Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Evolving challenges in hepatic fibrosis

Nature Reviews Gastroenterology & Hepatology volume 7, pages 425–436 (2010)Cite this article

Subjects

Abstract

Continued elucidation of the mechanisms of hepatic fibrosis has yielded a comprehensive and nuanced portrait of fibrosis progression and regression. The paradigm of hepatic stellate cell (HSC) activation remains the foundation for defining events in hepatic fibrosis and has been complemented by progress in a number of new areas. Cellular sources of extracellular matrix beyond HSCs have been identified. In addition, the role of chemokine, adipokine, neuroendocrine, angiogenic and NAPDH oxidase signaling in the pathogenesis of hepatic fibrosis has been uncovered, as has the contribution of extracellular matrix stiffness to fibrogenesis. There is also increased awareness of the contribution of innate immunity and greater understanding of the complexity of gene regulation in HSCs and myofibroblasts. Finally, both apoptosis and senescence have been recognized as orchestrated programs that eliminate fibrogenic cells during resolution of liver fibrosis. Ironically, the progress that has been made has highlighted the growing disparity between advances in the experimental setting and their translation into new diagnostic tools and treatments. As a result, focus is shifting towards overcoming key translational challenges in order to accelerate the development of new therapies for patients with chronic liver disease.

Key Points

  • Progress in defining the cellular and molecular basis of hepatic fibrosis has brought us to a juncture where translation of these discoveries into diagnostic tools and treatments is nearing reality

  • Novel therapeutic targets continue to be unearthed by new discoveries, including the emergence of the hepatic stellate cell (HSC) as an immunoregulatory cell type

  • HSCs are also now known to participate in adipokine, angiogenic and neuroendocrine signaling, interact with other resident cell types and be regulated by epigenetic and transcriptional mediators

  • Finding better noninvasive markers of fibrogenic activity and disease progression is a high priority in order to accelerate progress in developing antifibrotic drugs

  • Genetic markers that predict fibrosis progression risk, combined with new paradigms to stratify the risk of decompensation among patients with cirrhosis, should improve clinical trial design quality and patient selection for antifibrotic therapies

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: HSC activation.
Figure 2: Sources of fibrogenic cell types in hepatic fibrosis.
Figure 3: Diagnostic approaches to detecting liver fibrosis.
Figure 4: Implications of assessing the genetic risk of fibrosis progression for designing an antifibrotic drug trial.

Similar content being viewed by others

References

  1. Friedman, S. L. Mechanisms of hepatic fibrosis and therapeutic implications. Nat. Clin. Pract. Gastroenterol. Hepatol. 1, 98–105 (2004).

    PubMed  Google Scholar 

  2. Mitchell, A. E., Colvin, H. M. & Palmer Beasley, R. Institute of Medicine recommendations for the prevention and control of hepatitis B and C. Hepatology 51, 729–733 (2010).

    PubMed  Google Scholar 

  3. Davis, G. L., Alter, M. J., El-Serag, H., Poynard, T. & Jennings, L. W. Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression. Gastroenterology 138, 513–521, 521 e1–6 (2010).

    PubMed  Google Scholar 

  4. Lim, Y. S. & Kim, W. R. The global impact of hepatic fibrosis and end-stage liver disease. Clin. Liver Dis. 12, 733–746 (2008).

    PubMed  Google Scholar 

  5. Cheung, O. & Sanyal, A. J. Recent advances in nonalcoholic fatty liver disease. Curr. Opin. Gastroenterol. 25, 230–237 (2009).

    PubMed  Google Scholar 

  6. Bugianesi, E. Non-alcoholic steatohepatitis and cancer. Clin. Liver Dis. 11, 191–207 (2007).

    CAS  PubMed  Google Scholar 

  7. Hashizume, H. et al. Primary liver cancers with nonalcoholic steatohepatitis. Eur. J. Gastroenterol. Hepatol. 19, 827–834 (2007).

    PubMed  Google Scholar 

  8. Jemal, A. et al. Cancer statistics, 2009. CA Cancer J. Clin. 59, 225–249 (2009).

    PubMed  Google Scholar 

  9. Friedman, S. L. Mechanisms of hepatic fibrogenesis. Gastroenterology 134, 1655–1669 (2008).

    CAS  PubMed  Google Scholar 

  10. Schuppan, D. & Afdhal, N. H. Liver cirrhosis. Lancet 371, 838–851 (2008).

    CAS  PubMed Central  PubMed  Google Scholar 

  11. Jiao, J., Friedman, S. L. & Aloman, C. Hepatic fibrosis. Curr. Opin. Gastroenterol. 25, 223–229 (2009).

    PubMed Central  PubMed  Google Scholar 

  12. Parola, M. & Pinzani, M. Hepatic wound repair. Fibrogenesis Tissue Repair 2, 4 (2009).

    PubMed Central  PubMed  Google Scholar 

  13. Henderson, N. C. & Iredale, J. P. Liver fibrosis: cellular mechanisms of progression and resolution. Clin. Sci. (Lond.) 112, 265–280 (2007).

