Prediction of liver complications in patients with HCV-related cirrhosis with and without HIV coinfection: comparison of hepatic venous pressure gradient and transient elastography

Clin Infect Dis. 2013 Nov 21. [Epub ahead of print]

Pérez-Latorre L, Sánchez-Conde M, Rincón D, Miralles P, Aldámiz-Echevarría T, Carrero A, Tejerina F, Díez C, Bellón JM, Bañares R, Berenguer J.

Unidad de Enfermedades Infecciosas/VIH, Hospital General Universitario Gregorio Marañón, Madrid, Spain.

Abstract

Background. Hepatic venous pressure gradient (HVPG) is the best indicator of prognosis in patients with compensated cirrhosis. We compared HVPG and transient elastography (TE) for the prediction of liver-related events (LRE) in patients with HCV-related cirrhosis with or without HIV coinfection. Methods. Retrospective review of all consecutive patients with compensated HCV-related cirrhosis who were assessed simultaneously using TE and HVPG between January 2005 and December 2011. We used receiver operating characteristic (ROC) curves to determine the ability of TE and HVPG to predict the first LRE (liver decompensation or hepatocellular carcinoma). Results. The study included 60 patients, 36 of whom were coinfected with HIV. After a median follow-up of 42 months, 6 patients died, 8 experienced liver decompensations, and 7 were diagnosed with hepatocellular carcinoma. The area under the ROC curve (AUROC) (95% confidence interval) of TE and HVPG for prediction of LRE in all patients was 0.85 (0.73-0.97) and 0.76 (0.63-0.89) (P=0.13); for HIV-infected patients, the AUROC was 0.85 (0.67-1.00) and 0.81 (0.64-0.97), (P=0.57); and for non-HIV-infected patients the AUROC was 0.88 (0.75-1.00) and 0.77 (0.57-0.97) (P=0.19). Based on the AUROC values, 2 TE cutoff points were chosen to predict the absence (< 25 kPa) or presence (≥ 40 kPa) of LRE, thus enabling correct classification of 82% of patients. Conclusions. Our data suggest that TE is at least as valid as HVPG for predicting LRE in patients with compensated HCV-related cirrhosis coinfected or not with HIV.

PMID: 24265358 [PubMed - as supplied by publisher]

Source

Liver Stiffness Is Associated With Risk of Decompensation, Liver Cancer, and Death in Patients With Chronic Liver Diseases: A Systematic Review and Meta-analysis

Clin Gastroenterol Hepatol. 2013 Dec;11(12):1573-1584.e2. doi: 10.1016/j.cgh.2013.07.034. Epub 2013 Aug 15.

Singh S, Fujii LL, Murad MH, Wang Z, Asrani SK, Ehman RL, Kamath PS, Talwalkar JA.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota. Electronic address: singh.siddharth2@mayo.edu.

Abstract

BACKGROUND & AIMS: Liver stiffness measurement (LSM), using elastography, can independently predict outcomes of patients with chronic liver diseases (CLDs). However, there is much variation in reporting and consistency of findings. We performed a systematic review and meta-analysis to evaluate the association between LSM and outcomes of patients with CLDs.

METHODS: We performed a systematic review of the literature, through February 2013, for studies that followed up patients with CLDs prospectively for at least 6 months and reported the association between baseline LSM and subsequent development of decompensated cirrhosis or hepatocellular carcinoma (HCC), as well as mortality. Summary relative risk (RR) estimates per unit of LSM and 95% confidence intervals (CIs) were estimated using the random effects model.

RESULTS: Our final analysis included 17 studies, reporting on 7058 patients with CLDs. Baseline LSM was associated significantly with risk of hepatic decompensation (6 studies; RR, 1.07; 95% CI, 1.03-1.11), HCC (9 studies; RR, 1.11; 95% CI, 1.05-1.18), death (5 studies; RR, 1.22; 95% CI, 1.05-1.43), or a composite of these outcomes (7 studies; RR, 1.32; 95% CI, 1.16-1.51). We observed considerable heterogeneity among studies-primarily in the magnitude of effect, rather than the direction of effect. This heterogeneity could not be explained by variations in study locations, etiologies and stages of CLD, techniques to measure liver stiffness, adjustment for covariates, or method of imputing relationship in the meta-analysis.

CONCLUSIONS: Based on a meta-analysis of cohort studies, the degree of liver stiffness is associated with risk of decompensated cirrhosis, HCC, and death in patients with CLDs. LSM therefore might be used in risk stratification.

Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

KEYWORDS: CI, CLD, Cancer, Cirrhosis, Elastography, HCC, HCV, HR, HVPG, LSM, LT, MELD, MRE, Outcomes, Prognosis, RR, TE, chronic liver disease, confidence interval, hazard ratio, hepatic venous pressure gradient, hepatitis C virus, hepatocellular carcinoma, liver stiffness measurement, liver transplantation, magnetic resonance elastography, model for end-stage liver disease, relative risk, transient elastography

PMID: 23954643 [PubMed - in process]

Source

Staging chronic hepatitis C in seven categories using fibrosis biomarker (FibroTest) and transient elastography (FibroScan)

Journal of Hepatology

Article in Press

Thierry Poynard, Julien Vergniol, Yen Ngo, Juliette Foucher, Mona Munteanu, Wassil Merrouche, Massimo Colombo, Vincent Thibault, Eugene Schiff, Clifford A. Brass, Janice K. Albrecht Marika Rudler,Olivier Deckmyn, Pascal Lebray, Dominique Thabut, Vlad Ratziu,Victor de Ledinghen, on behalf of FibroFrance Study Group, the Epic3 Study Group and the Bordeaux HCV Study Group.

Received 8 October 2013; received in revised form 15 November 2013; accepted 19 November 2013. published online 27 November 2013.
Accepted Manuscript

Abstract

Background and Aims

FibroTest (FT) and Transient Elastography (TE) have been validated as noninvasive markers of METAVIR fibrosis stages from F0 to F4 using biopsy, and as prognostic markers of liver related mortality in patients with chronic hepatitis C. The aim was to extend the validation of FT and TE as markers of critical steps defined by occurrence of cirrhosis without complications (F4.1), esophageal varices (F4.2), and severe complications (F4.3): primary liver cancer, variceal bleeding, or decompensation (ascites, encephalopathy, or jaundice).

Methods

The updated individual data of 3927 patients (1046 cirrhotics) without complications at baseline were pooled from three prospective cohorts called “EPIC”, “Paris” and “Bordeaux” cohorts.

Results

At 5 years among 501 patients without varices at baseline (F4.1), varices occurred in 19 patients F4.2 incidence of 4.0% (95%CI 2.2-5.8). The predictive performance (AUROC) of FT was 0.77 (0.66-0.84; P<0.001).

At 10 years severe complications occurred in 203 patients, F4.3 incidence of 13.4% (9.6-17.1), including primary liver cancer in 84 patients 6.4%(3.5-9.3). FT was predictive (Cox adjusted on treatment) of severe complications AUROC 0.79(76-82); P<0.0001, including primary liver cancer AUROC 0.84(80-87); P<0.0001. Similarly TE was predictive of severe complications AUROC 0.77(72-81); P<0.0001, including primary liver cancer AUROC 0.86(81-90); P<0.0001.

Conclusion

FibroTest and TE increase were associated with the occurrence of all severe complications including hepatocellular carcinoma, hepatic insufficiency and variceal bleeding. FibroTest increase was also associated with the occurrence of esophageal varices.

Keywords: FibroTest, Elastography, Fibrosis stages, Cirrhosis complications, Prognostic factors, Hepatocellular carcinoma, Surrogate markers

No full text is available. To read the body of this article, please view the PDF online.

Source

Progression of liver fibrosis in HIV/hepatitis C virus-coinfected individuals on antiretroviral therapy with early stages of liver fibrosis at baseline

HIV Medicine

Early View (Online Version of Record published before inclusion in an issue)

Original Research

R Sanmartín¹, J Tor¹, A Sanvisens¹, JJ López¹, A Jou², R Muga¹, I Ojanguren³,  E Barluenga⁴, S Videla²,R Planas⁵, B Clotet^1,2,6, C Tural^1,2,*

Article first published online: 19 NOV 2013

DOI: 10.1111/hiv.12105

© 2013 British HIV Association

Abstract

Keywords: HIV/HCV coinfection;  liver biopsy;  liver fibrosis;  transient elastometry

Objectives

The aim of the study was to assess the progression of liver fibrosis in HIV/hepatitis C virus (HCV)-coinfected patients with no or mild-to-moderate fibrosis (stages F0−F2).

