Hepatitis: Alexander G

Shankar A, Alexander G. · Department of Hepatology, Addenbrooke's Hospital, Cambridge. · Br J Hosp Med (Lond). · Pubmed #19229150 No free full text.

Abstract: Hepatitis C is an important problem that often requires liver transplantation. However, outcomes have not improved in line with liver transplants for other indications. This article explores the issues surrounding this difficult area of transplant hepatology.

Gee I, Alexander G. · Department of Gastroenterology, Leicester Royal Infirmary, Leicester LE1 5WW, UK. · Postgrad Med J. · Pubmed #16344300 links to  free full text

Abstract: Liver transplantation is a useful treatment for end stage liver disease of all aetiologies but recurrent disease presents an ongoing challenge, particularly for hepatitis C virus (HCV) where recurrence is almost universal. Immunosuppression is needed for all patients after transplantation and should be tailored to the individual patient, with particular problems being noted for those with HCV. The longer term effects of immunosuppression, particularly renal failure and the adverse effects of certain treatments on the liver graft, have become more important as survival improves and results are studied for longer periods after transplantation.

Alexander G, Walsh K. · Department of Medicine, Addenbrooke's Hospital, Cambridge, UK. · Int J Clin Pract. · Pubmed #11070570 No free full text.

Abstract: Both hepatitis B and hepatitis C are spread parenterally. Chronic hepatitis C is fast becoming the leading indication for liver transplantation. Most infected patients go on to develop chronic hepatitis, with approximately 20% developing liver cirrhosis or hepatocellular carcinoma after 20 years. Standard treatment now is with a combination of alpha-interferon and ribavirin, which is successful in up to 40% of patients. A vaccine is still a remote possibility and prevention remains all-important. Despite having a successful vaccine, chronic hepatitis B remains an important cause of liver cirrhosis and hepatocellular carcinoma. Treatments for active hepatitis include alpha-interferon and the newer nucleoside analogues such as lamivudine and adefovir. In patients undergoing liver transplantation, recurrence of hepatitis B in the graft can be reduced with a combination of hepatitis B immunoglobulin and these nucleoside analogues.

Walsh K, Alexander G. · Department of Medicine, University of Cambridge, Box 157, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK. · Postgrad Med J. · Pubmed #10775280 links to  free full text

Abstract: Alcohol is a major cause of liver cirrhosis in the Western world and accounts for the majority of cases of liver cirrhosis seen in district general hospitals in the UK. The three most widely recognised forms of alcoholic liver disease are alcoholic fatty liver (steatosis), acute alcoholic hepatitis, and alcoholic cirrhosis. The exact pathogenesis of alcoholic liver injury is still not clear but immune mediated and free radical hepatic injury are thought to be important. There is increasing interest in genetic factors predisposing to hepatic injury in susceptible individuals. Diagnosis is based on accurate history, raised serum markers such as gamma-glutamyltransferase, mean corpuscular volume, and IgA and liver histology when obtainable. Abstinence is the most important aspect of treatment. Newer drugs such as acamprosate and naltrexone are used to reduce alcohol craving. Vitamin supplements and nutrition are vital while corticosteroids have a role in acute alcoholic hepatitis where there is no evidence of gastrointestinal haemorrhage or sepsis. Liver transplantation has excellent results in abstinent patients with end stage liver disease but there are concerns about recidivism after transplant.

Crosbie O, Alexander G. · Addenbrooke's NHS Trust Cambridge UK. · Transplantation. · Pubmed #10551633 No free full text.

This publication has no abstract.

Alexander G, Baba CS, Chetri K, Negi TS, Choudhuri G. · Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India. · BMC Gastroenterol. · Pubmed #16164746 links to  free full text

Abstract: BACKGROUND: The use of Lamivudine in chronic hepatitis B (CHB) is well known, however the reported rate of HBeAg sero-conversion and its durability post-treatment have varied considerably. We undertook the present study to study the effect of Lamivudine on HBeAg loss and seroconversion rates in Indian patients of CHB in relation to frequency, predictors and durability. METHODS: We treated 60 patients of e antigen positive CHB (with active viral replication and ongoing necro-inflammatory activity) with Lamivudine. They were followed up by monthly aminotransferases, and 3 monthly HBeAg and anti-HBe. Those who attained HBeAg sero-conversion were advised to discontinue Lamivudine after 6 months and followed up every 3 months thereafter, to see for relapse. Treatment was given for maximum of 3 years if not sero-converted. RESULTS: The annual incremental loss of HBeAg in patients receiving Lamivudine was 25 (41.6%) at end of 1st year, 33 (55%) at 2nd year and 35 (58.3%) at 3rd year. The corresponding rates for full sero-conversion were 17/60 (28.6%), 22/60 (36.6%) and 24/60 (40%) in the 3 years. HBeAg loss correlated with increased pre-therapy ALT levels (p = 0.002) and decreased pretreatment HBV-DNA levels (p = 0.004). The presence of cirrhosis had no influence on the rate of HBeAg loss. Relapse occurred in 35% (7/20) post-treatment at median time of 6 months. CONCLUSION: Indian patients showed a higher rate of HBeAg sero-conversion in the first year of Lamivudine treatment. This correlated with baseline ALT and inversely with HBV-DNA levels. Relapse rate after treatment was high and occurred soon after stopping treatment.

