Non-invasive diagnosis of hepatic cirrhosis by transit-time analysis of an ultrasound contrast agent

doi:10.1016/S0140-6736(98)06373-9

The Lancet

Volume 353, Issue 9164, 8 May 1999, Pages 1579-1583

https://doi.org/10.1016/S0140-6736(98)06373-9 Get rights and content

Summary

Background

Hepatic cirrhosis is accompanied by several haemodynamic changes including arterialisation of the liver, intrahepatic shunts, pulmonary arteriovenous shunts, and a hyperdynamic circulatory state. We postulated that the hepatic first pass of a bolus of an ultrasound contrast agent injected into a peripheral vein is accelerated in patients with cirrhosis. We investigated this first pass in patients with diffuse liver disease and in normal controls to assess whether it provides useful differential diagnostic information.

Methods

We enrolled 15 patients with biopsy-proven cirrhosis, 12 patients with biopsy-proven non-cirrhotic diffuse liver disease, and 11 normal controls. We carried out continuous spectral doppler ultrasonography of a hepatic vein from 20 s before to 3 min after a peripheral intravenous bolus injection of 2·5 g Levovist. The intensity of the doppler signal was measured and used to plot time-intensity curves.

Findings

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. 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). We found highly significant differences between the patients with cirrhosis and each of the other two groups for all variables (P<0·005), whereas we found no significant differences between non-cirrhotic patients and controls.

Interpretation

Our preliminary study suggests that analysis of liver transit time of a bolus of ultrasound contrast agent provides useful information about haemodynamic changes in patients with cirrhosis. 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.

Introduction

Imaging techniques and, in particular, ultrasonography, which is the most widely used modality for imaging of the liver, are neither sensitive nor specific in the diagnosis of hepatic cirrhosis.1, 2, 3, 4 Liver biopsy therefore remains an essential part of the diagnostic work-up of patients with suspected cirrhosis.

Microbubble contrast agents have been developed for ultrasonography.⁵ These agents are confined to the intravascular space and enhance doppler signals by about 20 dB. Levovist (Schering AG, Berlin, Germany) is a galactose-based microbubble agent. Levovist is safe with no substantial adverse events reported.⁶ Its main indication is to improve technically difficult doppler examinations by providing a stronger doppler signal. However, bolus injections of microbubble agents can also be used for kinetic studies of the microbubble first pass, and thus to assess transit times. This principle has been applied in studies of breast tumours,7, 8 but could also be applied in studies of the liver. The doppler signal changes that occur during the microbubble first pass can be quantified by measurement of the intensity (loudness) of the spectral doppler signal; this intensity correlates well with the microbubble concentration in vitro and in vivo.9, 10

Hepatic cirrhosis is accompanied by several regional hepatic and general haemodynamic changes. First, there is arterialisation of the liver.11, 12 Second, intrahepatic shunts between the branches of the hepatic artery, the portal vein, and the hepatic veins are formed.11, 12, 13, 14 Third, pulmonary arteriovenous shunts are commonly found in patients with cirrhosis.15, 16, 17 Fourth, this population of patients has a hyperdynamic circulatory state with increased cardiac output and reduced systemic vascular resistance.18, 19 These factors might be helpful in diagnosing hepatic cirrhosis with ultrasonography, provided a sonographic tool was available to measure these changes. Duplex doppler ultrasound has been disappointing in this respect.12, 20, 21

We postulated that the haemodynamic changes in patients with cirrhosis would result in a characteristic (earlier) hepatic venous signal from a microbubble bolus injected into a peripheral vein. The purpose of this pilot study was to assess whether quantitative dynamic doppler ultrasonography of a hepatic vein after an intravenous bolus injection of Levovist can be used to study haemodynamic changes in patients with cirrhosis and with non-cirrhotic diffuse liver disease, and to assess whether any of these changes provide useful differential diagnostic clues.

Section snippets

Methods

The inclusion criteria for patients in the study were biopsy-proven cirrhosis or other diffuse liver disease, or a strong clinical suspicion of cirrhosis or diffuse liver disease with a biopsy scheduled for the near future. There were 38 participants: 11 normal volunteers (five men, six women, mean age 32·9 years, range 25–45) with no history or clinical signs of liver disease; 12 patients (six men, six women, 45·3, 24–68) with different types of biopsy-proven non-cirrhotic diffuse liver

Results

In the cirrhosis group, conventional ultrasonography showed typical features of cirrhosis (hepatic dysmorphism, abnormal liver texture, irregular liver contour, signals of portal hypertension) in seven participants, non-specific features of diffuse liver disease (abnormal liver texture, hepatosplenomegaly) in six, and normal liver in two.

Diagnostic time-intensity curves with a clearly identifiable start and peak were obtained for all participants (figure 2). Mean values and SDs for the four

Discussion

This novel technique provides clinically useful functional information about haemodynamic changes in patients with hepatic cirrhosis. Assessment of the arrival time of a peripherally injected microbubble bolus in a hepatic vein allowed discrimination of patients with biopsy-proven cirrhosis from normal controls and patients with non-cirrhotic diffuse liver disease. In this pilot series of 38 participants, an arrival time of less than 24 s was 100% sensitive and 96% specific for the diagnosis of

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Early ReportNon-invasive diagnosis of hepatic cirrhosis by transit-time analysis of an ultrasound contrast agent

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Methods

Results

Discussion

Gastroenterology

Semin Ultrasound CT MR

Lancet

Acad Radiol

J Hepatol

Am J Med

J Hepatol

Am J Med

Am J Med

Am J Surg

Hepatology

Gastroenterology

Lancet

Gastroenterology

Accuracy of ultrasonography in diagnosis of hepatocellular disease

Am J Roentgenol

Diffuse disease of the liver: radiologic-pathologic correlation

Radiographics

Echo-enhancing agents: safety

Early Report
Non-invasive diagnosis of hepatic cirrhosis by transit-time analysis of an ultrasound contrast agent