What Complications Can Arise From Percutaneous Liver Biopsy?

AGA Journals 

What Complications Can Arise From Percutaneous Liver Biopsy?

Kristine Novak

A unique complication of portal vein thrombosis after a percutaneous liver biopsy is reported in the January issue of Clinical Gastroenterology and Hepatology.

Liver biopsies are collected to aid in diagnosis of liver disease and staging of fibrosis, but complications can include pain, bleeding, puncture of another organ, and rare events such as biliary peritonitis, sepsis and shock, bilious pleural effusion, pseudoaneurysm of intercostal artery, and fragmentation of the biopsy needle.

Nicole Boschuetz et al report the case of a 64-year-old woman who had 25 days of dull constant right upper quadrant abdominal pain that began 1 day after a percutaneous liver biopsy. She had previously undergone cholecystectomy and sphincterotomy for reported sphincter of Oddi dysfunction.

Continue to article: http://journalsblog.gastro.org/what-complications-can-arise-from-percutaneous-liver-biopsy/

Liver biopsy, mental health did not affect HCV treatment

Liver biopsy, mental health did not affect HCV treatment

Kluck J. Hepat Res Treat. 2013;doi:10.1155/2013/653976.

June 20, 2013

Having a pretreatment liver biopsy did not predict whether patients completed a full treatment course for hepatitis C, researchers reported. In subsequent analyses, the presence of a psychiatric disorder also did not affect treatment completion.

Using a computerized patient record system, researchers examined the effect of having liver biopsy and the presence of psychiatric disorders on the the treatment response and completion rates among 375 HCV-infected veterans who were being treated at the VA Philadelphia Medical Center. Treatment, which began within 1 year of the biopsy, included combination pegylated interferon plus ribavirin for 24 weeks for HCV genotypes 2 and 3, or 48 weeks for HCV genotypes 1 and 4.

Sustained virological response was achieved in 31% of patients, and 45% completed the full treatment course.

The researchers hypothesized that having an invasive procedure such as a liver biopsy would make patients more aware of their disease and “psychologically” motivate them to complete the extensive HCV treatment. Additionally, HCV treatment has been associated with psychiatric adverse effects — including anxiety, depression and posttraumatic stress disorder — which also may lead to treatment discontinuation.

However, of the patients who received a liver biopsy, 44% completed treatment vs. 46% of those with no biopsy.

Although biopsy status had no effect on treatment completion, the researchers said having a biopsy may be associated with treatment uptake. For example, the biopsy rate among the cohort was 23% vs. the biopsy rate among those at the VA center who were untreated (3.8%).

Psychiatric disorders, which were based on ICD-9 codes, progress notes and prescription records, were common in the cohort (59.7% having at least one disorder), but did not significantly alter the treatment course.

The most common reasons for discontinuation among those with psychiatric disorders were medication-related adverse effects, virological failure and loss to follow-up.

“Interestingly, our study showed that the rates of HCV therapy discontinuation due to psychiatric-related adverse drug effects were similar between patients with a mental health disorder at baseline and with no mental health disorder at baseline,” the researchers wrote.

Disclosure: The researchers report no relevant financial disclosures.

http://www.healio.com/infectious-disease/hepatitis-resource-center-2013/liver-biopsy-mental-health-did-not-affect-hcv-treatment

EASL: Liver Imaging Tests Vie to Replace Biopsy

Also See- FDA Approves FibroScan for Noninvasive Liver Diagnosis


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.

Action Points

Note that these studies were published as abstracts and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

Note that multiple studies demonstrate the ability of novel imaging modalities to predict liver fibrosis in patients with liver disease.

Be aware that there are limitations to these new technologies, including the fact that many do not perform well in obese patients.

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.

EASL Coverage @ MedPage Today

http://www.medpagetoday.com/MeetingCoverage/EASL/38707

The Age-Old Debate of Whether to Biopsy in HCV: My Answer for 2013

ClinicalThought™ @ CCO

Interact with experts and peers.

 

The Age-Old Debate of Whether to Biopsy in HCV: My Answer for 2013

Mark S. Sulkowski MD

With interferon-free, all-oral therapies on the near-term horizon, I am increasingly comfortable relying on patient history, physical exam, routine laboratory tests, and liver imaging as well as noninvasive serum markers to obtain a picture of liver health.

 

The Age-Old Debate of Whether to Biopsy in HCV: My Answer for 2013

As Raymond T. Chung, MD, pointed out in a recent Clinical Thought, the US Centers for Disease Control and Prevention now recommend that all persons born between 1945 and 1965 undergo a 1-time screening for HCV. The idea is that this will identify persons who are infected and offer them the opportunity for management of their hepatitis C infection, in turn reducing the risk of cirrhosis, end-stage liver disease, and hepatocellular carcinoma. Management of HCV disease can include a number of things, including reduction in alcohol intake and, in some patients, reduction in body weight. It also includes consideration of HCV treatment but, in 2013, does it include a liver biopsy?

Continue reading....

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Additional articles @ CCO:

Management of Acute HCV Infection in the DAA Era
Jan 23 2013

A recent patient experience has underscored some key issues regarding the vigilance required and current management considerations with acute HCV infection.

 

Anemia Management During PI-based HCV Therapy: Ribavirin Dose Reduction is the Right Course of Action

Last Comment: 1/20/2013

Here’s the new thinking for the management of anemia with triple therapy including telaprevir or boceprevir: We need to dose reduce ribavirin in patients with anemia, and we need to do it relatively aggressively.

Today after reading the above article at CCO written by Mark S. Sulkowski MD, I added information and a few videos about a non-invasive test for liver fibrosis called Magnetic Resonance Elastography, or MRE.

Magnetic Resonance Elastography

An early 2008 study showed this imaging technology developed by Mayo Clinic could identify liver fibrosis with high accuracy in patients with liver disease. The video was released simultaneously with the Mayo study.



In April of last year a newer video was released by Mayo which highlights a patient with hepatitis C, and explains the imaging technique



In December 2012 a study published in the journal of Japanese Society for Magnetic Resonance in Medicine evaluated the use of magnetic resonance (MR) elastography (MRE) for staging liver fibrosis in patients with chronic hepatitis C and compared the ability of MRE and serum fibrosis markers for discriminating each stage of fibrosis. Investigators concluded that MRE was a reliable technique for staging liver fibrosis and discriminating liver fibrosis stages in patients with chronic hepatitis C.

 

Lastly, in an article directed at the medical industry more then at patients, Whitney L.J. Howell writes that for assessing liver disease a MRE is an alternative to having an invasive liver biopsy, with comments by Richard Ehman, a leader of the Mayo Clinic team that developed MRE.

 

MR Elastography Growing as Preferred Modality for Liver Diagnosis

By Whitney L.J. Howell |January 24, 2013

Once available only to radiologists who purchased new MRI equipment, MR elastography technology is becoming widely available as an upgrade feature to older machines. This expansion not only greatly improves patient care, industry experts said, but it also impacts costs and efficiency.

MR Elastography (MRE) — now available at 100 locations on five continents — is the industry-preferred method for assessing liver stiffness or elasticity. This condition characterizes liver disease and is most often diagnosed through palpation. However, there is a limit to how much tissue providers can feel. While conventional MRI is a powerful tool, liver disease, such as fibrosis or cirrhosis, creates no anatomical changes to the organ, making identification difficult and often requiring a needle biopsy.

“MR elastography provides a safer, more comfortable, non-invasive alternative to liver biopsy for assessing liver disease,” said Richard Ehman, MD, professor and chair of radiology at the Mayo Clinic in Minnesota, noting that needle biopsies are often painful.

Being able to analyze liver health in a faster, more reliable way is particularly important now, he said, as the level of obesity and the associated fatty liver disease is rising in the United States. Currently 1 in 3 Americans lives with fatty liver disease, and within 10 years, he said, this condition will be the leading cause for liver transplant. MRE is also beneficial in diagnosing and treating the 25 percent of Hepatitis C patients who develop liver fibrosis, the large build-up of proteins in the liver that eventually leads to cirrhosis.

