Hepatitis: Taylor-Robinson SD

Cobbold JF, Taylor-Robinson SD. · No affiliation provided · Hepatology. · Pubmed #18220278 No free full text.

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Grier S, Lim AK, Patel N, Cobbold JF, Thomas HC, Cox IJ, Taylor-Robinson SD. · No affiliation provided · World J Gastroenterol. · Pubmed #16773702 links to  free full text

Abstract: Patients who are chronically infected with the hepatitis C virus often develop chronic liver disease and assessment of the severity of liver injury is required prior to considering viral eradication therapy. This article examines the various assessment methods currently available from gold standard liver biopsy to serological markers and imaging. Ultrasound is one of the most widely used imaging modalities in clinical practice and is already a first-line diagnostic tool for liver disease. Microbubble ultrasound contrast agents allow higher resolution images to be obtained and functional assessments of microvascular change to be carried out. The role of these agents in quantifying the state of hepatic injury is discussed as a viable method of determining the stage and grade of liver disease in patients with hepatitis C. Although currently confined to specialist centres, the availability of microbubble contrast-enhanced ultrasound will inevitably increase in the clinical setting.

Forton DM, Thomas HC, Taylor-Robinson SD. · No affiliation provided · J Hepatol. · Pubmed #12873826 No free full text.

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Forton DM, Taylor-Robinson SD, Thomas HC. · No affiliation provided · J Hepatol. · Pubmed #11867190 No free full text.

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Gomaa AI, Khan SA, Leen EL, Waked I, Taylor-Robinson SD. · Department of Hepatology and Gastroenterology, Division of Medicine, Imperial College London, St Mary's Hospital Campus, South Wharf Road, London W2 1NY, United Kingdom. · World J Gastroenterol. · Pubmed #19294759 links to  free full text

Abstract: Hepatocellular carcinoma (HCC) is one of the commonest cancers worldwide, particularly in parts of the developing world, and is increasing in incidence. This article reviews the current modalities employed for the diagnosis of HCC, including serum markers, radiological techniques and histological evaluation, and summarises international guidelines for the diagnostic approach to HCC.

Gomaa AI, Khan SA, Toledano MB, Waked I, Taylor-Robinson SD. · Department of Hepatology and Gastroenterology, Imperial College London, St Mary's Hospital Campus, Praed Street, London W2 1NY, United Kingdom. · World J Gastroenterol. · Pubmed #18666317 links to  free full text

Abstract: Hepatocellular carcinoma (HCC) is the commonest primary malignant cancer of the liver in the world. Given that the burden of chronic liver disease is expected to rise owing to increasing rates of alcoholism, hepatitis B and C prevalence and obesity-related fatty liver disease, it is expected that the incidence of HCC will also increase in the foreseeable future. This article summarizes the international epidemiology, the risk factors and the pathogenesis of HCC, including the roles of viral hepatitis, toxins, such as alcohol and aflatoxin, and insulin resistance.

Ladep NG, Taylor-Robinson SD. · University of Jos, Jos University Teaching Hospital, Nigeria. · Clin Med. · Pubmed #17990704 No free full text.

Abstract: Nigeria is the most populous country in Africa but, despite extensive oil deposits, little of the country's recently found wealth has filtered through into the healthcare sector. Nigerian hospitals are poorly equipped and infrastructure for interventional procedures is mostly lacking. Liver disease is common, owing to the high prevalence of hepatitis B and hepatitis C, which often coexist with HIV infection. Antiviral treatments are expensive and drugs are commonly unavailable, even if they can be afforded. Therapy for end-stage liver disease is difficult, since endoscopic services are not widespread. A new training programme for oesophageal variceal band ligation at Jos University Teaching Hospital, Central Nigeria, aided by educational bursaries from the Royal College of Physicians, however, provides some promise in improving healthcare standards. The work of agencies, such as the Tropical Health and Educational Trust has fostered direct one-to-one links between UK hospitals and healthcare workers in a variety of African countries and offers a model for future development, albeit on a local, rather than a national or international, basis.

Forton DM, Taylor-Robinson SD, Thomas HC. · Hepatology Section, Division of Medicine A, Faculty of Medicine, Imperial College London, UK. · Eur J Gastroenterol Hepatol. · Pubmed #16538103 No free full text.

