Showing posts with label noninvasive tests for fibrosis. Show all posts
Showing posts with label noninvasive tests for fibrosis. Show all posts

Tuesday, April 4, 2017

Noninvasive tests for fibrosis - Editorial: combining elastography with blood test for fibrosis assessment in chronic hepatitis C

Invited Editorial

Editorial: combining elastography with blood test for fibrosis assessment in chronic hepatitis C Authors H. D. Trivedi, M. Lai

First published: 3 April 2017
DOI: 10.1111/apt.14011

Editorial: combining elastography with blood test for brosis assessment in chronic hepatitis C 
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The imprecision and invasive nature of the liver biopsy has led to the development of several validated non-invasive fibrosis markers, which have decreased the need for liver biopsy in chronic hepatitis C patients. In the realm of highly effective oral therapies, management is affected by the presence or absence of severe fibrosis, which would warrant surveillance screening for hepatocellular carcinoma and oesophageal varices. Vibration controlled transient elastography (VCTE) is a validated non-invasive modality that is widely used with an AUROC of 0.90 for detecting advanced fibrosis.[1] The limitation of VCTE is its potential overestimation of fibrosis, particularly in those with obesity or increased necroinflammatory activity.[2, 3] In contrast, serologic markers have historically led to underestimation of fibrosis levels.[4, 5] Combination of VCTE with other markers have shown favorable results[1] and have been proposed by national guidelines.[6, 7]

Calés et al. evaluated the performance of a serologic test (FibroMeterV2G) with VCTE (Fibroscan) as two separate constitutive tests, as well as a single combined test (FibroMeterVCTE2G), for the detection of severe fibrosis in hepatitis C patients.[8] They found increased accuracy with the combination test, compared to individual tests alone, especially when there was concordance between the tests, validating the recommendation of using combined tests. The authors conclude that if the constitutive tests are concordant, then the diagnosis can be accepted, and if discordant, FibroMeterVCTE2G should be pursued. However, in cases (3.2%) of strict discordance, the FibroMeterVCTE2G is unreliable for detecting severe fibrosis (accuracy of 44%) and requires alternative measures for fibrosis (i.e. liver biopsy). The authors projected a reduction in the liver biopsy rates from 28% to 1% with the use of this diagnostic algorithm.

This study validates EASL-ALEH and AASLD-IDSA recommendations to combine biomarkers with VCTE and shows the combined test to have improved accuracy, especially when there is concordance, eliminating the need for an invasive liver biopsy in the majority of patients. However, the claim that the liver biopsy rate is reduced from 28% to 1% should be taken with some caution as the authors did not provide the invalid and failure rate of VCTE, one of major components in their combination test. Although VCTE has revolutionised the non-invasive measurement of fibrosis, unreliable results and failure to obtain results have been reported in 3% and 16% of cases, respectively, mostly due to obesity and operator experience.[3] It would be important to see how the combined test performs in the United States population, which has a higher mean body mass index than this study cohort from France. While the accuracy of the FibroMeterVCTE2G is excellent, it still leaves 8% of patients misclassified, making it important that the clinician still thoroughly evaluates the patient's clinical, radiologic and laboratory data. The role of this combination test in monitoring the progression or regression of fibrosis, as well as its applicability to other chronic liver disease is an important avenue for research.

Wednesday, March 1, 2017

Developing a new algorithm to diagnose advanced liver fibrosis: A lift or a nudge in the right direction?

