Hepatology International

, Volume 7, Issue 2, pp 749–757 | Cite as

Magnitude of contrast-enhanced ultrasonography as a noninvasive predictor for hepatic fibrosis: comparison with liver stiffness measurement and serum-based models

  • Akinobu Tawada
  • Hitoshi MaruyamaEmail author
  • Hidehiro Kamezaki
  • Taro Shimada
  • Hiroyuki Ishibashi
  • Masanori Takahashi
  • Tatsuo Kanda
  • Keiichi Fujiwara
  • Fumio Imazeki
  • Osamu Yokosuka
Original Article



To elucidate the efficiency of contrast-enhanced ultrasonography alone and in combination with other noninvasive models for grading hepatic fibrosis.


This prospective study included 74 patients with four grades (F1–F4) of chronic liver disease (17, 20, 18, and 19 patients, respectively). Diagnostic performances of the contrast parameter (time to the maximum intensity ratio between the right portal vein and liver parenchyma from the onset of contrast enhancement in the right portal vein) assessed by ultrasonography, liver stiffness measurement (LSM), FIB-4 test, and type IV collagen 7s were compared with histological findings.


Greatest areas under the receiver operating characteristics curve (Az) with the single model were 0.83 (95 % confidence interval 0.71–0.91) for marked fibrosis (≥F2) by FIB-4 test; 0.85 (0.73–0.92) for advanced fibrosis (≥F3) by LSM, and 0.92 (0.83–0.96) by type IV collagen 7s for cirrhosis (F4). When combined, Az for marked fibrosis was ≥0.82; the best Az value was 0.87 (0.74–0.94) for the combination of contrast parameter with FIB-4. Similarly, the Az for advanced fibrosis was ≥0.82, and the best Az value was 0.89 (0.78–0.94) for the combination of contrast parameter with LSM. The Az for cirrhosis was ≥0.95, and the best Az was 0.99 (0.97–1.00) for the combination of contrast parameter with LSM.


The contrast parameter is a promising predictor for grading hepatic fibrosis when combined with LSM or FIB-4.


