Hepatitis: Chapman RW

Alvarez F, Berg PA, Bianchi FB, Bianchi L, Burroughs AK, Cancado EL, Chapman RW, Cooksley WG, Czaja AJ, Desmet VJ, Donaldson PT, Eddleston AL, Fainboim L, Heathcote J, Homberg JC, Hoofnagle JH, Kakumu S, Krawitt EL, Mackay IR, MacSween RN, Maddrey WC, Manns MP, McFarlane IG, Meyer zum Büschenfelde KH, Zeniya M. · Institute of Liver Studies, King's College Hospital, London, UK. · J Hepatol. · Pubmed #10580593 No free full text.

This publication has no abstract.

Chapman RW. · Dept of Gastroenterology, Oxford Radcliffe Hospital, Headington, UK. · Ann Oncol. · Pubmed #10436847 No free full text.

Abstract: 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.

Christie JM, Chapman RW. · Department of Gastroenterology, John Radcliffe Hospital, Oxford. · Hosp Med. · Pubmed #10396412 No free full text.

Abstract: 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.

Dinesen L, Caspary WF, Chapman RW, Dietrich CF, Sarrazin C, Braden B. · John Radcliffe Hospital, Oxford, United Kingdom. · Dig Liver Dis. · Pubmed #18339592 No free full text.

Abstract: 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).

Granito A, Muratori P, Muratori L, Pappas G, Cassani F, Worthington J, Ferri S, Quarneti C, Cipriano V, de Molo C, Lenzi M, Chapman RW, Bianchi FB. · Department of Internal Medicine, Cardioangiology, Hepatology, Alma Mater Studiorum, University of Bologna, Policlinico Sant'Orsola-Malpighi, Bologna, Italy. · Aliment Pharmacol Ther. · Pubmed #17767467 No free full text.

Abstract: 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. · Peter Medawar Building for Pathogen Research, Nuffield Department of Clinical Medicine, University of Oxford, South Parks Road, Oxford, UK. · J Hepatol. · Pubmed #17475362 No free full text.

Abstract: 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.

Martins EB, Chapman RW. · Department of Clinical Medicine, Hospital Universitário, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. · Curr Opin Gastroenterol. · Pubmed #17031201 No free full text.

Abstract: 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.

Chapman RW. · Department of Hepatology/Gastroenterology, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK. · Gut. · Pubmed #12077082 links to  free full text

This publication has no abstract.

Chapel HM, Christie JM, Peach V, Chapman RW. · Department of Clinical Immunology, John Radcliffe Hospital, Oxford, OX3 9DU, England. · Clin Immunol. · Pubmed #11358426 No free full text.

Abstract: 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.

Christie JM, Chapel H, Chapman RW, Rosenberg WM. · Gastroenterology Unit, John Radcliffe Hospital, Oxford, UK. · Hepatology. · Pubmed #10498657 No free full text.

Abstract: 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.