ORIGINAL ARTICLE. Received November 9, 2009; accepted February 10, 2010.

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1 LIVER TRANSPLANTATION 16: , 2010 ORIGINAL ARTICLE Contrast-Enhanced Ultrasound for the Evaluation of Hepatic Artery Stenosis After Liver Transplantation: Potential Role in Changing the Clinical Algorithm Rong-Qin Zheng, 1 Ren Mao, 1 Jie Ren, 1 Er-Jiao Xu, 1 Mei Liao, 1 Ping Wang, 1 Min-Qiang Lu, 2 Yang Yang, 2 Chang-Jie Cai, 2 and Gui-Hua Chen 2 Departments of 1 Medical Ultrasonics and 2 Liver Transplantation, Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People s Republic of China Hepatic artery stenosis (HAS) is a common complication in liver transplant patients. Conventional angiography remains the gold standard for diagnosis. Recently, contrast-enhanced ultrasound (CEUS) has begun providing real-time angiographiclike images of vessels and allowing the accurate diagnosis of arterial diseases such as hepatic artery thrombosis. The purpose of this study was to evaluate the efficacy of CEUS in depicting HAS after liver transplantation. Forty-seven liver transplant recipients underwent CEUS examinations with the intravenous injection of microbubble contrast agents. The reference standard was conventional angiography for 15 patients and computed tomographic angiography for 32 patients. The presence, degree, location, and type of HAS were evaluated. For the detection of HAS by CEUS, the following was found: an accuracy of 91.5% (43/47), a sensitivity of 92.3% (36/39), a specificity of 87.5% (7/8), a positive predictive value of 97.3% (36/37), and a negative predictive value of 70% (7/10). CEUS corrected false-positive findings on color Doppler ultrasound in 7 of 47 cases (14.9%). The accuracy of CEUS in identifying the location and type of HAS was 92.3% (36/39) and 84.6% (33/39), respectively. CEUS is a useful noninvasive technique for the detection of HAS in liver transplant patients because it provides comprehensive information, including the presence, location, degree, and type. A positive CEUS finding suggests angiography as the next step rather than a computed tomography scan and may thereby alter the clinical imaging algorithm. Liver Transpl 16: , VC 2010 AASLD. Received November 9, 2009; accepted February 10, Hepatic artery (HA) complications after orthotopic liver transplantation, including stenosis and thrombosis, are leading causes of graft failure with high morbidity and mortality. 1,2 Hepatic artery stenosis (HAS) occurs in 4% to 11% of liver transplant recipients. 3,4 Early and accurate detection of HAS is of utmost importance because most stenoses are treatable with interventional procedures and, if untreated, may progress to hepatic artery thrombosis (HAT) and consequently biliary ischemia, necrosis, and graft loss. 5,6 Conventional angiography remains the gold standard for the assessment of HA patency. However, it is not an ideal screening tool because of its invasiveness, high cost, and potential complications. Even though color Doppler ultrasound (CDUS) is the routine method in the clinical algorithm for the follow-up of vascular complications because it is portable, inexpensive, and noninvasive, a thorough study relies on a technically experienced operator and the condition of the patient. 7 Moreover, extensive collateral circulation and massive liver necrosis or systemic hypotension can result in diagnostic errors. 8,9 Abbreviations: AA, abdominal aorta; AG, artery graft; CAx, celiac axis; CDUS, color Doppler ultrasound; CEUS, contrastenhanced ultrasound; CnTI, contrast-tuned imaging; CT, computed tomography; CTA, computed tomographic angiography; HA, hepatic artery; HAS, hepatic artery stenosis; HAT, hepatic artery thrombosis; MRA, magnetic resonance angiography; MVD, microvascular display; SA, splenic artery; UCA, ultrasound contrast agent. Address reprint requests to Gui-Hua Chen, Department of Liver Transplantation, Third Affiliated Hospital, Sun Yat-Sen University, 600 Tianhe Road, Guangzhou, , People s Republic of China. Telephone: þ ; FAX: þ ; zhengrongqin@hotmail.com DOI /lt Published online in Wiley InterScience ( VC 2010 American Association for the Study of Liver Diseases.

