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1 Imaging Sciences Department, MRC Clinical Sciences Centre, Imperial College
London, Hammersmith Hospital, Du Cane Rd., London W12 0HS, UK.
2 Department of Medicine A, Faculty of Medicine, Imperial College London,
Hammersmith Hospital, London W12 0HS, UK.
3 Department of Medical Imaging, Kaohsiung Medical University, Kaohsiung,
Taiwan.
4 Department of Histopathology, Faculty of Medicine, Imperial College London,
St. Mary's Hospital, Praed St., London W12 1NY, UK.
5 Department of Medicine, Faculty of Medicine, Imperial College London, St.
Mary's Hospital, London W12 1NY, UK.
Received June 3, 2004;
accepted after revision August 17, 2004.
Address correspondence to A. K. P. Lim.
Abstract
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SUBJECTS AND METHODS. Sixty-five patients with biopsy-proven
HCV-related liver disease were recruited, and Doppler sonography was performed
by one operator. The patients were classified into one of the following three
groups on the basis of the Ishak-modified histologic activity index (HAI)
fibrosis (F) and necroinflammatory (NI) scores: mild hepatitis (F 
2 and
NI 3), moderate or severe hepatitis (3 F < 6 or NI 
4), or
cirrhosis (F = 6/6). We measured the following Doppler indexes: main hepatic
artery peak velocity (Vmax) and resistive index, main portal vein
peak velocity (Vmax), and maximal portal vein diameter and
circumference that allowed calculation of the portal vein congestive index
(portal vein area and portal vein velocity). The ratio of the hepatic artery
velocity (Vmax) to the portal vein velocity (Vmax) was
also calculated, and the phasicity (triphasic, biphasic, or monophasic) of the
hepatic veins of each patient was recorded. We also measured the maximal
spleen length longitudinally.
RESULTS. A total of 65 patients with liver disease (mild hepatitis, n = 20; moderate or severe hepatitis, n = 25; cirrhosis, n = 20) with biopsy-proven HCV-related liver disease were studied. Optimal hepatic arterial traces were obtained in only 30 patients and portal vein circumference in 18 patients. No significant differences were observed in the Doppler indexes with increasing severity of liver disease. Five (29%) of 17 patients with mild hepatitis had an abnormal hepatic vein trace (i.e., biphasic or monophasic) compared with 11 (55%) of 20 patients with moderate or severe hepatitis and 12 (60%) of 20 patients with cirrhosis. The only index to show a significant intergroup difference was splenic length (analysis of variance, p < 0.001), but there was still overlap between the groups.
CONCLUSION. Doppler-derived indexes, which have previously been recommended for the assessment of severity in chronic liver disease, are difficult to reproduce reliably and therefore have a limited clinical role in the noninvasive assessment of hepatic fibrosis or inflammation.
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Changes in the hemodynamic circulation of the liver occur as chronic liver disease progresses to cirrhosis. Doppler sonography can provide a quantitative measure of blood flow to the liver; thus, numerous groups of researchers have investigated the utility of Doppler sonography as a noninvasive method of assessing the degree of hepatic fibrosis. The measurement of relative flow or velocity in the hepatic artery or vein and in the portal vein has been the major approach [7-14]. However, there is much controversy with regard to the reproducibility of these studies and to whether these Doppler indexes correlate with disease stage and grade.
Positive correlation studies have typically involved the velocity ratios of the hepatic artery to the portal vein [11] or the resistive index (RI) in the hepatic artery calculated from Doppler sonography [12]. However, many of these studies did not allow characterization of precirrhotic disease because uniform histologic stratification was not possible [10-14]. None, to our knowledge, has investigated chronic liver disease due to a single cause prospectively, and there have been several negative studies in which researchers have not been able to reproduce these findings [10]. To delineate the role of Doppler indexes in patients with precirrhotic disease and in cirrhosis more definitively, we chose therefore to investigate a cohort of patients with HCV-related liver disease, which has a well-delineated histologic scoring profile. Our aim was to correlate the sonographic and Doppler findings with the well-recognized Ishak-modified Histologic Activity Index (HAI) Grading and Staging System [3].
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All subjects consumed less than 20 g of alcohol daily, and none was taking regular medication. All provided written informed consent. This study conformed to the guidelines outlined by the 1975 Declaration of Helsinki, and permission was obtained from the Research Ethics Committee of the Hammersmith Hospital, London.
Histologic Grading and Staging (Ishak-Modified HAI System)
All liver biopsies were interpreted by a single independent liver
pathologist and were assessed for necroinflammation (0- to 18-point scale) and
fibrosis (0- to 6-point scale). They were scored according to the
Ishak-modified HAI system [3].