What Is MRE and How Does It Work?

Approved by the FDA in 2009, MRE is a non-invasive, highly-sensitive method for determining the level of liver disease through the use of low-frequency mechanical waves. It is designed to facilitate faster diagnosis and avoid potentially dangerous — and often inaccurate — liver biopsies, said Ehman, who pioneered the MRE technology and worked with GE Healthcare to bring it to market.

Once installed, this tool pumps 60 Hz waves through a plastic tube to a small, non-metallic drum placed over the abdomen. Slower wave movement correlates to higher stiffness. Standard MRI imaging captures the miniscule movements of the tissue, and, using a special algorithm, converts the data into a color-scale picture that corresponds to the level of liver stiffness.

MRE differs from ultrasound elastography. With the ultrasound method, a probe is pushed across tissue, and a scanner records how the tissue deforms. However, Ehman said, this doesn’t provide a quantitative measure of the tissue’s actual stiffness.

According to Ehman, an MRE scan can be completed with four breath holds — approximately a minute — and is often conducted and billed as part of other abdominal MRI protocols. Based on the color-scale picture, radiologists can instantaneously know whether the patient has a healthy or diseased liver. Liver tissue stiffness is measured in kiloPascals (kPa), with a normal liver having a stiffness of roughly 2 kPa, the same consistency of fat inside the body. Diseased livers range from 3 kPa to more than 10 kPa.

Since MRE’s FDA approval, GE Healthcare has been the main vendor for the tool with its MR Touch product. Siemens has also worked with the Mayo Clinic to provide MRE on its existing MAGNETOM Aera and Skyra MR machines.

Overall, said Richard Hausmann, GE’s president and CEO officer of global MR business, MRE greatly enhances what MRI studies provide.

“MRE offers an accurate assessment of stiffness in the liver, even for deeper tissues not reached by palpation,” he said. “It’s helped increase confidence in diagnoses in this area, and it’s one piece in an attempt to make overall diagnosis less invasive.”

Benefits to Patients and Providers
MRE offers several benefits to patients, Ehman said, but one of the biggest is that it side-steps the need for a needle biopsy. Liver tissue is heterogeneous, so a biopsy based on only a small piece of tissue from one location is predisposed to inaccuracy. In a 2010 article in Clinical Anatomy, Ehman reported MRE achieves a 99 percent-accurate diagnosis rate.

“MR elastography provides images that show the status of liver tissue over large cross-sectional areas,” he said. “So, it may provide a reliable assessment of the extent of liver fibrosis.”

Biopsies are also expensive, carrying a price tag of up to $2,000, and can sometimes lead to complications. In fact, 1 in every 10,000 patients who undergo a liver biopsy dies, Ehman said.
MRE can also hasten treatment for Hepatitis C-induced fibrosis. By analyzing more tissue than a physician can with palpation, MRE can identify which patients are developing the condition and would benefit from existing medication. Early diagnosis and access to appropriate drugs is critical in treating this chronic infection.

Using this tool also offers positives to providers. Test results are immediate, eliminating the delay caused by waiting on pathology results. Because the procedure is non-invasive, providers can request it be done repeatedly to assess whether prescribed liver therapy is working or if the condition is progressing. In addition, Ehman said, pharmaceutical companies can also use the technology during clinical trials to gauge success rates.

There is a challenge, however, to using the technology, Hausmann said.
“Providers must have a robust, high-quality, and stable system to use these sensitive contrast sequences,” he said. “You need a stable, high-quality electronic system and additional small, MR compatible acoustic devices.”

You could also encounter difficulty if you’re imaging a patient with liver disease due to iron overload, Ehman said. The high iron levels black out the MR image. However, new technology is under development to eliminate that problem.

Future Use
Although MRE is only currently approved for use with the liver, Ehman said it could potentially be effective in identifying and diagnosing other types of cancer, such as breast or prostate, because these malignancies also present as being harder than healthy tissue. GE’s Hausmann predicted potential MRE applications in cardiology with heart attack patients and in neurology with patient’s living with Alzheimer’s.

However, Ehman said, the next anticipated application will be with the benign tumors of the head known as meningioma. If surgeons can remove the tumors, patients often make a full recovery. By simply adding a pillow-like device under the head, technologists can send the MRE mechanical waves through the skull to assess the stiffness of these masses.

Not only could using MRE improve patient care and outcomes, but it could also enable the radiologist to more fully prepare surgeons.

“Some of these tumors are very hard and stiff, and surgeons have to remove them in little pieces, carefully dissecting the overlying tissue. That can lead to 10 or more hours of surgery,” Ehman said. “Others are so soft they can literally be removed by suction in about two hours. Using MRE to determine how stiff a tumor is can help surgeons know what they’re facing.”

Source - Diagnostic Imaging

National patterns and predictors of liver biopsy use for management of hepatitis C

National patterns and predictors of liver biopsy use for management of hepatitis C

Journal of Hepatology
Volume 57, Issue 2 , Pages 252-259, August 2012

Erik J. Groessl, Lin Liu, Samuel B. Ho, Fasiha Kanwal, Allen L. Gifford, Steven M. Asch Received 15 August 2011; received in revised form 16 February 2012; accepted 12 March 2012. published online 18 April 2012.

Background & Aims

Liver biopsy remains the standard, recommended method for assessing liver damage associated with chronic hepatitis C (HCV) infection. However, there is considerable debate about how liver biopsy should best be used, especially with the advent of more efficacious antiviral therapies. To identify the factors that influence the use of liver biopsy for HCV patients, we describe variations in liver biopsy use at the delivery system and patient level in a national VA sample.

Methods

We analyzed VA HCV registry data for 171,893 VA patients with confirmed chronic HCV. Delivery system characteristics included geographic region and specialist time. Patient characteristics included antiviral treatment indicators, contraindications, volume of healthcare visits, and demographic variables. Logistic regression was used to explore correlates of biopsy use.

Results

Liver biopsy use in the VA system increased from 1997 to 2003 but began declining in 2004. Rates of liver biopsy from 2004 to 2006 varied by VA region, ranging from 5% to 18%. Treatment contraindications and laboratory tests were significantly associated with more biopsies. Demographic variables (higher age, lower BMI, race/ethnicity, and less% service connected disability) were associated with fewer biopsies. Regional variability remained significant independent of volume of care and specialist time.

Conclusions

Liver biopsy rates in the VA system have variability that seems unrelated to clinical need. New antiviral therapies and non-invasive assessment techniques may create additional uncertainty for the role of liver biopsy, perhaps explaining its decline in recent years. The availability of more effective antiviral therapies may also affect biopsy rates in the future.

http://www.journal-of-hepatology.eu/article/S0168-8278(12)00276-0/abstract?elsca1=etoc&elsca2=email&elsca3=0168-8278_201208_57_2&elsca4=gastroenterology

It’s Not Easy to Diagnose Intermediate-Stage Liver Fibrosis

It’s Not Easy to Diagnose Intermediate-Stage Liver Fibrosis

Posted on June 11, 2012
by Kristine Novak, PhD, Science Editor

Biopsy has a low level of diagnostic performance for liver fibrosis stages F2 and F1. The recommendation for biopsy analysis, instead of non-invasive tests, for diagnosis of intermediate stages of fibrosis is therefore misleading, according to the June issue of Clinical Gastroenterology and Hepatology.

Noninvasive tests such as FibroTest are used to stage fibrosis in patients with chronic liver diseases, but there has been controversy over their accuracy. This is because it’s not clear if results from these tests can be compared with those from biopsies—no one knows if biopsy analysis is the best way to identify patients with early or intermediate-stage fibrosis.

Thierry Poynard et al. investigated the limitations of using biopsy analysis as the standard for analysis of fibrosis tests. They analyzed large surgical samples of livers from 20 consecutive patients with chronic liver diseases or normal liver (surrounding tumors). They also analyzed digitized images of 27,869 virtual biopsies of different lengths and data from 6500 patients with interpretable FibroTest results who also underwent biopsy analysis.