2 730 ZHENG ET AL. Contrast-enhanced ultrasound (CEUS) provides realtime angiographic-like images of vessels and allows the accurate diagnosis of arterial diseases such as HAT after transplantation and carotid artery lesions. 10,11 However, to our knowledge, the performance of CEUS in the delineation of HAS after liver transplantation has not yet been investigated. The purpose of this study was to evaluate the efficacy of CEUS in depicting HAS after orthotopic liver transplantation and its potential role in changing the clinical algorithm. PATIENTS AND METHODS Patients From March 2005 to December 2008, 485 liver transplants were performed at our institution. CEUS examination was performed in 53 of these patients who were suspected of having HAS on CDUS with a focal highvelocity jet faster than 2 m/second at the extrahepatic portion of the HA or the tardus parvus waveform at the intrahepatic arteries, regardless of the liver function and clinical presentation. 8 However, 6 of these patients were excluded because follow-up clinical or radiology data were not available. Therefore, 47 patients (40 men and 7 women) were included in this study. The interval between transplantation and CEUS was 6 days to 49 months (mean ¼ 179 days). The mean age of the patients was 46.2 years (age range ¼ years). The underlying diseases were post hepatitis B cirrhosis (n ¼ 13), post hepatitis C cirrhosis (n ¼ 1), hepatocellular carcinoma secondary to hepatitis B (n ¼ 29), fulminant hepatitis B (n ¼ 3), and Wilson s disease (n ¼ 1). Written, informed consent was obtained from all recipients. The study was approved by the institutional ethics review board and was in compliance with the Declaration of Helsinki. Conventional angiography findings were obtained for 15 patients, and the other 32 patients underwent computed tomographic angiography (CTA). For clinical treatment, 2 patients underwent retransplantation because of irreversible liver failure, and 15 underwent interventional stent placement. CEUS Examination All patients were examined by an experienced staff radiologist (J.R.) with more than 5 years of experience with CEUS of the liver; the identities of the patients and their clinical information were known to the radiologist, but the other imaging results were not. The ultrasound contrast agent (UCA) was SonoVue (Bracco, Milan, Italy), which consists of phospholipidstabilized microbubbles (mean diameter ¼ 2.5 lm) containing sulfur hexafluoride gas and can pass through the pulmonary capillaries. The contrast agent was reconstituted with 5 ml of a 0.9% sodium chloride solution and was injected as a bolus of 0.5 to 1 ml through a 20-gauge needle into the antecubital vein; this was followed by a flush of 5 ml of a 0.9% sodium chloride solution. Two ultrasound machines were used for CEUS in our study according to their availability; they included a Technos MPX DU8 (Esaote Biomedica, Genoa, Italy) using a contrast-tuned imaging (CnTI) technique and a CA430E probe (frequency ¼ MHz) and an Acuson Sequoia 512 (Siemens Medical Solutions, Mountain View, Ca) using a microvascular display (MVD) technique and a 4V1 vector transducer (frequency ¼ MHz). After the long-axis view of the extrahepatic artery was identified on CDUS, the CnTI or MVD mode was initiated, and the imaging depth, gain, and focus were adjusted for optimal target conspicuity. One focus was positioned at the bottom of the target. Mechanical index values ranged from 0.06 to 0.10 for CnTI and from 0.34 to 0.36 for MVD. The timer was activated at the beginning of the intravenous contrast agent injection. For observation of the HA, it was scanned along its course in the early arterial phase within 30 seconds. In our imaging protocols, 1 to 3 bolus injections were performed to mainly observe the proper, left, and right HAs. The maximum injection volume of UCAs for each patient was 3 ml. Dynamic imaging of the HA was stored in the hard disk of the scanner and transferred to a high-performance personal computer for later analysis. Conventional Angiography Conventional