Abstract: Patients with chronic hepatitis C virus (HCV) infection frequently describe neuropsychological symptoms. Although hepatic encephalopathy is the best established neurological association of HCV infection, there is a growing body of literature on cerebral dysfunction, occurring at an early stage of chronic HCV infection, well before the development of cirrhosis. In this review we describe recent studies that have documented mild, but significant neurocognitive impairment in HCV infection. These deficits in patients with minimal or absent liver disease do not appear to be attributable to a history of substance abuse, coexistent depression or hepatic encephalopathy. Recent studies employing in-vivo magnetic resonance spectroscopy have suggested that a biological mechanism associated with the virus may be responsible. The hypothesis that HCV infection of the central nervous system may be related to the reported neuropsychological symptoms and cognitive impairment is supported by molecular virological studies of post-mortem brain tissue.

Forton DM, Allsop JM, Cox IJ, Hamilton G, Wesnes K, Thomas HC, Taylor-Robinson SD. · Liver Unit, Division of Medicine, Faculty of Medicine, Imperial College London, St Mary's Hospital Campus, London, UK. · AIDS. · Pubmed #16251829 No free full text.

Abstract: Numerous studies have reported associations between chronic hepatitis C virus (HCV) infection and fatigue, depression and impairments in health-related quality of life, which are independent of the severity of liver disease. Although there are a large number of potential explanations for these symptoms, including a history of substance abuse and associated personality types, or the effect of the diagnosis of HCV infection itself, there has been recent interest in the possibility of a biological effect of HCV infection on cerebral function. There is emerging evidence of mild, but significant neurocognitive impairment in HCV infection, which cannot be wholly attributed to substance abuse, co-existent depression or hepatic encephalopathy. Impairments are predominantly in the domains of attention, concentration and information processing speed. Furthermore, in-vivo cerebral magnetic resonance spectroscopy studies in patients with hepatitis C and normal liver function have reported elevations in cerebral choline-containing compounds and reductions in N-acetyl aspartate, suggesting that a biological mechanism may underlie the cognitive findings. The recent detection of HCV genetic sequences in post-mortem brain tissue raises the intriguing possibility that HCV infection of the central nervous system may be related to the reported neuropsychological symptoms and cognitive impairment.

Forton DM, Thomas HC, Taylor-Robinson SD. · Hepatology Section, Division of Medicine A, Faculty of Medicine, Imperial College, London, United Kingdom. · Metab Brain Dis. · Pubmed #15554429 No free full text.

Abstract: Hepatic encephalopathy is the most obvious neurological consequence of chronic hepatitis C virus (HCV) infection. There are also case reports of HCV-associated cerebral vasculitis. This review is concerned with the possibility of an effect of HCV on cerebral dysfunction, occurring at an early stage of chronic infection, prior to the development of cirrhosis and unrelated to vasculitis. There is emerging evidence of mild, but significant neurocognitive impairment in HCV infection, which cannot be attributed to substance abuse, coexistent depression, or hepatic encephalopathy. In vivo magnetic resonance spectroscopy and neurophysiological studies have suggested that a biological mechanism may underlie these cognitive findings. The recent detection of HCV genetic sequences in postmortem brain tissue raises the intriguing possibility that HCV infection of the central nervous system may be related to the reported neuropsychological symptoms and cognitive impairment.

Forton DM, Taylor-Robinson SD, Thomas HC. · Hepatology Section, Division of Medicine A, Faculty of Medicine, Imperial College London, UK. · J Viral Hepat. · Pubmed #12614463 No free full text.

Abstract: A number of studies have reported an association between chronic hepatitis C (HCV) infection and significant impairments in health-related quality of life (QOL), which are independent of the severity of liver disease. There are numerous reports documenting the prevalence of symptoms such as fatigue and depression in chronic HCV infection, which may in part account for the reductions in quality of life. Although there are a large number of potential explanations for these symptoms, including depression and anxiety associated with the diagnosis of HCV infection or substance abuse, there has been recent interest in the possibility of a biological effect of HCV infection on cerebral function. There is emerging evidence of mild, but significant neurocognitive impairment in HCV infection, which cannot be attributed to substance abuse, coexistent depression or hepatic encephalopathy. In vivo magnetic resonance spectroscopy and neurophysiological studies have suggested that a biological mechanism may underlie these cognitive findings. The recent detection of HCV genetic sequences in post mortem brain tissue raises the intriguing possibility that HCV infection of the central nervous system may be related to the reported neuropsychological symptoms and cognitive impairment.