Ultrasonography Liver stiffness Fibrosis Cirrhosis FIB-4 Type IV collagen 7s 



Autoimmune hepatitis


Area under the receiver operating characteristics curve


Chronic hepatitis B


Chronic hepatitis C


Type IV collagen 7s


Liver stiffness measurement


Nonalcoholic steatohepatitis


Negative predictive value


Positive predictive value


Receiver operating characteristics curve


  1. 1.
    Tandon P, Garcia-Tsao G. Portal hypertension and hepatocellular carcinoma: prognosis and beyond. Clin Gastroenterol Hepatol 2006;4:1318–1319CrossRefGoogle Scholar
  2. 2.
    Nissen NN, Martin P. Hepatocellular carcinoma: the high-risk patient. J Clin Gastroenterol 2002;35:S79–S85CrossRefGoogle Scholar
  3. 3.
    Williams R. Global challenges in liver disease. Hepatology 2006;44:521–526CrossRefGoogle Scholar
  4. 4.
    Bravo AA, Sheth SG, Chopra S. Liver biopsy. N Engl J Med 2001;344:495–500CrossRefGoogle Scholar
  5. 5.
    Scheuer PJ. Liver biopsy in chronic hepatitis: 1968-78. Gut 1978;19:554–557CrossRefGoogle Scholar
  6. 6.
    Regev A, Berho M, Jeffers LJ, et al. Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection. Am J Gastroenterol 2002;97:2614–2618CrossRefGoogle Scholar
  7. 7.
    Bedossa P, Dargere D, Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C. Hepatology 2003;38:1449–1457CrossRefGoogle Scholar
  8. 8.
    McPherson S, Stewart SF, Henderson E, et al. Simple non-invasive fibrosis scoring system can reliable exclude advanced fibrosis in patients with non-alcoholic fatty liver disease. Gut 2010;59:1265–1269CrossRefGoogle Scholar
  9. 9.
    Yoneda M, Mawatari H, Fujita K, et al. Type IV collagen 7s domain is an independent clinical marker of the severity of fibrosis in patients with nonalcoholic steatohepatitis before cirrhotic stage. J Gastroenterol 2007;42:375–381CrossRefGoogle Scholar
  10. 10.
    Castera L, Vergniol J, Foucher J, et al. Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterology 2005;128:343–350CrossRefGoogle Scholar
  11. 11.
    Ziol M, Handra-Luca A, Kettaneh A, et al. Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with chronic hepatitis C. Hepatology 2005;41:48–54CrossRefGoogle Scholar
  12. 12.
    Ishibashi H, Maruyama H, Takahashi M, et al. Assessment of hepatic fibrosis by analysis of the dynamic behaviour of microbubbles during contrast ultrasonography. Liver Int 2010;30:1355–1363CrossRefGoogle Scholar
  13. 13.
    Albrecht T, Blomley MJ, Cosgrove DO, et al. Non-invasive diagnosis of hepatic cirrhosis by transit-time analysis of an ultrasound contrast agent. Lancet 1999;353:1579–1583CrossRefGoogle Scholar
  14. 14.
    Blomley MJ, Lim AK, Harvey CJ, et al. Liver microbubble transit time compared with histology and Child-Pugh score in diffuse liver disease: a cross sectional study. Gut 2003;52:1188–1193CrossRefGoogle Scholar
  15. 15.
    Staub F, Tournoux-Facon C, Roumy J, et al. Liver fibrosis staging with contrast-enhanced ultrasonography: prospective multicenter study compared with METAVIR scoring. Eur Radiol 2009;19:1991–1917CrossRefGoogle Scholar
  16. 16.
    Orlacchio A, Bolacchi F, Petrella MC, et al. Liver contrast enhanced ultrasound perfusion imaging in the evaluation of chronic hepatitis C fibrosis: preliminary results. Ultrasound Med Biol 2011;37:1–6CrossRefGoogle Scholar
  17. 17.
    Desmet VJ, Gerber M, Hoofnagle JH, et al. Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology 1994;19:1513–1520CrossRefGoogle Scholar
  18. 18.
    Imbert-Bismut F, Ratziu V, Pieroni L, et al. Biochemical markers of liver fibrosis in patients with hepatitis C virus infection: a prospective study. Lancet 2001;357:1069–1075CrossRefGoogle Scholar
  19. 19.
    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;38:518–526CrossRefGoogle Scholar
  20. 20.
    Guechot J, Laudat A, Loria A, et al. Diagnostic accuracy of hyaluronan and type III procollagen amino-terminal peptide serum assays as markers of liver fibrosis in chronic viral hepatitis C evaluated by ROC curve analysis. Clin Chem 1996;42:558–563PubMedGoogle Scholar
  21. 21.
    Lok AS, Ghany MG, Goodman ZD, et al. Predicting cirrhosis in patients with hepatitis C based on standard laboratory tests: results of the HALT-C cohort. Hepatology 2005;42:282–292CrossRefGoogle Scholar
  22. 22.
    Vallet-Pichard A, Mallet V, Nalpas B, et al. FIB-4: an inexpensive and accurate marker of fibrosis in HCV infection. Comparison with liver biopsy and fibrotest. Hepatology 2007;46:32–36CrossRefGoogle Scholar
  23. 23.
    Fontana RJ, Goodman ZD, Dienstag JL, et al. Relationship of serum fibrosis markers with liver fibrosis stage and collagen content in patients with advanced chronic hepatitis C. Hepatology 2008;47:789–798CrossRefGoogle Scholar
  24. 24.
    Sebastiani G, Halfon P, Castera L, et al. SAFE biopsy: a validated method for large-scale staging of liver fibrosis in chronic hepatitis C. Hepatology 2009;49:1821–1827CrossRefGoogle Scholar

Copyright information

© Asian Pacific Association for the Study of the Liver 2012

Authors and Affiliations

  • Akinobu Tawada
    • 1
  • Hitoshi Maruyama
    • 1
    Email author
  • Hidehiro Kamezaki
    • 1
  • Taro Shimada
    • 1
  • Hiroyuki Ishibashi
    • 1
  • Masanori Takahashi
    • 1
  • Tatsuo Kanda
    • 1
  • Keiichi Fujiwara
    • 1
  • Fumio Imazeki
    • 1
  • Osamu Yokosuka
    • 1
  1. 1.Department of Medicine and Clinical OncologyChiba University Graduate School of MedicineChibaJapan

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