Gut and Liver 2017; 11(1): 9-10 Another Face of Contrast-Enhanced Ultrasonography: A Diagnostic Tool for Cirrhosis
Author Information
Soung Won Jeong
Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Soonchunhyang University College of Medicine, Seoul, Korea

Soung Won Jeong, Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Soonchunhyang University College of Medicine, 59 Daesagwan-ro, Yongsan-gu, Seoul 04401, Korea, Tel: +82-2-710-3076, Fax: +82-2-709-9696, E-mail:
© The Korean Society of Gastroenterology, the Korean Society of Gastrointestinal Endoscopy, the Korean Society of Neurogastroenterology and Motility, Korean College of Helicobacter and Upper Gastrointestinal Research, Korean Association the Study of Intestinal Diseases, the Korean Association for the Study of the Liver, Korean Pancreatobiliary Association, and Korean Society of Gastrointestinal Cancer. All rights reserved.

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Contrast-enhanced ultrasonography (CEUS) is a useful noninvasive diagnostic tool allowing accurate differentiation between benign and malignant liver tumors and the diagnosis of small, new liver nodules during surveillance for hepatocellular carcinoma (HCC).1 CEUS also can be applied to guide and assess locoregional HCC therapy.2,3 Low mechanical index ultrasound in combination with ultrasound contrast agent allows the real-time assessment of tumor vascularity and enhancement throughout the different vascular phases including arterial, portal venous, and delayed phases.4 However, CEUS has another useful function to detect the change of blood flow. When liver fibrosis progresses to cirrhosis, this is accompanied by intrahepatic hemodynamic changes including liver arterialization, and intra-hepatic and pulmonary arteriovenous shunting. Although Doppler ultrasound is the first-line imaging tool for blood flow, this cannot be used to analyze flow in capillaries and sinusoids; the flow is too slow to produce a Doppler signal.5 However, the microbubbles of CEUS acts as a blood pool tracer and enables arrival and transit time measurements and can analyze the change of blood flow in capillaries and sinusoids of cirrhosis. The hepatic vein arrival time (HVAT) is the time taken, commencing at injection, for the microbubble contrast agent to arrive at the hepatic vein.6 Although liver biopsy is the gold standard for diagnosis of fibrosis, the procedure is invasive and sampling errors might affect the accuracy of the results. Therefore, there is a great need to find a non-invasive method for the assessment of hepatic fibrosis. Recently, several authors have used CEUS to diagnose cirrhosis. In the present issue of Gut and Liver, Kim et al.7 investigated the HVAT measured by CEUS to assess hepatic fibrosis in cirrhosis based on a systematic review (SR) and meta-analysis (MA). The authors identified that the measurement of HVAT by CEUS exhibited an increased accuracy and correlation for the detection of cirrhosis. The HVAT of cirrhotic patients was shorter than that of noncirrhotic patients; this reduction was accompanied by an increase in the severity of liver disease attributable to intrahepatic hemodynamic changes. These reflect capillarization of the sinusoids or the arteriovenous or portovenous shunts.8,9 Many studies have reported the relationship between HVAT and the severity of liver histological grade. However, the reported accuracy and usefulness have been inconsistent across studies. In their SR and MA, the cited authors evaluated 12 studies on a total of 844 patients with (principally) hepatitis B or C virus infections. All were case control studies comparing patients with biopsy-confirmed cirrhosis to control groups. In terms of the contrast agent, five studies used Levovist (Schering AG) and six SonoVue (Bracco SpA). Sonazoid (GE Healthcare) and Definity (Lantheus Medical Imaging) were each used in one study. The HVAT was measured using the Doppler test in nine of 12 studies, and the remaining three studies were assessed by visual inspection. The diagnostic accuracy of CEUS was high. The integrated sensitivity was 0.83 (95% confidence interval [CI], 0.77 to 0.89), the specificity 0.75 (95% CI, 0.69 to 0.79), and the summary receiver operating characteristic area under the curve 0.74 (standard error, 0.14). However, study heterogeneity was also high.

