- Email: [email protected]
Caution before embracing serum markers of liver fibrosis in clinical practice
April 2005
CORRESPONDENCE
2. Jalan R, Olde Damink SWM, Deutz NEP, Lee A, Hayes PC. Treatment of uncontrolled intracranial hypertension in acute liver failure with moderate hypothermia. Lancet 1999;354:1164 –1168. 3. Jalan R. Intracranial hypertension in acute liver failure: pathophysiological basis of rational management. Semin Liver Dis 2003;23: 271–282. 4. Ede RJ, Gimson AE, Bihari D, Williams R. Controlled hyperventilation in the prevention of cerebral edema in fulminant hepatic failure. J Hepatol 1986;2:43–51. 5. Forbes A, Alexander GJ, O’Grady JG, et al. Thiopental infusion in the treatment of intracranial hypertension complicating fulminant hepatic failure. Hepatology 1989;10:306 –310. 6. Hoofnagle JH, Carithers RL, Chapiro C, Ascher NL. Fulminant hepatic failure: summary of a workshop. Hepatology 1995:21:240 –252. 7. Vaquero J, Belanger M, Cote J, Butterworth R. Mild hypothermia attenuates acetaminophen-induced hepatic necrosis in mice: therapeutic implications. Hepatology 2004;40:220A. 8. Fu T, Blei AT, Takamura N, Lin T, Guo D, Li H, O’Gorman MR, Soriano HE. Hypothermia inhibits Fas-mediated apoptosis of primary mouse hepatocytes in culture. Cell Transplant 2004;13: 667– 676. doi:10.1053/j.gastro.2005.02.049
Caution Before Embracing Serum Markers of Liver Fibrosis in Clinical Practice Dear Sir: We read with interest the study by Rosenberg et al.1 reporting the use of an algorithm comprising age and 3 serum markers of fibrosis in the detection of hepatic fibrosis associated with a spectrum of chronic liver diseases. Further attempts at exploring noninvasive methods of estimating histologic damage are welcome, particularly given the increasing awareness of the limitations of liver biopsy, but we suggest cautious appraisal of the data before such surrogate markers are embraced in clinical practice. Serum biomarkers of hepatic fibrosis such as hyaluronic acid and procollagen-III N-terminal propeptide, both included in the study algorithm, are limited by their lack of specificity to the liver with levels being influenced by concurrent systemic conditions and the fact that their clearance is dependent on renal and hepatic function. Furthermore, they may be influenced by hepatic inflammation.2 Rosenberg et al. provide no information regarding the potential effect of hepatic inflammation on their algorithm. This would be of interest as the majority of their cohort had chronic viral hepatitis, and such analysis may help to explain the less impressive performance of the algorithm in hepatitis C relative to nonalcoholic fatty liver disease and alcoholic liver disease. The clinical validity of a new test, especially one that aims to provide quantitative information, is highly dependent on its reproducibility in the target population. Although the performance characteristics of the individual bioassays were reported in healthy donors, reproducibility data on the actual algorithm in patients with liver disease are lacking. The stated reference ranges of the serum markers were broad and dependent on sex and age. (On this latter point, the age range of the subjects appears to be misstated as “19 –25 years.”) Combining these markers would tend to magnify individual variations and this is evident in the box-and-whisker plots, which reveal considerable overlap of the algorithm across all grades of fibrosis. Nevertheless, despite the wide interindividual variability, a feature of most biological assays, the potential intraindividual stability of such tests justifies serial testing to track progression within an individual. Before the current cross-sectional data are extended longitudinally, a
1145
requisite for true clinical validation, the intraindividual variation of the algorithm in health and liver disease should be determined. The cost and complexity of calculating algorithms and panels of biochemical markers in multicomponent tests lessen their clinical appeal. The current algorithm involves logarithmic transformation of data and selection of varying thresholds for specific diseases to obtain satisfactory diagnostic characteristics. As noted by an editorialist,3 the diagnostic accuracy of the algorithm is comparable to previously published tests in that it is best only at the extreme ends of the fibrotic spectrum. Furthermore, the superiority of fibrotic markers and biochemical panels over simple indices such as prothrombin time4 and aminotransferases5 as histologic predictors remains questionable. In this regard, we6,7 and others8 have confirmed the usefulness of the AST/ALT ratio as a marker of advanced fibrosis or cirrhosis. This simple index has also been shown to be of prognostic value in cirrhosis.9 