Advertisement

Metabolic Changes in Different Stages of Liver Fibrosis: In vivo Hyperpolarized 13C MR Spectroscopy and Metabolic Imaging

  • Chung-Man Moon
  • Sang-Soo ShinEmail author
  • Suk-Hee Heo
  • Hyo-Soon Lim
  • Myeong-Ju Moon
  • Suchithra Poilil Surendran
  • Ga-Eon Kim
  • Il-Woo Park
  • Yong-Yeon Jeong
Research Article
  • 83 Downloads

Abstract

Purpose

The objective was to assess metabolic changes in different stages of liver fibrosis using hyperpolarized C-13 magnetic resonance spectroscopy (MRS) and metabolic imaging.

Procedures

Mild and severe liver fibrosis were induced in C3H/HeN mice (n = 14) by injecting thioacetamide (TAA). Other C3H/HeN mice (n = 7) were injected with phosphate buffer saline (PBS) (7.4 pH) as normal controls. Hyperpolarized C-13 MRS was performed on the livers of the mice, which was accompanied by intravoxel incoherent motion (IVIM) diffusion-weighted imaging with 12 b values. The differential metabolite ratios, apparent diffusion coefficient values, and IVIM parameters among the three groups were analyzed by a one-way analysis of variance test.

Results

The ratios of [1-13C]lactate/pyruvate, [1-13C]lactate/total carbon (tC), [1-13C]alanine/pyruvate, and [1-13C] alanine/tC were significantly higher in both the mild and severe fibrosis groups than in the normal control group (p < 0.05). While the [1-13C]lactate/pyruvate and [1-13C]lactate/tC ratios were not significantly different between mild and severe fibrosis groups, the ratios of [1-13C]alanine/pyruvate and [1-13C]alanine/tC were significantly higher in the severe fibrosis group than in the mild fibrosis group (p < 0.05). In addition, D* showed a significantly lower value in the severe fibrosis group than in the normal or mild fibrosis groups and negatively correlated with the levels of [1-13C] lactate and [1-13C]alanine.

Conclusions

Our findings suggest that it might be possible to differentiate mild from severe liver fibrosis using the cellular metabolic changes with hyperpolarized C-13 MRS and metabolic imaging.