    CAS  Google Scholar 

  14. Baertschiger, R. M. et al. Fibrogenic potential of human multipotent mesenchymal stromal cells in injured liver. PLOS ONE 4, e6657 (2009).

    PubMed Central  PubMed  Google Scholar 

  15. Miyata, E. et al. Hematopoietic origin of hepatic stellate cells in the adult liver. Blood 111, 2427–2435 (2008).

    CAS  PubMed  Google Scholar 

  16. Russo, F. P. et al. The bone marrow functionally contributes to liver fibrosis. Gastroenterology 130, 1807–1821 (2006).

    PubMed  Google Scholar 

  17. Forbes, S. J. et al. A significant proportion of myofibroblasts are of bone marrow origin in human liver fibrosis. Gastroenterology 126, 955–963 (2004).

    PubMed  Google Scholar 

  18. Fujimiya, T. et al. Pathological roles of bone-marrow-derived stellate cells in a mouse model of alcohol-induced fatty liver. Am. J. Physiol. Gastrointest. Liver Physiol. 297, G974–G980 (2009).

    PubMed  Google Scholar 

  19. Strieter, R. M. & Mehrad, B. New mechanisms of pulmonary fibrosis. Chest 136, 1364–1370 (2009).

    PubMed Central  PubMed  Google Scholar 

  20. Grande, M. T. & Lopez-Novoa, J. M. Fibroblast activation and myofibroblast generation in obstructive nephropathy. Nat. Rev. Nephrol. 5, 319–328 (2009).

    CAS  PubMed  Google Scholar 

  21. Kisseleva, T. et al. Bone marrow-derived fibrocytes participate in pathogenesis of liver fibrosis. J. Hepatol. 45, 429–438 (2006).

    CAS  PubMed  Google Scholar 

  22. Higashiyama, R. et al. Negligible contribution of bone marrow-derived cells to collagen production during hepatic fibrogenesis in mice. Gastroenterology 137, 1459–1466 (2009).

    CAS  PubMed  Google Scholar 

  23. Kalluri, R. & Neilson, E. G. Epithelial-mesenchymal transition and its implications for fibrosis. J. Clin. Invest. 112, 1776–1784 (2003).

    CAS  PubMed Central  PubMed  Google Scholar 

  24. Lin, S. L., Kisseleva, T., Brenner, D. A. & Duffield, J. S. Pericytes and perivascular fibroblasts are the primary source of collagen-producing cells in obstructive fibrosis of the kidney. Am. J. Pathol. 173, 1617–1627 (2008).

    CAS  PubMed Central  PubMed  Google Scholar 

  25. Humphreys, B. D. et al. Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis. Am. J. Pathol. 176, 85–97 (2010).

    CAS  PubMed Central  PubMed  Google Scholar 

  26. Zeisberg, M. et al. Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition. J. Biol. Chem. 282, 23337–23347 (2007).

    CAS  PubMed  Google Scholar 

  27. Omenetti, A. et al. Hedgehog signaling regulates epithelial-mesenchymal transition during biliary fibrosis in rodents and humans. J. Clin. Invest. 118, 3331–3342 (2008).

    CAS  PubMed Central  PubMed  Google Scholar 

  28. Omenetti, A. et al. Repair-related activation of hedgehog signaling promotes cholangiocyte chemokine production. Hepatology 50, 518–527 (2009).

    CAS  PubMed  Google Scholar 

  29. Choi, S. S. & Diehl, A. M. Epithelial-to-mesenchymal transitions in the liver. Hepatology 50, 2007–2013 (2009).

    CAS  PubMed  Google Scholar 

  30. Taura, K. et al. Hepatocytes do not undergo epithelial-mesenchymal transition in liver fibrosis in mice. Hepatology 51, 1027–1036 (2010).

    PubMed  Google Scholar 

  31. Wells, R. G. The epithelial-to-mesenchymal transition in liver fibrosis: here today, gone tomorrow? Hepatology 51, 737–740 (2010).

    CAS  PubMed  Google Scholar 

  32. Kordes, C. et al. CD133+ hepatic stellate cells are progenitor cells. Biochem. Biophys. Res. Commun. 352, 410–417 (2007).

    CAS  PubMed  Google Scholar 

  33. Sawitza, I., Kordes, C., Reister, S. & Haussinger, D. The niche of stellate cells within rat liver. Hepatology 50, 1617–1624 (2009).

    CAS  PubMed  Google Scholar 

  34. Roskams, T. Relationships among stellate cell activation, progenitor cells, and hepatic regeneration. Clin. Liver Dis. 12, 853–860 (2008).

    PubMed  Google Scholar 

  35. Seki, E. et al. CCR1 and CCR5 promote hepatic fibrosis in mice. J. Clin. Invest. 119, 1858–1870 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  36. Seki, E. et al. CCR2 promotes hepatic fibrosis in mice. Hepatology 50, 185–197 (2009).

