What is liver fibrosis?

In 1997 a group of European investigators convened by Professor Michael Arthur embarked on a project led by Professor William Rosenberg funded by Bayer Healthcare to identify serum markers of liver fibrosis. This program of research has been continuously active for over a decade and has resulted in the identification of a panel of direct markers that have been validated, CE marked, and are now being marketed in Europe by iQur Limited and Siemens.

Discovery
The original European Liver Fibrosis project recruited over 1,000 patients having investigation with a liver biopsy at 13 centres across Europe. The subjects had a wide range of CLD reflecting clinical practice. Over 40% had CHC or CHB. All patients had a fasting serum sample taken at the time of their biopsy. This was sent to a central laboratory for analysis of a panel of candidate analytes representing direct markers of fibrosis as well as a number of indirect makers. The individual sandwich ELISA test for each of the direct markers were carefully developed to a high standard of accuracy, reproducibility and repeatability. Using logistic regression and multivariate analysis, those markers that most accurately reflected the stage of liver fibrosis assigned by a central pathologist were identified in a “training” cohort of 521 patients and then confirmed in a “validation” cohort of 400. This revealed that the combination of HA, P3NP and TIMP-1 combined in an algorithm, originally incorporating Age, could be used to determine the severity of liver fibrosis with good accuracy.14 Subsequently, the team have established that Age could be omitted from the algorithm to generate the Enhanced Liver Fibrosis test or ELF Test.


External Validation
Subsequent to the original study, investigators around the world have conducted validation studies in independent populations to further assess the performance of the markers. Studies in CHC, NAFLD and PBC have all confirmed that the markers accurately reflect the severity of fibrosis as staged on liver biopsy15-19. In these studies the area under the receiver operator characteristic curve (AUROC) ranges around 0.8. This level of performance is considered to be a threshold for acceptance in clinical practice.

 

Longitudinal Follow-up
However, the investigators have been limited in their ability to assess the performance of the markers by the errors inherent in biopsy staging. In an attempt to overcome this “glass ceiling,” the ELF team have begun to investigate the ability of the serum markers to predict long-term clinical outcomes of CLD including the development of portal hypertension, decompensation of CLD, the development of hepatocellular cancer, liver transplantation and death from liver disease, as well as all cause mortality. Whilst not yet complete, interim analysis of the 7-year follow-up of over 500 patients has shown that the ELF markers are at least as good, if not better than liver histology at predicting clinical outcome. Similar work has been conducted in a cohort of patients with PBC.20

 

Advantages Over Single Markers
Systematic reviews of the literature have consistently shown that single markers of fibrosis can detect cirrhosis with some degree of accuracy. However, single-marker tests are less accurate than panels of markers in detecting lesser degrees of fibrosis.21,22 While the detection of cirrhosis is important, clinical judgement can often identify patients who are likely to have end-stage CLD. It is of greater importance to be able to detect patients with mild or moderate fibrosis, which is usually asymptomatic, in order to be able to intervene with lifestyle modification or treatment before the liver becomes irreparably damaged. It is in the screening and management of patients with CLD that the ELF markers have great potential.

 

Advantages Compared to Indirect Markers
The careful and extensive validation program employed by the ELF development team has taken years to come to fruition. A number of algorithms derived employing indirect markers that are available in general clinical chemistry laboratories as routine analytes. While the performance of many of these algorithms, such as Fibrotest/Fibrosure, APRI, Forns Index and Hepascore is good, the majority are unreliable in patients undergoing treatment for viral hepatitis (where aminotransferases are altered due to therapy) or when bilirubin levels may be elevated due to haemolysis (such as when ribavirin is administered) or cholestasis.23-29

 

Use in Clinical Practice and Impact on Patient Management
The coming year will see the introduction of the ELF test into clinical practice, and its impact in the management of patients will begin to be appreciated. Doctors in primary care are flooded with patients with obesity and hazardous drinking all of whom could be at risk of CLD. The ability to use a simple blood test to accurately identify those with significant liver disease will greatly aid triage and the appropriate targeting of interventions including weight loss, exercise and drug interventions. In secondary care, the ELF test will be of great use in the early evaluation of patients with a wide range of CLD. It will not replace liver biopsy in the detailed assessment of liver inflammation, architectural damage of pathology. However it can be used to prioritise patients for investigation, to determine the severity of fibrosis in patients unwilling or unable to undergo biopsy, and to complement biopsy given the inaccuracies that surround histological staging arising from sampling error and observer error. Once a diagnosis of CLD has been made, most patients will undergo some form of treatment and long-term follow-up. Further repeated biopsies are not acceptable in the vast majority of patients, but further knowledge of the severity of fibrosis, its progression or regression would be highly valuable to both the patient and the doctor. The ELF test will make this information accessible through a simple blood test that could be repeated at frequent intervals.
 

Figure 1 AUROC curve of ELF predicting stages 0,1 Vs 2-6 in NAFLD cohort (none or mild fibrosis from significant fibrosis Ishak classification)

Future Developments
While the introduction of the ELF test represents a major advance in the diagnostic armoury available for the clinical screening and management of CLD, further challenges remain. The ELF markers have been developed for a range of CLD. In specific diseases, other combinations of markers may perform better. So far, the development of algorithms such as ELF has relied on the testing of candidate markers. New discovery approaches such as metabonomics, proteomics and transcriptomics that make no assumptions about the relevance of specific molecules to disease processes may uncover new markers that complement or enhance the existing panels. Imaging of the liver using a variety of modalities, including ultrasound, elastography and magnetic resonance imaging, has advanced in parallel with minimally-invasive marker testing.30,31 The integration of these complementary modalities should further increase the diagnostic power available to clinicians. Determining the optimal combinations and suitability for specific CLD will be challenging.