Methods

Liver fibrosis was reassessed by transient elastometry (TE) between January 2009 and November 2011 in HIV/HCV-coinfected patients with stage F0−F2 fibrosis in a liver biopsy performed between January 1997 and December 2007. Patients with liver stiffness at the end of follow-up < 7.1 kPa were defined as nonprogressors, and those with values ≥ 9.5 kPa or who died from liver disease were defined as progressors. Cirrhosis was defined as a cut-off of 14.6 kPa. The follow-up period was the time between liver biopsy and TE. Cox regression models adjusted for age, gender and liver fibrosis stage at baseline were applied.

Results

The median follow-up time was 7.8 years [interquartile range (IQR) 5.5–10 years]. The study population comprised 162 patients [115 (71%) nonprogressors and 47 (29%) progressors; 19 patients (11.7%) had cirrhosis]. The median time from the diagnosis of HCV infection to the end of follow-up was 20 years (IQR 16.3–23.1 years). Three progressors died from liver disease (1.8%). The variables associated with a lower risk of progression were age ≤ 38 years (hazard ratio (HR) 0.32; 95% confidence interval (CI) 0.16–0.62; P = 0.001], having received interferon (HR 2.18; 95% CI 1.14–4.15; P = 0.017), being hepatitis B virus surface antigen (HBsAg) negative (HR 0.20; 95% CI 0.04–0.92; P = 0.039), and baseline F0−F1 (HR 0.43; 95% CI 0.28–0.86; P = 0.017).

Conclusions

A high proportion of patients with stage F0−F2 fibrosis progress to advanced liver fibrosis. Advanced liver fibrosis must be included in the list of diseases associated with aging. Our results support the recommendation to offer HCV antiviral therapy to HIV/HCV-coinfected patients at early stages of liver fibrosis.

Source

The Effect of Vitamin E (Mixed Tocotrienol) on the Liver Stiffness Measurement Measured by Transient Elastography (FibroScan) among NAFLD Patients

Abstract

Speaker: Eduward E.J. Thendiono

Author: Eduward Jansen Thendiono, Marylin Arguillas

Affiliation: Internal Medicine, Davao Doctors Hospital, Davao City, Philippines

Session: Distinguished Posters - NAFLD

Date: Friday - June 07, 2013 13:30-14:00

Location: Exhibition Hall

Subtopic: Clinical

Topic: NAFLD

Introduction: Vitamin E has been shown to slow down progression or cause regression of fibrosis stage among NAFLD patients. Transient Elastography (FibroScan) is a non-invasive tool that has been used to determine the stage of fibrosis among NAFLD patients and may be used for treatment monitoring.

Methods: NAFLD patients diagnosed by ultrasound who met the inclusion criteria were enrolled in the study. Liver Stiffness Measurement (LSM) was measured by FibroScan at base line and at the end of 3 months. A change in the LSM was the primary objective. Chi Square analysis was used to measure the change of LSM pre and post treatment. P value less than 0.05 was considered significant.

Patients were assigned to either the Life style Modification Advice Group (LMAG)—with nutritional counseling and advise to exercise—or the Treatment Group (Vitamin E as Mixed Tocotrienol 100 mg daily for 3 months plus lifestyle modification advise).

Result: Fifty-seven percent (38/67) of patients enrolled in both arms of the study improved --with decrease in their LSM measurements -- but 43% (29 of 67) did not.

Of those who improved 79% (30 / 38) were from the Treatment Group (Vitamin E) and 21% (8 / 38) were from the LMAG.

Twenty -nine (29) patients did not improve: 79% (23/29) from LMAG and only 6/29 (21%) from the Treatment Group. Chi-square analysis showed that treatment with Vitamin E had a significant effect (p= < 0.05) on improvement of LSM.

Conclusion: Vitamin E (mixed Tocotrienol) 100 mg daily for 3 months could decrease the LSM among NAFLD patients.

Source

Newly Approved Ultrasound Device Eliminates Risks and Pain of Liver Biopsy

DETROIT, Oct. 29, 2013 /PRNewswire/ -- Henry Ford Hospital is the first in Michigan to use a pioneering ultrasound device that can help patients with liver disease avoid invasive biopsies to manage their disorders.

FibroScan^® replaces repeated and sometimes painful liver biopsies for patients with chronic hepatitis C and B, fatty liver diseases and other hepatic disorders with a quick and painless procedure similar to the familiar ultrasound tests used to track pregnancy and diagnose internal diseases.

The device is based on a technology called transient elastography, which measures liver "stiffness" to assess disease and guide ongoing treatment.

"FibroScan^® is designed to measure liver fibrosis using a painless, non-invasive method of assessing many of the same conditions measured with biopsy," says Stuart Gordon, M.D., Director of Hepatology at Henry Ford Hospital. "It's an outpatient procedure taking less than 15 minutes."

At the annual meeting of the American Association for the Study of Liver Disease being held in Washington, DC, a multi-center study will be presented Monday, Nov. 4, which "confirms that (Fibroscan^®) very accurately assesses presence of cirrhosis in patients with chronic type B and C viral hepatitis."

Henry Ford Hospital was one of the seven U.S. institutions that conducted the study.

The patient feels only a slight vibration on the skin, the results are immediate and, because it does no harm, the procedure can be safely repeated as often as necessary.

About 150,000 people in the U.S. are diagnosed with chronic liver disease annually, about a fifth of them with cirrhosis, a scarring of the liver.

By one conservative estimate, more than 30,000 liver biopsies are performed in the U.S. each year, a number that led to medical discussions and calls for ways to make the procedure more "acceptable" to patients.

Cirrhosis and other diseases of the liver result from or cause hepatic fibrosis, in which fibrous scars develop as part of the liver's mechanism to heal its own damage.

Sometimes it's beneficial because the scar tissue surrounds and blocks off the cause of the damage. But often this scarring develops to the point that it interferes with liver function, as in cirrhosis.

For decades, a liver biopsy has been considered the "gold standard" for assessing liver disease. In most cases, the biopsy involves using a needle inserted through the skin and underlying tissue and into the liver to collect a sample of tissue. It's widely regarded as safe, but because it is invasive, it carries risks ranging from bleeding to rare instances of death. In addition, a proportion of liver biopsy patients complain of severe pain during the procedure.

Using FibroScan ^®, the skin in the area of the liver is first coated with a water-based gel. The doctor then passes an ultrasound sensor over the area to take 10 consecutive readings. The sensor produces vibrations that create a low-frequency seismic wave sent between the ribs and into the liver. The speed of the wave as it passes through the liver is used to determine the hardness or stiffness of the organ – the faster the wave, the harder the tissue.

The data collected during the readings are collected and analyzed in the console connected to the sensor, and provides immediate results on the presence and severity of liver fibrosis.

FibroScan^® is produced by Paris-based Echosens, entered the European market in 2003 and was already being used in more than 70 countries worldwide when it received approval by the U.S. Food and Drug Administration in April.

Note: To access Fibroscan^® a patient needs a physician referral. The cost is $200. Email: FIBROSCAN@hfhs.org.

SOURCE Henry Ford Hospital

Source

Spleen stiffness predicted risk for large, bleeding esophageal varices in cirrhotic patients

Provided by Healio

Sharma P. Am J Gastroenterol. 2013;doi:10.1038/ajg.2013.119.

May 23, 2013

Measuring spleen stiffness in patients with cirrhosis was an effective, noninvasive method of predicting and differentiating large and small esophageal varices and determining those at risk for bleeding, according to recent study results.

Using transient elastography (FibroScan), researchers measured spleen stiffness (SS) and liver stiffness (LS) in 200 consecutive patients with cirrhosis between September 2011 and March 2012. Other measurements conducted in some of the cohort included hepatic venous pressure gradient (HVPG), upper gastrointestinal endoscopy, LS-spleen diameter to platelet ratio score (LSPS) and platelet count to spleen diameter ratio (PSR).

Among 174 evaluable patients who met inclusion criteria and had valid LS and SS measurements, 124 (71%) had esophageal varices (EV). Seventy-eight patients had large EV (more than 5 mm); 46 had small varices (less than 5 mm). Patients with EV displayed a significant difference in median SS (54 kPa compared with 32 kPa), LS (51.4 kPa vs. 23.9 kPa), LSPS (6.1 vs. 2.5) and PSR (812 vs. 1,165) compared with patients without EV (P=.001 for all differences).

