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ABSTRACT: Primary biliary cirrhosis and primary sclerosing cholangitis are two cholestatic diseases characterised by hepatic accumulation of bile acids.
This study compares serum bile acid levels in patients with primary biliary cirrhosis and primary sclerosing cholangitis and from age and sex-matched non cholestatic donors.
Seventeen bile acids were quantified using liquid chromatography coupled to tandem mass spectrometry. Serum samples from cholestatic patients were compared with those of non-cholestatic donors.
The concentration of total bile acids, taurine and glycine conjugates of primary bile acids was elevated in both patients with primary biliary cirrhosis and primary sclerosing cholangitis when compared to non-cholestatic donors. Samples from primary sclerosing cholangitis patients displayed reduced levels of secondary acids, when compared to non cholestatic and primary biliary cirrhosis sera. The ratio of total glycine versus total taurine conjugates was reduced in patients with primary biliary cirrhosis, but not in primary sclerosing cholangitis.
The present study suggests that circulating bile acids are altered differentially in primary biliary cirrhosis and primary sclerosing cholangitis patients.
Digestive and Liver Disease 12/2011; 44(4):303-10. · 3.05 Impact Factor
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ABSTRACT: Previously published data suggest a hepatic vein transit time (HVTT) threshold of more than 24 s can distinguish mild to moderate from advanced fibrosis. In this study, we attempted to validate HVTT as a noninvasive index of hepatic fibrosis. Patients were scanned using real-time, pulse-inversion mode following bolus injections of the contrast agent Definity. HVTT was correlated with the degree of fibrosis obtained from contemporaneous liver biopsy. The study population included 40 patients with chronic liver disease and five healthy volunteers. Mean HVTT correlated with histologic grade as follows: absence/minimal fibrosis (n = 18), 25.6 ± 11.8 s; moderate fibrosis (n = 17), 21.5 ± 5.9 s; and severe fibrosis (n = 8), 20.9 ± 5.5 s, (p = .615). Poor sensitivity (57%) and specificity (43%) prevent validation of the previously published HVTT threshold as a surrogate marker of hepatic fibrosis. Further work investigating the different interaction of Definity, SonoVue and Levovist with the reticulo-endothelial system may help explain the discrepant results reported here.
Ultrasound in medicine & biology 12/2011; 37(12):1963-9. · 2.02 Impact Factor
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Teru Kumagi,
Joost P H Drenth,
Orlee Guttman,
Vicky Ng,
Les Lilly,
George Therapondos,
Yoichi Hiasa,
Kojiro Michitaka,
Morikazu Onji,
Yuji Watanabe,
Sambit Sen,
William Griffiths,
Eve Roberts, Jenny Heathcote,
Gideon M Hirschfield
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ABSTRACT: Biliary atresia is a progressive biliary injury which occurs only in infants.
To review the experience of patients surviving into adulthood without the need for liver transplantation in childhood.
A multicentre review of patients with biliary atresia treated surgically who survived into adulthood without the need for transplantation.
Twenty-two patients were identified across four centres. Median age at the last follow-up was 25 years (range: 18-46), and 21 patients had clinical features of portal hypertension. At last follow-up values of liver enzymes varied from normal to 15 × the upper limit of normal (ULN) for ALT (median 2.11 × ULN) and 9 × the ULN for ALP (median 2.02 × ULN). Six patients had a serum bilirubin > 50 μmol/l. Pruritus and jaundice were noted in 8 of 20 patients (40%) and 11 of 22 patients (50%) respectively. Thirteen patients (59.1%) were shown to have imaging features of sclerosing cholangitis, with strictures of intrahepatic bile duct(s) (IHBD), dilatation of IHBD (n = 8), or stone(s) within the IHBD (n = 5). A history of presumed bacterial cholangitis was present in 11 patients (50%). Successful pregnancies were recorded in three of fourteen female patients. Four patients underwent transplant between the ages of 20-27 years. Twenty-one patients (95.5%) were alive, including 18 (81.8%) with their native liver at the time of last follow-up.
Some patients treated for biliary atresia will survive into adulthood with their native liver, but commonly with secondary biliary disease including cholangitis and portal hypertension.
Liver international: official journal of the International Association for the Study of the Liver 11/2011; 32(3):510-8. · 3.82 Impact Factor
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Liver international: official journal of the International Association for the Study of the Liver 05/2011; 31(5):746-7. · 3.82 Impact Factor
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ABSTRACT: Our aim was to estimate the rate of progression to cirrhosis for those infected with hepatitis C virus (HCV) through injection drug use.