    CAS  PubMed  Google Scholar 

  37. Pinzani, M. & Marra, F. Cytokine receptors and signaling in hepatic stellate cells. Semin. Liver Dis. 21, 397–416 (2001).

    CAS  PubMed  Google Scholar 

  38. Wasmuth, H. E. et al. Antifibrotic effects of CXCL9 and its receptor CXCR3 in livers of mice and humans. Gastroenterology 137, 309–319, 319 e1–3 (2009).

    CAS  PubMed  Google Scholar 

  39. Marra, F. & Bertolani, C. Adipokines in liver diseases. Hepatology 50, 957–969 (2009).

    CAS  PubMed  Google Scholar 

  40. Ikejima, K., Okumura, K., Kon, K., Takei, Y. & Sato, N. Role of adipocytokines in hepatic fibrogenesis. J. Gastroenterol. Hepatol. 22 (Suppl. 1), S87–S92 (2007).

    CAS  PubMed  Google Scholar 

  41. Ding, X. et al. The roles of leptin and adiponectin: a novel paradigm in adipocytokine regulation of liver fibrosis and stellate cell biology. Am. J. Pathol. 166, 1655–1669 (2005).

    CAS  PubMed Central  PubMed  Google Scholar 

  42. Ebrahimkhani, M. R., Elsharkawy, A. M. & Mann, D. A. Wound healing and local neuroendocrine regulation in the injured liver. Expert Rev. Mol. Med. 10, e11 (2008).

    PubMed  Google Scholar 

  43. Teixeira-Clerc, F. et al. CB1 cannabinoid receptor antagonism: a new strategy for the treatment of liver fibrosis. Nat. Med. 12, 671–676 (2006).

    CAS  PubMed  Google Scholar 

  44. Munoz-Luque, J. et al. Regression of fibrosis after chronic stimulation of cannabinoid CB2 receptor in cirrhotic rats. J. Pharmacol. Exp. Ther. 324, 475–483 (2008).

    CAS  PubMed  Google Scholar 

  45. Deveaux, V. et al. Cannabinoid CB2 receptor potentiates obesity-associated inflammation, insulin resistance and hepatic steatosis. PLoS ONE 4, e5844 (2009).

    PubMed Central  PubMed  Google Scholar 

  46. Passino, M. A., Adams, R. A., Sikorski, S. L. & Akassoglou, K. Regulation of hepatic stellate cell differentiation by the neurotrophin receptor p75NTR. Science 315, 1853–1856 (2007).

    CAS  PubMed  Google Scholar 

  47. Kendall, T. J. et al. p75 Neurotrophin receptor signaling regulates hepatic myofibroblast proliferation and apoptosis in recovery from rodent liver fibrosis. Hepatology 49, 901–910 (2009).

    CAS  PubMed  Google Scholar 

  48. Fernandez, M. et al. Angiogenesis in liver disease. J. Hepatol. 50, 604–620 (2009).

    CAS  PubMed  Google Scholar 

  49. Novo, E. & Parola, M. Redox mechanisms in hepatic chronic wound healing and fibrogenesis. Fibrogenesis Tissue Repair 1, 5 (2008).

    PubMed Central  PubMed  Google Scholar 

  50. De Minicis, S. & Brenner, D. A. NOX in liver fibrosis. Arch. Biochem. Biophys. 462, 266–272 (2007).

    CAS  PubMed Central  PubMed  Google Scholar 

  51. Zhan, S. S. et al. Phagocytosis of apoptotic bodies by hepatic stellate cells induces NADPH oxidase and is associated with liver fibrosis in vivo. Hepatology 43, 435–443 (2006).

    CAS  PubMed  Google Scholar 

  52. Colmenero, J. et al. Effects of losartan on hepatic expression of non-phagocytic NADPH oxidase and fibrogenic genes in patients with chronic hepatitis C. Am. J. Physiol. Gastrointest. Liver Physiol. 297, G726–G734 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  53. Moreno, M. et al. Reduction of advanced liver fibrosis by short-term targeted delivery of an angiotensin receptor blocker to hepatic stellate cells in rats. Hepatology 51, 942–952 (2009).

    Google Scholar 

  54. Sanyal, A. J. et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N. Engl. J. Med. 362, 1–5 (2010).

    Google Scholar 

  55. Sanyal, A. A randomized controlled trial of pioglitazone or vitamin E for nonalcoholic steatohepatitis (PIVENS) [abstract]. Hepatology 50, 90A (2009).

    Google Scholar 

  56. Wells, R. G. The role of matrix stiffness in regulating cell behavior. Hepatology 47, 1394–1400 (2008).

    CAS  PubMed  Google Scholar 

  57. Georges, P. C. et al. Increased stiffness of the rat liver precedes matrix deposition: implications for fibrosis. Am. J. Physiol. Gastrointest. Liver Physiol. 293, G1147–G1154 (2007).

    CAS  PubMed  Google Scholar 

  58. Park, O. et al. Diverse roles of invariant natural killer T cells in liver injury and fibrosis induced by carbon tetrachloride. Hepatology 49, 1683–1694 (2009).

