Current Gastroenterology Reports

, Volume 3, Issue 1, pp 12–18 | Cite as

Hepatic fibrosis: Are any of the serum markers useful?

  • Sangik Oh
  • Nezam H. Afdhal


There is a clinical need for noninvasive measurement of liver fibrosis both to diagnose significant liver fibrosis and to monitor the effects of therapy on fibrogenesis and fibrolysis. Multiple clinical markers have been evaluated over the years, and as our understanding of the molecular process of liver scarring has advanced, newer markers have appeared. Serum markers include extracellular matrix proteins such as the N-terminal propeptide of collagen III, hyaluronan, YKL-40, laminin, metalloproteinases, and their inhibitors. Use of multiple markers has led to 90% sensitivity in diagnosing cirrhosis, but specificity is variable at about 60%. Automated systems to measure these markers are under development and are being evaluated for their ability to monitor fibrosis during and after therapy in multiple liver diseases, including hepatitis B and C. Although no individual fibrosis marker is clinically applicable today, we foresee a future in which monitoring fibrosis markers will replace sequential liver biopsy as a standard of care.


Chronic Hepatitis Hyaluronic Acid Laminin Chronic Liver Disease Liver Fibrosis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Qi Z, Atsuchi N, Ooshima A, et al.: Blockade of type beta transforming growth factor signaling prevents liver fibrosis and dysfunction in the rat. Proc Natl Acad Sci U S A 1999, 96: 2345–2349. This elegant animal study demonstrates that TGF-b plays an important role in liver fibrogenesis and suggests possible therapeutic implications.PubMedCrossRefGoogle Scholar
  2. 2.
    Aycock RS, Seyer JM: Collagens of normal and cirrhotic human liver. Connect Tissue Res 1989, 23:19–31.PubMedGoogle Scholar
  3. 3.
    Murawaki Y, Kusakabe Y, Hirayama C: Serum lysyl oxidase activity in chronic liver disease in comparison with serum levels of prolyl hydroxylase and laminin. Hepatology 1991, 14:1167–1173.PubMedGoogle Scholar
  4. 4.
    Hahn E, Wick G, Pencev D, Timpl R: Distribution of basement membrane proteins in normal and fibrotic human liver: collagen type IV, laminin, and fibronectin. Gut 1980, 21:63–71.PubMedGoogle Scholar
  5. 5.
    Matsumoto S, Yamamoto K, Nagano T, et al.: Immunohistochemical study on phenotypical changes of hepatocytes in liver disease with reference to extracellular matrix composition. Liver 1999, 19:32–38.PubMedCrossRefGoogle Scholar
  6. 6.
    Misaki M, Shima T, Yano Y, et al.: Basement membrane-related and type III procollagen-related antigens in serum of patients with chronic viral liver disease. Clin Chem 1990, 36:522–524.PubMedGoogle Scholar
  7. 7.
    Fabris P, Marranconi F, Bozzola L, et al.: Fibrogenesis serum markers in patients with chronic hepatitis C treated with alpha-IFN [see comments]. J Gastroenterol 1999, 34:345–350.PubMedCrossRefGoogle Scholar
  8. 8.
    Gallorini A, Plebani M, Pontisso P, et al.: Serum markers of hepatic fibrogenesis in chronic hepatitis type C treated with alfa-2A interferon. Liver 1994, 14:257–264.PubMedGoogle Scholar
  9. 9.
    Annoni G, Colombo M, Cantaluppi MC, et al.: Serum type III procollagen peptide and laminin (Lam-P1) detect alcoholic hepatitis in chronic alcohol abusers. Hepatology 1989, 9:693–697.PubMedCrossRefGoogle Scholar
  10. 10.
    Niemela O, Risteli J, Blake JE, et al.: Markers of fibrogenesis and basement membrane formation in alcoholic liver disease: relation to severity, presence of hepatitis, and alcohol intake [see comments]. Gastroenterology 1990, 98:1612–1619.PubMedGoogle Scholar
  11. 11.