The subdivision of patients into those with mild disease and those with
moderate or severe disease were based on the Ishak-modified HAI fibrosis (F)
and necroinflammatory (NI) scoring system: mild hepatitis (F 2 and NI
3) and moderate or severe hepatitis (3 F < 6 or NI 4). This
subdivision was used because it corresponded with the histologic separation
used in the current United Kingdom algorithm recommended for managing patients
with HCV-related liver disease
[1]. The pathologist was
blinded to the Doppler results and other clinical data.
Doppler Indexes Measured
All patients fasted overnight or for greater than 6 hr before the
sonography examination, which was performed between 9:00 am and 12 noon. All
studies were performed on a sonography system (Acuson Sequoia 512, Siemens
Medical Solutions) by a single experienced sonologist who was blinded to the
histology results of the patients. Ten parameters were measured. First, the
main hepatic artery peak velocity (Vmax) was measured in meters per
second at the porta hepatis with a Doppler angle of between 45° and
60°. Second, the hepatic artery RI value was calculated from the Doppler
trace using the following equation:
 |
The third parameter measured was portal vein peak velocity
(Vmax) in milliseconds at the porta hepatis with a Doppler angle of
between 45° and 60°. Fourth, portal vein diameter was measured in
centimeters at the crossing point with the hepatic artery. Fifth, portal vein
circumference was measured in centimeters at the crossing point with the
hepatic artery. Sixth, portal vein circumference was measured in centimeters
and was calculated using the following formula:
 |
The seventh parameter that was measured was the portal vein congestive
index in milliseconds using the following equation
[13]:
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The portal vein area was calculated using the formula [
(diameter /
2)2] [2].
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The ninth parameter was measurement of hepatic arterial circumference (in centimeters), which was attempted in all patients.
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Other Index Measured
The maximal spleen length was measured longitudinally (in centimeters) in
standard coronal section.
Statistical Analysis
The data were confirmed to be normally distributed. An analysis of variance
test was used for differences in the sonographic indexes and measurements
obtained above among the groups using the SPSS program (version 10.1,
Statistical Package for the Social Sciences). Pairwise comparisons using the
Holm-Bonferroni method were performed for observations between individual
groups of patients.
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Reproducible, accurate angle-corrected hepatic artery traces at the porta hepatis providing a true Vmax and thus RI were achieved in only 30 patients (Figs. 1A, and 1B). Accurate portal vein circumference was also difficult to obtain and was achieved in only 18 patients (Figs. 2A, and 2B). The portal vein congestive index could be accurately calculated in only 38 patients on the basis of a calculated area measurement using the portal vein diameter. We also tried to measure the hepatic artery circumference (the ninth item in the methodology) to calculate the Doppler perfusion index, as described by Walsh and colleagues [13], as the ratio of hepatic artery flow to total hepatic flow. However, it was difficult to measure reliably and could be achieved in only five patients.
Table 2 shows the number of patients (n = 56) with varying hepatic vein phasicity as documented at the time of examination. It is noteworthy that five (29%) of 16 patients with mild hepatitis had an abnormal hepatic vein trace (i.e., biphasic or monophasic) in comparison with 11 (55%) of 20 patients with moderate or severe hepatitis and 12 (60%) of 20 patients with cirrhosis. These waveforms are illustrated in Figures 3A, 3B, and 3C.
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There was a significant difference among the groups in splenic length measurements (analysis of variance, p < 0.001). Pairwise comparisons delineated significant differences between the group with mild hepatitis and the group with cirrhosis (p < 0.001) and between the group with moderate or severe hepatitis and the group with cirrhosis (p < 0.001). No difference was seen between the group with mild hepatitis and the group with moderate or severe hepatitis. Figure 4 illustrates these differences graphically and shows that there is some overlap between the groups. One patient had previously undergone splenectomy.
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Previous studies of patients with chronic liver disease have shown an increase in the hepatic artery RI value in patients with chronic liver disease, which has been thought to be related to the architectural derangement that occurs within the liver with increasing severity of disease [12-14]. A recent study by Piscaglia and colleagues [12] found that an increase in the RI value correlated with higher histologic fibrosis scores. However, there was no correlation with the overall histologic score, which takes into account both necrosis and inflammation. Their patient population was also not uniform, because it comprised a mixture of virus-related liver diseases. In our study, we also did not find any correlation between the RI value and the histologic scores, but our data set was small (30 patients). It has also been suggested that RI values measured within an intrahepatic branch, as opposed to the main artery at the porta hepatis, are more useful [14]; however, we were unable to reliably obtain an RI value for the main artery—let alone the intrahepatic branches—and found this to be a difficult task. Overall, the RI value is affected by many variables [12, 14, 15] such as patient age and heart rate, and most studies have shown no correlation with histology.