It would be interesting to see how the AST/ALT ratio fared in the current study. As a noninvasive, quantitative test of liver function, we have demonstrated that the 13C-caffeine breath test (CBT) also appears to reflect hepatic fibrosis. The CBT was highly reproducible both in healthy subjects and those with liver disease, and distinguished patients with cirrhosis of varying cause from patients with noncirrhotic, chronic active viral hepatitis.10 Extension of a preliminary study of patients with chronic hepatitis B11 has revealed that Metavir fibrosis stage is best correlated to the CBT compared with conventional indices and that the area under the receiver operating characteristic curve for the detection of advanced fibrosis (Metavir F3 or F4) for the CBT was 0.91 ⫾ 0.04. Additionally, CBT was not altered by short-term lamivudine therapy but improved significantly in responders to longer-term lamivudine (mean 1 year), whereas in those with persisting viremia and elevated ALT, CBT values remained stable or deteriorated (manuscript submitted). In conclusion, we commend the efforts of Rosenberg et al. to introduce another alternative to liver biopsy but suggest further analysis is required before clinical acceptance is achieved. We propose that the CBT represents a truly noninvasive method of assessing liver status that appears particularly sensitive to the effects of fibrosis. We speculate that the quantitative estimation of hepatic function (intimately linked to fibrosis) that is provided by the CBT may represent the most significant predictor of clinical outcomes in patients with liver disease. GORDON PARK PETER KATELARIS D. BRIAN JONES MENG NGU Department of Gastroenterology and Hepatology Concord Repatriation General Hospital Concord, Australia DAVID LE COUTEUR Center for Education and Research on Aging University of Sydney Concord Repatriation General Hospital Sydney, Australia 1. Rosenberg WM, Voelker M, Thiel R, Becka M, Burt A, Schuppan D, Hubscher S, et al. Serum markers detect the presence of liver fibrosis: a cohort study. Gastroenterology 2004;127:1704 –1713. 2. Trinchet JC, Hartmann DJ, Pateron D, Laarif M, Callard P, Ville G, Beaugrand M. Serum type I collagen and N-terminal peptide of type III procollagen in chronic hepatitis. Relationship to liver histology and conventional liver tests. J Hepatol 1991;12:139 –144.
1146
CORRESPONDENCE
3. Bissell DM. Assessing fibrosis without a liver biopsy: are we there yet? Gastroenterology 2004;127:1847–1849. 4. Oberti F, Valsesia E, Pilette C, Rousselet MC, Bedossa P, Aube C, Gallois Y, et al. Noninvasive diagnosis of hepatic fibrosis or cirrhosis. Gastroenterology 1997;113:1609 –1616. 5. Myers RP, Tainturier MH, Ratziu V, Piton A, Thibault V, ImbertBismut F, Messous D, et al. Prediction of liver histological lesions with biochemical markers in patients with chronic hepatitis B. J Hepatol 2003;39:222–230. 6. Park GJ-H, Lin BP, Ngu MC, Jones DB, Katelaris PH. Aspartate aminotransferase: alanine aminotransferase ratio in chronic hepatitis C infection: is it a useful predictor of cirrhosis? J Gastroenterol Hepatol 2000;15:386 –390. 7. Park GJ-H, Jones DB, Katelaris PH. Value of AST/ALT ratio as fibrotic predictor in chronic hepatitis C. Am J Gastroenterol 2005 (in press). 8. Sheth SG, Flamm SL, Gordon FD, Chopra S. AST/ALT ratio predicts cirrhosis in patients with chronic hepatitis C virus infection. Am J Gastroenterol 1998;93:44 – 48. 9. Giannini E, Risso D, Botta F, et al. Validity and clinical utility of the aspartate aminotransferase-alanine aminotransferase ratio in assessing disease severity and prognosis in patients with hepatitis C virus-related chronic liver disease. Arch Intern Med 2003;163: 218 –224. 10. Park GJ-H, Katelaris PH, Jones DB, Seow F, Le Couteur DG, Ngu MC. Validity of the 13C-caffeine breath test as a noninvasive, quantitative test of liver function. Hepatology 2003;38:1227–1236. 11. Park G J-H, Katelaris PH, Jones DB, Seow F, Lin BP, Le Couteur DG, Ngu MC. The 13C-caffeine breath test distinguishes cirrhosis in chronic hepatitis B and is unaffected by short-term lamivudine therapy. Gastroenterology 2004;126(Suppl 2):A710. doi:10.1053/j.gastro.2005.02.044