Although LS could not be used to differentiate between large and small varices (53 kPa vs. 45.3 kPa; P=.57), SS was greater and indicative of patients with large varices (56 kPa vs. 49 kPa; P=.001) compared with small varices. Patients who had variceal bleed (n=46) also had greater SS than nonbleeder (n=78) patients (58 kPa vs. 50.2 kPa; P=.001).

Among only patients who submitted to HVPG (n=52), a significant correlation was observed with SS (P=.001) and LSPS (P=.01), but not LS (P=.207).

“Given the need to screen patients with cirrhosis, noninvasive tests, such as SS, may help to identify patients at risk of having EVs, particularly large, and those at risk of bleeding,” the researchers concluded. “Spleen stiffness, along with liver stiffness measurement, could select patients with cirrhosis, who should undergo upper gastrointestinal endoscopy to decrease burden upon endoscopy units.”

Source

Liver Imaging Tests Vie to Replace Biopsy

By John Gever, Deputy Managing Editor, MedPage Today

Published: April 26, 2013

Reviewed by F. Perry Wilson, MD, MSCE; Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania

AMSTERDAM -- Although biopsy remains the gold standard for diagnosing liver fibrosis, imaging tests increasingly appear to be a viable way to garner equivalent information with less patient discomfort and risk, researchers said here.

In presentations at the meeting of the European Association for the Study of the Liver, scientists from across Europe reported on the strengths and weaknesses of various imaging modalities as tools for routine clinical practice.

There was no clear winner among transient elastography, magnetic resonance elastography (MRE), real-time shear wave elastography (RTSWE), and acoustic radiation force impulse (ARFI) imaging, but all appeared to be nearly as accurate as liver biopsy in quantitative assessment of fibrosis and for predicting outcomes such as death and cirrhotic decompensation.

The role of liver imaging for these purposes in the U.S. has recently come to the fore with the FDA's clearance last week of the Fibroscan transient elastography device. Fibroscan is the established leader in noninvasive fibrosis imaging and, according to its French manufacturer, Echosens, the U.S. is the last major market to approve its device.

All these forms of elastography work by setting up shear waves in the liver. Patterns of propagation of these waves correspond to the degree of liver stiffness, which in turn correlates with the level of fibrosis. All but MRE use ultrasound to generate the waves.

Studies presented here evaluated one or more of these technologies against another, with or without liver biopsy as a reference standard, and in a variety of patient populations.

Transient Elastography Versus Biopsy

Perhaps the most direct assessment was reported by Juan Macias, MD, of Hospital Universitario de Valme in Seville, Spain. He reported a retrospective analysis of 297 patients coinfected with HIV and hepatitis C virus (HCV) who had been tested with liver biopsy as well as transient elastography, with these tests performed within a year of each other. The study period covered 2005 to 2011.

Findings indicated that fibrosis stage as established from biopsies and liver stiffness measurements from transient elastography were equally accurate in predicting overall mortality and decompensation of cirrhosis.

Kaplan-Meier curves for patients with stage F4 fibrosis (overt cirrhosis) and for those with elastography measurements in the highest quintile (21 kPa and above) were nearly identical through up to 6 years of follow-up, for both all-cause death and for decompensation of cirrhosis, Macias reported.

Point estimates of the increased risk for these outcomes were somewhat higher in models based on biopsy findings than in the elastography-based analyses, but the error bars in the latter were markedly smaller.

For example, the risk of decompensation doubled with each increase in fibrosis stage (hazard ratio 2.00, 95% CI 1.32 to 3.00), whereas each 5-kPa increase in liver stiffness corresponded to a hazard ratio of 1.42 (95% CI 1.31 to 1.55).

"The noninvasive nature of [transient elastography] should favor its use instead of liver biopsy when the only issue is predicting the clinical outcome of liver disease in HIV-HCV coinfection," Macias told attendees.

ARFI Versus Transient Elastography

Acoustic radiation force impulse imaging is another up-and-coming imaging method for liver disease. Like transient elastography, it uses ultrasound to generate mechanical waves within the liver, but the nature of the waves and the interpretation of the resultant patterns differs.

Derek Bardou of CHU Angers in Angers, France, noted that the two technologies have been compared head-to-head in previous studies, with pooled data suggesting that ARFI is less accurate.

But transient elastography has a significant drawback -- it doesn't work on obese patients. Bardou pointed out that the previous analyses were all conducted on a per-protocol basis, such that patients for whom the transient elastography attempt failed to yield usable results were excluded.

He argued that a more stringent "intent-to-diagnose" analysis would be a better reflection of the utility of the two methods in routine practice.

From 2009 to early 2013, he and his colleagues used both methods on a total of 267 patients with chronic, noncancerous liver disease (patients with cirrhotic complications or sepsis were excluded) who also underwent liver biopsies. Areas under the receiver-operating characteristic (AUROC) curves for classifying patients' liver disease stage were calculated for both test types, with biopsy results serving as the reference standard.

The researchers found that, on a per-protocol basis, AUROC values with ARFI were indeed lower -- indicating poorer accuracy -- than those seen with transient elastography. In this analysis, Bardou and colleagues excluded 6.7% of patients in whom transient elastography could not be performed. ARFI failed in fewer than 1%.

But in the intent-to-diagnosis analysis involving all 267 patients, there was no significant difference in AUROC values for the two methods.

Bardou added that whole-liver results with ARFI were more accurate than findings only in the right lobe, the "classical" way to perform ARFI, he explained.

RTSWE Versus Transient Elastography Versus Biopsy

Another study reported here sought to validate real-time shear wave elastography as an alternative -- not necessarily superior -- to liver biopsy.

Giovanna Ferraioli, MD, of Italy's University of Pavia, presented findings from 88 patients with chronic liver disease of varied origin and 33 healthy controls.

Patients underwent both RTSWE (using the ElastPQ system) and transient elastography as well as biopsy. The controls had only the noninvasive testing.

RTSWE, in this study, involved a fixed "sample box" located a maximum of 70 mm below the Glisson's capsule within the liver. Patients held their breath for 2 to 4 seconds and 10 images were collected, with the median stiffness value in kPa used as the final result. As the name suggests, and unlike transient elastography, RTSWE delivers readings almost immediately. In some studies, it has appeared to be more accurate as well.

Both imaging methods showed stiffness values that progressed upward with the degree of fibrosis ascertained with the biopsies. RTSWE yielded somewhat more detail, in that the median values for each patient group stratified according to fibrosis stage (F0/1 to F4) tracked steadily higher. Transient elastography results for patients with F2 fibrosis, on the other hand, were nearly identical to those with F0/1 disease (5.45 versus 5.5 kPa).

Ferraioli and colleagues found that, as expected, RTSWE values in the healthy controls were lower than in patients with liver disease (median 3.3 kPa, interquartile range 3.7 to 4.0).

Transient elastography readings tended to be higher (median 3.8 kPa, interquartile range 4.5 to 5.0) and overlapped in the controls with those from patients with liver disease (median in F2 patients 5.45, interquartile range 4.3 to 8.0).

RTSWE "compares favorably" with transient elastography, Ferraioli concluded.

MR Elastography Versus Biopsy

Use of MRI equipment to analyze liver stiffness is an even newer approach. It, too, can be used to generate vibrations that propagate through the liver. Rocio Gallego-Duran, also of the Hospital Universio de Valme, reported on a validation study in which artificial neural networks were used to generate elastography values from MRI scans.

Her study involved 63 patients with biopsy-confirmed non-alcoholic fatty liver disease, including 32 with non-alcoholic steatohepatitis (NASH) and 25 with significant fibrosis.

The first 22 of these patients were used as a "training cohort" for fine-tuning the software settings to match biopsy results as closely as possible. The resulting model was then tested in the remaining 41 patients, serving as a validation cohort.

For diagnosing NASH, the model showed sensitivity of 77% and specificity of 90%, Gallego-Duran reported. Positive and negative predictive values were 89% and 79%, respectively.

The model was not quite as good at diagnosing fibrosis. With the best-performing cutoff values, sensitivity was 87% but specificity was only 63%. As a result, the positive predictive value was just 59%, although the negative predictive value was a respectable 89%.