Forton DM, Wright M, Knapp S, Thursz MR, Taylor-Robinson SD, Thomas HC. · Department of Medicine A, Imperial College and Liver Centre, St Mary's Hospital, London. · Clin Med. · Pubmed #12528970 No free full text.

Abstract: Hepatitis C infection is characterised by three key features, which are the consequence of a complex interaction between genetic determinants of immune and other host factors and viral characteristics: 1. A high rate of viral persistence after acute infection resulting from a combination of weak T cell responsiveness and specific viral mechanisms of immune escape. 2. Marked interindividual variability in end-organ damage (fibrosis and cirrhosis), probably due to host genetic polymorphisms in genes governing the immune response and fibrosis pathways in addition to viral pathogenicity factors. 3. Significant resistance to antiviral therapies. Viral mechanisms of antiviral resistance parallel those of viral persistence, and include the intriguing possibility that hepatitis C may infect immunologically privileged sites such as the central nervous system.

Taylor-Robinson SD. · Department of Medicine A, Imperial College School of Medicine, London. · Clin Med. · Pubmed #11358078 No free full text.

Abstract: In vivo magnetic resonance spectroscopy (MRS) provides a non-invasive 'window' on biochemical processes within the body. The technique is currently a research tool, but new developments in whole-body magnetic resonance imaging (MRI) may provide a role for clinical MRS in obtaining functional information at the end of a standard MRI examination. Applications of hepatic and cerebral MRS to chronic liver disease and its associated complications are specifically considered in this article. Changes in phosphorus-31 MRS with the underlying functional severity of the cirrhotic liver are discussed. These reflect increased turnover of cell membranes as the liver attempts to regenerate. Patterns of spectral abnormality in the transplanted liver are described, and also the potential use of the technique to assess the viability of the stored donor liver in the time period between organ harvesting and implantation in the transplant recipient. Metabolite abnormalities in the brain are defined in hepatic encephalopathy and in patients infected with the hepatitis C virus who have minimal hepatic inflammation. Future trends are considered: for example, the use of MRS as a non-invasive tool to assess the effectiveness of liver-directed gene therapy.

Thomas HC, Török ME, Forton DM, Taylor-Robinson SD. · Department of Medicine A, Imperial College School of Medicine at St. Mary's, London. · J Hepatol. · Pubmed #10622579 No free full text.

Abstract: The known mechanisms of hepatitis C virus (HCV) clearance and their failure in persistent infection are discussed. Interferon-alpha is the main treatment in chronic HCV but has shown poor sustained virological response rates when used as a monotherapy. The effects of interferon-a may include inhibition of HCV virion production by an effect on viral RNA and protein synthesis, enhancement of immune lysis of HCV infected cells, inhibition of hepatic fibrosis by an effect on TGFbeta, and an effect on HCV induced carcinogenesis. Mathematical modelling studies have provided insights into the mechanisms of action of interferon-alpha in chronic HCV. The two-phase plasma HCV RNA disappearance curve may reflect the presence of an interferon-resistant second site of HCV replication either within or outside the liver. Clinical observations and cerebral magnetic resonance scans provide evidence of functional cerebral impairment in HCV infected patients, raising the issue of the central nervous system (CNS) as a site for HCV replication. Recent studies using ribavirin in combination with interferon suggest that this approach doubles the sustained response rates obtained without having a major effect on the initial rate of HCV clearance (see Zeuzem paper). The potential mechanisms of action of ribavirin, although not yet fully understood, include inhibition of synthesis of GTP by an effect on inosine monophosphate dehydrogenase thereby limiting viral RNA synthesis, and enhancement of TH1 responses, which may assist viral clearance. There is no significant effect on HCV RNA polymerase activity. It is possible that ribavirin may have activity at extrahepatic sites of HCV infection, thus explaining the marked reduction in relapse rates with combination therapy, without an appreciable effect on initial antiviral response.