Das A, Hoare M, Davies N, Lopes AR, Dunn C, Kennedy PT, Alexander G, Finney H, Lawson A, Plunkett FJ, Bertoletti A, Akbar AN, Maini MK. · Division of Infection and Immunity, University College London, London W1T 4JF, England, UK. · J Exp Med. · Pubmed #18695005 links to  free full text

Abstract: The inflamed liver in chronic hepatitis B virus (HBV) infection (CHB) is characterized by a large influx of non-virus-specific CD8 T cells. Little is known about the functional capacity of these lymphocytes, which could provide insights into mechanisms of failure of viral control and liver damage in this setting. We compared the effector function of total circulating and intrahepatic CD8 T cells in CHB patients and healthy donors. We demonstrated that CD8 T cells from CHB patients, regardless of their antigen specificity, were impaired in their ability to produce interleukin-2 and proliferate upon TCR-dependent stimulation. In contrast, these CD8 T cells had preserved production of the proinflammatory cytokines interferon-gamma and tumor necrosis factor-alpha. This aberrant functional profile was partially attributable to down-regulation of the proximal T cell receptor signaling molecule CD3zeta, and could be corrected in vitro by transfection of CD3zeta or replenishment of the amino acid arginine required for its expression. We provide evidence for depletion of arginine in the inflamed hepatic microenvironment as a potential mechanism for these defects in global CD8 T cell signaling and function. These data imply that polarized CD8 T cells within the HBV-infected liver may impede proliferative antiviral effector function, while contributing to the proinflammatory cytokine environment.

Sarfraz S, Hamid S, Siddiqui A, Hussain S, Pervez S, Alexander G. · 1Department of Biological and Biomedical Sciences, Aga Khan University, Karachi, Pakistan. · BMC Microbiol. · Pubmed #18680610 links to  free full text

Abstract: BACKGROUND: A disrupted cell cycle progression of hepatocytes was reported in chronic hepatitis C virus (HCV) infection, which can contribute significantly in the associated pathogenesis. The present study aimed to further elaborate these disruptions by evaluating the expression of key cell cycle and apoptotic proteins in chronic HCV infection with particular reference to genotype 3. Archival liver biopsy specimens of chronic HCV-infection (n = 46) and normal histology (n = 5) were analyzed by immunohistochemistry using antibodies against proliferation marker Mcm-2, G1 phase marker Cyclin D1, S phase marker Cyclin A, cell cycle regulators p21 (CDK inhibitor) and p53 (tumor suppressor protein), apoptotic protein Caspase-3 and anti-apoptotic protein Bcl-2. RESULTS: Elevated Mcm-2 expression was observed in hepatocytes in chronic HCV infection, indicating increased cell cycle entry. Cyclin D1 expression was higher than cyclin A, which suggests a slow progression through the G1 phase. Expression of cell cycle regulators p21 and p53 was elevated, with no concordance between their expressions. The Mcm-2 and p21 expressions were associated with the fibrosis stage (p = 0.0001 and 0.001 respectively) and that of p53 with the inflammation grade (p = 0.051). Apoptotic marker, Caspase-3, was mostly confined to sinusoidal lining cells with little expression in hepatocytes. Anti-apoptotic protein, Bcl-2, was negligible in hepatocytes and detected principally in infiltrating lymphocytes. Expression of all these proteins was unrelated to the HCV genotype and were detected only rarely in the hepatocytes of normal liver. CONCLUSION: The results showed an arrested cell cycle state in the hepatocytes of chronic HCV infection, regardless of any association with genotype 3. Cell cycle arrest is characterized by an increased expression of p21, in relation to fibrosis, and of p53 in relation to inflammation. Furthermore, expression of p21 was independent of the p53 expression and coincided with the reduced expression of apoptotic protein Caspase-3 in hepatocytes. The altered expression of these cell cycle proteins in hepatocytes is suggestive of an impaired cell cycle progression that could limit the regenerative response of the liver to ongoing injury, leading to the progression of disease.