In statistical analyses, Poynard et al. found that the performance of biopsy was lower for the diagnosis of F2 vs F1 samples than for F1 vs F0 or F4 vs F3, even when 30-mm biopsy samples were used. The performance of FibroTest was also lower for the diagnosis of F2 vs F1 samples than for F1 vs F0 samples or F4 vs F3. However, the FibroTest had smaller percentage differences among values than biopsy analysis (see figure).

An increase of overall performance was observed with increasing biopsy length. However, the only comparison without a significant increase according to biopsy length was the diagnosis of F2 vs F1.
Poynard et al. conclude that because biopsy is not a perfect reference, the true performance of FibroTest and other biomarkers in evaluation of F1- and F2-stage fibrosis is unknown.

Progress in treatment of patients with hepatitis B and C virus infections has reduced the importance of identifying F2, which was the threshold for initiating treatment. However, because of the cost of these therapies, it is important to determine their efficacy in treating patients who have no progression beyond baseline stages of F0 or F1. Futhermore, in patients with HCV who are treated with pegylated interferon and ribavirin, stages of F4 vs F3 and F3 vs F2 are prognostic factors.

The authors say that the American Association for the Study of Liver Diseases guidelines from 2009, which state “These markers are useful for establishing the 2 ends of the fibrosis spectrum (minimal fibrosis and cirrhosis) but are less helpful in assessing the mid-ranges of fibrosis or for tracking fibrosis progression”, are wrong.

They acknowledge that biopsy provides much more information than just quantification of fibrosis—it is the only direct estimate of many hepatic features. But they say that the concept that there is a ‘gray zone’ for biomarkers, compared to biopsy, is misleading—because biopsy has an inherent 25% error, other methods are needed to compare accuracy of new diagnostic tools.
Read the article online.

Poynard T, Lenaour G, Vaillant JC, et al. Liver biopsy analysis has a low level of performance for diagnosis of intermediate stages of fibrosis. Clin Gastroenterol Hepatol 2012;10:657–663.e7.

http://agajournals.wordpress.com/2012/06/11/its-not-easy-to-diagnose-intermediate-stage-liver-fibrosis/

How far is noninvasive assessment of liver fibrosis from replacing liver biopsy in hepatitis C?

How far is noninvasive assessment of liver fibrosis from replacing liver biopsy in hepatitis C?

1. G. Sebastiani¹,
2. A. Alberti^1,2

Article first published online: 10 JAN 2012

DOI: 10.1111/j.1365-2893.2011.01518.x

Journal of Viral Hepatitis

Special Issue: How to Optimize Treatment of Hepatitis C

Volume 19, Issue Supplement s1, pages 18–32, January 2012

Download PDF

Abstract

1. Top of page
2. Abstract
3. Epidemiology and Natural History of Chronic Hepatitis C: the Impact of Liver Fibrosis
4. Liver Biopsy for Staging Fibrosis: the Perspective of Pathologists, Clinicians and Guidelines
5. Noninvasive Assessment of Liver Fibrosis: Serum Biomarkers
6. Noninvasive Assessment of Liver Fibrosis: Transient Elastography (Fibroscan^®)
7. Stepwise and Synchronous Combination Algorithms of Noninvasive Methods for Liver Fibrosis
8. Highlights
9. Acknowledgements and Disclosures
10. References

Summary. Chronic hepatitis C represents a major cause of progressive liver disease that can eventually evolve into cirrhosis and its end-stage complications. Formation and accumulation of fibrosis in the liver is the common pathway that leads to evolutive liver disease. Precise staging of liver fibrosis is essential for patient management in clinical practice because the presence of bridging fibrosis represents a strong indication for antiviral therapy, while cirrhosis requires a specific follow-up. Liver biopsy has always represented the standard of reference for assessment of hepatic fibrosis, but it has limitations: it is invasive, costly and prone to sampling errors. Recently, blood markers and instrumental methods have been proposed for the noninvasive assessment of liver fibrosis in hepatitis C. However, international guidelines do not recommend the widespread use of noninvasive methods for liver fibrosis in clinical practice. This is because of, in some cases, unsatisfactory accuracy and incomplete validation of others. Some studies suggest that the effectiveness of noninvasive methods for assessing liver fibrosis may increase when they are combined, and a number of sequential and synchronous algorithms have been proposed for this purpose, with the aim of reducing rather than substituting liver biopsies. This may represent a rational and reliable approach for implementing noninvasive assessment of liver fibrosis in clinical practice. It could allow more comprehensive first-line screening of liver fibrosis in hepatitis C than would be feasible with liver biopsy alone.

Epidemiology and Natural History of Chronic Hepatitis C: the Impact of Liver Fibrosis

1. Top of page
2. Abstract
3. Epidemiology and Natural History of Chronic Hepatitis C: the Impact of Liver Fibrosis
4. Liver Biopsy for Staging Fibrosis: the Perspective of Pathologists, Clinicians and Guidelines
5. Noninvasive Assessment of Liver Fibrosis: Serum Biomarkers
6. Noninvasive Assessment of Liver Fibrosis: Transient Elastography (Fibroscan^®)
7. Stepwise and Synchronous Combination Algorithms of Noninvasive Methods for Liver Fibrosis
8. Highlights
9. Acknowledgements and Disclosures
10. References

Chronic hepatitis C (CHC) is a major public health concern that affects about 200 million individuals worldwide and has a greater prevalence in Western countries [1]. Natural history studies indicate that approximately 10–20% of chronically infected patients with hepatitis C will develop severe liver cirrhosis and 1–5% will develop hepatocellular carcinoma (HCC) within two to three decades [2]. The event with the greatest impact on the natural history of CHC is the progressive formation and accumulation of liver fibrosis. This accumulation of fibrillar extracellular matrix (ECM) components is the hallmark of the natural history of the disease and significantly influences prognosis [2,3]. Indeed, there is a clear association between mild or no fibrosis at diagnosis and low risk of developing cirrhosis (25–30%) over the next 20 years. On the other hand, 100% of individuals with portal fibrosis develop cirrhosis, but this process takes 18–20 years. However, individuals with septal fibrosis develop cirrhosis sooner (8–10 years) [4]. Thus, early and accurate disease assessment and staging of fibrotic changes are critical for defining prognosis and indications for therapy in individual patients with CHC. In this view, two stages of liver fibrosis significantly modify the clinical management of patients with CHC: significant fibrosis, defined as at least portal fibrosis with few septa in liver histology, which represents a definitive indication to start antiviral treatment; and cirrhosis, which requires a specific follow-up including screening for oesophageal varices and for HCC by endoscopy, ultrasound and monitoring of alpha-fetoprotein levels [5].

Liver Biopsy for Staging Fibrosis: the Perspective of Pathologists, Clinicians and Guidelines

1. Top of page
2. Abstract
3. Epidemiology and Natural History of Chronic Hepatitis C: the Impact of Liver Fibrosis
4. Liver Biopsy for Staging Fibrosis: the Perspective of Pathologists, Clinicians and Guidelines
5. Noninvasive Assessment of Liver Fibrosis: Serum Biomarkers
6. Noninvasive Assessment of Liver Fibrosis: Transient Elastography (Fibroscan^®)
7. Stepwise and Synchronous Combination Algorithms of Noninvasive Methods for Liver Fibrosis
8. Highlights
9. Acknowledgements and Disclosures
10. References

Liver fibrosis staging systems

Liver biopsy has long remained the gold standard for assessment of liver fibrosis. It is based on direct histological assessment of the severity of liver disease, and several histological classification systems have been proposed to stage fibrosis and to grade necroinflammation in CHC (Table 1). The Knodell score is a quantitative score composed of four individual scores representing periportal and/or bridging necrosis (scored 0–10), intralobular degeneration and focal necrosis (scored 0–4), portal inflammation (scored 0–4) and fibrosis (scored 0–4) [6]. Although useful for assessing inflammatory activity, the Knodell score includes only three fibrosis stages, which limits its accuracy. The Ishak score, a revised version of the Knodell score that is frequently applied to CHC, preserves the grading and staging function of its predecessor while including six fibrosis stages [7]. Another widely used CHC classification system is the semiquantitative METAVIR system, which consists of grading and staging components [8,9].

