December 4, 2010

Reliability of transient elastography for the detection of fibrosis in Non-Alcoholic Fatty Liver Disease and chronic viral hepatitis

Journal Of Hepatology
Volume 54, Issue 1, Pages 64-71

Silvia Gaia, Silvia Carenzi, Angela L. Barilli, Elisabetta Bugianesi, Antonina Smedile, Franco Brunello, Alfredo Marzano, Mario Rizzetto

Received 7 January 2010; received in revised form 3 May 2010; accepted 2 June 2010.

Background & Aims
Transient elastography (TE) is validated in chronic hepatitis C (CHC) to evaluate hepatic fibrosis; however, limited data are available in chronic hepatitis B (CHB) and Non-Alcoholic Fatty Liver Disease (NAFLD). This prospective study is aimed to assess the accuracy and the efficacy of TE for the detection of fibrosis in patients with chronic liver disease of different etiology and to evaluate the effect of steatosis on the liver stiffness measurement (LSM).

TE was performed in 219 consecutive patients with chronic liver disease (35% CHC, 32% CHB, and 33% NAFLD) within 6months of the liver biopsy.

LSM was related to the fibrosis stage in each group (CHC: p=0.596, p<0.001; CHB: p=0.418, p<0.001; NAFLD: p=0.573, p<0.001), but the correlation was less strong in CHB and NAFLD than in CHC patients. In CHB patients with histological cirrhosis (F4), the median stiffness value was almost two times lower than in patients with severe fibrosis (F3). In NAFLD patients with advanced fibrosis (F3) and severe steatosis (>33%), the LSM values were lower than expected and were similar to those of patients with initial fibrosis (F1) and fat <33%. TE underestimated the stage of fibrosis in 75% of patients with F3 and steatosis >33%. At multiple logistic regression analysis, in CHC and CHB patients, LSM was the only predictive variable of severe fibrosis/cirrhosis (OR=1.42, p=0.003 and OR=1.354, p=0.003, respectively), while in NAFLD subjects BMI and AST (OR=1.433, p=0.002 and OR=1.053, p=0.020, respectively) but not LSM were independently related with advanced fibrosis and cirrhosis.

This study confirms that TE can be considered a valid support to detect fibrosis in chronic liver disease related to HCV but it should be interpreted cautiously in CHB and NAFLD patients, where host or disease-related factors may modify its accuracy.

Keywords: Transient elastography, Fibroscan, Liver fibrosis, Viral hepatitis, NAFLD

San Giovanni Battista Hospital, Gastroenterology, C. Bramante 88 10128, Italy

Corresponding author. Tel.: +39 3383153995.

PII: S0168-8278(10)00712-9
© 2010 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved


Insulin resistance predicts re-treatment failure in an efficacy study of peginterferon-α-2a and ribavirin in HIV/HCV co-infected patients

Journal of Hepatology
Volume 54, Issue 1, Pages 41-47

Marie-Louise C. Vachon 1† , Stephanie H. Factor 2† , Andrea D. Branch 1† , Maria-Isabel Fiel 3† , Maribel Rodriguez-Torres 4† , Norbert Bräu 56† , Richard K. Sterling 7† , Jihad Slim 8† , Andrew H. Talal 9† , Douglas T. Dieterich 1† , Mark S. Sulkowski 10†

Received 19 February 2010; received in revised form 11 June 2010; accepted 16 June 2010.

Background & Aims
Few studies evaluated the efficacy of HCV re-treatment and the predictors of response in HIV/HCV co-infected patients. The role of insulin resistance as a predictor of response in this population is unknown. The aim of this study is to evaluate the safety and efficacy of pegylated interferon-α-2a and ribavirin in re-treatment of HIV/HCV co-infected patients, predictors of sustained virological response, including insulin resistance, and the relationship between insulin resistance and liver histology.

