Evidence for neuroinflammation and neuroprotection in HCV infection-associated encephalopathy

Gut. 2010 Oct 6. [Epub ahead of print]

Bokemeyer M, Ding XQ, Goldbecker A, Raab P, Heeren M, Arvanitis D, Tillmann HL, Lanfermann H, Weissenborn K.

Hannover Medical School, Hannover, Germany.

Abstract

Objective Fatigue, mood disturbances and cognitive dysfunction are frequent in patients infected with hepatitis C virus (HCV) who have mild liver disease. The reason is still unclear. The present study aims to gain more insight into the pathomechanism by combining an extensive neuropsychological examination with magnetic resonance spectroscopy in four different brain regions in a patient group covering the whole spectrum of neuropsychiatric findings in patients afflicted with HCV who have only mild liver disease. Methods 53 HCV-positive patients with only mild liver disease and differing degrees of neuropsychiatric symptoms were studied with single-voxel MRS of the parietal white matter, occipital grey matter, basal ganglia and pons. Brain metabolite concentrations were quantitatively analysed by using LCmodel. MRS data were compared to those of 23 healthy controls adjusted for age, and analysed for relationships with the extent of neuropsychiatric symptoms. Results Choline (p=0.02), creatine (p=0.047) and N-acetyl-aspartate plus N-acetyl-aspartyl-glutamate (NN, p=0.02) concentrations in the basal ganglia and choline concentrations in the white matter (p=0.045) were significantly higher in the patients than in controls. Interestingly, the difference was most evident for the patients with low fatigue scores (eg, white matter: choline: p=0.001, creatine: p=0.003, NN: p=0.031). Myo-inositol differed significantly between groups in the white (p=0.001) and grey matter (p=0.003). Fatigue correlated negatively with white matter NN, choline and creatine and myo-inositol levels in white and grey matter and basal ganglia (p<0.01). Conclusion As the increase of choline, creatine and myo-inositol are usually interpreted to indicate glial activation and macrophage infiltration in chronic inflammation and slow virus infections of the brain the present data endorse the hypothesis, that HCV infection may induce neuroinflammation and brain dysfunction. The concomitant increase of NN and the negative correlation to the extent of fatigue suggest a cerebral compensatory process after HCV infection.

PMID: 20926642 [PubMed - as supplied by publisher]

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HCC Surveillance Inadequate in Patients With Cirrhosis

ISSUE: OCTOBER, 2010
VOLUME: 61:10

David Wild

Less than 20% of older patients with cirrhosis undergo surveillance regularly for hepatocellular carcinoma (HCC), according to a recent review of a large national database (Davila JA et al. Hepatology 2010;52:132-141). One expert believes that physicians and patients should do more to increase HCC vigilance.

“We need a three-pronged educational approach that includes all those involved in managing liver diseases,” said Lewis Roberts, MD, associate professor in the Department of Gastroenterology and Hepatology at Mayo Clinic School of Medicine, in Rochester, Minn. “Primary care physicians need to refer patients appropriately; specialists should initiate treatment and surveillance; and patients need to adhere to the disease management schedule. We know better surveillance equals better outcomes.”

To evaluate HCC surveillance in a large population, senior investigator Hashem El-Serag, MD, MPH, professor of medicine and chief of the Section of Gastroenterology and Hepatology at Baylor College of Medicine, Houston, and colleagues analyzed data from 1,873 cirrhotic patients with a diagnosis of HCC who were enrolled in the Surveillance, Epidemiology and End Results (SEER) program registry and the Medicare database. All subjects were over 65 years of age and had been diagnosed with HCC between 1994 and 2002. To determine the extent of HCC surveillance before diagnosis of the disease, the investigators examined the number of α-fetoprotein (AFP) and ultrasound tests undergone by the patients. They also conducted multiple regression analyses of patient and physician characteristics to establish any correlations with HCC surveillance.

The investigators found that within the three years before diagnosis of HCC, 17% (321 of 1,873) of subjects underwent regular surveillance, defined as an annual AFP or ultrasound test during at least two of the three years, while 38% (710 of 1,873) were administered an AFP or ultrasound test at least once during that period. Furthermore, the investigators found that approximately half (905 of 1,873) of all subjects were seen by a gastroenterologist, hepatologist or both at least once during the three years before HCC diagnosis. Patients in this group were 2.8 times more likely to undergo a regular surveillance regimen than those who were seen only by an internist or a family physician (P<0.001). However, those treated by both a gastroenterologist or hepatologist and an internist or a family physician were 4.5 times more likely to undergo regular HCC surveillance than those who received care by an internist or a family physician alone (P<0.001).

The authors noted that guidelines for HCC management were released from the American Association for the Study of Liver Diseases after the end of their study period in 2001, and that it is possible that HCC surveillance has improved since that time.

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Vertex at the 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD)

Vertex Oral Presentations

November 1, 2010 @ 5:00 p.m. ET

#LB-2 “Telaprevir in Combination with Peginterferon Alfa2a and Ribavirin for 24 or 48 weeks in Treatment-Naïve Genotype 1 HCV Patients who Achieved an Extended Rapid Viral Response: Final Results of Phase 3 ILLUMINATE Study”
Hynes Auditorium

November 2, 2010 @ 8:00 a.m. ET

#211 “Telaprevir in Combination with Peginterferon and Ribavirin in Genotype 1 HCV Treatment-Naïve Patients: Final Results of Phase 3 ADVANCE Study”
Hynes Auditorium

November 2, 2010 @ 11:45 a.m. ET

#227 “Long-term Follow-up of Patients with Chronic Hepatitis C Treated with Telaprevir in Combination with Peginterferon Alfa-2a and Ribavirin: Interim Analysis of the EXTEND Study”
Hynes Room 304/306

Vertex Poster Presentations

October 31, 2010 @ 8:00 a.m. ET

#805 “No Impact of Insulin Resistance on Antiviral Efficacy of Telaprevir-based Regimen in HCV Genotype 1 Treatment-Naïve Patients: Subanalysis of C208 Study”
Hynes Exhibit Hall C

#828 “Activity of Telaprevir Monotherapy or in Combination with Peginterferon-alfa-2a and Ribavirin in Treatment-naïve Genotype 4 Hepatitis-C Patients: Final Results of Study C210”
Hynes Exhibit Hall C

#1051 “Spontaneous Viral Clearance in a Patient With Chronic Hepatitis C who Relapsed After Telaprevir-based Treatment”
Hynes Exhibit Hall C

#899 “The Effect of Hepatitis C Treatment Response on Medical Costs: a 5-Year Longitudinal Analysis in a Managed Care Setting”
Hynes Exhibit Hall C

November 1, 2010 @ 8:00 a.m. ET

#LB-11 “Clinical Virology Results from Telaprevir Phase 3 Study ADVANCE”
Hynes Exhibit Hall C

Last Revised 10/05/10

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Fatty Liver Disease Linked to Heart Trouble

Mark Wilson Oct 23rd, 2010

Two studies presented this week to the American College of Gastroenterology convention show a definitive link between fatty liver disease and significant long term heart and cardiovascular problems.

The studies were conducted by multiple well known cardiovascular specialists who observed hundreds of heart patients as well as fatty liver disease patients. The studies confirm that patients diagnosed with fatty liver disease are at much higher risk for long term cardiovascular disease; along with heart disease comes numerous other problems such as elevated heart attack risk, high blood pressure, and countless other life threatening situations.

Both studies showed that nearly 70% of fatty liver disease patients are affected by long term heart trouble. The reported cases all showed significantly elevated blood pressure, as well as cholesterol and other major signs. For years doctors have suspected that fatty liver disease led to at least some heart trouble; but they never imagined that such a significant amount of people would be affected.

Follow up studies are already underway to discover if any other diseases are involved; they are expected to be complete sometime next year.