We searched the published literature for articles assessing cirrhosis in this population and abstracted data on cirrhosis prevalence, mean duration of infection, mean age, mean alanine aminotransferase (ALT) enzyme levels, proportion of males, proportion HIV co-infected, proportion consuming excessive alcohol, and study setting. Summary progression rates were estimated using weighted averages and random effects Poisson meta-regression. The impact of co-variates was assessed by estimating the posterior probability that the relative risk (RR) of progression exceeded 1.0.
A total of 47 published articles were identified. After adjusting for covariates in 44 studies representing 6457 patients, the estimated rate of progression to cirrhosis, was 8.1 per 1000 person-years (95% credible region (CR), 3.9-14.7). This corresponds to a 20-year cirrhosis prevalence of 14.8% (95% CR, 7.5-25.5). A 5% increase in the proportion of male participants and a 5% increase in the proportion consuming excessive alcohol were associated with faster progression (probability RR>1=0.97 and 0.92, respectively). A 5% increase in the proportion of HIV co-infected, an increase in ALT of 5 IU/L and studies in settings with a high risk of referral bias were not associated with faster progression (probability RR>1=0.42, 0.65, and 0.43, respectively).
Analysis of aggregate level data suggests that for patients who contracted HCV through injection drug use prognosis is poor in populations with many male patients and high levels of alcohol consumption.
Journal of Hepatology 08/2010; 53(2):245-51. · 9.26 Impact Factor
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ABSTRACT: Abstract Epidemiological data clearly indicate a link between chronic hepatitis C (CHC) and disturbed glucose homeostasis. The prevalences of both type 2 diabetes mellitus (T2DM) and insulin resistance (IR) are higher among those chronically infected with hepatitis C when compared with the general population and those with other causes of chronic liver disease. Both IR and diabetes are associated with adverse outcomes across all stages of CHC including the liver transplant population. The adverse effects that directly influence patient outcome are reduced responsiveness to antiviral therapy, more rapid progression of fibrosis to cirrhosis and a higher incidence of hepatocellular carcinoma. Although both viral and host factors are known to contribute to IR (and therefore the risk of T2DM), there is a paucity of evidence to support interventions targeting IR with pharmacotherapy or lifestyle intervention. The purpose of this review is to examine the impact of abnormalities of glucose homeostasis in CHC, and in so doing, to raise a number of questions. How do we identify those at risk of diabetes in CHC? Can we reduce the incidence of hepatoma and reduce transplant-related morbidity and mortality by preventing or treating diabetes? Can we improve the response to antiviral therapy by pretreating IR and T2DM in treatment candidates? Ultimately, can we cure two diseases, diabetes and CHC, with one treatment?
Liver international: official journal of the International Association for the Study of the Liver 03/2010; 30(3):356-64. · 3.82 Impact Factor
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Peter Ferenci,
Michael Fried,
Douglas Labrecque,
Jordi Bruix,
Morris Sherman,
Masao Omata, Jenny Heathcote,
Teehra Piratsivuth,
Mike Kew,
Jesse A Otegbayo, [......],
Salma Barakat Modawi,
Wolfgang Fleig,
Suliman Fedail,
Alan Thomson,
Aamir Khan,
Peter Malfertheiner,
George Lau,
Flair J Carillo,
Justus Krabshuis,
Anton Le Mair
Journal of clinical gastroenterology 03/2010; 44(4):239-45. · 2.21 Impact Factor
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ABSTRACT: Chronic hepatitis C virus (CHC) infection is treated with interferon/ribavirin, but only a subset of patients respond. Treatment nonresponders have marked pretreatment up-regulation of a subset of interferon stimulated genes (ISGs) in their livers, including ISG15. We here study how the nonresponder gene expression phenotype is influenced by clinical factors and uncover the cellular basis of the phenotype through ISG15 protein expression.
Seventy-eight CHC patients undergoing treatment were classified by clinical (gender, viral genotype, viral load, treatment outcome) and histologic (inflammation, fibrosis) factors and subjected to gene expression profiling on their pretreatment liver biopsies. An analysis of variance model was used to study the influence of individual factors on gene expression. ISG15 immunohistochemistry was performed on a subset of 31 liver biopsy specimens.
One hundred twenty-three genes were differentially expressed in the 78 CHC livers when compared with 20 normal livers (P < .001; fold change, > or =1.5-fold). Of genes influenced by a single factor, genotype (1 vs 2/3) influenced more genes (17) than any other variable; when treatment outcome was included in the analysis, this became the predominant influence (24 genes), and the effect of genotype was diminished. Treatment response was linked to cell-specific activation patterns: ISG15 protein up-regulation was more pronounced in hepatocytes in treatment nonresponders but in Kuppfer cells in responders.