This prospective, multi-centered study included HIV/HCV co-infected patients with prior interferon-based treatment failure. Patients received pegylated interferon-α-2a and ribavirin for 48weeks. Serum HCV RNA was measured 24weeks post treatment to assess sustained virological response. Insulin resistance was defined as HOMA-IR>2. Correlations between baseline insulin resistance and steatosis, and/or cirrhosis were determined.

Sustained virological response was achieved in 14/96 (15%) patients. 35% of patients with HOMA-IR<2 (6/17) achieved sustained virological response vs 14% (5/36) of those with HOMA-IR between 2–4, and 7% (3/41) of those with HOMA-IR>4 (p=0.01). In multivariable analysis, insulin resistance and log10 HCV RNA were negatively associated with sustained virological response [AOR 0.17; 95% CI 0.05–0.64, p=0.009, and AOR 0.36; 95% CI 0.14–0.93, p=0.04, respectively]. Steatosis and cirrhosis correlated with insulin resistance (p=0.02 and 0.03, respectively) but neither independently predicted sustained virological response. Discontinuations due to severe adverse events occurred in 8% of cases, and 2 patients died of unrelated causes.

In HIV/HCV co-infected patients undergoing re-treatment, sustained virological response rate is low; those patients without insulin resistance are significantly more likely to achieve sustained virological response.

Keywords: Insulin resistance, Hepatitis C virus, Chronic, HIV, Re-treatment, Antiviral therapy, Pegylated interferon alfa-2a, Ribavirin

1 Division of Liver Diseases, Mount Sinai School of Medicine, NY, USA
2 Division of Infectious Diseases, Mount Sinai School of Medicine, NY, USA
3 Department of Pathology, Mount Sinai School of Medicine, NY, USA
4 Fundacion de Investigacion de Diego, San Juan, PR, USA
5 Divisions of Infectious Diseases and Liver Diseases, Mount Sinai School of Medicine, NY, USA
6 Veterans Affairs Medical Center, Bronx, NY, USA
7 Division of Liver Diseases, Virginia Commonwealth University Health Systems, Richmond, VA, USA
8 Division of Infectious Diseases, St-Michael’s Medical Center, NY, USA
9 Division of Gastroenterology and Hepatology and Center for the Study of Hepatitis C, Weill Cornell Medical College, NY, USA
10 Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MA, USA

Corresponding author. Address: Mount Sinai School of Medicine, One, Gustave L. Levy Place, Box 1123, NY 10029, USA. Tel.: +1 212 659 8877; fax: +1 212 659 8377.

† On behalf of Hepatitis Resource Network (HRN)-004.

PII: S0168-8278(10)00715-4
© 2010 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.


Elastography for the diagnosis of severity of fibrosis in chronic liver disease: A meta-analysis of diagnostic accuracy

Articles in Press

E.A. Tsochatzis 1, K.S. Gurusamy 2, S. Ntaoula 1, E. Cholongitas 1, B.R. Davidson 2, A.K. Burroughs 1

Received 11 March 2010; received in revised form 16 July 2010; accepted 20 July 2010. published online 30 November 2010.
Uncorrected Proof

Background & Aims
Transient elastography is a non-invasive method of assessing hepatic fibrosis developed as an alternative to liver biopsy. We assessed the performance of elastography for diagnosis of fibrosis using meta-analysis.

MEDLINE, EMBASE, SCI, Cochrane Library, conference abstracts books, and article references were searched. We included studies using biopsy as a reference standard, with the data necessary to calculate the true and false positive, true and false negative diagnostic results of elastography for a fibrosis stage, and with a 3-month maximum interval between tests. Quality of studies was rated with the QUADAS tool.

We identified 40 eligible studies. Summary sensitivity and specificity was 0.79 (95% CI 0.74–0.82) and 0.78 (95% CI 0.72–0.83) for F2 stage and 0.83 (95% CI 0.79–0.86) and 0.89 (95% CI 0.87–0.91) for cirrhosis. After an elastography result at/over the threshold value for F2 or cirrhosis (“positive” result), the corresponding post-test probability for their presence (if pre-test probability was 50%) was 78%, and 88% respectively, while if values were below these thresholds (“negative” result) the post-test probability was 21% and 16%, respectively. No optimal stiffness cut-offs for individual fibrosis stages were validated in independent cohorts and cut-offs had a wide range and overlap within and between stages.