    Nouchi T, Worner TM, Sato S, Lieber CS: Serum procollagen type III N-terminal peptides and laminin P1 peptide in alcoholic liver disease. Alcohol Clin Exp Res 1987, 11:287–291.PubMedCrossRefGoogle Scholar
  12. 12.
    Laurent TC, Dahl IM, Dahl LB, et al.: The catabolic fate of hyaluronic acid. Connect Tissue Res 1986, 15:33–41.PubMedGoogle Scholar
  13. 13.
    Engstrom-Laurent A, Hallgren R: Circulating hyaluronate in rheumatoid arthritis: relationship to inflammatory activity and the effect of corticosteroid therapy. Ann Rheum Dis 1985, 44:83–88.PubMedGoogle Scholar
  14. 14.
    Laurent TC, Laurent UB, Fraser JR: Serum hyaluronan as a disease marker. Ann Med 1996, 28:241–253.PubMedGoogle Scholar
  15. 15.
    Manicourt DH, Triki R, Fukuda K, et al.: Levels of circulating tumor necrosis factor alpha and interleukin-6 in patients with rheumatoid arthritis: relationship to serum levels of hyaluronan and antigenic keratan sulfate. Arthritis Rheum 1993, 36:490–499.PubMedCrossRefGoogle Scholar
  16. 16.
    Wong VS, Hughes V, Trull A, et al.: Serum hyaluronic acid is a useful marker of liver fibrosis in chronic hepatitis C virus infection. J Viral Hepatol 1998, 5:187–192.CrossRefGoogle Scholar
  17. 17.
    Ninomiya T, Yoon S, Hayashi Y, et al.: Clinical significance of serum hyaluronic acid as a fibrosis marker in chronic hepatitis C patients treated with interferon-alpha: histological evaluation by a modified histological activity index scoring system. J Gastroenterol Hepatol 1998, 13:68–74.PubMedGoogle Scholar
  18. 18.
    Guechot J, Poupon RE, Giral P, et al.: Relationship between procollagen III aminoterminal propeptide and hyaluronan serum levels and histological fibrosis in primary biliary cirrhosis and chronic viral hepatitis C. J Hepatol 1994, 20:388–393.PubMedCrossRefGoogle Scholar
  19. 19.
    Ramadori G, Zohrens G, Manns M, et al.: Serum hyaluronate and type III procollagen aminoterminal propeptide concentration in chronic liver disease: relationship to cirrhosis and disease activity. Eur J Clin Invest 1991, 21:323–330.PubMedGoogle Scholar
  20. 20.
    Yamada M, Fukuda Y, Nakano I, et al.: Serum hyaluronan as a marker of liver fibrosis in hemophiliacs with hepatitis C virus-associated chronic liver disease. Acta Haematol 1998, 99:212–216.PubMedCrossRefGoogle Scholar
  21. 21.
    Murawaki Y, Ikuta Y, Koda M, et al.: Clinical significance of serum hyaluronan in patients with chronic viral liver disease. J Gastroenterol Hepatol 1996, 11:459–465.PubMedGoogle Scholar
  22. 22.
    Takamatsu S, Nakabayashi H, Okamoto Y, Nakano H: Noninvasive determination of liver collagen content in chronic hepatitis: multivariate regression modeling with blood chemical parameters as variables. J Gastroenterol 1997, 32:355–360.PubMedGoogle Scholar
  23. 23.
    Yamada M, Fukuda Y, Koyama Y, et al.: Serum hyaluronic acid reflects the effect of interferon treatment on hepatic fibrosis in patients with chronic hepatitis C. J Gastroenterol Hepatol 1996, 11:646–651.PubMedGoogle Scholar
  24. 24.
    Pares A, Delofeu R, Gimenez A, et al.: Serum hyaluronate reflects hepatic fibrogenesis in alcoholic liver disease and is useful as a marker of fibrosis. Hepatology 1996, 24:1399–1403.PubMedCrossRefGoogle Scholar
  25. 25.
    Bentsen KD, Horn T, Risteli J, et al.: Serum aminoterminal type III procollagen peptide and the 7S domain of type IV collagen in patients with alcohol abuse: relation to ultrastructural fibrosis in the acinar zone 3 and to serum hyaluronan. Liver 1987, 7:339–346.PubMedGoogle Scholar
  26. 26.