Key words

Liver fibrosis Hyperpolarized 13C MRS Metabolic imaging 

Notes

Funding Information

This work was supported by the funds from the National Research Foundation of Korea (2017R1A6A3A11030092; 2018R1D1A3B07043473), the Chonnam National University Hospital Research Institute of Clinical Medicine (CRI18091-2) and the Central Medical Service Co., Ltd. (CRE17181-7).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Faria SC, Ganesan K, Mwangi I, Shiehmorteza M, Viamonte B, Mazhar S, Peterson M, Kono Y, Santillan C, Casola G, Sirlin CB (2009) MR imaging of liver fibrosis: current state of the art. Radiographics 29:1615–1635CrossRefGoogle Scholar
  2. 2.
    Ebrahimi H, Naderian M, Sohrabpour AA (2016) New concepts on pathogenesis and diagnosis of liver fibrosis; a review article. Middle East J Dig Dis 8:166–178CrossRefGoogle Scholar
  3. 3.
    Manning DS, Afdhal NH (2008) Diagnosis and quantitation of fibrosis. Gastroenterology 134:1670–1681CrossRefGoogle Scholar
  4. 4.
    Harada TL, Saito K, Araki Y, Matsubayashi J, Nagao T, Sugimoto K, Tokuuye K (2018) Prediction of high-stage liver fibrosis using ADC value on diffusion-weighted imaging and quantitative enhancement ratio at the hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI at 1.5 T. Acta Radiol 59(5):509–516CrossRefGoogle Scholar
  5. 5.
    Petitclerc L, Sebastiani G, Gilbert G, Cloutier G, Tang A (2017) Liver fibrosis: review of current imaging and MRI quantification techniques. J Magn Reson Imaging 45:1276–1295CrossRefGoogle Scholar
  6. 6.
    Lurie Y, Webb M, Cytter-Kuint R, Shteingart S, Lederkremer GZ (2015) Non-invasive diagnosis of liver fibrosis and cirrhosis. World J Gastroenterol 21:11567–11583CrossRefGoogle Scholar
  7. 7.
    Moon CM, Oh CH, Ahn KY, Yang JS, Kim JY, Shin SS, Lim HS, Heo SH, Seon HJ, Kim JW, Jeong GW (2017) Metabolic biomarkers for non-alcoholic fatty liver disease induced by high-fat diet: in vivo magnetic resonance spectroscopy of hyperpolarized [1-13C]pyruvate. Biochem Biophys Res Commun 482:112–119CrossRefGoogle Scholar
  8. 8.
    Spielman DM, Mayer D, Yen YF, Tropp J, Hurd RE, Pfefferbaum A (2009) In vivo measurement of ethanol metabolism in the rat liver using magnetic resonance spectroscopy of hyperpolarized [1-13C]pyruvate. Magn Reson Med 62:307–313CrossRefGoogle Scholar
  9. 9.
    Kim GW, Oh CH, Kim JC, Yoon W, Jeong YY, Kim YH, Kim JK, Park JG, Kang HK, Jeong GW (2016) Noninvasive biomarkers for acute hepatotoxicity induced by 1,3-dichloro-2-propanol: hyperpolarized 13C dynamic MR spectroscopy. Magn Reson Imaging 34:159–165CrossRefGoogle Scholar
  10. 10.
    Moon CM, Shin SS, Lim NY, Kim SK, Kang YJ, Kim HO, Lee SJ, Beak BH, Kim YH, Jeong GW (2018) Metabolic alterations in a rat model of hepatic ischemia reperfusion injury: in vivo hyperpolarized 13C MRS and metabolic imaging. Liver Int 38(6):1117–1127CrossRefGoogle Scholar
  11. 11.
    Thomas RG, Moon MJ, Kim JH, Lee JH, Jeong YY (2015) Effectiveness of losartan-loaded hyaluronic acid (HA) micelles for the reduction of advanced hepatic fibrosis in C3H/HeN mice model. PLoS One 10:e0145512CrossRefGoogle Scholar
  12. 12.
    Crane JC, Olson MP, Nelson SJ (2013) SIVIC: open-source, standards-based software for DICOM MR spectroscopy workflows. Int J Biomed Imaging 2013:169526CrossRefGoogle Scholar
  13. 13.
    Daniels CJ, McLean MA, Schulte RF et al (2016) A comparison of quantitative methods for clinical imaging with hyperpolarized (13)C-pyruvate. NMR Biomed 29(4):387–399CrossRefGoogle Scholar
  14. 14.
    Le Bihan D, Breton E, Lallemand D (1988) Perfusion in intravoxel incoherent motion MR imaging. Radiology 168:497–505CrossRefGoogle Scholar
  15. 15.
    Batts KP, Ludwig J (1995) Chronic hepatitis: an update on terminology and reporting. Am J Surg Pathol 19:1409–1417CrossRefGoogle Scholar
  16. 16.
    Nelson SJ, Kurhanewicz J, Vigneron DB, Larson PEZ, Harzstark AL, Ferrone M, van Criekinge M, Chang JW, Bok R, Park I, Reed G, Carvajal L, Small EJ, Munster P, Weinberg VK, Ardenkjaer-Larsen JH, Chen AP, Hurd RE, Odegardstuen LI, Robb FJ, Tropp J, Murray JA (2013) Metabolic imaging of patients with prostate cancer using hyperpolarized [1-13C] pyruvate. Sci Transl Med 5:198ra108CrossRefGoogle Scholar
  17. 17.
    Cunningham CH, Lau JY, Chen AP et al (2016) Hyperpolarized 13C metabolic MRI of the human heart: initial experience. Circ Res 119(11):1177–1182CrossRefGoogle Scholar
  18. 18.
    Josan S, Billingsley K, Orduna J, Park JM, Luong R, Yu L, Hurd R, Pfefferbaum A, Spielman D, Mayer D (2015) Assessing inflammatory liver injury in an acute CCl4 model using dynamic 3D metabolic imaging of hyperpolarized [1-(13)C] pyruvate. NMR Biomed 28(12):1671–1677CrossRefGoogle Scholar
  19. 19.
    Wallace MC, Hamesch K, Lunova M, Kim Y, Weiskirchen R, Strnad P, Friedman SL (2015) Standard operating procedures in experimental liver research: thioacetamide model in mice and rats. Lab Anim 49:21–29CrossRefGoogle Scholar
  20. 20.
    Chan C, Berthiaume F, Lee K et al (2003) Metabolic flux analysis of cultured hepatocytes exposed to plasma. Biotechnol Bioeng 81(1):33–49CrossRefGoogle Scholar
  21. 21.
    Ansley JD, Isaacs JW, Rikkers LF, Kutner MH, Nordlinger BM, Rudman D (1978) Quantitative tests of nitrogen metabolism in cirrhosis: relation to other manifestations of liver disease. Gastroenterology 75:570–579Google Scholar
  22. 22.
    Elia M, Ilic V, Bacon S, Williamson DH, Smith R (1980) Relationship between the basal blood alanine concentration and the removal of an alanine load in various clinical states in man. Clin Sci (Lond) 58:301–309CrossRefGoogle Scholar
  23. 23.
    Xie B, Waters MJ, Schirra HJ (2012) Investigating potential mechanisms of obesity by metabolomics. J Biomed Biotechnol 2012:805683CrossRefGoogle Scholar
  24. 24.
    Christensen CE, Karlsson M, Winther JR, Jensen PR, Lerche MH (2014) Non-invasive in-cell determination of free cytosolic [NAD+]/[NADH] ratios using hyperpolarized glucose show large variations in metabolic phenotypes. J Biol Chem 289:2344–2352CrossRefGoogle Scholar
  25. 25.
    Mazzeo AT, Maimone S (2018) Acid-base disorders in liver disease. J Hepatol 68(3):617–618CrossRefGoogle Scholar
  26. 26.
    Bihari D, Gimson AE, Lindridge J, Williams R (1985) Lactic acidosis in fulminant hepatic failure. Some aspects of pathogenesis and prognosis. J Hepatol 1:405–416CrossRefGoogle Scholar
  27. 27.
    Funk GC, Doberer D, Kneidinger N, Lindner G, Holzinger U, Schneeweiss B (2007) Acid-base disturbances in critically ill patients with cirrhosis. Liver Int 27:901–909CrossRefGoogle Scholar
  28. 28.
    Zhang B, Liang L, Dong Y, Lian Z, Chen W, Liang C, Zhang S (2016) Intravoxel incoherent motion MR imaging for staging of hepatic fibrosis. PLoS One 11:e0147789CrossRefGoogle Scholar
  29. 29.
    Lu PX, Huang H, Yuan J, Zhao F, Chen ZY, Zhang Q, Ahuja AT, Zhou BP, Wáng YXJ (2014) Decreases in molecular diffusion, perfusion fraction and perfusion-related diffusion in fibrotic livers: a prospective clinical intravoxel incoherent motion MR imaging study. PLoS One 9:e113846CrossRefGoogle Scholar

Copyright information

© World Molecular Imaging Society 2019

Authors and Affiliations

  1. 1.Quantitative Medical Imaging SectionNational Institute of Biomedical Imaging and Bioengineering, National Institutes of HealthBethesdaUSA
  2. 2.Department of RadiologyChonnam National University Hospital, Chonnam National University Medical SchoolGwangjuSouth Korea
  3. 3.Department of RadiologyChonnam National University Hwasun HospitalHwasunRepublic of Korea
  4. 4.Department of PathologyChonnam National University HospitalGwangjuRepublic of Korea

Personalised recommendations