Gallego-Duran told attendees that the MRI-based technique holds some potential advantages over the ultrasound-based methods. Because it produces high-resolution images of the entire liver, it may provide a fuller picture of liver disease and can also reveal other types of liver injury. Patients' body fat also is not an issue for image quality, as it is for transient elastography, she said.

None of the studies had commercial funding.

All of the presenters declared that they had no relevant financial interests.

Primary source: European Association for the Study of the Liver
Source reference:
Macias J, et al "Performance of liver stiffness compared with liver biopsy to predict survival and decompensations of cirrhosis among HIV/HCV-coinfected patients" EASL 2013; Abstract 20.

Additional source: European Association for the Study of the Liver
Source reference:
Bardou D, et al "First intention-to-diagnose comparison of ARFI and Fibroscan in chronic liver diseases" EASL 2013; Abstract 15.

Additional source: European Association for the Study of the Liver
Source reference:
Ferraioli G, et al "Performance of ELASTPQ^® shear wave elastography technique for assessing fibrosis in chronic viral hepatitis" EASL 2013; Abstract 16.

Source

FDA Approves FibroScan® for Non-invasive Liver Diagnosis

PARIS, April 16, 2013 /PRNewswire/ --

- Echosens™ is pleased to announce that FibroScan® device received 510(k) clearance from the U.S. Food and Drug Administration (FDA) on April 5^th, 2013 and is now ready to market its pioneering technology in the United States.

Today, 1800 FibroScan® devices are used worldwide both in research and routine clinical practice. The United States of America is the last major market to approve FibroScan®.

(Logo: http://photos.prnewswire.com/prnh/20130415/607780-a )

(Photo: http://photos.prnewswire.com/prnh/20130415/607780-b )

FibroScan® is used in the clinical management of patients with liver disease such as chronic viral hepatitis C and B and fatty liver diseases. Based on a technology called transient elastography, FibroScan® assesses liver shear wave speed (expressed in meter per second) and equivalent stiffness (expressed in kilopascal) at 50 Hz in a rapid, simple, non-invasive and totally painless way.

Initially introduced in the European market in 2003, FibroScan® pioneered the quantitative elastography medical field. It received market clearances in China (2008), Canada (2009), Brazil (2010), Japan (2011) and is currently available in 70 countries.

With more than 660 peer-reviewed publications, FibroScan® is by far the elastography device with the largest body of evidence on its clinical usefulness. Moreover, the use of FibroScan® is also mentioned in guidelines and recommendations in different regions of the world: World Health Organization, European Association for the Study of Liver (EASL), Asian Pacific Association for the Study of Liver (APASL), etc.

FibroScan® is manufactured by Echosens™ (Paris, France). Since its foundation in 2001, Echosens™ has gathered strong leadership in quantitative elastography. Very active in research and development, Echosens™ holds 17 patent families mainly focused on its core technology: Vibration-Controlled Transient Elastography (VCTE™).

Contact Echosens™:
Aurélie Houet, Communication Manager
Tel: +33-1-44-82-78-50
Email: aurelie.houet@Echosens.com
http://www.echosens.com

SOURCE Echosens

Source

Ultrasound Dx of HCV Effective in Liver Transplant

By Michael Smith, North American Correspondent, MedPage Today

Published: March 04, 2012

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco.

Action Points

• A non-invasive diagnostic method, ultrasound-based transient elastography, can accurately pick up fibrosis and cirrhosis in patients with recurrent hepatitis C after a liver transplant.
• Note that the major limitation of the technique lies in interpreting results that correspond to intermediate stages of fibrosis.

A non-invasive diagnostic method can accurately pick up fibrosis and cirrhosis in patients with recurrent hepatitis C after a liver transplant, researchers reported.

In a meta-analysis, ultrasound-based transient elastography had excellent diagnostic accuracy in detecting cirrhosis, according to Jayant Talwalkar, MD, and colleagues at the Mayo Clinic in Rochester, Minn.

The major limitation of the technique lies in interpreting results that correspond to intermediate stages of fibrosis, Talwalkar and colleagues reported in the March issue of Liver Transplantation.

"Further studies that confirm our results could highlight the importance of [transient elastography] as a diagnostic tool for liver transplant recipients" with recurrent hepatitis C, Talwalkar said in a statement.

Hepatitis recurrence is common among transplant patients and is "universal" among those who are positive for hepatitis C RNA at the time of transplant, the researchers noted.

And the development of fibrosis is faster in the transplanted organ than in the native liver, resulting in rapid cirrhosis and graft failure. The "only practical approach for improving ... clinical outcomes" is early recognition of patients with progressive recurrent disease, Talwalkar and colleagues argued.

The gold standard for diagnosing fibrosis and cirrhosis is the liver biopsy, they noted, since the degree of inflammation and the stage of fibrosis can be directly measured.

And the stage of fibrosis is needed for the timing of antiviral therapy if patients are eligible, they added.

But there is evidence that liver biopsies -- as well as having the risk associated with an invasive procedure -- may actually understage fibrosis up to 30% of the time, Talwalkar and colleagues said.

To see how well transient elastography performs, they conducted a systematic literature review that turned up six high-quality studies of the issue, five with data on fibrosis and five with data on cirrhosis.

The studies included 470 patients, with a range from 50 to 124. Diagnostic cut-offs for significant fibrosis ranged from 7.1 to 10.1 kilopascals; the values for cirrhosis ranged from 10.5 to 26.5.

Analysis showed that transient elastography had a sensitivity and specificity of 83%, respectively, for detecting fibrosis. The diagnostic odds ratio was 30.5.

For cirrhosis, the sensitivity was 98% and specificity was 84%. The diagnostic odds ratio was 130.

The analysis "yielded excellent summary estimates of the sensitivity and specificity for detecting cirrhosis and good estimates for detecting significant fibrosis," the researchers concluded.

They cautioned that, for both patient subgroups, the results demonstrated varying degrees of statistical heterogeneity, probably owing to such things as differences in study design and "subtle variations in the technical performances" of the two diagnostic methods between studies.

The researchers did not report external support for the study or any potential conflicts.

Primary source: Liver Transplantation
Source reference:
Adebajo CO, et al "Ultrasound-based transient elastography for the detection of hepatic fibrosis in patients with recurrent hepatitis C virus after liver transplantation: a systematic review and meta-analysis" Liver Transpl 2012; 18: 323-331.

Source

Ultrasound technology proves accurate in diagnosing cirrhosis from recurrent hepatitis C

February 29, 2012

Researchers from the Mayo Clinic confirm that ultrasound-based transient elastography (TE) provides excellent diagnostic accuracy for detecting cirrhosis due to recurrent infection with hepatitis C virus (HCV) infection following liver transplantation. Findings from the study published in the March issue of Liver Transplantation, a journal of the American Association for the Study of Liver Diseases, suggest that detection of significant fibrosis is more accurate when comparing patients with chronic HCV of the native liver

According to the World Health Organization (WHO), chronic HCV affects up to 170 million people worldwide and could lead to more severe liver diseases such as cirrhosis and liver cancer. Experts estimate that on average 6,000 liver transplants are performed in the U.S. each year. Medical evidence shows that following liver transplantation recipients who are HCV RNA-positive at the time of transplantation are at risk of reinfection with HCV. Moreover, studies have determined that fibrotic tissue can develop more quickly in the transplanted liver resulting in rapid progression of cirrhosis and graft failure.

"The current gold standard for determining liver disease severity and progression is liver biopsy," explains lead author Dr. Jayant Talwalkar with the Mayo Clinic in Rochester, Minnesota. "However, biopsy following liver transplantation may not accurately determine fibrosis severity and non-invasive imaging technology has advanced to more accurately assess the severity of liver injury which includes an indirect assessment of elevated portal pressure." A prior study reported liver biopsy can understage cirrhosis in up to 30% of cases.

For the present study researchers reviewed studies of the diagnostic accuracy of ultrasound-based TE, a non-invasive technology used to assess fibrosis by measuring liver stiffness. The team analyzed the performance of TE compared to liver biopsy in detecting sever hepatic fibrosis caused by recurrent HCV post-transplantation. Compared to liver biopsy, TE is a reproducible diagnostic technique that is quick and painless for patients.