Harris HE, Eldridge KP, Harbour S, Alexander G, Teo CG, Ramsay ME, Anonymous00173. · Immunisation Department, Centre for Infections, Health Protection Agency, London, UK. · J Viral Hepat. · Pubmed #17305887 No free full text.

Abstract: Whether differences in the natural history of hepatitis C virus (HCV) can be explained by differences in the infecting HCV type is unknown. The aim of this study was to investigate whether the HCV type might influence the clinical outcome of infection. Study serum samples were assembled from 749 individuals enrolled into the UK HCV National Register from which data on clinical outcomes were extracted. HCV-RNA-positive specimens were genotyped and HCV-RNA-negative specimens serotyped. Logistic regression analysis was used to investigate the independent effect of HCV type on viral clearance by comparing patients who were HCV RNA negative (n = 86) with those who were HCV RNA positive (n = 508). The same method was used to investigate whether HCV type was associated with histological stage of liver disease. The prevalence of HCV type 1 among those who cleared infection was 69% and among those who remained HCV RNA positive was 51%: Type 1 infections were more likely to be HCV RNA negative than non-1 types (OR 0.47, 95% CI 0.29-0.78, P = 0.003). Type 1 infections were also more likely to be associated with histological stage scores above the median when compared with non-1 types (OR 2.03, 95% CI 1.07-3.83, P = 0.03). In conclusion, HCV type 1 infection was more often HCV RNA negative, suggesting that spontaneous clearance may occur more commonly with this type. Among the RNA-positive infections, type 1 infection may be more aggressive than types 2/3.

Choudhuri G, Somani SK, Baba CS, Alexander G. · Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014 (UP), India. · BMC Gastroenterol. · Pubmed #16098234 links to  free full text

Abstract: BACKGROUND: Autoimmune hepatitis (AIH) has been reported to show considerable geographical variation in frequency and clinical manifestations. It is considered a rare cause of liver disease in India. The present study was undertaken to determine the incidence, clinical, biochemical and histological profile of AIH in this part of the world. METHODS: Patients presenting with acute or chronic liver disease between January 1999 and June 2002 were evaluated prospectively. AIH was diagnosed using the international autoimmune hepatitis group criteria. Workup included clinical, biochemical, USG, viral markers, UGI endoscopy, AI markers (ANA, SMA, Anti-LKM, AMA, RF, p-ANCA) using indirect immunofluorescence and liver biopsy if possible. RESULTS: Forty-one of 2401 (1.70%) patients were diagnosed to have autoimmune liver disease. Out of these, 38 had autoimmune hepatitis and the rest 3 had primary biliary cirrhosis. The mean age of the patients of autoimmune hepatitis was 36.2 (15.9) years, 34 (89.4%) were females, and the duration of symptoms was 20.3 (20.5) months. Nineteen (50%) of them presented with chronic hepatitis, 13 (34.2%) as cirrhosis, 5 (13.1%) with acute hepatitis and 1 (2.6%) with cholestatic hepatitis. The presentations were jaundice in 21 (55.2%), pedal edema and hepatomegaly in 17 (44.7%), splenomegaly in 13 (34.2%), encephalopathy, abdominal pain in 9 (23.6%) and fever in 8 (21%). Twelve had esophageal varices and 3 had bled. Biochemical parameters were ALT 187 (360) U/L, AST 157 (193) U/L, ALP 246 (254) U/L, globulin 4.1 (1.6) g/dL, albumin 2.8 (0.9) g/dL, bilirubin 5.2 (7.4) mg/dL, prothrombin time 17 (7) sec and ESR 47 (17) sec. The autoimmune markers were SMA (24), ANA (15), both SMA and ANA (4), AMA (1), rheumatoid factor (2), pANCA (1), and Anti-LKM in none. Thirty (79%) patients had definite AIH and eight (21%) had probable AI hepatitis. Associated autoimmune diseases was seen in 15/38 (39.4%), diabetes 4, hypothyroidism 3, vitiligo 2, thrombocytopenia 2, rheumatoid arthritis 2, Sjogren's syndrome 1 and autoimmune polyglandular syndrome III in 1. Viral markers were positive in two patients, one presenting as acute hepatitis and HEV-IgM positive and another anti-HCV positive. CONCLUSION: In India, autoimmune hepatitis is uncommon and usually presents with chronic hepatitis or cirrhosis, acute hepatitis being less common. Age at presentation was earlier but clinical parameters and associated autoimmune diseases were similar to that reported from the west. Primary biliary cirrhosis is rare. Type II AIH was not observed.