    CAS  PubMed  Google Scholar 

  59. Gao, B., Radaeva, S. & Park, O. Liver natural killer and natural killer T cells: immunobiology and emerging roles in liver diseases. J. Leukoc. Biol. 86, 513–528 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  60. Notas, G., Kisseleva, T. & Brenner, D. NK and NKT cells in liver injury and fibrosis. Clin. Immunol. 130, 16–26 (2009).

    CAS  PubMed  Google Scholar 

  61. Connolly, M. K. et al. In liver fibrosis, dendritic cells govern hepatic inflammation in mice via TNF-alpha. J. Clin. Invest. 119, 3213–3225 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  62. Seki, E. et al. TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nat. Med. 13, 1324–1332 (2007).

    CAS  PubMed  Google Scholar 

  63. Seki, E. & Brenner, D. A. Toll-like receptors and adaptor molecules in liver disease: update. Hepatology 48, 322–335 (2008).

    CAS  PubMed  Google Scholar 

  64. Guo, J. et al. Functional linkage of cirrhosis-predictive single nucleotide polymorphisms of Toll-like receptor 4 to hepatic stellate cell responses. Hepatology 49, 960–968 (2009).

    CAS  PubMed  Google Scholar 

  65. Mencin, A., Kluwe, J. & Schwabe, R. F. Toll-like receptors as targets in chronic liver diseases. Gut 58, 704–720 (2009).

    CAS  PubMed  Google Scholar 

  66. Chakraborty, J. B. & Mann, D. A. NF-kappaB signalling: embracing complexity to achieve translation. J. Hepatol. 52, 285–291 (2010).

    CAS  PubMed  Google Scholar 

  67. Watanabe, A. et al. Inflammasome-mediated regulation of hepatic stellate cells. Am. J. Physiol. Gastrointest. Liver Physiol. 296, G1248–G1257 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  68. Muhanna, N. et al. Activation of hepatic stellate cells after phagocytosis of lymphocytes: a novel pathway of fibrogenesis. Hepatology 48, 963–977 (2008).

    CAS  PubMed  Google Scholar 

  69. Holt, A. P. et al. Liver myofibroblasts regulate infiltration and positioning of lymphocytes in human liver. Gastroenterology 136, 705–714 (2009).

    CAS  PubMed  Google Scholar 

  70. Mann, J. & Mann, D. A. Transcriptional regulation of hepatic stellate cells. Adv. Drug Deliv. Rev. 61, 497–512 (2009).

    CAS  PubMed  Google Scholar 

  71. Mann, J. et al. Regulation of myofibroblast transdifferentiation by DNA methylation and MeCP2: implications for wound healing and fibrogenesis. Cell Death Differ. 14, 275–285 (2007).

    CAS  PubMed  Google Scholar 

  72. Mann, J. et al. MeCP2 controls an epigenetic pathway that promotes myofibroblast transdifferentiation and fibrosis. Gastroenterology 138, 705–714, 714 e1–4 (2010).

    CAS  PubMed  Google Scholar 

  73. Fritz, D. & Stefanovic, B. RNA-binding protein RBMS3 is expressed in activated hepatic stellate cells and liver fibrosis and increases expression of transcription factor Prx1. J. Mol. Biol. 371, 585–595 (2007).

    CAS  PubMed Central  PubMed  Google Scholar 

  74. Guo, C. J., Pan, Q., Li, D. G., Sun, H. & Liu, B. W. miR-15b and miR-16 are implicated in activation of the rat hepatic stellate cell: an essential role for apoptosis. J. Hepatol. 50, 766–778 (2009).

    CAS  PubMed  Google Scholar 

  75. Venugopal, S. K. et al. Liver fibrosis causes down-regulation of miRNA-150 and miRNA-194 in hepatic stellate cells and their over-expression causes decreased stellate cell activation. Am. J. Physiol. Gastrointest. Liver Physiol. 298, G101–G106 (2009).

    PubMed Central  PubMed  Google Scholar 

  76. Oakley, F. et al. Angiotensin II activates I kappaB kinase phosphorylation of RelA at Ser 536 to promote myofibroblast survival and liver fibrosis. Gastroenterology 136, 2334–2344 e1 (2009).

    CAS  PubMed  Google Scholar 

  77. Buck, M. & Chojkier, M. A ribosomal S-6 kinase-mediated signal to C/EBP-beta is critical for the development of liver fibrosis. PLoS ONE 2, e1372 (2007).

    PubMed Central  PubMed  Google Scholar 

  78. Friedman, S. L. & Bansal, M. B. Reversal of hepatic fibrosis—fact or fantasy? Hepatology 43, S82–S88 (2006).

    CAS  PubMed  Google Scholar 

  79. Mallet, V. et al. Brief communication: the relationship of regression of cirrhosis to outcome in chronic hepatitis C. Ann. Intern. Med. 149, 399–403 (2008).

    PubMed  Google Scholar 

  80. Gonzalez, S. A. et al. Inverse association between hepatic stellate cell apoptosis and fibrosis in chronic hepatitis C virus infection. J. Viral Hepat. 16, 141–148 (2009).