Table 1. Staging systems for liver fibrosis in chronic hepatitis C 

Description	METAVIR (F)	Knodell	Ishak (F)	Batts–Ludwig (stage)
No fibrosis	0	0	0	0
Portal fibrosis without septa	1	1	1–2	1–2
Portal fibrosis with few septa	2	1	3	3
Septal fibrosis without cirrhosis	3	2	4	3
Cirrhosis	4	3	5–6	4

 

Liver biopsy and the pathologist: the problem of sampling error

The quality and the size of the specimen obtained through a percutaneous liver biopsy in CHC are also an important issue. The main drawbacks lie in sampling error and intraobserver/interobserver variability. In a study by Regev et al. [10], samples taken from both right and left lobes revealed a difference of fibrosis stage of at least one grade in 33.1% of patients, while fibrosis was underdiagnosed in 14.5% of them. Cirrhosis may be missed on a single, blind percutaneous liver biopsy in 10–30% of cases [11,12]. Additionally, there is a significant degree of subjectivity in the pathologic assessment of liver biopsy samples. In a detailed study, Colloredo et al. [13] carefully analysed the impact of sample size on the correct staging of liver fibrosis in patients with CHC. By progressively reducing the dimensions of the same liver biopsy, they reported that the smaller the sample analysed, the milder the stage of fibrosis diagnosed by the pathologist. Interestingly, Rousselet et al. [14] reported that, even more than biopsy dimensions, the level of experience of the pathologist impacts on the diagnostic interpretation of liver biopsies. Pathologists have tried to define the features of an adequate liver biopsy sample. Some authors suggest that it should contain more than five complete portal tracts and be at least 15 mm in length [15,16]. In a critical review, Guido and Rugge [17] suggested that a biopsy sample of 20 mm or more containing at least 11 complete portal tracts should be considered reliable for grading and staging. Other authors have recommended even larger samples, up to 25 mm in length [18], and Scheuer stated that ‘bigger is better’[19]. Very recently, the American Association for the Study of Liver Diseases has recommended a biopsy sample of at least 20–30 mm in length and containing at least 11 complete portal tracts. Moreover, in clinical practice, a simple (METAVIR) rather than complex (Ishak) scoring system has been recommended for liver fibrosis [20]. In a recent report, Mehta et al. [21] suggested that liver biopsy is the best available standard of reference, but not the gold standard. Indeed, the performance of any surrogate is generally evaluated by the area under the receiving operating characteristic curve (AUC), using liver biopsy as the reference. Because liver biopsy is not the gold standard but the best available standard, a perfect surrogate will never reach a maximal value (that is 1). Taking into account a range of accuracies of the biopsy and a range of prevalences of significant fibrosis (that influence the AUC), the authors demonstrated that in the most favourable scenario, an AUC > 0.90 cannot be achieved when assessing significant fibrosis, even for a perfect marker [21].

 

Liver biopsy and the clinician: the problem of invasiveness

Liver biopsy has clear advantages, because it gives direct information not only about fibrosis, but also about necroinflammatory activity, steatosis, hepatic iron deposits and possible comorbidities. Nevertheless, it also presents some drawbacks for the clinician, including invasiveness and cost (Table 2). Pain is the most common complication of percutaneous liver biopsy, occurring in up to 84% of patients [22]. When moderate-to-severe pain occurs, usually in a small percentage of cases, the possibility of a more serious complication should be considered. The most important complication of a liver biopsy is bleeding, which occurs in 1/2500 to 1/10 000 cases. Death of a patient as a consequence of liver biopsy is very rare, less than or equal to 1/10 000 biopsies [20]. Regarding the impact of operator experience on the rate of complications, contradictory evidence exists. One study showed that the rate of complications in percutaneous liver biopsy was 3.2% if the operator had performed <20 biopsies and only 1.1% if the operator had performed more than 100 biopsies [23]. On the contrary, Chevallier et al. [24] showed that operator experience did not influence the final histological diagnosis or the degree of pain suffered by the patient.

Table 2.  Pros and Cons of liver biopsy

Advantages

Direct assessment of liver fibrosis

Semiquantitative

Evaluation of coexisting disorders

Limitations

Sampling error

Intraobserver and interobserver variability

Hospitalization often required

Complications

Pain

Haemorrhage

Pneumothorax

Haemothorax

Perforated viscus

Infection

Availability

High cost

Trained physician required

Contraindications

Absolute: uncooperative patient, severe coagulopathy and extrahepatic biliary obstruction

Relative: ascites, morbid obesity, possible vascular lesions and amyloidosis

There is no clear consensus among clinicians about the role of liver biopsy in assessing liver fibrosis. A French survey of 1177 general practitioners concluded that liver biopsy may be refused by up to 59% of patients with hepatitis C and that 22% of the physicians share the same concern for the invasiveness of the procedure [25]. On this topic, a survey assessing consensus among Italian hepatologists on when and how to perform a liver biopsy in CHC showed great divergence in the management of the same subgroup of patients [26]. Another survey performed in a US clinical centre revealed that among 112 clinicians, 29.5% did not perform liver biopsy for the following reasons: concern about risks (72.7%), low reimbursement (66.7%) and logistic issues with space and recovery time (45.4%). Interestingly, biopsy without ultrasound guidance was routine practice for 53.2% of physicians [27]. A nationwide survey of French hepatologists regarding assessment of liver fibrosis in CHC revealed that only 4% of respondents still systematically performed liver biopsies [28].

Liver biopsy in the International Guidelines

The role of liver biopsy as reflected in the main international guidelines has evolved in recent years (Table 3). According to the 2002 Guidelines released by the National Institute of Health (NIH), liver biopsy is useful for defining the baseline state of liver disease and for informing treatment decisions by patients and healthcare providers regarding antiviral therapy [29]. Noninvasive tests do not currently provide the same information obtainable through liver biopsy. Information from a liver biopsy allows affected individuals to make more informed choices about the timing of antiviral treatment, thus liver biopsy can be a useful part of the informed consent process. Because a favourable response to current antiviral therapy occurs in 80% of patients infected with genotype 2 or 3, it may not always be necessary to perform a liver biopsy in these patients to make a treatment decision.

Table 3.  The role of liver biopsy across the main international guidelines 

Treatment guidelines	Role of liver biopsy
NIH, National Institute of Health; APASL, Asian Pacific Association for the Study of the Liver; AASLD, American Association for the Study of Liver Diseases; AISF, Italian Association for the Study of the Liver; and EASL, European Association for the Study of the Liver.
NIH (2002) (29)	Liver biopsy is useful in defining baseline abnormalities of liver disease and supporting decisions regarding antiviral therapy.
	Noninvasive tests do not currently provide the information that can be obtained through liver biopsy.
	Liver biopsy is a useful part of the informed consent process.
	As a favourable response to current antiviral therapy occurs in 80 per cent of patients infected with genotype 2 or 3, it may not be necessary to perform liver biopsy in these patients to make a decision to treat.
APASL (2007) (30)	Treatment is indicated in those patients with histological stage of F1 or above on liver biopsy.
	A liver biopsy is not mandatory to initiate therapy, especially if the subject is infected with HCV genotype 2 or 3.
	A liver biopsy before commencing therapy may provide information on prognosis.
AASLD (2009) (5)	A liver biopsy may be unnecessary in HCV genotype 2 and 3 infection. An ongoing debate exists for patients infected with HCV-1 because of lower rates of SVR.
	A liver biopsy should be considered in HCV patients to have more information for prognostic or therapeutic purposes.
	Available noninvasive tests may be useful in defining presence or absence of advanced fibrosis but should not replace liver biopsy in routine clinical practice.
AISF (2010) (31)	Patients with normal ALT.
	Antiviral treatment might be offered without the need for liver biopsy in patients with a high likelihood of achieving an SVR.
	In patients aged 50–65 years, and in those with a reduced likelihood of achieving an SVR, a liver biopsy may be used to evaluate the need for therapy, with treatment being recommended only for patients with fibrosis ≥F2 and a favourable HCV genotype.
	Biopsy and therapy are not recommended in elderly (>70 years) patients.
	Noninvasive assessments of fibrosis can be used to detect changes over time and indicate the need for biopsy or treatment on an individual patient basis.
EASL (2011)	Assessment of the severity of liver fibrosis is important in decision-making.
	Liver biopsy is still regarded as the reference method to assess the grade of inflammation and the stage of fibrosis.
	Transient elastography (TE) can be used to assess liver fibrosis.
	Noninvasive serum makers can be recommended for the detection of significant fibrosis (METAVIR score F2–F4).
	The combination of blood tests or the combination of transient elastography and a blood test improve accuracy and reduce the necessity of using liver biopsy to resolve uncertainty.

