A/Ro-52kD and centromere in autoimmune liver disease: a clue to diagnosis and prognosis of primary biliary cirrhosis. Aliment Pharmacol Ther, 26 (6), pp. 831-838. | Show Abstract | Read more

BACKGROUND: Primary biliary cirrhosis (PBC) may be associated with various rheumatological disorders. AIM: To investigate the frequency and significance of 'rheumatological' antinuclear antibodies in the field of autoimmune chronic liver disease, with special regard to PBC. METHODS: We studied 105 patients with PBC, 162 autoimmune liver disease controls (type 1 and 2 autoimmune hepatitis, primary sclerosing cholangitis), 30 systemic lupus erythematosus and 50 blood donors. Sera were tested for the presence of antibodies to extractable nuclear antigens (anti-ENA) by counterimmunoelectrophoresis, enzyme-linked and immunoblot (IB) assay, and for the presence of anti-centromere antibodies (ACA) by indirect immunofluorescence on HEp-2 cells and IB. RESULTS: The overall prevalence of IB-detected anti-ENA in PBC (30%) was higher than in type 1 autoimmune hepatitis (2.5%, P < 0.0001), type 2 autoimmune hepatitis (0%, P < 0.0001) and primary sclerosing cholangitis (11.5%, P = 0.006) and lower than in systemic lupus erythematosus (53%, P = 0.03). The most frequent anti-ENA reactivity in PBC was anti-SSA/Ro-52kD (28%). ACA were detected by IB in 21% PBC patients and never in the other subjects (P < 0.0001). Anti-SS-A/Ro/52kD positive PBC patients had at the time of diagnosis a more advanced histological stage (P = 0.01) and higher serum levels of bilirubin (P = 0.01) and IgM (P = 0.03) compared with negative ones. CONCLUSIONS: In the autoimmune liver disease setting, anti-SS-A/Ro-52kD and ACA have a high specificity for PBC and can thus be of diagnostic relevance in anti-mitochondrial antibodies negative cases. If confirmed in further studies with adequate follow-up, anti-SS-A/Ro-52kD antibodies might identify PBC patients with a more advanced and active disease.

Ward SM, Fox BC, Brown PJ, Worthington J, Fox SB, Chapman RW, Fleming KA, Banham AH, Klenerman P. 2007. Quantification and localisation of FOXP3+ T lymphocytes and relation to hepatic inflammation during chronic HCV infection. J Hepatol, 47 (3), pp. 316-324. | Show Abstract | Read more

BACKGROUND/AIMS: T lymphocyte-mediated immune reactions are closely involved in the pathogenesis of HCV-induced chronic liver disease. Regulatory T cells are able to suppress HCV-specific T lymphocyte proliferation and cytokine secretion during chronic HCV infection. We wished to address to what extent regulatory T cells exist in the livers of HCV+ individuals, and what the role of such cells might be in disease progression. METHODS: We analysed the frequency and distribution of FOXP3+ cells, along with CD4, CD8 and CD20+ cells, in liver biopsies of 28 patients with chronic HCV and 14 patients with PBC, and correlated these data with histological parameters. RESULTS: A striking number of FOXP3+ cells were present in the portal tract infiltrates of HCV-infected livers. FOXP3+ cells were largely CD4+ and there was a remarkably consistent ratio of total CD4+:FOXP3+ cells in liver across a wide range of disease states of around 2:1. This differed substantially from the ratio observed in PBC (10:1, P=0.001). CONCLUSIONS: An unexpectedly high proportion of the cellular infiltrate in persistent HCV infection comprises FOXP3+ cells. The relative proportion of FOXP3+ cells remains similar in both mild and severe fibrosis. These cells are likely to play a critical role in intrahepatic immune regulation, although their overall role in disease progression remains to be determined.

Anderson EM, Phillips-Hughes J, Chapman R. 2007. Sigmoid colonic perforation and pelvic abscess complicating biliary stent migration. Abdom Imaging, 32 (3), pp. 317-319. | Show Abstract | Read more

Endoscopically placed biliary stents are a well-established procedure for the treatment of benign and malignant causes of obstructive jaundice in patients unfit for definitive surgical intervention. Stent migration has been described, though in most instances the stent will pass or remain in the bowel lumen for extended periods of time. Only a few cases of clinically significant complications of stent migration have been reported. This is the first case report of a pelvic abscess complicating stenting for choledocholithiasis. As the numbers of stenting procedures continue to increase it may be anticipated that the numbers of complications will similarly increase.

Maggs JR, Chapman RW. 2007. Sclerosing cholangitis. Curr Opin Gastroenterol, 23 (3), pp. 310-316. | Show Abstract | Read more

PURPOSE OF REVIEW: Primary sclerosing cholangitis is a chronic cholestatic liver disease characterized by strictures of the biliary tree complicated by cirrhosis and cholangiocarcinoma. It is immune mediated, although the precise aetiology remains unknown. RECENT FINDINGS: Research into etiopathogenesis and epidemiology, diagnosis of cholangiocarcinoma, associations with inflammatory bowel disease and autoimmune pancreatitis, and medical therapy are discussed. SUMMARY: Multiple gene polymorphisms associated with primary sclerosing cholangitis have been investigated. Common inflammatory bowel disease-associated polymorphisms do not confer any susceptibility to primary sclerosing cholangitis; the role of intercellular adhesion molecule-1 gene polymorphisms and CCR5 mutations remain unclear. Elevated IgG4 has been demonstrated in a subgroup of primary sclerosing cholangitis patients, which may indicate an overlap with autoimmune pancreatitis and possible responsiveness to steroids. Biliary brush cytology may assist in diagnosis of cholangiocarcinoma, although further clinical indicators are required. Animal studies suggest the superiority of 24-norursodeoxycholic acid over ursodeoxycholic acid in reducing histological disease progress; translational studies in humans are now required.

Chapman RW. 2007. Primary sclerosing cholangitis Medicine, 35 (2), pp. 83-85. | Show Abstract | Read more

Primary sclerosing cholangitis (PSC) is a chronic, cholestatic liver disease caused by diffuse inflammation and fibrosis that can involve the entire biliary tree. The progressive pathological process obliterates intrahepatic and extrahepatic bile ducts, ultimately leading to biliary cirrhosis, portal hypertension and hepatic failure. The cause is unknown but it is closely associated with inflammatory bowel disease, particularly ulcerative colitis which occurs in about 70% of cases. Approximately 5-10% of patients with total ulcerative colitis will have coexisting PSC. Clinical symptoms include fatigue, intermittent jaundice, weight loss, right upper quadrant abdominal pain and pruritus. The clinical course of PSC is variable In symptomatic patients, median survival from presentation to death or liver transplantation is about 12 years. About 75% of asymptomatic patients survive 15 years or more. Patients die in hepatic failure following deepening cholestatic jaundice. About 30% die from bile duct carcinoma, which is often aggressive. The remainder die from colonic cancer or complications of colitis. Serum biochemical tests usually indicate cholestasis; the diagnosis is established by cholangiography. PSC has no curative treatment. Medical treatment with the bile acid ursodeoxycholic acid (UDCA) probably slows progression of the disease and acts as a chemoprotective agent against colonic dysplasia. Liver transplantation is the only option in young patients with PSC and advanced liver disease; 5-year survival is 80-90% in most centres. The disease will recur in the donor liver in 30% of patients after 5 years. © 2006.

Granito A, Muratori P, Muratori L, Pappas G, Cassani F, Worthington J, Guidi M, Ferri S, DE Molo C, Lenzi M et al. 2006. Antinuclear antibodies giving the 'multiple nuclear dots' or the 'rim-like/membranous' patterns: diagnostic accuracy for primary biliary cirrhosis. Aliment Pharmacol Ther, 24 (11-12), pp. 1575-1583. | Show Abstract | Read more

BACKGROUND: Serum antinuclear antibodies giving the 'multiple nuclear dots' or the 'rim-like/membranous' patterns are frequently detected by indirect immunofluorescence on HEp-2 cells in patients with primary biliary cirrhosis. AIM: To assess the accuracy of multiple nuclear dot and rim-like/membranous antinuclear antibodies for the diagnosis of primary biliary cirrhosis. METHODS: Sera from 4371 consecutive patients referred to our laboratory were analysed under code for antinuclear antibodies testing by indirect immunofluorescence on HEp-2 cells. RESULTS: Review of the clinical records of the 4371 patients allowed identification of 101 patients with antimitochondrial antibody-positive primary biliary cirrhosis and 22 with antimitochondrial antibody-negative variant. Multiple nuclear dot and/or rim-like/membranous patterns were found in 59 (1.3%) of the 4371 patients: 31 antimitochondrial antibody-positive primary biliary cirrhosis, 17 antimitochondrial antibody-negative primary biliary cirrhosis and 11 non-primary biliary cirrhosis. The specificity for primary biliary cirrhosis of both the antinuclear antibodies pattern was 99%. Positive predictive value and likelihood ratio for a positive test were 86% (95% CI: 72.7-94) and 221 (95% CI: 91.7-544) for multiple nuclear dot, 79% (95% CI: 62.2-90.1) and 132 (95% CI: 56.8-312.7) for rim-like/membranous, respectively. CONCLUSIONS: Multiple nuclear dot and rim-like/membranous antinuclear antibodies are rare findings. Their positivity strongly suggests the diagnosis of primary biliary cirrhosis, irrespective of antimitochondrial antibody status. The high specificity for primary biliary cirrhosis makes them a useful diagnostic tool especially in antimitochondrial antibody-negative patients.

MacFaul GR, Chapman RW. 2006. Sclerosing cholangitis. Curr Opin Gastroenterol, 22 (3), pp. 288-293. | Show Abstract | Read more

PURPOSE OF REVIEW: Primary sclerosing cholangitis is a chronic cholestatic liver disease characterized by strictures of the biliary tree complicated by cirrhosis and cholangiocarcinoma. It is immune mediated although the precise etiology remains unknown. RECENT FINDINGS: Research into etiopathogenesis, epidemiology, the relationship with inflammatory bowel disease, diagnosis of cholangiocarcinoma, medical therapy, and the outcome of liver transplantation are discussed. SUMMARY: It is likely that a number of patients previously diagnosed with primary sclerosing cholangitis have autoimmune pancreatitis in association with primary sclerosing cholangitis, a syndrome with distinct clinicopathological features including steroid responsiveness. Primary sclerosing cholangitis-inflammatory bowel disease probably represents a distinct inflammatory bowel disease phenotype, which has implications for colonoscopic surveillance of these patients. CA19-9 plays no surveillance role for the early detection of cholangiocarcinoma. The best-studied drug in primary sclerosing cholangitis is ursodeoxycholic acid, which, despite a range of potentially valuable actions on the cholestatic liver, has not yet been proved to make a substantial impression on the course of the disease. Orthotopic liver transplantation remains the only established long-term treatment for primary sclerosing cholangitis.

Chapman RW. 2006. Primary sclerosing cholangitis - Foreword SEMINARS IN LIVER DISEASE, 26 (1), pp. 1-1. | Read more

Cullen SN, Chapman RW. 2006. The medical management of primary sclerosing cholangitis. Semin Liver Dis, 26 (1), pp. 52-61. | Show Abstract | Read more

Primary sclerosing cholangitis raises several challenges for the physician. These include the identification of a drug regimen that slows or reverses the progression of the disease, the effective management of the symptoms of cholestasis, and the prevention of complications of the disease, including the development of colorectal cancer. The most studied drug in PSC is ursodeoxycholic acid, which, despite a range of potentially valuable actions on the cholestatic liver, has not yet been proven to make a substantial change in the course of the disease. However, it may yet prove to be sufficiently effective in the prevention of colorectal neoplasia to be prescribable for this reason alone. Better progress has been made in identifying agents that can alleviate pruritus and prevent the progression of osteopenia.

Worthington J, Chapman R. 2006. Primary sclerosing cholangitis. Orphanet J Rare Dis, 1 (1), pp. 41. | Show Abstract | Read more

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown aetiology characterised by inflammation and fibrosis of the biliary tree. The mean age at diagnosis is 40 years and men are affected twice as often as women. There is a reported annual incidence of PSC of 0.9-1.31/100,000 and point prevalence of 8.5-13.6/100,000. The onset of PSC is usually insidious and many patients are asymptomatic at diagnosis or have mild symptoms only such as fatigue, abdominal discomfort and pruritus In late stages, splenomegaly and jaundice may be a feature. In most, the disease progresses to cirrhosis and liver failure. Cholangiocarcinoma develops in 8-30% of patients. PSC is thought to be immune mediated and is often associated with inflammatory bowel disease, especially ulcerative colitis. The disease is diagnosed on typical cholangiographic and histological findings and after exclusion of secondary sclerosing cholangitis. Median survival has been estimated to be 12 years from diagnosis in symptomatic patients. Patients who are asymptomatic at diagnosis, the majority of whom will develop progressive disease, have a survival rate greater than 70% at 16 years after diagnosis. Liver transplantation remains the only effective therapeutic option for patients with end-stage liver disease from PSC, although high dose ursodeoxycholic acid may have a beneficial effect.

MacFaul GR, Chapman RW. 2005. Sclerosing cholangitis. Curr Opin Gastroenterol, 21 (3), pp. 348-353. | Show Abstract | Read more

PURPOSE OF REVIEW: Primary sclerosing cholangitis is a chronic cholestatic liver disease characterized by strictures of the biliary tree. It is immune mediated, although the precise cause remains unknown. Recent reports have shown a higher prevalence and burden of disease than was previously suspected. RECENT FINDINGS: The research into the etiopathogenesis, epidemiology, diagnosis of cholangiocarcinoma, medical and surgical therapy, and timing and outcome of liver transplantation is discussed. SUMMARY: Genetic heterogeneity among patients with primary sclerosing cholangitis is supported, and further gene polymorphisms associated with protection against primary sclerosing cholangitis have been elucidated. Bile duct injury seems to be a multistep process. Magnetic resonance cholangiopancreatography is a cost-effective and accurate way of diagnosing primary sclerosing cholangitis in comparison with endoscopic retrograde cholangiopancreatography. Ursodeoxycholic acid may have a role as a colorectal and hepatobiliary cancer chemopreventive agent. Liver transplantation remains the only treatment in end-stage disease. The 5-year and 10-year patient and graft survival rates are comparable with those in patients without primary sclerosing cholangitis, but there is a higher rate of retransplantation for primary sclerosing cholangitis in most centers. Hepatobiliary malignancy is found in a minority of patients at transplantation, although 5-year survival rates for these patients are still promising.

Cullen SN, Chapman RW. 2005. Review article: current management of primary sclerosing cholangitis. Aliment Pharmacol Ther, 21 (8), pp. 933-948. | Show Abstract | Read more

The management of primary sclerosing cholangitis (PSC) is hindered by incomplete understanding of the pathogenesis of the disease and the lack of good prognostic models. Few large randomized controlled trials of drug therapy have been published. Best practice in the management of PSC is currently based therefore on careful interpretation of the available evidence, close observation of individual patients and clinical experience of the disease. Drug therapy is useful for alleviating symptoms. Ursodeoxycholic acid may slow progression of the disease and reduce the frequency of complications. Consensus is emerging on the issues of screening for the malignant complications of PSC and the indications for liver transplantation are becoming broader and encompassing the earliest stages of cholangiocarcinoma. In view of the rarity of the disease in the general population, large international collaborations to study PSC are necessary to provide clearer answers in areas of uncertainty, and these are now beginning to emerge.

Pushkaran B, Adams D, Chapman R, Keeling D. 2005. Activated protein C resistance acquired through liver transplantation. Blood Coagul Fibrinolysis, 16 (3), pp. 215-216. | Show Abstract | Read more

Coagulation factors are produced by the liver. It is well recognized that liver transplantation can cure haemophilia. We described a case of thrombophilia acquired due to liver transplantation from a donor with heritable thrombophilia.

Worthington J, Cullen S, Chapman R. 2005. Immunopathogenesis of primary sclerosing cholangitis. Clin Rev Allergy Immunol, 28 (2), pp. 93-103. | Show Abstract | Read more

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown etiology;however, lymphocytic portal tract infiltration is suggestive of an immune-mediated basis for PSC. Associations with inflammatory bowel disease--especially ulcerative colitis--and with other auto-immune diseases, together with genetic associations, further suggest that PSC may be an immune-mediated disease. The immunogenetics of PSC have been the subject of active research, and several human leukocyte antigen (HLA)- and non-HLA-associated genes have been implicated in the development of the disease. Lymphocytes derived from the inflamed gut may enter the liver via the enterohepatic circulation to cause hepatic disease.PSC may be triggered in genetically susceptible individuals by infections or toxins entering the portal circulation through a permeable colon and, therefore, evoking an abnormal immune response.

Björnsson E, Simren M, Olsson R, Chapman RW. 2005. Fatigue is not a specific symptom in patients with primary biliary cirrhosis. Eur J Gastroenterol Hepatol, 17 (3), pp. 351-357. | Show Abstract | Read more

BACKGROUND: Fatigue has been reported to be common in patients with primary biliary cirrhosis (PBC). Limited data exist on comparison with fatigue in the general population and comparison with patients with other chronic gastrointestinal disorders are lacking. METHOD: We enrolled 96 patients with PBC (87 females); mean age 63 (range 34-65) who completed the Fatigue Impact Scale (FIS). In comparison we included matched controls from the general population, patients with organic (OGD) and functional GI disorders (FGD). Liver function test and the latest liver biopsy were analysed and correlated with fatigue scores. RESULTS: The mean duration of PBC was 7.4 years, the mean bilirubin 13 micromol/l. Twelve per cent of patients had cirrhosis, 29% were in stage I on Ludwig's histology score and 30% and 29% were in stages II and III, respectively. The PBC patients had a median FIS total score of 29 in comparison with 38 in GP controls (P<0.05). Patients with OGD and FGD had more severe fatigue (FIS total score 67 and 59 (P<0.01 compared with PBC)). Fatigue in the PBC patients did not correlate with liver tests and histology stage. CONCLUSION: PBC patients had less severe fatigue measured with the FIS than controls from the GP and patients with OGD and FGD. This study also confirms results of other studies showing no correlation with fatigue in PBC and liver disease parameters. These results argues strongly against fatigue as a specific symptom in PBC.

Björnsson E, Simren M, Olsson R, Chapman RW. 2004. Fatigue in patients with primary sclerosing cholangitis. Scand J Gastroenterol, 39 (10), pp. 961-968. | Show Abstract | Read more

BACKGROUND: The occurrence of fatigue in primary sclerosing cholangitis (PSC), its impact on quality of life and the role of concomitant inflammatory bowel disease (IBD) and coexisting irritable bowel syndrome (IBS) is unexplored. METHODS: Ninety-three patients with PSC, associated with IBD in 80% of cases and 77 patients with IBD alone, were enrolled in the study. The patients completed the following questionnaires: the Fatigue Impact Scale (FIS), the Psychological General Well-Being Index (PGWB), the Gastrointestinal Symptom Rating Scale (GSRS), the Beck Depression Inventory (BDI) and diagnostic criteria for IBS. Questionnaire data were related to liver tests and the latest liver biopsy in the PSC patients. Two sex- and age matched controls from the general population (GP) were assigned to each PSC patient and these controls completed the FIS and the BDI. RESULTS: Total fatigue score did not differ significantly between patients with PSC and IBD alone. Median total fatigue score among GP subjects was 39 (13-72), which was higher than in PSC (19 (6-52) (P = 0.02)) and in IBD patients (19 (5-35) (P < 0.0001)). PGWB and GSRS scores did not differ between patients with PSC and IBD alone. Depression and general health (PGWB) were independent predictors for total fatigue score in PSC. No correlation was observed between fatigue in PSC and the severity of the liver disease. CONCLUSIONS: Fatigue in patients with PSC is related to depression but not to the severity of the liver disease. Both the PSC and IBD patients had lower total fatigue scores than subjects from the general population. This argues against fatigue as a specific symptom of PSC and IBD patients.

MacFaul GR, Chapman RW. 2004. Sclerosing cholangitis. Curr Opin Gastroenterol, 20 (3), pp. 275-280. | Show Abstract | Read more

PURPOSE OF REVIEW: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by strictures of the biliary tree. It is closely associated with inflammatory bowel disease, particularly ulcerative colitis, although the precise etiology remains unknown. The prevalence of PSC, with its attendant medical burdens, appears to be higher than previously estimated; consequently, increasing numbers of patients are being diagnosed and treated in secondary care. RECENT FINDINGS: Research into etiopathogenesis, epidemiology, small-duct PSC, and associations with cholangiocarcinoma and colorectal carcinoma are discussed, along with medical therapy and transplantation. SUMMARY: Small-duct PSC is a distinct clinical entity associated with a benign course and minimal risk of cholangiocarcinoma compared with large-duct PSC. The incidence of gall bladder cancer is increased in patients with PSC, and yearly ultrasonographic screening, with cholecystectomy for gall bladder polyps, is recommended. Recent pilot studies have suggested that high-dose ursodeoxycholic acid (20 mg/kg body weight) may slow liver fibrosis and cholangiographic appearances. Importantly, ursodeoxycholic acid has also been shown to reduce the incidence of colonic dysplasia and colorectal cancer in patients with PSC and ulcerative colitis. Endoscopic therapy, usually balloon dilatation, is effective for benign dominant strictures that are causing jaundice. Liver transplant remains the only treatment in end-stage disease; however, posttransplant recurrence of PSC occurs in as many as one third of patients. Colorectal cancer develops posttransplant in 5 to 10% of those with inflammatory bowel disease. Annual screening colonoscopy is recommended for all patients with PSC with coexisting inflammatory bowel disease.

Yang X, Cullen SN, Li JH, Chapman RW, Jewell DP. 2004. Susceptibility to primary sclerosing cholangitis is associated with polymorphisms of intercellular adhesion molecule-1. J Hepatol, 40 (3), pp. 375-379. | Show Abstract | Read more

BACKGROUND/AIMS: Intercellular adhesion molecule-1 (ICAM-1, CD54) gene polymorphisms have been implicated in the susceptibility to a range of inflammatory diseases, including inflammatory bowel disease (IBD). Primary sclerosing cholangitis (PSC) is an immune-mediated chronic cholestatic liver disease associated with IBD. ICAM-1 is expressed on proliferating bile ducts and interlobular bile ducts in late stage PSC and serum levels of soluble intercellular adhesion molecules are increased in PSC. The aim of this study was to analyse ICAM-1 gene polymorphisms in PSC patients. METHODS: In this study, 104 patients with PSC and 213 healthy controls were recruited from Oxfordshire Caucasians. PCR with sequence-specific primers (PCR-SSP) was used to detect both ICAM-1 biallelic polymorphisms G241R and K469E. The results were controlled for the HLA haplotypes associated with PSC. RESULTS: The E/E frequency of K469E in PSC was 12% (12/104), significantly lower than that in controls (24%, 51/213;P = 0.009; Pc = 0.02; OR, 0.41). The occurrence of the haplotype G241-E469/G241-E469 in PSC was 4% (4/104), significantly lower than the control group (13%, 28/213; P = 0.01; Pc = 0.04; OR, 0.26). There was no difference between PSC and control groups in the frequencies of the genotype R241G or in allele frequencies of K469E. CONCLUSIONS: The E469E homozygote status for ICAM-1 is associated with protection against PSC.

Cullen S, Chapman R. 2003. Primary sclerosing cholangitis. Autoimmun Rev, 2 (6), pp. 305-312. | Show Abstract | Read more

Primary sclerosing cholangitis (PSC) is a fibrosing disease of the intra- and extra-hepatic bile ducts, and is closely associated with inflammatory bowel disease. It is immune mediated, rather than being a classical autoimmune disease. A range of immune abnormalities have been demonstrated in PSC, in particular the findings of a range of autoantibodies, a portal tract infiltrate of functional T cells, a restricted T-cell receptor repertoire, and aberrant expression of HLA molecules on biliary epithelial cells. The immunogenetics of PSC is currently under study and to date 4 key HLA haplotypes associated with PSC have been developed. The trigger factor for the initiation of the immune response may be the ingress of bacteria or other toxic metabolites into the portal circulation through a diseased and permeable bowel wall.

Merryweather-Clarke AT, Cadet E, Bomford A, Capron D, Viprakasit V, Miller A, McHugh PJ, Chapman RW, Pointon JJ, Wimhurst VLC et al. 2003. Digenic inheritance of mutations in HAMP and HFE results in different types of haemochromatosis. Hum Mol Genet, 12 (17), pp. 2241-2247. | Show Abstract | Read more

Haemochromatosis (HH) is a clinically and genetically heterogeneous disease caused by inappropriate iron absorption. Most HH patients are homozygous for the C282Y mutation in the HFE gene. However, penetrance of the C282Y mutation is incomplete, and other genetic factors may well affect the HH phenotype. Ferroportin and TFR2 mutations also cause HH, and two HAMP mutations have recently been reported that causes juvenile haemochromatosis (JH) in the homozygous state. Here, we report evidence for digenic inheritance of HH. We have detected two new HAMP mutations in two different families, in which there is concordance between severity of iron overload and heterozygosity for HAMP mutations when present with the HFE C282Y mutation. In family A, the proband has a JH phenotype and is heterozygous for C282Y and a novel HAMP mutation Met50del IVS2+1(-G). This is a four nucleotide ATGG deletion which causes a frameshift. The proband's unaffected mother is also heterozygous for Met50del IVS2+1(-G), but lacks the C282Y mutation and is heterozygous for the HFE H63D mutation. Met50del IVS2+1(-G) was absent from 642 control chromosomes. In family B, a second novel, less severe HAMP mutation, G71D, was identified. This was detected in the general population at an allele frequency of 0.3%. We propose that the phenotype of C282Y heterozygotes and homozygotes may be modified by heterozygosity for mutations which disrupt the function of hepcidin in iron homeostasis, with the severity of iron overload corresponding to the severity of the HAMP mutation.