Developing a new algorithm to diagnose advanced liver fibrosis: A lift or a nudge in the right direction?
Leon A. Adams, Richard K. Sterlinga

Publication stage: In Press Accepted Manuscript
Published online: February 17, 2017

View Full Text Article Online or  Download PDF (328 KB)

Accurate identification of liver disease severity and fibrosis stage is paramount in the management of those with chronic liver disease. In the past, this was often done by liver biopsy. However, due to it’s invasiveness and risks of bleeding, pain, and sampling error, non-invasive assessment of liver disease has gained increasing attention over the last decade. Non-invasive tests can be divided into serum tests and imaging tests. Although standard “liver function” tests, such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are inaccurate when used alone, several models have been developed that use them in combination with other markers of advanced liver disease, such as platelet count. Of those models that utilize routine, readily available tests, the AST-Platelet Ratio Index (APRI) and FIB-4 have gained the most attention[[1], [2]]. Both APRI and FIB-4 have high specificity and negative predictive value’s (NPV) for advanced fibrosis or cirrhosis[[1], [2]]. However, both have only moderate positive predictive values (PPV) and many patients fall in between the upper and lower cut-offs giving an indeterminate result. More complex serum panels have been developed including Fibrosure/Fibrotest[3] and Fibrometer[4], which may offer additional accuracy compared to APRI or FIB-4 but have extra cost. In addition, the alternative non-invasive imaging tests, such as vibration controlled transient elastrography (VCTE)[5] or magnetic resonance elastrography (MRE)[6] are generally only available in specialized centers, leaving many with chronic liver disease inadequately assessed. Because one serum or imaging test alone does not provide 100% sensitivity and specificity, there has been an attempt to combine tests, either performed together or sequentially[[4], [7], [8], [9], [10], [11], [12], [13], [14], [15]]. Thus, the rationale for the study by Boursier and colleagues published in the current issue of the Journal of Hepatology was to develop such a test as part of an algorithm to more accurately and easily identify advanced liver disease[16].

To that goal, the study aimed to develop and validate a stepwise algorithm that could be easily used by all providers to facilitate detection of advanced fibrosis in those with chronic liver disease. The cohort studied consisted of 3754 subjects with chronic liver disease who had undergone liver biopsy and VCTE, who were divided 2:1 into a derivation and validation set. They initially evaluated the utility of both APRI and FIB-4 as an initial screening test. Because FIB-4 outperformed APRI (higher sensitivity), they used it to compare to their new “first line test” which included age, gender, gamma-GT (GGT), AST, platelet count, and prothrombin time (PT). Each of these variables was assigned a number (0-4 depending on the variable and cut off) in the “easy LIver Fibrosis Test (eLIFT), with a score of at least 8 providing 80% sensitivity for advanced fibrosis. In a core group of 1946 subjects, they found that while FIB-4 and eLIFT had similar sensitivity (77-78%), eLIFT had higher specificity (91%), NPV (79%), and PPV (91%) with fewer false positive results than FIB-4, especially in those over age 60. They concluded that eLIFT was better than FIB-4 as a general screening test.

Subsequently, they determined what should be the “second line test” by comparing APRI, FIB-4, liver stiffness by VCTE, and Fibrometer (with or without VCTE) and found that FibrometerVCTE had the highest number of biopsies avoided (81%). A new algorithm was proposed with eLIFT as the initial screening test followed by FibrometerVCTE in those with an eLIFT score ≥ 8 for confirmation. Using this two-step strategy, 46% of patients (33% with eLIFT score <8 and 14% with eLIFT ≥ 8 but FibrometerVCTE <0.384) would not need to see a specialist thus avoiding liver biopsy or additional testing. This two-step approach found that 34% had advanced fibrosis (eLIFT >8 and FibrometerVCTE ≥ 0.715) leaving only 19% with an indeterminate result that might go on to liver biopsy. This combined strategy worked better than FIB-4 or FibrometerVCTE alone in identifying those with advanced fibrosis. Finally, they followed 1275 patients longitudinally (median follow-up 2.9 years) to determine if the eLIFT-FibrometerVCTE strategy could predict liver-related and all-cause mortality. Although eLIFT and FIB-4 had similar performance for all-cause mortality, FibrometerVCTE had the best performance for predicting liver-related mortality.