In 2007, the Asian Pacific Association for the Study of the Liver released a consensus statement about the management of CHC [30]. Overall, treatment is indicated in those patients with histological stage of F1 or above on liver biopsy. Patients with HCV genotype 2 or 3 can be treated regardless of stage. A liver biopsy is not mandatory before initiating therapy, especially if the subject is infected with HCV genotype 2 or 3. However, a liver biopsy before commencing therapy might provide information on prognosis.

More recently, the AASLD guidelines state that a liver biopsy should be considered in patients with CHC if the patient and healthcare provider want information regarding fibrosis stage for prognostic purposes or to make a treatment decision [5]. There is agreement that the high rate of sustained virological response in persons with genotype 2 or 3 infections means that biopsy is not necessary in these cases. There is, however, an ongoing debate about whether a biopsy is warranted for persons infected with HCV genotype 1, because of lower rates of SVR. Even more uncertain is whether a biopsy is necessary in persons infected with other, less common HCV genotypes (4 through 6). The currently available noninvasive tests may be useful for detecting the presence or absence of advanced fibrosis in persons with CHC infection, but should not replace the liver biopsy in routine clinical practice.

The recent guidelines from the Italian Association for the Study of the Liver put particular emphasis on the role of liver biopsy in patients with normal ALT levels [31]. Antiviral treatment might be offered without the need for liver biopsy in patients with a high likelihood of achieving an SVR (e.g. patients aged <50 years with highly treatable HCV genotype and low viral loads), in the absence of any contraindication and co-factors of poor responsiveness. In patients aged 50–65 years, and in those with a reduced likelihood of achieving an SVR, a liver biopsy may be used to evaluate the need for therapy, with treatment being recommended only for patients with more severe fibrosis (>F2) and a higher probability of responding, depending on the HCV genotype. Biopsy and therapy are not recommended in elderly patients (>70 years). Instead, it is recommended that these patients adopt lifestyle changes and undergo periodic ALT determinations. Noninvasive assessments of fibrosis can be used to detect changes over time and consequently indicate the need for biopsy or treatment on an individual basis.

The most recent guidelines about the management of CHC come from the European Association for the Study of the Liver (EASL) [32]. According to these, assessment of the severity of liver fibrosis is important in decision-making in patients with CHC. Liver biopsy is still regarded as the reference method to assess the grade of inflammation and the stage of fibrosis. Transient elastography can be used to assess liver fibrosis in patients with CHC. Noninvasive serum makers can be recommended for the detection of significant fibrosis (METAVIR score F2–F4). Interestingly, the EASL guidelines state also that the combination of blood tests or the combination of transient elastography and a blood test improve accuracy and reduce the necessity of using liver biopsy to resolve uncertainty.

In summary, current guidelines state that staging of liver fibrosis may be unnecessary in highly treatable HCV genotypes, while it may still have a role in HCV genotype 1 because of the lower SVR rate. Interestingly, the role of noninvasive methods for liver fibrosis has progressively evolved across the guidelines, starting from the NIH, in which they were not considered adequate, and moving towards the most recent guidelines (from American, Italian and European Associations), which do not recommend that noninvasive methods replace liver biopsy, but suggest that they may be used on an individual basis, especially to define the presence or absence of significant liver fibrosis and to reduce the number of liver biopsies.

Noninvasive Assessment of Liver Fibrosis: Serum Biomarkers

1. Top of page
2. Abstract
3. Epidemiology and Natural History of Chronic Hepatitis C: the Impact of Liver Fibrosis
4. Liver Biopsy for Staging Fibrosis: the Perspective of Pathologists, Clinicians and Guidelines
5. Noninvasive Assessment of Liver Fibrosis: Serum Biomarkers
6. Noninvasive Assessment of Liver Fibrosis: Transient Elastography (Fibroscan^®)
7. Stepwise and Synchronous Combination Algorithms of Noninvasive Methods for Liver Fibrosis
8. Highlights
9. Acknowledgements and Disclosures
10. References

Millions of people worldwide are affected by CHC, but only 20–40% of them will ever develop liver fibrosis during their lifetime. Indeed, it would be unrealistic and extremely costly to stage liver fibrosis in all affected individuals with liver biopsies. On the other hand, fibrosis stage is the most important prognostic factor and is decisive for starting antiviral therapy in most cases. Currently, liver biopsy should be considered a diagnostic bottleneck for large-scale screening of liver fibrosis in CHC. Therefore, new noninvasive tests are necessary to limit the use of biopsies. During the past two decades, scientific interest has been focused in this direction and numerous potential serum biomarkers for the assessment of liver fibrosis have been evaluated [16,33].

Serum biomarkers can be broadly divided into direct or indirect. Direct markers are fragments of liver matrix components, such as hyaluronan and products of collagen synthesis or degradation produced by hepatic stellate cells (HSCs) during the fibrotic process, and the molecules involved in regulating fibrosis. Consequently, this group of biomarkers reflects the metabolism of hepatic ECM and has a pathophysiologic rationale. However, the routine clinical use of direct markers of liver fibrosis may be limited by test availability in some hospital settings.

In contrast, the indirect markers are biochemical parameters measurable in the peripheral blood that are routinely performed in patients with CHC. They are an indirect expression of liver damage and have a statistical association with liver fibrosis stage. These include molecules synthesized, regulated or excreted by the liver, such as clotting factors, bilirubin, transaminases and albumin.

While direct markers of liver fibrosis reflect the process of fibrogenesis, indirect markers satisfy the request for a simple and easy-to-perform marker [16,33]. An overview of the most validated biomarkers in CHC and of their performance is presented in Tables 4 & 5.
 

Direct markers for liver fibrosis

The most investigated direct markers of liver fibrosis in CHC include hyaluronan, laminin, procollagen III, type IV collagen and YKL-40 (Tables 4 & 5). Hyaluronan is a glycosaminoglycan synthesized in HSCs and degraded by the liver sinusoidal cells [34] and has been extensively studied in CHC. In a study conducted in 326 patients, the AUC for significant fibrosis was 0.86 and the specificity 95%, while the AUC for cirrhosis was 0.92 and the specificity 89.4% when a cut-off level of 110 μg/L was used [34]. However, another cohort study with more than 400 cases has reported a lower AUC (0.73) for significant fibrosis [35]. In that study, cirrhosis could be excluded with a 100% negative predictive value (NPV) using a cut-off value of 50 μg/L; the AUC (0.97) was excellent as well. Similar results were reported in another study of 486 patients in which hyaluronan levels <60 μg/L excluded cirrhosis with a 99% NPV [36].

Laminin is a noncollagenous glycoprotein synthesized by HSCs. Its diagnostic value is inferior to that of hyaluronan and type IV collagen [37]. In a detailed study of 243 patients with chronic liver diseases, laminin was 77% accurate for detection of significant fibrosis in CHC [38]. Another study of 37 patients with CHC showed a slightly better performance (AUC = 0.82) [39].

YKL-40 is a glycoprotein that belongs to the chitinase family. It is strongly expressed in human cartilage and liver and preformed adequately at detecting significant fibrosis in 109 patients with CHC (AUC, 0.81; sensitivity, 78%; specificity, 81%) [40]. In the same study, however, performance in predicting cirrhosis was lower (AUC = 0.795).