Six studies were identified, with five studies that evaluated significant fibrosis and cirrhosis. Analysis of the pooled estimates showed TE had a sensitivity and specificity of 83%, respectively for detecting fibrosis. Of the five studies analyzing TE for detecting cirrhosis, sensitivity estimates were 98% and specificity at 84%. "Ultrasound-based TE provides excellent diagnostic accuracy for identifying cirrhosis caused by recurrent HCV following liver transplantation," concludes Dr. Talwalkar. "Further studies that confirm our results could highlight the importance of TE as a diagnostic tool for liver transplant recipients infected with HCV."

More information: "Ultrasound-based Transient Elastography for the Detection of Hepatic Fibrosis in Patients with Recurrent HCV after Liver Transplantation: Systematic Review and Meta-analysis." Corlan O. Adebajo, Jayant A. Talwalkar, John J. Poterucha, W. Ray Kim, and Michael R. Charlton. Liver Transplantation; (DOI: 10.1002/lt.22460) Published online: February 24, 2012; Print Issue Date: March 2012.

Provided by Wiley (news : web)

Source

Liver stiffness predicts clinical outcome in HIV/HCV-coinfected patients with compensated liver cirrhosis

Hepatology. 2012 Jan 25. doi: 10.1002/hep.25616. [Epub ahead of print]

Merchante N, Rivero-Juárez A, Téllez F, Merino D, Ríos-Villegas MJ, Márquez-Solero M, Omar M, Macías J, Camacho A, Pérez-Pérez M, Gómez-Mateos J, Rivero A, Pineda JA; on behalf of the Grupo Andaluz para el Estudio de las Hepatitis Víricas (HEPAVIR) de la Sociedad Andaluza de Enfermedades Infecciosas (SAEI).

Source

Unidad de Enfermedades Infecciosas, Hospital Universitario de Valme, Sevilla. nicolasmerchante@gmail.com.

Abstract

Our aim was to assess the predictive value of liver stiffness (LS), measured by transient elastography (TE), for clinical outcome in HIV/HCV-coinfected patients with compensated liver cirrhosis. This was a prospective cohort study of 239 consecutive HIV/HCV-coinfected patients with a new diagnosis of cirrhosis, done by TE, and no previous decompensation of liver disease. The time from diagnosis to the first liver decompensation and death from liver disease, as well as the predictors of these outcomes, were evaluated. After a median (Q1-Q3) follow-up of 20 (9-34) months, 31 (13%, 95% confidence interval [CI]: 9%-17%) patients developed a decompensation. The incidence of decompensation was 6.7 cases per 100 person-years (95% CI, 4.7-9-6). Fourteen (8%) out of 181 patients with a baseline LS < 40 kPa developed a decompensation versus 17 (29%) out of 58 with a LS = 40 kPa (p=0.001). Factors independently associated with decompensation were Child-Turcotte-Pugh (CTP) class B versus A (hazard ratio [HR] 7.7; 95% CI 3.3-18.5; p<0.0001), log-plasma HCV RNA load (HR 2.1; 95% CI 1.2-3.6; p=0.01), hepatitis B virus coinfection (HR, 10.3; 95% CI, 2.1-50.4; p=0.004) and baseline LS (HR 1.03; 95% CI 1.01-1.05; p=0.02). Fifteen (6%, 95% CI: 3.5%-9.9%) patients died, 10 of them due to liver disease, and one underwent liver transplantation. CTP class B (HR 16.5; 95% CI 3.4-68.2; p<0.0001) and previous exposure to HCV therapy (HR 7.4; 95% CI 1.7-32.4, p=0.007) were independently associated with liver-related death; baseline LS (HR 1.03; 95% CI 0.98-1.07; p=0.08) was of borderline significance. CONCLUSION: LS predicts the development of hepatic decompensations and liver-related mortality in HIV/HCV-coinfected with compensated cirrhosis and provides additional prognostic information to that provided by CTP score. (HEPATOLOGY 2012.).

Source

Comparison of nine blood tests and transient elastography for liver fibrosis in chronic hepatitis C: The ANRS HCEP-23 study

Journal of Hepatology
Volume 56, Issue 1 , Pages 55-62, January 2012

Jean-Pierre Zarski, Nathalie Sturm, Jérôme Guechot, Adeline Paris, Elie-Serge Zafrani, Tarik Asselah, Renée-Claude Boisson, Jean-Luc Bosson, Dominique Guyader, Jean-Charles Renversez, Jean-Pierre Bronowicki, Marie-Christine Gelineau, Albert Tran, Candice Trocme, Victor De Ledinghen, Elisabeth Lasnier, Armelle Poujol-Robert, Frédéric Ziegler, Marc Bourliere, Hélène Voitot, Dominique Larrey, Maria Alessandra Rosenthal-Allieri, Isabelle Fouchard Hubert, François Bailly, Michel Vaubourdolle, The ANRS HCEP 23 Fibrostar Group

Received 21 October 2010; received in revised form 13 April 2011; accepted 3 May 2011. published online 20 July 2011.

Abstract

Background & Aims

Blood tests and transient elastography (Fibroscan™) have been developed as alternatives to liver biopsy. This ANRS HCEP-23 study compared the diagnostic accuracy of nine blood tests and transient elastography (Fibroscan™) to assess liver fibrosis, vs. liver biopsy, in untreated patients with chronic hepatitis C (CHC).

Methods

This was a multicentre prospective independent study in 19 French University hospitals of consecutive adult patients having simultaneous liver biopsy, biochemical blood tests (performed in a centralized laboratory) and Fibroscan™. Two experienced pathologists independently reviewed the liver biopsies (mean length=25±8.4mm). Performance was assessed using ROC curves corrected by Obuchowski’s method.

Results

Fibroscan™ was not interpretable in 113 (22%) patients. In the 382 patients having both blood tests and interpretable Fibroscan™, Fibroscan™ performed similarly to the best blood tests for the diagnosis of significant fibrosis and cirrhosis. Obuchowski’s measure showed Fibrometer® (0.86), Fibrotest® (0.84), Hepascore® (0.84), and interpretable Fibroscan™ (0.84) to be the most accurate tests. The combination of Fibrotest®, Fibrometer®, or Hepascore® with Fibroscan™ or Apri increases the percentage of well classified patients from 70–73% to 80–83% for significant fibrosis, but for cirrhosis a combination offers no improvement. For the 436 patients having all the blood tests, AUROC’s ranged from 0.82 (Fibrometer®) to 0.75 (Hyaluronate) for significant fibrosis, and from 0.89 (Fibrometer® and Hepascore®) to 0.83 (FIB-4) for cirrhosis.

Conclusions

Contrarily to blood tests, performance of Fibroscan™ was reduced due to uninterpretable results. Fibrotest®, interpretable Fibroscan™, Fibrometer®, and Hepascore® perform best and similarly for diagnosis of significant fibrosis and cirrhosis.

Source

Noninvasive assessment of liver fibrosis (and Biopsy)

Download the pdf here
Hepatology
June 2011

Doris Nguyen1 and Jayant A. Talwalkar2,3

rom the 1Mayo Medical School, 2Center for Advanced Imaging Research, and 3Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN

"The gold standard for detecting liver fibrosis remains percutaneous liver biopsy, although this procedure is not without its own inherent limitations.....Despite the proliferation of investigations and clinical experiences with noninvasive methods for detecting hepatic fibrosis, there remain a number of critical questions about the clinical effectiveness of these approaches"

Case Scenario

A 48-year-old male with a previous longstanding history of intravenous drug abuse is evaluated for a diagnosis of hepatitis C and elevated liver biochemical tests. The aspartate aminotransferase is 59 U/L, and the alanine aminotransferase is 68 U/L. The serum bilirubin is 0.8 mg/dL with an indirect fraction of 0.5 mg/dL, the serum creatinine is 1.1 mg/dL, and the international normalized ratio is 1.0. The serum albumin is 3.9 g/dL. Ultrasound imaging reveals a coarse echotexture without evidence of ascites or intra-abdominal collateral veins. The hepatitis C virus genotype is 1b, and the viral load is 5.6 x 106 IU. You recommend a liver biopsy to determine activity and the stage of fibrosis. The patient asks you whether you can get the same information with blood tests or noninvasive imaging, that is, he wants to know the role of serum markers, ultrasound-based transient elastography (TE), and magnetic resonance elastography (MRE) in such situations.