Chapman RW. 2003. To perform or not to perform liver biopsy: an alternative view. Gut, 52 (8), pp. 1227. | Read more

Chapman RW. 2003. Medical treatment of primary sclerosing cholangitis with ursodeoxycholic acid. Dig Liver Dis, 35 (5), pp. 306-308. | Read more

Björnsson E, Chapman RW. 2003. Sclerosing cholangitis. Curr Opin Gastroenterol, 19 (3), pp. 270-275. | Show Abstract | Read more

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disorder characterized by strictures and dilatations of the biliary tree. The median survival has been reported to be 12 years from diagnosis but patients diagnosed during the last decade have been shown to have longer survival of a median of 18 years. Small duct PSC seems to be an entity of its own and rarely progresses to large duct PSC and the prognosis of small duct PSC is much better than in large duct disease. Cholangiocarcinoma does not develop in patients with small duct PSC according to recently published studies. Autoantibodies binding to biliary epithelial cells have been demonstrated in sera from patients with PSC but the pathogenic role of these remains to be determined. It is suggested that inflammatory bowel disease is accelerated after orthotopic liver transplantation. MR cholangiopancreatography is increasingly used in clinical practice and has been reported to have similar diagnostic accuracy as ERCP. However, lack of standardization of this novel technology makes it unclear if it can supersede ERCP as a diagnostic tool in PSC at the present time. Better diagnostic tests to detect cholangiocarcinoma in patients with PSC are urgently needed.

Chapman RW. 2003. The management of primary sclerosing cholangitis. Curr Gastroenterol Rep, 5 (1), pp. 9-17. | Show Abstract | Read more

Primary sclerosing cholangitis (PSC) is a chronic cholestatic hepatobiliary disease that usually progresses to biliary cirrhosis and liver failure; it also predisposes to cholangiocarcinoma. The cause of PSC is unknown, although evidence suggests that the tissue damage is mediated by the immune system. There is an unexplained close association between PSC and inflammatory bowel disease, particularly in ulcerative colitis, which coexists in the majority of patients with PSC. No medical therapy has been proven to halt or reverse disease progression; however, recent preliminary evidence suggests that ursodeoxycholic acid (UDCA) in a high dose of 20 to 25 mg/kg may slow the disease process. Evidence from a pilot study suggests that the combination of UDCA and immunosuppressive therapy, such as prednisolone or azathioprine, may also increase efficacy. For patients with end-stage PSC, liver transplantation remains the only effective therapy, although there is clear evidence that PSC may recur in the liver allograft.

Björnsson E, Boberg KM, Cullen S, Fleming K, Clausen OP, Fausa O, Schrumpf E, Chapman RW. 2002. Patients with small duct primary sclerosing cholangitis have a favourable long term prognosis. Gut, 51 (5), pp. 731-735. | Show Abstract | Read more

BACKGROUND: Patients with cholestatic liver function tests and histological features of primary sclerosing cholangitis (PSC) but a normal cholangiogram are considered to have small duct PSC. The natural history of this condition is unknown. METHODS: Thirty three patients with small duct PSC were identified among patients admitted for diagnostic workup of cholestatic liver function tests in one centre in the UK (Oxford) and one centre in Norway (Oslo). A total of 260 patients with large duct PSC were compared, and prognosis in terms of death, cholangiocarcinoma, biochemical features, histological features, and symptoms analysed. RESULTS: Mean age at diagnosis was 38 years and 39 years in small duct and large duct PSC, respectively. Mean follow up was 106 months in small duct and 105 months in large duct patients. Four patients originally considered to have small duct developed large duct PSC. Two of these underwent liver transplantation during follow up. Of the remainder who did not develop large duct PSC, two patients died during follow up: one of liver failure and the other of cardiac death unrelated to her liver disease. A total of 122 (47%) large duct patients either required liver transplantation (34 patients) or died (88 patients). Small duct patients had a significantly better survival compared with large duct patients. Among small duct patients, none developed cholangiocarcinoma compared with 28 of 260 (11%) large duct patients. CONCLUSIONS: Patients with small duct PSC seem to have a good prognosis in terms of survival and development of cholangiocarcinoma. Small duct PSC progresses to large duct PSC in a small proportion of patients.

Mitchell SA, Thyssen M, Orchard TR, Jewell DP, Fleming KA, Chapman RW. 2002. Cigarette smoking, appendectomy, and tonsillectomy as risk factors for the development of primary sclerosing cholangitis: a case control study. Gut, 51 (4), pp. 567-573. | Show Abstract | Read more

BACKGROUND AND AIMS: The strong clinical association between primary sclerosing cholangitis (PSC) and ulcerative colitis (UC) suggests common factors in their pathogenesis. Smoking, previous appendectomy, and tonsillectomy have been associated with a decreased risk of developing UC. In this study, our aim was to examine these risk factors in patients with PSC with and without underlying inflammatory bowel disease (IBD). METHODS: The smoking habits and history of previous appendectomy and/or tonsillectomy of 170 patients with PSC, 41 without underlying IBD, 170 patients with UC but normal liver function tests, and 170 age and sex matched community controls were obtained by questionnaire. RESULTS: A total of 112 PSC patients (66%) had never smoked compared with 66 controls (39%). Only 12 PSC patients (7%) were current smokers versus 43 controls (25%). The resultant odds ratio of having PSC was 0.17 (95% confidence interval (CI) 0.08-0.35) among current smokers and 0.33 (95% CI 0.21-0.52) among ever (former+current) smokers. Among former smokers, the odds of having PSC were also significantly decreased (odds ratio 0.45, 95% CI 0.26-0.73; p<0.05). In the subgroup of PSC patients without IBD, only 5% were current smokers versus 26% of matched controls, and never smokers were overrepresented (68% v 37%). The rate of previous appendectomy was similar in all three study groups (14%, 12%, and 13%) but the frequency of tonsillectomy was reduced in the PSC group (21% v 31%; p=0.05). CONCLUSION: PSC, like UC, is a disease of non-smokers as the odds of having PSC was significantly decreased among current and former smokers. The association between non-smoking and PSC was independent of whether the PSC patient had underlying IBD. Previous tonsillectomy but not appendectomy may also be associated with a decreased risk of PSC but this warrants further study.

Boberg KM, Bergquist A, Mitchell S, Pares A, Rosina F, Broomé U, Chapman R, Fausa O, Egeland T, Rocca G, Schrumpf E. 2002. Cholangiocarcinoma in primary sclerosing cholangitis: risk factors and clinical presentation. Scand J Gastroenterol, 37 (10), pp. 1205-1211. | Show Abstract | Read more

BACKGROUND: Primary sclerosing cholangitis (PSC) confers a high risk of cholangiocarcinoma (CC) development. Since patients at risk of CC may be selected for early liver transplantation, it is a challenge to identify any predisposing factors. We compared the presentation and natural history of a large number of PSC patients with and without later CC development to identify features associated with risk of CC. METHODS: Clinical and laboratory data from presentation and follow-up were collected from 394 PSC patients from five European countries. The cohort included 48 (12.2%) patients with CC. RESULTS: CC was diagnosed within the first year after diagnosis of PSC in 24 (50%) cases and in 13 (27%) patients at intended liver transplantation. Jaundice, pruritus, abdominal pain and fatigue were significantly more frequent at diagnosis of PSC in the group that developed CC, but not after exclusion of cases diagnosed within the first year. Inflammatory bowel disease was diagnosed at least 1 year before PSC more often among patients with CC development than among those without (90% and 65%, respectively: P = 0.001). The duration of inflammatory bowel disease before diagnosis of PSC was significantly longer in patients who developed CC than in the remaining group (17.4 years and 9.0 years, respectively: P=0.009 in multivariate analysis). CONCLUSIONS: A high proportion of CC cases is diagnosed within the first year after diagnosis of PSC. A long history of inflammatory bowel disease is a risk factor for CC development.

Chapman RW. 2002. To perform or not to perform liver biopsy-that is the question. Gut, 51 (1), pp. 9-10. | Read more

Mitchell SA, Mee AS, Smith GD, Palmer KR, Chapman RW. 2002. Alverine citrate fails to relieve the symptoms of irritable bowel syndrome: results of a double-blind, randomized, placebo-controlled trial. Aliment Pharmacol Ther, 16 (6), pp. 1187-1195. | Show Abstract | Read more

BACKGROUND: Alverine citrate has been used in the treatment of irritable bowel syndrome for many years. AIMS: To compare the efficacy and safety of a new formulation of alverine citrate, a 120-mg capsule, with placebo given three times daily for 12 weeks. METHODS: One hundred and seven patients with irritable bowel syndrome were entered into this three-centre, double-blind, randomized, placebo-controlled, parallel group trial. The primary end-point was relief of abdominal pain indicated by improvement in the scores for severity and frequency. Secondary efficacy variables included scores for other clinical symptoms and for overall well-being. RESULTS: The severity and frequency of abdominal pain improved in 66% and 68% of patients treated with alverine citrate vs. 58% and 69% of the placebo group, but these differences were not significant. The mean percentage reduction in the scores for abdominal pain from baseline to the final assessment, although greater in the alverine citrate group (43.7%) compared with the placebo group (33.3%), was not statistically significant. CONCLUSIONS: Alverine citrate is no better than placebo at relieving the symptoms of irritable bowel syndrome. Future trials should be designed to take into account the high and persistent placebo response seen in this condition.

Chapman RW. 2002. Small duct primary sclerosing cholangitis. J Hepatol, 36 (5), pp. 692-694. | Read more

Cullen SN, Jewell DP, Chapman RW. 2002. Susceptibility to primary sclerosing cholangitis is associated with a polymorphism of the MMP-9 (gelatinase B) gene GUT, 50 pp. A30-A31.

Cullen SN, Ahmad T, Chapman RW, Jewell DP. 2002. No association between Nod2 polymorphisms and susceptibility to, or progression of, primary sclerosing cholangitis GUT, 50 pp. A119-A119.

Boberg KM, Rocca G, Egeland T, Bergquist A, Broomé U, Caballeria L, Chapman R, Hultcrantz R, Mitchell S, Pares A et al. 2002. Time-dependent Cox regression model is superior in prediction of prognosis in primary sclerosing cholangitis. Hepatology, 35 (3), pp. 652-657. | Show Abstract | Read more

More precise prognostic models are needed for prediction of survival in patients with primary sclerosing cholangitis (PSC), particularly for the selection of candidates for liver transplantation. The aim of this study was to develop a time-dependent prognostic model for the calculation of updated short-term survival probability in PSC. Consecutive clinical and laboratory follow-up data from the time of diagnosis were collected from the files of 330 PSC patients from 5 European centers, followed for a median of 8.4 years since diagnosis. Time-fixed and time-dependent Cox regression analyses, as well as the additive regression model, were applied. The reliability of the models was tested by a cross-validation procedure. Bilirubin (on a logarithmic scale), albumin, and age at diagnosis of PSC were identified as independent prognostic factors in multivariate analysis of both the time-fixed and the time-dependent Cox regression models. The importance of bilirubin was more pronounced in the time-dependent model (hazard ratio [HR], 2.84) than in the time-fixed analysis (hazard ratio, 1.51). The additive regression model indicated that once the patients survive beyond the first 5 years, the impact on prognosis of albumin at diagnosis ceases. The time-dependent prognostic model was superior to the time-fixed variant in assigning low 1-year survival probabilities to patients that actually survived less than 1 year. In conclusion, a time-dependent Cox regression model has the potential to estimate a more precise short-term prognosis in PSC compared with the traditional time-fixed models.

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28

Scopus

Mitchell SA, Mee AS, Smith GD, Palmer KR, Chapman RW. 2002. Alverine citrate fails to relieve the symptoms of irritable bowel syndrome: Results of a double-blind, randomized, placebo-controlled trial Alimentary Pharmacology and Therapeutics, 16 (6), pp. 1187-1195. | Show Abstract | Read more

Background: Alverine citrate has been used in the treatment of irritable bowel syndrome for many years. Aims: To compare the efficacy and safety of a new formulation of alverine citrate, a 120-mg capsule, with placebo given three times daily for 12 weeks. Methods: One hundred and seven patients with irritable bowel syndrome were entered into this three-centre, double-blind, randomized, placebo-controlled, parallel group trial. The primary end-point was relief of abdominal pain indicated by improvement in the scores for severity and frequency. Secondary efficacy variables included scores for other clinical symptoms and for overall well-being. Results: The severity and frequency of abdominal pain improved in 66% and 68% of patients treated with alverine citrate vs. 58% and 69% of the placebo group, but these differences were not significant. The mean percentage reduction in the scores for abdominal pain from baseline to the final assessment, although greater in the alverine citrate group (43.7%) compared with the placebo group (33.3%), was not statistically significant. Conclusions: Alverine citrate is no better than placebo at relieving the symptoms of irritable bowel syndrome. Future trials should be designed to take into account the high and persistent placebo response seen in this condition.

Saich R, Chapman R. 2002. What's new in … Liver disorders: part 2 Medicine, 30 (11), pp. 1-3. | Show Abstract | Read more

The worldwide morbidity and mortality from viral hepatitis remains a huge health problem. Treatment of viral hepatitis has been stimulated by the development of effective new drugs for both hepatitis B and C. This overview covers some of the most recent developments in hepatology. © 2006 Elsevier Ltd.

Saich R, Chapman R. 2002. What's new in … Liver disorders Medicine, 30 (11), pp. 1-4. | Show Abstract | Read more

The new millennium has already proved to be an exciting time in hepatobiliary disease. In the developed world, the epidemic of obesity leading to metabolic syndrome has aroused academic and commercial interest in non-alcoholic fatty liver disease (NAFLD). This update covers some of the most recent developments in hepatology. © 2006 Elsevier Ltd.

Boberg KM, Bergquist A, Mitchell S, Pares A, Rosina F, Broome U, Chapman R, Fausa O, Rocca G, Schrumpf E. 2001. Cholangiocarcinoma in primary sclerosing cholangitis is associated with long-standing inflammatory bowel disease. A long-term follow-up of 394 primary sclerosing cholangitis patients. HEPATOLOGY, 34 (4), pp. 355A-355A.

Bjornsson E, Boberg KM, Schrumpf E, Fleming K, Chapman R. 2001. Patients with small duct primary sclerosing cholangitis have favorable long term prognosis. HEPATOLOGY, 34 (4), pp. 365A-365A.

Boberg KM, Spurkland A, Rocca G, Egeland T, Saarinen S, Mitchell S, Broomé U, Chapman R, Olerup O, Pares A et al. 2001. The HLA-DR3,DQ2 heterozygous genotype is associated with an accelerated progression of primary sclerosing cholangitis. Scand J Gastroenterol, 36 (8), pp. 886-890. | Show Abstract | Read more

BACKGROUND: An improvement of prognostic models in primary sclerosing cholangitis (PSC) is needed. In particular, inclusion of prognostic markers that are independent of the disease stage would be advantageous. We investigated whether HLA class II genes associated with PSC are also related to disease progression. METHODS: The study included 265 PSC patients from five European countries with a median follow-up of 9.1 years. The end-points were death (n = 38) or liver transplantation (n = 52). Thirty patients developed cholangiocarcinoma during follow-up. RESULTS: The DRB1*03,DQA1*0501, DQB1*02 (i.e. DR3,DQ2) heterozygous genotype was associated with an increased risk of death or liver transplantation (hazard ratio = 1.63; 95% confidence interval (CI) = 1.06-2.52). The presence of a DQ6 encoding haplotype (DQB1*0603 or DQB1*0602) in DR3,DQ2 negative individuals was associated with a reduced risk of death or liver transplantation (hazard ratio = 0.57; 95% CI = 0.36-0.88). There was a trend towards an increased risk of developing cholangiocarcinoma among DR4,DQ8 positive patients, but this did not reach significance (odds ratio = 2.27; 95% CI = 0.78-6.62). CONCLUSION: The DR3,DQ2 heterozygous genotype is associated with a more rapid progression of PSC, whereas HLA-DQ6 is associated with a retarded disease progression. It is possible that the DR4,DQ8 haplotype is related to cholangiocarcinoma development.

Cullen S, Chapman R. 2001. Aetiopathogenesis of primary sclerosing cholangitis. Best Pract Res Clin Gastroenterol, 15 (4), pp. 577-589. | Show Abstract | Read more

The aetiology and pathogenesis of PSC have not yet been clearly defined. The hypothesis that PSC is an immune mediated disease is supported by associations with HLA haplotypes, the presence of autoantibodies, increased levels of total serum immunoglobulins and the association with other autoimmune diseases. PSC does not, however, have many of the characteristics of classical autoimmunity, particularly the usual female preponderance of disease and lack of a good response to immunosuppression. Non-immune mechanisms such as bacterial infection, ischaemia and toxicity are also clearly important in the development of the disease and these factors may trigger peribiliary inflammation and cytokine-induced hepatic fibrosis. PSC may be triggered in genetically susceptible individuals by toxic or infectious agents gaining access to the liver via a diseased and permeable colon.

Sandborn WJ, Loftus EV, Colombel JF, Fleming KA, Seibold F, Homburger HA, Sendid B, Chapman RW, Tremaine WJ, Kaul DK et al. 2001. Evaluation of serologic disease markers in a population-based cohort of patients with ulcerative colitis and Crohn's disease. Inflamm Bowel Dis, 7 (3), pp. 192-201. | Show Abstract | Read more

BACKGROUND: The sensitivity of assays for antineutrophil cytoplasmic antibody (ANCA), anti-Saccharomyces cerevisiae antibody (ASCA), and antipancreatic antibody (PAB) in different laboratories is unknown. Likewise, the sensitivity and diagnostic usefulness of these assays in patients with inflammatory bowel disease (IBD) in the community is unknown. METHODS: An incidence cohort of 290 patients with IBD were offered participation in the study. Blood was obtained from 162 patients (56%) (83 with ulcerative colitis, 79 with Crohn's disease) who agreed to participate. ANCA was determined in five laboratories. ASCA in two laboratories, and PAB in one laboratory. RESULTS: In ulcerative colitis, the sensitivity of ANCA determined in five laboratories varied widely, ranging from 0-63%. In Crohn's disease, the sensitivity of ASCA determined in two laboratories did not vary significantly, ranging from 39-44%; and the sensitivity of PAB determined in one laboratory was 15%. The optimal diagnostic usefulness was obtained from one laboratory where the positive predictive values of a positive ANCA assay combined with a negative ASCA assay for ulcerative colitis, and a negative ANCA combined with a positive ASCA for Crohn's disease, were 75% and 86%, respectively. CONCLUSIONS: In patients with IBD, the sensitivity of ANCA varied widely in different laboratories, whereas the prevalence of ASCA was similar. The positive predictive values of the ANCA assay combined with the ASCA assay for ulcerative colitis and Crohn's disease are high enough to be clinically useful.

Satsangi J, Chapman RW, Haldar N, Donaldson P, Mitchell S, Simmons J, Norris S, Marshall SE, Bell JI, Jewell DP, Welsh KI. 2001. A functional polymorphism of the stromelysin gene (MMP-3) influences susceptibility to primary sclerosing cholangitis. Gastroenterology, 121 (1), pp. 124-130. | Show Abstract | Read more

BACKGROUND AND AIMS: We have investigated the influence of a biallelic polymorphism of the promoter region of stromelysin (matrix metalloproteinase 3) on susceptibility to primary sclerosing cholangitis (PSC). The 5A allele is associated with increased transcription, compared with wild-type (6A). METHODS: An allelic association study was performed: in stage 1, 52 PSC patients (43 with inflammatory bowel disease [IBD]) and 99 healthy subjects (HS) were genotyped. In stage 2, 59 PSC patients (49 IBD), 84 patients with uncomplicated ulcerative colitis, and 72 HS were genotyped. RESULTS: In stage 1, 5A carriage rate (90.4% vs. 72.7%; P = 0.012) and 5A allelic frequency (65.4% vs. 48.5%; P = 0.005) were increased, and 6A homozygosity was reduced in PSC (9.6% vs. 27.3%; P = 0.012). In stage 2, 5A allelic carriage was increased in PSC (93.2% vs. 76.4% in HS; P = 0.0092) and 6A homozygosity was reduced (6.8% vs. 23.8% in HS; P = 0.0092). Portal hypertension was associated with 5A homozygosity in PSC (P = 0.035; odds ratio [OR], 3.88). In the combined data set, 5A allelic frequencies (63.5% vs. 49.4%; P = 0.001; OR, 1.78) and 5A carriage rates (91.9% vs. 74.2%; P = 0.0002; OR, 3.92) were increased, and 6A homozygosity was reduced in PSC (8.1% vs. 25.7%; P = 0.0002; OR, 0.25). Overall, portal hypertension was associated with 5A homozygosity (P = 0.0192; OR, 3.12). CONCLUSIONS: Stromelysin polymorphism may influence susceptibility and disease progression in PSC.

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European Pubmed Central

Chapel HM, Christie JM, Peach V, Chapman RW. 2001. Five-year follow-up of patients with primary antibody deficiencies following an outbreak of acute hepatitis C. Clin Immunol, 99 (3), pp. 320-324. | Show Abstract | Read more

This report is the 5-year follow-up of those 25 UK patients with primary antibody deficiencies infected with hepatitis C virus (HCV), type 1a, from one batch of contaminated anti-HCV-screened intravenous immunoglobulin in 1993-1994. Of these patients, who were reported previously (1, 2), 2 cleared HCV spontaneously, 18 received early interferon-alpha (IFN) treatment for 6 months, and 5 declined treatment or treatment was contraindicated. The clinical course of this cohort was followed prospectively using serial standardized questionnaires. Seven patients (54% of those who had completed therapy) had a sustained response (normal transaminase levels, negative serum HCV RNA) for 5 years posttreatment. Eight patients died: 3 from decompensated cirrhosis, 2 from pneumonia but with evidence of liver failure, and 3 from unrelated causes. One further patient developed decompensated cirrhosis but was successfully transplanted. Seven patients remain chronically infected; only 1 patient is symptomatic but 1 further patient has evidence of progressive fibrosis on liver histology. In conclusion, within 5 years, rapid end-stage HCV liver disease has been seen in 6/25 (24%) patients. Seven patients, (54% of those fully treated) remain well after treatment, making 9/25 (36% of the cohort) clear of virus after 5 years. Those who completed early treatment with IFN had a relatively high sustained response rate compared to previous studies in both immunodeficient and immunocompetent patients.

Norris S, Kondeatis E, Collins R, Satsangi J, Clare M, Chapman R, Stephens H, Harrison P, Vaughan R, Donaldson P. 2001. Mapping MHC-encoded susceptibility and resistance in primary sclerosing cholangitis: the role of MICA polymorphism. Gastroenterology, 120 (6), pp. 1475-1482. | Show Abstract | Read more

BACKGROUND & AIMS: Recent studies suggest that major histocompatibility complex-encoded susceptibility to primary sclerosing cholangitis (PSC) maps to the HLA B-TNFA region on chromosome 6p21.3. METHODS: The present study uses a standard polymerase chain reaction protocol to investigate the 16 common alleles of the MICA locus as candidates in 2 patient populations (King's College Hospital, London, and John Radcliffe Hospital, Oxford). RESULTS: The MICA*002 allele was found in 4 of 62 (6.4%) patients and none of 50 patients vs. 41 of 118 (35%) controls (pc = 0.00018, odds ratio [OR] = 0.12, and P = 0.0000016, OR = 0.0, respectively). Overall, the MICA*008 allele was more common in PSC (gene frequency 66% vs. 48% of controls, P = 0.0023, OR = 2.11). However, unlike MICA*002 in which the difference was a result of the absence of MICA*002 heterozygotes, the MICA*008 association may be caused by an increased frequency of MICA*008 homozygosity in patients (58% vs. 22%, pc = 0.000015, OR = 5.01 and 58% vs. 22%, P = 0.0000056, OR = 4.51, respectively). Though MICA*008 is found on the ancestral 8.1 haplotype, stratification analysis indicates that this association is independent of B8 and other HLA haplotypes associated with PSC. CONCLUSIONS: The MICA*002 allele has a strong dominant effect in reducing the risk of PSC, whereas the increased risk of disease associated with MICA*008 may be a recessive effect requiring 2 copies of the MICA*008 allele.

Harcourt G, Hellier S, Bunce M, Satsangi J, Collier J, Chapman R, Phillips R, Klenerman P. 2001. Effect of HLA class II genotype on T helper lymphocyte responses and viral control in hepatitis C virus infection. J Viral Hepat, 8 (3), pp. 174-179. | Show Abstract | Read more

Hepatitis C virus (HCV) infection is very common worldwide, but has a broad range of outcomes. A minority of patients are able to clear infection spontaneously, and this is thought to be due to the emergence and maintenance of effective cell-mediated immunity, particularly CD4+ T lymphocyte responses. Furthermore, genetic studies have indicated that HLA class II genotype strongly influences the outcome of infection. We have therefore investigated the influence of the protective HLA class II haplotype (DQB1*0301, which is in tight linkage disequilibrium with DRB1*1101) on the CD4+ T lymphocyte responses to HCV. We observe a strong association between this genotype and maintenance of a multispecific CD4+ T helper response. The effect on T helper responses was also maintained after combination interferon-alpha/ribavirin therapy, although the latter influenced the pattern of viral antigens to which patients responded. This is the first disease in which an association of HLA genotype with clinical outcome has been linked to an alteration of the immunological phenotype. The selection of protective peptides in those with the favourable HLA class II genotype may point in the direction of suitable vaccine candidates.