Lim AK, Patel N, Hamilton G, Mylvahan K, Kuo YT, Goldin RD, Taylor-Robinson SD. · Department of Imaging Sciences, Faculty of Medicine, Imperial College London, Robert Steiner MRI Unit, MRC Clinical Sciences Centre, Hammersmith Hospital, Du Cane Rd., London W12 0HS, United Kingdom. · AJR Am J Roentgenol. · Pubmed #17885051 links to  free full text

Abstract: OBJECTIVE: An increase in the ratio of phosphomonoester (PME) to phosphodiester (PDE) during 31P MR spectroscopy of the liver has been observed with increasing severity of hepatitis C-related liver disease. The purpose of this study was to investigate the utility of 31P MR spectroscopy as a biomarker of response to interferon and ribavirin treatment. SUBJECTS AND METHODS: Forty-seven patients with biopsy-proven hepatitis C undergoing viral eradication treatment with interferon and ribavirin underwent hepatic 31P MR spectroscopy at 1.5 T (voxel size, 70 x 70 x 70 mm; TR, 10,000; number of signals averaged, 48). All underwent baseline imaging before treatment and repeated imaging at 6-month intervals after the start of treatment. RESULTS: All patients underwent follow-up imaging 6 months after the start of treatment; 25 patients, 12 months; and 10 patients, 18 months after the start of treatment. According to the Ishak histologic scoring system, nine patients had mild hepatitis; 30 patients, moderate to severe hepatitis; and eight patients, cirrhosis. Thirty-two patients responded to antiviral treatment. Among these patients, 25 had a decrease in PME/PDE ratio on follow-up imaging. Among responders the mean baseline PME/PDE ratio decreased from 0.27 +/- 0.02 (standard error) to 0.16 +/- 0.01 after treatment (paired Student's t test, p < 0.001). Among the 15 virologic nonresponders, the ratios were similar in six patients; six other patients had an increase on follow-up imaging. In the latter nonresponder group, the mean baseline PME/PDE ratio was 0.21 +/- 0.03 compared with 0.31 +/- 0.08 after treatment (paired Student's t test, p =0.24). CONCLUSION: The in vivo hepatic PME/PDE ratio decreased in patients with hepatitis C who responded to antiviral treatment and remained similar or increased in patients without a virologic response. These results suggest that PME and PDE can be used as biomarkers in a noninvasive test of response to treatment.

Khan SA, Toledano MB, Taylor-Robinson SD. · Department of Hepatology and Gastroenterology, Imperial College London London UK. · HPB (Oxford). · Pubmed #18773060 links to  free full text

Abstract: Cholangiocarcinoma (CCA) is a fatal cancer of the biliary epithelium, arising either within the liver (intrahepatic, ICC) or in the extrahepatic bile ducts (extrahepatic ECC). Globally, CCA is the second most common primary hepatic malignancy. Several recent epidemiological studies have shown that the incidence and mortality rates of ICC are increasing. This review of the literature on the international epidemiological rates of CCA, both intra- and extrahepatic, explores possible explanations for the trends found. The possible role of epidemiological artifact in the findings is discussed and the known risk factors for CCA are summarized. These include primary sclerosing cholangitis, liver fluke infestation, congenital fibropolycystic liver, bile duct adenomas, and biliary papillomatosis, hepatolithiasis, chemical carcinogens such as nitrosamines, Thorotrast, chronic viral hepatitis, cirrhosis, chronic non-alcoholic liver disease and obesity. Potential pathways involved in the molecular pathogenesis of CCA are also summarized.

Forton DM, Hamilton G, Allsop JM, Grover VP, Wesnes K, O'Sullivan C, Thomas HC, Taylor-Robinson SD. · Hepatology Section, Division of Medicine, Imperial College London, St. Mary's Hospital, London, United Kingdom. · J Hepatol. · Pubmed #18538439 No free full text.

