The hemodynamic changes which accompany hepatic cirrhosis mainly include arterialization of the liver, intrahepatic shunts, pulmonary arteriovenous shunts, and a hyperdynamic circulatory state. All of these changes will make the hepatic first pass of contrast agent injected into a peripheral vein faster in a cirrhotic liver compared with normal liver.

Albrecht et al[25] studied the hepatic vein transit time using continuous spectral Doppler ultrasonography and Levovist. They found patients with cirrhosis showed a much earlier onset of enhancement (arrival time; mean 18.3 s) and peak enhancement (mean 55.5 s) than controls (49.8 s and 97.5 s) or patients with non-cirrhotic diffuse liver disease (35.8 s and 79.7 s). All patients with cirrhosis had an arrival time of the bolus of less than 24 s, whereas the arrival time was 24 s or more in 22 of the 23 other participants. Taking a hepatic vein arrival time of 24 s as the diagnostic criteria for liver cirrhosis, the sensitivity and specificity were 100% and 96%, respectively. They also found that peak enhancement was higher in patients with cirrhosis (mean 48.7 units) than in the other two groups (12.5 and 12.3 units, respectively). They concluded that analysis of liver transit time of a bolus of UCA provides useful information about haemodynamic changes in patients with cirrhosis, and measurement of the arrival time of the bolus allows discrimination of patients with cirrhosis from controls and from patients with non-cirrhotic diffuse liver disease, and has potential as a non-invasive test for cirrhosis. Bang et al[26] compared pulse inversion imaging with spectral Doppler quantification in assessment of the arrival of a contrast agent in the hepatic veins in six patients. They found the hepatic vein arrival times measured by two different methods were within 2 s apart in five patients and within 5 s apart in one patient. They believe pulse inversion imaging will be a simple and accurate method for evaluation of hepatic vein arrival time. Sugimoto et al[27] evaluated hepatic vein arrival time using Levovist and pulse inversion imaging in 15 patients. They found that the time-acoustic intensity curves for hepatic vein could be classified as a gradual-rising curve which was seen in all controls and non-cirrhotic patients and a rapid-rising curve which was seen in all cirrhotic patients. They also showed that the hepatic vein arrival time was significantly earlier in cirrhotic patients compared with normal and hepatitis patients (18 s vs 31 s, 30 s), respectively. They believe CEUS and hepatic vein transit time is a useful noninvasive diagnosis method for liver cirrhosis with high sensitivity and specificity.

With the development of contrast specific techniques and the emergence of new generation contrast agent, real-time CEUS became a powerful tool for evaluation of liver cirrhosis. Ridolfi et al[28] tried to use low MI CEUS with SonoVue to evaluate the severity of chronic hepatitis C. They found the mean hepatic vein arrival time decreased progressively with increasing severity of liver disease, all patients with liver cirrhosis had a hepatic vein arrival time of 17 s or less, whereas values of 18 s or more were recorded for all controls and for almost all patients (20/22) with non-cirrhotic liver disease. But within the group of chronic hepatitis C, Metavir scores of fibrosis and necro-inflammatory changes had no significant effect on hepatic vein arrival times. They concluded that hepatic vein arrival time might be a simple and non-invasive method for reliably excluding cirrhosis with signs of portal hypertension, but not for assessing the severity of either chronic hepatitis C or cirrhosis. Lim et al[29] compared Levovist and SonoVue in evaluation of hepatic vein arrival time in 40 hepatitis C-related liver disease patients and 25 normal volunteers. They found that mean hepatic vein arrival times in control, mild hepatitis, moderate or severe hepatitis, and cirrhosis groups were 38.3, 47.5, 29.5 and 17.6 s, respectively, with Levovist; and 29.4, 27.4, 22.9 and 16.4 s, respectively, with SonoVue. The hepatic vein arrival time decreased as severity increased in imaging with both contrast agents. There was no significant difference in hepatic vein arrival time between mild and moderate hepatitis groups with SonoVue; however, there were significant differences in hepatic vein arrival time between all patient groups using Levovist. Hepatic vein arrival time of SonoVue was shorter than that of Levovist in all groups except the cirrhosis group where the hepatic vein arrival time of the two contrast agents was similar. Although hepatic vein arrival time seems to fulfill the task of diagnosis of liver cirrhosis, some researchers also found that the hepatic vein transit time was accelerated in the liver with metastatic liver tumors[37-39]. This is the main limitation of using hepatic vein transit time to diagnose liver cirrhosis since there may be many other situations which will also result in similar hemodynamic changes.