This study has several strengths; the large patient population enabled comparison of several methods of fibrosis assessment and detected relatively small differences in test performance. Furthermore, the proposed algorithm was accurate across a wide spectrum liver disease increasing applicability and attractiveness to implement in the community. In addition, eLIFT and FibrometerVCTE were demonstrated to be prognostic of liver related outcomes, re-enforcing the appropriateness to use them as tests to guide patient management. Nevertheless, the eLIFT test utilizes some serum tests that may not be routinely ordered by community physicians, such as prothrombin time, which in itself may suffer inter-laboratory variability. In addition, the use of AST and GGT in the eLIFT algorithm, resulted in a reduction in specificity in the setting of alcoholic liver disease. Nevertheless, this was resolved when combined with the FibrometerVCTE. The FibrometerVCTE was developed using the M probe, which provides higher values than the XL probe and has a lower success rate in obesity, limiting applicability in this population. For these reasons, independent validation will be important to confirm the accuracy of the eLIFT-FMVCTE algorithm. Lastly, the study population was not identified from the general population, and so caution should be exercised in trying to extrapolate this algorithm to screen for fibrosis in the general population.

Combining non-invasive algorithms is an attractive way of increasing diagnostic accuracy for liver fibrosis, however uncertainty exists on the best way to combine tests and which tests to use. For example, tests may be used concurrently with discordant results leading to a diagnostic biopsy. Alternatively two modalities may be combined into one diagnostic formula, or thirdly, tests may be used sequentially, with the first being a screening test and the second used following an indeterminate screen or as a confirmatory test for a positive screening test. The approach by Boursier utilizes a combination of firstly, a two-step approach using eLIFT as a screening test and FibrometerVCTE as the confirmatory test, which in itself combines VCTE and a serum test[16]. Thus, this approach requires three non-invasive tests to be performed, adding to the complexity and cost.

In addition to the current study, a range of alternative combination strategies have been examined (outlined in Table 1), primarily among patients with chronic hepatitis C (CHC)[[7], [8], [9], [14], [15], [16], [17], [18], [19]]. These have included the SAFE algorithm which sequentially combines APRI and Fibrotest[8], sequential APRI and Hepascore[13], concurrent Fibrotest and Fibroscan[14] and combining Fibrometer and Fibroscan into one diagnostic model[15]. In non-alcoholic fatty liver disease, concurrent Fibroscan and NAFLD Fibrosis Score and sequential FIB4 and BARD have been proposed[[7], [12]], whilst in chronic hepatitis B, a combination of concurrent ALT with Fibroscan followed by the Enhanced Liver Fibrosis Score or the Forns index has been examined[[9], [10]] Overall, these studies demonstrate an increase in diagnostic accuracy and higher predictive values with multiple non-invasive tests compared with single tests, particularly for the determination of moderate degrees of fibrosis (e.g. METAVIR F2+).

Table 1Cross-sectional studies (n>200) examining the accuracy of combination non-invasive fibrosis tests in the prediction of advanced fibrosis or cirrhosis.
AuthornLiver DiseaseOutcomeAlgorithmsDiagnostic AccuracySensitivitySpecificityNPVPPV
Boursier 2009332MixedCirrhosisAPRI → Fibrotest80%44%93%81%71%
Fibrotest + Fibroscan94%89%96%96%90%
Fibrometer / Fibroscan91%75%97%91%91%
Sebastiani 20092035HCVCirrhosisAPRI → Fibrotest92%90%93%56%99%
Castera 2010302HCVCirrhosisAPRI → Fibrotest89%86%90%94%78%
Fibrotest + Fibroscan96%89%98%96%95%
Sebastiani 20121013HCVCirrhosisAPRI → Fibrotest91%82%92%98%57%
APRI + Fibrotest.94%73%97%96%73%
Boursier 20121785HCVCirrhosisAPRI → Fibrotest89%61%93%95%56%
Fibrotest + Fibroscan94%86%95%98%76%
Fibrometer / Fibroscan87%----
Crisan 2012446HCVAdvanced fibrosisAPRI + FIB4 + Fibrometer89%84%91%94%76%
APRI + FIB4 + Fibrotest85%88%83%95%68%
APRI + FIB4 + Fibroscan86%62%100%59%100%
Wong 2014323HBVAdvanced fibrosisFibroscan + ELF-65-66%86-92%79-80%76-85%
Petta 2014321NAFLDAdvanced fibrosisFibroscan + FIB4-42-85%97-100%91-98%71-100%
Fibroscan + NFS-25-83%100%93-99%100%
FIB4 + NFS-14-35%100%88-91%100%
Boursier 20171946MixedAdvanced fibrosiseLIFT → Fibrometer/Fibroscan-78%91%79%91%