The Problem

In the United States alone, an estimated 150,000 persons annually are diagnosed with chronic liver disease with nearly 30,000 (20%) individuals having cirrhosis at initial presentation.1 Disease-related complications of cirrhosis, in turn, are mediated by the development and progression of hepatic fibrosis.

Hepatic fibrogenesis is a maladaptative wound-healing process that occurs in response to chronic, injurious stimuli affecting hepatocytes. This results in a stereotypical inflammatory response leading to hepatic stellate cell activation that produces a nonuniform accumulation of extracellular matrix complexes that constitute hepatic fibrosis. The crosslinking of collagen fibrils within extracellular matrix leads to fibrous scar formation and eventual distortion of the hepatic architecture. Notably, the progression of hepatic fibrosis is not a continuous, linear process but rather a discontinuous, stuttering phenomenon that is greatly influenced by factors such as age, sex, race, alcohol exposure, and obesity.2

The gold standard for detecting liver fibrosis remains percutaneous liver biopsy, although this procedure is not without its own inherent limitations. These include (1) a small but significant risk for procedure-related complications such as pain or bleeding, (2) inaccurate staging from sampling error in up to 25% of cases, and (3) inter- and intraobserver variability in biopsy interpretation.3, 4 Because of these reasons and wide availability of serum diagnostic tests, the use of diagnostic liver biopsy in clinical practice is declining.5

From a clinical perspective, the greatest limitation with liver biopsy is sampling variability and its effect on fibrosis staging. Several investigations have documented that sampling error is present in a variety of liver diseases.6, 7 Furthermore, the performance of biopsies involving the right and left liver lobes in the same patient does not reduce sampling error, because substantial discordance in fibrosis stage is observed.7 Although the optimal liver biopsy specimen characteristics (≥20 mm in length with ≥11 portal tracts) have been identified to minimize the effects from sampling error,8 the typical specimen obtained in clinical practice often fails to meet these standards.

Serum Markers and Elastography Imaging

Serum Markers.

A variety of serum markers have been developed for identifying patients who are at risk for clinically significant hepatic fibrosis (defined by stages F2-F4). These markers are classified as direct (representing components of extracellular matrix) or indirect (reflecting hepatic inflammation and function). Indirect markers may be used alone or combined with direct markers to form panels. The practical advantages of serum fibrosis markers include their noninvasiveness, potential for widespread availability, and reproducibility when serial examinations are performed using the same laboratory (Table 1).9

Among indirect serum marker panels, the most widely used and validated technique worldwide is called the FibroTest. This proprietary panel contains five variables including total bilirubin, haptoglobin, gamma glutamyl transpeptidase, α2-macroglobulin, and apolipoprotein A. Several independent and combined analyses have demonstrated excellent diagnostic performance for the detection of histological stage F4 fibrosis (i.e., cirrhosis) among patients with chronic hepatitis C. Additional studies in patients with chronic hepatitis B, alcoholic liver disease, nonalcoholic fatty liver disease, as well as studies conducted in the general population, are emerging in support of this method as well. However, serum markers including FibroTest are less accurate in detecting the presence of intermediate stages of fibrosis as compared to the detection of cirrhosis.9, 10

There are specific limitations associated with the use of FibroTest and serum marker panels in general. False positive results can be attributable to (1) decreases in haptoglobin from hemolysis, (2) increases in total bilirubin from conditions such as Gilbert's syndrome and cholestasis, and (3) increases in α2-macroglobulin and haptoglobin from systemic as well as hepatic inflammation.9, 10 Because of the variability of components in assays and analyzers, FibroTest can only be performed in validated reference laboratories as opposed to local outpatient or hospital-based labs where other testing is typically performed.

Ultrasound-Based TE.

This imaging modality uses a transducer probe which emits low-frequency (50 Hz) vibrations into the liver for measuring liver stiffness. The examination is performed over the right lateral intercostal spaces with the patient lying in the dorsal decubitus position and the right arm being in maximal abduction. The propagating shear wave induced by these vibrations is detected by a pulse-echo acquisition, and the velocity of the wave is then calculated. Liver stiffness is proportional to shear wave velocity as expressed by the equation for Young's modulus (expressed as E = 3pv2, where v is the shear velocity and p is the density of tissue, assumed to be constant). Liver stiffness is measured in kilopascals. Requirements for accurate TE measurement of mean liver stiffness include (1) an interquartile range for measurements within 30% of the median value and (2) a ratio of successful measurements to the total number of acquisitions ≥60%.11

In two meta-analyses,12, 13 the pooled estimates for the diagnosis of cirrhosis with TE were excellent, with sensitivity and specificity values approaching 90%. Reported diagnostic threshold (or cutoff) values for cirrhosis have ranged between 11 and 17 kPa in studies of patients with chronic hepatitis C. Results of TE from studies in other etiologies of liver disease such as chronic hepatitis B, alcohol, and nonalcoholic fatty liver disease are emerging. Despite its excellent accuracy for detecting cirrhosis, liver stiffness is an insensitive predictor for esophageal varices and should not dictate which patients should or should not be screened for esophageal varices by endoscopy.14 For the detection of hepatic fibrosis between stages 2-4, however, the pooled estimates of sensitivity and specificity are reduced to between 70% and 80%.12, 13

Magnetic Resonance Elastography.

MRE uses a modified phase-contrast imaging sequence to detect propagating shear waves within the liver. Acoustic shear waves are generated by a pneumatic driver placed directly over the upper abdomen for propagation into liver tissue. Subsequently, liver stiffness values are calculated from wave displacement patterns displayed as color-encoded images (elastograms). Region-of-interest analysis throughout four cross-sectional slices of liver (avoiding vascular structures) is then performed to calculate mean liver stiffness.15 Elasticity quantification by MRE is based on the formula representing shear modulus, which is equivalent to one-third of the Young's modulus used with TE.

Initial prospective studies have demonstrated the feasibility and diagnostic accuracy in detecting hepatic fibrosis with MRE. As with TE, the detection of cirrhosis by MRE is highly accurate with sensitivity and specificity values exceeding 90%, respectively. In contrast to TE, however, studies of MRE to date identify a higher diagnostic accuracy for detecting intermediate to severe fibrosis (F2-F4) with sensitivity and specificity values each in the 80%-85% range.16, 17

Although the reproducibility of TE is excellent within experienced centers, its accuracy is diminished when obesity and narrow rib interspaces are encountered.18 In a recent 5-year prospective study with 13,369 examinations, the probability of technical failure or generation of invalid results was independently associated with a body mass index > 30 kg/m2.19 The development of a specialized probe for obese patients may reduce the frequency of technically limited examinations in the future. The reproducibility of MRE is also excellent,20 yet reliance on individual operators does not exist, because imaging processes are essentially automated. Furthermore, MRE is not significantly affected by obesity or rib interspace width.

For both MRE and TE, it should also be noted that other pathophysiological processes including severe inflammation, cholestasis, and hepatic congestion may independently contribute to liver stiffness.12, 13, 18

Areas of Uncertainty

Despite the proliferation of investigations and clinical experiences with noninvasive methods for detecting hepatic fibrosis, there remain a number of critical questions about the clinical effectiveness of these approaches.

For both serum fibrosis markers and elastography imaging techniques, a number of investigators have proposed diagnostic algorithms to assist with defining the stage of fibrosis. For example, it has been suggested that liver biopsy may be deferred in patients with chronic hepatitis C and liver stiffness values from TE ≤ 6 kPa (which suggest nonsignificant fibrosis) or ≥12 kPa (which indicate advanced fibrosis). Intermediate values, however, would require liver biopsy for detecting fibrosis stage if relevant for individualized cases. Although these algorithms are intuitively helpful, they have yet to be externally validated among independent populations.

Studies of noninvasive tests to assess disease progression or prognosis with or without liver disease therapy are just beginning to emerge.21 These results are widely anticipated, because many believe the link between important clinical outcomes and results of noninvasive testing provide the highest level of validation for these methods.

Other potential areas for future research include (1) defining the role of combined versus sequential noninvasive test approaches to improve fibrosis detection, (2) further defining the role of noninvasive testing in special populations (i.e., pediatrics), and (3) determining the clinical utility of such testing as a screening tool for liver disease in general populations.