Reply. Park et al are correct in pointing out that hyaluronic acid (HA) and procollagen III N-terminal peptide are not specific markers of liver fibrosis. However, they are important constituents of liver matrix and many previous studies have demonstrated associations between elevated serum levels of these molecules and liver fibrosis. Extra hepatic fibrosis may be one of the factors explaining the discrepancy between high negative predictive value (NPV) rates and low positive predictive value (PPV) rates reported in studies using single markers.1 The ELF study excluded conditions associated with extrahepatic fibrosis to try and minimize the effect of nonspecific fibrosis. Further studies will be required to determine the influence of fibrotic co-morbid conditions on the performance of the ELF algorithm. Certain co-morbidities may preclude the use of the test as is the case with hemolysis and the Fibrotest and excess alcohol consumption with the Forns Index. The effect of inflammation on the performance of the algorithm should be examined. The severity of histological inflammation was not recorded as part of the ELF study but was examined by including aminotransferase levels in the algorithm as a surrogate marker of inflammation. This did not enhance the performance of the algorithm. We agree that it is important to evaluate the performance of each component of the algorithm in both health and disease. Space in the journal prevented us from presenting the data but the immunoassays were subjected to extensive validation using samples from healthy subjects and donors with a range of diseases including chronic liver diseases for linearity, parallelism, cross-reactivity, interference, precision, reagent, calibrator, and sample stability, and Hook effect (data are on file with Bayer Healthcare). Performance characteristics were excellent. However, we agree that further investigation of the performance of the algorithm, as well as external validation are required.
GASTROENTEROLOGY Vol. 128, No. 4
In many of their comments Park et al refer to tests and studies that differentiate cirrhosis from lesser stages of hepatic fibrosis. In our primary analysis we evaluated the ability of the ELF algorithm to differentiate Scheuer fibrosis stages 0 and 1 from stages 2, 3, and 4. This distinction is widely held as the comparison between mild and moderate/severe (significant) fibrosis. Many studies have reported excellent performance of noninvasive markers in differentiating cirrhosis from other stages of fibrosis, as did we. However, this distinction is often obvious in clinical practice while the differentiation of lesser degrees of fibrosis is important but impossible without a biopsy. Thus, many of the comments made by Park et al are not relevant to the ELF study. Park et al advance the case for simple tests and single markers but in a systematic review Gebo et al2 concluded that “panels of markers may have the greatest value in predicting the absence or no more than minimal fibrosis on biopsy and in predicting the presence of cirrhosis on biopsy.” We reject criticism of the algorithm for being mathematically complex. In our report we have presented the calculation that is performed to generate a fibrosis score in order to be transparent. In clinical use these workings would be performed by computer in a laboratory with only the final score, or an interpretation being reported. By analogy the method used to measure aminotransferase levels is complex but only the final result and not the chemical reactions employed or the method used to measure absorbancy is provided to clinicians. While simpler individual assays may entail less complexity their poor performance negates the advantage of simplicity over panels of markers. Park et al cite the caffeine breath test as an example of a simple test,3 though we would not consider it to be as easy to perform as a blood test. However, this test can only differentiate between cirrhotic and noncirrhotic patients. It is not accurate in differentiating patients with lesser degrees of fibrosis from healthy subjects and, as in other studies, patients with specific co-morbidities were excluded. Many of the existing panels of markers perform at similar levels in the studies to date. Further investigation is required, particularly analysis of the ability of panels of markers to predict clinical outcomes. WILLIAM ROSENBERG University of Southampton Southampton, England 1. McHutchison JG, Blatt LM, de Medina M, Craig JR, Conrad A, Schiff ER, Tong MJ. Measurement of serum hyaluronic acid in patients with chronic hepatitis C and its relationship to liver histology. Consensus Interferon Study Group. J Gastroenterol Hepatol 2000; 15:945–951. 2. Gebo KA, Herlong HF, Torbenson MS, Jenckes MW, Chander G, Ghanem KG, El-Kamary SS, Sulkowski M, Bass EB. Role of liver biopsy in management of chronic hepatitis C: a systematic review. Hepatology 2002;36:S161–S172. 3. Park GJH, Katelaris PH, Jones DB, Seow F, Le Couteur DG, Ngu MC. Validity of the 13C caffeine breath test as a noninvasive, quantitative test of liver function. Hepatology 2003;38:1227–1236. doi:10.1053/j.gastro.2005.02.045
Biomarkers as a First-Line Estimate of Injury in Chronic Liver Diseases: Time for a Moratorium on Liver Biopsy? Dear Sir: We acknowledge the excellent publication by Rosenberg et al1 and share their belief that thoroughly validated, noninvasive serum
