European Radiology

, Volume 22, Issue 8, pp 1709–1716 | Cite as

MR T1ρ as an imaging biomarker for monitoring liver injury progression and regression: an experimental study in rats with carbon tetrachloride intoxication

  • Feng Zhao
  • Yi-Xiang J Wang
  • Jing Yuan
  • Min Deng
  • Hing Lok Wong
  • Eagle S. H. Chu
  • Minnie Y. Y. Go
  • Gao-Jun Teng
  • Anil T. Ahuja
  • Jun Yu



Recently it was shown that the magnetic resonance imaging (MRI) T1ρ value increased with the severity of liver fibrosis in rats with bile duct ligation. Using a rat carbon tetrachloride (CCl4) liver injury model, this study further investigated the merit of T1ρ relaxation for liver fibrosis evaluation.


Male Sprague-Dawley rats received intraperitoneal injection of 2 ml/kg CCl4 twice weekly for up to 6 weeks. Then CCl4 was withdrawn and the animals were allowed to recover. Liver T1ρ MRI and conventional T2-weighted images were acquired. Animals underwent MRI at baseline and at 2 days, 2 weeks, 4 weeks and 6 weeks post CCl4 injection, and they were also examined at 1 week and 4 weeks post CCl4 withdrawal. Liver histology was also sampled at these time points.


Liver T1ρ values increased slightly, though significantly, on day 2, and then increased further and were highest at week 6 post CCl4 insults. The relative liver signal intensity change on T2-weighted images followed a different time course compared with that of T1ρ. Liver T1ρ values decreased upon the withdrawal of the CCl4 insult. Histology confirmed the animals had typical CCl4 liver injury and fibrosis progression and regression processes.


MR T1ρ imaging can monitor CCl4-induced liver injury and fibrosis.

Key Points

• MR T1ρ is a valuable imaging biomarker for liver injury/fibrosis.

• Liver T1ρ was only mildly affected by oedema and acute inflammation.

• Liver MR T1ρ decreased when liver fibrosis and injury regressed.


T1ρ Liver fibrosis Liver cirrhosis CCl4 Imaging biomarker 



This study was supported by a direct grant for research of The Chinese University of Hong Kong (2041607), by Hong Kong RGC General Research Fund 475911, by Hong Kong ITF grant ITS/021/10, and by a grant from the Research Grants Council of the Hong Kong SAR (Project No.SEG_CUHK02).


Yi-Xiang J. Wang, Jing Yuan and Jun Yu applied for a patent related to T1ρ MR imaging for detection and assignment of grade to liver fibrosis.