Fibroscan available in 729 patients. Mixed liver disease included patients with liver disease realted to alcohol, hepatitis c virus (HCV), hepatitis B virus (HBV), non-alcoholic fatty liver disease (NAFLD) and other causes. “→” indicates sequentially performed tests, “+” indicates concurrent tests, “/” indicates combined tests into one formula, ELF=Enhanced Liver Fibrosis score, APRI= AST to platelet ratio index.

Determining the optimal combination of tests is difficult as studies have been performed in different diseases, used different cut-offs and aimed to predict different stages of fibrosis. Notably, the only independent prospective multi-center evaluation of a range of non-invasive fibrosis tests including Fibrotest, Fibrometer, Hepascore, APRI and Fibroscan, found no difference in percentage of well-classified patients or biopsies avoided between synchronous combinations of the above tests, for the prediction of cirrhosis in patients with CHC[11]. However, other studies have found the combination of Fibroscan and a serum test (Fibrotest) is more accurate than the combination of two sequential serum tests incorporated into the SAFE algorithm (APRI and Fibrotest)[[14], [15]]. Using a serum based test in combination with elastography is an appealing strategy as they assess different pathophysiological properties associated with fibrosis, and thus this is currently suggested by EASL Guidelines[20]. However, the requirement for a concurrent Fibroscan limits the applicability of this strategy into the community. The ideal algorithm to screen the general population should be a combination of an inexpensive, accessible and highly sensitive test to minimize missed diagnoses, followed by a highly specific test to confirm the diagnosis. To this end, the eLIFT cut-off of eight was chosen to aim for 80% sensitivity, which translated to up to one third of patients with advanced fibrosis being missed but only 3-4% of cirrhotics. One option to minimize false negative cases would be to lower the eLIFT threshold, however this would be at the cost of a greater false positive rate and needless referral for further assessment. Other potential screening tests include FIB4 and APRI in combination given their wide-spread availability and low cost followed by elastrography in those with discordant or increased results above the lower threshold.

Because one test is often inadequate to answer both questions: which patient has minimal liver disease (F0-1) and secondly, which patient has advanced fibrosis (F3-4), it is clear that non-invasive fibrosis markers should not be used in isolation but incorporated into clinical acumen, imaging and other biochemical tests. Overall accuracy and predictive values are improved if two non-invasive fibrosis assessments are used. A sensitive, easy to perform screening test is required for community practitioners (e.g. serum test). More expensive and accurate confirmatory tests such as complex serum models or elastography, can then be done in the hepatology clinic. Currently, further independent comparisons are required to determine the optimal algorithms, however this will also be influenced by factors such including expense and availability. Of equal importance however, is the need to change the paradigm of liver disease assessment in the community to include fibrosis algorithms rather than relying on standard liver enzymes. Until then the current study is a nudge in the right direction.