Elastography theoretically has good sensitivity and specificity for cirrhosis (and less for lesser degrees of fibrosis); however, it should be cautiously applied to everyday clinical practice because there is no validation of the stiffness cut-offs for the various stages. Such validation is required before elastography is considered sufficiently accurate for non-invasive staging of fibrosis.

1 The Royal Free Sheila Sherlock Liver Centre and Division of Surgery, Royal Free Hospital, London NW3 2QG, UK
2 University Department of Surgery, Royal Free Hospital, London NW3 2QG, UK

Corresponding author. Address: The Royal Free Sheila Sherlock Liver Centre and Division of Surgery, Royal Free Hospital, Pond Street, Hampstead, London NW3 2QG, UK. Tel.: +44 2074726229; fax: +44 2074726226.

PII: S0168-8278(10)00825-1
© 2010 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.


Induction Pegylated Interferon Alfa-2a and High Dose Ribavirin Do Not Increase SVR in Heavy Patients With HCV Genotype 1 and High Viral Loads

Volume 139, Issue 6 , Pages 1972-1983, December 2010

K. Rajender Reddy, Mitchell L. Shiffman, Maribel Rodriguez–Torres, Hugo Cheinquer, Djamal Abdurakhmanov, Igor Bakulin, Viacheslav Morozov, Giovanni Faria Silva, Natalia Geyvandova, Carol Stanciu, Michael Rabbia, Michael McKenna, James A. Thommes, Stephen A. Harrison, PROGRESS Study Investigators

Received 28 May 2010; accepted 17 August 2010. published online 06 September 2010.


Background & Aims
Patients infected with hepatitis C virus (HCV) genotype 1, body weight ≥85 kg, and high baseline viral load respond poorly to standard doses of pegylated interferon (peginterferon) and ribavirin. We evaluated intensified therapy with peginterferon alfa-2a plus ribavirin.

This double-blind randomized trial included HCV genotype 1-infected outpatients from hepatology clinics with body weight ≥85 kg and HCV RNA titer ≥400,000 IU/mL. Patients were randomized to 180 μg/wk peginterferon alfa-2a for 48 weeks plus 1200 mg/day ribavirin (standard of care) (group A, n = 191) or 1400/1600 mg/day ribavirin (group B, n = 189). Additional groups included 360 μg/wk peginterferon alfa-2a for 12 weeks then 180 μg/wk peginterferon alfa-2a for 36 weeks plus 1200 mg/day ribavirin (group C, n = 382) or 1400/1600 mg/day ribavirin (group D, n = 383). Follow-up lasted 24 weeks after treatment.

Sustained virologic response rates (HCV RNA level <15 IU/mL at end of follow-up) in groups A, B, C, and D were 38%, 43%, 44%, and 41%, respectively. There were no significant differences among the 4 groups or between pooled peginterferon alfa-2a regimens (A + B vs C + D: odds ratio [OR], 1.08; 95% confidence interval [CI], 0.83–1.39; P = .584) or pooled ribavirin regimens (A + C vs B + D: OR, 1.00; 95% CI, 0.79–1.28; P = .974).

In patients infected with HCV genotype 1 who are difficult to treat (high viral load, body weight ≥85 kg), a 12-week induction regimen of peginterferon alfa-2a and/or higher-dose ribavirin is not more effective than the standard regimen.

Keywords: Chronic Hepatitis C, Tolerability of High-Dose Pegylated Interferon, Steatosis and Response to HCV Therapy, Tolerability of High-Dose Ribavirin


Factors associated with sustained virological response in liver transplant recipients with recurrent hepatitis C

Transplant Proc. 2010 Nov;42(9):3647-51.

Pillai AA, Lee VS, Wang E, Rinella ME, Levitsky J.