Marshall A, Rushbrook S, Morris LS, Scott IS, Vowler SL, Davies SE, Coleman N, Alexander G. · University of Cambridge Department of Medicine, Addenbrooke's Hospital, Cambridge, UK. · Liver Transpl. · Pubmed #15776414 links to  free full text

Abstract: Although graft infection with hepatitis C virus (HCV) occurs in virtually all patients transplanted for HCV-related liver disease, the outcome ranges from minimal disease to the rapid development of cirrhosis. Induction of hepatocyte cell cycle entry followed by inhibition of cell cycle progression has been proposed as a potential mechanism whereby HCV may cause hepatocyte dysfunction and may promote fibrogenesis. The aim of this study was to assess whether early hepatocyte cell cycle entry might predict subsequent fibrosis progression in patients with graft HCV infection after liver transplantation. Liver biopsies from 21 liver transplant recipients diagnostic of graft HCV infection but before development of significant fibrosis were studied. Patients were classed as nonprogressors, intermediate progressors, or rapid progressors according to the rate of fibrosis progression calculated from the most recent biopsy. Minichromosome maintenance protein 2 (Mcm-2), a highly sensitive and specific marker of cell cycle entry, and cyclin-dependent kinase inhibitor p21 were detected by immunohistochemistry. Hepatocyte Mcm-2 expression increased significantly according to rate of fibrosis. For nonprogressors, the median percentage of positive hepatocytes was 5.3% (range, 0.92%-11.2%) compared with 20.7% (4.6%-43.7%) in intermediate progressors and 23.7% (11.6%-55.2%) in rapid progressors (P = 0.002). By contrast, there was no evidence of a difference in hepatocyte p21 expression. Median values and ranges were 3.4% (range, 1.1%-30%), 13.3% (range, 1.4%-42.3%), and 11.8% (range, 7.6%-52.3%) for nonprogressors, intermediate progressors, and rapid progressors, respectively (P = 0.11). In conclusion, hepatocyte cell cycle entry may be important in the pathogenesis of posttransplant HCV hepatitis. Early assessment of hepatocyte Mcm-2 expression could help identify patients at high risk for progressive fibrosis before it occurs.

Marshall A, Rushbrook S, Davies SE, Morris LS, Scott IS, Vowler SL, Coleman N, Alexander G. · Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Hills Road, Cambridge CB2 2QQ, England, UK. · Gastroenterology. · Pubmed #15633121 No free full text.

Abstract: BACKGROUNDS & AIMS: An increased risk of hepatitis C virus (HCV)-related cirrhosis is associated with hepatic steatosis, older age, and high alcohol consumption, which could be explained by synergistic effects on cell proliferation. We aimed to investigate hepatocyte cell cycle state and phase distribution in chronic HCV infection. METHODS: Liver biopsy specimens diagnostic for chronic HCV (70), liver regeneration following transplant-related ischemic-reperfusion injury (15), and "normal" liver adjacent to colorectal cancer metastasis (10) were studied. Immunohistochemistry was used to detect cell cycle phase markers cyclin D1 (maximal in G 1 ), cyclin A (S), cyclin B1 (cytoplasmic during G 2 ) and phosphorylated histone 3 protein (mitosis), mini-chromosome maintenance protein 2 (Mcm-2; present throughout the cell cycle), and cyclin-dependent kinase inhibitor p21, which inhibits G 1 /S progression. RESULTS: Hepatocyte Mcm-2 expression was elevated in chronic HCV and liver regeneration (13% vs 26.4%) but negligible in "normal" liver. In proportion to Mcm-2, there was no difference in cyclin D1 between chronic HCV infection and liver regeneration (51.6% of Mcm-2-positive hepatocytes vs 52.6%). In contrast, there was a striking reduction in cyclin A (3% vs 16.3%), cyclin B1 (.4% vs 2.3%), and phosphorylated histone 3 protein (0% vs 3.8%) in chronic HCV infection compared with liver regeneration. In chronic HCV infection, Mcm-2 and p21 expression were associated with fibrosis stage and positive serum HCV RNA. CONCLUSIONS: The data are consistent with hepatocyte G 1 arrest in chronic HCV infection. This could impair hepatocellular function and limit hepatic regeneration.

McKeon D, Day A, Parmar J, Alexander G, Bilton D. · CF Unit, Papworth Hospital NHS Trust, Papworth Everard, Cambridge, UK. · J Cyst Fibros. · Pubmed #15463908 No free full text.

