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.
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
William Rosenberg MD, D.Phil
Professor of Hepatology,
The Liver Group,
University of Southampton,
Julie Parkes MD
Public Health Science & Medical Statistics,
University of Southampton,
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, 1449-1457. 2003.