    Nyberg A, Engstrom-Laurent A, Loof L: Serum hyaluronate in primary biliary cirrhosis: a biochemical marker for progressive liver damage. Hepatology 1988, 8:142–146.PubMedCrossRefGoogle Scholar
  27. 27.
    Oberti F, Valsesia E, Pilette C, et al.: Noninvasive diagnosis of hepatic fibrosis or cirrhosis. Gastroenterology 1997, 113:1609–1616. This prospective study evaluated several different noninvasive means of assessing the degree of hepatic fibrosis, and serum hyaluronate was found to be the most sensitive screening test, with a sensitivity of 97% and specificity of 73%.PubMedCrossRefGoogle Scholar
  28. 28.
    Murawaki Y, Ijuta Y, Koda M, Kawasaki H: Serum type III procollagen peptide, type IV collagen 7S domain, central triple-helix of type IV collagen and tissue inhibitor of metalloproteinases in patients with chronic viral liver disease: relationship to liver histology. Hepatology 1994, 20:780–787.PubMedCrossRefGoogle Scholar
  29. 29.
    Yabu K, Kiyosawa K, Mori H, et al.: Serum collagen type IV for the assessment of fibrosis and resistance to interferon therapy in chronic hepatitis C. Scand J Gastroenterol 1994, 29:474–479.PubMedGoogle Scholar
  30. 30.
    Johansen JS, Moller S, Price PA, et al.: Plasma YKL-40: a new potential marker of fibrosis in patients with alcoholic cirrhosis? Scand J Gastroenterol 1997, 32:582–590.PubMedCrossRefGoogle Scholar
  31. 31.
    Johansen JS, Christoffersen P, Moller S, et al.: Serum YKL-40 is increased in patients with hepatic fibrosis. J Hepatol 2000, 32:911–920. The serum concentration of YKL-40, a relatively new serum marker of liver fibrosis, is shown here to correlate with liver fibrosis from many different liver diseases.PubMedCrossRefGoogle Scholar
  32. 32.
    Nunes D, Keaveny A, Maldanado N, et al.: Comparative study of YKL-40 (Chondrex), procollagen III peptide and hyaluronan for the diagnosis of hepatitis C associated liver fibrosis [abstract]. Hepatology 1998, 28:408AGoogle Scholar
  33. 33.
    Annoni G, Cargnel A, Colombo M, Hahn EG: Persistent elevation of the aminoterminal peptide of procollagen type III in serum of patients with acute viral hepatitis distinguishes chronic active hepatitis from resolving or chronic persistent hepatitis. J Hepatol 1986, 2:379–388.PubMedCrossRefGoogle Scholar
  34. 34.
    Montalto G, Soresi M, Aaragena F, et al.: Procollagen III and laminin in chronic viral hepatopathies [in French]. Presse Med 1996, 25:59–62.PubMedGoogle Scholar
  35. 35.
    Teare JP, Sherman D, Greenfield SM, et al.: Comparison of serum procollagen III peptide concentrations and PGA index for assessment of hepatic fibrosis [see comments]. Lancet 1993, 342:895–898.PubMedCrossRefGoogle Scholar
  36. 36.
    Trinchet JC, Hartmann DJ, Pateron D, et al.: 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.PubMedCrossRefGoogle Scholar
  37. 37.
    Gabrielli GB, Capra F, Casaril M, et al.: Serum laminin and type III procollagen in chronic hepatitis C: diagnostic value in the assessment of disease activity and fibrosis. Clin Chim Acta 1997, 265:21–31.PubMedCrossRefGoogle Scholar
  38. 38.
    Raedsch R, Stiehl A, Waldherr R, et al.: Procollagen-type IIIpeptide serum concentrations in chronic persistent and chronic active hepatitis and in cirrhosis of the liver and their diagnostic value. Z Gastroenterol 1982, 20:738–743.PubMedGoogle Scholar
  39. 39.
    Remmel T, Remmel H, Salupere V: Aminoterminal propeptide of type III procollagen and hyaluronan in patients with primary biliary cirrhosis: markers of fibrosis in primary biliary cirrhosis. J Gastroenterol Hepatol 1996, 11:1016–1020.PubMedGoogle Scholar
  40. 40.
    Mutimer DJ, Bassendine MF, Kelly P, James OF: Is measurement of type III procollagen amino propeptide useful in primary biliary cirrhosis? J Hepatol 1989, 9:184–189.PubMedCrossRefGoogle Scholar