Collagen molecules have also been used as markers. Type IV collagen performed well for detecting significant fibrosis (AUC = 0.83) [39]. Several studies evaluated the use of procollagen III in CHC. However, in comparative studies, procollagen III performed less well than type IV collagen and hyaluronan [34,40].

Panels of markers for liver fibrogenesis have also been proposed, as a strategy for increasing diagnostic performance. Fibrometer^® (BioLiveScale, Angers, France) is a patented test that combines patient age, platelets, prothrombin index, AST, 2-macroglobulin, hyaluronan and urea and has an AUC in the range of 0.85–0.89 for significant fibrosis and 0.91 for cirrhosis in patient with CHC [41,42]. However, large-scale independent studies confirming this good performance are still lacking.

In the initial report on a panel of markers known as Fibrospect^® (Prometheus Lab., San Diego, CA) [hyaluronan, tissue inhibitor of metalloproteinase-1 (TIMP-1) and 2-macroglobulin] indicated an AUC of 0.832 for significant fibrosis, with a positive predictive value (PPV) of 74.3% and a NPV of 75.8% [43]. Subsequent studies revealed an AUC ranging from 0.82 to 0.87 for diagnosis of significant fibrosis, with 71.8–93% sensitivity, 66–73.9% specificity and an overall test accuracy ranging from 73.1% to 80.2% [44–46]. The performance of hyaluronan, Fibrospect^® and YKL-40 in diagnosing significant fibrosis in CHC were compared, and interestingly, the AUC of Fibrospect^® was only 0.66, compared with hyaluronan, which had an AUC of 0.76 [47].

A panel known as Hepascore^® (Pathwest, University of Western Australia, Australia) (bilirubin, GT, hyaluronan, 2-macroglobulin, age and sex) performed very well in CHC, with AUC ranging from 0.79 to 0.85 for diagnosis of significant fibrosis and from 0.89 to 0.94 for cirrhosis [42,48]. Becker et al. [49] validated Hepascore^® in almost 400 patients with CHC, reporting an AUC for significant fibrosis of 0.81–0.83.

The ELF study group has proposed a panel of direct noninvasive markers that includes age, hyaluronan, type III collagen and TIMP-1. In a cohort study of more than one thousand patients with chronic liver disease, this panel detected advanced fibrosis with AUC 0.77 in patients with CHC [50]. Unfortunately, large-scale independent studies are still lacking for most of these panels.

 

Indirect markers for liver fibrosis

Indirect noninvasive markers for liver fibrosis include a growing number of serum parameters and their combinations that are generally economical and routinely measured in patients with CHC. The AST-to-ALT ratio (AAR) was one of the first indirect markers for staging liver fibrosis in patients with CHC. An increase in AAR reflects progressive impairment of liver functional (normal value <0.8), while a ratio >1 is indicative of cirrhosis [51]. In CHC, the AAR has an accuracy ranging from 60% to 83.6%, sensitivity between 31.5% and 81.3% and specificity between 55.3% and 100% in distinguishing cirrhotic from noncirrhotic patients [51,52]. The overall performance of AAR was very variable across studies, with an AUC ranging from 0.51 to 0.83. The AAR does not identify significant fibrosis, and its value can be altered by the use of alcohol [38].

The AST-to-platelet ratio index (APRI) has been proposed as another simple score. It is calculated through AST and platelet count, thus it has virtually no cost [53]. APRI can be used to confirm or exclude both significant fibrosis (cut-off 1.5 and 0.5, respectively) and cirrhosis (cut-off 1 and 2, respectively), but in both cases, there is an intermediate range of values in which the performance is not satisfactory and 30–50% of cases cannot be classified. To date, APRI is one of the most investigated noninvasive markers for liver fibrosis [16]. In the initial study by Wai et al. [53], APRI was highly accurate for predicting significant fibrosis and cirrhosis, with an AUC of 0.88 and 0.94, respectively. More recent studies, however, show variable performance in CHC, with AUC ranging between 0.69 and 0.88 for significant fibrosis and between 0.61 and 0.94 for cirrhosis [16,54]. Interestingly, a recent systematic review of the diagnostic accuracy of APRI indicated that the major strength of this index is its good performance in excluding HCV-related fibrosis [55]. The authors concluded that future studies of novel markers need to demonstrate improved accuracy and cost-effectiveness compared with this economical and widely available index. A further evolution of APRI is the Lok index, which combines platelet count, International Normalised Ratio (INR) and AAR [56]. The Lok index uses two cut-off values for the diagnosis of cirrhosis: 0.2 to rule out cirrhosis and 0.5 to confirm cirrhosis. Lok index values between 0.2 and 0.5 are considered unclassified. In a cohort study of 1141 patients with CHC, Lok et al. (56) report an AUC of 0.78–0.81 for diagnosis of cirrhosis, with 86% NPV for 0.2 cut-off and 75% PPV for 0.5 cut-off. Subsequent studies reported similar diagnostic performance but no clear advantage compared with APRI [57]. The main limit of this index is that it does not provide information about significant fibrosis. Forns et al. [58] developed a simple panel for the prediction of fibrosis based on routine clinical variables: age, GT, cholesterol levels and platelet count. Forns’ index uses two cut-off values, 4.2 to exclude significant fibrosis and 6.9 to confirm significant fibrosis. Values between 4.2 and 6.9 are considered unclassified. The index has been extensively investigated in CHC. In a detailed study including 476 patients with CHC, Forns’ index had good diagnostic performance (AUC of 0.81–0.86) for diagnosis of significant fibrosis [58]. Notably, the lower cut-off value (4.2) had 96% NPV to exclude significant fibrosis. On the other hand, the upper cut-off value (6.9) had only 66% PPV to confirm significant fibrosis. Interestingly, subsequent studies reported a slightly lower performance, with an AUC ranging from 0.76 to 0.79 [42,54]. Its main limits are a lack of information regarding cirrhosis and a significant number of unclassified cases. Another combination of simple markers, named Fib-4, is based on AST, ALT, age and platelet count [59]. Fib-4 uses two cut-off values: 1.45 to exclude significant fibrosis and 3.25 to confirm significant fibrosis. In a detailed study of 592 HCV-infected patients, Fib-4 correctly identified patients with severe fibrosis with an AUC of 0.85 [59]. Similar results have been reported by other authors [60]. This index does not provide information about cirrhosis and leaves a considerable group of patients unclassified.

 

The most validated noninvasive serum test in CHC: Fibrotest^®

Fibrotest^® (Biopredictive, Paris, France) (GT, total bilirubin, haptoglobin, apolipoprotein A1 and 2-macroglobulin – adjusted for gender and age) is the most validated liver fibrosis panel in CHC, with more than 50 studies conducted [16,61,62]. Although many of these were conducted by the group that patented the test, the total number of patients included in independent studies approaches 5,000 [41,42,54,59,63–67]. Factors causing error for Fibrotest^® include conditions that alter its single components, including Gilbert’s syndrome, haemolysis and extrahepatic cholestasis. The first report suggested that Fibrotest^® values (from 0 to 1) correlate with liver fibrosis stages according to METAVIR classification [68]. The AUC of Fibrotest^® ranges from 0.74 to 0.87 for significant fibrosis and from 0.71 to 0.87 for cirrhosis [16,54,65,68]. One of the first independent, prospective studies to compare the performance of Fibrotest^® to other noninvasive markers was from our Unit [54]. In this comparative study, the performance of Fibrotest^®, APRI and Forns’ index was tested in 190 patients with CHC. Fibrotest^® was the most accurate: AUC 0.81 for significant fibrosis and 0.71 for cirrhosis. A recent systematic review by independent investigators included nine studies, with a total of 1679 cases of CHC [69]. The authors found that Fibrotest^® has excellent diagnostic accuracy for identifying of HCV-related cirrhosis, but is less useful for earlier stages of fibrosis. They concluded that Fibrotest^® and other noninvasive tests for liver fibrosis are not ready to replace liver biopsy. Interestingly, the use of Fibrotest^® has been recommended recently in France by the Haute Autorité de Santé for first-line assessment of liver fibrosis in patients with CHC, because validation in several studies was considered adequate.

