Karaciğer fibrozu nedir?

What is liver fibrosis?
Liver fibrosis is the scarring process that represents the liver’s response to injury. In the same way as skin and other organs heal wounds through deposition of collagen and other matrix constituents so the liver repairs injury through the deposition of new collagen. Over time this process can result in cirrhosis of the liver, in which the architectural organization of the functional units of the liver becomes so disrupted that blood flow through the liver and liver function become disrupted. Once cirrhosis has developed, the serious complications of liver disease may occur, including portal hypertension, liver failure and liver cancer. The risk of liver cancer is greatly increased once cirrhosis develops, and cirrhosis should be considered to be a pre-malignant condition. Cirrhosis and liver cancer are now among the top ten causes of death worldwide, and in many developed countries liver disease is now one of the top 5 causes of death in middle-age.1,2

The biology of liver fibrosis
The main liver cells that produce matrix are Hepatic Stellate Cells (HSC). This resident cell population exist in a resting phenotype as the body’s major store of vitamin A. However on activation they transform to adopt a myofibroblast phenotype capable of secreting collagen. This fibrous tissue can then be remodelled through digestion of matrix by matrix metaloproteinases (MMPs). In turn the digestion of matrix is checked through the inhibition of MMPs by tissue inhibitors of matrixmetaloproteinases (TIMPs) of which TIMP-1 is of major importance. Liver fibrosis, previously thought to be merely the accumulation of scar tissue, is now recognised to be a dynamic process that can progress or regress over periods as short as months.3

What are the causes of liver fibrosis?
All chronic liver diseases (CLD) can lead to liver fibrosis. Over many years the principle causes of CLD have been chronic viral hepatitis B (CHB) and alcoholic liver disease (ALD). While rates of alcoholism and ALD are falling in many countries, hazardous drinking amongst young people is resulting in alarming rates of ALD in several northern European countries.4,5 Over the last few decades two other diseases have emerged to make a major contribution to the burden of CLD. Chronic hepatitis C (CHC) and non-alcoholic fatty liver disease (NAFLD) are recognised to have already had a major impact on CLD incidence. Hepatitis C virus (HCV) is transmitted in blood and blood products through unsafe injection practices and the therapeutic use of infected blood products. It is thought that the world prevalence of CHC is nearly 200 million people.6,7 In the developed world with rapidly increasing rates of obesity, NAFLD is considered to represent a major cause of significant fibrosis. Although it appears that only a minority of patients with NAFLD (maybe 20%) develop significant fibrosis, due to the vast prevalence of the at-risk overweight population, NAFLD may give rise to an epidemic of liver fibrosis.8,9

Liver Fibrosis
Overview Page
Minimally-invasive markers of liver fibrosis
The ELF Program

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
1. Griffiths C, Rooney C, Brock A. Leading causes of death in England and Wales - how should we group causes? Health Statistics Quarterly 28, 6-17. 2005.
2. Bosetti C, Levi F, Zatonski WA, Negri E, LaVecchia C. Worldwide mortality from cirrhosis: An update to 2002. Journal of Hepatology 46(5), 827-839. 1-5-2007.
3. Friedman SL. Liver fibrosis - from bench to bedside. J Hepatol 2003; 38 Suppl 1:S38-S53.
4. Leon DA, McCambridge J. Liver cirrhosis mortality rates in Britain, 1950 to 2002 26. Lancet 2006; 367(9511):645.
5. Leon DA, Saburova L, Tomkins S, Andreev E, Kiryanov N, McKee M et al. Hazardous alcohol drinking and premature mortality in Russia: a population based case-control study Lancet 2007; 369(9578):2001-2009.
6. World Health Organisation. Hepatitis C. WHO Fact Sheet 2000 (164):[1-4]
7. Shepard CW, Finelli L, Alter MJ. Global epidemiology of hepatitis C virus infection. Lancet Infect Dis. 5, 558-567. 2005.
8. Farrell GC LC. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology 43[2 Suppl 1], S99-S112. 2006.
9. Day CP. Natural History of NAFLD: Remarkably benign in the absence of cirrhosis. Gastroenterology 2005; 129:375-377.

Bizle İletişime Geçin

Minimally-Invasive Markers

Minimally-Invasive markers of liver fibrosis, why they are needed

The traditional reference standard for detecting and assessing liver fibrosis has been transabdominal needle biopsy of the liver. In this procedure a hollow needle is passed into the liver to remove 1/50,000th of the organ that is assessed histologically. Because of the small sample size and the patchy distribution of some liver pathology there is a significant degree of sampling error. The procedure is painful (~30% of cases), hazardous (causes bleeding in ~1 in 1,000 cases), and even death (1 in 10,000). The histological examination of the biopsy by pathologists is time consuming and subject to inter-observer variability. The hazards, costs and many sources of error in biopsy interpretation make this method of assessment of fibrosis a poor reference standard.10-13. In addition repeated sampling of the liver is considered to be unacceptable for research purposes and so cannot be used to determine the natural history of disease or the effect of therapies directed either at the fibrotic process itself or the underlying cause of CLD (such as antiviral treatment). These numerous problems with obtaining and interpreting liver biopsies have fuelled the search for alternative methods for assessing the severity of liver fibrosis. Serum markers are extremely attractive candidates as they can be standardized and automated.

What they are

Serum markers can be divided into direct and indirect markers of fibrosis. Direct markers are fragments of the liver matrix components produced by HSC during the fibrotic process and the molecules involved in regulating the progression and regression of fibrosis. These include hyaluronic acid (HA), collagens IV and VI, amino terminal fragment of procollagen III (P3NP) and MMPs and TIMP-1. Indirect makers of fibrosis include molecules released into the blood due to liver inflammation (such as aminotransferases- ALT and AST), molecules synthesised, regulated or excreted by the liver (such as clotting factors, cholesterol and bilirubin), and processes that become deranged as liver function becomes impaired, such as insulin resistance.

Liver Fibrosis

Overview Page
What is liver fibrosis?
The ELF Program

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
10. Regev A, Berho M, Jeffers LJ, Milikowski C, Molina EG, Pyrsopoulos NT, et al. Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection. Am J Gastroenterol 2002; 97(10):2614-2618.
11. Colloredo G, Guido M, Sonzogni A, Leandro G. Impact of liver biopsy size on histological evaluation of chronic viral hepatitis: the smaller the sample, the milder the disease. Journal of Hepatology 2003; 39:1-6.
12. Rousselet MC, Michalak S, Dupre F, Croue A, Bedossa P, Saint-Andre JP, et al. Sources of variability in histological scoring of chronic viral hepatitis. Hepatology 2005; 41(2):257-264.
(13) Bedossa P, Dargere D, Paradis V. Sampling Variability of Liver Fibrosis in Chronic Hepatitis C. Hepatology 38[6], 1449-1457. 2003.

The ELF Program

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.

elf-figure
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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