CORRESPONDENCE
2. Jalan R, Olde Damink SWM, Deutz NEP, Lee A, Hayes PC. Treatment of uncontrolled intracranial hypertension in acute liver failure with moderate hypothermia. Lancet 1999;354:1164 –1168. 3. Jalan R. Intracranial hypertension in acute liver failure: pathophysiological basis of rational management. Semin Liver Dis 2003;23: 271–282. 4. Ede RJ, Gimson AE, Bihari D, Williams R. Controlled hyperventilation in the prevention of cerebral edema in fulminant hepatic failure. J Hepatol 1986;2:43–51. 5. Forbes A, Alexander GJ, O’Grady JG, et al. Thiopental infusion in the treatment of intracranial hypertension complicating fulminant hepatic failure. Hepatology 1989;10:306 –310. 6. Hoofnagle JH, Carithers RL, Chapiro C, Ascher NL. Fulminant hepatic failure: summary of a workshop. Hepatology 1995:21:240 –252. 7. Vaquero J, Belanger M, Cote J, Butterworth R. Mild hypothermia attenuates acetaminophen-induced hepatic necrosis in mice: therapeutic implications. Hepatology 2004;40:220A. 8. Fu T, Blei AT, Takamura N, Lin T, Guo D, Li H, O’Gorman MR, Soriano HE. Hypothermia inhibits Fas-mediated apoptosis of primary mouse hepatocytes in culture. Cell Transplant 2004;13: 667– 676. doi:10.1053/j.gastro.2005.02.049
Caution Before Embracing Serum Markers of Liver Fibrosis in Clinical Practice Dear Sir: We read with interest the study by Rosenberg et al.1 reporting the use of an algorithm comprising age and 3 serum markers of fibrosis in the detection of hepatic fibrosis associated with a spectrum of chronic liver diseases. Further attempts at exploring noninvasive methods of estimating histologic damage are welcome, particularly given the increasing awareness of the limitations of liver biopsy, but we suggest cautious appraisal of the data before such surrogate markers are embraced in clinical practice. Serum biomarkers of hepatic fibrosis such as hyaluronic acid and procollagen-III N-terminal propeptide, both included in the study algorithm, are limited by their lack of specificity to the liver with levels being influenced by concurrent systemic conditions and the fact that their clearance is dependent on renal and hepatic function. Furthermore, they may be influenced by hepatic inflammation.2 Rosenberg et al. provide no information regarding the potential effect of hepatic inflammation on their algorithm. This would be of interest as the majority of their cohort had chronic viral hepatitis, and such analysis may help to explain the less impressive performance of the algorithm in hepatitis C relative to nonalcoholic fatty liver disease and alcoholic liver disease. The clinical validity of a new test, especially one that aims to provide quantitative information, is highly dependent on its reproducibility in the target population. Although the performance characteristics of the individual bioassays were reported in healthy donors, reproducibility data on the actual algorithm in patients with liver disease are lacking. The stated reference ranges of the serum markers were broad and dependent on sex and age. (On this latter point, the age range of the subjects appears to be misstated as “19 –25 years.”) Combining these markers would tend to magnify individual variations and this is evident in the box-and-whisker plots, which reveal considerable overlap of the algorithm across all grades of fibrosis. Nevertheless, despite the wide interindividual variability, a feature of most biological assays, the potential intraindividual stability of such tests justifies serial testing to track progression within an individual. Before the current cross-sectional data are extended longitudinally, a
1145
requisite for true clinical validation, the intraindividual variation of the algorithm in health and liver disease should be determined. The cost and complexity of calculating algorithms and panels of biochemical markers in multicomponent tests lessen their clinical appeal. The current algorithm involves logarithmic transformation of data and selection of varying thresholds for specific diseases to obtain satisfactory diagnostic characteristics. As noted by an editorialist,3 the diagnostic accuracy of the algorithm is comparable to previously published tests in that it is best only at the extreme ends of the fibrotic spectrum. Furthermore, the superiority of fibrotic markers and biochemical panels over simple indices such as prothrombin time4 and aminotransferases5 as histologic predictors remains questionable. In this regard, we6,7 and others8 have confirmed the usefulness of the AST/ALT ratio as a marker of advanced fibrosis or cirrhosis. This simple index has also been shown to be of prognostic value in cirrhosis.9 It would be interesting to see how the AST/ALT ratio fared