Tuesday, April 12, 2016

European Consortium Seeks to Replace Liver Biopsies with Painless MRI Scans

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FibroScan® New Generation Extends Access to Non-invasive Liver Diagnosis

European Consortium Seeks to Replace Liver Biopsies with Painless MRI Scans

OXFORD, England, April 12, 2016 /PRNewswire/ --

Thousands of patients in Europe with liver disease could be saved from having painful and expensive needle biopsies in the future, after a multi-million Euro grant was awarded to a consortium of hospitals to use a faster and safer MRI called LiverMultiScan, developed by Perspectum Diagnostics.
Fuelled by rising levels of obesity, Non-Alcoholic Fatty Liver Disease (NAFLD) affects up to a quarter of the European population and left untreated can lead to cirrhosis and liver failure. The historic method of diagnosing NAFLD is by liver biopsy, which in addition to being costly and painful, samples only a tiny fraction (1/50,000th) of the liver. LiverMultiScan, which is being showcased at the forthcoming International Liver Congress in Barcelona (April 13 - 17th) is a non-invasive alternative which accurately measures liver fat and other metrics, and can help doctors detect early disease.

"A cost-effective tool for non-invasive liver tissue characterisation would be a major step forward in the treatment of patients with liver diseases such as non-alcoholic fatty liver disease," explains Dr. Minneke Coenraad from Leiden University Medical Centre, one of the investigators leading the study.

Supported by the Horizon 2020 SME instrument, the RADiCAL trial (Rapid Assessment and Diagnosis in Chronic Adult Liver disease) will compare the cost of patient care using liver biopsy with that of using LiverMultiScan. 2,000 patients suspected of a diagnosis of NAFLD will be recruited to centres in Germany, the Netherlands and Portugal. Each patient will be randomised to either follow the current diagnostic pathway with biopsy, or to have early access to state-of-the-art MRI with LiverMultiScan, to determine the presence and extent of disease. At the end of the trial, the cost-effectiveness and patient-reported outcome measures of the two diagnostic pathways will be compared.

Dr Rajarshi Banerjee, CEO of Perspectum Diagnostics, says "We are delighted that the H2020 funding body recognises the enormous potential for LiverMultiScan to replace unnecessary biopsies. There is a real opportunity here, not only to make significant economic savings at a time when all health services are under pressure, but also to reduce the number of patients having to undergo what can be a stressful and painful procedure."

Doctors and patients can learn more about LiverMultiScan and the RADiCAL MRI technology by visiting Booth 2100 at the International Liver Congress in Barcelona April 13-17th, or visiting

About LiverMultiScan

LiverMultiscan was introduced in Europe and the U.S. as a research device in 2014. It is now installed in leading medical institutions on three continents. The technology offers a quantitative liver assessment in a safe, non-invasive 15-minute MRI scan. LiverMultiScan is manufactured by Mirada Medical, and has CE-marking and FDA-clearance.

About Perspectum Diagnostics

Perspectum Diagnostics is a medical imaging company founded by scientists and physicians from the University of Oxford. It has pioneered the use of quantitative magnetic resonance imaging to accurately detect and measure biomarkers of liver disease.

Perspectum Diagnostics
Oxford Centre for Innovation |New Road | Oxford OX1 1BY
Tel: +44-(0)1865-261457

Saturday, April 9, 2016

Promising new blood test is first of its kind to detect liver scarring

Promising new blood test is first of its kind to detect liver scarring
Team develop a DNA-based test that determines the degree of fibrosis in the liver -- this could be a replacement for a liver biopsy

Newcastle University

Newcastle scientists and medics have developed a new type of genetic blood test that diagnoses scarring in the liver - even before someone may feel ill.

It is the first time an epigenetic signature in blood has been discovered which is diagnostic of the severity of fibrosis for people with Non-alcoholic Fatty Liver Disease (NAFLD).

NAFLD, caused by being overweight or having diabetes, affects one in three people in the UK and may progress to cirrhosis and liver failure, requiring a transplant.

Scientific breakthrough

Publishing in the academic journal GUT, the Newcastle team describe the proof of principle research in which they measure specific epigenetic markers to stratify NAFLD patients into mild or severe liver scarring, known as fibrosis.