Regulatory & Cost Considerations

A major advantage of noninvasive testing is that no serious adverse effects from these techniques is recognized. Economic considerations apply for proprietary serum marker panels as well as TE and MRE. Regarding FibroTest, the U.S. Food and Drug Administration (FDA) has determined that approval is not currently required. FibroTest is currently available in the United States and is marketed as Fibrosure by LabCorp. Recent estimates of cost for this test are approximately US $300 to US $400, which typically includes shipping and processing of the blood sample as well as reporting the test result. At the moment, ultrasound-based TE is not approved for use in the United States by the FDA. In Europe, for example, the price of a TE unit is approximately 80,000 to 100,000 (US $100,000 to US $130,000), and the annual fees for calibrating measurement probes is approximately 3000 to 5000 (US $4000 to US $6500). MRE was first approved by the FDA in 2010, and is becoming available as a commercial upgrade for standard MRI systems. MRE requires less than a minute of acquisition time and can be added as part of a standard MRI examination of the abdomen. The estimated cost of MRE, if performed as a stand-alone examination, is unknown at this time, but is expected to be similar to that of TE.

Recommendations

There is no evidence for cirrhosis or severe inflammation based on routine clinical studies in the case presented here. The patient's hepatitis C viral genotype is not favorable in terms of probability of treatment response. Thus, obtaining further information about the degree of liver injury from hepatitis C could be an important factor in deciding to pursue or defer antiviral therapy. In this setting, the initial use of a noninvasive test over liver biopsy would be preferred, because it appears the patient may be reluctant to undergo invasive testing (Fig. 1). The use of FibroTest or TE or MRE imaging will be helpful if evidence for cirrhosis or minimal to no fibrosis is predicted by these tests. Should the results of noninvasive testing be indeterminate, then a liver biopsy may need to be performed for stage confirmation. If the patient is discovered to have no or minimal fibrosis and chooses not to pursue antiviral therapy, then longitudinal assessment with elastography imaging to detect fibrosis progression by an increase in liver stiffness is preferred.

Source

How to assess liver fibrosis in chronic hepatitis C: serum markers or transient elastography vs. liver biopsy?

Liver International
Special Issue: Proceedings of the 4th Paris Hepatitis Conference. The publication of this supplement was supported by an unrestricted educational grant from F. Hoffmann-Laroche Ltd.
Volume 31, Issue Supplement s1, pages 13–17, January 2011

Laurent Castera 1, Pierre Bedossa 2

Article first published online: 4 JAN 2011
DOI: 10.1111/j.1478-3231.2010.02380.x
© 2011 John Wiley & Sons A/S

Author Information

1 Department of Hepatology, Hôpital St André & Haut Lévêque, Bordeaux University Hospital, Bordeaux, France
2 Department of Pathology, Beaujon Hospital, Assistance Publique-Hôpitaux de Paris, INSERM, Paris-Diderot University, Paris, France

* Correspondence: Correspondence Laurent Castera, MD, PhD, Service d' Hépatologie, Hǒpital Beaujon, Assistance Publique Hǒpitaux de Paris, 100 Boulevard du Général Leclerc, 92110 Clichy, France Tel: +33 5 57 65 64 39 Fax: +33 5 57 65 64 45 e-mail: laurent.castera@chu-bordeaux.fr

Keywords:
FibroScan; liver biopsy; liver fibrosis; non-invasive; serum biomarkers; transient elastography

Abstract

The assessment of liver fibrosis is a major issue in the management of patients with chronic hepatitis C. Liver biopsy has traditionally been considered the gold standard for the evaluation of tissue damage, including fibrosis. In addition, it detects associated lesions such as steatosis, steatohepatitis or iron overload, which provide useful information for patient management and prognosis. Liver biopsy is, however, an invasive procedure, with a risk of rare but potentially life-threatening complications and it is prone to sampling errors. These limitations have led to the development of non-invasive methods. Currently available tests rely on two different but complementary approaches: (i) a ‘biological’ approach based on the dosage of serum biomarkers of fibrosis; (ii) a ‘physical’ approach based on the measurement of liver stiffness, using transient elastography. Although significant progress has been made in the non-invasive diagnosis of fibrosis, it is increasingly clear that these methods will not completely replace liver biopsy. Instead, non-invasive methods and liver biopsy should be used in an integrated approach for more efficient and convenient management of patients with chronic hepatitis C. The aim of this review is to discuss the advantages and limitations of liver biopsy and non-invasive methods and the perspectives for their use in clinical practice.

Liver fibrosis is a result of excessive extracellular matrix deposition in the liver in response to chronic inflammatory injury triggered by persistent hepatitis C virus in the liver. Hepatic fibrosis is determined by the replication balance between fibrogenesis and fibrosis degradation. When this balance favours fibrogenesis, there is a resulting accumulation of collagen and extracellular matrix, leading eventually to cirrhosis. Liver fibrosis and its end-point cirrhosis are the main causes of morbidity and mortality in patients with hepatitis C virus (HCV) infection (1, 2). Besides the development of antiviral drugs, there are intensive efforts to develop drugs to effectively target the mechanism of fibrogenesis or to eliminate fibrous tissue once it has accumulated in the liver (3). Therefore, the assessment of liver fibrosis is a major issue in the management of patients with chronic HCV infection (4, 5).

Liver biopsy

For many years, liver biopsy has been considered the gold standard for the evaluation of tissue damage including fibrosis. Histological assessment is based on semiquantitative scoring systems (METAVIR, Ishak score) (4, 5). Fibrosis is scored in stages while necroinflammation is evaluated by grade. Staging fibrosis is an assessment of the combination of the amount of fibrosis and architectural disorganization. These semiquantitative histological scores have been used successfully for years in both clinical trials and for individual evaluation.

However, liver biopsy has certain drawbacks. Because liver biopsy only samples a very small part of the whole organ, there is a risk that this part might be irrelevant in the evaluation of lesions that are heterogeneously distributed throughout the entire liver (5). This may be true for tissue fibrosis. There is extensive literature showing that increasing the length of the liver biopsy decreases the risk of sampling error (6, 7). Except for cirrhosis, for which microfragments may be sufficient (8), a 25 mm long biopsy is considered an optimal specimen for accurate evaluation, while 15 mm is considered sufficient in most studies.

Observer variation is another potential limitation of biopsy that is related to the difference between pathologist's interpretation of the biopsy (6, 9, 10). The use of histopathological scoring systems for the evaluation of fibrosis has limited this drawback and several studies have shown that agreement between pathologists is satisfactory, especially when the staging of fibrosis is performed by specialized liver pathologists (9, 10). Thus, although liver biopsy has its limitations, appropriate precautions may reduce the flaws inherent in this method.

Because liver biopsy is invasive, the only serious limitations are the potential adverse effects and complications that have been comprehensively reviewed elsewhere (11). Transient and moderate pain along with anxiety and discomfort are common (12, 13). Severe complications such as haemoperitoneum, biliary peritonitis and pneumothorax are rare (0.3–0.5%). Death is exceedingly rare, but has been reported occasionally for biopsies in advanced liver diseases, haemorrhagical tumours and in patients with major comorbidities. A biopsy via the transjugular route considerably reduces the risk of bleeding in patients with advanced liver disease and coagulation disorders. Biopsy performed by a trained physician, limiting the number of passes and ultrasound guidance can significantly decrease the risk of complications, thus increasing the safety of biopsy. Nevertheless, a liver biopsy should be performed only after carefully balancing the risks of the procedure with the potential benefits in terms of patient management. Despite these limitations, liver biopsy provides invaluable information that none of the non-invasive markers provide. Although the evaluation of fibrosis is a major decision criterion for hepatologists, fibrosis is only one of the many elementary histopathological features present on liver biopsy. In effect, fibrosis is not an autonomous feature, but scar tissue resulting from other pathobiological mechanisms such as inflammatory, degenerative or dystrophical processes. The simultaneous evaluation of necroinflammation (portal tract inflammation, interface hepatitis, lobular inflammation) shows whether fibrosis is the result of a past event that has stabilized or even regressed or is an ongoing process that may continue to worsen. Associated lesions such as steatosis, steatohepatitis, iron overload, etc., which provide useful information for patient management and prognosis, can also frequently be detected with biopsy (14).

Finally, in difficult diseases such as hepatitis C, liver biopsy may also reveal that abnormal liver function tests are related to unexpected liver diseases other than hepatitis C (15). Clearly, all this information may influence patient management. Therefore, limiting the definition of chronic liver disease to the extent of fibrosis is an oversimplification that may be misleading.