The discovery of the ELF markers represents the dawn of a new era of early detection of treatable liver disease and the effective monitoring of CLD to evaluate the impact of interventions and the course of disease.

Disadvantages of Liver Biopsy
• Morbidity & mortality
• Sampling error
• Ordinal categorical variable to assess continuous biological process
• Costly & time consuming: requires hospital visit and expert
• Inter-observer variability: kappa scores 0.4-0.6
• Error rate: up to 25-35% of ≥1 stage
• Less experienced pathologists perform less well than “expert”
• Cannot perform repeat biopsy at short intervals to assess liver disease or effects of therapeutics due to the hazards

Liver Fibrosis
Overview Page
What is liver fibrosis?
Minimally-Invasive markers of liver fibrosis

Part of the article “Biomarkers of liver disease: the enhanced liver fibrosis test”

As published in CLI October 2007
www.cli-online.com

The authors
William Rosenberg MD, D.Phil
Professor of Hepatology,
The Liver Group,
University of Southampton,
Southampton, UK

Julie Parkes MD
Public Health Science & Medical Statistics,
University of Southampton,
Southampton, UK

References
14. Rosenberg WM, Voelker M, Thiel R, Becka M, Burt A, Schuppan D et al. Serum markers detect the presence of liver fibrosis: a cohort study. Gastroenterology 2004; 127(6):1704-1713.

15. Parkes J, Bialek SR,Bell BP ,Terrault N, Zaman A, Sofair A, Guha IN, Cross R, Harris S, Roderick PJ, Rosenberg WMC. European Liver fibrosis markers accurately distinguish fibrosis severity in a cohort of patients with Chronic Hepatitis C; an external validation study. Hepatology 44[Suppl 1]. 2006.

16. Parkes J, Cross R, Harris S, Ryder S, Irving W, Zaitoun A. The Trent Hepatitis C Research Group, Rosenberg WMC. European liver fibrosis markers accurately distinguish fibrosis severity in Chronic Hepatitis C. Journal of Hepatology. 40 [Suppl 1]. 2005.

17. Guha IN, Aithal GP, Parkes J, Roderick PJ, Harris S, Cross R, Kaye P, Ryder SD, Rosenberg, WM. European liver fibrosis markers in Non Alcoholic Fatty Liver Disease (NAFLD); an external validation study. Hepatology 44 Suppl 1. 2006.

18. Parks J, Mayo M, Cross R, Harris S, Roderick PJ, Coombs B, Huet B. The PUMPS Investigators and W.M. Rosenberg . European liver fibrosis markers accurately distinguish fibrosis severity in primary biliary cirrhosis; an external validation study. Hepatology 44 Suppl 1. 2006.

19. Non-invasive markers of fibrosis in non-alcoholic fatty liver disease: validating the European Liver Fibrosis panel and exploring simple markers. Hepatology 2007 (in press).

20. Mayo M., Parkes J, Huet B, Combes B, Mills S, Markin R, et al. Serum fibrosis markers predict future clinical decompensation in primary biliary cirrhosis bettter than liver biopsy, bilirubin, or Mayo risk score. Hepatology 44 Suppl 1. 2006.

21. Guha IN, Parkes J, Roderick PR, Harris S, Rosenberg WM. Non-invasive markers associated with liver fibrosis in non-alcoholic fatty liver disease 2. GUT 2006; 55(11):1650-1660.

22. Parkes J, Guha IN, Roderick P, Rosenberg W. Performance of serum marker panels for liver fibrosis in chronic hepatitis C. Journal of Hepatology 2006; 44:462-474.

23. Imbert-Bismut F, Ratziu V, Pieroni L, Charlotte F, Benhamou Y, Poynard T. Biochemical markers of liver fibrosis in patients with hepatitis C virus infection: a prospective study. Lancet 2001; 357(9262):1069-1075.

24. Ratziu V, Massard J, Charlotte F, Messous D, Imbert-Bismut F, Bonyhay L et al. Diagnostic value of biochemical markers (Fibro Test-FibroSURE) for the prediction of liver fibrosis in patients with non-alcholic fatty liver disease. BMC Gastroenterology 2006; 6(6):1-13.

25. Wai CT, Greenson JK, Fontana RJ, Kalbfleisch JD, Marrero JA, Conjeevaram HS et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C.. Hepatology 2003; 38(2):518-526.

26. Forns X, Ampurdanes S, Llovet JM, Aponte J, Quinto L, Martinez-Bauer E et al. Identification of chronic hepatitis C patients without hepatic fibrosis by a simple predictive model.. Hepatology 2002; 36(4 Pt 1):986-992.

27. Patel K, Muir AJ, McHutchison JG. Validation of a simple predictive model for the identification of mild hepatic fibrosis in chronic hepatitis C patients.. Hepatology 2003; 37(5):1222-1223.

28. Hepascore: An accurate validated predictor of liver fibrosis in chronic hepatitis C infection. Clinical Chemistry 51 (10) 1-7.

29. Cales P, Oberti F, Michalak S, Hubert-Fouchard I, Rousselet MC, Konate A et al. A novel panel of blood markers to assess the degree of liver fibrosis 10. Hepatology 2005; 42(6):1373-1381.

30. Ganne-Carríe N, Ziol M, Ledinghen V, Douvin C, Marcellin P, Castera L et al. Accuracy of liver stiffness measurement for the diagnosis of cirrhosis in patients with chronic liver disease. Hepatology 2006; 44:1511-1517.

31. Foucher J,Chanteloup E, Vergniol J, Castera L,Le Bail B, Adhoute X, Bertet J, Couzigou P, de Ledinghen V. Diagnosis of cirrhosis by transient elastography (FibroScan): a prospective study. GUT 2006; 55(3):403-408.

 

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