Subharmonic Aided Pressure Estimation (SHAPE)

  • Ipshita Gupta
  • John R. EisenbreyEmail author
  • Flemming Forsberg


Portal hypertension results from obstruction of the portal blood flow. An increase of over 5 mmHg in the pressure gradient between the portal vein and the inferior vena cava (IVC) or the hepatic vein defines portal hypertension. The current clinical technique for measuring the hepatic venous pressure gradient (HVPG) is invasive. Noninvasive techniques have very poor sensitivity for portal pressure estimation and are therefore, not accurate enough to be used routinely for diagnosis of portal hypertension. Thus, an alternative accurate, noninvasive ultrasound based procedure would be a major development in the diagnosis of portal hypertension making the diagnosis safer, quicker and cheaper. Our group has proposed the use of ultrasound contrast agents as pressure sensors (i.e., Subharmonic Aided Pressure Estimation, SHAPE) for noninvasive, quantitative pressure estimation in portal hypertension. SHAPE is based on the inverse relationship between the subharmonic amplitude of the microbubbles and the ambient pressure change. A pilot study was conducted with 45 patients; the SHAPE gradient between the portal and hepatic veins was in good overall agreement with the clinical HVPG measurements (r = 0.82). Patients at increased risk for variceal hemorrhage (HVPG >12 mmHg) had a significantly higher mean subharmonic gradient than patients with lower HVPGs (1.93 dB ± 0.61 vs 21.47 dB ± 0.29; p < 0.001), with a sensitivity of 100% and a specificity of 81%, indicating that SHAPE may be a useful tool for the diagnosis of clinically important portal hypertension. A large, multi-center trial is now underway and early results appear to confirm these initial findings.


Ultrasound Noninvasive Pressure estimation Portal hypertension Contrast agent Subharmonic 