    CAS  PubMed  Google Scholar 

  81. Oakley, F. et al. Inhibition of inhibitor of kappaB kinases stimulates hepatic stellate cell apoptosis and accelerated recovery from rat liver fibrosis. Gastroenterology 128, 108–120 (2005).

    CAS  PubMed  Google Scholar 

  82. Jiang, J. X., Mikami, K., Venugopal, S., Li, Y. & Torok, N. J. Apoptotic body engulfment by hepatic stellate cells promotes their survival by the JAK/STAT and Akt/NF-kappaB-dependent pathways. J. Hepatol. 51, 139–148 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  83. Krizhanovsky, V. et al. Senescence of activated stellate cells limits liver fibrosis. Cell 134, 657–667 (2008).

    CAS  PubMed Central  PubMed  Google Scholar 

  84. Regev, A. et al. Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection. Am. J. Gastroenterol. 97, 2614–2618 (2002).

    PubMed  Google Scholar 

  85. Ratziu, V. et al. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology 128, 1898–1906 (2005).

    PubMed  Google Scholar 

  86. Bedossa, P., Dargere, D. & Paradis, V. Sampling variability of liver fibrosis in chronic hepatitis C. Hepatology 38, 1449–1457 (2003).

    PubMed  Google Scholar 

  87. Goodman, Z. D. et al. Fibrosis progression in chronic hepatitis C: morphometric image analysis in the HALT-C trial. Hepatology 50, 1738–1749 (2009).

    PubMed  Google Scholar 

  88. Calvaruso, V. et al. Computer-assisted image analysis of liver collagen: relationship to Ishak scoring and hepatic venous pressure gradient. Hepatology 49, 1236–1244 (2009).

    PubMed  Google Scholar 

  89. Everhart, J. E. et al. Prognostic value of Ishak fibrosis stage: findings from the hepatitis C antiviral long-term treatment against cirrhosis trial. Hepatology 51, 585–594 (2010).

    PubMed  Google Scholar 

  90. Castera, L. Transient elastography and other noninvasive tests to assess hepatic fibrosis in patients with viral hepatitis. J. Viral Hepat. 16, 300–314 (2009).

    PubMed  Google Scholar 

  91. Vizzutti, F., Arena, U., Marra, F. & Pinzani, M. Elastography for the non-invasive assessment of liver disease: limitations and future developments. Gut 58, 157–160 (2009).

    PubMed  Google Scholar 

  92. Pinzani, M., Vizzutti, F., Arena, U. & Marra, F. Technology Insight: noninvasive assessment of liver fibrosis by biochemical scores and elastography. Nat. Clin. Pract. Gastroenterol. Hepatol. 5, 95–106 (2008).

    CAS  PubMed  Google Scholar 

  93. Arena, U. et al. Acute viral hepatitis increases liver stiffness values measured by transient elastography. Hepatology 47, 380–384 (2008).

    CAS  PubMed  Google Scholar 

  94. Vigano, M. et al. Transient elastography assessment of the liver stiffness dynamics during acute hepatitis B. Eur. J. Gastroenterol. Hepatol. 22, 180–184 (2009).

    Google Scholar 

  95. Carrion, J. A. et al. Liver stiffness identifies two different patterns of fibrosis progression in patients with hepatitis C virus recurrence after liver transplantation. Hepatology 51, 23–34 (2010).

    CAS  PubMed  Google Scholar 

  96. Talwalkar, J. A. et al. Magnetic resonance imaging of hepatic fibrosis: emerging clinical applications. Hepatology 47, 332–342 (2008).

    PubMed  Google Scholar 

  97. Bonekamp, S., Kamel, I., Solga, S. & Clark, J. Can imaging modalities diagnose and stage hepatic fibrosis and cirrhosis accurately? J. Hepatol. 50, 17–35 (2009).

    PubMed  Google Scholar 

  98. Taouli, B. et al. Diffusion-weighted MRI for quantification of liver fibrosis: preliminary experience. AJR Am. J. Roentgenol. 189, 799–806 (2007).

    PubMed  Google Scholar 

  99. Hagiwara, M. et al. Advanced liver fibrosis: diagnosis with 3D whole-liver perfusion MR imaging--initial experience. Radiology 246, 926–934 (2008).

    PubMed  Google Scholar 

  100. Barash, H. et al. Functional magnetic resonance imaging monitoring of pathological changes in rodent livers during hyperoxia and hypercapnia. Hepatology 48, 1232–1241 (2008).

    PubMed  Google Scholar 

  101. Fahey, B. J., Nightingale, K. R., Nelson, R. C., Palmeri, M. L. & Trahey, G. E. Acoustic radiation force impulse imaging of the abdomen: demonstration of feasibility and utility. Ultrasound Med. Biol. 31, 1185–1198 (2005).