Along with heart disease comes a significantly elevated risk for obesity in patients. Doctors are currently working to develop new treatments for fatty liver disease, although they have been unsuccessful at this point. Currently the most common treatment method is a special fatty liver diet, designed specifically to help reduce the symptoms and impact of the disease. As always the research is ongoing; largely because fatty liver disease affects nearly ¼ of all Americans. Unfortunately doctors are still unable to treat the disease effectively so obesity and heart disease are likely to continue spreading thanks to fatty liver disease

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Stem Cell Grants for UC Davis Doctors

Posted on: Saturday, October 23, 2010 - Press Release

Research to explore innovative treatment for non-healing wounds and an alternative to liver transplantation

(SACRAMENTO, Calif.) — California's stem cell agency voted to fund two new grants to UC Davis School of Medicine physicians for their work in regenerative medicine research. Roslyn Rivkah Isseroff, professor of dermatology, and Mark Zern, professor of internal medicine, were among the scientists from around the state whose Early Translational study proposals were approved by the California Institute for Regenerative Medicine’s governing board in Los Angeles.

The funding enables Isseroff to further explore her innovative work to create a bandage-like material composed of stem cells and a collagen framework that can be applied to chronic wounds to prompt rapid healing. Zern’s research is designed to establish clinically useful methods of generating human liver cells that could be used to repair an injured liver. Known as hepatocytes, these cells provide a safer and less expensive treatment than whole-liver transplantation.

Their combined grants will total approximately $9.7 million over a three-year period.

"Drs. Isseroff and Zern are doing amazing work,” said Jan Nolta, professor of internal medicine, director of the UC Davis Institute for Regenerative Cures and co-principal investigator on the Isseroff wound-repair grant. “Their research is rapidly advancing the field of regenerative medicine and helping to develop innovative new medical treatments. These grants will help tremendously in our mission to bring stem cell-based treatments to our patients who currently lack other options."

Stem cells offer the unique potential to restore tissues damaged by injury or disease. CIRM’s Early Translational awards are designed to support scientific investigations that show promise for developing clinical applications from laboratory research.

Isseroff, who also serves as chief of dermatology and director of the wound clinic at the Veterans Affairs Northern California Health Care System, has long been frustrated by the challenges of treating the chronic, non-healing wounds of diabetics. Foot ulcers, in particular, affect between 15 to 25 percent of the approximately 21 million Americans who have diabetes. Eighty-five percent of lower-limb amputations are preceded by active foot ulcers.

Isseroff’s research, conducted in collaboration with scientists from Germany’s Technical University of Munich, will combine mesenchymal stem cells (stem cells extracted from a donor’s fat or bone marrow) with a collagen scaffolding upon which to build and regenerate new tissue. The stem cells secrete potent stimulatory molecules that can have reparative properties to restore blood flow and heal damaged tissue. Isseroff envisions a therapeutic biological product that will one day allow physicians to simply rinse a living bandage-like material and apply it to wounds for rapid tissue repair.

Scientists are keenly interested in stem cells because they have the potential to develop into many different cell types in the body, such as liver, kidney, brain or heart cells. When unspecialized stem cells divide into specialized cells, the process is called “differentiation.” Understanding what triggers stem cell differentiation and how to direct it to areas of the body are among the key areas of regenerative medicine research.

Zern, who also directs the Transplant Research Program at UC Davis, is working to develop an alternative to liver transplants. Whole-organ transplantation continues to have very high costs and complex challenges, including a lack of viable donor organs. More than a 1,000 people die each year while on a waiting list for a new liver. Tens of thousands of other people never get on the lists because of the lack of available donor organs.

Zern’s research involves comparing approved lines of human embryonic stem cells with other types of stem cells to determine which will be the most effective cell type to transplant into people with liver disease. He and his research team will differentiate the stem cells to act like liver cells while also ensuring that the cells are safe. Zern’s goal is to create a safe and unlimited supply of liver cells for treating people with liver injury, liver failure or inherited liver disease. Developing methods to generate unlimited amounts of liver-like cells would provide regenerative treatments that could offer a better, less invasive alternative to whole-organ transplantation.

UC Davis is playing a leading role in regenerative medicine, with nearly 150 scientists working on stem cell-related research projects on the Davis and Sacramento campuses. It now has received 19 grants from the California Institute for Regenerative Medicine (CIRM), the state stem cell agency, totaling more than $61 million. In 2010, the UC Davis Institute for Regenerative Cures, a facility supported by CIRM, opened its doors on the university's Sacramento campus. This $62 million facility is the university's hub for stem cell science. It includes Northern California's largest academic Good Manufacturing Practice laboratory, with state-of-the-art equipment and manufacturing rooms for cellular and gene therapies. UC Davis also has a Translational Human Embryonic Stem Cell Shared Research Facility in Davis and a collaborative partnership with the Institute for Pediatric Regenerative Medicine at Shriners Hospital for Children Northern California. The stem cell research work is facilitated by the resources of the Clinical and Translational Science Center at UC Davis, which was formed in 2005 to enhance collaborations that bring new treatments to people more quickly. For more information, visit healthsystem.ucdavis.edu/stemcellresearch/.

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Current Status and Future of Liver Transplantation

Semin Liver Dis 2010; 30(4): 411-421
DOI: 10.1055/s-0030-1267541
© Thieme Medical Publishers

Robert M. Merion 1,2

1 Section of Transplantation, University of Michigan, Ann Arbor, Michigan
2 Arbor Research Collaborative for Health, Ann Arbor, Michigan

ABSTRACT

Liver transplantation has rapidly advanced from an experimental therapy to a mainstream treatment option for a wide range of acute and chronic liver diseases. Indications for liver transplant have evolved to include previously contraindicated conditions such as hepatocellular carcinoma and alcohol-related liver disease. Cirrhosis from chronic hepatitis C infection remains the most common indication today. Multidisciplinary evaluation for liver transplantation is intended to confirm the patient's suitability and identify the appropriate timing of transplant, although the latter is problematic as a result of the ongoing donor organ shortage. Deceased liver donors have been increasing in number, but increasing donor age has been associated with less satisfactory posttransplant results. Living donor liver transplant is a dramatic but very infrequent procedure; risk to the living donor is of paramount concern. The main focus of deceased donor allocation has transitioned from waiting time to estimation of the likelihood of death without transplant (medical urgency), and now relies upon a laboratory-based Model for End-Stage Liver Disease (MELD) score for candidates with chronic liver disease. Those with acute liver failure are prioritized ahead of those with chronic conditions. Although not used as a direct criterion for allocation, development of the concept of transplant survival benefit, i.e., the extra years of life attributable to transplant, has facilitated better ordering of those candidates likely to have the most benefit, while restricting access to those whose lives will be extended minimally or not at all. Overall posttransplant outcomes have steadily improved, with unadjusted 5-year patient survival rates of 77% among patients transplanted with MELD score between 15 and 20, and 72% for those with MELD scores between 21 and 30.

KEYWORDS
Liver transplantation - indications - waiting list - deceased organ donation - surgical technique - living donor liver transplant

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Modeling the Probability of Sustained Virological Response to Therapy with Pegylated Interferon plus Ribavirin in Patients Coinfected with Hepatitis C Virus and HIV

15 November 2010

Volume 51, Number 10

Clinical Infectious Diseases 2010;51:1209–1216
© 2010 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2010/5110-0014$15.00
DOI: 10.1086/656811

HIV/AIDS
MAJOR ARTICLE

Jose Medrano, 1 Karin Neukam, 3 Norma Rallón, 1 Antonio Rivero, 4 Salvador Resino, 2 Susanna Naggie,6 Antonio Caruz, 5 Aida Calvino, 2 Juan Macías, 3 Jose Miguel Benito, 1 Carlos Sánchez‐Piedra, 1 Eugenia Vispo, 1 Pablo Barreiro, 1 John McHutchison, 6 Juan Antonio Pineda, 3 and Vincent Soriano 1

1 Department of Infectious Diseases, Hospital Carlos III, and 2 Laboratory of Molecular Epidemiology of Infectious Diseases, National Centre of Microbiology, Instituto de Salud Carlos III, Majadahonda, Madrid, 3 Infectious Diseases Unit, Hospital Universitario de Valme, Grupo Guadalquivir, Seville, 4 Infectious Diseases Unit, Hospital Universitario Reina Sofia, Grupo Guadalquivir, Cordoba, and 5 Immunogenetics Unit, Faculty of Sciences, Universidad de Jaen, Jaen, Spain; and 6 Duke Clinical Research Institute, Durham, North Carolina

Background.A single‐nucleotide polymorphism (SNP) near the IL28B gene (rs12979860) strongly predicts sustained virological response to pegylated interferon plus ribavirin (pegIFN‐RBV) treatment for chronic hepatitis C virus (HCV) infection. Given that therapy is poorly tolerated and rates of response are lower in patients coinfected with HCV and human immunodeficiency virus (HIV), the recognition of predictors of response is a high priority in this population.