Abstract: BACKGROUND/AIMS: Abnormal cerebral metabolism and cognitive impairments have been reported in patients with chronic hepatitis C (HCV) but studies have failed to demonstrate a relationship between these findings. METHODS: Twenty-five HCV-positive patients with histologically-mild liver disease were studied with cerebral proton magnetic resonance spectroscopy (MRS), using acquisition parameters to quantify myo-inositol (mI) and other metabolites in frontal white matter (FWM). Patients underwent automated attention and working memory tests (Cognitive Drug Research test system). RESULTS: The mean mI/ creatine ratio in the HCV+ve patients (0.64, SD 0.21) was significantly higher (p=0.02) than in healthy controls (0.52, SD 0.10). On cognitive testing, the HCV+ve patients showed impairments in 2/4 composite scores, reflecting working memory and attention, compared to normative data from healthy volunteers (p<0.005) and HCV-ve controls (p=0.03). There was a significant association between elevated FWM mI/creatine and prolonged working memory reaction times (R=0.72, p=0.002). CONCLUSIONS: Elevated FWM mI/ creatine is a feature of HIV-related minor cognitive-motor disorder. It is associated with infection and immune activation of microglial cells. The similar findings in this study suggest that cerebral immune activation may also occur in HCV infection. This may underlie the mild neurocognitive impairment and neuropsychological symptoms observed in a proportion of patients.

Lim AK, Patel N, Eckersley RJ, Goldin RD, Thomas HC, Cosgrove DO, Taylor-Robinson SD, Blomley MJ. · Imaging Sciences Department, Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Rd, London W12 0HS, England. · Radiology. · Pubmed #16720867 links to  free full text

Abstract: PURPOSE: To prospectively compare transit times of Levovist and SonoVue in healthy volunteers and patients with biopsy-proved hepatitis C-related liver disease. MATERIALS AND METHODS: Institutional review board approval and informed consent were obtained. Forty patients and 25 healthy volunteers were examined. Subjects fasted, a bolus of SonoVue (0.6 mL) was injected into a cubital fossa vein, and hepatic venous time-intensity profiles were measured with spectral Doppler tracing. This was repeated with two injections of Levovist (2 g) and another injection of SonoVue. Time-intensity curves of spectral Doppler signals of right and middle hepatic veins were analyzed. A sustained signal intensity increase of 10% above baseline levels indicated hepatic vein transit time (HVTT). Carotid artery audio intensity was measured in volunteers. Analysis of variance and t tests were used for statistical analysis. RESULTS: Twelve patients had mild hepatitis; 18, moderate or severe hepatitis; and 10, cirrhosis. Mean HVTTs in control, mild hepatitis, moderate or severe hepatitis, and cirrhosis groups were 38.3 seconds +/- 2.4 (standard error), 47.5 seconds +/- 6.5, 29.5 seconds +/- 10.8, and 17.6 seconds +/- 5.0, respectively, with Levovist (P < .001) and 29.4 seconds +/- 6.9, 27.4 seconds +/- 9.3, 22.9 seconds +/- 4.7, and 16.4 seconds +/- 4.9, respectively, with SonoVue (P < .001). HVTT decreased as severity increased at imaging with both contrast agents. There was no significant difference in HVTT between mild and moderate hepatitis groups with SonoVue; however, there were significant differences in HVTT between all patient groups with Levovist. HVTT of SonoVue was shorter than that of Levovist in all groups (P < .001) except the cirrhosis group; in this group, HVTT of the two contrast agents was similar (P = .05). No difference was observed in mean cardiopulmonary transit time for SonoVue or Levovist (9.1 seconds +/- 2.4 [standard error] and 8.4 seconds +/- 2.5, respectively, P = .18). CONCLUSION: HVTT was significantly shorter with SonoVue than with Levovist; there was no significant difference in cardiopulmonary transit time.

Lim AK, Patel N, Eckersley RJ, Kuo YT, Goldin RD, Thomas HC, Cosgrove DO, Taylor-Robinson SD, Blomley MJ. · Imaging Sciences Department, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, Du Cane Rd., London W12 0HS, UK. · AJR Am J Roentgenol. · Pubmed #15908541 links to  free full text