    PubMed  Google Scholar 

  102. Friedrich-Rust, M. et al. Liver fibrosis in viral hepatitis: noninvasive assessment with acoustic radiation force impulse imaging versus transient elastography. Radiology 252, 595–604 (2009).

    PubMed  Google Scholar 

  103. Smith, J. O. & Sterling, R. K. Systematic review: Non-invasive methods of fibrosis analysis in chronic hepatitis C. Aliment. Pharmacol. Ther. 30, 557–576 (2009).

    CAS  PubMed  Google Scholar 

  104. Smith, M. W. et al. Gene expression patterns that correlate with hepatitis C and early progression to fibrosis in liver transplant recipients. Gastroenterology 130, 179–187 (2006).

    CAS  PubMed  Google Scholar 

  105. Leroy, V. et al. Prospective comparison of six non-invasive scores for the diagnosis of liver fibrosis in chronic hepatitis C. J. Hepatol. 46, 775–782 (2007).

    PubMed  Google Scholar 

  106. Gressner, O. A., Weiskirchen, R. & Gressner, A. M. Biomarkers of hepatic fibrosis, fibrogenesis and genetic pre-disposition pending between fiction and reality. J. Cell. Mol. Med. 11, 1031–1051 (2007).

    CAS  PubMed Central  PubMed  Google Scholar 

  107. Nunes, D. et al. Noninvasive markers of liver fibrosis are highly predictive of liver-related death in a cohort of HCV-infected individuals with and without HIV infection. Am. J. Gastroenterol. doi: 10.1038/ajg.2009.746.

    Google Scholar 

  108. Ngo, Y. et al. A prospective analysis of the prognostic value of biomarkers (FibroTest) in patients with chronic hepatitis C. Clin. Chem. 52, 1887–1896 (2006).

    CAS  PubMed  Google Scholar 

  109. Mayo, M. J. et al. Prediction of clinical outcomes in primary biliary cirrhosis by serum enhanced liver fibrosis assay. Hepatology 48, 1549–1557 (2008).

    PubMed  Google Scholar 

  110. Sebastiani, G. et al. SAFE biopsy: a validated method for large-scale staging of liver fibrosis in chronic hepatitis C. Hepatology 49, 1821–1827 (2009).

    PubMed  Google Scholar 

  111. Castera, L. et al. Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterology 128, 343–350 (2005).

    PubMed  Google Scholar 

  112. Fontana, R. J. et al. Serum fibrosis marker levels decrease after successful antiviral treatment in chronic hepatitis C patients with advanced fibrosis. Clin. Gastroenterol. Hepatol. 7, 219–226 (2009).

    CAS  PubMed  Google Scholar 

  113. Nobili, V. et al. Performance of ELF serum markers in predicting fibrosis stage in pediatric non-alcoholic fatty liver disease. Gastroenterology 136, 160–167 (2009).

    CAS  PubMed  Google Scholar 

  114. de Ledinghen, V. et al. Diagnosis of hepatic fibrosis and cirrhosis by transient elastography in HIV/hepatitis C virus-coinfected patients. J. Acquir. Immune Defic. Syndr. 41, 175–179 (2006).

    PubMed  Google Scholar 

  115. Sanchez-Conde, M. et al. Comparison of transient elastography and liver biopsy for the assessment of liver fibrosis in HIV/hepatitis C virus-coinfected patients and correlation with noninvasive serum markers. J. Viral Hepat. 17, 280–286 (2009).

    PubMed  Google Scholar 

  116. Berenguer, J. et al. Sustained virological response to interferon plus ribavirin reduces liver-related complications and mortality in patients coinfected with human immunodeficiency virus and hepatitis C virus. Hepatology 50, 407–413 (2009).

    CAS  PubMed  Google Scholar 

  117. Russo, M. W. et al. Early hepatic stellate cell activation is associated with advanced fibrosis after liver transplantation in recipients with hepatitis C. Liver Transpl. 11, 1235–1241 (2005).

    PubMed  Google Scholar 

  118. Armuzzi, A. et al. Review article: breath testing for human liver function assessment. Aliment. Pharmacol. Ther. 16, 1977–1996 (2002).

    CAS  PubMed  Google Scholar 

  119. Petrolati, A. et al. 13C-methacetin breath test for monitoring hepatic function in cirrhotic patients before and after liver transplantation. Aliment. Pharmacol. Ther. 18, 785–790 (2003).

    CAS  PubMed  Google Scholar 

  120. Ripoll, C. et al. Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis. Gastroenterology 133, 481–488 (2007).

    CAS  PubMed  Google Scholar 

  121. Talwalkar, J. A. Antifibrotic therapies—emerging biomarkers as treatment end points. Nat. Rev. Gastroenterol. Hepatol. 7, 59–61 (2010).

    CAS  PubMed  Google Scholar 

  122. Hold, G. L., Untiveros, P., Saunders, K. A. & El-Omar, E. M. Role of host genetics in fibrosis. Fibrogenesis Tissue Repair 2, 6 (2009).

