A Doppler Waveform Index to Characterize Hepatic Vein Velocity Pattern and Evaluate Hepatic Fibrosis

Jan Fog Pedersen, MD,1 Lone Galmstrup Madsen, MD,2 Vibeke Andree Larsen, MD,1 Ole Hamberg, MD,2 Thomas Horn, MD,3 Birgitte Federspiel, MD,3 Peter Bytzer, MD2 Department of Radiology, Glostrup Hospital, University of Copenhagen, DK-2600 Glostrup, Denmark Department of Medical Gastroenterology, Glostrup Hospital, University of Copenhagen, DK-2600 Glostrup, Denmark 3 Department of Pathology, Herlev Hospital, University of Copenhagen, DK-2730 Herlev, Denmark
2 1

Received 7 April 2006; accepted 2 August 2007

ABSTRACT: Purpose. To describe a Doppler waveform index representing the hepatic vein ow velocity pattern and to examine its relationship to the degree of hepatic brosis. Methods. Doppler waveforms were obtained in 66 patients scheduled for percutaneous liver needle biopsy and categorized as normal (with a retrograde ow phase) or abnormal (without retrograde ow). Waveforms were also characterized using a hepatic vein waveform index (HVWI): (maximum 2 minimum velocity)/(maximum velocity). Biopsy specimens were graded for brosis. Results. There was a highly signicant decrease in HVWI with increasing brosis score in the biopsy (p < 0.001, Jonckheere trend test). The biopsy showed cirrhosis in 14 of 29 patients (48%) with absent retrograde ow and 5 of 37 patients (14%) with a normal ow pattern. Using HVWI as the criterion, cirrhosis was present in 13 of 21 (62%) patients with HVWI < 0.75, in 6 of 31 (19%) patients with 0.75 < HVWI < 1.50, and in none of 14 (0%) patients with HVWI > 1.50. Conclusions. HVWI is inversely correlated to the degree of liver brosis and may be more efcient than the presence or absence of retrograde ow in C diagnosing and grading hepatic brosis. V 2008 Wiley Periodicals, Inc. J Clin Ultrasound 36:208211, 2008; Published online in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/jcu.20446 Keywords: hepatic vein; Doppler; ultrasonography; cirrhosis, brosis

he hepatic vein Doppler waveform normally shows a triphasic pattern with 2 hepatofugal phases related to atrial and ventricular diastole, and a short phase of retrograde (hepatopetal) ow caused by the pressure increase in the right atrium at atrial systole.1 The waveform pattern is traditionally categorized as triphasic, biphasic (without a retrograde ow phase), and at (monophasic, with monotonous hepatofugal ow throughout the cardiac cycle). Arbitrarily, absence of the retrograde ow phase (biphasic and monophasic waveforms) is considered abnormal. This is seen in approximately 3 out of 4 patients with cirrhosis and may also be seen in brosis, elevated aminotransferases, fatty liver, chronic hepatitis C, and metastatic liver disease.27 An abnormal waveform may even be seen in patients with no sign of liver disease.8 In an attempt to more precisely describe and quantify the Doppler waveform, we describe a hepatic vein waveform index (HVWI) and report its correlation with the degree of liver brosis.

PATIENTS AND METHODS

Correspondence to: J.F. Pedersen

' 2008 Wiley Periodicals, Inc.

We examined a consecutive series of patients who underwent percutaneous liver needle biopsy and sonographic examination that included recording of the hepatic vein Doppler waveform 5 days before the biopsy. The reasons for liver biopsy were alcoholic liver disease or chronic viral hepatitis in most patients (>75%); the remaining
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HEPATIC VEIN DOPPLER WAVEFORM INDEX

FIGURE 2. Hepatic vein waveform index in 66 patients with liver brosis. 0, no brosis; 1, mild brosis; 2, moderate brosis; 3, severe brosis; 4, cirrhosis. There is a strong negative correlation between the index and the brosis score (p < 0.001, Jonckheere trend test).