Gow PJ, Fleming KA, Chapman RW. 2001. Primary sclerosing cholangitis associated with rheumatoid arthritis and HLA DR4: is the association a marker of patients with progressive liver disease? J Hepatol, 34 (4), pp. 631-635. | Show Abstract | Read more

In four cases we describe the unique association of primary sclerosing cholangitis (PSC) and rheumatoid arthritis (RA). In three of the cases the liver disease was unusually progressive, proceeding to cirrhosis in 14, 18 and 48 months from diagnosis. The three cases with progressive liver disease and ulcerative colitis were all HLA type DR4. The fourth patient also suffered from coeliac disease in addition to PSC and RA and has remained asymptomatic over 7 years of follow-up. RA in association with PSC may serve as a clinical marker of patients at high risk of progression to cirrhosis who need to be kept under particularly close observation. In addition, PSC needs to be considered in the differential diagnosis of all patients with RA and cholestatic liver function tests. This is especially important given the link between PSC and an increased risk of colonic carcinoma, and thus the need for surveillance colonoscopy.

Sayer J, Cullen S, Rees M, Long R, Chapman R. 2001. Iron deficiency anaemia in pre-menopausal women GUT, 48 pp. A92-A92.

Jayaram H, Satsangi J, Chapman RW. 2001. Increased colorectal neoplasia in chronic ulcerative colitis complicated by primary sclerosing cholangitis: fact or fiction? Gut, 48 (3), pp. 430-434. | Show Abstract | Read more

It is well accepted that patients with ulcerative colitis (UC) are at increased risk of developing colorectal carcinoma. Since 1992, several studies have examined the hypothesis that patients with concomitant primary sclerosing cholangitis (PSC) are at significantly increased risk of developing colorectal cancer or dysplasia. The size, design, end points, and populations involved in these studies have varied but critical review suggests that colorectal cancer is more common in the setting of PSC. Although the data do not allow exact quantification of the increased relative risk, there are nevertheless implications, both for understanding disease pathogenesis and for clinical practice.

Mitchell SA, Mee AS, Palmer KR, Chapman RW. 2001. Alverine citrate (Spasmonal) fails to relieve the symptoms of irritable bowel syndrome: Results of a double blind, randomised placebo controlled trial GUT, 48 pp. A46-A46.

Collier J, Chapman R. 2001. Combination therapy with interferon-alpha and ribavirin for hepatitis C: practical treatment issues. BioDrugs, 15 (4), pp. 225-238. | Show Abstract | Read more

Combination therapy with ribavirin and interferon (IFN)-alpha for 6 to 12 months is currently the treatment of choice for chronic hepatitis C infection. The overall sustained response rate to treatment, defined as loss of hepatitis C virus (HCV) from serum 6 months after completion of treatment, is 40%. The indications for treatment are serum HCV RNA positivity, abnormal serum transaminases and the presence of portal fibrosis and/or moderate/severe inflammation. Response rates are lower in genotype 1 than in genotype 2 or 3 and in the presence of a high viral load. Anaemia is the most common adverse event and is due to ribavirin; neuropsychiatric adverse effects due to IFNalpha lead to premature cessation of therapy in 10 to 20% of patients. The current recommended dose of interferon is 3MU given subcutaneously 3 times a week. However, it is likely that longer-acting pegylated interferons, which may be more effective and can be administered once weekly, will in the future replace currently used IFNalpha.

Mitchell SA, Bansi DS, Hunt N, Von Bergmann K, Fleming KA, Chapman RW. 2001. A preliminary trial of high-dose ursodeoxycholic acid in primary sclerosing cholangitis. Gastroenterology, 121 (4), pp. 900-907. | Show Abstract | Read more

BACKGROUND & AIMS: Ursodeoxycholic acid (UDCA) is used for the treatment of cholestatic liver diseases including primary biliary cirrhosis (PBC) for which it has a positive effect on laboratory values, may delay the development of liver failure and prolong the transplant-free disease period. Standard doses of UDCA (8-15 mg/kg daily) have been shown to be ineffective in the treatment of primary sclerosing cholangitis (PSC). We report on the findings (clinical, biochemical, histological, and cholangiographic) and side effects of a 2-year double-blind placebo-controlled preliminary study of high-dose UDCA in PSC patients. METHODS: Twenty-six patients with PSC were randomized to high-dose (20 mg/kg daily) UDCA or placebo. Cholangiography and liver biopsy were performed at entry and after 2 years. Symptoms, clinical signs, and liver biochemical tests were recorded at 3 monthly intervals. RESULTS: High-dose UDCA did not influence symptoms, but there was a significant improvement in liver biochemistry (serum alkaline phosphatase, P = 0.03; gamma-glutamyl transferase, P = 0.01) and a significant reduction in progression in cholangiographic appearances (P = 0.015) and liver fibrosis as assessed by disease staging (P = 0.05). In the treatment group, a significant increase in total bile acids and saturation with UDCA >70% confirmed patient compliance. No significant side effects were reported. CONCLUSIONS: High-dose UDCA may be of clinical benefit in PSC, but trials with a larger number of participants and of longer duration are required to establish whether the effect of high-dose UDCA on liver biochemistry, histology, and cholangiography in patients with PSC is translated into improved long-term survival.

Martins EB, Chapman RW. 2001. Sclerosing cholangitis. Curr Opin Gastroenterol, 17 (5), pp. 458-462. | Show Abstract | Read more

Primary sclerosing cholangitis is a chronic cholestatic disease that may have an autoimmune basis. Most patients have a circulating antineutrophil cytoplasmic antibody that appears to be targeted against a 50-kD nuclear envelope protein. The clinical applications of this antibody have not yet been defined. Other autoantibodies directed against antigens, such as cathepsin G, elastase, and anticardiolipin, may also be detected in some patients. It is suggested that primary sclerosing cholangitis may have a bacterial cause. Helicobacter gene sequences have been detected in liver tissues in primary sclerosing cholangitis. The role of Helicobacter spp and other bacteria in the etiopathogenesis of primary sclerosing cholangitis remains to be determined. Primary sclerosing cholangitis may overlap with autoimmune hepatitis in some cases, although the real prevalence of this association remains to be determined. Many prognostic models have been created, but they lack cross-validation, and their clinical usefulness remains limited. Endoscopic retrograde cholangiography remains the gold standard for diagnosis, but magnetic resonance imaging may be a viable alternative in many cases. Clinical trials with cladibrine, pentoxifylline, and budesonide have failed to demonstrate benefits. Orthotopic liver transplantation remains the only effective treatment.

Gow PJ, Peacock SE, Chapman RW. 2001. Wilson's disease presenting with rapidly progressive visual loss: another neurologic manifestation of Wilson's disease? J Gastroenterol Hepatol, 16 (6), pp. 699-701. | Show Abstract | Read more

Wilson's disease (WD) is a rare autosomal recessive disorder of copper metabolism resulting in copper-induced tissue damage that primarily involves the liver and central nervous system. The neurologic manifestations of WD almost universally involve a derangement of basal ganglia function or psychiatric disturbance. We report the case of a 46-year-old man presenting with end-stage liver disease caused by WD who had associated rapidly progressive optic neuropathy. We also discuss the possible association between the two conditions.

Mitchell SA, Grove J, Spurkland A, Boberg KM, Fleming KA, Day CP, Schrumpf E, Chapman RW, European Study Group of Primary Sclerosing Cholangitis. 2001. Association of the tumour necrosis factor alpha -308 but not the interleukin 10 -627 promoter polymorphism with genetic susceptibility to primary sclerosing cholangitis. Gut, 49 (2), pp. 288-294. | Show Abstract | Read more

BACKGROUND AND AIMS: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown aetiology. Abnormalities in immune regulation and genetic associations suggest that PSC is an immune mediated disease. Several polymorphisms within the tumour necrosis factor alpha (TNF-alpha) and interleukin 10 (IL-10) promoter genes have been described which influence expression of these cytokines. This study examines the possible association between polymorphisms at the -308 and -627 positions in the TNF-alpha and IL-10 promoter genes, respectively, and susceptibility to PSC. METHODS: TNF-alpha -308 genotypes were studied by polymerase chain reaction (PCR) in 160 PSC patients from Norway and the UK compared with 145 ethnically matched controls. IL-10 -627 genotypes were studied by PCR in 90 PSC patients compared with 84 ethnically matched controls. RESULTS: A total of 16% of Norwegian PSC patients and 12% of British PSC patients were homozygous for the TNF2 allele compared with 3% and 6% of respective controls. The TNF2 allele was present in 60% of PSC patients versus 30% of controls (OR(combined data)=3.2 (95% confidence intervals (CI) 1.8--4.5); p(corr)=10(-5)). The association between the TNF2 allele and susceptibility to PSC was independent of the presence of concurrent inflammatory bowel disease (IBD) in the PSC patients; 61% of PSC patients without IBD had TNF2 compared with 30% of controls (OR(combined data)=3.2 (95% CI 1.2--9.0); p(corr)=0.006 ). There was no difference in the -627 IL-10 polymorphism distributions between patients and controls in either population. The increase in TNF2 allele in PSC patients only occurs in the presence of DRB1*0301 (DR3) and B8. In the combined population data, DRB1*0301 showed a stronger association with susceptibility to PSC than both the TNF2 and B8 alleles (OR(combined data)=3.8, p(corr)=10(-6) v OR(combined data)=3.2, p(corr)=10(-5) v OR(combined data )=3.41, p(corr)=10(-4), respectively). CONCLUSIONS: This study identified a significant association between possession of the TNF2 allele, a G-->A substitution at position -308 in the TNF-alpha promoter, and susceptibility to PSC. This association was secondary to the association of PSC with the A1-B8-DRB1*0301-DQA1*0501-DQB1*0201 haplotype. No association was found between the IL-10 -627 promoter polymorphism and PSC.

Gow PJ, Chapman RW. 2001. Modern management of oesophageal varices. Postgrad Med J, 77 (904), pp. 75-81. | Show Abstract | Read more

Haemorrhage from oesophageal varices is a life threatening emergency with a mortality rate in the order of 30%-50%. In the last three decades there have been many advances in the treatment and prevention of variceal bleeding. Over recent years the introduction of new pharmaceutical agents that reduce portal pressure, endoscopic variceal ligation, transjugular intrahepatic portosystemic shunt, and the availability of liver transplantation have further increased the therapeutic options available to the physician treating this disorder. This article reviews the literature regarding therapies available in the treatment of haemorrhage from oesophageal varices and provides guidelines to aid the physicians in clinical decision making.

Foster GR, Chapman R. 2000. Combination treatment for hepatitis C is not being given. BMJ, 321 (7265), pp. 899. | Read more

Lechner F, Wong DK, Dunbar PR, Chapman R, Chung RT, Dohrenwend P, Robbins G, Phillips R, Klenerman P, Walker BD. 2000. Analysis of successful immune responses in persons infected with hepatitis C virus. J Exp Med, 191 (9), pp. 1499-1512. | Show Abstract | Read more

Although hepatitis C virus (HCV) infection is very common, identification of patients during acute infection is rare. Consequently, little is known about the immune response during this critical stage of the disease. We analyzed the T lymphocyte response during and after acute resolving HCV infection in three persons, using interferon (IFN)-gamma enzyme-linked immunospot (ELISPOT) and human histocompatibility leukocyte antigen (HLA) peptide tetramer assays. Acute infection was associated with a broadly directed T helper and cytotoxic T lymphocyte (CTL) response, which persisted after resolution of clinical hepatitis and clearance of viremia. At the earliest time point studied, highly activated CTL populations were observed that temporarily failed to secrete IFN-gamma, a "stunned" phenotype, from which they recovered as viremia declined. In long-term HCV-seropositive persons, CTL responses were more common in persons who had cleared viremia compared with those with persistent viremia, although the frequencies of HCV-specific CTLs were lower than those found in persons during and after resolution of acute HCV infection. These studies demonstrate a strong and persistent CTL response in resolving acute HCV infection, and provide rationale to explore immune augmentation as a therapeutic intervention in chronic HCV infection.

Satsangi J, Simmons J, Marshall S, Mitchell S, Chapman RW, Welsh KI, Jewell DP. 2000. CCR5 Delta 32 polymorphism in inflammatory bowel disease: Further association with ulcerative colitis and with primary sclerosing cholangitis. GASTROENTEROLOGY, 118 (4), pp. A337-A337. | Read more

Satsangi J, Haldar N, Donaldson P, Marshall S, Norris S, Mitchell S, Jewell DP, Chapman RW, Welsh KI. 2000. A regulatory polymorphism of the stromelysin gene (MMP-3) strongly influences susceptibility to primary sclerosing cholangitis (PSC) and progression to portal hypertension. GASTROENTEROLOGY, 118 (4), pp. A1014-A1015. | Read more

Sandborn WJ, Loftus EV, Colombel JF, Fleming K, Seibold F, Homburger HA, Sendid B, Chapman RW, Tremaine WJ, Kaul DK et al. 2000. Utility of perinuclear anti-neutrophil cytoplasmic antibodies (pANCA), anti-saccharomyces cerevisiae (ASCA), and anti-pancreatic antibodies (APA) as serologic markers in a population based cohort of patients with Crohn's disease (CD) and ulcerative colitis (UC). GASTROENTEROLOGY, 118 (4), pp. A106-A106. | Read more

Hellier SC, Satsangi JJ, Christie JM, Chapman RW, Ken WI. 2000. Chemokine receptor CCR5 polymorphisms do not affect disease progression in hepatitis C virus infection. GASTROENTEROLOGY, 118 (4), pp. A943-A943. | Read more

Hellier SC, Martin-Ginolhac M, Phillips RE, Chapman RW, Klenerman P. 2000. Do mutations in CD81 affect clinical outcome in patients with chronic hepatitis C infection? GASTROENTEROLOGY, 118 (4), pp. A939-A939. | Read more

Boberg KM, Mitchell S, Broome U, Pares A, Rosina F, Bergquist A, Chapman R, Fause O, Rocca G, Schrumpf E. 2000. Natural history of primary sclerosing cholangitis. A longterm follow-up study of 394 European primary sclerosing cholangitis patients JOURNAL OF HEPATOLOGY, 32 pp. 32-32. | Read more

Rocca G, Boberg KM, Egeland T, Bergquist A, Broome U, Caballeria L, Chapman R, Hultcrantz R, Mitchell S, Pares A et al. 2000. New time dependent prognostic models for primary sclerosing cholangitis (PSC) JOURNAL OF HEPATOLOGY, 32 pp. 207-207. | Read more

Hellier S, Martin-Ginolhac M, Phiilips R, Chapman R, Klenerman P. 2000. Do mutations in CD 81 affect clinical outcome uv patients with chronic hepatitis C infection? JOURNAL OF HEPATOLOGY, 32 pp. 92-92. | Read more

Martins EB, Chapman RW. 2000. Sclerosing cholangitis. Curr Opin Gastroenterol, 16 (5), pp. 444-449. | Show Abstract | Read more

Primary sclerosing cholangitis is a chronic cholestatic liver disease of unknown etiology. Immunogenetic factors are considered important in its pathogenesis. The genetic susceptibility to primary sclerosing cholangitis is associated, in part, with the HLA HLA-DRB1, DQA1, DQB1 haplotype. Liver histology in primary sclerosing cholangitis is characterized by a portal inflammatory infiltrate mostly composed of memory T cells. Many patients eventually will develop cholangiocarcinoma, and inactivation of the p16 tumor-suppressor gene might be involved in neoplastic transformation. Alcohol consumption might be a risk factor for cholangiocarcinoma, and, in some patients, elevation of serum CA19-9 marks the neoplastic transformation. To date, no medical treatment has been proven effective. Endoscopic therapy might be useful in some patients, but controlled studies are lacking. Liver transplantation remains the only effective treatment. Posttransplant survival and quality of life are continuously improving despite the fact that the disease may recur in some patients after transplantation. Nevertheless, patient selection and timing of indication for liver transplantation remain uncertain.

Mitchell SA, Chapman RW. 2000. Primary sclerosing cholangitis. Clin Rev Allergy Immunol, 18 (2), pp. 185-214. | Read more

Gow PJ, Chapman RW. 2000. Simultaneous occurrence of focal nodular hyperplasia and primary sclerosing cholangitis in a young female. Eur J Gastroenterol Hepatol, 12 (5), pp. 565-567. | Show Abstract | Read more

We report the case of a 22-year-old female with primary sclerosing cholangitis who was found, during hepatic imaging, to have a large liver mass. Imaging techniques and histological examination confirmed the mass to be focal nodular hyperplasia. A review of the literature indicates that the simultaneous occurrence of these two hepatic pathologies is unique. The differential diagnosis of hepatic masses in primary sclerosing cholangitis is discussed. Focal nodular hyperplasia needs to be included in the differential diagnosis of hepatic lesions in primary sclerosing cholangitis.

Gow PJ, Chapman RW. 2000. Liver transplantation for primary sclerosing cholangitis. Liver, 20 (2), pp. 97-103. | Show Abstract | Read more

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown aetiology that is progressive in most symptomatic patients, advancing toward cirrhosis and liver failure. Liver transplantation is the only therapeutic option for patients with end stage liver disease resulting from this disorder. The results of transplantation for PSC are excellent with one-year survival rates of 90-97% and five-year survival rates of 80-85%, but are closely related to pre-transplant Child-Pugh stage. Recurrence of PSC after liver transplantation is common, occurring in up to 20% of patients, but it appears to have little effect on patient survival, as survival of patients with recurrent PSC is similar to that of those without evidence of recurrence. Cholangiocarcinoma is a catastrophic complication of PSC and as yet no reliable screening method exists. The results of liver transplantation for patients with clinically apparent cholangiocarcinoma are extremely poor, however in patients in whom a microscopic tumour is detected in the explanted liver, survival is similar to those transplanted with PSC without cholangiocarcinoma. Activity of inflammatory bowel disease (IBD) appears to be more severe after transplantation, especially in units where steroid immunosuppression is withdrawn early. Colon cancer appears within the first few years after transplantation in approximately 7% of patients with IBD who are transplanted for PSC. Annual colonoscopy in this population seems prudent.

Christie JM, Chapel H, Chapman RW, Rosenberg WM. 1999. Immune selection and genetic sequence variation in core and envelope regions of hepatitis C virus. Hepatology, 30 (4), pp. 1037-1044. | Show Abstract | Read more

How Hepatitis C Virus (HCV) causes persistent infection is unknown. One hypothesis is that HCV evades the host immune response through mutation in immune epitopes. We have investigated mutations in the HCV genome to see if they cluster within immune epitopes; and we have studied the effect of antibody deficiency on mutation rates. We studied patients with chronic hepatitis C, 3 with antibody deficiency and 3 with normal immunity. Regions of the core and envelope genes of HCV, encoding cytotoxic (CTL), and B cell epitopes were sequenced at 2 time points, 2 years apart. The diversity of quasispecies increased with time. The HCV genetic mutation rate was higher than previously predicted. The cryptic nucleotide mutation rate in core was similar to that observed in envelope, suggesting that the error rate of the HCV RNA polymerase is similar in both regions. In contrast, the coding mutation rate was decreased in core and increased in envelope. No genetic mutation was seen in any of the core CTL epitopes despite detectable cellular responses. All patients had mutations within a previously described envelope CTL epitope but did not exhibit immune responses to either index or mutated peptides. There was no difference in mutation rates in any cellular or humoral epitopes between patients with antibody deficiency and normal immunity. Thus we have found no evidence that mutations were selected by T-lymphocytes or antibodies. These findings implicate alternative virus-host interactions in the selection of HCV mutations.

Spurkland A, Saarinen S, Boberg KM, Mitchell S, Broome U, Caballeria L, Ciusani E, Chapman R, Ercilla G, Fausa O et al. 1999. HLA class II haplotypes in primary sclerosing cholangitis patients from five European populations. Tissue Antigens, 53 (5), pp. 459-469. | Show Abstract | Read more

The association of primary sclerosing cholangitis (PSC) to HLA class II genes was studied by comparing patients from five different European populations. Deduced HLA-DRB1, DQA1, DQB1 haplotypes of 256 PSC patients from England, Italy, Norway, Spain and Sweden were compared to those observed in 764 ethnically-matched controls. Increased frequencies of the DRB1*03, DQA1*0501, DQB1*02 (RR=3.0, P<0.00001) and the DRB1*13, DQA1*0103, DQB1*0603 haplotypes (RR=2.4, P<0.0001) were observed in all five patient groups. A total of 16% of the PSC patients were homozygous for the DRB1*03, DQA1*0501, DQB1*02 haplotype compared to 1% of the controls (RR=20, P<0.0001). The DRB1*04, DQA1*03, DQB1*0302 haplotype was significantly reduced in frequency(RR=0.4, P<0.00001). Among Norwegian, Swedish and British patients that did not carry neither the DRB1*03, DQA1*0501, DQB1*02 nor the DRB1*13, DQA1*0103, DQB1*0603 haplotype, an increased frequency of the DRB1*15, DQA1*0102, DQB1*0602 haplotype was observed (RR=2.0, P<0.0001). Thus, PSC was found to be positively associated to three different HLA class II haplotypes (i.e. the DRB1*03, DQA1*0501, DQB1*02, the DRB1*15, DQA1*0102, DQB1*0602 and the DRB1*13, DQA1*0103, DQB1*0603 haplotypes) and negatively associated to one HLA class II haplotype (i.e. the DRB1*04, DQB1*0302 haplotype).

Christie JM, Chapman RW. 1999. Combination therapy for chronic hepatitis C: interferon and ribavirin. Hosp Med, 60 (5), pp. 357-361. | Show Abstract | Read more

Hepatitis C virus (HCV) infection is one of the commonest causes of liver cirrhosis and hepatocellular carcinoma. This review deals with treatment of chronic HCV infection with a combination of interferon and ribavirin. Recent trials have shown that approximately 40% of patients will clear HCV with combination treatment. This is an important advance in the treatment of this serious viral infection.

Sandborn WJ, Loftus EV, Kaul D, Zinsmeister A, Tremaine WJ, Homburger HA, Colombel JF, Sendid B, Chapman RW, Fleming K et al. 1999. Evaluation of perinuclear anit-neutrophil cytoplasmic antibodies (pANCA), anti-saccharomyces cerevisiae (ASCA), and anti-pancreatic antibodies (APA) as serologic markers in a population based cohort of patients with Crohn's disease and ulcerative colitis GASTROENTEROLOGY, 116 (4), pp. A811-A811.

Cullen SN, Chapman RW. 1999. Dissecting intramural haematoma of the oesophagus exacerbated by heparin therapy. QJM, 92 (2), pp. 123-124. | Read more

Chapman RW. 1999. Risk factors for biliary tract carcinogenesis. Ann Oncol, 10 Suppl 4 (SUPPL. 4), pp. 308-311. | Show Abstract | Read more

Cholangiocarcinoma has a worldwide distribution which accounts for about 10-15% of all cases of primary hepatobiliary malignancy. Although, in the majority of cases, no aetiological factor can be identified, a number of risk factors have been shown to be important in the development of cholangiocarcinoma; most of these factors share long standing inflammation and chronic injury of the biliary epithelium. Primary sclerosing cholangitis is an uncommon disease, characterized by stricturing, fibrosis and inflammation of the biliary tree which is closely associated with chronic inflammatory bowel disease, particularly ulcerative colitis. It is commonly associated with cholangiocarcinoma and between 10-20% of patients with primary sclerosing cholangitis will go on to develop a cholangiocarcinoma. The rare congenital fibropolycystic diseases of the biliary system are associated with increased risks of cholangiocarcinoma, particularly choledochal cysts and Caroli's disease. Choledochal cysts are associated with a 10% overall incidence of cholangiocarcinoma: there is a 1% cumulative risk which plateaus after 15-20 years. However, the risk is diminished in children who present under the age of 10 years where the over all risk is 0.7%. This compares with the 14% over all risk of patients presenting over the age of 20 years. In the Far East, other forms of chronic inflammation associated with cholangiocarcinoma include infestation with liver flukes. Clonorchis sinensis and Opisthorchis viverinni. Cholangiocarcinoma is also rarely seen in association with cirrhosis and has been weakly linked to hepatitis C infection.

Winfield JS, Fortier S, Catford WN, Pita S, Orr NA, Blumenfeld Y, Chapman R, Chappell SPG, Clarke NM, Curtis N et al. 1999. Structure of Be-11 from the (p, d) reaction in inverse kinematics JOURNAL OF PHYSICS G-NUCLEAR AND PARTICLE PHYSICS, 25 (4), pp. 755-757. | Show Abstract | Read more

We have performed the 11Be(p, d) 10Be reaction in inverse kinematics. The 10Be were detected in the SPEG spectrometer and the deuterons detected in a silicon array in coincidence. The yield to the first excited state (2+) of 10Be is greater than that to the 0+ ground state, and increases with angle. Strong population of the two-alpha plus two-neutron states near 6 MeV (in the two-centre shell-model description) is observed. The ultimate goal is to study the microscopic structure of 11Be from the extracted spectroscopic factors.

Martins EB, Chapman RW. 1999. Sclerosing cholangitis. Curr Opin Gastroenterol, 15 (5), pp. 436-441. | Show Abstract | Read more

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease that progresses to death as a result of liver failure or cholangiocarcinoma. Susceptibility to PSC is associated with the HLA A1-B8-DR3 haplotype, and new associations with HLA C and tumor necrosis factor genes have been detected. A circulating antineutrophil cytoplasmic antibody is found in many patients with PSC, but its antigen or antigens have not been identified. Some studies suggest that this antigen may be an anti-nuclear membrane protein rather than cytoplasmic. Diagnosis of PSC is based on endoscopic retrograde cholangiography, but magnetic resonance cholangiography is a promising noninvasive alternative. Medical treatment remains elusive. In highly selected patients, endoscopic or even surgical treatment can be tried. Orthotopic liver transplantation remains the only effective therapy, but inflammatory bowel disease may run a more aggressive clinical course after this procedure. Sclerosing cholangitis may recur after transplantation, but this has had no clinical implications to date.

Kennedy MM, Hunt NCA, Christie J, Graham A, Chapman RW, Fleming KA. 1999. Perivenular fibrosis in chronic HCV hepatitis. JOURNAL OF PATHOLOGY, 187 pp. 8A-8A.