BACKGROUND: Antiviral therapy has achieved sustained virological response (SVR) in less than one third of orthotopic liver transplantation (OLT) patients with recurrent hepatitis C.

AIM: The aim of this study was to identify predictors of SVR in OLT patients treated with pegylated interferon and ribavirin (PEG+RBV) for recurrent hepatitis C virus (HCV).

METHODS: We analyzed data from our transplantation database for 62 subjects treated with PEG+RBV between August 2001 and September 2008. After univariate examination for factors known to be associated with SVR, significant associations (P < .05) were probed using multivariate logistic regression. Kaplan-Meier patient and graft survival analyses were compared between patients with (n = 19; 30.6%) versus without SVR.

RESULTS: On univariate analysis, longer duration of therapy, low pretreatment HCV RNA (<1 million IU/mL), and early virological response (EVR) were associated with SVR. On multivariate analysis, only low pretreatment HCV RNA predicted SVR. Patient survival was significantly higher in the SVR group.

CONCLUSIONS: Covariates associated with SVR among OLT patients with recurrent HCV were similar to the pretransplantation group. Potentially modifiable risk factors, such as obesity, diabetes mellitus, and metabolic syndrome, were not significant predictors of treatment response. Patient survival was associated with SVR, highlighting the impact of successful HCV therapy on long-term post-OLT outcomes.

Copyright © 2010 Elsevier Inc. All rights reserved.

PMID: 21094833 [PubMed - in process]


Importance of hepatitis vaccination in patients with chronic liver disease

South Med J. 2010 Dec;103(12):1223-31.

Kumar M, Herrera JL.

From the Division of Gastroenterology, University of South Alabama College of Medicine, Mobile, AL.


Acute hepatitis A or B infection can be lethal in patients with chronic liver disease. Safe and effective vaccines are currently available to prevent hepatitis A and B. Despite wide availability of vaccines, most patients with chronic liver disease are not immunized, in part due to nonuniform and inconsistent current recommendations for this population. A better understanding of the importance of preventing acute hepatitis A and B in patients with chronic liver disease and a proactive approach to vaccination by primary care physicians can positively influence the outcome of patients with chronic liver disease.

PMID: 21057383 [PubMed - in process]


Assessment of liver fibrosis before and after antiviral therapy by different serum marker panels in patients with chronic hepatitis C

Alimentary Pharmacology & Therapeutics
Early View (Articles online in advance of print)

S. M. Martinez 1, G. Fernández-Varo 2, P. González 1, E. Sampson 3, M. Bruguera 1, M. Navasa 1, W. Jiménez 2, J. M. Sánchez-Tapias 1, X. Forns 1

Article first published online: 26 OCT 2010
DOI: 10.1111/j.1365-2036.2010.04500.x
© 2010 Blackwell Publishing Ltd

Author Information
1 Liver Unit, Hospital Clinic, IDIBAPS and Ciberehd, Barcelona, Spain.
2 Department of Biochemistry and Molecular Genetics, Hospital Clinic, IDIBAPS and Ciberehd, Barcelona, Spain.
3 Siemens Healthcare Diagnostics, Tarrytown, NY, USA.

*Correspondence: Dr X. Forns, Liver Unit, Hospital Clinic, IDIBAPS and Ciberehd, Villarroel 170, Barcelona 08036, Spain. E-mail:



Background  Liver biopsy is the reference standard to assess liver fibrosis in chronic hepatitis C.

Aim  To validate and compare the diagnostic performance of non-invasive tests for prediction of liver fibrosis severity and assessed changes in extracellular matrix markers after antiviral treatment.

Methods  The performances of Forns’ score, AST to platelet ratio index (APRI), FIB-4 index and Enhanced Liver Fibrosis (ELF) score were validated in 340 patients who underwent antiviral therapy. These scores were determined 24 weeks after treatment in 161 patients.