in the current study. As a noninvasive, quantitative test of liver function, we have demonstrated that the 13C-caffeine breath test (CBT) also appears to reflect hepatic fibrosis. The CBT was highly reproducible both in healthy subjects and those with liver disease, and distinguished patients with cirrhosis of varying cause from patients with noncirrhotic, chronic active viral hepatitis.10 Extension of a preliminary study of patients with chronic hepatitis B11 has revealed that Metavir fibrosis stage is best correlated to the CBT compared with conventional indices and that the area under the receiver operating characteristic curve for the detection of advanced fibrosis (Metavir F3 or F4) for the CBT was 0.91 ⫾ 0.04. Additionally, CBT was not altered by short-term lamivudine therapy but improved significantly in responders to longer-term lamivudine (mean 1 year), whereas in those with persisting viremia and elevated ALT, CBT values remained stable or deteriorated (manuscript submitted). In conclusion, we commend the efforts of Rosenberg et al. to introduce another alternative to liver biopsy but suggest further analysis is required before clinical acceptance is achieved. We propose that the CBT represents a truly noninvasive method of assessing liver status that appears particularly sensitive to the effects of fibrosis. We speculate that the quantitative estimation of hepatic function (intimately linked to fibrosis) that is provided by the CBT may represent the most significant predictor of clinical outcomes in patients with liver disease. GORDON PARK PETER KATELARIS D. BRIAN JONES MENG NGU Department of Gastroenterology and Hepatology Concord Repatriation General Hospital Concord, Australia DAVID LE COUTEUR Center for Education and Research on Aging University of Sydney Concord Repatriation General Hospital Sydney, Australia 1. Rosenberg WM, Voelker M, Thiel R, Becka M, Burt A, Schuppan D, Hubscher S, et al. Serum markers detect the presence of liver fibrosis: a cohort study. Gastroenterology 2004;127:1704 –1713. 2. Trinchet JC, Hartmann DJ, Pateron D, Laarif M, Callard P, Ville G, Beaugrand M. Serum type I collagen and N-terminal peptide of type III procollagen in chronic hepatitis. Relationship to liver histology and conventional liver tests. J Hepatol 1991;12:139 –144.
1146
CORRESPONDENCE
3. Bissell DM. Assessing fibrosis without a liver biopsy: are we there yet? Gastroenterology 2004;127:1847–1849. 4. Oberti F, Valsesia E, Pilette C, Rousselet MC, Bedossa P, Aube C, Gallois Y, et al. Noninvasive diagnosis of hepatic fibrosis or cirrhosis. Gastroenterology 1997;113:1609 –1616. 5. Myers RP, Tainturier MH, Ratziu V, Piton A, Thibault V, ImbertBismut F, Messous D, et al. Prediction of liver histological lesions with biochemical markers in patients with chronic hepatitis B. J Hepatol 2003;39:222–230. 6. Park GJ-H, Lin BP, Ngu MC, Jones DB, Katelaris PH. Aspartate aminotransferase: alanine aminotransferase ratio in chronic hepatitis C infection: is it a useful predictor of cirrhosis? J Gastroenterol Hepatol 2000;15:386 –390. 7. Park GJ-H, Jones DB, Katelaris PH. Value of AST/ALT ratio as fibrotic predictor in chronic hepatitis C. Am J Gastroenterol 2005 (in press). 8. Sheth SG, Flamm SL, Gordon FD, Chopra S. AST/ALT ratio predicts cirrhosis in patients with chronic hepatitis C virus infection. Am J Gastroenterol 1998;93:44 – 48. 9. Giannini E, Risso D, Botta F, et al. Validity and clinical utility of the aspartate aminotransferase-alanine aminotransferase ratio in assessing disease severity and prognosis in patients with hepatitis C virus-related chronic liver disease. Arch Intern Med 2003;163: 218 –224. 10. Park GJ-H, Katelaris PH, Jones DB, Seow F, Le Couteur DG, Ngu MC. Validity of the 13C-caffeine breath test as a noninvasive, quantitative test of liver function. Hepatology 2003;38:1227–1236. 11. Park G J-H, Katelaris PH, Jones DB, Seow F, Lin BP, Le Couteur DG, Ngu MC. The 13C-caffeine breath test distinguishes cirrhosis in chronic hepatitis B and is unaffected by short-term lamivudine therapy. Gastroenterology 2004;126(Suppl 2):A710. doi:10.1053/j.gastro.2005.02.044