  41. 41.
    Takahara T, Furui K, Yata Y, et al.: Dual expression of matrix metalloproteinase-2 and membrane-type 1-matrix metalloproteinase in fibrotic human livers. Hepatology 1997, 26:1521–1529.PubMedCrossRefGoogle Scholar
  42. 42.
    Takahara T, Frui K, Funaki J, et al.: Increased expression of matrix metalloproteinase-II in experimental liver fibrosis in rats. Hepatology 1995, 21:787–795.PubMedCrossRefGoogle Scholar
  43. 43.
    Kasahara A, Hayashi N, Mochizuki K, et al.: Circulating matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-1 as serum markers of fibrosis in patients with chronic hepatitis C: relationship to interferon response. J Hepatol 1997, 26:574–583.PubMedCrossRefGoogle Scholar
  44. 44.
    Walsh KM, Timms P, Campbell S, et al.: Plasma levels of matrix metalloproteinase-2 (MMP-2) and tissue inhibitors of metalloproteinases -1 and -2 (TIMP-1 and TIMP-2) as noninvasive markers of liver disease in chronic hepatitis C: comparison using ROC analysis. Dig Dis Sci 1999, 44:624–630. This study used receiver operating characteristic (ROC) analysis to determine the sensitivity of the matrix metalloproteinases and tissue inhibitors of metalloproteinases in detecting liver diseases.PubMedCrossRefGoogle Scholar
  45. 45.
    Murawaki Y, Ikuta Y, Okamoto K, et al.: Serum matrix metalloproteinase-3 (stromelysin-1) concentration in patients with chronic liver disease. J Hepatol 1999, 31:474–481.PubMedCrossRefGoogle Scholar
  46. 46.
    Roulot D, Durand H, Coste T, et al.: Quantitative analysis of transforming growth factor beta 1 messenger RNA in the liver of patients with chronic hepatitis C: absence of correlation between high levels and severity of disease. Hepatology 1995, 21:298–304.PubMedGoogle Scholar
  47. 47.
    Annoni G, Weiner FR, Zern MA: Increased transforming growth factor-beta 1 gene expression in human liver disease [see comments]. J Hepatol 1992, 14:259–264.PubMedCrossRefGoogle Scholar
  48. 48.
    Roulot D, Sevcsik AM, Coste M, et al.: Role of transforming growth factor beta type II receptor in hepatic fibrosis: studies of human chronic hepatitis C and experimental fibrosis in rats [see comments]. Hepatology 1999, 29:1730–1738.PubMedCrossRefGoogle Scholar
  49. 49.
    Powell EE, Edwards-Smith CJ, Hay JL, et al.: Host genetic factors influence disease progression in chronic hepatitis C. Hepatology 2000, 31:828–833. The authors evaluate the genetic factors influencing the rate of fibrosis progression and suggest an association between inheritance of high TGF-β1 and angiotensinogen producing genotypes and progressive hepatic fibrosis.PubMedCrossRefGoogle Scholar
  50. 50.
    Flisiak R, Pytel-Krolczuk B, Prokopowicz D: Circulating transforming growth factor beta(1) as an indicator of hepatic function impairment in liver cirrhosis. Cytokine 2000, 12:677–681.PubMedCrossRefGoogle Scholar
  51. 51.
    Castilla A, Prieto J, Fausto N: Transforming growth factors beta 1 and alpha in chronic liver disease. Effects of interferon alfa therapy [see comments]. N Engl J Med 1991, 324:933–940.PubMedCrossRefGoogle Scholar
  52. 52.
    Bedossa P, Poynard T, Mathurin P, et al.: Transforming growth factor beta 1: in situ expression in the liver of patients with chronic hepatitis C treated with alpha interferon. Gut 1993, 34:S146-S147.PubMedGoogle Scholar

Copyright information

© Current Science Inc 2001

Authors and Affiliations

  • Sangik Oh
    • 1
  • Nezam H. Afdhal
    • 1
  1. 1.Harvard Medical SchoolBeth Israel Deaconess Medical CenterBostonUSA

Personalised recommendations