Abstract: OBJECTIVE: Many authors have claimed that Doppler sonography indexes are of value in grading and assessing diffuse liver disease. However, there is much controversy regarding the reliability and reproducibility of these techniques. We performed a prospective study to evaluate whether these methods can grade disease in a well-stratified cohort of patients with hepatitis C virus (HCV)-related liver disease. SUBJECTS AND METHODS: Sixty-five patients with biopsy-proven HCV-related liver disease were recruited, and Doppler sonography was performed by one operator. The patients were classified into one of the following three groups on the basis of the Ishak-modified histologic activity index (HAI) fibrosis (F) and necroinflammatory (NI) scores: mild hepatitis (F < or = 2 and NI < or = 3), moderate or severe hepatitis (3 < or = F < 6 or NI > or = 4), or cirrhosis (F = 6/6). We measured the following Doppler indexes: main hepatic artery peak velocity (Vmax) and resistive index, main portal vein peak velocity (Vmax), and maximal portal vein diameter and circumference that allowed calculation of the portal vein congestive index (portal vein area and portal vein velocity). The ratio of the hepatic artery velocity (Vmax) to the portal vein velocity (Vmax) was also calculated, and the phasicity (triphasic, biphasic, or monophasic) of the hepatic veins of each patient was recorded. We also measured the maximal spleen length longitudinally. RESULTS: A total of 65 patients with liver disease (mild hepatitis, n = 20; moderate or severe hepatitis, n = 25; cirrhosis, n = 20) with biopsy-proven HCV-related liver disease were studied. Optimal hepatic arterial traces were obtained in only 30 patients and portal vein circumference in 18 patients. No significant differences were observed in the Doppler indexes with increasing severity of liver disease. Five (29%) of 17 patients with mild hepatitis had an abnormal hepatic vein trace (i.e., biphasic or monophasic) compared with 11 (55%) of 20 patients with moderate or severe hepatitis and 12 (60%) of 20 patients with cirrhosis. The only index to show a significant intergroup difference was splenic length (analysis of variance, p < 0.001), but there was still overlap between the groups. CONCLUSION: Doppler-derived indexes, which have previously been recommended for the assessment of severity in chronic liver disease, are difficult to reproduce reliably and therefore have a limited clinical role in the noninvasive assessment of hepatic fibrosis or inflammation.

Lim AK, Taylor-Robinson SD, Patel N, Eckersley RJ, Goldin RD, Hamilton G, Foster GR, Thomas HC, Cosgrove DO, Blomley MJ. · Imaging Sciences Department, MRC Clinical Services Centre, Faculty of Medicine, Imperial College, The Robert Steiner MR Unit, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK. · Gut. · Pubmed #15591518 links to  free full text

Abstract: BACKGROUND AND AIMS: A reliable non-invasive assessment of the severity of diffuse liver disease is much needed. We investigated the utility of hepatic vein transit times (HVTT) for grading and staging diffuse liver disease in a cohort of patients with hepatitis C virus (HCV) infection using an ultrasound microbubble contrast agent as a tracer. MATERIALS AND METHODS: Eighty five untreated patients with biopsy proven HCV induced liver disease were studied prospectively. All were HCV RNA positive on polymerase chain reaction testing. Based on their histological fibrosis (F) and necroinflammatory (NI) scores, untreated patients were divided into mild hepatitis (F < or =2/6, NI < or =3/18), moderate/severe hepatitis (3 < or =F <6 or NI > or =4), and cirrhosis (F=6/6) groups. In addition, 20 age matched healthy volunteers were studied. After an overnight fast, a bolus of contrast agent (Levovist) was injected into an antecubital vein and spectral Doppler signals were recorded from both the right and middle hepatic veins for analysis. HVTTs were calculated as the time from injection to a sustained rise in Doppler signal >10% above baseline. The Doppler signals from the carotid artery were also measured in 60 patients and carotid delay times (CDT) calculated as the difference between carotid and hepatic vein arrival times. The earliest HVTT in each patient was used for analysis. RESULTS: Mean (SEM) HVTT for the control, mild hepatitis, moderate/severe hepatitis, and cirrhosis groups showed a monotonic decrease of 38.1 (2.8), 38.8 (2.4), 26.0 (2.4), and 15.8 (0.8) seconds, respectively. Mean (SEM) CDT for the control, mild hepatitis, moderate/severe hepatitis, and cirrhosis patients again showed progressive shortening of 30.3 (2.6), 25.9 (2.6), 14.8 (2.1), and 5.6 (1.2) seconds, respectively. There were significant differences between the groups for HVTT (ANOVA, p<0.001) and CDT (ANOVA, p<0.001). There was 100% sensitivity and 80% specificity for diagnosing cirrhosis and 95% sensitivity and 86% specificity for differentiating mild hepatitis from more severe liver disease. CONCLUSION: We have shown, for the first time, that HVTT using an ultrasound microbubble contrast agent can assess HCV related liver disease with clear differentiation between mild hepatitis and cirrhosis. There were significant differences between these two groups and the moderate/severe hepatitis group. CDT offers no additional benefit or greater differentiation than HVTT and can be omitted, thus simplifying this technique. HVTT may complement liver biopsy and may also be a useful alternative for assessment of liver disease in patients who have contraindications to biopsy.