Chapman RW. 1998. The colon and PSC: new liver, new danger? Gut, 43 (5), pp. 595-596. | Read more

Mitchell SA, Thyssen M, Mitchell M, Orchard TR, Jewell DP, Fleming KA, Chapman RW. 1998. Cigarette smoking, appendectomy and tonsillectomy as risk factors for the development of primary sclerosing cholangitis (PSC): A case control study. HEPATOLOGY, 28 (4), pp. 446A-446A.

Saarinen S, Boberg KM, Spurkland A, Mitchell S, Broome U, Rosina F, Chapman R, Pares A, Olerup O, Schrumpf E. 1998. HLA class II haplotypes in primary sclerosing cholangitis patients from five ethnic groups. HEPATOLOGY, 28 (4), pp. 445A-445A.

Boberg KM, Rocca G, Spurkland A, Broome U, Chapman R, Mitchell S, Pares A, Rosina F, Schrumpf E. 1998. Prognostic indicators of primary sclerosing cholangitis determined by a cox phase-specific time-dependent model. HEPATOLOGY, 28 (4), pp. 445A-445A.

Mitchell SA, Spurkland A, Boberg K, Chapman RW, Fleming KA, Schrumpf E, Cholangit ESGPS. 1998. Is the 308 polymorphism in the tumor necrosis factor (alpha) (TNF alpha) promoter region a marker of disease susceptibility in European patients with primary sclerosing cholangitis (PSC)? HEPATOLOGY, 28 (4), pp. 238A-238A.

Kennedy MM, Hunt NCA, Christie J, Graham A, Chapman RW, Fleming KA. 1998. Perivenular fibrosis in chronic HCV hepatitis. HEPATOLOGY, 28 (4), pp. 687A-687A.

Mitchell SA, Chapman R, Fleming K. 1998. Role of interleukin-10 in the pathogenesis of primary sclerosing cholangitis and primary biliary cirrhosis? GUT, 43 (1), pp. 153-153.

Christie J, Healey C, Fleming K, Chapman R, Rosenberg W. 1998. Genetic variation in Immune epitopes in core and envelope regions of hepatitis C virus GUT, 43 (1), pp. 159-159.

Cameron BJ, Bansi DS, Ali R, Chapman RW, Fleming KA. 1998. Characterization of the antigen for the antineutrophil cytoplasmic antibody specific for primary sclerosing cholangitis (PSC) ulcerative colitis (UC). GASTROENTEROLOGY, 114 (4), pp. A1218-A1218. | Read more

Christie JML, Fleming K, Chapman RW, Rosenberg WMC. 1998. CD8(+) T lymphocyte (CD8(+)L) responses in acute and chronic hepatitis C virus (HCV) infection. GASTROENTEROLOGY, 114 (4), pp. A1227-A1227. | Read more

Shanahan J, Rosenberg W, Chapman RW, Fleming KA. 1998. Deposition of complement C9 in primary sclerosing cholangitis (PSC). GASTROENTEROLOGY, 114 (4), pp. A1340-A1340.

Shanahan J, Hunt N, Chapman RW, Fleming KA. 1998. Liver cell proliferation in primary sclerosing cholangitis (PSC), as assessed by anti-KI-67 labelling. GASTROENTEROLOGY, 114 (4), pp. A1340-A1340. | Read more

Cameron BJ, Bansi DS, Ali R, Chapman RW, Fleming KA. 1998. Characterisation of the antigen for the antineutrophil cytoplasmic antibody specific for primary sclerosing cholangitis GUT, 42 pp. A87-A87.

Christie J, Fleming K, Chapman R, Rosenberg W. 1998. CD8+ lymphocyte (CD8+L) responses in acute hepatitis C virus (HCV) infection GUT, 42 pp. A21-A21.

Martins EB, Chapman RW. 1998. Sclerosing cholangitis CURRENT OPINION IN GASTROENTEROLOGY, 14 (5), pp. 408-412. | Show Abstract | Read more

Primary sclerosing cholangitis is a chronic cholestatic liver disease of unknown etiology that causes progressive obliterative fibrosis of the biliary tree, ultimately leading to death from liver failure or cholangiocarcinoma. The majority of patients have a circulating antineutrophil cytoplasmic antibody, which does not have a high enough sensitivity to be a good disease marker. Patients with ulcerative colitis and sclerosing cholangitis are at a higher risk for the development of colonic dysplasia and neoplasia, and yearly colonoscopic surveillance may be warranted. To date there is no effective treatment. Endoscopic stenting may be tried in selected cases. Orthotopic liver transplantation remains the only proven therapeutic option in end stage disease. Five-year survival after liver transplantation is 85%. However, if a cholangiocarcinoma is present at the time of transplantation survival decreases markedly. The disease may recur after transplantation, but this does not appear to have any clinical implications. Post-tranplant patients who have ulcerative colitis who are receiving immunossuppresive therapy are also at a high risk for the development of colon cancer.

Mitchell SA, Chapman RW. 1998. The management of primary sclerosing cholangitis. Clin Liver Dis, 2 (2), pp. 353-x. | Show Abstract | Read more

Primary sclerosing cholangitis is a chronic cholestatic liver disease characterized by a progressive, obliterating fibrosis of the intrahepatic and extrahepatic bile ducts. The pathogenesis of PSC is unknown, but it is thought to be an immune-mediated disease. Although the role of cupruretics, immunosuppressants (corticosteroids, azathioprine, tacrolimus, methotrexate), antifibrogenic agents, and ursodeoxycholic acid in the treatment of primary sclerosing cholangitis is reviewed, none of these agents has been shown to retard or reverse the rate of disease progression. Of these therapies, ursodeoxycholic acid at high doses looks the most promising, but large trials are needed to establish whether treatment with high-dose ursodeoxycholic acid influences the morbidity and mortality associated with primary sclerosing cholangitis.

Shanahan J, Rosenberg W, Chapman R, Fleming K. 1998. Deposition of complement C 9 in primary sclerosing cholangitis. JOURNAL OF PATHOLOGY, 186 pp. 32A-32A.

Christie JM, Healey CJ, Watson J, Wong VS, Duddridge M, Snowden N, Rosenberg WM, Fleming KA, Chapel H, Chapman RW. 1997. Clinical outcome of hypogammaglobulinaemic patients following outbreak of acute hepatitis C: 2 year follow up. Clin Exp Immunol, 110 (1), pp. 4-8. | Show Abstract | Read more

In 1994, an outbreak of hepatitis C virus (HCV) infection, genotype 1a, occurred in 30 hypogammaglobulinaemic patients in the UK from one batch of contaminated anti-HCV screened intravenous immunoglobulin. This study aimed to study prospectively the outcome of HCV in hypogammaglobulinaemic patients, and to assess the response to early treatment with interferon-alpha, 6 million units three times weekly for 6 months. Data were collected using standardized questionnaires. Five patients with secondary hypogammaglobulinaemia due to lymphoid malignancy were not treated and all have died of their primary malignancy. Of 25 patients with primary hypogammaglobulinaemia, one resolved HCV infection before treatment, 17 commenced on treatment, and seven declined or treatment was contra-indicated. Thirteen of 17 patients completed therapy and seven (54%) have a sustained response (normal transaminases, negative serum HCV RNA) at 6 and 12 months after treatment. Two of the 12 patients with primary hypogammaglobulinaemia, who were not treated or failed to complete treatment, have cleared the virus. Liver biopsy was performed in patients not clearing HCV and was abnormal in all. Four patients developed liver failure within 2 years, of whom three have died and one has been successfully transplanted. In conclusion, HCV can cause rapid severe liver disease in hypogammaglobulinaemic patients. Early treatment with high-dose interferon-alpha results in a high clearance of HCV.

Mitchell SA, Fleming K, Chapman R. 1997. Cytokine profiles in primary sclerosing cholangitis (PSC) and autoimmune liver diseases: Comparing expression in the periphery and the liver. HEPATOLOGY, 26 (4), pp. 400-400.

Mitchell SA, Fleming K, Chapman R. 1997. Decreased interleukin-10 mRNA expression in primary sclerosing cholangitis and primary biliary cirrhosis: A role for IL10 in the pathogenesis? HEPATOLOGY, 26 (4), pp. 1253-1253.

Broomé U, Chapman RW. 1997. Ulcerative colitis: sclerosing cholangitis today, cancer tomorrow? Gut, 41 (4), pp. 571-572. | Read more

Christie JML, Dike AE, Mitchell SA, Kurtz JB, Teo C, Rosenberg W, Fleming K, Chapman RW. 1997. Incidence and outcome of hepatitis C infection in blood product recipients: Experience of the Oxford blood centre within the National HCV Lookback Program. HEPATOLOGY, 26 (4), pp. 66-66.

Mitchell SA, Bansi D, Christie J, Fleming KA, Chapman RW. 1997. Down regulation of interferon gamma and up regulation of interleukin-10 by ursodeoxycholic acid (UDCA) in primary sclerosing cholangitis (PSC). HEPATOLOGY, 26 (4), pp. 814-814.

Bansi DS, Bauducci M, Bergqvist A, Boberg K, Broome U, Chapman R, Fleming K, Jorgensen R, Lindor K, Rosina F, Schrumpf E. 1997. Detection of antineutrophil cytoplasmic antibodies in primary sclerosing cholangitis: a comparison of the alkaline phosphatase and immunofluorescent techniques. Eur J Gastroenterol Hepatol, 9 (6), pp. 575-580. | Show Abstract | Read more

BACKGROUND: The reported prevalence of antineutrophil cytoplasmic antibodies (ANCA) in primary sclerosing cholangitis (PSC) varies considerably (26-85%). Part of this may reflect methodological differences but part may reflect the differences in the patient groups analysed. To resolve this issue we compared the sensitivity and specificity of the immunoalkaline phosphatase (IALP) and immunofluorescence (IF) techniques in four different populations. METHOD: Sera from four centres were tested blind on alcohol-fixed neutrophils using both techniques. PATIENTS: USA: 14 PSC, 14 primary biliary cirrhosis (PBC); Sweden: 32 PSC, 3 autoimmune hepatitis (AIH), 14 PBC, 11 chronic liver disease; Norway: 32 PSC, 14 AIH, 13 PBC, 1 hepatitis C. Italy: 8 PSC, 14 PBC, 8 viral hepatitis. Thirty-six normal healthy volunteers from Oxford, together with positive and negative controls, were also tested. RESULTS: The healthy controls were all ANCA negative. The diagnostic sensitivity and specificity, respectively, of ANCA for PSC using the IALP technique for the different test sera were: USA 71% and 93%, Sweden 66% and 96%, Norway 69% and 46%, Italy 50% and 95%. The diagnostic sensitivity and specificity, respectively, of the IF technique on the same sera were: USA 50% and 86%, Sweden 56% and 86%, Norway 47% and 61%, Italy 50% and 91%. Overall, combining all four groups, detection of ANCA using the IALP technique gave a diagnostic sensitivity of 66% with a specificity of 74% for PSC. In contrast, the IF technique gave an overall diagnostic of only 51% (P = 0.044, compared with IALP) with a specificity of 73%. Although overall the IALP technique was more sensitive than IF, the differences in sensitivity and specificity between the two techniques did not reach statistical significance for any individual group. Furthermore, the small differences in sensitivity between the four groups using either technique were not significant. However, the IALP technique had greater specificity in the US, Swedish and Italian groups compared with the Norwegian group (P < 0.05) whereas no statistically significant differences in specificity were noted between the groups using the IF technique. CONCLUSION: This study shows that the IALP method of ANCA detection is at least as sensitive as IF for the serological diagnosis of PSC. Indeed, combining data from all four centres, the IALP technique was significantly more sensitive than IF. We therefore recommend the use of the IALP technique, which is also easier to interpret and does not require the use of a specialist fluorescent microscope. The lack of a wide variation in sensitivity between IALP and IF for any individual patient group reported in this study suggests that the previously reported regional differences in ANCA prevalence in PSC of between 26% and 85% may be patient, related, rather than due to ethnic or methodological differences in ANCA detection, perhaps reflecting possible disease heterogeneity within PSC, or case selection bias. Further studies are needed to investigate this intriguing possibility. Such differences, if confirmed, will need to be taken into account when assessing the use of ANCA as a serological marker of PSC.

Christie J, Healey C, Fleming K, Chapel H, Chapman R, Rosenberg W. 1997. Conservation within cytotoxic T lymphocyte epitopes in hepatitis C virus in chronic infection. GASTROENTEROLOGY, 112 (4), pp. A1243-A1243.

Mitchell S, Fleming K, Chapman R. 1997. Enhanced cytokine mRNA expression in Primary Sclerosing Cholangitis (PSC) and autoimmune liver diseases. GASTROENTEROLOGY, 112 (4), pp. A1334-A1334.

Mitchell S, Bansi D, Hunt N, Christie J, Fleming K, Chapman R. 1997. High dose ursodeoxycholic acid (UDCA) in primary sclerosing cholangitis (PSC): Results after two years of a randomised double-blind, placebo-controlled trial. GASTROENTEROLOGY, 112 (4), pp. A1335-A1335.

Mitchell SA, Bansi D, Hunt N, Christie J, Fleming K, Chapman R. 1997. High dose ursodeoxycholic acid (UDCA) in primary sclerosing cholangitis (PSC): Results after two years of a randomised double-blind, placebo-controlled trial. GUT, 40 pp. TH115-TH115.

Martins EB, Chapman RW. 1997. Sclerosing cholangitis CURRENT OPINION IN GASTROENTEROLOGY, 13 (5), pp. 416-421. | Show Abstract | Read more

Primary sclerosing cholangitis is a chronic cholestatic liver disease of unknown etiology that leads to progressive obliterative fibrosis of the biliary tree, ultimately progressing to death from liver failure or cholangiocarcinoma. Immune-mediated factors are thought to be involved in its pathogenesis, as suggested by the presence of circulating antineutrophil cytoplasmic antibodies, mainly IgG1 and IgG3. This test is not yet useful as a diagnostic tool because sensitivity and specificity vary widely according to the different detection methods used. A small subset of T cells bearing the γ-δ receptor may also be involved in its pathogenesis. Cigarette smoking appears to be protective. No medical treatment is of proven benefit, and median survival from diagnosis is 12 years. Ursodeoxycholic acid was considered a promising drug, but no important benefits were demonstrated in a large, randomized, controlled trial. In selected patients endoscopic treatment of major extrahepatic strictures may be tried. Orthotopic liver transplantation remains the only effective treatment, but the disease may recur in some patients.

Mitchell SA, Chapman RW. 1997. Review article: the management of primary sclerosing cholangitis. Aliment Pharmacol Ther, 11 (1), pp. 33-43. | Show Abstract | Read more

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by a progressive obliterating fibrosis of the intrahepatic and extrahepatic bile ducts. The pathogenesis of PSC is poorly understood but it is thought to be an immune-mediated disease. The optimal therapy which successfully improves symptoms, delays progression towards liver failure and transplantation and prevents the onset of cholangiocarcinoma remains elusive. Although current treatments are used to manage cholestasis and its consequences and some of the more general complications of the disease, none of the current therapeutic agents have been shown to retard and reverse the rate of disease progression. The role of cupruretics, corticosteroids, methotrexate, antifibrogenic agents and ursodeoxycholic acid in the treatment of PSC is reviewed. Orthotopic liver transplantation remains the only therapeutic option for advanced PSC but the timing of transplantation remains controversial and the possibility of recurrence of the disease in the graft is increasingly recognised. It is likely that greater insight into the pathogenetic mechanisms involved in PSC will allow therapy to be targetted more specifically at the biliary epithelium.

Healey CJ, Chapel H, Simmonds P, Chapman RWG. 1996. Hepatitis G virus in intravenous immunoglobulin - Reply GASTROENTEROLOGY, 111 (5), pp. 1399-1400.

Cobb CA, Curtis GD, Bansi DS, Slade E, Mehal W, Mitchell RG, Chapman RW. 1996. Increased prevalence of Listeria monocytogenes in the faeces of patients receiving long-term H2-antagonists. Eur J Gastroenterol Hepatol, 8 (11), pp. 1071-1074. | Show Abstract | Read more

BACKGROUND: Human listeriosis is an uncommon infection caused by the Gram-positive organism Listeria monocytogenes. OBJECTIVE: To investigate the effects of therapeutic gastric acid suppression on faecal isolation of L. monocytogenes and the incidence of human listeriosis. METHODS: Five stool specimens from each of 20 patients on continuous H2-antagonist therapy and two faecal samples from each of 47 healthy controls were investigated for the presence of Listeria spp. RESULTS: A higher faecal isolation rate of L. monocytogenes was detected amongst the patients (20%) compared with the controls (2.1%) (P < 0.025). All subjects with stools positive for Listeria spp. were female, this sex difference being significant in the patient group (P < 0.0036) compared with controls. No patient, however, developed listeriosis. CONCLUSION: Patients on long-term gastric acid suppressive therapy may be at increased risk of faecal carriage of L. monocytogenes.

Christie J, Healey C, Watson J, Wong S, Durridge M, Snowdon N, Rosenberg W, Fleming K, Chapel H, Chapman R. 1996. Treatment and outcome of acute hepatitis C infection in hypogammaglobulinaemia - 2 year follow-up of the UK Gammagard outbreak. HEPATOLOGY, 24 (4), pp. 1089-1089.

Bansi D, Chapman R, Fleming K. 1996. Antineutrophil cytoplasmic antibodies in chronic liver diseases: prevalence, titre, specificity and IgG subclass. J Hepatol, 24 (5), pp. 581-586. | Show Abstract | Read more

BACKGROUND/AIMS: Antineutrophil cytoplasmic antibodies are reported in patients with chronic liver disease, but controversy exists about their prevalence and specificity. We aimed to find the prevalence and specificity of antineutrophil cytoplasmic antibodies in chronic liver diseases by determination of antineutrophil cytoplasmic antibody titre and IgG subclass. METHODS: One hundred and eight-four sera were studied: 63 primary sclerosing cholangitis, 28 autoimmune hepatitis, 34 primary biliary cirrhosis, 12 alcoholic liver disease, five large duct obstruction, four haemochromatosis, one chronic cholestatic syndrome, one cryptogenic cirrhosis and 36 normal individuals. Antineutrophil cytoplasmic antibodies were detected on alcohol-fixed neutrophils using an alkaline phosphatase technique. The IgG subclass of antineutrophil cytoplasmic antibodies was determined using monoclonal antibodies: HP 6001 for IgG1, HP 6002 for IgG2, HP 6050 for IgG3 and SK 44 for IgG4 (Sigma Immunochemicals). RESULTS: Antineutrophil cytoplasmic antibodies were detected in 65% of primary sclerosing cholangitis patients at a serum dilution of 1:5, dropping to 49% at 1:50. For autoimmune hepatitis, antineutrophil cytoplasmic antibodies were detected in 49% at 1:5, dropping to 11% at 1:50. Only 6% of primary biliary cirrhosis patients were antineutrophil cytoplasmic antibody-positive at 1:5, dropping to 3% at 1:50. All other controls were antineutrophil cytoplasmic antibody negative at 1:5. The presence of antineutrophil cytoplasmic antibodies in primary sclerosing cholangitis correlated with involvement of the intra- and extrahepatic biliary tree (p = 0.016, Fisher's exact test), but no other clinical parameters. Determination of the IgG subclass of antineutrophil cytoplasmic antibody in 33 primary sclerosing cholangitis and 11 autoimmune hepatitis patients revealed a predominance of IgG1 in both groups (94% and 82% of all IgG antineutrophil cytoplasmic antibodies, respectively), with a similar distribution of IgG2, IgG3 and IgG4 antineutrophil cytoplasmic antibodies between the groups. CONCLUSIONS: Antineutrophil cytoplasmic antibodies are specific to the autoimmune liver diseases, particularly primary sclerosing cholangitis and autoimmune hepatitis. Titres are highest in primary sclerosing cholangitis, with a diagnostic sensitivity of 49% and specificity of 89% at 1:50, making it a useful serological marker for this disease. The lack of correlation with any marker of activity and the association of antineutrophil cytoplasmic antibody with extent of biliary tract involvement suggest that antineutrophil cytoplasmic antibodies arises as a result of the disease or related process rather than being a cause of it. The detection of antineutrophil cytoplasmic antibodies in autoimmune hepatitis, together with a similar IgG subclass distribution of primary sclerosing cholangitis and autoimmune hepatitis antineutrophil cytoplasmic antibodies, may reflect similar mechanisms of immune regulation and a possible overlap syndrome. Future identification of the antigens against which this antineutrophil cytoplasmic antibody are directed should help to clarify this point, as well as allowing the development of a more sensitive and specific serological test for diagnostic purposes.

Martins EB, Graham AK, Chapman RW, Fleming KA. 1996. Elevation of gamma delta T lymphocytes in peripheral blood and livers of patients with primary sclerosing cholangitis and other autoimmune liver diseases. Hepatology, 23 (5), pp. 988-993. | Show Abstract | Read more

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease that is possibly an autoimmune disease. Although gamma delta T cells represent a small proportion of the total T-cell population in healthy individuals, there is evidence to suggest a role for these cells in autoimmunity. Accordingly, the aim of this study was to investigate the population of gamma delta T cells in patients with PSC, compared with other chronic liver diseases. An elevation in the percentage and absolute numbers of gamma delta T cells was found in the peripheral blood of patients with PSC (8.66% and 0.13 x 10(-6)/L [P < .01 and < .05, respectively]) and autoimmune hepatitis (AIH) (8.03% and 0.13 x 10(-6)/L [both P < 0.001]) compared with controls (4.10% and 0.06 x 10(-6)/L). We also found an elevation in the percentage and absolute numbers of gamma delta T cells in the portal areas of patients with PSC (10.55% and 4.33 [P < .001 and < .001, respectively]), AIH (7.16% and 4.55 [P = .001 and < .001, respectively]), and primary biliary cirrhosis (PBC) (5.57% and 3.49 [P = .008 and < .001, respectively]) when compared with controls (2.23% and 0.81). These findings suggest a role for gamma delta T cells in the mechanism of immune damage in autoimmune liver diseases.

Healey CJ, Sabharwal NK, Daub J, Davidson F, Yap PL, Fleming KA, Chapman RW, Simmonds P, Chapel H. 1996. Outbreak of acute hepatitis C following the use of anti-hepatitis C virus--screened intravenous immunoglobulin therapy. Gastroenterology, 110 (4), pp. 1120-1126. | Show Abstract | Read more

BACKGROUND & AIMS: Hepatitis C virus (HCV) infection has been associated with intravenous (IV) immunoglobulin (Ig), and plasma donations used to prepare IV Ig are now screened to prevent transmission. Thirty-six patients from the United Kingdom received infusions from a batch of anti-HCV antibody-screened intravenous Ig (Gammagard; Baxter Healthcare Ltd., Thetford, Norfolk, England) that was associated with reports of acute hepatitis C outbreak in Europe. The aim of this study was to document the epidemiology of this outbreak. METHODS: Forty-six patients from the United Kingdom treated with Gammagard (34 exposed and 12 unexposed to the batch) returned epidemiological questionnaires. RESULTS: Eighty-two percent of the exposed patients (28 of 34) became positive for HCV RNA. Eighteen percent of the patients (6 of 34) who had infusions with this batch tested negative for HCV RNA, but 2 of the patients had abnormal liver function and subsequently seroconverted to anti-HCV antibody positive. Twenty-seven percent of the patients (9 of 34) developed jaundice, and 79% (27 of 34) had abnormal liver transferase levels. Virus isolates (n=21), including an isolate from the implicated batch, were genotype 1a and virtually identical by sequence analysis of the NS5 region, consistent with transmission from a single source. CONCLUSIONS: Hepatitis C infection can be transmitted by anti-HCV-screened IV Ig. Careful documentation of IV Ig batch numbers and regular biochemical monitoring is recommended for all IV Ig recipients.

Bansi D, Christie J, Fleming K, Chapman R. 1996. High-dose ursodeoxycholic acid in primary sclerosing cholangitis a randomised double-blind placebo-controlled trial GASTROENTEROLOGY, 110 (4), pp. A1146-A1146.

Bansi D, Boberg K, Broome U, Chapman R, Fleming K, Jorgensen R, Lindor K, Schrumpf E. 1996. Detection of antineutrophil cytoplasmic antibody in primary sclerosing cholangitis: Comparison of the alkaline phosphatase and immunofluorescent techniques. GASTROENTEROLOGY, 110 (4), pp. A1146-A1146.

Healey C, McAdam S, Plebanski M, Chapman R, Rosenberg W. 1996. Cytotoxic T lymphocyte epitopes in hepatitis C virus identified with HLA assembly assays. GASTROENTEROLOGY, 110 (4), pp. A1209-A1209.

Bansi DS, McWilliams F, Scholey G, Ferry B, Chappel H, Fleming KA, Chapman RW. 1996. Antigen specificity of antineutrophil antibodies in ulcerative colitis, primary sclerosing and autoimmune hepatitis. GASTROENTEROLOGY, 110 (4), pp. A1146-A1146.

Martins E, Chapman RW. 1996. Sclerosing cholangitis CURRENT OPINION IN GASTROENTEROLOGY, 12 (5), pp. 466-470. | Show Abstract | Read more

Primary sclerosing cholangitis is a chronic cholestatic liver disease of unknown etiology that leads to progressive obliterative fibrosis of the biliary tree. The disease progresses in most patients to death from liver failure or cholangiocarcinoma. The etiology remains obscure, but immune-mediated factors are thought to be involved in its pathogenesis, as suggested by the strong HLA associations and a circulating antineutrophil cytoplasmic antibody. The neutrophil antigen remains unknown, and this test is not yet useful as a diagnostic tool. Biliary expression of heat shock proteins is enhanced, but this phenomenon is nonspecific and is also seen in other forms of chronic cholestasis. The disease is strongly associated with ulcerative colitis, and the risk of colorectal cancer is high. Patients may have biliary calculi, previously thought to exclude the diagnosis. Endoscopic retrograde cholangiopancreatography remains the gold standard for diagnosis, but false-positive results are a possibility. Liver biopsy is nonspecific and subjected to sampling variability. No medical treatment is of proven benefit, and surgical procedures are best avoided. Orthotopic liver transplantation remains the only effective treatment, and the 5-year survival rate is up to 89%.