There are several issues to comment regarding this SR and MA. First, the results varied with the contrast agent used and the method employed to measure HVAT. As the HVAT is influenced by the microbubble extraction rate due to phagocytosis, Sonazoid with higher extraction rate by Kupffer cells showed lower diagnostic accuracies compared to Levovist and SonoVue that undergoes less phagocytosis and remains mainly in the blood vessels. In terms of HVAT calculation, visual inspection was associated with a lower diagnostic accuracy than US/Doppler evaluation. Finally, a study using SonoVue as the contrast agent and US/Doppler to calculate the HVAT afforded high sensitivity (1.0) and specificity (0.93). Secondly, this SR and MA evaluated only 12 studies and the characteristics of each study was various according to patient characteristics, etiology of cirrhosis, contrast agents, and the calculating method of HVAT. Indeed, the unified cutoff value of HVAT for diagnosing the fibrosis and cirrhosis is required using the effective contrast agent and HVAT measurement such as Sonovue combined with US/ Doppler. Future large number of randomized controlled studies with homogenous patient characteristics and methodology is needed. Thirdly, there have been many diagnostic approaches for liver fibrosis including invasive methods with liver biopsy, hepatic venous pressure gradient, and nonivasive approach with transient elastography (FibroScan), magnetic resonance imaging, magnetic resonance spectroscopy, and serum markers. Recently, Kim et al.7 prospectively evaluated the relationship between hepatic venous pressure gradient and HVAT and there was a significant negative correlation, suggesting that HVAT is useful for the noninvasive prediction of clinically significant portal hypertension in patients with compensated cirrhosis.10 However, there are few studies to compare CEUS with other noninvasive diagnostic tests including FibroScan. CEUS is minimally invasive and uses shunt-related diagnostic approach based on intra and extrahepatic hemodynamic changes. It is essential to find the suitable position of CEUS in the diagnosis of cirrhosis.


This study was supported by the Soonchunhyang University Research Fund.

  1. Ryu, SW, Bok, GH, and Jang, JY (2014). Clinically useful diagnostic tool of contrast enhanced ultrasonography for focal liver masses: comparison to computed tomography and magnetic resonance imaging. Gut Liver. 8, 292-297.
    Pubmed KoreaMed CrossRef
  2. Park, KH, Kwon, SH, and Lee, YS (2015). Predictive factors of contrast-enhanced ultrasonography for the response to transarterial chemoembolization in hepatocellular carcinoma. Clin Mol Hepatol. 21, 158-164.
    Pubmed KoreaMed CrossRef
  3. Minami, T, Minami, Y, and Chishina, H (2014). Combination guidance of contrast-enhanced US and fusion imaging in radiofrequency ablation for hepatocellular carcinoma with poor conspicuity on contrast-enhanced US/fusion imaging. Oncology. 87, 55-62.
    Pubmed CrossRef
  4. Nicolau, C, Vilana, R, and Catalá, V (2006). Importance of evaluating all vascular phases on contrast-enhanced sonography in the differentiation of benign from malignant focal liver lesions. AJR Am J Roentgenol. 186, 158-167.
  5. Desser, TS, Sze, DY, and Jeffrey, RB (2003). Imaging and intervention in the hepatic veins. AJR Am J Roentgenol. 180, 1583-1591.
    Pubmed CrossRef
  6. Albrecht, T, Blomley, MJ, and Cosgrove, DO (1999). Non-invasive diagnosis of hepatic cirrhosis by transit-time analysis of an ultrasound contrast agent. Lancet. 353, 1579-1583.
    Pubmed CrossRef
  7. Kim, G, Shim, KY, and Baik, SK (2017). Diagnostic accuracy of hepatic vein arrival time performed with contrast-enhanced ultrasonography for cirrhosis: a systematic review and meta-analysis. Gut Liver. 11, 93-101.
  8. Baik, SK (2010). Haemodynamic evaluation by Doppler ultrasonography in patients with portal hypertension: a review. Liver Int. 30, 1403-1413.
    Pubmed CrossRef
  9. Grier, S, Lim, AK, and Patel, N (2006). Role of microbubble ultrasound contrast agents in the non-invasive assessment of chronic hepatitis C-related liver disease. World J Gastroenterol. 12, 3461-3465.
    Pubmed KoreaMed CrossRef
  10. Kim, MY, Suk, KT, and Baik, SK (2012). Hepatic vein arrival time as assessed by contrast-enhanced ultrasonography is useful for the assessment of portal hypertension in compensated cirrhosis. Hepatology. 56, 1053-1062.
    Pubmed CrossRef
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