Abstract: BACKGROUND: Cystic fibrosis liver disease (CFLD) occurs in 37% of patients with CF. To date and to the best of our knowledge, there has not been a documented case of hepatocellular carcinoma in association with cirrhosis and CF. CASE REPORT: A 32-year-old lady with cystic fibrosis (CF) presented for her annual review. She had been diagnosed with CFLD since early adolescence. A routine ultrasound of her liver revealed lesions consistent with hepatocellular carcinoma. This was confirmed on histology. She had no risk factors for hepatitis, and thorough investigation revealed no other cause for her chronic liver disease. She was also found to be pregnant at the time of diagnosis. Her tumour was considered too large for resection and liver transplantation and she was referred to a national centre for laser ablative therapy. CONCLUSION: It is our concern that with the increased life expectancy of patients with CF and the chronic nature of CFLD that this may be an increasingly recognised complication amongst the CF adult population. Therefore, we have changed our practice to more intense surveillance of patients with established CFLD to incorporate biannual ultrasound imaging of the hepatic system and yearly serum concentration measurements of alpha-fetoprotein.

Jones TD, Hanlon M, Smith BJ, Heise CT, Nayee PD, Sanders DA, Hamilton A, Sweet C, Unitt E, Alexander G, Lo KM, Gillies SD, Carr FJ, Baker MP. · Biovation Ltd., Babraham, Cambridge, UK. · J Interferon Cytokine Res. · Pubmed #15450132 No free full text.

Abstract: Interferon-alpha (IFN-alpha), in conjunction with ribavirin, is the current standard for the treatment of chronic hepatitis C virus (HCV) infection. This treatment requires frequent dosing, with a significant risk of the development of anti-IFN-alpha neutralizing antibodies that correlates with lack of efficacy or relapse. We have developed an IFN-alpha linked to the Fc region of human IgG1 for improved half-life and less frequent dosing. We have also identified, using a human T cell proliferation assay, three regions of IFN-alpha2b that are potentially immunogenic, and a variant containing a total of six mutations within these regions was made. This variant was made as a fusion to Fc either with or without a flexible linker between the fusion partners. Both configurations of the variant were less active than native IFN-alpha alone, although the variant containing the flexible linker had in vitro antiviral activity within the range of other modified IFN-alphas currently in clinical use. Peptides spanning the modified regions were tested in T cell proliferation assays and found to be less immunogenic than native controls when using peripheral blood mononuclear cells (PBMCs) from both healthy individuals and HCV-infected patients who had been treated previously with IFN-alpha2b.

Aithal GP, Ramsay L, Daly AK, Sonchit N, Leathart JB, Alexander G, Kenna JG, Caldwell J, Day CP. · School of Clinical Medical Sciences (Hepatology), Medical School, University of Newcastle, Newcastle-upon-Tyne, United Kingdom. · Hepatology. · Pubmed #15122773 No free full text.

Abstract: Diclofenac is a nonsteroidal anti-inflammatory drug that causes rare but serious hepatotoxicity, the mechanism of which is unclear. The purpose of the present study was to explore the potential role played by the immune processes. Antibodies to diclofenac metabolite-modified liver protein adducts were detected in the sera of seven out of seven patients with diclofenac-induced hepatotoxicity, 12 of 20 subjects on diclofenac without hepatotoxicity, and none of four healthy controls. The antibodies recognized adducts expressed in livers from rats treated with multiple doses of diclofenac, but not in those given single doses. In addition, several potential diclofenac adducts were identified in the liver of a patient with diclofenac-induced hepatic failure, but not from a normal human donor liver, by immunoblotting with an adduct-selective rabbit antiserum. To determine whether or not polymorphisms in genes encoding cytokine-related proteins influence susceptibility to hepatotoxicity, genotyping for the polymorphisms -627 in the interleukin (IL)-10 gene, -590 in the IL-4 gene, and codon 551 in the IL-4 receptor (IL-4R) were performed on DNA from 24 patients on diclofenac with hepatotoxicity, 48 subjects on diclofenac without hepatotoxicity, and healthy controls. The frequencies of the variant alleles for IL-10 and IL-4 were higher in patients (OR [odds ratio]: 2.8 for IL-10; 2.6 for IL-4; 5.3 for IL-10 + IL-4) compared with healthy controls and subjects on diclofenac without hepatotoxicity (OR: 2.8 for IL-10; 1.2 for IL-4; 5.0 for IL-10 + IL-4). In conclusion, the observed polymorphisms, resulting in low IL-10 and high IL-4 gene transcription, could favor a T helper (Th)-2 mediated antibody response to neoantigenic stimulation associated with disease susceptibility.