Bansi DS, Chapman RW, Fleming KA. 1996. Prevalence and diagnostic role of antineutrophil cytoplasmic antibodies in inflammatory bowel disease. Eur J Gastroenterol Hepatol, 8 (9), pp. 881-885. | Show Abstract

BACKGROUND: Antineutrophil cytoplasmic antibodies (ANCA) are of proven diagnostic value in a variety of vasculitides, where they are also thought to play a pathogenic role. ANCA has also been detected in the serum of patients with idiopathic inflammatory bowel disease (IBD), both ulcerative colitis (UC) and Crohn's disease (CD), and primary sclerosing cholangitis (PSC) with or without concomitant IBD. Although the prevalence in PSC and UC is reported to be up to 85%, a much lower prevalence of around 10-20% has been reported in CD. AIM: To determine ANCA prevalence in a group of British patients with IBD and evaluate their use as a serological marker to distinguish between UC and CD. METHODS: A total of 99 UC-only patients (44 males, median age 50) and 41 CD patients (11 males, median age 47) were tested for ANCA using an alkaline phosphatase technique at a 1:5 serum dilution. Controls were other diarrhoeal diseases including 17 coeliac disease (4 males, median age 41), 23 irritable bowel syndrome (5 males, median age 42), 5 infectious colitis (2 male, median age 64) and 36 healthy volunteers (13 males, median age 43). RESULTS: ANCA was detected in 42/99 (42.4%) UC patients but in only 2/41 (5%) CD (P < 0.0001). All ANCA were perinuclear in distribution. No ANCA was detected in the control sera. The sensitivity of the test for the diagnosis of UC was 42% with a specificity of 98%. In patients with UC, no association was found between presence of ANCA and age, sex, disease extent, treatment or activity. However, ANCA-positive UC patients had longer median duration of disease (50 months vs. 29 months, P = 0.037). Both CD ANCA-positive patients had colonic involvement, but one also had ileal disease. Both had inactive disease and one was on mesalazine. CONCLUSIONS: ANCA is highly specific for UC and may be a helpful diagnostic test in distinguishing UC from CD and other diarrhoeal illnesses. Although ANCA positivity may reflect disease heterogeneity within UC, no association with clinical features or treatment of UC was demonstrated and it is therefore unlikely to play a pathogenic role. The correlation with disease duration needs further investigation.

Bansi DS, Lo S, Chapman RW, Fleming KA. 1996. Absence of antineutrophil cytoplasmic antibodies in relatives of UK patients with primary sclerosing cholangitis and ulcerative colitis. Eur J Gastroenterol Hepatol, 8 (2), pp. 111-116. | Show Abstract | Read more

OBJECTIVE: Perinuclear antineutrophil cytoplasmic antibodies (ANCA) have been reported in patients and relatives of patients with ulcerative colitis and primary sclerosing cholangitis, suggesting that ANCA may be a genetic marker of disease susceptibility. The reported frequency of ANCA in relatives has varied greatly, between 0 and 30%. We therefore studied the prevalence of ANCA in unaffected first-degree relatives of British patients with primary sclerosing cholangitis and ulcerative colitis. DESIGN: Thirty-six patients with ulcerative colitis, 33 with primary sclerosing cholangitis and 187 relatives were studied. Ninety-seven relatives were from the primary sclerosing cholangitis proband and 90 were from the ulcerative colitis proband. As an environmental control, 32 spouses were included: 14 from the primary sclerosing cholangitis group and 18 from the ulcerative colitis group. Eighteen healthy volunteers were additional controls. METHODS: ANCA was detected using immunoalkaline phosphatase method. RESULTS: Only 3 of 97 (3%) of the primary sclerosing cholangitis proband relatives had ANCA. One of these had ulcerative colitis, one had rheumatoid arthritis and the third systemic lupus erythematosus. Both rheumatoid arthritis and system lupus erythematosus are known to exhibit ANCA. All other sera were negative. CONCLUSION: ANCA was found only in patients with primary cholangitis and ulcerative colitis and not in their healthy first-degree relatives. ANCA is therefore not a genetic marker for increased disease susceptibility to primary sclerosing cholangitis or ulcerative colitis in the British population.

Bansi DS, Fleming KA, Chapman RW. 1996. Importance of antineutrophil cytoplasmic antibodies in primary sclerosing cholangitis and ulcerative colitis: prevalence, titre, and IgG subclass. Gut, 38 (3), pp. 384-389. | Show Abstract | Read more

Antineutrophil cytoplasmic antibodies (ANCA) have been reported in up to 87% of patients with primary sclerosing cholangitis with or without ulcerative colitis (PSC +/- UC) and in 68% of those with UC only. Compared with other liver and diarrhoeal diseases, ANCA have high specificity for PSC (+/- UC) and UC only. This study aimed to determine the prevalence and significance of ANCA in these two diseases and whether the ANCA titre or IgG subclass, or both, could distinguish between PSC + UC and UC only. Subjects included 63 patients with PSC, 85 with UC, 17 with coeliac disease, and 10 with dermatitis herpeteformis and 36 normal subjects. ANCA was detected using the immunoalkaline phosphatase method. The IgG subclass of ANCA was determined in 27 PSC + UC and 30 UC only patients using a panel of mouse monoclonal antibodies specific for the IgG subclasses. At a serum dilution of 1:5, ANCA had a diagnostic sensitivity of 65% for all PSC and 45% for UC only. For PSC + UC the sensitivity was 70% at 1:5 (p = 0.004 v UC only). At 1:50, the sensitivity values were 54% and 25% respectively for PSC + UC and UC only (p = 0.0006). In PSC, ANCA positivity was significantly associated with extensive involvement of the biliary tree but not with other clinical parameters. In UC only, the median disease duration was significantly greater in ANCA positive patients. The PSC + UC ANCA showed increased IgG3 compared with UC only ANCA (p < 0.05), together with increased IgG2 and IgG4 (p = NS). ANCA is a diagnostic marker in PSC and UC. While the higher titres and different IgG subclass distribution of ANCA in PSC + UC patients compared with those with UC only may reflect differences in underlying immune regulation, determination of the ANCA titre and IgG subclass is unlikely to have a role in distinguishing between PSC + UC and UC only ANCA. Future identification of the antigen(s) for ANCA should allow the development of a more sensitive and specific test for the diagnosis of these two conditions and also determine if ANCA is associated with UC or PSC.

Martins EB, Chapman RW, Marron K, Fleming KA. 1996. Biliary expression of heat shock protein: a non-specific feature of chronic cholestatic liver diseases. J Clin Pathol, 49 (1), pp. 53-56. | Show Abstract | Read more

AIM: To analyse the expression of heat shock protein (HSP) 60 in biliary epithelium in auto-immune liver conditions and also in chronic cholestatic and other liver diseases. METHODS: Hepatic expression of HSP-60 in frozen liver biopsy specimens from patients with primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), auto-immune hepatitis (AIH), obstructive jaundice (LDO), alcoholic liver disease (ALD), and from normal controls was studied by immunohistochemistry using the APAAP technique and confocal laser scanning microscopy. RESULTS: Increased expression of HSP-60 was demonstrated in the biliary epithelium of patients with PBC, LDO and, to a lesser extent, with PSC. Focal, weaker, biliary epithelial expression of HSP-60 was observed in AIH, ALD and normal liver tissue. Increased expression was also seen on Kupffer cells in LDO and in hepatocytes in areas of piecemeal necrosis in AIH. CONCLUSION: Enhanced biliary expression of HSP-60 is a common feature of chronic biliary disease irrespective of aetiology and is not specific to auto-immune diseases.

Bansi DS, McWilliams F, Scholey G, Ferry B, Chappel H, Fleming KA, Chapman RW. 1996. Antigen specificity of antineutrophil antibodies in ulcerative colitis, primary sclerosing cholangitis and autoimmune hepatitis HEPATOLOGY, 23 (1), pp. T5-T5.

Bansi DS, Fleming KA, Chapman RW. 1995. Antineutrophil cytoplasmic antibodies in autoimmune hepatitis. Gastroenterology, 109 (6), pp. 2049-2050. | Read more

BANSI D, GUNSON B, NEUBERGER J, FLEMING K, CHAPMAN R. 1995. ANTINEUTROPHIL CYTOPLASMIC ANTIBODIES AFTER LIVER-TRANSPLANTATION FOR PRIMARY SCLEROSING CHOLANGITIS HEPATOLOGY, 22 (4), pp. 1139-1139.

BANSI D, BOBERG K, BROOME U, CHAPMAN R, FLEMING K, JORGENSEN R, LINDOR K, SCHRUMPF E. 1995. DETECTION OF ANTINEUTROPHIL CYTOPLASMIC ANTIBODY IN PRIMARY SCLEROSING CHOLANGITIS - COMPARISON OF THE ALKALINE-PHOSPHATASE AND IMMUNOFLUORESCENT TECHNIQUES HEPATOLOGY, 22 (4), pp. 1140-1140.

MARTINS EB, CHAPMAN RW, FLEMING KA. 1995. ARE BILE-DUCT EPITHELIAL-CELLS CAPABLE OF ACTING AS PROFESSIONAL ANTIGEN-PRESENTING CELLS IN PRIMARY SCLEROSING CHOLANGITIS HEPATOLOGY, 22 (4), pp. 10-10.

MARTINS EB, FLEMING KA, CHAPMAN RW. 1995. INTERFERON-GAMMA PRODUCTION IN PRIMARY SCLEROSING CHOLANGITIS HEPATOLOGY, 22 (4), pp. 1391-1391.

Mehal WZ, Culshaw KD, Tillotson GS, Chapman RW. 1995. Antibiotic prophylaxis for ERCP: a randomized clinical trial comparing ciprofloxacin and cefuroxime in 200 patients at high risk of cholangitis. Eur J Gastroenterol Hepatol, 7 (9), pp. 841-845. | Show Abstract

OBJECTIVE: To compare the efficacy and safety of oral ciprofloxacin and intravenous cefuroxime in patients at high risk of cholangitis after endoscopic retrograde cholangiopancreatography (ERCP). DESIGN: Prospective, randomized study. SETTING: A primary and tertiary referral centre. PATIENTS: A series of 232 consecutive patients who either had radiological evidence of biliary obstruction or were aged over 70 years were randomly assigned to receive either oral ciprofloxacin or intravenous cefuroxime before and after ERCP. Two-hundred and nine patients finished the study, with 23 being excluded because of withdrawal of consent or incomplete ERCP. INTERVENTIONS: Patients underwent ERCP: blood samples were taken for culture, full blood count and biochemistry before and after the procedure. Clinical follow-up was carried out 7 and 42 days after ERCP. MAIN OUTCOME MEASURES: Clinical, bacteriological or biochemical evidence of cholangitis, septicaemia or adverse drug reactions, and the cost of both protocols. RESULTS: Follow-up was recorded in all 209 patients who completed the study. By 42 days after ERCP, three patients had died (cholangiocancer, pancreatic cancer and renal failure). Cholangitis was diagnosed in one patient from each of the two trial groups. Blood cultures from the patient on ciprofloxacin gave negative results, but a post-ERCP blood sample from the patient on cefuroxime grew Pseudomonas aeruginosa, which was sensitive to ciprofloxacin. There were no serious side-effects in either study group, but two patients assigned to ciprofloxacin became too nauseous to take the medication. The cost of the cefuroxime protocol was l7.56 pounds per patient, compared with 4.76 pounds per patient for the ciprofloxacin protocol. CONCLUSION: A pre- and post-ERCP oral ciprofloxacin regime is safe and provides effective prophylaxis against ERCP-induced cholangitis and septicaemia in high-risk patients. It is also more economical than a regime of intravenous cefuroxime and does not require nursing staff with training in intravenous techniques.

Ryley NG, Fleming KA, Chapman RW. 1995. Focal destructive cholangiopathy associated with amoxycillin/clavulanic acid (Augmentin). J Hepatol, 23 (3), pp. 278-282. | Show Abstract | Read more

Amoxycillin/clavulanic acid (Augmentin) has been widely used as a broad spectrum antibiotic since its introduction in 1981, since which time a number of reports of adverse hepatic reaction to the drug combination have been published. This paper describes five patients presenting with cholestatic illness within 8 weeks of a course of amoxycillin/clavulanic acid. The clinical picture indicated a direct link between the illness and the drug combination. Hepatic histology revealed a distinctive focal destructive cholangiopathy in all five patients, which has not previously been reported. Two also showed a granulomatous reaction, which has only previously been reported in one patient. Parallels are drawn with other diseases displaying bile duct destruction, and it is suggested that immunologically mediated drug-induced biliary damage may be involved. One of the five patients developed chronic liver disease with persistence of cholestatic liver biochemical tests, which has not previously been reported. The severity of the reaction and its prolonged course merit wider recognition of the possible adverse hepatic reaction to amoxycillin/clavulanic acid.

Healey CJ, Chapman RW, Fleming KA. 1995. Liver histology in hepatitis C infection: a comparison between patients with persistently normal or abnormal transaminases. Gut, 37 (2), pp. 274-278. | Show Abstract | Read more

Forty two cases of confirmed hepatitis C virus (HCV) infection with available liver histology were studied. Most patients, 23 of 42 (55%) had abnormal liver function tests but 19 of 42 (45%) had persistently normal liver transaminases (mean aspartate transaminase (AST) 24.1 IU/l, mean follow up 10 months). Histological examinations in the group with normal AST activities were normal in two of 19 (11%), showed non-specific reactive hepatitis in eight of 19 (42%), chronic persistent hepatitis in six of 19 (31%), and chronic active hepatitis in three of 19 (16%). Twenty three of 42 (55%) had either persistently or temporary raised liver transaminases (mean AST 96.2 IU/l, mean follow up 16 months). Histological examinations in this second group with abnormal liver biochemistry showed reactive hepatitis in five of 23 (22%), chronic persistent hepatitis in six of 23 (26%), chronic active hepatitis in 10 of 23 (43%), and cirrhosis in two (9%). Average alcohol intake was significantly higher in the group within abnormal liver function (17.8 v 6.4 units, p = 0.01). Although serious pathology was more frequent in the abnormal transaminase group, significant liver pathology (chronic persistent hepatitis or chronic active hepatitis) was found in nine of 19 (47%) of cases with repeatedly normal transaminases. Liver biopsy is advised in all cases of chronic hepatitis C infection to accurately assess both the degree of fibrosis and the current activity of the disease.

Rosenberg WM, Prince C, Kaklamanis L, Fox SB, Jackson DG, Simmons DL, Chapman RW, Trowell JM, Jewell DP, Bell JI. 1995. Increased expression of CD44v6 and CD44v3 in ulcerative colitis but not colonic Crohn's disease. Lancet, 345 (8959), pp. 1205-1209. | Show Abstract | Read more

Immune mechanisms, possibly involving cell-surface molecules such as CD44, have been invoked to explain the pathogenesis of inflammatory bowel disease. We used monoclonal antibodies against epitopes encoded within the variable region of CD44 to investigate CD44 isoform expression in colon, small intestine, and liver in patients with various intestinal disorders and in controls. Biopsy samples from patients with ulcerative colitis showed significantly increased epithelial expression of CD44 isoforms containing the v6 and v3 epitopes, detected with antibodies 2F10 and 3G5, respectively. CD44v6 was detected on colonic crypt epithelial cells in 23 of 25 ulcerative colitis samples compared with 3 of 18 colonic Crohn's disease samples (p = 3.0 x 10(-6); odds ratio 57.5 [95% CI 6.83-702]) and 3 of 52 controls (22 normal colon, 10 infective colitis, 2 radiation colitis, and 18 colonic Crohn's disease; p < 1 x 10(-8); odds ratio 199 [25.5-2294]). No significant expression of CD44v6, CD44v3, or CD44v8/9 was found in samples of normal proximal colon from 4 patients with distal ulcerative colitis, whereas samples from the affected area showed staining for CD44v6 and CD44v3. No expression of CD44 variants was found in 15 samples of normal small intestine, 11 small-bowel pouchitis, 8 coeliac disease, 3 small-bowel Crohn's disease, 6 normal liver, 6 primary biliary cirrhosis, or 9 primary sclerosing cholangitis. The high intensity of CD44v6 and v3 epitope expression on crypt epithelial cells in ulcerative colitis suggests that CD44 isoforms may have an important role in ulcerative colitis. Their detection could have diagnostic potential in differentiating ulcerative colitis from other forms of colonic inflammation including Crohn's disease.

Chapman RW. 1995. The enigma of anti-neutrophil antibodies in ulcerative colitis primary sclerosing cholangitis: important genetic marker or epiphenomenon? Hepatology, 21 (5), pp. 1473-1474. | Read more

HEALEY CJ, WATSON J, DURRIDGE M, SNOWDON N, CHRISTIE J, WONG S, READ J, KURTZ J, FLEMING KA, CHAPEL H, CHAPMAN RWG. 1995. TREATMENT OF ACUTE HEPATITIS-C WITH ALPHA-INTERFERON IN HYPOGAMMAGLOBULINEMIA - THE UK GAMMAGARD OUTBREAK GASTROENTEROLOGY, 108 (4), pp. A1082-A1082.

Bloom S, Fleming K, Chapman R. 1995. Adhesion molecule expression in primary sclerosing cholangitis and primary biliary cirrhosis. Gut, 36 (4), pp. 604-609. | Show Abstract | Read more

There are conflicting reports regarding intercellular adhesion molecule-1 (ICAM-1) expression in primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC). Expression of adhesion molecules ICAM-1, lymphocyte adhesion molecule-1 (LFA-1), vascular cell adhesion molecule (VCAM), and E-selectin was examined together with HLA-DR in 16 liver biopsy specimens showing PSC and 12 specimens showing PBC. These were compared with biopsy specimens showing large duct obstruction (n = 7), chronic active hepatitis (n = 4), alcoholic liver disease (n = 4), and normal liver histological results (n = 5). ICAM-1 was detected on biliary epithelium in five of seven PSC specimens of histological stage 3 or 4, but not in nine early PSC specimens or in specimens from disease controls. In PBC, ICAM-1 was positive on three of 12 cases, two stage 2, and one stage 3. Nine of 16 PSC specimens (three of nine early, six of seven late disease) and six of 10 PBC specimens (three early, three late disease) were positive for HLA-DR. LFA-1 stained infiltrating inflammatory cells in PSC, PBC, and disease controls. In conclusion, ICAM-1 expression on biliary epithelium in PSC occurs mainly in late stage disease and therefore may be secondary to previous events inducing inflammation rather than of primary pathogenic importance. ICAM-1 expression in PBC is less common and not clearly associated with a particular disorder. Previous reports of ICAM-1 prevalence may have been biased towards end stage, pre-transplantation biopsy specimens.

BANSI DS, LO SK, FLEMING KA, CHAPMAN RW. 1995. ANTINEUTROPHIL CYTOPLASMIC ANTIBODIES ARE ABSENT IN UNAFFECTED RELATIVES OF PATIENTS WITH PRIMARY SCLEROSING CHOLANGITIS AND ULCERATIVE-COLITIS GASTROENTEROLOGY, 108 (4), pp. A1028-A1028.

BANS DS, CHAPMAN RW, FLEMING KA. 1995. ANTINEUTROPHIL CYTOPLASMIC ANTIBODY TITER BUT NOT IGG SUBCLASS DISTINGUISHES BETWEEN PRIMARY SCLEROSING CHOLANGITIS AND AUTOIMMUNE HEPATITIS GASTROENTEROLOGY, 108 (4), pp. A1028-A1028.

BANSI DS, CHAPMAN RW, FLEMING KA. 1995. IGG SUBCLASS DISTRIBUTION OF ANTINEUTROPHIL CYTOPLASMIC ANTIBODIES IN PRIMARY SCLEROSING CHOLANGITIS AND ULCERATIVE-COLITIS GASTROENTEROLOGY, 108 (4), pp. A1029-A1029.

MARTINS EB, CHAPMAN RW, FLEMING KA. 1995. PRODUCTION OF INTERFERON-ALPHA BY LIVER AND PERIPHERAL-BLOOD T-LYMPHOCYTES IN PRIMARY SCLEROSING CHOLANGITIS GASTROENTEROLOGY, 108 (4), pp. A1118-A1118.

ROSENBERG WMC, PRINCE C, KAKLAMANIS L, JACKSON D, SIMMONS DLI, JEWELL DP, CHAPMAN RW, TROWELL JM, BELL JI. 1995. ULCERATIVE-COLITIS IS DIFFERENTIATED FROM OTHER COLONIC INFLAMMATION BY CD44-V3 AND CD44-V6 EXPRESSION GASTROENTEROLOGY, 108 (4), pp. A906-A906.

Chapman R. 1995. Does HLA status influence prognosis in primary sclerosing cholangitis? Gastroenterology, 108 (3), pp. 937-940. | Read more

MARTINS EB, CHAPMAN RW. 1995. SCLEROSING CHOLANGITIS CURRENT OPINION IN GASTROENTEROLOGY, 11 (5), pp. 452-456. | Show Abstract | Read more

Primary sclerosing cholangitis is a chronic cholestatic liver disease of unknown etiology that leads to progressive obliterative fibrosis of the biliary tree. It is strongly associated with ulcerative colitis. The disease progresses in most patients to death from liver failure or cholangiocarcinoma. Although the etiology remains unknown, it is clearly immune mediated, confirmed by the close association with the autoimmune haplotype HLA A1, B8, DR3, DR52a. In addition, in over 70% of cases, antineutrophil cytoplasmic antibody that does not disappear after liver transplantation circulates. The neutrophil antigen remains unknown. The gold standard for diagnosis remains endoscopic retrograde cholangiopancreatography. The clinical course is variable, and patients may be asymptomatic at presentation. Median survival ranges from 12 to 21 years. The diagnosis of cholangiocarcinoma in primary sclerosing cholangitis remains difficult to establish, although serum markers such as carcinoembryonic antigen and carbohydrate antigen CA 19-9, and histologic markers such as dysplasia may suggest the development of bile duct cancer. No medical treatment is of proven benefit, but ursodeoxycholic acid is the most promising therapy. Orthotopic liver transplantation remains the only effective treatment and the results are excellent, with a 5-year survival rate higher than 70%.

Healey CJ, Smith DB, Walker JL, Holmes EC, Fleming KA, Chapman RW, Simmonds P. 1995. Acute hepatitis C infection after sexual exposure. Gut, 36 (1), pp. 148-150. | Show Abstract | Read more

A case is described of a woman with acute hepatitis C infection whose partner had chronic hepatitis C infection and where heterosexual contact was the only major risk factor. Infection of both partners was confirmed serologically and by the finding of virus RNA by reverse transcription and polymerase chain reaction amplification. Nucleotide sequence analysis of the NS5 region (RNA polymerase) was used to show that both partners were infected with virus of the same genotype (1a). The nucleotide sequence of virus RNA found in the female patient is closest to variants cocirculating in the male contact, consistent with transmission having occurred between the two.

Lo SK, Fleming KA, Chapman RW. 1994. A 2-year follow-up study of anti-neutrophil antibody in primary sclerosing cholangitis: relationship to clinical activity, liver biochemistry and ursodeoxycholic acid treatment. J Hepatol, 21 (6), pp. 974-978. | Show Abstract | Read more

A specific anti-neutrophil antibody was recently described in primary sclerosing cholangitis and was detected using an indirect immunoalkaline phosphatase method. The present study examined the relationship of this antibody with respect to time, clinical activity, liver biochemistry, histology and ursodeoxycholic acid treatment. Fourteen patients with primary sclerosing cholangitis were followed up at regular intervals for 2 years. Clinical activity, liver biochemistry, histology and anti-neutrophil antibody titre were determined during the study period. A fluctuating course of the anti-neutrophil antibody was noted in both untreated patients and in those who were on ursodeoxycholic acid. This finding will have clinical implications if anti-neutrophil antibody is used to screen for potential primary sclerosing cholangitis in the future. The results suggest that several determinations of the antibody would need to be carried out over a period of time. No correlation was found between the antibody titre, clinical activity, liver biochemistry or histology. Anti-neutrophil antibody in primary sclerosing cholangitis probably has no pathogenic significance and is an epiphenomenon.

Mehal WZ, Lo SK, Chapman RW, Fleming KA. 1994. The immunogenetic basis for anti-neutrophil cytoplasmic antibody production in primary sclerosing cholangitis and ulcerative colitis. J Hepatol, 21 (5), pp. 910-911. | Read more

HEALEY CJ, SABHARWAL NK, MCOMISH F, CHAPMAN RW, FLEMING KA, SIMMONDS P, CHAPEL H. 1994. OUTBREAK OF ACUTE HEPATITIS-C FOLLOWING INTRAVENOUS IMMUNOGLOBULIN THERAPY HEPATOLOGY, 20 (4), pp. A249-A249.

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European Pubmed Central

Martins EB, Fleming KA, Garrido MC, Hine KR, Chapman RW. 1994. Superficial thrombophlebitis, dysplasia, and cholangiocarcinoma in primary sclerosing cholangitis. Gastroenterology, 107 (2), pp. 537-542. | Show Abstract | Read more

Cholangiocarcinoma occurs in approximately 10% of patients with primary sclerosing cholangitis. Usually, liver failure, rapidly progressing jaundice, and an increase in alkaline phosphatase levels are suggestive diagnostic features. We report two cases of patients with primary sclerosing cholangitis who developed cholangiocarcinoma without jaundice and with no changes in their serum biochemistry. Both patients were taking ursodeoxycholic acid at the time of tumor diagnosis. Initial suspicion of malignancy was based on the development of superficial thrombophlebitis. Liver histology showed evidence of bile duct epithelial dysplasia in areas free from tumor in one patient, and in the other, bile duct epithelial dysplasia preceded the appearance of cholangiocarcinoma by at least 18 months. In one of the cases, the dysplastic epithelium stained positively for carcinoembryonic antigen. The histological finding of bile duct epithelial dysplasia in patients with primary sclerosing cholangitis may suggest either imminent or actual development of cholangiocarcinoma and may thus affect consideration of orthotopic liver transplantation. In addition, the development of superficial thrombophlebitis in patients with primary sclerosing cholangitis should arouse suspicion of the presence of cholangiocarcinoma even if there is no evidence of deterioration of the liver function or a dominant stricture on endoscopic retrograde cholangiography.