  1. 1.
    Davis GL, Albright JE, Cook SF, Rosenberg DM (2003) Projecting future complications of chronic hepatitis C in the United States. Liver Transpl 9:331–338PubMedCrossRefGoogle Scholar
  2. 2.
    Charlton M (2004) Nonalcoholic fatty liver disease: a review of current understanding and future impact. Clin Gastroenterol Hepatol 2:1048–1058PubMedCrossRefGoogle Scholar
  3. 3.
    Zhou K, Lu LG (2009) Assessment of fibrosis in chronic liver diseases. J Dig Dis 10:7–14PubMedCrossRefGoogle Scholar
  4. 4.
    Wallace K, Burt AD, Wright MC (2008) Liver fibrosis. Biochem J 411:1–18PubMedCrossRefGoogle Scholar
  5. 5.
    Wanless IR, Nakashima E, Sherman M (2000) Regression of human cirrhosis. Morphologic features and the genesis of incomplete septal cirrhosis. Arch Pathol Lab Med 124:1599–1607PubMedGoogle Scholar
  6. 6.
    Arthur MJ (2002) Reversibility of liver fibrosis and cirrhosis following treatment for hepatitis C. Gastroenterology 122:1525–1528PubMedCrossRefGoogle Scholar
  7. 7.
    Veldhuijzen IK, Toy M, Hahné SJ, De Wit GA, Schalm SW, de Man RA, Richardus JH (2010) Screening and early treatment of migrants for chronic hepatitis B virus infection is cost-effective. Gastroenterology 138:522–530PubMedCrossRefGoogle Scholar
  8. 8.
    Leung NW, Lai CL, Chang TT, Guan R, Lee CM, Ng KY, Lim SG, Wu PC, Dent JC, Edmundson S, Condreay LD, Chien RN, Asia Hepatitis Lamivudine Study Group (2001) Extended lamivudine treatment in patients with chronic hepatitis B enhances hepatitis B e antigen seroconversion rates: results after 3 years of therapy. Hepatology 33:1527–1532PubMedCrossRefGoogle Scholar
  9. 9.
    Hammel P, Couvelard A, O’Toole D, Ratouis A, Sauvanet A, Fléjou JF, Degott C, Belghiti J, Bernades P, Valla D, Ruszniewski P, Lévy P (2001) Regression of liver fibrosis after biliary drainage in patients with chronic pancreatitis and stenosis of the common bile duct. N Engl J Med 344:418–423PubMedCrossRefGoogle Scholar
  10. 10.
    Oh MK, Winn J, Poordad F (2008) Review article: diagnosis and treatment of non-alcoholic fatty liver disease. Aliment Pharmacol Ther 28:503–522PubMedCrossRefGoogle Scholar
  11. 11.
    Asadullah K, Sterry W, Volk HD (2003) Interleukin-10 therapy—review of a new approach. Pharmacol Rev 55:241–269PubMedCrossRefGoogle Scholar
  12. 12.
    Huang YH, Shi MN, Zheng WD, Zhang LJ, Chen ZX, Wang XZ (2006) Therapeutic effect of interleukin-10 on CCl4-induced hepatic fibrosis in rats. World J Gastroenterol 12:1386–1391PubMedGoogle Scholar
  13. 13.
    Friedman SL (2008) Hepatic fibrosis—overview. Toxicology 254(3):120–9PubMedCrossRefGoogle Scholar
  14. 14.
    Afdhal NH, Nunes D (2004) Evaluation of liver fibrosis: a concise review. Am J Gastroenterol 99:1160–1174PubMedCrossRefGoogle Scholar
  15. 15.
    Talwalkar JA, Yin M, Fidler JL, Sanderson SO, Kamath PS, Ehman RL (2008) Magnetic resonance imaging of hepatic fibrosis: emerging clinical applications. Hepatology 47:332–342PubMedCrossRefGoogle Scholar
  16. 16.
    Janes CH, Lindor KD (1993) Outcome of patients hospitalized for complications after outpatient liver biopsy. Ann Intern Med 118:96–98PubMedGoogle Scholar
  17. 17.
    Poniachik J, Bernstein DE, Reddy KR, Jeffers LJ, Coelho-Little ME, Civantos F, Schiff ER (1996) The role of laparoscopy in the diagnosis of cirrhosis. Gastrointest Endosc 43:568–571PubMedCrossRefGoogle Scholar
  18. 18.
    Ratziu V, Charlotte F, Heurtier A, Gombert S, Giral P, Bruckert E, Grimaldi A, Capron F, Poynard T, LIDO Study Group (2005) Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology 128:1898–1906PubMedCrossRefGoogle Scholar
  19. 19.