  1. 1.
    Navarro V, Rossi S, Herrine S. Hepatic cirrhosis. Pharmacology and therapeutics: principles to practice. Saunders-Elsevier, Philadelphia, PA, USA. 2008. p. 505–26.Google Scholar
  2. 2.
    Sanyal AJ, Bosch J, Blei A, Arroyo V. Portal hypertension and its complications. Gastroenterology. 2008;134(6):1715–28.CrossRefPubMedGoogle Scholar
  3. 3.
    Bosch J, Garcia-Pagan JC, Berzigotti A, Abraldes JG. Measurement of portal pressure and its role in the management of chronic liver disease. Semin Liver Dis. 2006;26(4):348–62.CrossRefPubMedGoogle Scholar
  4. 4.
    Iwakiri Y. Pathophysiology of portal hypertension. Clin Liver Dis. 2014;18(2):281–91.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Garcia-Tsao G, Groszmann RJ, Fisher RL, et al. Portal pressure, presence of gastroesophageal varices and variceal bleeding. Hepatology. 1985;5(3):419–24.CrossRefPubMedGoogle Scholar
  6. 6.
    Groszmann RJ, Garcia-Tsao G, Bosch J, et al. Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis. N Engl J Med. 2005;353(21):2254–61.CrossRefPubMedGoogle Scholar
  7. 7.
    Kalambokis G, Manousou P, Vibhakorn S, et al. Transjugular liver biopsy – indications, adequacy, quality of specimens, and complications – a systematic review. J Hepatol. 2007;47(2):284–94.CrossRefPubMedGoogle Scholar
  8. 8.
    Kumar A, Khan NM, Anikhindi SA, et al. Correlation of transient elastography with hepatic venous pressure gradient in patients with cirrhotic portal hypertension: a study of 326 patients from india. World J Gastroenterol. 2017;23(4):687–96.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Cokkinos DD, Dourakis SP. Ultrasonographic assessment of cirrhosis and portal hypertension. Curr Med Imaging Rev. 2009;5(1):62–70.CrossRefGoogle Scholar
  10. 10.
    Lafortune M, Marleau D, Breton G, et al. Portal venous system measurements in portal-hypertension. Radiology. 1984;151(1):27–30.CrossRefPubMedGoogle Scholar
  11. 11.
    Choi YJ, Baik SK, Park DH, et al. Comparison of Doppler ultrasonography and the hepatic venous pressure gradient in assessing portal hypertension in liver cirrhosis. J Gastroenterol Hepatol. 2003;18(4):424–9.CrossRefPubMedGoogle Scholar
  12. 12.
    Kim MY, Jeong WK, Baik SK. Invasive and non-invasive diagnosis of cirrhosis and portal hypertension. World J Gastroenterol. 2014;20(15):4300–15.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Goldberg BB, Liu JB, Forsberg F. Ultrasound contrast agents – a review. Ultrasound Med Biol. 1994;20(4):319–33.CrossRefPubMedGoogle Scholar
  14. 14.
    Stride EP, Coussios CC. Cavitation and contrast: the use of bubbles in ultrasound imaging and therapy. Proc Inst Mech Eng H. 2010;224(H2):171–91.CrossRefPubMedGoogle Scholar
  15. 15.
    Forsberg F, Shi WT, Goldberg BB. Subharmonic imaging of contrast agents. Ultrasonics. 2000;38(1–8):93–8.CrossRefPubMedGoogle Scholar
  16. 16.
    Forsberg F, Liu JB, Shi WT, et al. In vivo pressure estimation using subharmonic contrast microbubble signals: proof of concept. IEEE Trans Ultrason Ferroelectr Freq Control. 2005;52(4):581–3.CrossRefPubMedGoogle Scholar
  17. 17.
    Shankar PM, Krishna PD, Newhouse VL. Subharmonic backscattering from ultrasound contrast agents. J Acoust Soc Am. 1999;106(4):2104–10.CrossRefPubMedGoogle Scholar
  18. 18.
    Daeichin V, Bosch JG, Needles A, et al. Subharmonic, non-linear fundamental and ultraharmonic imaging of microbubble contrast at high frequencies. Ultrasound Med Biol. 2015;41(2):486–97.CrossRefPubMedGoogle Scholar
  19. 19.
    Shi WT, Forsberg F, Raichlen JS, Needleman L, Goldberg BB. Pressure dependence of subharmonic signals from contrast microbubbles. Ultrasound Med Biol. 1999;25(2):275–83.CrossRefPubMedGoogle Scholar
  20. 20.
    Halldorsdottir VG, Dave JK, Leodore LM, et al. Subharmonic contrast microbubble signals for noninvasive pressure estimation under static and dynamic flow conditions. Ultrason Imaging. 2011;33(3):153–64.CrossRefPubMedGoogle Scholar
  21. 21.
    Sontum PC. Physicochemical characteristics of sonazoid (tm), a new contrast agent for ultrasound imaging. Ultrasound Med Biol. 2008;34(5):824–33.CrossRefPubMedGoogle Scholar
  22. 22.
    Landmark KE, Johansen PW, Johnson JA, et al. Pharmacokinetics of perfluorobutane following intravenous bolus injection and continuous infusion of sonazoid (tm) in healthy volunteers and in patients with reduced pulmonary diffusing capacity. Ultrasound Med Biol. 2008;34(3):494–501.CrossRefPubMedGoogle Scholar
  23. 23.
    Bouakaz A, De Jong N. Wfumb safety symposium on echo-contrast agents: nature and types of ultrasound contrast agents. Ultrasound Med Biol. 2007;33(2):187–96.CrossRefPubMedGoogle Scholar
  24. 24.
    Dave JK, Halldorsdottir VG, Eisenbrey JR, et al. Investigating the efficacy of subharmonic aided pressure estimation for portal vein pressures and portal hypertension monitoring. Ultrasound Med Biol. 2012;38(10):1784–98.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Eisenbrey JR, Dave JK, Halldorsdottir VG, et al. Chronic liver disease: noninvasive subharmonic aided pressure estimation of hepatic venous pressure gradient. Radiology. 2013;268(2):581–8.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Malinchoc M, Kamath PS, Gordon FD, et al. A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts. Hepatology. 2000;31(4):864–71.CrossRefPubMedGoogle Scholar
  27. 27.
    Dave JK, Halldorsdottir VG, Eisenbrey JR, et al. On the implementation of an automated acoustic output optimization algorithm for subharmonic aided pressure estimation. Ultrasonics. 2013;53(4):880–8.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Kamath PS, Wiesner RH, Malinchoc M, et al. A model to predict survival in patients with end-stage liver disease. Hepatology. 2001;33(2):464–70.CrossRefPubMedGoogle Scholar
  29. 29.
    Maruyama H, Shimada T, Ishibashi H, et al. Delayed periportal enhancement: a characteristic finding on contrast ultrasound in idiopathic portal hypertension. Hepatol Int. 2012;6(2):511–9.CrossRefPubMedGoogle Scholar
  30. 30.
    Zhang CX, Hu J, Hu KW, et al. Noninvasive analysis of portal pressure by contrast-enhanced sonography in patients with cirrhosis. J Ultrasound Med. 2011;30(2):205–11.CrossRefPubMedGoogle Scholar
  31. 31.
    Jansen C, Bogs C, Verlinden W, et al. Shear-wave elastography of the liver and spleen identifies clinically significant portal hypertension: a prospective multicentre study. Liver Int. 2017;37(3):396–405.CrossRefPubMedGoogle Scholar
  32. 32.
    Gupta I, Eisenbrey J, Stanczak M, et al. Effect of pulse shaping on subharmonic aided pressure estimation in vitro and in vivo. J Ultrasound Med. 2017;36(1):3–11.Google Scholar
  33. 33.
    Halldorsdottir VG, Dave JK, Eisenbrey JR, et al. Subharmonic aided pressure estimation for monitoring interstitial fluid pressure in tumours – in vitro and in vivo proof of concept. Ultrasonics. 2014;54(7):1938–44.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Ipshita Gupta
    • 1
  • John R. Eisenbrey
    • 1
    Email author
  • Flemming Forsberg
    • 1
  1. 1.Thomas Jefferson UniversityPhiladelphiaUSA

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