Bloom S, Fleming K, Chapman R, Neuberger J, Hubscher S. 1994. Inappropriate expression of blood group antigens in hepatic allografts. Hepatology, 19 (4), pp. 876-881. | Show Abstract | Read more

We examined the expression of blood group antigens of the ABO, Lewis and Kell antigen systems using monoclonal antibodies and immunohistochemical study on 42 liver allograft specimens from 33 patients who underwent liver transplantation between 1986 and 1991 to learn whether altered blood group antigen expression might have a bearing on the immunopathogenesis of transplant rejection. Specimens were obtained at intervals of 0 days to 3 yr after transplant; they yielded the following histological diagnoses; time zero (n = 4), acute rejection (n = 4), pure cholestasis (n = 4), biliary obstruction (n = 4), early chronic rejection (n = 4), end-stage chronic rejection (n = 15) and miscellaneous late posttransplant biopsies (n = 7). Aberrant expression of blood group antigens was observed in 5 of 15 patients with chronic rejection. Two transplants into the same group O patient showed aberrant expression of AB antigens on hepatocytes, with a canalicular pattern, in group O-transplanted livers. In all three cases in which a group O liver was transplanted into a group A recipient and histological signs of chronic rejection were present, antibody staining showed acquisition of recipient blood phenotype by the donor liver bile ducts, endothelium or both. Aberrant expression of ABO antigens was seen only in chronic rejection. In seven cases we noted canalicular staining of periportal hepatocytes with the Lewis antibodies, normally confined to ducts and ductules. This was associated with severe cholestasis in six of the seven cases and may have represented early ductular metaplasia. These changes in carbohydrate cell surface phenotype may play a role in regulation of hepatic allograft susceptibility to immune-mediated damage.

MARTINS EB, CHAPMAN RW, FLEMING KA. 1994. ENHANCED BILE-DUCT EXPRESSION OF HEAT-SHOCK PROTEIN IS A NONSPECIFIC FEATURE OF BILE-DUCT DISEASE HEPATOLOGY, 19 (4), pp. I98-I98.

MARTINS EB, HEALEY CJ, CHAPMAN RW, FLEMING KA. 1994. INCREASED ACTIVATION OF PERIPHERAL-BLOOD AND LIVER T-LYMPHOCYTES IN PATIENTS WITH PRIMARY SCLEROSING CHOLANGITIS AND AUTOIMMUNE LIVER-DISEASES HEPATOLOGY, 19 (4), pp. I98-I98.

MARTINS EB, CHAPMAN RW, FLEMING KA. 1994. GAMMA/DELTA-T-CELLS IN PRIMARY SCLEROSING CHOLANGITIS AND AUTOIMMUNE HEPATITIS ARE ACTIVATED AND PREFERENTIALLY USE THE V-DELTA-1 GENE-PRODUCT GASTROENTEROLOGY, 106 (4), pp. A940-A940.

MARTINS EB, FLEMING KA, CHAPMAN RW. 1994. CYTOKINE PROFILE IN AUTOIMMUNE LIVER-DISEASES USING THE REVERSE HEMOLYTIC PLAQUE-ASSAY GASTROENTEROLOGY, 106 (4), pp. A940-A940.

Mehal WZ, Lo YM, Wordsworth BP, Neuberger JM, Hubscher SC, Fleming KA, Chapman RW. 1994. HLA DR4 is a marker for rapid disease progression in primary sclerosing cholangitis. Gastroenterology, 106 (1), pp. 160-167. | Show Abstract | Read more

BACKGROUND/AIMS: Primary sclerosing cholangitis (PSC) is an inflammatory disease of the biliary tree associated with an increase in the HLA alleles DR3, DR52a, DR2, Dw2, and a decrease in DR4. However, it is not certain which of these alleles provides the primary associations. Our aim was to establish the primary HLA associations with PSC and to assess the ability of HLA alleles to mark for disease progression. METHODS: By applying molecular techniques to archival tissue, we have genotyped 83 PSC patients from two populations and 131 controls for the alleles HLA DR2, DR3, DR4, DRw12, DR52a, and Dw2. RESULTS: HLA DR3, DR52a, DR2, and Dw2 were all significantly increased in PSC, with the relative risk for DR52a and Dw2 being greater than for DR3 and DR2, respectively. HLA DR4 was significantly decreased, but this may be artifactual to the DR3, DR2 increase. HLA DR4 and not DR52a marks for rapid disease progression in both our PSC populations. CONCLUSIONS: HLA DR52a and Dw2 are the best candidate alleles for providing the known HLA association with PSC. HLA DR4 and not DR52a marks for rapid disease progression in our two PSC populations.

Mehal WZ, Gregory WL, Lo YM, Cross SJ, Fleming KA, Bassendine MF, James OF, Campbell RD, Chapman RW, Rosenberg WM. 1994. Defining the immunogenetic susceptibility to primary biliary cirrhosis. Hepatology, 20 (5), pp. 1213-1219. | Show Abstract | Read more

Primary biliary cirrhosis is a chronic cholestatic disease, thought to be immune-mediated with genetic susceptibility encoded in the major histocompatibility complex. In northern Europeans, the best established associations are with HLA-DR8 and the complement allele, C4B2. These associations could be due to a single susceptibility locus on an extended haplotype linking HLA-DR8 and C4B2 or to both HLA-DR8 and C4B2 independently conferring disease susceptibility. C4B2 genotyping was performed on 64 patients with primary biliary cirrhosis and 61 controls matched for ethnic background and frequency of HLA-DR8. C4B2 was associated with HLA-DR8 (p < 0.05) in PBC. No difference in the frequency of C4B2 was detected between control and disease populations, suggesting that HLA-DR8 and C4B2 are in linkage disequilibrium and that C4B2 is not a susceptibility locus for PBC. Taq I polymorphisms were screened in the disease and control populations with the cosmid probe G91, located midway between the HLA-DR and complement loci. One G91 restriction fragment (G91A) was found to be associated with both HLA-DR8 and C4B2, at equal frequency in health and disease, providing evidence of an HLA-DR8-G91A-C4B2 extended haplotype. The frequency of G91A was the same in the disease and control populations, suggesting that G91A does not confer disease susceptibility. These findings establish G91 as the telomeric boundary for disease susceptibility associated with HLA-DR8, encoded on chromosome six. These studies help define the immunogenetic susceptibility locus for primary biliary cirrhosis.

Rosenberg WM, Ryley NG, Trowell JM, McGee JO, Chapman RW. 1993. Dextropropoxyphene induced hepatotoxicity: a report of nine cases. J Hepatol, 19 (3), pp. 470-474. | Show Abstract | Read more

Nine patients are described with jaundice, upper abdominal pain and malaise attributable to dextropropoxyphene hepatotoxicity. In each case the history was suggestive of large bile duct obstruction. All patients underwent ultrasound examination and percutaneous liver biopsy. Three patients also underwent endoscopic retrograde cholangio pancreatography. The histological features of the biopsies concur with previously reported cases of dextropropoxyphene hepatotoxicity. The histological changes seen on biopsy were remarkably constant, consisting of centrilobular cholestasis, portal tract inflammation and bile duct abnormalities, in all cases mimicking large bile duct obstruction. Fifteen previous patients with probable dextropropoxyphene hepatotoxicity have been described. The occurrence of 9 further cases at one centre, 6 presenting within 12 months, suggests that it is much more common than previously assumed and may be misdiagnosed as large bile duct obstruction.

MEHAL WZ, GREGORY W, CROSS SJ, FLEMING KA, CAMPBELL RD, JAMES OFW, BASSENDINE MF, CHAPMAN RW, ROSENBERG WMC. 1993. COMPLEMENT C4B2 AND HLA DR8 GENOTYPING EXPLAINS THEIR KNOWN ASSOCIATIONS IN PBC HEPATOLOGY, 18 (4), pp. A216-A216. | Read more

Lo SK, Chapman RW, Fleming KA. 1993. Investigation of the specific autoantigen of primary sclerosing cholangitis by western blot and immunoprecipitation. Hepatology, 18 (2), pp. 469-474. | Read more

Bloom S, Heryet A, Fleming K, Chapman RW. 1993. Inappropriate expression of blood group antigens on biliary and colonic epithelia in primary sclerosing cholangitis. Gut, 34 (7), pp. 977-983. | Show Abstract | Read more

The distribution of carbohydrate antigens of the ABO, Lewis, and Kell systems was examined in biliary and colonic epithelial of 11 patients with primary sclerosing cholangitis (PSC) using a panel of 11 monoclonal antibodies. Controls consisted of 27 liver biopsy specimens (11 normal, six alcoholic liver disease, five extrahepatic obstruction, and five primary biliary cirrhosis) and 24 colonic biopsy specimens (six normal, four Crohn's disease, and 14 ulcerative colitis). There was inappropriate staining with anti-A (four of six, 66%) and anti-B (nine of 11, 81%) in biliary epithelium of PSC patients compared with normal and disease controls. Expression of Lewis antigens was increased in patients with cholestatic liver disease. Ninety one per cent of PSC patients showed a similar pattern of inappropriate staining by anti-A and anti-B antibodies in colonic epithelium compared with 33% of normal and 42% of inflammatory bowel disease controls. There is inappropriate expression of A and B carbohydrate antigens in biliary and colonic epithelium in PSC. Whether these oncofetal antigens are implicated in the pathogenesis of this condition is discussed.

Mehal WZ, Esiri MM, Lo YM, Chapman RW, Fleming KA. 1993. Detection of reactivation and size variation in the regulatory region of JC virus in brain tissue. J Clin Pathol, 46 (7), pp. 646-649. | Show Abstract | Read more

AIMS: To develop a sensitive and specific polymerase chain reaction (PCR) based system for detecting genomic variation in JC virus. To apply this system to formalin fixed, paraffin wax embedded brain tissue from patients with and without progressive multifocal leucoencephalopathy (PML). METHODS: A pair of primers (JC1 and JC2) were designed to be complementary to the early and late regions of JC and BK polyomaviruses, respectively. A third primer (JC3), internal to JC1 and JC2, was designed to be specific for JC virus. The specificity of JC3 was investigated by amplifying plasmids with BK or JC virus genomes. Sensitivity was estimated by titration of a plasmid containing JC virus genome. Seven brains from patients with PML (PMLB) and 30 from patients without PML (non-PMLB) were amplified using JC1 and JC2, followed by JC1 and JC3. Amplification of the beta globin gene was used as an amplification control. RESULTS: Amplification with JC1 and JC2 was common for JC and BK viruses, but with JC1 and JC3 it was specific for JC virus. The sensitivity of the system was 25 copies of JC plasmid per 10 microliters of digested tissue. Five out of seven PMLB and 28 of the 30 non-PMLB amplified for beta globin, but only the PMLB gave a signal with polyoma primers. Hypervariation of the length of the regulatory region of the JC isolates in the PML tissues was consistent with the presence of multiple strains of JC. CONCLUSIONS: Variation in the regulatory region of JC virus can be specifically and sensitively detected from routinely processed, paraffin wax embedded brain tissue. Variation in the regulatory region is common in PML derived JC strains, but JC virus was not detectable in non-PMLB tissue.

Fowlie S, Jones HW, Hignett C, Rosenberg W, Chapman RW. 1993. Investigation of colonic symptoms: the value of flexible sigmoidoscopy. Br J Clin Pract, 47 (4), pp. 185-186. | Show Abstract

Colonic symptoms and large-bowel disease are common in elderly people, but the optimum investigative schema is not well established. Double-contrast barium enema (DCBE) and full colonoscopy share several drawbacks; both require colonic preparation which at best causes stool frequency and urgency, at worse dehydration and hypovolaemia. Many physicians feel that in the elderly this represents such a risk that inpatient preparation is preferred. Both investigations may involve much discomfort and distress. Rigid sigmoidoscopy is the traditional first colonic examination in patients with colonic symptoms, but will detect fewer than 10% of significant colonic lesions. Further investigation is almost always needed in elderly patients.

Gregory WL, Mehal W, Dunn AN, Cavanagh G, Chapman R, Fleming KA, Daly AK, Idle JR, James OF, Bassendine MF. 1993. Primary biliary cirrhosis: contribution of HLA class II allele DR8. Q J Med, 86 (6), pp. 393-399. | Show Abstract | Read more

Primary biliary cirrhosis is a chronic cholestatic disease of unknown aetiology which predominantly affects middle-aged women. It is thought to be autoimmune in nature, but unlike many autoimmune diseases no clear HLA association has been described. Several studies have suggested conflicting associations with HLA class II, although a DR8 association is most frequently described. To test the hypothesis that primary biliary cirrhosis is associated with a certain HLA class II locus we genotyped 130 patients with the disease from the north-east region of England and 363 local healthy controls. HLA-DRB1 and confirmatory DQA and DQB genotypes were determined by TaqI restriction fragment DNA length polymorphism analysis. In addition, a polymerase chain reaction technique (double ARMS) was used to investigate the DRB3 locus (DR52) in 98 primary biliary cirrhosis patients and 107 local controls. We found an increased frequency of HLA-DR8 (18.5% vs 9.2%, p < 0.005, relative risk of 2.0 [1.3-3.1]) in the primary biliary cirrhosis group. HLA-DR8-positive primary biliary cirrhosis patients had a higher serum bilirubin level (p = 0.03) than DR8-negative patients. There was no difference in the DR52 frequencies and no association with markers of disease severity. These results support earlier serological findings, although the association between primary biliary cirrhosis and DR8 is weaker than previously described. In addition, DR8-positivity may identify a clinical subgroup with a worse prognosis.

MEHAL WZ, LO SK, WORDSWORTH PB, CHAPMAN RW, FLEMING KA. 1993. HLA DRW52A AND DW2 ARE NOT ASSOCIATED WITH THE DEVELOPMENT OF ANTI NEUTROPHIL ANTIBODY TYPE1 (ANCA1) IN ULCERATIVE-COLITIS (UC) GASTROENTEROLOGY, 104 (4), pp. A743-A743.

MEHAL WZ, HUBSCHER SG, WORDSWORTH BP, NEUBERGER JM, FLEMING KA, CHAPMAN RW. 1993. IMMUNOGENETIC FACTORS IN THE CLINICAL COURSE OF PRIMARY SCLEROSING CHOLANGITIS (PSC) GASTROENTEROLOGY, 104 (4), pp. A953-A953.

Campbell AP, Cobb CA, Chapman RW, Kettlewell M, Hoang P, Haot BJ, Jewell DP. 1993. Cap polyposis--an unusual cause of diarrhoea. Gut, 34 (4), pp. 562-564. | Show Abstract | Read more

'Cap polyposis' is a poorly recognised condition with distinct clinical, sigmoidoscopic, and pathological features that may be confused with other inflammatory conditions of the large intestine including pseudomembranous colitis and idiopathic chronic inflammatory bowel disease. The pathogenesis is unknown but on the basis of the characteristic histological appearances, which are similar to those seen in situations where mucosal prolapse is the underlying mechanism, it has been suggested that the latter may be an important aetiological factor. Two cases are described. Histological features in the first (presence of intramucosal elastin) and clinical features in the second (rectal prolapse) support the above hypothesis.

MEHAL WZ, CULSHAW KD, TILLOTSON GS, CHAPMAN RW. 1993. ANTIBIOTIC-PROPHYLAXIS FOR ERCP - A RANDOMIZED CLINICAL-TRIAL OF CIPROFLOXACIN VERSUS CEFUROXIME GASTROENTEROLOGY, 104 (4), pp. A370-A370.

LO SK, CHAPMAN RW, DOOLEY JS, FLEMING KA. 1993. ABERRANT HLA-DR ANTIGEN EXPRESSION BY BILE-DUCT EPITHELIUM IN PRIMARY SCLEROSING CHOLANGITIS IS DOWN-REGULATED BY URSODEOXYCHOLIC ACID GASTROENTEROLOGY, 104 (4), pp. A943-A943.

MEHAL WZ, DRISCOLL PC, SMITH MJ, CHAPMAN RW, FLEMING KA. 1993. COMPARISON OF THE 2 ALLELES ASSOCIATED WITH PRIMARY SCLEROSING CHOLANGITIS (PSC) USING COMPUTER MODELING BASED ON THE CLASS 1 CRYSTALLINE-STRUCTURE GASTROENTEROLOGY, 104 (4), pp. A953-A953.

MEHAL WZ, GREGORY W, CROSS SJ, FLEMING KA, CAMPBELL RD, JAMES OFW, BASSENDINE MF, CHAPMAN RW, ROSENBERG WMC. 1993. LOCALIZATION OF THE IMMUNOGENETIC SUSCEPTIBILITY IN PRIMARY BILIARY-CIRRHOSIS (PBC) GASTROENTEROLOGY, 104 (4), pp. A953-A953.

Lo SK, Chapman RW, Cheeseman P, Charlton CP, Walker-Smith JA, Mieli-Vergani G, Fleming KA. 1993. Antineutrophil antibody: a test for autoimmune primary sclerosing cholangitis in childhood? Gut, 34 (2), pp. 199-202. | Show Abstract | Read more

The detection of an antineutrophil antibody which is highly sensitive and specific for adult primary sclerosing cholangitis using indirect immunoalkaline phosphatase has been previously described. In this study, the diagnostic potential of this method in childhood primary sclerosing cholangitis is described. A range of 72 blinded children's sera (36 boys), aged six months to 21 years (10 primary sclerosing cholangitis, eight autoimmune chronic active hepatitis, 10 alpha-1 antitrypsin deficiency, 12 extrahepatic bile duct atresia, 11 ulcerative colitis and 21 normal subjects) was assayed. Eight of the 10 primary sclerosing cholangitis patients were correctly identified. Three patients with chronic active hepatitis also showed the characteristic primary sclerosing cholangitis pattern of staining. No ulcerative colitis patients or any other patients showed this pattern of staining. All normal subjects were negative. As in adult primary sclerosing cholangitis, there is a specific antineutrophil antibody in childhood primary sclerosing cholangitis and this provides further evidence towards an autoimmune aetiology of this condition. The test may have diagnostic potential.

Lo SK, Chapman RW, Fleming KA. 1993. Tissue distribution of autoantigen specific for primary sclerosing cholangitis. J Clin Pathol, 46 (3), pp. 246-249. | Show Abstract | Read more

AIM: To investigate the tissue distribution of the autoantigen specific for primary sclerosing cholangitis. METHODS: A range of normal frozen tissues including nervous system, muscle, uterus, ovary, prostate, pancreas, thyroid, salivary gland, adrenal gland, colon, gall bladder, stomach, jejunum, aorta, skin, kidney, liver, spleen and thymus was sectioned, fixed with acetone, and air-dried. Normal bone marrow and HL60, K562, and U937 cells were cytocentrifuged on to slides, air-dried, and alcohol fixed. Four sera from primary sclerosing cholangitis with high titre antibody (> 1/100) were used to screen the tissues using either two-step or APAAP immunohistochemistry. Normal sera were used as controls. RESULTS: Positive signal was detected in neutrophils in spleen with three out of four primary sclerosing cholangitis sera while one out of four primary sclerosing cholangitis sera stained spindle cells in the liver. All four sera stained mature neutrophils of the normal bone marrow. Some bone marrow neutrophil precursors (metamyelocytes and myelocytes) were also positive. All other tissues, including HL60, K562, and U937 cells, were negative. Normal sera were negative on all tissues. CONCLUSION: Antigen specific for primary sclerosing cholangitis seems to be unique to neutrophil polymorphs and is present only after myeloblast differentiation of the myeloid cell line. The antigen may be within the secondary granule of the neutrophil polymorph.

Morris C, Chapman R, Mayou R. 1992. The outcome of unexplained dyspepsia. A questionnaire follow-up study of patients after endoscopy. J Psychosom Res, 36 (8), pp. 751-757. | Show Abstract | Read more

Ninety-three consecutive patients referred to a gastroenterology unit with unexplained dyspeptic symptoms were sent a postal questionnaire 6-12 months after endoscopy. It inquired into their current physical symptoms and subjective improvement since investigation, satisfaction with treatment, past history and current psychological well-being. A comparison group of 47 patients with peptic disease were similarly surveyed. Those with unexplained dyspepsia reported more current physical symptoms, more dissatisfaction with their treatment and less subjective improvement than those with peptic disease. The two groups were similar in terms of psychological distress but previous consultation for abdominal and other somatic complaints were more common in those with unexplained dyspepsia. The implications for management of dyspeptic patients are discussed.

Dickson ER, Murtaugh PA, Wiesner RH, Grambsch PM, Fleming TR, Ludwig J, LaRusso NF, Malinchoc M, Chapman RW, Kaplan MM. 1992. Primary sclerosing cholangitis: refinement and validation of survival models. Gastroenterology, 103 (6), pp. 1893-1901. | Show Abstract | Read more

The natural history of primary sclerosing cholangitis was studied in 426 patients from five medical centers. The median follow-up time was 3.0 years (range, 0.01-16.6 years); 100 patients had died by the time of last follow-up. Survival analysis (Cox proportional-hazards regression) was used to identify the variables most useful in predicting survival of patients with primary sclerosing cholangitis. Serum bilirubin concentration, histological stage on liver biopsy, age, and the presence of splenomegaly were independent predictors of a high risk of dying. A mathematical model to predict survival of patients with primary sclerosing cholangitis (based on referral values of those predictors) was statistically validated using two methods. Confidence intervals for predicting patient-specific survival probabilities are also presented. This model to predict survival could be used to stratify participants in therapeutic trials, counsel patients and their families, decide on candidacy for and timing of liver transplantation, and provide mathematical controls for evaluating the efficacy of therapies for primary sclerosing cholangitis, including transplantation.

MEHAL WZ, SNOOK JA, RUDENSKI A, KAY JDS, CHAPMAN RW. 1992. PROCOLLAGEN-III PEPTIDE AS AN INDICATOR OF HEPATIC FIBROGENESIS IN PRIMARY SCLEROSING CHOLANGITIS EUROPEAN JOURNAL OF GASTROENTEROLOGY & HEPATOLOGY, 4 (11), pp. 937-941.

GREGORY W, MEHAL W, DALY AK, DUNN AN, CAVANAGH G, CHAPMAN R, IDLE J, JAMES OFW, BASSENDINE MF. 1992. ANALYSIS OF MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-II GENOTYPE IN PRIMARY BILIARY-CIRRHOSIS USING RFLP AND PCR HEPATOLOGY, 16 (4), pp. A61-A61.

Lo SK, Fleming KA, Chapman RW. 1992. Prevalence of anti-neutrophil antibody in primary sclerosing cholangitis and ulcerative colitis using an alkaline phosphatase technique. Gut, 33 (10), pp. 1370-1375. | Show Abstract | Read more

The detection of a nuclear anti-neutrophil antibody in patients with primary sclerosing cholangitis (PSC), using an immunoperoxidase technique, was recently reported by us. Subsequently, detection of a cytoplasmic anti-neutrophil antibody was reported by others, using a two stage procedure of enzyme linked immunosorbent assay followed by an immunofluorescent method. Detection of cytoplasmic anti-neutrophil antibody in PSC, which, in contrast to that two stage procedure, uses a simple one step immuno-alkaline phosphatase method is now reported. Normal human neutrophils were cytocentrifuged, ethanol fixed, and then incubated with coded patients' sera. Rabbit anti-human immunoglobulin conjugated with alkaline phosphatase was used to detect the bound antibody. Fast red was used to visualise the reaction. Twenty three of 30 (77%) PSC patients showed positive granular cytoplasmic staining (with some perinuclear accentuation) with a network of cytoplasmic filaments. Fifteen of 45 (33%) ulcerative colitis patients and 1 of 3 chronic active hepatitis patients showed similar staining. Thirty five of 152 patients with ulcerative colitis, chronic active hepatitis, and a variety of other liver diseases showed a different pattern of cytoplasmic labelling, with no surrounding filaments. Seventy nine patients, including seven PSC patients and 33 normal subjects, were negative. In comparison, 86% of PSC patients, 57% of patients with primary biliary cirrhosis, 50% of normal subjects, and well over 60% of patients with ulcerative colitis, Crohn's disease, alcoholic liver disease, and chronic active hepatitis were positive using the one step immunofluorescent method. This method is more specific for PSC than those described in recent reports and may be of diagnostic importance.

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LO SK, HERRMANN R, CHAPMAN RW, FLEMING KA, SHEARMAN J, CUSICK P, DOOLEY JS. 1992. URSODEOXYCHOLIC ACID IN PRIMARY SCLEROSING CHOLANGITIS - A DOUBLE-BLIND PLACEBO CONTROLLED TRIAL HEPATOLOGY, 16 (4), pp. A92-A92.

BLOOM SL, HERYET A, FLEMING K, CHAPMAN RW. 1992. ADHESION MOLECULE EXPRESSION IN PRIMARY SCLEROSING CHOLANGITIS (PSC) HEPATOLOGY, 16 (4), pp. A162-A162.

MEHAL WZ, FLEMING KA, CHAPMAN RW. 1992. A SURVEY OF CYTOMEGALOVIRUS (CMV) DNA IN PRIMARY SCLEROSING CHOLANGITIS (PSC) LIVER-TISSUES USING A SENSITIVE POLYMERASE CHAIN-REACTION (PCR) BASED ASSAY HEPATOLOGY, 16 (2), pp. 546-546.