Some researchers also studied the micro-hemodynamic changes which follow liver cirrhosis using CEUS. Giuseppetti et al[33] used the destruction and replenishment CEUS technique to evaluate the changes in hepatic parenchymal blood flow in cirrhotic patients and normal patients. Pulse inversion harmonic imaging was obtained at progressively increasing pulse intervals of 2, 4, 7 and 10 s in the same scan plane during infusion of Levovist (300 mg/mL, 150 mL/h). Pulse intervals vs signal intensity (PI-SI) plots were made to illustrate the speed of blood in the liver parenchyma. They found the slope of the PI-SI plot of the Child A cirrhotic patients was significantly lower than the slope of the normal controls and of the Child C cirrhotic patients; conversely, no significant differences were found between the slope of the patients with Child C cirrhosis and of the normal controls. The slope of the patients with liver cirrhosis presented with a significantly higher variability than was observed in the normal controls. They explained their findings by suggesting the slope of the PI-SI plot obtained by placing the ROI in a region of parenchyma reflects the average speed of both the arterial and the venous components of the microcirculation. They thought that liver perfusion was provided mainly by the portal circulation in most patients with Child A cirrhosis, and because the velocity of the portal blood flow is reduced, an overall reduction of the average velocity of the parenchymal blood is observed. In patients with Child C cirrhosis and advanced disease, however, the portal component of the hepatic blood flow can be markedly reduced, with increased arterial perfusion and significant portosystemic venous and arteriovenous shunting. These hemodynamic changes can cause a prevalence of the arterial component of the microcirculation, with higher velocity flows, causing an overall increase of the average velocity of the parenchymal blood.

Some researchers have tried to use enhancement level of liver parenchyma on CEUS to diagnose liver cirrhosis based on the theory of diminished or function damage of Kupffer cells accompanied with the hepatic cirrhosis. Fujita et al[34] used Levovist and stimulated acoustic emission imaging, and studied 114 patients with alcoholic liver disease and other chronic liver disease. They compared the enhancement level of the hepatic parenchyma and right kidney at 20 s, 90 s, and 5 min after injection of Levovist. The contrast patterns of the liver and kidney were divided into three patterns. In pattern A, only the kidney was strongly enhanced at 20 s, both liver and kidney were strongly enhanced at 90 s, and only the liver was enhanced at 5 min. In pattern B, both the liver and the kidney were strongly enhanced at 20 s and 90 s, but only the liver was strongly enhanced at 5 min. In pattern C, both the liver and the kidney were strongly enhanced at 20 s and 90 s, and both organs were weakly enhanced at 5 min. They found 83% of normal livers showed pattern A, whereas pattern B was found in 60%-86% of patients with chronic liver disease, and almost all of the patients with alcoholic liver cirrhosis had pattern C. They supposed that Kupffer cell dysfunction in liver cirrhosis resulted in slower clearance of contrast agent and thus weak enhancement of liver parenchyma in pattern C. Gasparini et al[35] studied 10 normal volunteers, 16 Child A and 16 Child C cirrhotic patients with CEUS using Levovist. They found the enhancement level of liver parenchyma in late phase (7 min after administration of contrast agent) decreased significantly both in patients with Child A (P < 0.05) and Child C (P < 0.001) cirrhosis compared with normal liver, and a statistically significant signal intensity decrease was also observed from the patients with Child A to those with Child C cirrhosis

(P < 0.01). Their explanation was that the decreased uptake of the Levovist microbubbles by the reticuloendothelial system in cirrhotic liver due to impaired functional capacity of the Kupffer cells secondary to increased portosystemic shunting of blood resulted in the observed difference between the groups. Kaneko et al[36] compared the parenchyma enhancement with the degree of liver dysfunction using pulse-inversion ultrasonography and Levovist. They found there was a significant inverse correlation between the gray scale of the liver parenchyma and the hepatic fibrosis index (r = -0.809, P < 0.01). The average signal intensity of the liver parenchyma was 144.5 in a normal liver, 133.6 in chronic hepatitis, and 102.6 in liver cirrhosis, demonstrating a significant difference between a normal and cirrhotic liver (P < 0.01). They concluded that the signal intensity of a microbubble disruption of the liver parenchyma in the late phase of enhancement with Levovist could reflect the degree of hepatic fibrosis.