Genotype is a surrogate marker for the nonresponder phenotype. This phenotype manifests as differential gene expression and is driven by activation of different cell types: hepatocytes in treatment nonresponders and macrophages in treatment responders.
Gastroenterology 11/2009; 138(3):1123-33.e1-3. · 11.68 Impact Factor
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ABSTRACT: Upregulation of interferon (IFN)-stimulated genes (ISGs), including IFN-stimulated gene 15 (ISG15) and other members of the ISG15 pathway, in pre-treatment liver tissue of patients chronically infected with hepatitis C virus (HCV) is associated with subsequent treatment failure (pegylated IFN-alpha/ribavirin). This study assessed the effect of ISG15 on HCV production in vitro. The levels of ISG15 and of its conjugation to target proteins (ISGylation) were increased by plasmid transfection, but ISGylation was inhibited by small interfering RNA directed against the E1 activating enzyme, Ube1L, in Huh7.5 cells. Cells were infected with HCV FL-J6/JFH virus, and HCV RNA and viral titres were determined. Levels of both HCV RNA and virus increased when levels of ISG15 and ISGylation were increased, and decreased when ISGylation was inhibited. The effects of ISGylation on HCV were independent of upstream IFN signalling: IFN-alpha-induced ISG expression was not altered by Ube1L knockdown. Thus, although ISG15 has antiviral activity against most viruses, ISG15 promotes HCV production. HCV might exploit ISG15 as a host immune evasion mechanism, and this may in part explain how increased expression of ISGs, especially ISG15, correlates with subsequent IFN-based treatment failure.
Journal of General Virology 10/2009; 91(Pt 2):382-8. · 3.36 Impact Factor
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Jenny Heathcote
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ABSTRACT: All but about 10% of patients with chronic hepatitis C (CHC) (predominantly those infected with genotype 1) can respond to some degree to 'combination' therapy with interferon (IFN) and ribavirin. The slower the virological response to treatment, the less likely sustained viral clearance will take place. Many factors influence response to antiviral therapy; most cannot be reversed (e.g. sex, age, cirrhosis, genotype and viral load). A sustained viral clearance is considerably facilitated by compliance with full-dose therapy for the prescribed time. The potential cause(s) for non-response need(s) to be ascertained before attempting retreatment. The 10% of patients who are true 'null' responders may respond to the new specifically targeted antiviral therapies but whether the response can be sustained off-therapy is unclear. Adjunctive therapies may facilitate response to retreatment if intolerance to treatment leading to diminished or absent doses was problematic in the past. Retreatment with a long-acting IFN and an adequate ribavirin dose (15 mg/kg), but given for 72 weeks in prior relapsers following 48 weeks of treatment, will enhance sustained virological response (SVR) rates. No benefit is gained from changing one pegylated IFNalpha (PEG IFNalpha) to another unless the treatment duration is extended. Only alpha-interferons are effective. For those individuals who still fail to achieve SVR, recruitment to trials of new treatments should be encouraged particularly for those with advanced liver disease. Lifestyle modification may be appropriate in attempt to reduce the chance of complications of liver disease, namely hepatocellular carcinoma, by smoking cessation, eliminating obesity and increasing coffee consumption.
Liver international: official journal of the International Association for the Study of the Liver 02/2009; 29 Suppl 1:49-56. · 3.82 Impact Factor
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ABSTRACT: Gene expression profiling has the potential to unravel molecular mechanisms behind gene regulation and identify gene targets for therapeutic interventions. As microarray technology matures, the number of microarray studies has increased, resulting in many different datasets available for any given disease. The increase in sensitivity and reliability of measurements of gene expression changes can be improved through a systematic integration of different microarray datasets that address the same or similar biological questions.
Traditional effect size models can not be used to integrate array data that directly compare treatment to control samples expressed as log ratios of gene expressions. Here we extend the traditional effect size model to integrate as many array datasets as possible. The extended effect size model (MAID) can integrate any array datatype generated with either single or two channel arrays using either direct or indirect designs across different laboratories and platforms. The model uses two standardized indices, the standard effect size score for experiments with two groups of data, and a new standardized index that measures the difference in gene expression between treatment and control groups for one sample data with replicate arrays. The statistical significance of treatment effect across studies for each gene is determined by appropriate permutation methods depending on the type of data integrated. We apply our method to three different expression datasets from two different laboratories generated using three different array platforms and two different experimental designs. Our results indicate that the proposed integration model produces an increase in statistical power for identifying differentially expressed genes when integrating data across experiments and when compared to other integration models. We also show that genes found to be significant using our data integration method are of direct biological relevance to the three experiments integrated.