Shearman JD, Chapman RW, Satsangi J, Ryley NG, Weatherhead S. 1992. Misuse of ecstasy. BMJ, 305 (6848), pp. 309. | Read more

CHAPMAN RW. 1992. REVIEW IN DEPTH - PRIMARY SCLEROSING CHOLANGITIS - RECENT DEVELOPMENTS - OVERVIEW EUROPEAN JOURNAL OF GASTROENTEROLOGY & HEPATOLOGY, 4 (4), pp. 259-260.

Mehal WZ, Hattersley AT, Chapman RW, Fleming KA. 1992. A survey of cytomegalovirus (CMV) DNA in primary sclerosing cholangitis (PSC) liver tissues using a sensitive polymerase chain reaction (PCR) based assay. J Hepatol, 15 (3), pp. 396-399. | Show Abstract | Read more

Reactivation of cytomegalovirus (CMV) has been implicated as a possible etiological agent in primary sclerosing cholangitis (PSC) partly because of the ability of CMV infection to cause hepatobiliary damage, and further because of the recent recognition of a PSC-like syndrome in AIDS patients, many of whom have hepatobiliary infection with CMV. Direct evidence of CMV infection in PSC has come from a study detecting CMV DNA in 7/7 PSC livers, but only 5/20 controls. We have developed an assay for CMV-DNA by amplification of the immediate early region of CMV using the polymerase chain reaction, followed by Southern blotting and 32P oligoprobing of the amplification product. This system has an average sensitivity of at least 25 copies of CMV-DNA per 5000 formalin-fixed paraffin-embedded cells. 37 PSC and 19 control samples of formalin-fixed paraffin-embedded hepatobiliary tissues were studied. Amplification for the beta-globin in each sample was used as an amplification control, and fetal lung with known CMV infection as the CMV-positive control. 37/37 PSC tissues amplified for beta-globin, and one of these was positive for CMV-DNA. All 19 controls amplified for beta-globin, with none being positive for CMV. The lack of CMV-DNA in 35/36 PSC samples at a level of 25 copies per 5000 cells, we believe, rules out any significant CMV reactivation in these tissues, and suggests that CMV replication and re-activation is not responsible for the progression of PSC.

BLOOM SL, IRELAND A, RYLEY NG, CHAPMAN RW, LINDSELL D. 1992. CORRELATION BETWEEN HEPATIC ULTRASOUND AND HISTOLOGY EUROPEAN JOURNAL OF GASTROENTEROLOGY & HEPATOLOGY, 4 (1), pp. 39-42. | Show Abstract

Objective: To correlate findings in routine departmental hepatic ultrasound examinations with histological findings at liver biopsy. Design: Retrospective comparison of ultrasound findings and histology assessed independently by different observers. Setting: Patients admitted to teaching hospital for liver biopsy. Patients, participants: 102 patients admitted for liver biopsy who had hepatic ultrasound examinations within a few days of biopsy. Main outcome measures: Sensitivity and specificity of ultrasound examination compared with histology. Results: Including patients with mild non-specific fatty changes on histology, ultrasound had a sensitivity and specificity of 95% and 37%, respectively, for detecting normal livers. Ultrasound was highly specific for detecting fatty change but sensitivity was poor for mild fatty change compared with moderate/severe fatty change (24% versus 81%). Ultrasound was similarly specific (85%) for fibrosis or cirrhosis but less sensitive (31%). 80% of alcoholic liver disease patients had an abnormal though not necessarily diagnostic scan. Conclusions: A normal ultrasound by no means excludes parenchymal liver disease, while an abnormal scan is strong evidence of significant pathology. Ultrasound examination is less sensitive than liver biopsy in assessing the degree of hepatic fibrosis.

DALTON HR, MERRETT MN, BARR H, BRITTON BJ, CHAPMAN RW. 1992. ENDOSCOPICALLY PLACED BILIARY STENTS FOR IMPACTED COMMON BILE-DUCT STONES IN THE ELDERLY - RESULTS OF LONG-TERM FOLLOW-UP GUT, 33 (2), pp. S13-S13.

LO SK, CHAPMAN RW, FLEMING KA. 1992. TISSUE DISTRIBUTION OF AN AUTOANTIGEN SPECIFIC FOR PRIMARY SCLEROSING CHOLANGITIS (PSC) JOURNAL OF PATHOLOGY, 168 pp. A149-A149.

MEHAL WZ, WORDSWORTH BP, TAYLOR CJ, BELL JI, FLEMING KA, CHAPMAN RW. 1991. INABILITY TO ATTRIBUTE SUSCEPTIBILITY TO PRIMARY SCLEROSING CHOLANGITIS TO SPECIFIC AMINO-ACID POSITIONS OF THE HLA-DRW52A ALLELE NEW ENGLAND JOURNAL OF MEDICINE, 325 (17), pp. 1252-1252.

FARRANT JM, HAYLLAR K, LO SK, CHAPMAN RW, WILLIAMS R. 1991. SURVIVAL AND USE OF A PROGNOSTIC MODEL IN PRIMARY SCLEROSING CHOLANGITIS GUT, 32 (10), pp. A1249-A1250.

Dorudi S, Chapman RW, Kettlewell MG. 1991. Carcinoma of the gallbladder in ulcerative colitis and primary sclerosing cholangitis. Report of two cases. Dis Colon Rectum, 34 (9), pp. 827-828. | Show Abstract | Read more

The authors present the cases of two patients with carcinoma of the gallbladder complicating chronic ulcerative colitis. Both patients had concomitant primary sclerosing cholangitis. Twelve such cases of gallbladder carcinoma have been reported in the literature. The presence of primary sclerosing cholangitis in patients with ulcerative colitis is associated with malignancy of the extrahepatic biliary tree. It is suggested that, if colectomy is necessary, the liver should be biopsied and a cholecystectomy performed if the gallbladder is deemed abnormal.

Lo YM, Mehal WZ, Wordsworth BP, Chapman RW, Fleming KA, Bell JI, Wainscoat JS. 1991. HLA typing by double ARMS. Lancet, 338 (8758), pp. 65-66. | Read more

MEHAL WZ, WORDSWORTH PB, BELL JL, FLEMING KA, CHAPMAN RW. 1991. OLIGONUCLEOTIDE DNA TYPING ANALYSIS OF THE HLA DRB3 LOCUS IN PATIENTS WITH PRIMARY SCLEROSING CHOLANGITIS (PSC) GUT, 32 (7), pp. A839-A839.

Ireland A, Hartley L, Ryley N, McGee JO, Trowell JM, Chapman RW. 1991. Raised gamma-glutamyltransferase activity and the need for liver biopsy. BMJ, 302 (6773), pp. 388-389. | Read more

LO SK, CHAPMAN RW, CUSIK P, FLEMING KA. 1991. ANTINEUTROPHIL ANTIBODY AND PRIMARY SCLEROSING CHOLANGITIS JOURNAL OF PATHOLOGY, 163 (2), pp. A170-A170.

Olerup O, Broomé U, Einarsson K, Mehal WZ, Wordsworth BP, Taylor CJ, Bell JI, Fleming KA, Chapman RW, Park MS, Terasaki PI. 1991. Inability to attribute susceptibility to primary sclerosing cholangitis to specific amino acid positions of the HLA-DRw52a allele. N Engl J Med, 325 (17), pp. 1251-1252. | Show Abstract | Read more

To the Editor: Many diseases with a suspected autoimmune cause have been associated with alleles of the HLA Class II region. A few of the HLA-associated diseases have been related to specific amino acids or epitopes of the domains of the Class II molecules distal to polymorphic membranes, such as insulin-dependent diabetes mellitus1 and selective IgA deficiency.2 Only two of the HLA-associated diseases are associated nearly 100 percent of the time with a specific Class I or II allele: ankylosing spondylitis with HLA-B27 and cataplectic narcolepsy with HLA-DR2. Prochazka et al.3 have suggested that primary sclerosing cholangitis might also have. . . © 1991, Massachusetts Medical Society. All rights reserved.

Chapman RW. 1991. Aetiology and natural history of primary sclerosing cholangitis--a decade of progress? Gut, 32 (12), pp. 1433-1435. | Read more

Chapman RW. 1991. Role of immune factors in the pathogenesis of primary sclerosing cholangitis. Semin Liver Dis, 11 (1), pp. 1-4. | Read more

BLOOM S, HERRYAT A, FLEMING K, CHAPMAN RW. 1990. INAPPROPRIATE EXPRESSION OF BLOOD-GROUP ANTIGENS ON THE BILIARY EPITHELIUM IN PRIMARY SCLEROSING CHOLANGITIS (PSC) HEPATOLOGY, 12 (4), pp. 840-840.

BLOOM SL, LINDSELL D, RYLEY N, CHAPMAN RW. 1990. CORRELATION BETWEEN HEPATIC ULTRASOUND AND HISTOLOGY IN 102 PATIENTS HEPATOLOGY, 12 (4), pp. 978-978.

Bickerstaff KI, Berry AR, Chapman RW, Britton BJ. 1990. Endoscopic sphincterotomy for the palliation of ampullary carcinoma. Br J Surg, 77 (2), pp. 160-162. | Show Abstract | Read more

Palliative endoscopic sphincterotomy was performed on 17 patients with adenocarcinoma of the ampulla of Vater. An endoprosthesis was inserted immediately after the sphincterotomy in four of the patients. Fourteen patients made uncomplicated recoveries from the procedure and their jaundice resolved completely. Early complications developed in three patients. One patient died from haemorrhage. Two patients, both of whom had an endoprosthesis, developed cholangitis. The endoprosthesis was removed and another inserted in one patient and the other underwent surgery. Both thereafter made uncomplicated recoveries. Jaundice subsequently recurred in eight patients and further endoscopic treatment was successful in five of these patients. Eleven patients died between 4 days and 23 months after the sphincterotomy with a median survival of 12 months. Four patients remain alive between 3 and 17 months after treatment. The results indicate that reasonable palliation can be achieved safely by endoscopic sphincterotomy.

Chapman RW, Forman D, Peto R, Smallwood R. 1990. Liver transplantation for acute hepatic failure? Lancet, 335 (8680), pp. 32-35. | Show Abstract | Read more

In the absence of definitive medical treatment for severe fulminant hepatic failure, liver transplantation may be appropriate in selected patients. However, uniform and easily applicable criteria for diagnosis of severity and analysis of results are needed to prevent unnecessary transplantation and to ensure that patients who may benefit are appropriately treated. Previous regimens for treatment of fulminant hepatic failure were often advocated, on the basis of data from historical controls, for several years until controlled trials failed to show any benefit. To obtain reliable information more rapidly than achieved before, a controlled trial between specialist liver transplant units is needed to establish the role of emergency hepatic transplantation in patients with fulminant hepatic failure.

Iveson TJ, Ryley NG, Kelly PM, Trowell JM, McGee JO, Chapman RW. 1990. Diclofenac associated hepatitis. J Hepatol, 10 (1), pp. 85-89. | Show Abstract | Read more

Diclofenac is a widely used non-steroidal anti-inflammatory drug, being the most commonly prescribed of its kind in the world. This paper describes five cases of hepatitis with clinical features indicating a direct link with diclofenac. All the patients presented with an acute hepatitis, three being jaundiced. They gave a history of taking diclofenac up to the time of presentation, four of the five having started the drug within the previous 3 months. There were no other features in the histories to suggest alternative causes for the liver dysfunction. Liver function tests were grossly abnormal in all cases, showing a hepatitic picture. A liver biopsy was performed in 4 cases, and showed features of an acute hepatitis with inflammation and hepatocyte damage dominating. The liver dysfunction returned to normal on drug withdrawal in four of the five cases, with full recovery by 3 months. One patient developed steroid-responsive chronic active hepatitis. Hepatotoxicity associated with diclofenac is documented, but previously only a few isolated cases have been described. The occurrence of five cases in one gastroenterology unit over a 12-month period suggests that hepatitis associated with diclofenac may be commoner than previously supposed.

Chapman RW. 1990. The immunology of primary sclerosing cholangitis. Springer Semin Immunopathol, 12 (1), pp. 121-128. | Show Abstract | Read more

A number of recent studies have been discussed which provide strong evidence that genetic and immunological factors are important in the pathogenesis of PSC. Current evidence suggests that PSC is, like primary biliary cirrhosis, an immunologically mediated disease [8]. It seems likely that the immunological destruction of the biliary system is triggered in genetically predisposed individuals by viruses or bacteria [8]. The association with ulcerative colitis may be explained by the passage of viral or bacterial organisms across the damaged colonic epithelial barrier into the systemic circulation. Further studies are needed to confirm this attractive hypothesis. © 1990 Springer-Verlag.

Snook JA, Chapman RW, Sachdev GK, Heryet A, Kelly PM, Fleming KA, Jewell DP. 1989. Peripheral blood and portal tract lymphocyte populations in primary sclerosing cholangitis. J Hepatol, 9 (1), pp. 36-41. | Show Abstract | Read more

The relative distribution of lymphocyte subpopulations in the blood and liver of patients with primary sclerosing cholangitis (PSC) and related diseases has been studied using immunoenzyme techniques. The peripheral blood CD4/CD8 T lymphocyte ratio was significantly higher in active ulcerative colitis (UC) and in PSC with inactive UC than in inactive UC alone. In contrast, no relationship with disease activity was seen in Crohn's disease. The portal tract t lymphocyte count per high power field (mean +/- S.D.) was higher in pre-cirrhotic PSC (173 +/- 105) and primary biliary cirrhosis (PBC: 210 +/- 110) than in histologically normal liver (42 +/- 27). However, the overall portal tract CD4/CD8 ratio was similar in PSC (1.49), PBC (1.89) and normal controls (1.63). The results are consistent with immunological involvement in the pathogenesis of PSC, but argue against the hypothesis that changes in the peripheral blood T cell subsets are due to sequestration at the site of tissue inflammation.

Snook JA, Chapman RW, Fleming K, Jewell DP. 1989. Anti-neutrophil nuclear antibody in ulcerative colitis, Crohn's disease and primary sclerosing cholangitis. Clin Exp Immunol, 76 (1), pp. 30-33. | Show Abstract

We have previously described circulating autoantibodies to a portal tract antigen in patients with primary sclerosing cholangitis. In this study the antigen has been shown by double-labelling studies to be specifically located in the nuclei of tissue neutrophils. Using isolated peripheral blood neutrophils and an immunoperoxidase technique, anti-neutrophil nuclear antibody (ANNA) was found in the serum of 84% of patients with primary sclerosing cholangitis (PSC: n = 32) with a median titre of 1/1000 and a peak titre of 1/500,000. ANNA was also detected in 86% of patients with inflammatory bowel disease alone (IBD: n = 76) with a median titre of 1/10 and a peak titre of 1/10,000. In contrast, only 12% of controls had ANNA, and in none was the titre greater than 1/10. In PSC the ANNA titre correlated with the serum aspartate transaminase concentration, suggesting that it is related to disease activity. In IBD the titre of ANNA was significantly higher in patients with recently active disease. There was no significant difference between the titres seen in ulcerative colitis and Crohn's disease. ANNA was not associated with neutropaenia. The results provide further evidence of involvement of autoimmune mechanisms in inflammatory bowel disease and primary sclerosing cholangitis.

Bickerstaff KI, Chapman RW, Britton BJ. 1989. Endoscopic sphincterotomy. Br J Surg, 76 (3), pp. 316. | Read more

Snook JA, Kelly P, Chapman RW, Jewell DP. 1989. Fibrolamellar hepatocellular carcinoma complicating ulcerative colitis with primary sclerosing cholangitis. Gut, 30 (2), pp. 243-245. | Show Abstract | Read more

This case report describes the previously undocumented association between fibrolamellar hepatocellular carcinoma and ulcerative colitis complicated by primary sclerosing cholangitis.

Bickerstaff KI, Berry AR, Chapman RW, Britton J. 1989. Endoscopic sphincterotomy for bile duct stones: an institutional review of 272 patients. Ann R Coll Surg Engl, 71 (6), pp. 384-386. | Show Abstract

The results of the first 283 endoscopic sphincterotomies (ES) attempted in Oxford for bile duct stones are described. Endoscopic sphincterotomy was achieved in 272 patients (96%) and complete duct clearance was achieved in 88% of these patients; an overall success rate of 85%. Complications occurred in 26 patients (10%), five of whom required an emergency laparotomy. Eight patients died within 30 days of ES but only two deaths were attributed directly to the procedure. Although the sphincterotomies were performed by several endoscopists in varying stages of training, the results are similar to those from other large reports. In the last year of the study (1987), 58 patients were referred from within the Oxfordshire District which suggests an annual demand for ES for bile duct stones of 11 patients per 100,000 of population.

Mahida YR, Chapman RW, Jewell DP. 1988. Association of small intestinal diverticulosis with chronic pancreatitis leading to severe malabsorption. Report of three cases. Postgrad Med J, 64 (757), pp. 893-896. | Show Abstract | Read more

Three cases of chronic pancreatitis occurring in patients with small intestinal diverticulosis and bacterial overgrowth are reported. In two of the cases, pancreatic supplements were therapeutically beneficial (the third being unable to tolerate them). Two of the patients also developed diverticular perforation. The possible nature of the association between small intestinal diverticulosis and chronic pancreatitis is discussed.

SNOOK JA, CHAPMAN RW, FLEMING K, JEWELL DP. 1988. ANTI-NEUTROPHIL NUCLEAR ANTIBODY IN INFLAMMATORY BOWEL-DISEASE AND PRIMARY SCLEROSING CHOLANGITIS GUT, 29 (10), pp. A1494-A1494.

SNOOK JA, RUDENSKI A, HERRMANN R, KAY JDS, DOOLEY J, MCINTYRE N, JEWELL DP, CHAPMAN RW. 1988. SERUM PROCOLLAGEN III N-TERMINAL PEPTIDE IN PRIMARY SCLEROSING CHOLANGITIS HEPATOLOGY, 8 (5), pp. 1417-1417.

Chapman RW, Kelly PM, Heryet A, Jewell DP, Fleming KA. 1988. Expression of HLA-DR antigens on bile duct epithelium in primary sclerosing cholangitis. Gut, 29 (4), pp. 422-427. | Show Abstract | Read more

The expression of HLA class I (HLA-A, B, C) and class II (HLA-DR) antigens on the biliary epithelium of 10 patients (nine men) with primary sclerosing cholangitis (PSC) was investigated using an immunoperoxidase technique on cryostat sections. Five patients were staged as grade II and five grade III on hepatic histology. None were cirrhotic. as grade II and five grade III on hepatic histology. None were cirrhotic. Controls were nine patients with primary biliary cirrhosis (PBC), five with extra hepatic biliary obstruction, 15 with other forms of chronic liver disease and six with normal livers. Bile ducts from the normal subjects and patients with chronic liver disease did not express HLA-DR antigens. In contrast, all 10 of the PSC biopsies showed varying degrees of HLA-DR staining of the biliary epithelium. Expression of DR antigens was also found on the bile ducts of all five patients with extra hepatic biliary obstruction and in six of nine patients with PBC. Expression of HLA class I antigens was seen on the biliary epithelium of all the biopsies examined. Increased numbers of helper and suppressor T-cells were seen in the portal tracts of all the PSC patients. This study has confirmed that aberrant expression of HLA-DR may occur on the biliary epithelium of some, but not all, patients with PBC. In addition, the study has shown that aberrant expression of HLA-DR always occurs in PCS at an early stage of histological liver damage. While this may be important in the pathogenesis of PSC, the aberrant expression in extra hepatic biliary obstruction suggests that it may be a secondary phenomenon.

Saunders D, Sillery J, Chapman R. 1988. Effect of calcium carbonate and aluminum hydroxide on human intestinal function. Dig Dis Sci, 33 (4), pp. 409-413. | Show Abstract | Read more

The effect of calcium carbonate (6 g daily) and of aluminum hydroxide (Amphojel, 7.2 g daily) on human gastrointestinal function was examined because these popular antacids have a documented effect on fecal fat, an undocumented association with constipation, and a putative ability to ameliorate cocarcinogenic effects of bile acids and fatty acids on colonic mucosa. Intake-output studies were conducted over periods of three weeks during which time dietary intake was controlled (20 g fiber daily), and the order of treatment (control, calcium carbonate, aluminum hydroxide) was randomized. Neither calcium carbonate nor aluminum hydroxide altered the mean intestinal transit time of eight subjects. Calcium carbonate increased daily output of feces from 106 +/- 30 (SD) to 131 +/- 41 g, of fecal fatty acids from 7.9 +/- 1.4 to 16.8 +/- 5.4 mmol, and of fecal 3 alpha-hydroxy-bile acids from 411 +/- 223 to 769 +/- 505 mumol. Aluminum hydroxide increased daily output of feces to 143 +/- 43 g, of fecal fatty acids to 12.4 +/- 5 mmol, and of fecal bile acids to 735 +/- 592 mumol. Both Ca2+ and Al3+ precipitated deoxycholate when these ions were incubated in vitro. These observations help to explain how these two antacids may lower blood lipids and ameliorate the effects of fecal bile acids and fatty acids on colonic mucosa.

Bickerstaff KI, Berry AR, Chapman RW, Britton J. 1988. Early postoperative endoscopic sphincterotomy for retained biliary stones. Ann R Coll Surg Engl, 70 (6), pp. 350-351. | Show Abstract

Endoscopic sphincterotomy was attempted on 18 patients with retained biliary stones. Endoscopy was performed within 2 weeks of the operation in 13 patients and within 3 weeks in 5 patients. A T-tube was present in 14 patients and 6 patients had multiple stones. Sphincterotomy and complete duct clearance was achieved in 17 patients (94%) and a complication (haemorrhage) occurred in one patient (6%).

SNOOK JA, FLEMING KA, HERYET A, KELLY P, JEWELL DP, CHAPMAN RW. 1987. PORTAL TRACT LYMPHOCYTE POPULATIONS IN PRIMARY SCLEROSING CHOLANGITIS GUT, 28 (10), pp. A1330-A1330.

CHAPMAN RW, KELLY P, HERYAT A, JEWELL DP, FLEMING K. 1987. EXPRESSION OF HLA-DR ANTIGENS ON BILE-DUCT EPITHELIUM IN PRIMARY SCLEROSING CHOLANGITIS GASTROENTEROLOGY, 92 (5), pp. 1724-1724.

Key NS, Kelly PM, Emerson PM, Chapman RW, Allan NC, McGee JO. 1987. Oesophageal varices associated with busulphan-thioguanine combination therapy for chronic myeloid leukaemia. Lancet, 2 (8567), pp. 1050-1052. | Show Abstract | Read more

5 patients receiving continuous busulphan and 6-thioguanine for chronic myeloid leukaemia (CML) were found to have oesophageal varices associated with abnormal liver function tests. 3 of these cases presented with gastrointestinal haemorrhage and 1 patient died. The 2 other cases had varices discovered at endoscopy. Nodular regenerative hyperplasia (NRH) of the liver was identified as the cause of portal hypertension in the 4 patients on whom liver biopsies were done. The administration of busulphan and thioguanine in combination is likely to be associated with the development of NRH, with portal hypertension and oesophageal varices occurring in a substantial proportion of cases.

Dixon JM, Chapman RW, Berry AR. 1987. Carcinoid tumour of the ampulla of Vater presenting as acute pancreatitis. Gut, 28 (10), pp. 1296-1297. | Show Abstract | Read more

The first report of a carcinoid tumour of the ampulla of Vater causing acute pancreatitis is presented. The pancreatitis resulted from ampullary obstruction and diversion of the bile through the pancreas. Endoscopic retrograde cholangiopancreatography established the correct diagnosis, making this the first occasion in which a carcinoid tumour of the ampulla of Vater has been correctly diagnosed before surgery.

Chapman RW, Selby WS, Jewell DP. 1986. Controlled trial of intravenous metronidazole as an adjunct to corticosteroids in severe ulcerative colitis. Gut, 27 (10), pp. 1210-1212. | Show Abstract | Read more

A prospective double blind controlled trial was undertaken to examine the role of metronidazole as an adjunct to corticosteroids in the management of severe ulcerative colitis. Thirty nine patients with severe ulcerative colitis were randomised on admission to hospital to receive either intravenous metronidazole 500 mg eight hourly (19 patients) or an identical intravenous placebo (20 patients). The two groups were similar with respect to age, sex, and the extent of colitis. In addition all patients received a standard intravenous regimen consisting of methyl prednisolone 16 mg six hourly and parenteral nutrition together with a twice daily hydrocortisone 100 mg enema. Treatment was continued for five days when the patients were formally assessed. Fourteen of 19 patients (74%) receiving metronidazole and 14/20 (70%) receiving placebo were substantially improved, or in remission at the end of five days. Five patients treated with metronidazole and six with placebo had no improvement and all proceeded to urgent colectomy with no operative mortality. There were three late deaths, one in the metronidazole and two in the placebo group. These results do not support the routine use of intravenous metronidazole in the treatment of severe ulcerative colitis.