FIGURE 1. Hepatic vein waveform index (HVWI) is calculated as (maximum velocity 2 minimum velocity)/(maximum velocity) and yields a more detailed characterization of the Doppler waveforms. (A, B) The 2 waveforms exhibit retrograde ow and are considered normal. (C, D) There are no retrograde ow phases in the 2 tracings, which are considered abnormal.

causes were autoimmune, toxic, metabolic, or hereditary liver disease. No patient had atrial brillation. After exclusion of 2 patients because of insufcient biopsy material, the study comprised 66 patients (37 females and 29 males) with a mean age of 51 years (range, 1981 years). The fasting patients were examined with an Acuson XP10 ultrasound scanner equipped with a 3.5-MHz convex probe (Siemens Ultrasound, Mountain View, CA). The Doppler sampling gate was placed so that in nonforced end expiration it would sample the right hepatic vein 46 cm proximal to the conuence with the inferior vena cava. The Doppler tracings were recorded on lm. After completion of the study, all tracings were evaluated blindly without knowledge about the pathology report, in one session, and HVWI was calculated as (maximum velocity 2 minimum velocity)/(maximum velocity) (Figure 1). Two pathologists blinded to the Doppler ndings examined the biopsy specimens and graded brosis. In case of disagreement, they both re-examined the specimens to reach a consensus. Fibrosis was graded as: 0, no brosis; 1, mild brosis; 2, moderate brosis; 3, severe brosis; and 4, cirrhosis.9
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The Jonckheere test for ordered alternatives10 was used to analyze the relationship between degree of brosis and HVWI, our hypothesis being that the median HVWI value decreases as the brosis increases from grade 0 to grade 4. To illustrate the capability of HVWI in discriminating cirrhosis from noncirrhosis, we constructed a receiver operating characteristic curve.11 The study was approved by the Research Ethics Committee of Copenhagen County (#KA 96205). Informed consent was obtained from all patients.

RESULTS

There was a highly signicant decrease in HVWI with increasing brosis score in the biopsy (p < 0.001) (Figure 2). Histopathologic examination showed cirrhosis in 14 of 29 patients with absent retrograde ow in the hepatic vein, and in 5 of 37 patients with a normal waveform, corresponding to a sensitivity of 74% and a specicity of 72%. The receiver operating characteristic curve (Figure 3) illustrates the relation between sensitivity and specicity at different cutoff points; the classical criterion (present or absent retrograde ow) is marked B in Figure 3. We tested the index by arbitrarily setting 2 cutoff levels, at 0.75 (sensitivity 68%, specicity 83%) and 1.50 (sensitivity 100%, specicity 30%) (A and C, respectively, in Figure 3). If the 2 cutoff levels were combined, cirrhosis was found in 13 of 21 (62%) patients with HVWI < 0.75, in 6 of 31 (19%) patients with 0.75 < HVWI < 1.50, and in none of 14 (0%) patients with HVWI > 1.50. 209

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FIGURE 3. Receiver operating characteristic curve showing relation between sensitivity and specicity when various cutoff points of HVWI are used to discriminate between cirrhosis and noncirrhosis. HVWI cutoff values of 0.75, 1.00, and 1.50 are shown at A, B, and C, respectively.