High-throughput genomics data provide a rich and complex source of information that could play a key role in deciphering intricate molecular networks behind disease. Here we propose an extension of the traditional effect size model to allow the integration of as many array experiments as possible with the aim of increasing the statistical power for identifying differentially expressed genes.
BMC Bioinformatics 08/2008; 9:305. · 2.75 Impact Factor
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ABSTRACT: Autoinflammatory liver disease represents an important aspect of global hepatological practice. The three principal disease divisions recognized are autoimmune hepatitis, primary sclerosing cholangitis and primary biliary cirrhosis. Largely, but not exclusively, these diseases are considered to be autoimmune in origin. Increased recognition of outlier and overlap syndromes, changes in presentation and natural history, as well as the increased awareness of IgG4-associated sclerosing cholangitis, all highlight the limitations of the classic terminology. New insights continue to improve the care given to patients, and have arisen from carefully conducted clinical studies, therapeutic trials, as well as genetic and laboratory investigations. The challenges remain to treat patients before liver injury becomes permanent and to prevent the development of organ failure.
Hepatology Research 06/2008; 38(8):745-61. · 2.20 Impact Factor
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Liver international: official journal of the International Association for the Study of the Liver 03/2008; 28(2):155-7. · 3.82 Impact Factor
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ABSTRACT: Prior investigation has identified factors associated with response to treatment in hepatitis C including viral genotype and titre, body weight, hepatic fibrosis, and adherence to therapy. The lower response rate of African-Americans relative to whites has been previously described, but studies of other racial or ethnic groups remain limited.
To determine whether Asian race is an independent marker for response to antiviral therapy in hepatitis C.
Data on treatment-naïve patients from a large multicenter study of combination therapy with peginterferon alfa-2a (180 mug SC each week) and ribavirin (800 mg daily) were analyzed retrospectively to identify factors associated with an SVR, defined as an undetectable serum HCV RNA at least 24 wk after completion of therapy.
SVR occurred in 45% of 384 whites and 65% of 52 Asians (P= 0.0047) who were treatment naïve. In a multivariate logistic regression analysis that adjusted for all the aforementioned factors known to be associated with treatment response, Asian race was shown to be an independent predictor of achieving an SVR (OR 2.22, 95% CI 1.11-4.46). Other independent predictors of SVR include viral genotype, body mass index, degree of hepatic fibrosis, and adherence with ribavirin.
Asians are more likely to achieve an SVR to treatment with peginterferon alfa-2a and ribavirin than whites with chronic hepatitis C, suggesting a genetic influence on the antiviral response.
The American Journal of Gastroenterology 11/2007; 102(10):2181-8. · 7.28 Impact Factor
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10/2007: pages 341 - 352; , ISBN: 9780470986981
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ABSTRACT: The diagnosis of this condition in the absence of any neurological findings may pose a dilemma. In 2001, experts from The 8th International Conference on Wilson disease (WD) and Menkes disease in Leipzig, Germany proposed a scoring system that may facilitate diagnosis of WD.
Three patients were identified as having an atypical presentation of WD as they all presented after the age 40. Two of the three presented with established cirrhosis, and none had any neuropsychiatric manifestations. All three patients fulfilled the Leipzig diagnostic criteria proposed by EASL prior to confirmatory mutation analysis. Patient A died of liver failure despite treatment. Patients B and C have remained with stable liver disease on chelation therapy.
We believe these patients represent a group most likely to be missed in the diagnostic work-up of liver disease due to a combination of atypical features such as older age of onset, presence of other confounders for liver disease, and sometimes absence of Kayser-Fleischer rings. The Leipzig scoring system proposed in 2003 was helpful in support of an initial diagnosis of Wilson disease in these patients, validated later by genetic testing.
Journal of Hepatology 10/2007; 47(3):428-33. · 9.26 Impact Factor
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Jenny Heathcote
The American Journal of Gastroenterology 01/2007; 101(12 Suppl):S630-2. · 7.28 Impact Factor
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ABSTRACT: Modulation of the host innate immune response is an attractive means of inhibiting hepatitis C virus (HCV) replication. Having previously determined that expression of the interferon-sensitive gene (ISG)15 protease USP18 is increased in the liver biopsy specimens of patients who do not respond to interferon (IFN)-alfa therapy, we hypothesized that USP18 might hinder the ability of IFN to inhibit HCV replication.