Noninvasive Assessment of Liver Fibrosis: Transient Elastography (Fibroscan^®)

1. Top of page
2. Abstract
3. Epidemiology and Natural History of Chronic Hepatitis C: the Impact of Liver Fibrosis
4. Liver Biopsy for Staging Fibrosis: the Perspective of Pathologists, Clinicians and Guidelines
5. Noninvasive Assessment of Liver Fibrosis: Serum Biomarkers
6. Noninvasive Assessment of Liver Fibrosis: Transient Elastography (Fibroscan^®)
7. Stepwise and Synchronous Combination Algorithms of Noninvasive Methods for Liver Fibrosis
8. Highlights
9. Acknowledgements and Disclosures
10. References

The measurement of liver stiffness by transient elastography is a validated method for the noninvasive assessment of liver fibrosis. Liver stiffness is measured through a device called Fibroscan^® (Echosens, Paris, France), which consists of an ultrasound transducer probe mounted on the axis of a vibrator. Vibrations of mild amplitude and low frequency are transmitted by the transducer, inducing an elastic shear wave that propagates through the underlying tissues: the stiffer the tissue, the faster the shear wave propagates [70]. Fibroscan^® examination is painless and rapid (<5 min). It is performed with the patient in the supine position, with the right arm tucked behind the head. The probe transducer is placed on the skin, between the rib bones at the level of the right lobe of the liver where a biopsy would be performed. The operator performs 10 valid acquisitions, and then Fibroscan^® software calculates the median value. The software itself determines whether each measurement is successful or not. Results are expressed in kiloPascals (kPa). Liver stiffness values range from 2.5 to 75 kPa. According to the manufacturer, the validity of a Fibroscan^® examination should be based on two parameters: the interquartile range (IQR), which reflects the variability of the validated measures, should not exceed 30% of the median value; and the success rate, which is the percentage of valid measurement, should be at least 60%[64,70]. Fibroscan^® results are interpreted on the basis of cut-off values expressed in kPa: according to various studies of patients with CHC, significant fibrosis is defined by a cut-off value ranging from 5.2 to 8.9 and cirrhosis is diagnosed by a cut-off value ranging from 10.1 to 17.6 [64,70–75]. Table 6 summarizes some of the studies assessing the performance of Fibroscan^® in CHC. In a number of studies, the accuracy of Fibroscan^® was similar to that of noninvasive serum markers for the diagnosis of significant fibrosis, sometimes with inadequate figures (AUC < 0.80). On the other hand, for the diagnosis of cirrhosis, all studies revealed an excellent AUC (>0.90). Indeed, a recent meta-analysis investigated the performance of Fibroscan^® [76]. The authors concluded that for the diagnosis of significant fibrosis, Fibroscan^® is not sufficient for use in clinical practice. Inclusion of Fibroscan^® in an algorithm with a combination of noninvasive serum markers may be considered. On the other hand, Fibroscan^® can be used in clinical practice as an excellent tool for the confirmation of cirrhosis when other parameters are inconclusive. Like Fibrotest^®, the French health authorities also consider Fibroscan^® to be validated for first-line assessment of liver fibrosis in patients with CHC.


Table 6. Performance of Fibroscan® in chronic hepatitis C in various studies 

Reference	Cut-off for ≥F2 (kPa)	Cut-off for F4 (kPa)	AUC for ≥F2	AUC for F4	Number of patients included
70	7.6	14.4	0.88	0.99	106
64	7.1	12.5	0.83	0.95	183
74	8.7	14.5	0.79	0.97	327
75	6.8	17.6	0.79	0.91	935
73	7.8	14.8	0.91	0.98	150
72	8.9	10.1	0.89	0.97	187
71	5.2	12.9	0.75	0.90	913

Limitations and risk factors for error with Fibroscan^®

Considering the widespread use of the Fibroscan^® technique, a number of studies have analysed risk factors for error and the limitations of Fibroscan^® (Table 7). Fibroscan^® can be difficult to perform in obese patients or in those with narrow intercostal space and is impossible in patients with ascites [70]. Failure rates range between 2.4% and 9.4% among studies [64,70,77]. The reproducibility of Fibroscan^® examination has been investigated in a detailed study of 200 patients by Fraquelli et al. [77]. Considering intraobserver and interobserver agreement, the authors concluded that Fibroscan^® is highly reproducible. Factors associated with inter- and intraobserver variability were BMI > 25, high-grade hepatic steatosis and mild fibrosis (F0–F1 by METAVIR). Although Fibroscan^® has excellent reproducibility, its applicability may not be as wide as that of biomarkers. In a very recent study, liver stiffness measurements were uninterpretable in nearly one in five cases (failure to obtain any measurement in 4% and unreliable results not meeting the manufacturer’s recommendations in 17%) [78]. The principal reasons were obesity and limited operator experience. A report suggested that acute viral hepatitis increases liver stiffness measured by Fibroscan^®, thus the authors recommend that the extent of necroinflammatory activity should be carefully considered in future studies, particularly in patients with absent or low-stage liver fibrosis [79]. Recently, Millonig et al. [80] reported that liver stiffness correlates significantly with bilirubin levels in patients with extrahepatic cholestasis, which causes false-positive Fibroscan^® results. Accordingly, Fibroscan^® results tend to normalize following successful biliary drainage. Another cause of false positivity has been suggested by a case report in which vascular hepatic congestion led to elevated Fibroscan^® results to a level unambiguously diagnostic for liver cirrhosis [81]. This increase in elastometry was entirely reversible upon correction of cardiovascular dysfunction. A detailed study of 254 patients with CHC showed that the ratio of IQR to ‘median value of liver stiffness’ was associated with discordance between Fibroscan^® measurement and liver biopsy, indicating overestimation of liver fibrosis [82].

Table 7. Limitations and risk factors for error with Fibroscan®

Limitations	Risk factors for error
Failure in 5% of cases (especially obese)	Acute viral hepatitis
Unreliable results in 15% of cases (obesity, ascites and limited operator experience)	Obesity
Interobserver and intraobserver variability influenced by liver steatosis, overweight and mild fibrosis stages	Extrahepatic cholestasis
Lower performance for diagnosis of significant fibrosis	Vascular hepatic congestion
Unable to discriminate between intermediate stages of fibrosis	Ratio interquartile range/median value

Stepwise and Synchronous Combination Algorithms of Noninvasive Methods for Liver Fibrosis

1. Top of page
2. Abstract
3. Epidemiology and Natural History of Chronic Hepatitis C: the Impact of Liver Fibrosis
4. Liver Biopsy for Staging Fibrosis: the Perspective of Pathologists, Clinicians and Guidelines
5. Noninvasive Assessment of Liver Fibrosis: Serum Biomarkers
6. Noninvasive Assessment of Liver Fibrosis: Transient Elastography (Fibroscan^®)
7. Stepwise and Synchronous Combination Algorithms of Noninvasive Methods for Liver Fibrosis
8. Highlights
9. Acknowledgements and Disclosures
10. References

The accuracy of noninvasive methods for liver fibrosis varies among studies and is not considered adequate to warrant substituting this method for liver biopsy or implementing it in clinical practice. Indeed, although the most recent guidelines for management of CHC mention the possible use of noninvasive methods for liver fibrosis, they do not recommend their widespread use [5,31,32]. A number of studies have suggested that the diagnostic performance of noninvasive methods, especially for the diagnosis of significant fibrosis, may be improved by combining single tests into diagnostic algorithms [62]. The goal of combination algorithms is to use noninvasive methods when they have adequate accuracy, while reserving liver biopsy only to those patients in whom such tests are sufficiently accurate. In clinical practice, combination algorithms can provide the following information (and response): (i) presence/absence of significant fibrosis (whether to administer antiviral therapy); (ii) presence/absence of liver cirrhosis (whether to commence screening for oesophageal varices and HCC); and (iii) unclassifiable (liver biopsy needed to stage hepatic fibrosis). The combination approach may avoid the diagnostic bottleneck represented by liver biopsy, and it may stimulate general practitioners and patients to perform the initial screening for liver fibrosis in CHC. With this approach, liver biopsy and noninvasive markers for liver fibrosis may have a synergistic effect towards the goal of correctly classifying fibrosis in most patients with CHC. Table 8 summarizes a number of proposed sequential or synchronous combination algorithms for noninvasive detection of liver fibrosis.