Chapman RW, Cottone M, Selby WS, Shepherd HA, Sherlock S, Jewell DP. 1986. Serum autoantibodies, ulcerative colitis and primary sclerosing cholangitis. Gut, 27 (1), pp. 86-91. | Show Abstract | Read more

The aetiology of primary sclerosing cholangitis is unknown, but it is closely associated with ulcerative colitis. Serum anticolon antibodies, crossreacting with portal tracts, have been reported in patients with ulcerative colitis but no studies have been carried out in primary sclerosing cholangitis. The frequency of serum anticolon antibodies and portal tract antibodies have been measured in 24 patients with primary sclerosing cholangitis and ulcerative colitis; 15 patients with primary sclerosing cholangitis without ulcerative colitis; 77 patients without primary sclerosing cholangitis: 25 patients with Crohn's colitis; 10 patients with primary biliary cirrhosis; 22 patients with extrahepatic biliary obstruction and 20 normal controls. Serum anticolon and portal tract antibodies were detected using immunoperoxidase techniques on normal colon and obstructed human liver. Tissue typing was undertaken using a standard microcytotoxicity technique. The frequency of anticolon antibodies was markedly increased in primary sclerosing cholangitis patients with ulcerative colitis (62.5%) compared with patients with ulcerative colitis (17%) and Crohn's colitis (16%) (chi 2 = 17.9; p less than 0.001). The antibodies were almost entirely of IgG and IgA classes in all groups. Anticolon antibodies were not found in sera from any other group. Sera from eight of 15 patients with primary sclerosing cholangitis, ulcerative colitis and anticolon antibody reacted with portal tracts of human obstructed liver. This reaction was also seen in four of nine patients with ulcerative colitis and primary sclerosing cholangitis and in three of 15 patients with primary sclerosing cholangitis alone. Portal tract antibody was of IgG class and was not present in sera from any other groups. Unlike anticolon antibody, there was a close relationship between HLA-B8 phenotype and the portal tract antibody (p<0.02; chi 2 = 6.04). Absorption studies confirmed that the anticolon antibody is distinct from portal tract antibody.

Cited:

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Chapman RW, Cottone M, Selby WS, Shepherd HA, Sherlock S, Jewell DP. 1986. Serum autoantibodies, ulcerative colitis and primary sclerosing cholangitis Gut, 27 (1), pp. 86-91. | Show Abstract | Read more

The aetiology of primary sclerosing cholangitis is unknown, but it is closely associated with ulcerative colitis. Serum anticolon antibodies, crossreacting with portal tracts, have been reported in patients with ulcerative colitis but no studies have been carried out in primary sclerosing cholangitis. The frequency of serum anticolon antibodies and portal tract antibodies have been measured in 24 patients with primary sclerosing cholangitis and ulcerative colitis; 15 patients with primary sclerosing cholangitis without ulcerative colitis; 77 patients without primary sclerosing cholangitis: 25 patients with Crohn's colitis; 10 patients with primary biliary cirrhosis; 22 patients with extrahepatic biliary obstruction and 20 normal controls. Serum anticolon and portal tract antibodies were detected using immunoperoxidase techniques on normal colon and obstructed human liver. Tissue typing was undertaken using a standard microcytotoxicity technique. The frequency of anticolon antibodies was markedly increased in primary sclerosing cholangitis patients with ulcerative colitis (62.5%) compared with patients with ulcerative colitis (17%) and Crohn's colitis (16%) (χ2 = 17.9; p<0.001). The antibodies were almost entirely of IgG and IgA classes in all groups. Anticolon antibodies were not found in sera from any other group. Sera from eight of 15 patients with primary sclerosing cholangitis, ulcerative colitis and anticolon antibody reacted with portal tracts of human obstructed liver. This reaction was also seen in four of nine patients with ulcerative colitis and primary sclerosing cholangitis and in three of 15 patients with primary sclerosing cholangitis alone. Portal tract antibody was of IgG class and was not present in sera from any other groups. Unlike anticolon antibody, there was a close relationship between HLA-B8 phenotype and the portal tract antibody (p<0.02; χ2 = 6.04). Absorption studies confirmed that the anticolon antibody is distinct from portal tract antibody.

Mendelson RM, Chapman RG, Shepherd HA. 1986. Endoscopic retrograde pancreatic parenchymography Clinical Radiology, 37 (2), pp. 200-201. | Read more

Barbatis C, Grases P, Shepherd HA, Chapman RW, Trowell J, Jewell DP, McGee JO. 1985. Histological features of sclerosing cholangitis in patients with chronic ulcerative colitis. J Clin Pathol, 38 (7), pp. 778-783. | Show Abstract | Read more

Primary sclerosing cholangitis was diagnosed radiologically in 16 of 681 patients (2.2%) with chronic ulcerative colitis in a follow up study at the gastroenterology unit in Oxford. On the basis of established histological criteria, the liver biopsy was considered diagnostic in only half of the cases. The histological findings in these cases were therefore reassessed to determine whether the accuracy of biopsy diagnosis could be improved. The most common specific histological feature was periductal concentric fibrosis of small interlobular bile ducts, even in the absence of inflammation. Other common features were bile ductular proliferation associated with diminution or absence of interlobular bile ducts. Degeneration of bile duct epithelium and diffuse infiltration of portal tracts by mononuclear cells and polymorphonuclear leucocytes were accompanying features. Piecemeal necrosis without rosette formation was found in about half the biopsies. When all these features were considered together a biopsy diagnosis of primary sclerosing cholangitis was established in 14 of 16 cases.

Chapman RW, Jewell DP. 1985. Primary sclerosing cholangitis--an immunologically mediated disease? West J Med, 143 (2), pp. 193-195. | Show Abstract

Primary sclerosing cholangitis (PSC) is an uncommon, chronic disorder characterized by inflammatory fibrosis usually involving the entire biliary tree. The etiology has been unknown, but PSC is closely associated with ulcerative colitis, which coexists in more than two thirds of patients with PSC. In recent studies 3% to 5% of all patients with ulcerative colitis had PSC. We propose that PSC is, at least in part, an immunologically mediated disease; it is closely associated with human leckocyte antigens B8 and DR3, and circulating autoantibodies to colon and portal tract are frequently present. The anticolon antibody cross-reacts with enteric Escherichia coli. The disease may possibly be triggered in susceptible patients with ulcerative colitis by immunization with antigens shared between enteric microorganisms and the biliary system.

CHAPMAN RW, SELBY WS, JEWELL DP. 1985. ROLE OF METRONIDAZOLE IN THE MANAGEMENT OF SEVERE ULCERATIVE-COLITIS GUT, 26 (5), pp. A566-A566.

Chapman RW. 1985. Primary sclerosing cholangitis. J Hepatol, 1 (2), pp. 179-186. | Read more

Chapman RW, Sillery JK, Graham MM, Saunders DR. 1985. Absorption of starch by healthy ileostomates: effect of transit time and of carbohydrate load. Am J Clin Nutr, 41 (6), pp. 1244-1248. | Show Abstract | Read more

Recently, breath hydrogen studies and intubation techniques have indicated that in excess of 10% of starch in normal foods may be malabsorbed in the small intestine and enter the colon. We evaluated starch absorption in healthy subjects with ileostomy. First, unabsorbed starch was quantified in ileostomy effluent from six ileostomates who ingested constant diets of wheat and potato starch for four days. Daily unabsorbed starch ranged from 1.3% to 5.0% of total ingested starch. Second, starch from a radiolabeled solid meal containing 50 g potato starch was measured under control conditions and after altering transit time with either loperamide, or magnesium citrate. Loperamide significantly decreased the amount of unabsorbed starch in all six ileostomates (p less than 0.05), while magnesium citrate significantly increased starch malabsorption in all six subjects (p less than 0.05). Third, starch absorption was measured after single solid meals containing 25, 50, 75, and 100 g potato starch. There was a linear relationship between starch input and output. Mean output expressed as a percent of input remained constant. We conclude that the degree of starch malabsorption by the small intestine of ileostomates may be less than that estimated by indirect methods in intact humans. The amount of unabsorbed starch is directly related to the quantity ingested and to the small intestinal transit time.

Chapman RW, Sillery J, Fontana DD, Matthys C, Saunders DR. 1985. Effect of oral dioctyl sodium sulfosuccinate on intake-output studies of human small and large intestine. Gastroenterology, 89 (3), pp. 489-493. | Show Abstract | Read more

Dioctyl sodium sulfosuccinate (DSS) is an anionic detergent that is used widely as a laxative and promoted as a stool softener. Although many anecdotal reports attest to the laxative and stool softening efficacy of DSS, no controlled trials have been performed to document the effect of DSS on small or large bowel function in humans. We have compared, therefore, the effects of 100 mg of DSS three times daily (the maximum recommended dose) with placebo in a randomized, single blind, crossover study in two groups of subjects. First, 6 healthy ileostomates were studied while they ate a constant diet for 8 days. Dioctyl sodium sulfosuccinate administered for 4 days did not increase the daily ileal output of carbohydrate, total fatty acids, bile acids, nitrogen, or water. Cholesterol excretion was decreased while taking DSS (p less than 0.05). Second, 6 healthy volunteers were studied while eating a constant diet of 20 g of fiber plus 30 radiopaque markers daily so that mean daily transit time could be measured. After equilibration, a 7-day collection of stool was weighed and lyophylized to measure fecal water. Dioctyl sodium sulfosuccinate had no effect on stool weight, stool frequency, stool water, or mean transit time. We conclude that 300 mg/day of DSS does not increase ileal or colonic output of solids or water in healthy human subjects.

CHAPMAN RW, SILLERY J, SAUNDERS DR. 1984. PHYSIOLOGICAL STARCH MALABSORPTION - DIRECT QUANTITATION IN ILEOSTOMATES AND EFFECT OF SMALL BOWEL TRANSIT-TIME GUT, 25 (10), pp. 1158-1159.

Chapman RW. 1984. Primary Sclerosing Cholangitis Digestive Diseases, 2 (1), pp. 42-51. | Read more

CHAPMAN RW, SILLERY J, SAUNDERS DR. 1984. DIOCTYL SODIUM SULFOSUCCINATE (DSS), 300 MG DAILY, DOES NOT INCREASE HUMAN ILEAL OR COLONIC OUTPUT GUT, 25 (10), pp. 1156-1156.

BARBATIS C, SHEPHERD HA, CHAPMAN RW, TROWELL J, JEWELL DPJ, MCGEE JO. 1983. THE HISTOLOGICAL FEATURES OF SCLEROSING CHOLANGITIS ASSOCIATED WITH CHRONIC ULCERATIVE-COLITIS JOURNAL OF PATHOLOGY, 140 (2), pp. 125-125.

CHAPMAN RW, SELBY W, SHEPHERD H, SHERLOCK S, JEWELL DP. 1983. SERUM ANTI-COLON ANTIBODIES, ULCERATIVE-COLITIS, AND SCLEROSING CHOLANGITIS GUT, 24 (5), pp. A474-A474.

Shepherd HA, Selby WS, Chapman RW, Nolan D, Barbatis C, McGee JO, Jewell DP. 1983. Ulcerative colitis and persistent liver dysfunction. Q J Med, 52 (208), pp. 503-513. | Show Abstract

Six hundred and eighty-one patients with ulcerative colitis who attend the outpatient clinic in Oxford have been screened for the presence of persistently abnormal liver function tests. Of the 21 patients (3.0 per cent) found with abnormal liver function 17 (2.4 per cent) were shown by cholangiography to have primary sclerosing cholangitis. The liver biopsies from those patients demonstrated a wide range of histological features and were diagnostic of primary sclerosing cholangitis in only 50 per cent of the patients. When persistently abnormal liver function tests are demonstrated in patients with ulcerative colitis it is likely that primary sclerosing cholangitis will be present (81 per cent of patients in this study), and in order to make a reliable diagnosis it is necessary to perform cholangiography in addition to liver biopsy. A close association with primary sclerosing cholangitis and histocompatibility antigens HLA B8 and DR3 is also reported.

Cited:

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Scopus

Shepherd HA, Selby WS, Chapman RWG, Nolan D, Barbatis C, McGee JO, Jewell DP. 1983. Ulcerative colitis and persistent liver dysfunction Quarterly Journal of Medicine, 52 (208), pp. 503-513. | Show Abstract

Six hundred and eighty-one patients with ulcerative colitis who attend the outpatient clinic in Oxford have been screened for the presence of persistently abnormal liver function tests. Of the 21 patients (3.0 per cent) found with abnormal liver function 17 (2.4 per cent) were shown by cholangiography to have primary sclerosing cholangitis. The liver biopsies from those patients demonstrated a wide range of histological features and were diagnostic of primary sclerosing cholangitis in only 50 per cent of the patients. When persistently abnormal liver function tests are demonstrated in patients with ulcerative colitis it is likely that primary sclerosing cholangitis will be present (81 per cent of patients in this study), and in order to make a reliable diagnosis it is necessary to perform cholangiography in addition to liver biopsy. A close association with primary sclerosing cholangitis and histocomptability antigens HLA B8 and DR3 is also reported.

Chapman RW, Morgan MY, Bell R, Sherlock S. 1983. Hepatic iron uptake in alcoholic liver disease. Gastroenterology, 84 (1), pp. 143-147.

Cited:

28

WOS

BASS NM, CHAPMAN RW, OREILLY A, SHERLOCK S. 1983. PRIMARY SCLEROSING CHOLANGITIS ASSOCIATED WITH ANGIOIMMUNOBLASTIC LYMPHADENOPATHY GASTROENTEROLOGY, 85 (2), pp. 420-424.

Chapman RW, Varghese Z, Gaul R, Patel G, Kokinon N, Sherlock S. 1983. Association of primary sclerosing cholangitis with HLA-B8. Gut, 24 (1), pp. 38-41. | Show Abstract | Read more

The frequency of HLA antigens was studied in 25 patients with primary sclerosing cholangitis and compared with a control group of 562 kidney donors. Fourteen patients also had ulcerative colitis. A significant increase in the frequency of HLA-B8 (60%) was found in the primary sclerosing cholangitis patients compared with controls (25%) (p less than 0.001). HLA-B8 was found in eight patients with ulcerative colitis. The frequency of HLA-B12 was significantly decreased (8%) compared with controls (30%) (p less than 0.02). Piecemeal necrosis was observed on liver histology in 66% of HLA-B8 positive and 50% of HLA-B8 negative patients. Low titres of serum autoantibodies were frequently found in the primary sclerosing cholangitis group but did not correspond to the presence of HLA-B8. Raised serum concentrations of IgM and IgG were not related to HLA-B8. This study has shown that in patients with primary sclerosing cholangitis there exists a disease susceptibility gene closely associated with the B locus of the major histocompatibility complex which may be modified by other factors such as ulcerative colitis. Patients with ulcerative colitis and HLA-B8 may be particularly liable to develop primary sclerosing cholangitis.

Chapman RW, Morgan MY, Boss AM, Sherlock S. 1983. Acute and chronic effects of alcohol on iron absorption. Dig Dis Sci, 28 (4), pp. 321-327. | Read more

Chapman RW, Morgan MY, Laulicht M, Hoffbrand AV, Sherlock S. 1982. Hepatic iron stores and markers of iron overload in alcoholics and patients with idiopathic hemochromatosis. Dig Dis Sci, 27 (10), pp. 909-916. | Show Abstract | Read more

Liver iron concentrations were determined in 60 alcoholics with liver disease of varying severity, 15 patients with untreated idiopathic hemochromatosis, and 16 control subjects with biliary tract disease. Mean liver iron concentrations (microgram/100 mg dry weight) were significantly greater in the alcoholics (156.4 +/- 7.8 (SEM); P less than 0.05) and in patients with idiopathic hemochromatosis (2094.5 +/- 230.7; P less than 0.01) than in control subjects (53.0 +/- 7.0). Liver iron concentrations of greater than 140 micrograms/100 were found in 17 alcoholics (29%) and in all 15 patients with idiopathic hemochromatosis. Liver iron concentrations greater than 1000 micrograms/100 mg were found in all patients with idiopathic hemochromatosis but in none of the alcoholics. In the alcoholics no relationship existed between liver iron concentrations and the amount of alcohol consumed daily, the length of the drinking history, the amount of beverage iron consumed daily, or the severity of the liver disease. Serum ferritin concentrations reflected iron stores in patients with hemochromatosis and in alcoholics with minimal liver disease. However, in alcoholics with significant liver disease serum ferritin concentrations did not reflect iron stores accurately, although with normal values iron overload is unlikely. Serum iron concentration and percentage saturation of total iron-binding capacity were of little value in assessing iron status in either alcoholics or patients with hemochromatosis. Measurement of the liver iron concentration clearly differentiates between alcoholics with significant siderosis and patients with idiopathic hemochromatosis.

Chapman RW, Bassendine MF, Laulicht M, Gorman A, Thomas HC, Sherlock S, Hoffbrand AV. 1982. Serum ferritin and binding of serum ferritin to concanavalin A as a tumor marker in patients with primary liver cell cancer and chronic liver disease. Dig Dis Sci, 27 (2), pp. 111-116. | Read more

Whorwell PJ, Eade OE, Chapman R, Smith CL, Fisher JA. 1981. Comparison between admission and next-day endoscopy in the management of acute upper gastrointestinal haemorrhage. Digestion, 21 (1), pp. 18-20. | Show Abstract | Read more

In a prospective study, a comparison between immediate and next-day endoscopy has been made in 100 patients with acute upper gastrointestinal haemorrhage. Neither regime was statistically superior to the other. It is concluded that in the majority of patients immediate emergency endoscopy is unnecessary.

Chapman R. 1980. Porphyria cutanea tarda and beta-thalassaemia minor with iron overload. Br Med J, 281 (6247), pp. 1070. | Read more

MURRAY C, CHAPMAN R, ISAACSON P, BAMFORTH J. 1978. CIMETIDINE AND MALIGNANT GASTRIC-ULCERS LANCET, 1 (8073), pp. 1092-1092. | Read more

Chapman R, Dawe C, Whorwell PJ, Wright R. 1978. Ulcerative colitis in association with Takayasu's disease. Am J Dig Dis, 23 (7), pp. 660-662. | Show Abstract | Read more

A case of total ulcerative colitis associated with large-vessel disease consistent with a diagnosis of Takayasu's disease is described in a 21-year-old Pakistani female. The possible relationship between the two disorders is discussed.

Chapman R, Conway N. 1976. Carotid shudder as a sign of ascending aorta dissection. Br Med J, 1 (6013), pp. 811. | Read more

Culver EL, Chapman RW. 2011. Systematic review: management options for primary sclerosing cholangitis and its variant forms - IgG4-associated cholangitis and overlap with autoimmune hepatitis. Aliment Pharmacol Ther, 33 (12), pp. 1273-1291. | Show Abstract | Read more

BACKGROUND: Primary sclerosing cholangitis (PSC) remains a challenging disease to manage. The main goals are prevention of disease progression and reduction of the increased cancer risk. AIMS: To review the management strategies for PSC and its variant forms based on published studies. METHODS: Publications were identified using Pubmed, Medline and Ovid search engines. RESULTS: Distinguishing PSC from variants, such as IgG4-associated cholangitis, and overlap with autoimmune hepatitis is essential to guide treatment decisions. There is no proven efficacious medical treatment for PSC. Ursodeoxycholic acid has been disappointing in low and moderate doses, and potentially dangerous in higher doses, although its role and optimal dose in chemoprevention requires investigation. The novel bile acid, 24-norursodeoxycholic acid, has shown promise in mouse models; human trials are in progress. Dominant strictures are optimally managed by dilatation and stenting to relieve obstructive complications, although exclusion of biliary malignancy is essential. Liver transplantation is the only proven therapy for those with advanced disease. Cholangiocarcinoma remains the most unpredictable and feared complication. In highly selected groups, neo-adjuvant chemoradiation with liver transplantation seems promising, but requires further validation. Screening for inflammatory bowel disease and surveillance for colorectal carcinoma should not be overlooked. CONCLUSIONS: The effective management of PSC and its variants is hindered by uncertainties regarding pathogenesis of disease and factors responsible for its progression. Genome studies may help to identify further targets for drug therapy and factors leading to malignant transformation.

Culver EL, Chapman RW. 2011. Systematic review: Management options for primary sclerosing cholangitis and its variant forms - IgG4-associated cholangitis and overlap with autoimmune hepatitis Alimentary Pharmacology and Therapeutics, | Show Abstract | Read more

Background Primary sclerosing cholangitis (PSC) remains a challenging disease to manage. The main goals are prevention of disease progression and reduction of the increased cancer risk. Aims To review the management strategies for PSC and its variant forms based on published studies. Methods Publications were identified using Pubmed, Medline and Ovid search engines. Results Distinguishing PSC from variants, such as IgG4-associated cholangitis, and overlap with autoimmune hepatitis is essential to guide treatment decisions. There is no proven efficacious medical treatment for PSC. Ursodeoxycholic acid has been disappointing in low and moderate doses, and potentially dangerous in higher doses, although its role and optimal dose in chemoprevention requires investigation. The novel bile acid, 24-norursodeoxycholic acid, has shown promise in mouse models; human trials are in progress. Dominant strictures are optimally managed by dilatation and stenting to relieve obstructive complications, although exclusion of biliary malignancy is essential. Liver transplantation is the only proven therapy for those with advanced disease. Cholangiocarcinoma remains the most unpredictable and feared complication. In highly selected groups, neo-adjuvant chemoradiation with liver transplantation seems promising, but requires further validation. Screening for inflammatory bowel disease and surveillance for colorectal carcinoma should not be overlooked. Conclusion The effective management of PSC and its variants is hindered by uncertainties regarding pathogenesis of disease and factors responsible for its progression. Genome studies may help to identify further targets for drug therapy and factors leading to malignant transformation. © 2011 Blackwell Publishing Ltd.

Chapman R, Fevery J, Kalloo A, Nagorney DM, Boberg KM, Shneider B, Gores GJ, American Association for the Study of Liver Diseases. 2010. Diagnosis and management of primary sclerosing cholangitis. Hepatology, 51 (2), pp. 660-678. | Read more

Webster GJM, Pereira SP, Chapman RW. 2009. Autoimmune pancreatitis/IgG4-associated cholangitis and primary sclerosing cholangitis--overlapping or separate diseases? J Hepatol, 51 (2), pp. 398-402. | Show Abstract | Read more

Autoimmune pancreatitis is a recently described fibroinflammatory disease which is characterised by raised serum levels of IgG4 (in >70% of cases), and an IgG4-positive lymphoplasmacytic tissue infiltrate. A favourable and rapid clinical response to oral steroid therapy is often seen. Biliary involvement is common, and the term IgG4-associated cholangitis has recently been coined. The cholangiographic appearances of IgG4-associated cholangitis and primary sclerosing cholangitis can be difficult to differentiate. Moreover, raised levels of serum IgG4 have been recently found in 9% of patients with primary sclerosing cholangitis (a much higher frequency than for other gastrointestinal diseases), and those with raised levels appear to progress more rapidly to liver failure. Here we review the similarities and differences between the biliary disease in autoimmune pancreatitis and primary sclerosing cholangitis, and address the issue of disease overlap. Improvements in understanding the relationship between these conditions might lead to an enhanced understanding of the aetiopathogenesis, and improved treatment of both conditions.

Björnsson E, Boberg KM, Cullen S, Fleming K, Clausen OP, Fausa O, Schrumpf E, Chapman RW. 2002. Patients with small duct primary sclerosing cholangitis have a favourable long term prognosis. Gut, 51 (5), pp. 731-735. | Show Abstract | Read more

BACKGROUND: Patients with cholestatic liver function tests and histological features of primary sclerosing cholangitis (PSC) but a normal cholangiogram are considered to have small duct PSC. The natural history of this condition is unknown. METHODS: Thirty three patients with small duct PSC were identified among patients admitted for diagnostic workup of cholestatic liver function tests in one centre in the UK (Oxford) and one centre in Norway (Oslo). A total of 260 patients with large duct PSC were compared, and prognosis in terms of death, cholangiocarcinoma, biochemical features, histological features, and symptoms analysed. RESULTS: Mean age at diagnosis was 38 years and 39 years in small duct and large duct PSC, respectively. Mean follow up was 106 months in small duct and 105 months in large duct patients. Four patients originally considered to have small duct developed large duct PSC. Two of these underwent liver transplantation during follow up. Of the remainder who did not develop large duct PSC, two patients died during follow up: one of liver failure and the other of cardiac death unrelated to her liver disease. A total of 122 (47%) large duct patients either required liver transplantation (34 patients) or died (88 patients). Small duct patients had a significantly better survival compared with large duct patients. Among small duct patients, none developed cholangiocarcinoma compared with 28 of 260 (11%) large duct patients. CONCLUSIONS: Patients with small duct PSC seem to have a good prognosis in terms of survival and development of cholangiocarcinoma. Small duct PSC progresses to large duct PSC in a small proportion of patients.

Mitchell SA, Thyssen M, Orchard TR, Jewell DP, Fleming KA, Chapman RW. 2002. Cigarette smoking, appendectomy, and tonsillectomy as risk factors for the development of primary sclerosing cholangitis: a case control study. Gut, 51 (4), pp. 567-573. | Show Abstract | Read more

BACKGROUND AND AIMS: The strong clinical association between primary sclerosing cholangitis (PSC) and ulcerative colitis (UC) suggests common factors in their pathogenesis. Smoking, previous appendectomy, and tonsillectomy have been associated with a decreased risk of developing UC. In this study, our aim was to examine these risk factors in patients with PSC with and without underlying inflammatory bowel disease (IBD). METHODS: The smoking habits and history of previous appendectomy and/or tonsillectomy of 170 patients with PSC, 41 without underlying IBD, 170 patients with UC but normal liver function tests, and 170 age and sex matched community controls were obtained by questionnaire. RESULTS: A total of 112 PSC patients (66%) had never smoked compared with 66 controls (39%). Only 12 PSC patients (7%) were current smokers versus 43 controls (25%). The resultant odds ratio of having PSC was 0.17 (95% confidence interval (CI) 0.08-0.35) among current smokers and 0.33 (95% CI 0.21-0.52) among ever (former+current) smokers. Among former smokers, the odds of having PSC were also significantly decreased (odds ratio 0.45, 95% CI 0.26-0.73; p<0.05). In the subgroup of PSC patients without IBD, only 5% were current smokers versus 26% of matched controls, and never smokers were overrepresented (68% v 37%). The rate of previous appendectomy was similar in all three study groups (14%, 12%, and 13%) but the frequency of tonsillectomy was reduced in the PSC group (21% v 31%; p=0.05). CONCLUSION: PSC, like UC, is a disease of non-smokers as the odds of having PSC was significantly decreased among current and former smokers. The association between non-smoking and PSC was independent of whether the PSC patient had underlying IBD. Previous tonsillectomy but not appendectomy may also be associated with a decreased risk of PSC but this warrants further study.

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