Reply. Park et al are correct in pointing out that hyaluronic acid (HA) and procollagen III N-terminal peptide are not specific markers of liver fibrosis. However, they are important constituents of liver matrix and many previous studies have demonstrated associations between elevated serum levels of these molecules and liver fibrosis. Extra hepatic fibrosis may be one of the factors explaining the discrepancy between high negative predictive value (NPV) rates and low positive predictive value (PPV) rates reported in studies using single markers.1 The ELF study excluded conditions associated with extrahepatic fibrosis to try and minimize the effect of nonspecific fibrosis. Further studies will be required to determine the influence of fibrotic co-morbid conditions on the performance of the ELF algorithm. Certain co-morbidities may preclude the use of the test as is the case with hemolysis and the Fibrotest and excess alcohol consumption with the Forns Index. The effect of inflammation on the performance of the algorithm should be examined. The severity of histological inflammation was not recorded as part of the ELF study but was examined by including aminotransferase levels in the algorithm as a surrogate marker of inflammation. This did not enhance the performance of the algorithm. We agree that it is important to evaluate the performance of each component of the algorithm in both health and disease. Space in the journal prevented us from presenting the data but the immunoassays were subjected to extensive validation using samples from healthy subjects and donors with a range of diseases including chronic liver diseases for linearity, parallelism, cross-reactivity, interference, precision, reagent, calibrator, and sample stability, and Hook effect (data are on file with Bayer Healthcare). Performance characteristics were excellent. However, we agree that further investigation of the performance of the algorithm, as well as external validation are required.
GASTROENTEROLOGY Vol. 128, No. 4
In many of their comments Park et al refer to tests and studies that differentiate cirrhosis from lesser stages of hepatic fibrosis. In our primary analysis we evaluated the ability of the ELF algorithm to differentiate Scheuer fibrosis stages 0 and 1 from stages 2, 3, and 4. This distinction is widely held as the comparison between mild and moderate/severe (significant) fibrosis. Many studies have reported excellent performance of noninvasive markers in differentiating cirrhosis from other stages of fibrosis, as did we. However, this distinction is often obvious in clinical practice while the differentiation of lesser degrees of fibrosis is important but impossible without a biopsy. Thus, many of the comments made by Park et al are not relevant to the ELF study. Park et al advance the case for simple tests and single markers but in a systematic review Gebo et al2 concluded that “panels of markers may have the greatest value in predicting the absence or no more than minimal fibrosis on biopsy and in predicting the presence of cirrhosis on biopsy.” We reject criticism of the algorithm for being mathematically complex. In our report we have presented the calculation that is performed to generate a fibrosis score in order to be transparent. In clinical use these workings would be performed by computer in a laboratory with only the final score, or an interpretation being reported. By analogy the method used to measure aminotransferase levels is complex but only the final result and not the chemical reactions employed or the method used to measure absorbancy is provided to clinicians. While simpler individual assays may entail less complexity their poor performance negates the advantage of simplicity over panels of markers. Park et al cite the caffeine breath test as an example of a simple test,3 though we would not consider it to be as easy to perform as a blood test. However, this test can only differentiate between cirrhotic and noncirrhotic patients. It is not accurate in differentiating patients with lesser degrees of fibrosis from healthy subjects and, as in other studies, patients with specific co-morbidities were excluded. Many of the existing panels of markers perform at similar levels in the studies to date. Further investigation is required, particularly analysis of the ability of panels of markers to predict clinical outcomes. WILLIAM ROSENBERG University of Southampton Southampton, England 1. McHutchison JG, Blatt LM, de Medina M, Craig JR, Conrad A, Schiff ER, Tong MJ. Measurement of serum hyaluronic acid in patients with chronic hepatitis C and its relationship to liver histology. Consensus Interferon Study Group. J Gastroenterol Hepatol 2000; 15:945–951. 2. Gebo KA, Herlong HF, Torbenson MS, Jenckes MW, Chander G, Ghanem KG, El-Kamary SS, Sulkowski M, Bass EB. Role of liver biopsy in management of chronic hepatitis C: a systematic review. Hepatology 2002;36:S161–S172. 3. Park GJH, Katelaris PH, Jones DB, Seow F, Le Couteur DG, Ngu MC. Validity of the 13C caffeine breath test as a noninvasive, quantitative test of liver function. Hepatology 2003;38:1227–1236. doi:10.1053/j.gastro.2005.02.045
Biomarkers as a First-Line Estimate of Injury in Chronic Liver Diseases: Time for a Moratorium on Liver Biopsy? Dear Sir: We acknowledge the excellent publication by Rosenberg et al1 and share their belief that thoroughly validated, noninvasive serum