Dr Quentin Anstee, Clinical Senior Lecturer at Newcastle University, Consultant Hepatologist within the Newcastle Hospitals and joint senior author explained what it could mean for patients: "This scientific breakthrough has great promise because the majority of patients show no symptoms.

"Routine blood tests can't detect scarring of the liver and even more advanced non-invasive tests can really only detect scarring at a late stage when it is nearing cirrhosis. We currently have to rely on liver biopsy to measure fibrosis at its early stages - by examining a piece of the liver under the microscope.

"We know that the presence of even mild fibrosis of the liver predicts a worse long-term outcome for patients with NAFLD and so it's important to be able to detect liver scarring at an early stage."

Providing a scale of damage

In this first stage of research the team developed the blood analysis in 26 patients with NAFLD. The test detects chemical changes on tiny amounts of "cell-free" DNA that are released into the blood when liver cells are injured. Changes in DNA methylation at genes like PPARγ that controls scar formation are then used to stratify patients by fibrosis severity.

Senior author Dr Jelena Mann of Newcastle University's Institute for Cellular Medicine added: "This is the first time that a DNA methylation 'signature' from the blood has been shown to match the severity of a liver disease.

"It opens up the possibility of an improved blood test for liver fibrosis in the future."

Dr Timothy Hardy is a hepatology registrar within Newcastle Hospitals and a Medical Research Council-funded clinical research training fellow at the University. He conducted the research as part of his PhD project and said: "We are now working on confirming these findings in a larger group of patients.

"If we are able to accurately tell the extent of a person's liver damage with a blood test, and even track the scarring as it gets better or worse, it could provide reassurance for patients, save NHS resources and avoid patients having to undergo a liver biopsy."

This research is part of Newcastle University's response to the challenges and opportunities presented by an ageing population. Newcastle University is a world leader in the field at its Campus for Ageing and Vitality, the location for a new £40m National Centre for Ageing Science and Innovation (NASI). This research was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre.

The research was made possible through Newcastle Academic Health Partners, a collaboration involving Newcastle Upon Tyne Hospitals NHS Foundation Trust, Northumberland, Tyne and Wear NHS Foundation Trust and Newcastle University. This partnership harnesses world-class expertise to ensure patients benefit sooner from new treatments, diagnostics and prevention strategies.



Plasma DNA Methylation: A Potential Biomarker for Stratification of Liver Fibrosis in Non Alcoholic Fatty Liver Disease. Timothy Hardy, Mujdat Zeybel, Christopher P. Day, Christian Dipper, Steven Masson, Stuart McPherson, Elsbeth Henderson, Dina Tiniakos, Steve White, Jeremy French, Derek A. Mann, Quentin M. Anstee and Jelena Mann.

Gut: DOI 10.1136/gutjnl-2016-311526

4 stages of Non-alcoholic Fatty Liver Disease

NAFLD is very common in patients who are overweight, obese or have type 2 diabetes. It develops in four stages. Most people will only ever develop the first stage, usually without realising it.

In a small number of cases it can progress and eventually lead to liver damage, cirrhosis and liver cancer if not detected and managed.

The main stages of NAFLD are:

1. Steatosis ("fatty liver") - a build-up of fat in the liver cells that is often picked up as an incidental finding during tests carried out for another reason
2. Non-alcoholic steatohepatitis (NASH) - a more serious form of NAFLD, where the liver has become inflamed; this is estimated to affect up to 5% of the UK population
3. Fibrosis - where persistent inflammation causes scar tissue to form in the liver, but the liver is still able to function normally
4. Cirrhosis - the most severe stage, occurring after years of inflammation, where the liver shrinks and becomes scarred and lumpy; this damage is permanent and can lead to liver failure (where the liver stops working properly) and liver cancer

It can take years for fibrosis or cirrhosis to develop and the presence of this scarring predicts those people with the worse prognosis. It's important to make lifestyle changes to prevent the disease from getting worse.