Results  Forns’ score, APRI, FIB-4 and ELF score showed comparable diagnostic accuracies for significant fibrosis [area under the receiver operating characteristic curve (AUROC) 0.83, 0.83, 0.85 and 0.81, respectively]. To identify cirrhosis, FIB-4 index showed a significantly better performance over APRI and ELF score (AUROC 0.89 vs. 0.83 and 0.82, respectively). ELF score decreased significantly in patients with sustained virological response (SVR) (P < 0.0001) but remained unchanged in nonresponders. Non-1 hepatitis C virus (HCV) genotype, baseline lower HCV RNA, glucose, hyaluronic acid and higher cholesterol levels were independently associated with SVR.

Conclusions  Simple panel markers and ELF score are accurate at identifying significant fibrosis and cirrhosis in chronic hepatitis C. A decrease in ELF score after antiviral treatment reflects the impact of viral clearance in hepatic extracellular matrix and probably in the improvement of liver fibrosis.


Silymarin use and liver disease progression in the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis trial

Alimentary Pharmacology & Therapeutics
Early View (Articles online in advance of print)

N. D. Freedman 1, T. M. Curto 2, C. Morishima 3, L. B. Seeff 4, Z. D. Goodman 5, E. C. Wright 6, R. Sinha 1, J. E. Everhart 7, the HALT-C Trial Group 1

Article first published online: 2 NOV 2010
DOI: 10.1111/j.1365-2036.2010.04503.x
Published 2010. This article is a US Government work and is in the public domain in the USA.

Author Information

1 Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Rockville, MD, USA.
2 New England Research Institutes, Watertown, MA, USA.
3 Division of Virology, Department of Laboratory Medicine, University of Washington, Seattle, WA, USA.
4 Division of Digestive Diseases and Nutrition, and Liver Diseases Branch, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
5 Division of Hepatic Pathology, Armed Forces Institute of Pathology, Washington, DC, USA.
6 Office of the Director, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
7 Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.

* Correspondence: Dr N. D. Freedman, Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Blvd, EPS/320, MSC 7232, Rockville, MD 20852, USA. E-mail:



Background  Silymarin is the most commonly used herbal product for chronic liver disease; yet, whether silymarin protects against liver disease progression remains unclear.

Aim  To assess the effects of silymarin use on subsequent liver disease progression in 1049 patients of the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) trial who had advanced fibrosis or cirrhosis and had failed prior peginterferon plus ribavirin treatment.

Methods  Patients recorded their use of silymarin at baseline and were followed up for liver disease progression (two point increase in Ishak fibrosis score across baseline, year 1.5, and year 3.5 biopsies) and over 8.65 years for clinical outcomes.

Results  At baseline, 34% of patients had used silymarin, half of whom were current users. Use of silymarin was associated (P < 0.05) with male gender; oesophageal varices; higher ALT and albumin; and lower AST/ALT ratio, among other features. Baseline users had less hepatic collagen content on study biopsies and had less histological progression (HR: 0.57, 95% CI: 0.33–1.00; P-trend for longer duration of use=0.026). No effect was seen for clinical outcomes.

Conclusions  Silymarin use among patients with advanced hepatitis C-related liver disease is associated with reduced progression from fibrosis to cirrhosis, but has no impact on clinical outcomes ( #NCT00006164).


New York City widens pool of kidney donors

Wed Dec 1, 2010 11:47am EST

NEW YORK (Reuters) - New York City is changing its kidney donors program to allow organs to be recovered from people who die of heart attacks outside hospitals.

The pilot program, launched on Wednesday by New York City Mayor Michael Bloomberg and the New York Organ Donation Network, overrides rules that restrict the donation of kidneys to cardiac arrest victims who died inside hospitals.

"This new pilot program will help us test a process that could transform the way we donate organs and help save many lives," Bloomberg said in a statement.

Under the program, an Organ Preservation Team will respond to cases of cardiac arrest when an organ donor card is found, or if the deceased is a registered donor. Bodies will then be moved by ambulance to Bellevue hospital for final next-of-kin consent and the transplant operation.