Methods.A baseline noninvasive index was derived on the basis of the probability of achieving sustained virological response in a group of 159 HIV‐HCV–coinfected patients treated at one clinic in Spain. The index was then validated using data from a separate cohort of 86 coinfected individuals. Only individuals who had completed a course of pegIFN‐RBV therapy and had validated outcomes were considered.

Results.The final score included 4 variables: 2 host‐related variables (IL28B SNP rs12979860 and liver stiffness) and 2 HCV‐related variables (genotype and viral load). The area under the receiver operating characteristic curve was 0.89 in the derivation group and 0.85 in the validation group.

Conclusions.The probability of achieving sustained virological response with pegIFN‐RBV therapy in HIV‐HCV–coinfected patients can be reliably estimated prior to initiation of therapy using an index that includes 4 noninvasive parameters.

Received 1 May 2010; accepted 28 July 2010; electronically published 19 October 2010.

Reprints or correspondence: Dr Vincent Soriano, Dept of Infectious Diseases, Hospital Carlos III, Calle Sinesio Delgado 10, Madrid 28029, Spain (vsoriano@dragonet.es).
 
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A new index for non-invasive assessment of liver fibrosis

World J Gastroenterol. 2010 October 14; 16(38): 4809–4816.

Published online 2010 October 14. doi: 10.3748/wjg.v16.i38.4809.
PMCID: PMC2955250

Copyright ©2010 Baishideng Publishing Group Co., Limited. All rights reserved.

Naohiro Ichino, Keisuke Osakabe, Toru Nishikawa, Hiroko Sugiyama, Miho Kato, Shiho Kitahara, Senju Hashimoto, Naoto Kawabe, Masao Harata, Yoshifumi Nitta, Michihito Murao, Takuji Nakano, Yuko Arima, Hiroaki Shimazaki, Koji Suzuki, and Kentaro Yoshioka

Naohiro Ichino, Keisuke Osakabe, Koji Suzuki, Faculty of Medical Technology, School of Health Sciences, Fujita Health University, Toyoake, Aichi 470-1192, Japan

Toru Nishikawa, Hiroko Sugiyama, Miho Kato, Shiho Kitahara, Department of Clinical Laboratory, Fujita Health University Hospital, Toyoake, Aichi 470-1192, Japan

Senju Hashimoto, Naoto Kawabe, Masao Harata, Yoshifumi Nitta, Michihito Murao, Takuji Nakano, Yuko Arima, Hiroaki Shimazaki, Kentaro Yoshioka, Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, Toyoake, Aichi 470-1192, Japan

Author contributions: Ichino N, Osakabe K and Yoshioka K designed the research; Nishikawa T, Sugiyama H, Kato M and Kitahara S performed the measurement of liver stiffness; Hashimoto S, Kawabe N, Harata M, Nitta Y, Murao M, Nakano T, Arima Y and Shimazaki H provided the collection of clinical data; Yoshioka K and Kawabe N performed the histological assessment; Ichino N analyzed the data; Suzuki K performed the statistical analysis; Ichino N and Yoshioka K wrote the manuscript.

Correspondence to: Kentaro Yoshioka, MD, Professor, Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, 1-98 Demgakugakubo, Kutsukake, Toyoake, Aichi 470-1192, Japan. kyoshiok@fujita-hu.ac.jp Telephone: +81-562-932324 Fax: +81-562-938601

Received June 14, 2010; Revised July 19, 2010; Accepted July 26, 2010.
 

Abstract

 

AIM: To construct and evaluate a new non-invasive fibrosis index for assessment of the stage of liver fibrosis.

 

METHODS: A new fibrosis index (Fibro-Stiffness index) was developed in 165 of 285 patients with chronic hepatitis C, and was validated in the other 120 patients where liver biopsy was performed. Its usefulness was compared with liver stiffness (LS) measured by FibroScan, the aminotransferase-to-platelet ratio index, the Forns index and the FibroIndex.

 

RESULTS: The Fibro-Stiffness index consists of LS, platelet count and prothrombin time. The values of the Fibro-Stiffness index differed significantly between neighboring fibrosis stages except F0-F1. The area under the receiver operating characteristics curves of the Fibro-Stiffness index for prediction of F ≥ 2 (0.90), F ≥ 3 (0.90) and F = 4 (0.92) in the estimation group and those for F ≥ 3 (0.93) and F = 4 (0.97) in the validation group were the highest among the 5 methods examined. The accuracy of the Fibro-Stiffness index had highest values for F ≥ 2, F ≥ 3 and F = 4 in both the estimation and validation groups. The diagnostic performance for F = 4 was improved by a combination of the Fibro-Stiffness index with serum hyaluronic acid level.

 

CONCLUSION: The Fibro-Stiffness index was constructed and validated. It showed superior diagnostic performance to other indices for F ≥ 2, 3 and 4.

 

Keywords: Non-invasive fibrosis index, Fibro-Stiffness index, Chronic hepatitis C, Liver stiffness, Liver fibrosis

 

INTRODUCTION

 

The stage of liver fibrosis is important in the clinical management of chronic hepatitis C, since the treatment and prognosis of chronic hepatitis depend on the fibrosis stage[¹]. In chronic viral hepatitis, the presence of significant fibrosis (F ≥ 2) indicates the need for antiviral therapies, and the outcome of therapy should be assessed by the improvement in fibrosis stage. Furthermore, the risk of hepatocellar carcinoma or bleeding from esophageal varices is high in patients with advanced fibrosis[^2,3]. Liver biopsy is the gold standard for the assessment of fibrosis stage in chronic hepatitis. However, liver biopsy is an invasive and expensive procedure, and its accuracy is sometimes questionable because of sampling errors, inadequate specimens and the subjectivity of diagnosis[^4,5].

 

Non-invasive assessment of liver fibrosis is a major objective that has been encouraging many approaches, such as routine laboratory tests and serum markers of fibrosis[^6-12]. The aminotransferase-to-platelet ratio index (APRI)[¹¹], the Forns index[⁶], the FibroTest[⁷] and the FibroIndex[¹²] have been proposed for use as non-invasive fibrosis indices. Transient elastography with the use of a new apparatus, FibroScan (EchoSens, Paris, France) for measurement of liver stiffness (LS) has been developed[¹³]. LS measured by FibroScan has been reported to correlate with stage of fibrosis in various liver diseases[^13-24]. It was used for assessing the effect of treatment in chronic hepatitis C[²⁵].

 

In the present study, we developed a new fibrosis index, the Fibro-Stiffness index, consisting of LS, platelet count and prothrombin time from 165 patients with chronic hepatitis C (estimation group) to improve the diagnostic efficacy of LS. We also tried a combination of Fibro-Stiffness index and routinely available laboratory tests to improve its diagnostic performance. These results in the estimation group were validated in 120 patients with chronic hepatitis C (validation group).

 

MATERIALS AND METHODS

 

Patients

In 285 consecutive patients with chronic hepatitis C virus infection, liver biopsy was performed at Fujita Health University Hospital from July 2004 to February 2009 (Table 1).
 
