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
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,
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.