    Bravo AA, Sheth SG, Chopra S (2001) Liver biopsy. N Engl J Med 344:495–500PubMedCrossRefGoogle Scholar
  20. 20.
    Friedman SL, Bansal MB (2006) Reversal of hepatic fibrosis: fact or fantasy? Hepatology 43(Suppl):S82–S88PubMedCrossRefGoogle Scholar
  21. 21.
    Wang YX, Yuan J, Chu ES, Go MY, Huang H, Ahuja AT, Sung JJ, Yu J (2011) T1ρ MR imaging is sensitive to evaluate liver fibrosis: an experimental study in a rat biliary duct ligation model. Radiology 259:712–719PubMedCrossRefGoogle Scholar
  22. 22.
    Sirlin CB (2011) Science to practice: can t1ρ imaging be used to diagnose and assess the severity of hepatic fibrosis? Radiology 259:619–620PubMedCrossRefGoogle Scholar
  23. 23.
    Constandinou C, Henderson N, Iredale JP (2005) Modeling liver fibrosis in rodents. Methods Mol Med 117:237–250PubMedGoogle Scholar
  24. 24.
    Iredale JP (2007) Models of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organ. J Clin Invest 117:539–548PubMedCrossRefGoogle Scholar
  25. 25.
    Iredale JP, Benyon RC, Pickering J, McCullen M, Northrop M, Pawley S, Hovell C, Arthur MJ (1998) Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors. J Clin Invest 102:538–549PubMedCrossRefGoogle Scholar
  26. 26.
    Charagundla SR, Borthakur A, Leigh JS, Reddy R (2003) Artifacts in T(1rho)-weighted imaging: correction with a self-compensating spin-locking pulse. J Magn Reson 162:113–121PubMedCrossRefGoogle Scholar
  27. 27.
    Witschey WR, Borthakur A, Elliott MA, Fenty M, Sochor MA, Wang C, Reddy R (2008) T1rho-prepared balanced gradient echo for rapid 3D T1rho MRI. J Magn Reson Imaging 28:744–754PubMedCrossRefGoogle Scholar
  28. 28.
    Aguirre DA, Behling CA, Alpert E, Hassanein TI, Sirlin CB (2006) Liver fibrosis: noninvasive diagnosis with double contrast material-enhanced MR imaging. Radiology 239:425–437PubMedCrossRefGoogle Scholar
  29. 29.
    Salameh N, Larrat B, Abarca-Quinones J, Pallu S, Dorvillius M, Leclercq I, Fink M, Sinkus R, Van Beers BE (2009) Early detection of steatohepatitis in fatty rat liver by using MR elastography. Radiology 253:90–97PubMedCrossRefGoogle Scholar
  30. 30.
    Bonekamp S, Kamel I, Solga S, Clark J (2009) Can imaging modalities diagnose and stage hepatic fibrosis and cirrhosis accurately? J Hepatol 50:17–35PubMedCrossRefGoogle Scholar
  31. 31.
    Cheung JS, Fan SJ, Gao DS, Chow AM, Man K, Wu EX (2010) Diffusion tensor imaging of liver fibrosis in an experimental model. J Magn Reson Imaging 32:1141–1148PubMedCrossRefGoogle Scholar
  32. 32.
    Santyr GE, Henkelman RM, Bronskill MJ (1989) Spin locking for magnetic resonance imaging with application to human breast. Magn Reson Med 12:25–37PubMedCrossRefGoogle Scholar
  33. 33.
    Akella SV, Regatte RR, Gougoutas AJ, Borthakur A, Shapiro EM, Kneeland JB, Leigh JS, Reddy R (2001) Proteoglycan induced changes in T1 ρ-relaxation of articular cartilage at 4T. Magn Reson Med 46:419–423PubMedCrossRefGoogle Scholar
  34. 34.
    Szyperski T, Luginbühl P, Otting G, Güntert P, Wüthrich K (1993) Protein dynamics studied by rotating frame 15N spin relaxation times. J Biomol NMR 3:151–164PubMedGoogle Scholar
  35. 35.
    Knispel RR, Thompson RT, Pintar MM (1974) Dispersion of proton spin-lattice relaxation in tissues. J Magn Reson 14:44–51Google Scholar
  36. 36.
    Duvvuri U, Goldberg AD, Kranz JK, Hoang L, Reddy R, Wehrli FW, Wand AJ, Englander SW, Leigh JS (2001) Water magnetic relaxation dispersion in biological systems: the contribution of proton exchange and implications for the noninvasive detection of cartilage degradation. Proc Natl Acad Sci USA 98:12479–12484PubMedCrossRefGoogle Scholar
  37. 37.