Table 1
Characteristics of the 165 patients in the estimation group and the 120 patients in the validation group (mean ± SD)
 
From July 2004 to September 2007, 165 of these patients (estimation group) were used to develop the Fibro-Stiffness index. From October 2007 to February 2009, the other 120 patients (validation group) were used to validate the diagnostic performance of the Fibro-Stiffness index. The usefulness of the Fibro-Stiffness index was compared with LS, the APRI, the Forns index and the FibroIndex.Clinical data were collected within 3 d of liver biopsy. Sections were stained with hematoxylin-eosin stain and Azan stain. Liver biopsy specimens were assessed by 2 hepatologists (Yoshioka K and Kawabe N). When fibrosis stages evaluated by 2 hepatologists differed, the higher fibrosis stage was adopted. Fibrosis stage, determined according to the METAVIR score, was classified as F0, no fibrosis; F1, portal fibrosis without septa; F2, few septa; F3, numerous septa without cirrhosis; and F4, cirrhosis.
 
Liver stiffness measurement
 
LS measurement by transient elastography was performed with FibroScan (EchoSens, Paris, France) within a week of liver biopsy. FibroScan is equipped with a probe including an ultrasonic transducer and a vibrator. A vibration of mild amplitude and low frequency is transmitted from the vibrator placed on the body surface toward the liver through the intercostal space. The vibration induces an elastic shear wave that propagates through the liver tissue. The pulse-echo ultrasound acquisitions follow the propagation of the shear wave and determine its velocity. The velocity is directly related to tissue stiffness; the harder the tissue, the faster the shear wave propagates. LS is calculated from velocity and expressed in kilopascals (kPa). Ten successful acquisitions were performed on each measurement, and the median value was adopted as representative of LS.

Statistical analysis

The end point was the discrimination between F0 and F1-4, between F0-1 and F2-4, between F0-2 and F3-4 and between F0-3 and F4, using a combination of LS and relevant biochemical or hematological variables. Variables that correlated significantly with fibrosis stage in the estimation group were identified by univariate analyses (analysis of variance). Then the independent predictors of fibrosis stage were assessed by multiple regression analysis (ordinal logistic regression). A predictive index was constructed by modeling the values of the independent variables and their coefficient of regression. The difference of fibrosis indices between neighboring fibrosis stages were estimated by the Tukey-Kramer test. The optimal discriminate cut-off values of each fibrosis index were assessed from the area under the receiver operating characteristics (ROC) curves (AUCs). The optimal discriminating cut-off values were determined at the maximum total of sensitivity and specificity. The statistical analysis was performed by JMP® (SAS Institute, Cary, NC, USA).
 

RESULTS

 

Development of the Fibro-Stiffness Index

LS, platelet count, prothrombin time, aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, γ globulin, total cholesterol and hyaluronic acid were significantly correlated with fibrosis stage in the estimation group (Table 2). Among these variables, LS (P < 0.0001), platelet count (P = 0.0408), and prothrombin time (P = 0.0066) were identified as independent predictors of fibrosis stage by multiple regression analysis (Table 3). By multiple regression analysis, the estimated values of LS, platelet count and prothrombin time were calculated as -0.2662, 0.0749 and 0.0560, respectively. The optimum intercept was also calculated as 5.7710. Thus the Fibro-Stiffness index was constructed with these 3 variables: Fibro-Stiffness index = 5.7710 - 0.2662 [LS (kPa)] + 0.0749 [platelet count (× 104/mL)] + 0.0560 [prothrombin time (%)].
 
Table 2
Variables associated with fibrosis stage in the estimation group (165 patients ) in univariate analysis (mean ± SD)
 
Table 3
Multiple regression predicting liver fibrosis stage with liver stiffness and laboratory data in the estimation group
 
Comparison of Fibro-Stiffness index with LS, the APRI, the Forns index and the FibroIndex in the estimation group
 
Fibro-Stiffness index was compared with LS, the APRI, the Forns index and the FibroIndex in the estimation group (Figure ​1). The values of Fibro-Stiffness index and LS significantly differed between neighboring fibrosis stages except F0-F1 (Figure 1A and ​B). The APRI did not significantly differ between any neighboring stages (Figure ​1C). The Forns index significantly differed only between F1 and F2 (Figure ​1D). The FibroIndex significantly differed between F1 and F2 and between F3 and F4 (Figure 1E).
 
Figure 1
Correlation between 5 noninvasive methods for assessment of fibrosis and stage of fibrosis in the estimation group. A: Fibro-Stiffness index: ρ = -0.7626, P < 0.0001; B: Liver stiffness measured by FibroScan: ρ = -0.7340, P < (more ...)
 
ROC analysis for comparison of diagnostic performance of the Fibro-Stiffness index with LS, the APRI, the Forns index and the FibroIndex in the estimation group
 
The ROC analysis of the Fibro-Stiffness index, LS, the APRI, the Forns index and the FibroIndex was performed to discriminate between fibrosis stages (Table 4). The AUC of the Fibro-Stiffness index was the highest for discriminating F ≥ 2, F ≥ 3 and F = 4 among the 5 examined methods. The AUC of the FibroIndex was the highest for discriminating F ≥ 1.
 
Table 4
Assessment of liver fibrosis stages classification by liver fibrosis indices
 
Optimal discriminating cut-off values of the Fibro-Stiffness index, LS, the APRI, the Forns index and the FibroIndex were determined by ROC analysis. The cut-off values of the Fibro-Stiffness index for F ≥ 1, F ≥ 2, F ≥ 3 and F = 4 were 11.09, 10.12, 9.87 and 8.51, respectively (Table 4). The diagnostic performance was assessed by sensitivity, specificity, accuracy, positive and negative predictive values, and likelihood ratio. Regarding accuracy, the values of the Fibro-Stiffness index for F ≥ 2, F ≥ 3 and F = 4 were the highest among the 5 examined methods. The value of the APRI was the highest for F ≥ 1.
 
Improvement of diagnostic performance by combination of the Fibro-Stiffness index with laboratory tests
 
The negative predictive value for F ≥ 1 and the positive predictive value for F4 with the Fibro-Stiffness index were rather low. Thus a combination of the Fibro-Stiffness index with AST, ALT, albumin, γ globulin, total cholesterol and hyaluronic acid, which were correlated with fibrosis stages and not included in the Fibro-Stiffness index was examined to improve diagnostic performance in each fibrosis stage. Optimal discriminating cut-off values of these laboratory tests for F ≥ 1 and F = 4 were calculated by ROC analysis (not shown). In F ≥ 1, the best combination for improvement of diagnostic performance was the Fibro-Stiffness index ≤ 10.09 or AST ≥ 51 IU/L. The negative predictive value for F ≥ 1 was improved by this combination compared to the Fibro-Stiffness index alone, although it was same as that of the APRI (Table 4). The combination of the Fibro-Stiffness index ≤ 8.51 and serum hyaluronic acid ≥ 68 ng/mL was the best combination for F = 4. The negative predictive value for F4 was improved by this combination, and was the highest among the 6 examined methods.

Validation of performance of the Fibro-Stiffness index, its combination with AST for F ≥ 1, and its combination with hyaluronic acid for F4

The results in the estimation group were validated in the validation group of 120 patients with chronic hepatitis C (Table 5). The AUC of the Fibro-Stiffness index was the highest for F ≥ 3 and F = 4 among the 5 examined methods. The AUC of the FibroIndex was the highest for F ≥ 1 and that of LS was the highest for F ≥ 2.
 
Table 5
Validation of liver fibrosis stages classification by liver fibrosis indices
 

The accuracy of the Fibro-Stiffness index for F ≥ 3 and F = 4 was 86.7% and 85.8%, respectively, similar to the values in estimation group, and the highest value among all the 5 methods. For F ≥ 1, the accuracy of the FibroIndex was the highest. For F ≥ 2, the accuracy of LS was the highest.

 

The combination of the Fibro-Stiffness index and AST for F ≥ 1 improved the negative predictive value, although it was lower than that of the FibroIndex, and the accuracy was lower than those of the APRI and the FibroIndex. The combination of the Fibro-Stiffness index and hyaluronic acid for F = 4 improved the positive predictive value, and its accuracy and positive predictive value were the highest among all the 6 examined methods.