Forton DM, Karayiannis P, Mahmud N, Taylor-Robinson SD, Thomas HC. · Hepatology Section, Division of Medicine, Faculty of Medicine, Imperial College London, 10th Floor, QEQM Building, St. Mary's Hospital, South Wharf Road, London W2 1NY, United Kingdom. · J Virol. · Pubmed #15113899 links to  free full text

Abstract: Reports of cerebral dysfunction in chronic hepatitis C virus (HCV) infection have led to the suggestion that HCV may infect the central nervous system (CNS). We used reverse transcription-PCR, cloning, and sequencing to define quasispecies for the HCV internal ribosomal entry site (IRES) and hypervariable region 1 (HVR1) in autopsy-derived brain, liver, lymph node, and serum samples. There was evidence of tissue compartmentalization of sequences in the brain in two patients, with between 24 and 55% of brain-derived IRES sequences absent from the serum, and significant phylogenetic and phenetic clustering of the brain and lymph node HVR1 sequences. The IRES initiates cap-independent translation of the viral polyprotein. Two unique brain-derived IRES mutations (C(204)-->A and G(243)-->A), which have previously been associated with lymphoid replication and altered translational efficiency in cell culture, were found in one patient. We used a dicistronic reporter vector to test whether brain-derived variants showed altered IRES-mediated translational efficiency, which might favor CNS infection. The translational efficiencies of the brain-derived IRES sequences were generally reduced compared to those of the master serum and liver sequences in rabbit reticulocyte cell lysates and two human cell lines, HuH7 (liver) and CHME3 (microglial). The C(204)-->A and G(243)-->A mutations showed preserved translational efficiency in HuH7 cells but reduced efficiency in CHME3 cells. Our data provide evidence that the CNS is a site of HCV replication, consistent with the recent demonstration of negative-strand HCV RNA in brain, and suggest that IRES polymorphisms may be important as a viral strategy of reduced translation to favor latency in the CNS.

Lim AK, Patel N, Hamilton G, Hajnal JV, Goldin RD, Taylor-Robinson SD. · Robert Steiner MRI Unit, Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, UK. · Hepatology. · Pubmed #12668971 No free full text.

Abstract: Liver biopsy remains the gold standard for characterizing diffuse liver disease and is associated with significant morbidity and, rarely, mortality. Our aim was to investigate whether a noninvasive technique, in vivo phosphorus 31 ((31)P)-magnetic resonance spectroscopy (MRS), could be used to assess the severity of hepatitis C virus (HCV)-related liver disease. Fifteen healthy controls and 48 patients with biopsy-proven HCV-related liver disease were studied prospectively. Based on their histologic fibrosis (F) and necroinflammatory (NI) scores, patients were divided into mild hepatitis (F <or= 2/6, NI <or= 3/18), moderate/severe hepatitis (3 <or= F < 6 or NI >or= 4/18), and cirrhosis (F = 6/6). Hepatic (31)P MR spectra were obtained using a 1.5-T spectroscopy system. Quantitation of the (31)P signals was performed in the time domain using the Advanced MAgnetic RESonance algorithm. There was a monotonic increase in the mean +/- 1 standard error phosphomonoester (PME) to phosphodiester (PDE) ratios for the control, mild disease, moderate disease, and cirrhosis groups: 0.15 +/- 0.01, 0.18 +/- 0.02, 0.25 +/- 0.02, 0.38 +/- 0.04, respectively (ANOVA, P <.001). An 80% sensitivity and specificity was achieved when using a PME/PDE ratio less than or equal to 0.2 to denote mild hepatitis and a corresponding ratio greater than or equal to 0.3 to denote cirrhosis. No other significant spectral changes were observed. In conclusion, (31)P MRS can separate mild from moderate disease and these 2 groups from cirrhosis. The ability to differentiate these populations of patients has therapeutic implications and (31)P MRS, in some situations, would not only complement a liver biopsy but could replace it and be of particular value in assessing disease progression.