Stepwise combination algorithm: SAFE biopsy and Bourliere’s algorithm

We proposed an approach called Sequential Algorithms for Fibrosis Evaluation (SAFE) biopsy that combines APRI and Fibrotest^® in series, with the aim of increasing diagnostic accuracy and reducing the number of liver biopsies necessary to correctly stage liver fibrosis, while minimizing misclassified cases [54]. These two methods were chosen because they are the most validated biomarkers in the literature and they are widely available. The stepwise modelling of the algorithms for significant fibrosis and cirrhosis aimed to achieve >90%. In the model, APRI is used as a first-line test because it is simple and economical, while Fibrotest^® is used as a second-line test because it is more accurate but costly. Liver biopsy is reserved as a third-line test in cases where noninvasive markers do not show adequate accuracy and/or in unclassified cases (only for APRI). In the initial study on patients with CHC, SAFE biopsy algorithms had excellent performance for both significant fibrosis and cirrhosis. More recently, SAFE biopsy has been validated in a multicenter, international study that enrolled more than 2035 patients with CHC for whom APRI and Fibrotest^® were available; liver histology was used as a reference standard [83]. To date, this is the largest independent study on noninvasive biomarkers for liver fibrosis. As shown in Table 8, diagnostic performance was excellent and SAFE biopsy was able to avoid about 50% of liver biopsies for significant fibrosis and 80% for cirrhosis.

A stepwise algorithm combining Hepascore^®, a patented test, and APRI was recently proposed [48,67]. The authors reported high diagnostic accuracy (91%), while avoiding 45% of liver biopsies for diagnosing significant fibrosis. However, the main limitation of this algorithm is that Hepascore^® is not as validated in the literature as APRI, Fibrotest^® and Forns’ index. Moreover, validation studies are needed to confirm the very good accuracy reported in this initial study.

 

Synchronous combination algorithms: Bordeaux algorithm, Leroy algorithm, Fibropaca algorithm and Angers’ algorithm

Castera et al. [64] have proposed an algorithm based on the concordance between Fibrotest^® and Fibroscan^® in CHC. This algorithm results in increased accuracy, especially for the diagnosis of significant fibrosis, with respect to the single methods. A recent collaborative study compared the algorithm combining Fibroscan^® and Fibrotest^® (the Bordeaux algorithm) and SAFE biopsy in 302 patients with CHC [84]. For the diagnosis of significant fibrosis, the Bordeaux algorithm avoided more liver biopsies, but SAFE biopsy had a significantly higher performance. For the diagnosis of cirrhosis, the Bordeaux algorithm showed a significantly higher accuracy. On the other hand, the Bordeaux algorithm uses Fibrotest^® and Fibroscan^® in all patients, while SAFE biopsy uses Fibrotest^®, which has virtually no cost, in the subgroup of patients that are not well classified by APRI.

A synchronous combination approach has also been proposed for clinical use. Bourliere et al. [85] proposed a combination algorithm of APRI, Fibrotest^® and Forns’ index, which performed very well for both significant fibrosis and cirrhosis, avoiding about 50% of liver biopsies for significant fibrosis and about 80% for diagnosis of cirrhosis. Another synchronous algorithm proposed by Leroy et al. [42], based on the concordance of Fibrotest^® and APRI, had excellent performance for the diagnosis of significant fibrosis; however, relatively few liver biopsies were avoided, compared with other combination algorithms. Cales and colleagues reported that a combination of Fibrometer^® and Fibrotest^®, named Angers’ algorithm, may avoid 44.8% of liver biopsies with an overall accuracy of 95.3% [86]. The authors suggest that synchronous combination algorithms may be more effective than sequential algorithms such as SAFE biopsy. However, their synchronous algorithm combining Fibrometer^® and Fibrotest^® has some disadvantages when compared to SAFE biopsy. First, it uses two patented tests, with an average cost of €100 each, in all patients, while SAFE biopsy uses only one (Fibrotest^®) and only in about half of the cases. Another important issue is that the SAFE biopsy, Fibropaca and Bordeaux algorithms all employ widely available and validated tests. Although Fibrometer^® performed well in studies by the patenting group, its external validation is poor [41,66].

 

Combination algorithms of noninvasive methods in clinical practice: a synergistic approach aimed at reducing rather than eliminating liver biopsy

A less invasive approach to staging liver fibrosis in CHC undoubtedly implies many advantages in clinical practice, including broader first level screening, higher patient compliance and lower screening costs. Some special subgroups may benefit even more from less invasive screening, such as elderly HCV carriers and those with normal ALT levels. Indeed, a number of eminent hepatologists have recently agreed on the strategy of combining noninvasive methods to improve diagnostic accuracy for liver fibrosis.

In a recent review, Pinzani et al. [87] have proposed applying two unrelated noninvasive methods in CHC and performing liver biopsy only in a subgroup of patients. Similarly, Manning and Afdhal [33] have proposed annual measurements of biomarkers and Fibroscan^® in patients with CHC. The choice of algorithm for use in clinical practice can be based on local availability of component tests, test reliability and validation, and patient comorbidities. Importantly, the APASL has recently produced the first consensus recommendations on liver fibrosis, which also recommend the stepwise algorithm approach. The main conclusions of these guidelines are as follows: (i) noninvasive tests are useful for identifying only those patients with no fibrosis or extreme levels of fibrosis; (ii) staging of liver fibrosis in the intermediate range cannot be satisfactorily predicted by any of the available tests; and (iii) a stepwise algorithm incorporating noninvasive markers of fibrosis may reduce the number of liver biopsies by about 30% [88].

Highlights

1. Top of page
2. Abstract
3. Epidemiology and Natural History of Chronic Hepatitis C: the Impact of Liver Fibrosis
4. Liver Biopsy for Staging Fibrosis: the Perspective of Pathologists, Clinicians and Guidelines
5. Noninvasive Assessment of Liver Fibrosis: Serum Biomarkers
6. Noninvasive Assessment of Liver Fibrosis: Transient Elastography (Fibroscan^®)
7. Stepwise and Synchronous Combination Algorithms of Noninvasive Methods for Liver Fibrosis
8. Highlights
9. Acknowledgements and Disclosures
10. References

Liver fibrosis staging represents a parameter of paramount importance for the management and prognosis of patients with CHC. Currently, it is inconceivable to stage fibrosis with liver biopsy in all patients because it is an invasive procedure with a number of drawbacks. Noninvasive methods are accurate for diagnosing both significant fibrosis and cirrhosis, the main clinical end-points. Combining noninvasive methods may optimize diagnostic performance. Algorithms for this purpose could drastically reduce the number of biopsies needed to correctly classify liver fibrosis in CHC. However, available data indicate that liver biopsy cannot be completely substituted with noninvasive assessment. The most rational approach is to screen patients first with algorithms that combine the most validated noninvasive methods for liver fibrosis and then perform a liver biopsy only when the accuracy of noninvasive methods is not reliable.

Acknowledgements and Disclosures

1. Top of page
2. Abstract
3. Epidemiology and Natural History of Chronic Hepatitis C: the Impact of Liver Fibrosis
4. Liver Biopsy for Staging Fibrosis: the Perspective of Pathologists, Clinicians and Guidelines
5. Noninvasive Assessment of Liver Fibrosis: Serum Biomarkers
6. Noninvasive Assessment of Liver Fibrosis: Transient Elastography (Fibroscan^®)
7. Stepwise and Synchronous Combination Algorithms of Noninvasive Methods for Liver Fibrosis
8. Highlights
9. Acknowledgements and Disclosures
10. References

Giada Sebastiani and Alfredo Alberti contributed to the conception and first draft of the article. All authors approved the final version of the article. Alfredo Alberti is the guarantor. None of the authors of this manuscript has declared any conflict of interest within the last 3 years which may arise from being named as an author on the manuscript.

References