"We are hopeful that it will prove to be an effective and efficient way of honoring donor wishes and making more organs available for life-saving transplants," said Health and Hospitals Corporation President and CEO Alan Aviles.

New York City Fire Commissioner Salvatore Cassano said the new program would benefit both those receiving new organs and those who wished to donate at the time of their death.

The program is funded with a $1.5 million grant from the Department of Health Resources and Services Administration. The pilot program covers Manhattan and runs until May when it will be reviewed for possible expansion.

According to city officials, nearly 8,000 New Yorkers are awaiting organ transplants. Nationally, over 109,000 are waiting for organs, a list to which a new name is added every 13 minutes. Approximately 6,500 people die each year because a transplant is not available.

(Reporting by Bernd Debusmann Jr.; Editing by Mark Egan and Jerry Norton)


Anemia in Treated-HCV Patients Bodes Well for Sustained Virologic Response

NEW YORK (Reuters Health) Dec 01 - Anemia that develops in patients infected with hepatitis C virus (HCV) during treatment with peginterferon-alfa and ribavirin (PEG-IFN/RBV) may be a good sign, new research hints.

In a large study, researchers found that patients who developed anemia were more likely to achieve sustained virologic response (SVR) than those who did not, despite decreased RBV dosing following a decline in hemoglobin levels. In addition, the virologic relapse rate wasn't increased in patients who cut back on RBV dose.

These data "firmly underscore the recommendation for RBV dose reduction as the primary strategy for management of treatment-related anemia," write Dr. Mark S. Sulkowski, of Johns Hopkins University School of Medicine in Baltimore, and colleagues in the November 10th issue of Gastroenterology.

They also found that the use of erythropoiesis-stimulating agents (ESAs) minimized discontinuation of treatment in patients with early-onset anemia, leading to higher SVR rates in this subgroup.

Anemia is seen in up to 30% of treated HCV patients and often leads to RBV dose reduction and/or discontinuation of treatment, Dr. Sulkowski and colleagues note in their report.

However, because lower SVR rates have been reported in patients who cut back on RBV, "many clinicians and patients prefer to avoid this strategy and instead use ESAs (off-label) to improve anemia-related symptoms while maintaining RBV dose," the investigators note.

Nonetheless, "considerable uncertainty exists regarding the role of adjuvant ESAs during HCV treatment," they point out.

Dr. Sulkowski's team evaluated the relationship between treatment-related anemia, ESA use, and treatment outcomes in 3,023 treatment-naive patients with HCV genotype 1. All were treated for up to 48 weeks with a standard PEG-IFN/RBV regimen. ESAs were allowed for patients with hemoglobin levels less than 10 g/dL after RBV dose reduction.

Anemia occurred in 28.6% of study patients. Most of these patients lowered their RBV dose and 51.9% were given an ESA.

"Unexpectedly," the investigators say, the SVR rate was significantly higher in anemic patients than nonanemic patients (difference, +12% for anemic patients).

Moreover, SVR rates were associated with the magnitude of hemoglobin decrease. SVR rates were 43.7% in patients with an absolute hemoglobin decline greater than 3 grams per deciliter compared with 29.9% in those with a maximum decline of 3 grams per deciliter.

Patients with early-onset anemia (after 8 weeks or less of treatment) had significantly higher SVR rates with ESA use than those with later onset anemia. Those with early-onset anemia were also less apt to discontinue treatment due to adverse events (12.6% vs. 30.1%; P < 0.001).

ESAs didn't affect SVR or discontinuation rates among patients with late-onset anemia, suggesting that these patients are "not likely to benefit from adjuvant ESAs," the authors note.

The finding that RBV dose reduction wasn't associated with lower SVR rates is important, they say. "ESAs should not be used solely to avoid RBV dose reduction in anemic patients."

"Prospective, randomized controlled trials are needed to define the optimal role of adjuvant ESAs during HCV treatment regimens that include PEG-IFN/RBV," they conclude.

Gastroenterology. Posted November 10, 2010. Abstract