    PubMed Central  PubMed  Google Scholar 

  123. Weber, S., Gressner, O. A., Hall, R., Grunhage, F. & Lammert, F. Genetic determinants in hepatic fibrosis: from experimental models to fibrogenic gene signatures in humans. Clin. Liver Dis. 12, 747–757 (2008).

    PubMed  Google Scholar 

  124. Wasmuth, H. E. et al. The Marburg I variant (G534E) of the factor VII-activating protease determines liver fibrosis in hepatitis C infection by reduced proteolysis of platelet-derived growth factor BB. Hepatology 49, 775–780 (2009).

    CAS  PubMed  Google Scholar 

  125. Asselah, T. et al. Genetics, genomics, and proteomics: implications for the diagnosis and the treatment of chronic hepatitis C. Semin. Liver Dis. 27, 13–27 (2007).

    CAS  PubMed  Google Scholar 

  126. Huang, H. et al. A 7 gene signature identifies the risk of developing cirrhosis in patients with chronic hepatitis C. Hepatology 46, 297–306 (2007).

    CAS  PubMed  Google Scholar 

  127. Huang, H. et al. Identification of two gene variants associated with risk of advanced fibrosis in patients with chronic hepatitis C. Gastroenterology 130, 1679–1687 (2006).

    CAS  PubMed  Google Scholar 

  128. Marcolongo, M. et al. A seven-gene signature (cirrhosis risk score) predicts liver fibrosis progression in patients with initially mild chronic hepatitis C. Hepatology 50, 1038–1044 (2009).

    CAS  PubMed  Google Scholar 

  129. Wasmuth, H. E. et al. CC chemokine receptor 5 delta32 polymorphism in two independent cohorts of hepatitis C virus infected patients without hemophilia. J. Mol. Med. 82, 64–69 (2004).

    CAS  PubMed  Google Scholar 

  130. Hillebrandt, S. et al. Complement factor 5 is a quantitative trait gene that modifies liver fibrogenesis in mice and humans. Nat. Genet. 37, 835–843 (2005).

    CAS  PubMed  Google Scholar 

  131. Hung, T. M. et al. A novel nonsynonymous variant of matrix metalloproteinase-7 confers risk of liver cirrhosis. Hepatology 50, 1184–1193 (2009).

    CAS  PubMed  Google Scholar 

  132. Freedman, N. D. et al. Coffee intake is associated with lower rates of liver disease progression in chronic hepatitis C. Hepatology 50, 1360–1369 (2009).

    CAS  PubMed  Google Scholar 

  133. Ruhl, C. E. & Everhart, J. E. Coffee and tea consumption are associated with a lower incidence of chronic liver disease in the United States. Gastroenterology 129, 1928–1936 (2005).

    PubMed  Google Scholar 

  134. Modi, A. A. et al. Increased caffeine consumption is associated with reduced hepatic fibrosis. Hepatology 51, 201–209 (2010).

    CAS  PubMed  Google Scholar 

  135. Chan, E. S. et al. Adenosine A(2A) receptors play a role in the pathogenesis of hepatic cirrhosis. Br. J. Pharmacol. 148, 1144–1155 (2006).

    CAS  PubMed Central  PubMed  Google Scholar 

  136. Chan, H. L. et al. Hepatitis B virus genotype C is associated with more severe liver fibrosis than genotype B. Clin. Gastroenterol. Hepatol. 7, 1361–1366 (2009).

    PubMed  Google Scholar 

  137. Bochud, P. Y. et al. Genotype 3 is associated with accelerated fibrosis progression in chronic hepatitis C. J. Hepatol. 51, 655–666 (2009).

    CAS  PubMed  Google Scholar 

  138. Macias, J. et al. Fast fibrosis progression between repeated liver biopsies in patients coinfected with human immunodeficiency virus/hepatitis C virus. Hepatology 50, 1056–1063 (2009).

    CAS  PubMed  Google Scholar 

  139. Pinzani, M. & Vizzutti, F. Fibrosis and cirrhosis reversibility: clinical features and implications. Clin. Liver Dis. 12, 901–913 (2008).

    PubMed  Google Scholar 

  140. Ramachandran, P. & Iredale, J. P. Reversibility of liver fibrosis. Ann. Hepatol. 8, 283–291 (2009).

    PubMed  Google Scholar 

  141. Garcia-Tsao, G., Friedman, S., Iredale, J. & Pinzani, M. Now there are many (stages) where before there was one: In search of a pathophysiological classification of cirrhosis. Hepatology 51, 1445–1449 (2010).

    PubMed  Google Scholar 

  142. Ghany, M. G. et al. Predicting clinical and histologic outcomes based on standard laboratory tests in advanced chronic hepatitis C. Gastroenterology 138, 136–146 (2010).

    CAS  PubMed  Google Scholar 

  143. Kazemi, F. et al. Liver stiffness measurement selects patients with cirrhosis at risk of bearing large oesophageal varices. J. Hepatol. 45, 230–235 (2006).

    PubMed  Google Scholar 

  144. Masuzaki, R. et al. Risk assessment of hepatocellular carcinoma in chronic hepatitis C patients by transient elastography. J. Clin. Gastroenterol. 42, 839–843 (2008).