 

DISCUSSION

 

In the present study, we constructed a new fibrosis index for non-invasive assessment of liver fibrosis, the Fibro-Stiffness index, using LS, platelet count and prothrombin time. LS measured by FibroScan has been reported to correlate with stage of liver fibrosis in various liver diseases[^13-24]. Previous studies also confirmed that platelet count and prothrombin time also correlated with stage of liver fibrosis[^6,11,26-29]. A decrease in the platelet count is caused by splenomegaly and reduced production of thrombopoietin, accompanied by the advance of liver fibrosis. Prolongation of prothrombin time is caused by reduced production of coagulation factors by the liver with advanced fibrosis. The Fibro-Stiffness index, which combines these 3 factors, was shown to be a highly accurate index to estimate fibrosis stage in chronic hepatitis C.

 

So far, several non-invasive fibrosis indices such as the APRI[¹¹], the Forns index[⁶], the FibroIndex[¹²], and the FibroTest[⁷] have been developed. The Fibro-Stiffness index showed its superior correlation with fibrosis stage compared with the APRI, the Forns index and the FibroIndex. The Fibro-Stiffness index and LS showed a significant difference between neighboring fibrosis stages except between F0 and F1 in the estimation group. The AUC of the Fibro-Stiffness index was the highest among the 5 examined methods for F ≥ 2, F ≥ 3 and F = 4 in the estimation group, and for F ≥ 3 and F = 4 in the validation group. The AUCs of the APRI, the Forns index and the FibroIndex for predicting F4 in the present study were similar to the values reported in their respective original manuscripts (APRI, 0.88; Forns index, 0.81; FibroIndex, 0.86)[^6,11]. Therefore, the results of the present study can be considered to be appropriate. The superiority of the Fibro-Stiffness index was further demonstrated by the accuracy values. The accuracy of the Fibro-Stiffness index was highest for F ≥ 2, F ≥ 3 and F = 4 in both the estimation group and validation group.

 

Although the Fibro-Stiffness index was shown to be a highly accurate index, the positive predictive value was rather low for F4. A combination of the Fibro-Stiffness index and hyaluronic acid was shown to improve the diagnostic performance. Serum hyaluronic acid has been reported to be useful for diagnosis of liver fibrosis and cirrhosis[^8,30]. In the estimation group and in the validation group, both the accuracy and positive predictive value of the combination of the Fibro-Stiffness index and hyaluronic acid were higher than those of the Fibro-Stiffness index alone, and were the highest among all the 6 examined methods. The fact that a combination of the Fibro-Stiffness index and hyaluronic acid enables us to diagnose F4 with a sensitivity of 91%-100% and positive predictive value of 48%-57% is important, because the risk of hepatocellar carcinoma or bleeding from esophageal varices is high in patients with F4[^2,3].

 

For predicting F ≥ 1, the Fibro-Stiffness index was inferior to the other fibrosis indices in terms of sensitivity, accuracy and negative predictive value. The combination of Fibro-Stiffness index with AST improved sensitivity, accuracy and negative predictive value in both the estimation group and the validation group. However, the combination of Fibro-Stiffness index with AST was still inferior to the APRI in the estimation group, and inferior to the FibroIndex and the APRI in the validation group. Further investigation is necessary to improve the diagnostic efficacy of the Fibro-Stiffness index for F ≥ 1.

 

In chronic viral hepatitis, the presence of significant fibrosis (F ≥ 2) indicates the need for antiviral therapies. The Fibro-Stiffness index showed a highly accurate diagnostic performance for F ≥ 2 in both the estimation group and validation group. Thus the patients with a Fibro-Stiffness index of ≥ 10.12 which indicate F ≥ 2 will be candidates for liver biopsy or interferon treatment.

 

In conclusion, a new fibrosis index for non-invasive assessment of liver fibrosis, the Fibro-Stiffness index, was constructed using LS measured by FibroScan, platelet count and prothrombin time and was validated. The Fibro-Stiffness index demonstrated superior diagnostic performance to LS alone, the APRI, the Forns index and the FibroIndex for F ≥ 2, F ≥ 3 and F = 4. The diagnostic performance of the Fibro-Stiffness index for F4 was further improved by combination with hyaluronic acid levels.

 

COMMENTS

 

Background

The stage of liver fibrosis is important for clinical management of chronic hepatitis C, since the treatment and prognosis of chronic hepatitis depend on the fibrosis stage. Liver biopsy is the gold standard for the assessment of fibrosis stage. However, it is an invasive and expensive procedure, and its accuracy is sometimes questionable.

Research frontiers

A number of non-invasive fibrosis indices, such as the aminotransferase-to-platelet ratio index (APRI), the Forns index and the FibroIndex have been proposed for assessment of liver fibrosis. Transient elastography with the use of a new apparatus, FibroScan, for measurement of liver stiffness (LS) was developed. LS has been reported to correlate with liver fibrosis in various liver diseases. So far no fibrosis indices incorporating LS have been reported. In the present study, we developed a new non-invasive fibrosis index, the Fibro-Stiffness index, which incorporated LS.

Innovations and breakthroughs

The Fibro-Stiffness index consists of LS, platelet count and prothrombin time. In the present study, its usefulness was compared with LS, the APRI, the Forns index and the FibroIndex. The diagnostic performance of the Fibro-Stiffness index was superior to other indices. Furthermore, the diagnostic performance of the Fibro-Stiffness index for F4 was further improved by combination with hyaluronic acid.

Applications

Using the Fibro-Stiffness index, it is possible to assess the stage of liver fibrosis of patients with chronic hepatitis C non-invasively, accurately and quantitatively. Therefore, the Fibro-Stiffness index is useful not only for the diagnosis of stage of liver fibrosis but also for the assessment of regression of liver fibrosis by interferon treatment in patients with chronic hepatitis C.

Terminology

Fibro-Stiffness index: a new non-invasive fibrosis index which we developed in the present study and consists of LS, platelet count and prothrombin time. Its diagnostic performance is superior to other indices.

Peer review

The authors proposed a novel index for non-invasive assessment of hepatic fibrosis. Its reliability was validated on another group of patients. I think the index is clinically useful and significant.

 

Footnotes

 

Peer reviewers: Dr. Assy Nimer, MD, Assistant Professor, Liver Unit, Ziv Medical Centre, Box 1008, Safed 13100, Israel; Munechika Enjoji, MD, PhD, Department of Clinical Pharmacology, Fukuoka University, 8-17-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan

 

S- Editor Tian L L- Editor Cant MR E- Editor Lin YP

 

References

 

1. NIH Consensus Statement on Management of Hepatitis C: 2002. NIH Consens State Sci Statements. 2002;19:1–46.

 

2. Ikeda K, Saitoh S, Suzuki Y, Kobayashi M, Tsubota A, Koida I, Arase Y, Fukuda M, Chayama K, Murashima N, et al. Disease progression and hepatocellular carcinogenesis in patients with chronic viral hepatitis: a prospective observation of 2215 patients. J Hepatol. 1998;28:930–938.

 

3. Zaman A, Hapke R, Flora K, Rosen HR, Benner K. Factors predicting the presence of esophageal or gastric varices in patients with advanced liver disease. Am J Gastroenterol. 1999;94:3292–3296.

 

4. Bedossa P, Dargère D, Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C. Hepatology. 2003;38:1449–1457.

 

5. Regev A, Berho M, Jeffers LJ, Milikowski C, Molina EG, Pyrsopoulos NT, Feng ZZ, Reddy KR, Schiff ER. Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection. Am J Gastroenterol. 2002;97:2614–2618.

 

6. Forns X, Ampurdanès S, Llovet JM, Aponte J, Quintó L, Martínez-Bauer E, Bruguera M, Sánchez-Tapias JM, Rodés J. Identification of chronic hepatitis C patients without hepatic fibrosis by a simple predictive model. Hepatology. 2002;36:986–992.

 

7. Imbert-Bismut F, Ratziu V, Pieroni L, Charlotte F, Benhamou Y, Poynard T. Biochemical markers of liver fibrosis in patients with hepatitis C virus infection: a prospective study. Lancet. 2001;357:1069–1075.

 

8. Murawaki Y, Ikuta Y, Okamoto K, Koda M, Kawasaki H. Diagnostic value of serum markers of connective tissue turnover for predicting histological staging and grading in patients with chronic hepatitis C. J Gastroenterol. 2001;36:399–406.

 

9. Poynard T, Bedossa P. Age and platelet count: a simple index for predicting the presence of histological lesions in patients with antibodies to hepatitis C virus. METAVIR and CLINIVIR Cooperative Study Groups. J Viral Hepat. 1997;4:199–208.

 

10. Rosenberg WM, Voelker M, Thiel R, Becka M, Burt A, Schuppan D, Hubscher S, Roskams T, Pinzani M, Arthur MJ. Serum markers detect the presence of liver fibrosis: a cohort study. Gastroenterology. 2004;127:1704–1713.

 

11. Wai CT, Greenson JK, Fontana RJ, Kalbfleisch JD, Marrero JA, Conjeevaram HS, Lok AS. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology. 2003;38:518–526.

 

12. Koda M, Matunaga Y, Kawakami M, Kishimoto Y, Suou T, Murawaki Y. FibroIndex, a practical index for predicting significant fibrosis in patients with chronic hepatitis C. Hepatology. 2007;45:297–306.

 

13. Sandrin L, Fourquet B, Hasquenoph JM, Yon S, Fournier C, Mal F, Christidis C, Ziol M, Poulet B, Kazemi F, et al. Transient elastography: a new noninvasive method for assessment of hepatic fibrosis. Ultrasound Med Biol. 2003;29:1705–1713.

 

14. Castéra L, Vergniol J, Foucher J, Le Bail B, Chanteloup E, Haaser M, Darriet M, Couzigou P, De Lédinghen V. Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterology. 2005;128:343–350.

 

15. Colletta C, Smirne C, Fabris C, Toniutto P, Rapetti R, Minisini R, Pirisi M. Value of two noninvasive methods to detect progression of fibrosis among HCV carriers with normal aminotransferases. Hepatology. 2005;42:838–845.

 

16. Corpechot C, El Naggar A, Poujol-Robert A, Ziol M, Wendum D, Chazouillères O, de Lédinghen V, Dhumeaux D, Marcellin P, Beaugrand M, et al. Assessment of biliary fibrosis by transient elastography in patients with PBC and PSC. Hepatology. 2006;43:1118–1124.

 

17. Foucher J, Chanteloup E, Vergniol J, Castéra L, Le Bail B, Adhoute X, Bertet J, Couzigou P, de Lédinghen V. Diagnosis of cirrhosis by transient elastography (FibroScan): a prospective study. Gut. 2006;55:403–408.

 

18. Fraquelli M, Rigamonti C, Casazza G, Conte D, Donato MF, Ronchi G, Colombo M. Reproducibility of transient elastography in the evaluation of liver fibrosis in patients with chronic liver disease. Gut. 2007;56:968–973.

 

19. Ganne-Carrié N, Ziol M, de Ledinghen V, Douvin C, Marcellin P, Castera L, Dhumeaux D, Trinchet JC, Beaugrand M. Accuracy of liver stiffness measurement for the diagnosis of cirrhosis in patients with chronic liver diseases. Hepatology. 2006;44:1511–1517.

 

20. Kim KM, Choi WB, Park SH, Yu E, Lee SG, Lim YS, Lee HC, Chung YH, Lee YS, Suh DJ. Diagnosis of hepatic steatosis and fibrosis by transient elastography in asymptomatic healthy individuals: a prospective study of living related potential liver donors. J Gastroenterol. 2007;42:382–388.

 

21. Ogawa E, Furusyo N, Toyoda K, Takeoka H, Otaguro S, Hamada M, Murata M, Sawayama Y, Hayashi J. Transient elastography for patients with chronic hepatitis B and C virus infection: Non-invasive, quantitative assessment of liver fibrosis. Hepatol Res. 2007;37:1002–1010.

 

22. Saito H, Tada S, Nakamoto N, Kitamura K, Horikawa H, Kurita S, Saito Y, Iwai H, Ishii H. Efficacy of non-invasive elastometry on staging of hepatic fibrosis. Hepatol Res. 2004;29:97–103.

 

23. Shaheen AA, Wan AF, Myers RP. FibroTest and FibroScan for the prediction of hepatitis C-related fibrosis: a systematic review of diagnostic test accuracy. Am J Gastroenterol. 2007;102:2589–2600.

 

24. Ziol M, Handra-Luca A, Kettaneh A, Christidis C, Mal F, Kazemi F, de Lédinghen V, Marcellin P, Dhumeaux D, Trinchet JC, et al. Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with chronic hepatitis C. Hepatology. 2005;41:48–54.

 

25. Arima Y, Kawabe N, Hashimoto S, Harata M, Nitta Y, Murao M, Nakano T, Shimazaki H, Kobayashi K, Ichino N, et al. Reduction of liver stiffness by interferon treatment in the patients with chronic hepatitis C. Hepatol Res. 2010;40:383–392.

 

26. Attallah AM, Shiha GE, Omran MM, Zalata KR. A discriminant score based on four routine laboratory blood tests for accurate diagnosis of severe fibrosis and/or liver cirrhosis in Egyptian patients with chronic hepatitis C. Hepatol Res. 2006;34:163–169.

 

27. Nitta Y, Kawabe N, Hashimoto S, Harata M, Komura N, Kobayashi K, Arima Y, Shimazaki H, Nakano T, Murao M, et al. Liver stiffness measured by transient elastography correlates with fibrosis area in liver biopsy in patients with chronic hepatitis C. Hepatol Res. 2009;39:675–684.

 

28. Naveau S, Poynard T, Benattar C, Bedossa P, Chaput JC. Alpha-2-macroglobulin and hepatic fibrosis. Diagnostic interest. Dig Dis Sci. 1994;39:2426–2432.

 

29. Poynard T, Aubert A, Bedossa P, Abella A, Naveau S, Paraf F, Chaput JC. A simple biological index for detection of alcoholic liver disease in drinkers. Gastroenterology. 1991;100:1397–1402.

 

30. Murawaki Y, Ikuta Y, Koda M, Nishimura Y, Kawasaki H. Clinical significance of serum hyaluronan in patients with chronic viral liver disease. J Gastroenterol Hepatol. 1996;11:459–465.

 

Source

Liver stiffness measurements in patients with HBV vs HCV chronic hepatitis: A comparative study

World J Gastroenterol. 2010 October 14; 16(38): 4832–4837.

Published online 2010 October 14. doi: 10.3748/wjg.v16.i38.4832.
PMCID: PMC2955253

Copyright ©2010 Baishideng Publishing Group Co., Limited. All rights reserved.

Ioan Sporea, Roxana Şirli, Alexandra Deleanu, Adriana Tudora, Alina Popescu, Manuela Curescu, and Simona Bota

Ioan Sporea, Roxana Şirli, Alexandra Deleanu, Adriana Tudora, Alina Popescu, Simona Bota, Department of Gastroenterology and Hepatology, University of Medicine and Pharmacy, 300736 Timişoara, Romania

Manuela Curescu, Department of Infectious Diseases, University of Medicine and Pharmacy, 300736 Timişoara, Romania

Author contributions: Sporea I wrote the paper, and designed and supervised the study; Şirli R, Deleanu A, Tudora A, Curescu M, Popescu A and Bota S performed the research; Şirli R and Deleanu A analyzed the data; Şirli R revised the manuscript.

Correspondence to: Dr. Ioan Sporea, Professor, Department of Gastroenterology and Hepatology, University of Medicine and Pharmacy, 300736 Timişoara, Romania. isporea@umft.ro Telephone: +40-256-309455 Fax: +40-256-488003

Received March 26, 2010; Revised May 26, 2010; Accepted June 2, 2010.
 

Abstract

 

AIM: To assess the values of liver stiffness (LS) in patients with hepatitis B virus (HBV) chronic hepatitis and to compare them with those in patients with hepatitis C virus (HCV) chronic hepatitis.

 

METHODS: The study included 140 patients with HBV chronic hepatitis, and 317 patients with HCV chronic hepatitis, in which LS was measured (FibroScan®-Echosens®) and liver biopsy was performed in the same session (assessed according to the Metavir score).

 

RESULTS: According to the Metavir score of the 140 HBV patients: one had F0, 32 had F1, 67 had F2, 33 had F3 and 7 had F4. Of the 317 HCV patients: 5 had F0, 34 had F1, 146 had F2, 93 had F3 and 39 had F4. For the same severity of fibrosis, the mean values of LS in HBV patients were similar to those in HCV patients: F1, 6.5 ± 1.9 kPa vs 5.8 ± 2.1 kPa (P = 0.0889); F2, 7.1 ± 2 kPa vs 6.9 ± 2.5 kPa (P = 0.3369); F3, 9.1 ± 3.6 kPa vs 9.9 ± 5 kPa (P = 0.7038); F4, 19.8 ± 8.6 kPa vs 17.3 ± 6.1 kPa (P = 0.6574). A significant direct correlation between LS measurements and fibrosis was found in HCV patients (Spearman’s r = 0.578, P < 0.0001), as well as in HBV patients (r = 0.408, P < 0.0001). The correlation was more significant in HCV than in HBV patients (Fisher’s Z-test, Z = 2.210, P = 0.0271).

 

CONCLUSION: In our group, the mean values of LS in patients with chronic B hepatitis were similar to those in patients with chronic HCV hepatitis, for the same stage of fibrosis. Also, LS was correlated with the severity of fibrosis both in HBV and HCV chronic hepatitis patients.

 

Keywords: Chronic B hepatitis, Chronic C hepatitis, Fibrosis, Transient elastography, Liver biopsy

INTRODUCTION

The non-invasive assessment of fibrosis in chronic hepatitis, especially of viral etiology, is accepted more and more, partially replacing liver biopsy (LB) in some countries[¹]. Guidelines from France[¹] recommend that the first-line test for untreated patients with hepatitis C virus (HCV) chronic hepatitis, with no comorbities, should be a non-invasive procedure (either FibroTest^® or FibroScan^®).

 

The non-invasive methods used for the evaluation of chronic hepatitis are: serum markers (the best known is FibroTest-ActiTest - a biochemical test which uses 6 serum biomarkers, correlated with the age and gender of the patient in a mathematical formula)[^2-5]; transient elastography (TE) (FibroScan^®)[^6,7]; SonoElastography (Real-Time Tissue Elastography)[^8-11] and magnetic resonance imaging elastography[^12,13].

 

Recent meta-analyses[^7,8] have tried to assess the practical value of TE for the evaluation of patients with chronic hepatitis. Many studies were published regarding the value of TE for evaluation of patients with HCV chronic hepatitis, but only a few studies in patients with chronic hepatitis B virus (HBV) infection. On the other hand, published data showed discordant results regarding liver stiffness (LS) in patients with HBV and HCV chronic hepatitis[^14,15].

 

The aim of our study was to determine whether the values of LS evaluated by means of TE (FibroScan^®) were similar for the same degree of fibrosis (evaluated by means of LB), in patients with chronic HBV and HCV hepatitis.

 

MATERIALS AND METHODS

 

Patients

Our study included a total of 457 successive patients, 140 with HBV chronic hepatitis and 317 with HCV chronic hepatitis. All the patients were referred to our department during a 2-year period (January 2008 to December 2009) for hepatitis assessment (according to the guidelines valid in Romania in that period, LB was mandatory for fibrosis staging). LS was evaluated in all patients by means of FibroScan, and LB was performed in the same session during the standard of care evaluation of patients with chronic hepatitis. The inclusion criteria were: (1) HCV chronic hepatitis: patients with positive anti-HCV antibodies for at least 6 mo, with or without cytolysis; detectable viral load by polymerase chain reaction (PCR); pathological lesions of chronic hepatitis demonstrated by LB; no signs of decompensated liver disease (actual or history of jaundice, ascites); and (2) HBV chronic hepatitis: patients with positive HBsAg for at least 6 mo, with or without cytolysis; positive or negative HBeAg; HBV DNA > 2000 IU/mL (> 10 000 copies/mL) by PCR; pathological lesions of chronic hepatitis demonstrated by LB; no signs of decompensated liver disease (actual or history of jaundice, ascites).

TE

TE was performed in all 457 patients with the FibroScan® (Echosens®, Paris, France) by 3 experienced physicians (each having performed more than 1000 TE examinations). In each patient, 10 valid measurements were performed, after which a median value of LS was obtained, measured in kilopascals (kPa). Only patients in which LS measurements had a success rate of at least 60%, with an interquartile range (IQR) < 30%, were included in our study. The success rate was calculated as the ratio of the number of successful acquisitions over the total number of acquisitions. IQR is the difference between the 75th percentile and the 25th percentile, essentially the range of the middle 50% of the data.

LB

Echo-assisted LB was performed in all 457 patients, using Menghini type modified needles, 1.4 and 1.6 mm in diameter. Only LB fragments of at least 2 cm, including at least 8 portal tracts, were considered adequate for the pathological interpretation. All the LBs were assessed according to the Metavir score, by a senior pathologist. Fibrosis was staged on a 0-4 scale: F0, no fibrosis; F1, portal fibrosis without septa; F2, portal fibrosis and few septa extending into lobules; F3, numerous septa extending to adjacent portal tracts or terminal hepatic venules and F4, cirrhosis.

Statistical analysis

For a statistical analysis of quantitative variables, the mean and standard deviation were calculated. Two-way ANOVA test and t-tests were performed, to compare mean values of LS in various fibrosis subgroups in HBV vs HCV patients. To compare correlations, Fisher’s Z test was used (hypotheses about the value of the population correlation coefficient ρ between variables X and Y can be tested using the Fisher transformation applied to the sample correlation coefficient r)[16]. The diagnostic performance of LS measurements was assessed using receiver operating characteristics (ROC) curves. ROC curves were used for the detection of significant fibrosis (F ≥ 2 Metavir) and severe fibrosis (F ≥ 3 Metavir). Optimal cut-off values for LS measurements were chosen to maximize the sum of sensitivity and specificity. The statistical analysis was performed using Microsoft Excel 2007, GraphPad Prism 5 and MedCalc programs. 
 

RESULTS

 

Patients

The subgroup of HBV patients consisted of 140 subjects (31 women, 109 men; mean age 39.2 ± 12.8 years). According to the Metavir scoring system, one had F0, 32 had F1, 67 had F2, 33 had F3 and 7 had F4.The subgroup of HCV patients consisted of 317 subjects (213 women, 104 men; mean age 49.7 ± 10.2 years). According to the Metavir scoring system, 5 had F0, 34 had F1, 146 had F2, 93 had F3 and 39 had F4.LS measurements by TE

The mean values of LS in HBV patients were not statistically significantly different from those of HCV patients for the same degree of fibrosis (Table 1).
 
Table 1
Mean values of liver stiffness according to fibrosis stage in patients with hepatitis B virus vs hepatitis C virus chronic hepatitis
 
A significant direct correlation of LS measurements with fibrosis was found to exist in HCV patients (Spearman’s correlation coefficient r = 0.578, P < 0.0001), as well as in HBV patients (r = 0.408, P < 0.0001). The correlation was more significant in HCV than in HBV patients (Fisher’s Z-test, Z = 2.210, P = 0.0271).The predictive values of LS measurements for the presence of significant fibrosis (F2), severe fibrosis (F3) and cirrhosis (F4) are presented in Table 2.
 
