Update on Cirrhosis -- The Role of Fibrosis Markers
Update on Cirrhosis -- The Role of Fibrosis Markers
New Orleans, Wednesday, May 19, 2004 -- Important new data presented at this year's Digestive Disease Week (DDW) meeting emphasized and reviewed the current state of noninvasive (serum) markers as surrogates for measuring fibrosis by liver biopsy. This report highlights some of the more key information from these proceedings and places it in relevant and appropriate context for the clinician.
Background and Context
The natural history of cirrhosis is such that chronic liver injury (and usually inflammation) leads first to fibrosis, and, if present over long periods of time, to cirrhosis. It would thus be ideal to be able to assess where in the disease progression each patient may be found. Currently, the primary method to assess the degree of fibrosis is liver biopsy. However, liver biopsy is known to be associated with morbidity and even mortality. Furthermore, physicians and patients alike often have a preference to avoid liver biopsy. Thus, there is considerable interest in the development of noninvasive markers of liver fibrosis (and liver function, for that matter).
During this year's DDW meeting, considerable interest was displayed in the area of fibrosis assessment. Reflective of this focus, a symposium entitled "Prognostic Markers of Liver Disease" was convened, as sponsored by the Liver and Biliary section, and a number of study abstracts were presented.
Serum Markers to Assess Fibrosis
A number of serum markers are currently available that can be used to assess liver fibrosis. The rationale for these tests is that they offer the advantage of measures of liver function or use mathematical formulas that take into account liver function, often in combination with markers that are fibrosis-specific. Examples of these types of tests are the APRI (a novel index, AST [aspartate aminotransferase]-to-platelet ratio index) and the Fibrotest. It is emphasized that in general, these tests are effective at excluding advanced fibrosis (cirrhosis) and minimal or no fibrosis. However, they typically do not accurately differentiate intermediate grades of fibrosis (ie, Metavir grades F1-F3), and thus indeterminate values become problematic in clinical practice. The more fibrosis-specific tests include definitive serum markers such as YKL-40, hyaluronic acid, collagens, fibronectins, and combinations of serum markers. Included in the "combination" category is the FibroSpect II, a unique noninvasive diagnostic panel to assist in the detection of liver fibrosis. This panel uses a combination of components in the fibrogenic cascade, such as hyaluronic acid, TIMP-1 (tissue inhibitor of metalloproteinase), and alpha-2-macroglobulin.
Patel and colleagues presented the results of a study assessing the utility of this serum panel in a cohort of 244 patients with hepatitis C-related liver disease. They found that this test had a 71% to 87% positive predictive value for differentiating mild fibrosis (Metavir F0-F1) from more severe (Metavir F2-F4) disease. Again, these findings are consistent with the general tenet that these tests are able to differentiate advanced liver disease from minimal disease, but highlight the concept that they lack the ability to discriminate among intermediate degrees of fibrosis.
The Future of Prognostic Markers
Scott L. Friedman emphasized the evolution of proteomics in this field, suggesting that fingerprints of the protein composition in the blood may be able to accurately reflect the fibrogenic activity of the liver. Recent work in this area has suggested the feasibility of this approach. This point was considerably strengthened by Hui and coworkers who assessed the utility of a novel non-electrophoresis-based proteomic technology, SELDI-TOF MS (surface-enhanced laser desorption/ionization time-of-flight mass spectrometry), in predicting different degrees of liver fibrosis in chronic hepatitis B. They used SELDI-TOF MS to perform protein profiling, followed by implementation of artificial neural networks to generate models for prediction of fibrosis. The results were striking in that they were able to identify 30 proteomic profiles that were significantly associated with fibrosis in patients with hepatitis B. When these investigators divided subjects into those with moderate/severe fibrosis (Ishak stage 3-4) and those with cirrhosis (Ishak stage 5-6), they were able to demonstrate that the method had a sensitivity and specificity of greater than 90% for prediction of either moderate/severe fibrosis or cirrhosis. These data suggest that this methodology may be extremely useful in the future for more precise assessment of fibrosis risk.
Concluding Remarks
At present, methods to accurately assess fibrosis noninvasively are in evolution, and although controversy about their usefulness exists, it is anticipated that as the methods become more refined, such noninvasive measurement of fibrosis will be readily feasible.
References
New Orleans, Wednesday, May 19, 2004 -- Important new data presented at this year's Digestive Disease Week (DDW) meeting emphasized and reviewed the current state of noninvasive (serum) markers as surrogates for measuring fibrosis by liver biopsy. This report highlights some of the more key information from these proceedings and places it in relevant and appropriate context for the clinician.