    PubMed  Google Scholar 

  145. Nagula, S., Jain, D., Groszmann, R. J. & Garcia-Tsao, G. Histological–hemodynamic correlation in cirrhosis—a histological classification of the severity of cirrhosis. J. Hepatol. 44, 111–117 (2006).

    PubMed  Google Scholar 

  146. Iredale, J. P. Models of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organ. J. Clin. Invest. 117, 539–548 (2007).

    CAS  PubMed Central  PubMed  Google Scholar 

  147. Popov, Y., Patsenker, E., Fickert, P., Trauner, M. & Schuppan, D. Mdr2 (Abcb4)−/− mice spontaneously develop severe biliary fibrosis via massive dysregulation of pro- and antifibrogenic genes. J. Hepatol. 43, 1045–1054 (2005).

    CAS  PubMed  Google Scholar 

  148. Lichtman, S. N., Wang, J. & Clark, R. L. A microcholangiographic study of liver disease models in rats. Acad. Radiol. 2, 515–521 (1995).

    CAS  PubMed  Google Scholar 

  149. Popov, Y. et al. Integrin alphavbeta6 is a marker of the progression of biliary and portal liver fibrosis and a novel target for antifibrotic therapies. J. Hepatol. 48, 453–464 (2008).

    CAS  PubMed  Google Scholar 

  150. Friedman, S. L. Reversibility of hepatic fibrosis and cirrhosis--is it all hype? Nat. Clin. Pract. Gastroenterol. Hepatol. 4, 236–237 (2007).

    PubMed  Google Scholar 

  151. Ghiassi-Nejad, Z. & Friedman, S. L. Advances in antifibrotic therapy. Expert Rev. Gastroenterol. Hepatol. 2, 803–816 (2008).

    PubMed Central  PubMed  Google Scholar 

  152. Rockey, D. C. Current and future anti-fibrotic therapies for chronic liver disease. Clin. Liver Dis. 12, 939–962 (2008).

    PubMed Central  PubMed  Google Scholar 

  153. Popov, Y. & Schuppan, D. Targeting liver fibrosis: strategies for development and validation of antifibrotic therapies. Hepatology 50, 1294–1306 (2009).

    CAS  PubMed  Google Scholar 

  154. Schoemaker, M. H. et al. PDGF-receptor beta-targeted adenovirus redirects gene transfer from hepatocytes to activated stellate cells. Mol. Pharm. 5, 399–406 (2008).

    CAS  PubMed  Google Scholar 

  155. Gonzalo, T. et al. Local inhibition of liver fibrosis by specific delivery of a PDGF kinase inhibitor to hepatic stellate cells. J. Pharmacol. Exp. Ther. 321, 856–865 (2007).

    CAS  PubMed  Google Scholar 

  156. Friedman, S. L. Targeting siRNA to arrest fibrosis. Nat. Biotechnol. 26, 399–400 (2008).

    CAS  PubMed  Google Scholar 

  157. Sato, Y. et al. Resolution of liver cirrhosis using vitamin A-coupled liposomes to deliver siRNA against a collagen-specific chaperone. Nat. Biotechnol. 26, 431–442 (2008).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Work in the author's laboratory is supported by NIH grants RO1DK37340, RO1DK56621, P20AA017067 and 1K05AA018408-01. This article highlights primarily recent studies and review articles of general interest to the readership. As a result many outstanding publications in the field could not be cited because of space constraints.

Author information

Authors and Affiliations

  1. Division of Liver Diseases, Mount Sinai School of Medicine, Box 1123, 1425 Madison Avenue, Room 1170C, New York, 10029, NY, USA

    Scott L. Friedman

Authors
  1. Scott L. Friedman
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

Scott L. Friedman is a consultant for Abbott, Amgen, Axcan Pharma, Human Genome Sciences, MDRNA, Onyx Pharmaceuticals, Salix Pharmaceuticals, Sanofi Aventis and Siemens Diagnostics (each less than US$5,000 per annum). He has stock ownership/equity and is a consultant for Angion Biomedica, Conatus Pharmaceuticals, Exalenz and Intercept Pharmaceuticals (each less than US$10,000 and less than 5%). He has restricted grants and contracts with Celera (to study the mechanisms linking fibrosis risk SNPs to pathogenesis) and Bayer/Onyx Pharmaceuticals (to study antifibrotic activity of sorafenib in hepatic fibrosis). He also holds US patents on noninvasive agents for diagnosis and prognosis of the progression of fibrosis (US Patent no. 6,264,949 B1) and KLF6, a novel growth inhibitory and tumor suppressor gene (US Patent no. US2005/0181374), and has four other US patents pending that relate to hepatic fibrosis and/or hepatocellular carcinoma.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Friedman, S. Evolving challenges in hepatic fibrosis. Nat Rev Gastroenterol Hepatol 7, 425–436 (2010). https://doi.org/10.1038/nrgastro.2010.97

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrgastro.2010.97

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing