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Hepatobiliary function assessed by 99mTc-mebrofenin cholescintigraphy in the evaluation of severity of steatosis in a rat model

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Abstract

Purpose

This study evaluated the utility of non-invasive assessment of hepatobiliary function by 99mTc-mebrofenin cholescintigraphy in a rat model of diet-induced steatosis.

Methods

Male Wistar rats (250–300 g) were fed a standard methionine- and choline-deficient (MCD) diet for up to 5 weeks, thereby inducing hepatic fat accumulation, progressive inflammation and fibrogenesis corresponding with clinical steatosis. 99mTc-mebrofenin pinhole scintigraphy was used to evaluate the hepatocyte mebrofenin uptake rate, the time of maximum hepatic uptake (T peak) and the time required for peak activity to decrease by 50% (T 1/2peak). Scintigraphic parameters were correlated with biochemical and serological parameters and with liver histopathology.

Results

MCD diet induced mild steatosis after 1 week and severe steatosis with prominent inflammation after 5 weeks. T peak, T 1/2peak prolonged and the uptake rate decreased significantly, while the severity of steatosis increased (p<0.05). There was a strong, significant correlation between the severity of steatosis (histopathology, hepatic triglyceride content) and the 99mTc-mebrofenin uptake rate (r 2=0.83, p<0.0001 and r 2=0.82, p<0.0001, respectively). In addition, the uptake rate correlated significantly with the increased inflammation (plasma and hepatic TNF-α, r 2=0.72, p<0.0001 and r 2=0.52, p=0.001, respectively). The correlation of the uptake rate with hepatocellular damage was weak (AST and ALT, r 2=0.29 and 0.32, respectively), but correlation with synthetic function was strong (prothrombin time, r 2=0.70, p<0.001).

Conclusion

Hepatobiliary function assessed by 99mTc-mebrofenin scintigraphy correlates with the extent and progression of steatosis. These results suggest a potential role for mebrofenin scintigraphy as a non-invasive functional follow-up method for disease progression in steatotic patients.

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References

  1. Underwood G. Prevalence of fatty liver in healthy male adults accidentally killed. Aviat Space Environ Med 1984;55:59–63

    Google Scholar 

  2. Hilden M, Christoffersen P, Juhl E, Dahlgaard JB. Liver histology in a ‘normal’ population—examinations of 503 consecutive fatal traffic casualties. Scand J Gastroenterol 1977;12:593–597

    Article  PubMed  CAS  Google Scholar 

  3. Diehl AM. Nonalcoholic steatohepatitis. Semin Liver Dis 1999;19:221–229

    Article  PubMed  CAS  Google Scholar 

  4. McGill DB, Rakela J, Zinsmeister AR, Ott BJ. A 21-year experience with major hemorrhage after percutaneous liver biopsy. Gastroenterology 1990;99:1396–1400

    PubMed  CAS  Google Scholar 

  5. Saadeh S, Younossi ZM, Remer EM, Gramlich T, Ong JP, Hurley M, et al. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology 2002;123:745–750

    Article  PubMed  Google Scholar 

  6. Pizarro M, Balasubramaniyan N, Solis N, Solar A, Duarte I, Miguel JF, et al. Bile secretory function in obese Zucker rat: evidence of cholestasis and altered bile canalicular transport function. Gut 2004;53:1837–1843

    Article  PubMed  CAS  Google Scholar 

  7. Elferink RO, Groen AK. Genetic defects in hepatobiliary transport. Biochem Biophys Acta 2002;1586:129–145

    PubMed  Google Scholar 

  8. Arrese M, Ananthanarayanan M, Suchy FJ. Hepatobiliary transport: molecular mechanisms of development and cholestasis. Pediatr Res 1998;44:141–147

    PubMed  CAS  Google Scholar 

  9. Trauner M, Meier PJ, Boyer JL. Molecular pathogenesis of cholestasis. N Engl J Med 1998;339:1217–1227

    Article  PubMed  CAS  Google Scholar 

  10. Krishnamurthy GT, Krishnamurthy S. Nuclear hepatology, a textbook of hepatobiliary diseases. Berlin Heidelberg New York: Springer, 2000

    Google Scholar 

  11. Daniel GB, DeNovo RC, Schultze AE, Schmidt D, Smit GT. Hepatic extraction efficiency of technetium-99m-mebrofenin in the dog with toxic-induced acute liver disease. J Nucl Med 1998;39:1286–1292

    PubMed  CAS  Google Scholar 

  12. Malhi H, Bhargava KK, Afriyie MO, Volenberg I, Schilsky ML, Palestro CJ, et al. 99mTc-mebrofenin scintigraphy for evaluating liver disease in a rat model of Wilson’s disease. J Nucl Med 2002;43:246–252

    PubMed  Google Scholar 

  13. Chavez- Cartaya R, Ramirez P, Fuente T, Pino DeSola G. Blood clearance of 99mTc-trimethyl-Br-IDA discriminates between different degrees of severe liver ischemia-reperfusion injury in the rat. Eur Surg Res 1997;29:346–355

    PubMed  CAS  Google Scholar 

  14. Erdogan D, Heijnen BHM, Bennink RJ, Kok M, Dinant S, Straatsburg IH, et al. Preoperative assessment of liver function: a comparison of technetium-99m mebrofenin scintigraphy with indocyanine green clearance test. Liver Int 2004;24:117–123

    Article  PubMed  CAS  Google Scholar 

  15. Koteish A, Diehl AM. Animal models of steatosis. Semin Liver Dis 2001;21:89–104

    Article  PubMed  CAS  Google Scholar 

  16. Habraken JB, de Bruin K, Shehata M, Booij J, Bennink R, van Eck Smit BL, et al. Evaluation of high-resolution pinhole SPECT using a small rotating animal. J Nucl Med 2001;12:1863–1869

    Google Scholar 

  17. Ekman M, Fjalling M, Holmberg S, Person H. IODIDA clearance rate: a method for measuring hepatocyte uptake function. Transplant Proc 1992;24:387–388

    PubMed  CAS  Google Scholar 

  18. Bennink RJ, Vetelainen R, DeBruin C, van Vliet AK, van Gulik TM. Imaging of liver function with dedicated animal dynamic pinhole scintigraphy in rats. Nucl Med Commun 2005;26:1008–1012

    Article  Google Scholar 

  19. Fritzberg AR. The evaluation of hepatocyte function with radiotracers. In: Billinghurst MW, Colombetti LG, editors. Studies of cellular function using radiotracers. Boca Raton, Fl: CRC Press; 1982. pp 73–92

    Google Scholar 

  20. Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology 2003;37:1202–1219

    Article  PubMed  Google Scholar 

  21. Folch J, Lees M, Sloane-Stanley GH. A simple method for the isolation and purification of total lipids from animal tissues. J Biol Chem 1957;226:497–502

    PubMed  CAS  Google Scholar 

  22. Colquhoun SD, Connelly CA, Vera DR. Portal-systemic shunts reduce asialoglycoprotein receptor density in rats. J Nucl Med 2001;42:110–116

    PubMed  CAS  Google Scholar 

  23. Nunn AD, Loberg MD, Conley RA. A structure–distribution relationship approach leading to the development of Tc-99m mebrofenin: an improved cholescintigraphic agent. J Nucl Med 1983;24:423–430

    PubMed  CAS  Google Scholar 

  24. Svensson G, Fjalling M, Gretarsdottir J, Jacobsson L, Holmberg SB. Kupffer cell and hepatocyte function in rat transplanted liver. Transpl Int 1992;5(Suppl 1):S417–S419

    PubMed  Google Scholar 

  25. Bennink RJ, Dinant S, Erdogan D, Heijnen BH, Straatsburg IH, van Vliet AK, et al. Preoperative assessment of postoperative remnant liver function using hepatobiliary scintigraphy. J Nucl Med 2004;45:965–971

    PubMed  Google Scholar 

  26. Loberg MD, Cooper M, Harvey E, Callery P, Faith W. Development of new radiopharmaceuticals based on N-substitution of iminodiacetic acid. J Nucl Med 1976;17:633–638

    PubMed  CAS  Google Scholar 

  27. Hendrikse HN, Kuipers F, Meijer C, Havinga R, Bijleveld CMA, Graaf TA, et al. In vivo imaging of hepatobiliary transport function mediated by multidrug resistance associated protein and P-glycoprotein. Cancer Chem Pharm 2004;24131–138

    Google Scholar 

  28. Cui Y, König J, Leier I, Buchholz U, Keppler D. Hepatic uptake of bilirubin and its conjugates by the human organic anion transporter SLC21A6. J Biol Chem 2000;276:9626–9630

    Article  PubMed  Google Scholar 

  29. Geier A, Zollner G, Dietrich CG, Wagner M, Fickert P, Denk H, et al. Effects of proinflammatory cytokines on rat organic anion transporters during the toxic liver injury and cholestasis. Hepatology 2003;38:345–354

    Article  PubMed  CAS  Google Scholar 

  30. Hartmann G, Cheung AK, Piquette-Miller M. Inflammatory cytokines, but not bile acids, regulate the expression of murine hepatic anion transporters in endotoxemia. J Pharmacol Exp Ther 2002;303:273–281

    Article  PubMed  CAS  Google Scholar 

  31. Joseph B, Bhargava KK, Tronco G, Kumaran V, Palestro CJ, Gupta S. Regulation of hepatobiliary transport activity and noninvasive identification of cytokine-dependent liver inflammation. J Nucl Med 2005;46:146–152

    PubMed  Google Scholar 

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Acknowledgements

We thank Wilmar de Graaf for his assistance in the histology analysis and Jaap Rip (Department of Vascular Medicine) for his assistance with triglyceride assays.

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Correspondence to Thomas M. van Gulik.

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Veteläinen, R.L., Bennink, R.J., de Bruin, K. et al. Hepatobiliary function assessed by 99mTc-mebrofenin cholescintigraphy in the evaluation of severity of steatosis in a rat model. Eur J Nucl Med Mol Imaging 33, 1107–1114 (2006). https://doi.org/10.1007/s00259-006-0125-3

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