Non-invasive methods for the assessment of liver fibrosis

There are two distinct approaches among the currently available non-invasive methods: (i) a physical approach based on the measurement of liver stiffness using transient elastography (TE); (ii) a biological approach based on serum biomarkers of fibrosis (16). Although complementary, these two approaches are based on different rationales and conceptions: TE measures liver stiffness in relation to elasticity, corresponding to a genuine and intrinsic physical property of the liver parenchyma, while serum biomarkers are a combination of several, not strictly liver-specific blood parameters optimized to mimic the stages of fibrosis as assessed by liver biopsy (17).

Numerous biomarkers have been proposed in hepatitis C (18, 19, 20) but the most widely used and validated with TE are the aspartate-to-platelet ratio index (APRI) (a free non-patented index) and the FibroTest (21, 22, 23).

The results of TE and serum biomarkers for the diagnosis of significant fibrosis have been shown to be equivalent in patients with chronic hepatitis C infection (24, 25). Indeed, in the largest study to date (n=1307) (25), comparing TE with several patented and non-patented biomarkers (FibroTest, Fibrometre, Hepascore and APRI) and using liver biopsy as a reference, the AUROCs of TE (0.76) did not differ from those of serum biomarkers (0.72–0.78).

In order to increase the diagnostic accuracy of these tests, the sequential combination of biomarkers (26, 27) or the concomitant combination of TE and biomarkers (24, 28, 29) has been proposed. The latter strategy may be more effective for diagnosing significant fibrosis, leading to a reduction in the use of liver biopsy in more than 70% of cases compared with 50% when using biomarkers (APRI and FibroTest) sequentially (30). Another advantage of combining two unrelated methods such as TE and biomarkers rather than two biomarkers is that TE provides a more direct measurement of liver structure than biomarkers and there is no relationship between the applicability of TE and biomarkers such as the FibroTest (28).

For the diagnosis of cirrhosis, the situation is different because TE appears to be the most accurate method compared with currently available biomarkers and routine blood tests, preventing the need for a liver biopsy in around 90% of cases (25, 31). As a result, a combination of both methods does not seem to increase the diagnostic accuracy (30).

Limitations of non-invasive methods

Serum markers

Although the applicability and interlaboratory reproducibility of different tests have been shown to be satisfactory for use in clinical practice (32, 33), interpretation of each test requires critical analysis to avoid false-positive or false-negative results (34).

Transient elastography

Although the reproducibility of TE has been shown to be excellent for inter- and intra-observer agreement (35, 36), its applicability may not be as good as that of biomarkers. Indeed, in our experience of more than 13 000 exams over a 5-year period, liver stiffness measurements (LSM) could not be interpreted in nearly one in five cases (failure to obtain any measurement in 4% and unreliable results that did not meet the manufacturer's recommendations in 17%) (37). The principal reasons were obesity, particularly increased waist circumference, and limited operator experience.

Finally, because the liver is an organ wrapped in an expandable but non-elastic envelope (Glisson's capsula), additional space-occupying tissue abnormalities independent of fibrosis, such as oedema and inflammation, cholestasis and congestion, may interfere with LSM. The risk of overestimating liver stiffness values has been reported in the case of alanine aminotransferase flares in patients with acute viral hepatitis or chronic hepatitis B (38, 39, 40) as well as in cases of extrahepatic cholestasis (41) or congestive heart failure (42).

How to use liver biopsy and non-invasive methods in clinical practice?

A liver biopsy should be performed in the case of comorbidities such as alcoholism or metabolic syndrome when non-invasive methods cannot be used or in any unclear situation such as discordant results of non-invasive tests. Conversely, liver biopsy should not be performed when the clinical diagnosis is obvious (cirrhosis) or when no benefit can be expected from the biopsy for patient management. Although there is no optimal threshold, the longer the specimen, the more accurate the staging will be (43). A 20–25 mm long biopsy is considered optimal although a robust evaluation is often possible on a 15 mm long biopsy. Ideally, the biopsy should be read by an experienced liver pathologist because it decreases the source of variability in the histological interpretation (44).

In naïve patients without comorbidities who are candidates for antiviral treatment, non-invasive tests can be used for the first-line staging of fibrosis. The use of either TE or several patented biomarkers (FibroTest, Fibrometer and Hepascore) has recently been recommended, based on an independent systematic review by the French Health Authorities (45). However, this strategy should also take into account HCV genotype, local availability of non-invasive methods and any clinically relevant variable. For instance, when there is a strong clinical suspicion of cirrhosis, in most cases the use of TE is enough to confirm the diagnosis without a liver biopsy. Conversely, a liver biopsy may be necessary to differentiate between F1 and F2 in genotype 1-infected patients before making a decision on antiviral treatment. In the same way, a liver biopsy may be useful to differentiate between F3 and F4 when cirrhosis is not clinically obvious and to decide when to start screening for hepatocellular carcinoma. However, with the availability of new antiviral treatments (46, 47), differentiating between F1 and F2 may not be as important for treatment indications.

When deciding on retreatment, a liver biopsy may be indicated to investigate the presence of factors of impaired response such as non-alcoholic steatohepatitis or to obtain a prognosis especially if a liver biopsy has not been performed previously.

Finally, non-invasive methods can be of interest in the follow-up of untreated patients (48). Given the slow rate of the progression of fibrosis in chronic hepatitis C, a non-invasive evaluation can be performed on a yearly basis.

Conclusion and perspectives

There is an urgent need to pursue the development of non-invasive tests in addition to a liver biopsy for the staging of fibrosis. Because of the conditional relationship with biopsy, the development of serum markers will always have obvious limitations. Promising preliminary results suggest that novel alternative imaging techniques such as magnetic resonance elastography, acoustic radiation force impulse imaging or perfusion computed tomography will eventually be refined to reach an acceptable level of accuracy, especially for the evaluation of early and intermediate stages of fibrosis (49–51). These might become less pertinent as antiviral treatments become more efficient, with fewer side effects.

Conflicts of interest

The authors have declared no potential conflicts.

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Significant changes in liver stiffness measurements in patients with chronic hepatitis B: 3-year follow-up study

Journal of Viral Hepatitis
Early View (Articles online in advance of print)

J. Fung, C.-L. Lai, D. K.-H. Wong, W.-K. Seto, I. Hung, M.-F. Yuen

Article first published online: 7 JAN 2011
DOI: 10.1111/j.1365-2893.2010.01428.x
© 2011 Blackwell Publishing Ltd

Author Information
Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
*Correspondence: Prof Man-Fung Yuen, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, China. E-mail: mfyuen@hkucc.hku.hk

Abstract

Keywords:
chronic hepatitis B;fibroscan;liver stiffness;longitudinal;transient elastography

Summary.  For patients with chronic hepatitis B (CHB) infection, changes in liver stiffness measurement (LSM) over time are not known. We examined changes longitudinally in a cohort of patients. Four hundred and twenty-six patients with CHB underwent transient elastography. Patients were followed regularly, and repeat elastography was performed at 3 years. Hepatitis serology, viral load and routine liver biochemistry were monitored. Of the 426 patients, 38 (9%) were hepatitis B e-antigen (HBeAg)-positive, 293 (69%) were HBeAg-negative and 95 (22%) were patients with prior hepatitis B surface antigen (HBsAg) seroclearance. A total of 110 patients received oral antiviral therapy. There was a significant decline of LSMs at the follow-up measurement compared to baseline (6.1 vs 7.8 kPa respectively, P = 0.002) in treated patients who had elevated alanine aminotransferase (ALT) at baseline and subsequent normalization after 3 years (normal ALT limit being 30 U/L for males and 19 U/L for females). In nontreated patients, only the patients with persistently normal ALT at both time points had significantly lower LSMs at the follow-up measurement compared to baseline: 4.9 vs 5.3 kPa, respectively, in patients who remained positive for HBsAg (P = 0.005) and 5.1 vs 5.4 kPa, respectively, in patients who had HBsAg seroclearance (P = 0.026). In patients who remained positive for HBsAg, independent factors associated with a significant decline in LSM of ≥1 kPa included antiviral therapy (P = 0.011) and the ALT levels at the follow-up time point (P = 0.024). Thus, in patients with CHB, a significant decline in LSM after 3 years was observed in treated patients with ALT normalization and in untreated patients who had persistently normal ALT. Antiviral therapy and follow-up ALT levels were independent significant factors associated with a decline in LSM.

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