The role of USP18 in IFN antiviral activity was examined using an in vitro model of HCV replication that reproduces the full viral life cycle. USP18 was silenced specifically using small inhibitory RNAs (siRNAs), and the dose response of HCV replication and infectious virus production to IFN-alfa was measured.
The siRNA knockdown of USP18 in human cells consistently potentiated the ability of IFN to inhibit HCV-RNA replication and infectious virus particle production by a factor of 1-2 log(10). USP18 knockdown also resulted in a number of cellular changes consistent with increased sensitivity to IFN. Decreasing USP18 expression led to increased cellular protein ISGylation in response to exogenous IFN-alfa, prolonged tyrosine phosphorylation of signal transducer and activation of transcription (STAT1), and a general enhancement of IFN-stimulated gene expression.
These data suggest that USP18 modulates the anti-HCV type I IFN response, and is a possible therapeutic target for the treatment of HCV infection.
Gastroenterology 12/2006; 131(5):1584-91. · 11.68 Impact Factor
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Morris Sherman,
Lawrence Cohen,
Mary Anne Cooper,
Magdy Elkashab,
Victor Feinman,
David Fletcher,
Nigel Girgrah, Jenny Heathcote,
Mark Levstik,
William B McNaull,
David Wong,
Florence Wong,
Colina Yim
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ABSTRACT: Today, combination antiviral therapy with pegylated interferon-alpha and ribavirin (RBV) allows many patients infected with hepatitis C virus (HCV) to achieve a sustained virological response, which is equivalent to cure. Data also support the clinical benefit of combination antiviral therapy in patients coinfected with HCV and HIV, and in patients who have received a liver transplant. Antiviral therapy with pegylated interferon-alpha and RBV is, however, associated with a high incidence and significant magnitude of anemia. This anemia may have several mechanisms, including bone marrow suppression and hemolysis. In addition, patients coinfected with HIV may have both pre-existing and RBV-associated anemia. Management of anemia in patients with HCV through RBV dose reduction or treatment discontinuation may compromise the effectiveness of treatment, because studies have demonstrated that treatment adherence or maintenance of antiviral therapy dose is an important predictor of sustained virological response. Anemia associated with combination antiviral therapy in patients with HCV is frequently associated with an inadequate or blunted endogenous erythropoietin response. Accumulating evidence now supports the use of recombinant human erythropoietin (rHuEpo) to manage anemia in these patients, with the objective of maintaining the RBV dose, but clinical standards are lacking. The present article reviews the data relevant to the use of rHuEpo in this patient population and proposes a set of clinical practice standards to assist clinicians in selecting patients for rHuEpo and in implementing rHuEpo therapy effectively.
Canadian journal of gastroenterology = Journal canadien de gastroenterologie 08/2006; 20(7):479-85. · 1.21 Impact Factor
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ABSTRACT: In the past, antiviral therapy has been given to 15% to 30% of patients infected with hepatitis C virus (HCV). The efficacy of therapy has recently improved with the addition of ribavirin and pegylated interferon. The aim of the present study was to identify the clinical, socioeconomic and health-system predictors of antiviral treatment for HCV.
A retrospective analysis of compensation claims data of patients who acquired HCV through blood transfusions between 1986 and 1990 was performed. The patients consisted of 2456 Canadian HCV-positive individuals. The authors reviewed narrative comments from physicians, and constructed univariate and multivariate logistic regression models, using receipt of antiviral therapy with interferon or interferon/ribavirin as the primary outcome.
Of the 2456 patients, approximately 30% appeared to be eligible, but only 16% received treatment. Univariate analyses suggested that the disease severity, age, HIV status and province of residence were associated with the likelihood of receiving treatment (P<0.01). The final, multivariable model indicated that in patients with HCV: intermediate disease severity (eg, fibrosis, P<0.0001); middle age (P<0.0001); HIV-negative status (P<0.0001); and province of residence (Quebec, P<0.0001; and Saskatchewan, P<0.0001) were independent predictors of treatment. Narrative comments of physicians emphasized the importance of age, HIV status and patient preferences in clinical decision-making.
Given the efficacy and cost-effectiveness of current antiviral therapy, treatment rates of HCV patients may be suboptimal. Further work is required to understand barriers to treatment related to geography, organization of medical care, age, medical provider and patient preferences.
Canadian journal of gastroenterology = Journal canadien de gastroenterologie 03/2006; 20(2):107-11. · 1.21 Impact Factor