Background and Context
The natural history of cirrhosis is such that chronic liver injury (and usually inflammation) leads first to fibrosis, and, if present over long periods of time, to cirrhosis. It would thus be ideal to be able to assess where in the disease progression each patient may be found. Currently, the primary method to assess the degree of fibrosis is liver biopsy. However, liver biopsy is known to be associated with morbidity and even mortality. Furthermore, physicians and patients alike often have a preference to avoid liver biopsy. Thus, there is considerable interest in the development of noninvasive markers of liver fibrosis (and liver function, for that matter).
During this year's DDW meeting, considerable interest was displayed in the area of fibrosis assessment. Reflective of this focus, a symposium entitled "Prognostic Markers of Liver Disease" was convened, as sponsored by the Liver and Biliary section, and a number of study abstracts were presented.
Serum Markers to Assess Fibrosis
A number of serum markers are currently available that can be used to assess liver fibrosis. The rationale for these tests is that they offer the advantage of measures of liver function or use mathematical formulas that take into account liver function, often in combination with markers that are fibrosis-specific. Examples of these types of tests are the APRI (a novel index, AST [aspartate aminotransferase]-to-platelet ratio index) and the Fibrotest. It is emphasized that in general, these tests are effective at excluding advanced fibrosis (cirrhosis) and minimal or no fibrosis. However, they typically do not accurately differentiate intermediate grades of fibrosis (ie, Metavir grades F1-F3), and thus indeterminate values become problematic in clinical practice. The more fibrosis-specific tests include definitive serum markers such as YKL-40, hyaluronic acid, collagens, fibronectins, and combinations of serum markers. Included in the "combination" category is the FibroSpect II, a unique noninvasive diagnostic panel to assist in the detection of liver fibrosis. This panel uses a combination of components in the fibrogenic cascade, such as hyaluronic acid, TIMP-1 (tissue inhibitor of metalloproteinase), and alpha-2-macroglobulin.
Patel and colleagues presented the results of a study assessing the utility of this serum panel in a cohort of 244 patients with hepatitis C-related liver disease. They found that this test had a 71% to 87% positive predictive value for differentiating mild fibrosis (Metavir F0-F1) from more severe (Metavir F2-F4) disease. Again, these findings are consistent with the general tenet that these tests are able to differentiate advanced liver disease from minimal disease, but highlight the concept that they lack the ability to discriminate among intermediate degrees of fibrosis.
The Future of Prognostic Markers
Scott L. Friedman emphasized the evolution of proteomics in this field, suggesting that fingerprints of the protein composition in the blood may be able to accurately reflect the fibrogenic activity of the liver. Recent work in this area has suggested the feasibility of this approach. This point was considerably strengthened by Hui and coworkers who assessed the utility of a novel non-electrophoresis-based proteomic technology, SELDI-TOF MS (surface-enhanced laser desorption/ionization time-of-flight mass spectrometry), in predicting different degrees of liver fibrosis in chronic hepatitis B. They used SELDI-TOF MS to perform protein profiling, followed by implementation of artificial neural networks to generate models for prediction of fibrosis. The results were striking in that they were able to identify 30 proteomic profiles that were significantly associated with fibrosis in patients with hepatitis B. When these investigators divided subjects into those with moderate/severe fibrosis (Ishak stage 3-4) and those with cirrhosis (Ishak stage 5-6), they were able to demonstrate that the method had a sensitivity and specificity of greater than 90% for prediction of either moderate/severe fibrosis or cirrhosis. These data suggest that this methodology may be extremely useful in the future for more precise assessment of fibrosis risk.
Concluding Remarks
At present, methods to accurately assess fibrosis noninvasively are in evolution, and although controversy about their usefulness exists, it is anticipated that as the methods become more refined, such noninvasive measurement of fibrosis will be readily feasible.
References
Wai CT, Greenson JK, Fontana RJ, et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology. 2003;38:518-526.
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;357:1069-1075.
Patel K, Nelson DR, Afdahl N, et al. Prospective evaluation of a serum (FibroSpect II) panel to predict fibrosis in chronic HCV Patients. Gastroenterology. 2004;126 (suppl 2):A-708. [S1645]
Friedman SL. Prognosticating in the future: Genomics and beyond. In: AGA Clinical Symposium -- Prognostic Markers of Liver Disease. Program and abstracts of Digestive Disease Week 2004; May 15-20, 2004; New Orleans, Louisiana.
Hui AY, Poon TCW, Chan HLY, et al. Serum proteomic profiling predicts liver fibrosis in chronic hepatitis B. Gastroenterology. 2004;126(suppl 2):A-669. [Abstract 145]
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