DISCUSSION

Absence of a retrograde ow phase is believed to reect increased stiffness of the liver parenchyma around the liver veins.1,4 Although absence of a retrograde ow phase is a convenient criterion, it is nominal, and the level of discrimination is arbitrary. We wanted to extract more information from the Doppler waveform by calculating an index of pulsatility. The index, which is zero in case of a at curve, increases with increasing pulsatility of the waveform, and will be >1 with the appearance of a retrograde ow phase (Figure 1). In a study in healthy volunteers, Coulden et al12 used a similar index and found only modest day-to-day variation in the index and no effect of the prandial state. Farrant and Meire13 suggested a visual scoring system, but neither of the 2 groups reported on the use of their criteria in patients with liver disease. Von Herbay et al7 calculated a venous pulsatility index (VPI) as VPI 5 Vmin/Vmax. This index is closely related to HVWI (HVWI 5 1-VPI). If expressed as HVWI, their results would yield a mean HVWI of 0.73, 0.81, and 1.50 in cirrhosis, brosis and controls, respectively. The corresponding values in our study are 0.73, 1.14, and 1.29, respectively, showing a very good agreement in the cirrhosis and control groups, and fair agreement in the more heterogeneous group of patients with brosis of various degrees. The 210

2 indices, VPI and HVWI, contain the same information, but we favor the latter, because it will be zero with a at, nonoscillating curve, and increase with pulsatility. We found a highly signicant inverse correlation between degree of brosis in the liver biopsy specimens and HVWI, which is in agreement with a previous report showing a signicantly higher brosis score in patients without retrograde ow.5 Because of the high range of indices within each grade of brosis, the index cannot and is not meant tobe used as a stand-alone parameter, but the correlation between index and brosis implies that HVWI might be a meaningful adjunct variable in the diagnosis and monitoring of patients with diffuse liver disease. As an example, we examined the efcacy of the index in diagnosing cirrhosis knowing full well that this diagnosis is generally based upon a range of sonographic ndings, and not on a single indicator. In our patient series, cirrhosis was diagnosed in 48% of patients without retrograde ow and in 14% patients with a normal triphasic waveform, whereas HVWI was able to separate the patients into 3 groups with high (62%), intermediate (19%), or low (0%) probability of cirrhosis when using HVWI < 0.75, 0.75 < HVWI < 1.50, and HVWI > 1.50 as cutoff levels, respectively. Future prospective studies are needed to test whether this index may qualify for inclusion in the established set of sonographic criteria for cirrhosis. In conclusion, we propose an index for a more precise characterization of the hepatic vein Doppler waveform. This index was signicantly correlated to the degree of brosis in the biopsy specimen of our subjects. We therefore recommend this index to be evaluated in the diagnosis and follow-up of patients with diffuse liver disease.

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HEPATIC VEIN DOPPLER WAVEFORM INDEX 5. Dietrich CF, Lee JH, Gottschalk R, et al. Hepatic and portal vein ow pattern in correlation with intrahepatic fat deposition and liver histology in patients with chronic hepatitis C. AJR Am J Roentgenolol 1998;171:437. 6. ODonohue J, Ng C, Catnach S, et al. Diagnostic value of Doppler assessment of the hepatic and portal vessels and ultrasound of the spleen in liver disease. Eur J Gastroenterol Hepatol 2004;16:147. 7. von Herbay A, Frieling T, Haussinger D. Association between duplex Doppler sonographic ow pattern in right hepatic vein and various liver diseases. J Clin Ultrasound 2001;29:25. 8. Pedersen JF, Dakhil AZ, Jensen DB, et al. Abnormal hepatic vein Doppler waveform in patients without liver disease. Br J Radiol 2005;78:242. 9. Odze RD, Goldblum JR Crawford JM, editors. Surgical Pathology of the GI Tract, Liver, Biliary Tract and Pancreas. Philadelphia: Saunders-Elsevier; 2004. p 808. 10. Siegel S, Castellan NJ. Nonparametric statistics for the behavioral sciences. 2nd edition. New York: McGraw-Hill; 1988. p 216. 11. McNeil BJ, Keller E, Adelstein SJ. Primer on certain elements of medical decision making. N Engl J Med 1975;293:211. 12. Coulden RA, Lomas DJ, Farman P, et al. Doppler ultrasound of the hepatic veins: normal appearances. Clin Radiol 1992;45:223. 13. Farrant P, Meire HB. Hepatic vein pulsatility assessment on spectral Doppler ultrasound. Br J Radiol 1997;70:829.

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