    Nguyen AM, Johannessen W, Yoder JH, Wheaton AJ, Vresilovic EJ, Borthakur A, Elliott DM (2008) Noninvasive quantification of human nucleus pulposus pressure with use of T1rho-weighted magnetic resonance imaging. J Bone Joint Surg (Am) 90:796–802CrossRefGoogle Scholar
  38. 38.
    Haris M, McArdle E, Fenty M, Singh A, Davatzikos C, Trojanowski JQ, Melhem ER, Clark CM, Borthakur A (2009) Early marker for Alzheimer’s disease: hippocampus T1rho estimation. J Magn Reson Imaging 29:1008–1012PubMedCrossRefGoogle Scholar
  39. 39.
    Nestrasil I, Michaeli S, Liimatainen T, Rydeen CE, Kotz CM, Nixon JP, Hanson T, Tuite PJ (2010) T1rho and T2rho MRI in the evaluation of Parkinson’s disease. J Neurol 257:964–968PubMedCrossRefGoogle Scholar
  40. 40.
    Fleiss JL (1986) Reliability of measurement. The design and analysis of clinical experiments. Wiley, New YorkGoogle Scholar
  41. 41.
    Deng M, Zhao F, Yuan J, Ahuja AT, Wang YX (2012) Liver MR T1ρ measurement in healthy human subjects at 3 T: a preliminary study with a two-dimensional fast-field echo sequence. Br J Radiol. doi: 10.1259/bjr/98745548
  42. 42.
    Hazle JD, Narayana PA, Dunsford HA (1990) Chronic carbon tetrachloride and phospholipase D hepatotoxicity in rat: in vivo 1H magnetic resonance, total lipid analysis, and histology. Magn Reson Med 15:211–228PubMedCrossRefGoogle Scholar
  43. 43.
    Proctor E, Chatamra K (1983) Controlled induction of cirrhosis in the rat. Br J Exp Pathol 64:320–30PubMedGoogle Scholar
  44. 44.
    Wang YX, Yan SX (2008) Biomedical imaging in the safety evaluation of new drugs. Lab Anim 42:433–441PubMedCrossRefGoogle Scholar
  45. 45.
    Wang YX (2010) In vivo biomedical imaging and spectroscopy in toxicogenomics and toxicoproteomics. Mol Cell Toxicol 6(Suppl):28Google Scholar
  46. 46.
    Wang H, Li J, Chen F, De Keyzer F, Yu J, Feng Y, Nuyts J, Marchal G, Ni Y (2010) Morphological, functional and metabolic imaging biomarkers: assessment of vascular-disrupting effect on rodent liver tumours. Eur Radiol 20:2013–26PubMedCrossRefGoogle Scholar
  47. 47.
    Chen F, Sun X, De Keyzer F, Yu J, Peeters R, Coudyzer W, Vandecaveye V, Landuyt W, Bosmans H, Van Hecke P, Marchal G, Ni Y (2006) Liver tumor model with implanted rhabdomyosarcoma in rats: MR imaging, microangiography, and histopathologic analysis. Radiology 239:554–562PubMedCrossRefGoogle Scholar
  48. 48.
    Johannessen W, Auerbach J, Wheaton AJ, Kurji A, Reddy R, Borthakur A, Elliott DM (2006) Assessment of human disc degeneration and proteoglycan content using T1rho MRI. Spine (Phila Pa 1976) 31:1253–1257CrossRefGoogle Scholar
  49. 49.
    Tsukamoto H, Matsuoka M, French SW (1990) Experimental models of hepatic fibrosis: a review. Semin Liver Dis 10:56–65PubMedCrossRefGoogle Scholar

Copyright information

© European Society of Radiology 2012

Authors and Affiliations

  • Feng Zhao
    • 1
  • Yi-Xiang J Wang
    • 1
  • Jing Yuan
    • 1
  • Min Deng
    • 1
  • Hing Lok Wong
    • 2
  • Eagle S. H. Chu
    • 3
  • Minnie Y. Y. Go
    • 3
  • Gao-Jun Teng
    • 4
  • Anil T. Ahuja
    • 1
  • Jun Yu
    • 3
  1. 1.Department of Imaging and Interventional Radiology, Prince of Wales HospitalThe Chinese University of Hong KongHong Kong SARChina
  2. 2.Jockey Club Centre for Osteoporosis Care and ControlSchool of Public Health and Primary Care, Prince of Wales Hospital, The Chinese University of Hong KongHong Kong SARChina
  3. 3.Institute of Digestive Disease and Department of Medicine and Therapeutics, Li Ka Shing Institute of Health SciencesThe Chinese University of Hong KongHong Kong SARChina
  4. 4.Department of Radiology, Zhongda HospitalSoutheast UniversityNanjingChina

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