Table 2
Predictive value of liver stiffness for the presence of significant fibrosis (F2), severe fibrosis (F3) and cirrhosis (F4) in hepatitis B virus vs hepatitis C virus patients
 

DISCUSSION

 

After a number of articles were published in France regarding the value of transient elastographic LS measurement in the evaluation of fibrosis in chronic hepatitis[17-22], numerous papers have been published in other countries[15,23-29] making this method a recognized test worldwide[30]. A meta-analysis published in 2008[30] proved that TE had an excellent diagnostic accuracy for the diagnosis of cirrhosis [mean area under the ROC (AUROC), 0.94 (95% CI: 0.93-0.95)]. However, a high variation of the AUROC was found regarding the diagnosis of significant fibrosis, dependent on the underlying liver disease [AUROC for significant fibrosis, 0.84 (95% CI: 0.82-0.86)].

 

The vast majority of studies assessing TE as compared to LB, were performed in patients with HCV chronic hepatitis[22,24,28,31,32]. At the same time, many studies were performed to evaluate this method in other chronic hepatopathies, such as nonalcoholic steatohepatitis, hemochromatosis and primary biliary cirrhosis[6,20,23,25].

 

Published studies regarding the value of LS measurement by means of TE in patients with HBV chronic hepatitis have shown conflicting results.

 

A Korean study performed by Seo et al[14] included 64 patients with chronic HBV hepatitis and 27 patients with chronic HCV hepatitis who underwent LB and TE in the same session (about two-thirds male; mean age 40 years, range 14-68 years). In that study, LS measurements were better correlated with the fibrosis score in patients with chronic HCV hepatitis than in those with chronic HBV hepatitis (0.773 vs 0.557, P < 0.001). The AUROC was larger in the group of patients with chronic HCV hepatitis (0.944, 0.982, and 0.958 for F ≥ 2, F ≥ 3, and F4, respectively) than in those with chronic HBV hepatitis (0.881, 0.863, and 0.850, respectively). The optimal cut-off values for F ≥ 2 and F ≥ 3 were similar for patients with chronic HCV hepatitis (7.05 and 11.4 kPa, respectively) and chronic HBV hepatitis (7.15 and 10.75 kPa, respectively). However, sensitivity and specificity were superior in patients with chronic HCV hepatitis. The conclusion of the study was that the efficacy of LS measurement for the assessment of liver fibrosis was superior in patients with chronic HCV hepatitis than in patients with chronic HBV hepatitis.

 

In a study performed by Ogawa et al[15] in 68 patients with chronic HBV hepatitis and 161 patients with chronic HCV hepatitis, the mean values of LS measurements were 3.5 kPa for F0, 6.4 kPa for F1, 9.5 kPa for F2, 11.4 kPa for F3, and 15.4 kPa for F4 in patients with chronic HBV infection, and 6.3 kPa for F0, 6.7 kPa for F1, 9.1 kPa for F2, 13.7 kPa for F3, and 26.4 kPa for F4 in those with chronic HCV infection. The values were significantly correlated with fibrosis stage for both groups of patients (HBV, r = 0.559, P = 0.0093, and HCV, r = 0.686, P < 0.0001). This study concluded that TE was an efficient and simple method for the evaluation of liver fibrosis in patients with chronic viral infection, both in HBV and HCV hepatitis.

 

Our study, performed on a large cohort of patients (457 subjects) aimed to find out if there were significant differences in LS in patients with HBV vs HCV chronic hepatitis for the same degree of fibrosis, as compared to the LB. LS measurement has a well established value for staging fibrosis in HCV chronic hepatitis, proved by 2 meta-analyses[7,30]. In patients with HBV chronic infection, data regarding LS measurement for fibrosis staging are conflicting. Why? One explanation could be that the necroinflammatory activity in HBV infection can vary with time, as well as the fact that fluctuations in aminotransferases can occur. Different studies have proposed various cut-off values for different stages of fibrosis, as seen in Table 3.

 

Table 3

Cut-off values for different stages of fibrosis in patients with hepatitis B virus chronic hepatitis, proposed by various authors (kPa)

 

In our cohort of 140 chronic HBV infected patients, the mean values for F1, F2, F3 and F4 were: 6.5, 7.1, 9.1 and 19.8 kPa, respectively, similar to those obtained in the study performed by Marcellin. Also, we must bear in mind that only the Marcellin study was performed in a Caucasian population (such as ours), the others being performed in Asian populations. In our study, the sensitivity of TE for cirrhosis prediction was better in HBV than in HCV patients, but this finding needs further confirmation since the number of F4 patients in the HBV group was small (only 7) vs 39 in the HCV group.

 

Regarding the correlation between fibrosis and LS, a significant direct correlation of TE measurements with fibrosis was found to exist in HCV patients (Spearman’s correlation coefficient r = 0.578, P < 0.0001), more significant than in HBV patients (r = 0.408, P < 0.0001) (Z = 2.210, P = 0.0271). Thus it is likely that the correlation between LS and fibrosis in HBV patients can be of use in clinical practice.

 

As mentioned earlier, high levels of aminotransferases can influence the LS values obtained by means of TE, so that LS measurements have to be interpreted in a biochemical context, otherwise there is a risk of overestimating the severity of fibrosis. Also this is why LS measurements are not performed in acute hepatitis or during alanine aminotransferase (ALT) flares in HBV chronic hepatitis[29,36]. In order to minimize the risk of overestimating fibrosis during ALT flares, Chan et al[34] calculated LS cut-off values for various stages of fibrosis considering also the aminotransferase levels. In this study, the LS cut-off value for F3 was 9 kPa in patients with normal ALT and 12 kPa in patients with ALT higher than 5 times the upper limit of normal. The cut-offs for cirrhosis were 12 kPa in patients with normal ALT and 13.4 kPa in those with high ALT.

 

In conclusion, in our study, LS measured by TE was correlated with the degree of fibrosis both in HBV and HCV patients, the correlation being more significant in HCV patients. Our data showed that there were no statistically significant differences between the mean values of LS in HBV and in HCV patients for the same degree of fibrosis.

 

COMMENTS

 

Background

Non-invasive methods for fibrosis assessment in chronic hepatitis, such as transient elastography (TE), are being accepted more and more, replacing the invasive methods, especially in hepatitis C virus (HCV) chronic hepatitis.

Research frontiers

Many studies have been published regarding the value of TE evaluation of patients with HCV chronic hepatitis, but only a few studies in chronic hepatitis B virus (HBV) infection, showing discordant results.Innovations and breakthroughs

This research article determined if the authors can also use liver stiffness (LS) measurement by TE for the evaluation of patients with HBV chronic hepatitis, and concluded that LS is correlated with fibrosis in both HBV and HCV patients, and that there are no statistically significant differences between the mean LS values in HBV vs HCV patients, for the same degree of fibrosis. These findings are concordant with previous studies by Wang et al, Marcellin et al, and Ogawa et al, indicating that the diagnostic accuracy of LS is comparable in HBV and HCV infection related fibrosis.

Applications

This study showed that LS evaluated by means of TE was correlated with degree of fibrosis in both HBV and HCV patients and that there were no statistically significant differences between the mean values of LS in HBV vs HCV patients for the same degree of fibrosis, so the authors can also use this method for the evaluation of patients with HBV chronic hepatitis in daily practice.

Terminology

TE (FibroScan) is an ultrasound-based method that uses the transmission of low frequency vibrations to create an elastic shear wave that propagates into the liver, followed by the detection of wave propagation velocity, which is proportional to the tissue stiffness, with faster wave progression occurring through stiffer tissue.

Peer review

The authors present the data from their research on whether the accuracy of LS measurement in estimating liver fibrosis differs in people with chronic HCV or HBV infection. Although many reports on small or large populations exist on the same issue, the readers of the journal may find reading the data interesting.
 

Footnotes

 

Peer reviewers: Ming-Lung Yu, MD, PhD, Professor, Division of Hepatology, Department of Medicine, Kaohsiung Medical University Hospital, 100 Tzyou 1st Rd, Kaohsiung 807, Taiwan, China; Ilker Tasci, MD, Associate Professor, Gulhane School of Medicine, Department of Internal Medicine, Etlik, Ankara, 06018, Turkey

S- Editor Tian L L- Editor Cant MR E- Editor Zheng XM
 

References

 

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