Forton DM, Thomas HC, Murphy CA, Allsop JM, Foster GR, Main J, Wesnes KA, Taylor-Robinson SD. · Hepatology Section, Division of Medicine A, Faculty of Medicine, Imperial College, St Mary's Hospital, London, UK. · Hepatology. · Pubmed #11826420 No free full text.

Abstract: Patients with chronic hepatitis C virus (HCV) infection frequently report fatigue, lassitude, depression, and a perceived inability to function effectively. Several studies have shown that patients exhibit low quality-of-life scores that are independent of disease severity. We therefore considered whether HCV infection has a direct effect on the central nervous system, resulting in cognitive and cerebral metabolite abnormalities. Twenty-seven viremic patients with biopsy-proven mild hepatitis due to HCV and 16 patients with cleared HCV were tested with a computer-based cognitive assessment battery and also completed depression, fatigue, and quality-of-life questionnaires. The HCV-infected patients were impaired on more cognitive tasks than the HCV-cleared group (mean [SD]: HCV-infected, 2.15 [1.56]; HCV-cleared, 1.06 [1.24]; P =.02). A factor analysis showed impairments in power of concentration and speed of working memory, independent of a history of intravenous drug usage (IVDU), depression, fatigue, or symptom severity. A subgroup of 17 HCV-infected patients also underwent cerebral proton magnetic resonance spectroscopy (1H MRS). The choline/creatine ratio was elevated in the basal ganglia and white matter in this group. Patients who were impaired on 2 or more tasks in the battery had a higher mean choline/creatine ratio compared with the unimpaired patients. In conclusion, these preliminary results demonstrate cognitive impairment that is unaccounted for by depression, fatigue, or a history of IVDU in patients with histologically mild HCV infection. The findings on MRS suggest that a biological cause underlies this abnormality.

Albrecht T, Blomley MJ, Cosgrove DO, Taylor-Robinson SD, Jayaram V, Eckersley R, Urbank A, Butler-Barnes J, Patel N. · Department of Imaging, Hammersmith Hospital, Imperial College of Science, Technology, and Medicine, London, UK. · Lancet. · Pubmed #10334257 No free full text.

Abstract: BACKGROUND: Hepatic cirrhosis is accompanied by several haemodynamic changes including arterialisation of the liver, intrahepatic shunts, pulmonary arteriovenous shunts, and a hyperdynamic circulatory state. We postulated that the hepatic first pass of a bolus of an ultrasound contrast agent injected into a peripheral vein is accelerated in patients with cirrhosis. We investigated this first pass in patients with diffuse liver disease and in normal controls to assess whether it provides useful differential diagnostic information. METHODS: We enrolled 15 patients with biopsy-proven cirrhosis, 12 patients with biopsy-proven non-cirrhotic diffuse liver disease, and 11 normal controls. We carried out continuous spectral doppler ultrasonography of a hepatic vein from 20 s before to 3 min after a peripheral intravenous bolus injection of 2.5 g Levovist. The intensity of the doppler signal was measured and used to plot time-intensity curves. FINDINGS: Patients with cirrhosis showed a much earlier onset of enhancement (arrival time; mean 18.3 s) and peak enhancement (mean 55.5 s) than controls (49.8 s and 97.5 s) or patients with non-cirrhotic diffuse liver disease (35.8 s and 79.7 s). All patients with cirrhosis had an arrival time of the bolus of less than 24 s, whereas the arrival time was 24 s or more in 22 of the 23 other participants. Peak enhancement was higher in patients with cirrhosis (mean 48.7 units) than in the other two groups (12.5 and 12.3 units, respectively). We found highly significant differences between the patients with cirrhosis and each of the other two groups for all variables (p<0.005), whereas we found no significant differences between non-cirrhotic patients and controls. INTERPRETATION: Our preliminary study suggests that analysis of liver transit time of a bolus of ultrasound contrast agent provides useful information about haemodynamic changes in patients with cirrhosis. Measurement of the arrival time of the bolus allows discrimination of patients with cirrhosis from controls and from patients with non-cirrhotic diffuse liver disease, and has potential as a non-invasive test for cirrhosis.

Cobbold JF, Wylezinska M, Cunningham C, Crossey ME, Thomas HC, Cox IJ, Patel N, Taylor-Robinson SD. · No affiliation provided · Gut. · Pubmed #17047120 No free full text.

This publication has no abstract.