Hirata and colleagues [11] have shown an increase in the ratio of the hepatic artery velocity to portal vein velocity with increasing fibrosis in a cohort of patients with HCV-related liver disease [11]. Our data did not concur with this finding, but we postulate that this discrepancy could, in part, be related to methodologic differences. Our velocity measurements were recorded from the main hepatic artery and portal vein as opposed to the right and left portal and arterial branches, as described in the study by Hirata and colleagues. This was because we had difficulty in obtaining accurate and reliable velocities of the branches, particularly of the hepatic arteries. The ratio of the hepatic artery velocity to portal vein velocity, which relies on maximal hepatic arterial velocity, is also subject to inaccuracies from cardiac output and age-related arterial fibrosis [11, 15]. Furthermore, the study by Hirata and colleagues did not elucidate whether there was a positive correlation when taking the overall histologic score rather than fibrosis alone. To the best of our knowledge, no other group has been able to reproduce these findings.
In a recent article, Bernatik and colleagues [10] concluded in their study of 43 patients with HCV and varying severity of liver disease that Doppler measurements of liver vasculature were not a valid surrogate marker of cirrhosis and that these measurements were a useful method to estimate the extent of hepatic fibrosis. This observation is also supported in the study by Walsh and colleagues [13], who concluded that hepatic blood flow indexes have no relationship to the severity of histologic liver injury in chronic hepatitis C. Our data are in agreement with these conclusions, and we found no correlation between histologic grade in HCV-related disease and Doppler indexes.
There was a higher proportion of abnormal hepatic vein traces (phasicity) in the moderate or severe hepatitis group and the cirrhosis group when compared with the mild hepatitis group. We can infer that an abnormal trace is likely to be associated with more severe liver disease, but this finding is not specific and we found overlap among the groups. This index would thus not be robust enough to separate precirrhotic disease. In this respect, our finding concurs with that in a previous study by Colli and colleagues [16].
Splenic enlargement is a recognized secondary sign of a cirrhotic liver [17, 18]. From our data, spleen length was the only index to show significant differences between mild hepatitis and moderate or severe hepatitis, when compared with the cirrhosis group. However, there was some overlap among the groups with no clear separation. This index thus offers no value as a noninvasive marker for assessing precirrhotic disease.
The literature review and supporting evidence from our data strongly suggest that Doppler sonography does not offer a reliable noninvasive method for characterizing chronic liver disease in patients with hepatitis C. In addition, the correlations in the studies require both complex measurements, which are difficult to reproduce, and mathematic corrections. These studies do not show a clear clinical application.
Limitations and Strengths
The main limitation of our study is that in most parameters studied, the
eventual number of reliable Doppler measurements that we were able to include
in the analysis was small. This, however, probably reflects the difficulty in
obtaining reproducible and accurate measurements of these vessels even by
experienced sonographers. There is also a lack of data from healthy control
subjects, but the main remit of this study was to investigate whether any of
the Doppler indexes could differentiate mild hepatitis from moderate or severe
disease because the former group would not be eligible for interferon
treatment. The main strength of our study is that it is prospective and in a
histologically well-stratified cohort of patients with liver disease
attributable to a single entity.
Recent Developments
The advent of sonographic contrast agents (microbubbles) has added a new
dimension to the capabilities of sonography in chronic liver disease. Recent
studies have shown that using microbubbles as a radiotracer—their
arrival time within a hepatic vein after injection in a peripheral arm
vein—is a highly sensitive marker of cirrhosis
[19,
20]. This functional technique
also shows promise in its ability to characterize precirrhotic disease
[20] and could be a simpler
and more reliable way of using the capabilities of sonography in assessing
patients with chronic liver disease. Another functional technique is MR
spectroscopy, which has also been shown to be able to characterize
precirrhotic disease in HCV-related liver disease
[21]. These techniques
together may complement one another and, in the future, could allow
noninvasive workup of patients with chronic liver disease.
In conclusion, our data have shown that Doppler sonography is not a reliable noninvasive method for assessing the severity of HCV-related liver disease because of the marked difficulty in reproducing the indexes measured by positive correlation studies mentioned in the literature. The clinical application is therefore questionable. Our findings also support the negative findings of work by some groups, fuelling this controversial area. This study is the most complete prospective one to date with respect to the indexes measured and, unlike previous studies, was performed in a histologically well-stratified group of patients.
Acknowledgments
This study was supported by the United Kingdom Department of Health; the
British Medical Research Council (MRC CEG:G99000178); the United Kingdom
National Health Service Research and Development Initiative (NHS R&D: RFG
581); Siemens (Acuson, Mountain View, CA, USA); and Kodak Radiology Fund,
Royal College of Radiologists, UK. We are also grateful to Mary Crossey,
Theresa Roguin, the staff of the Liver Unit at St. Mary's Hospital, and the
staff of the Gastroenterology Unit at Hammersmith Hospital, London, for help
with patient recruitment.
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