angiography was performed with a digital angiographic system (Advantx LCV, GE Medical Systems, Milwaukee, WI) via right femoral artery access. Selective catheterization of the celiac trunk and the common HA was conducted with the injection of iopamidol (Bracco Sine, Shanghai, China). CTA Computed tomography (CT) scans were performed with a GE Light Speed QX/I CT scanner (GE Medical Systems). The scan parameters were set as follows: a highspeed scan mode (pitch ¼ 6), a table speed of 15 mm per rotation, a slice thickness of 5.0 mm, a reconstruction slice thickness of 2.5 mm, and 1.0-mm intervals for the portal phase and hepatic venous phase. The scanning delay was 28 seconds for the HA phase, 70 to 75 seconds for the portal venous phase, and 100 seconds for the hepatic venous phase after a bolus injection of iopamidol (300 mg I/mL; Bracco Sine). CTA was reconstructed with maximum intensity projection, volume rendering, and multiplanar reformatting on an Advantage Workstation 3.1 (GE Medical Systems). Image Analysis Conventional angiography and CTA together with axial CT were considered as reference standards for the diagnosis. 7 All CEUS images were retrospectively analyzed by 2 reviewers (R.M. and R.-Q.Z.) without knowledge of the identity, clinical information, or other imaging findings in consensus to assess the HA. Diameter narrowing rates of the HA on CEUS were recorded and rated as

3 CONTRAST-ENHANCED ULTRASOUND OF HEPATIC ARTERY STENOSIS 731 follows: mild narrowing rate, <50%; moderate narrowing rate, 50% to 75%; and severe narrowing rate, >75%. Moderate and severe stenoses were defined as substantial stenosis. 8,12 With respect to the type of HAS, stenosis was classified to be single or multiple. The location of HAS (proper, left, or right HA or arterial interposition graft) was also recorded. RESULTS All 47 CEUS examinations were technically successful. On CEUS, the HA was filled with microbubbles in the early arterial phase and displayed as a white, tubular structure, whereas the echoes from background structures, including the portal vein and liver parenchyma, were suppressed; this produced angiographic-like images (Fig. 1). The examination time for each patient was 5 minutes or less. No adverse reactions to the microbubble contrast agent (SonoVue) were observed in any patients during the CEUS examination. Figure 1. Angiographic-like image of a normal HA (arrows) after liver transplantation on CEUS. Presence of HAS CEUS identified severe, moderate, and mild cases of HAS and a normal HA in 11 (23.4%), 26 (55.3%), 4 (8.6%), and 6 patients (12.8%), respectively. CEUS directly depicted substantial stenosis (severe and moderate HAS) in 37 patients (Fig. 2); the result was Figure 2. A 40-year-old male recipient with HAS at the anastomosis between the donor and recipient HAs. (A) CDUS shows a peak velocity of 4.15 m/second at the proper HA. (B) CEUS shows moderate stenosis (arrow), which (C) CTA confirms (arrow).

4 732 ZHENG ET AL. Figure 3. A 59-year-old man with a markedly tortuous and angulated HA. (A) CDUS shows the tardus parvus waveform (systolic accelerated time seconds) in the right intrahepatic arteries. (B) CEUS demonstrates multiple stenoses (arrows) of the HA. (C) Axial CT and (D) CTA show a tortuous HA without stenosis (arrow). confirmed in 36 patients by conventional angiography (n ¼ 13) and CTA (n ¼ 23). In 1 of 37 patients with moderate stenosis demonstrated on CEUS, a markedly tortuous HA without stenosis was shown on CTA (Fig. 3). In the remaining 10 patients who were all suspected of HAS because of the detection of the tardus parvus waveform at intrahepatic arteries on CDUS, CEUS demonstrated mild stenosis (n ¼ 4) and a normal HA (n ¼ 6). As shown in Table 1, 7 were confirmed by CTA (n ¼ 7), and this means that CEUS corrected false-positive findings on CDUS in 7 of 47 cases (14.9%). Moreover, the other 3 cases were confirmed to have substantial HAS by conventional angiography (n ¼ 2) and CTA (n ¼ 1). Among the 10 patients, 8 patients survived during a median follow-up of 21.3 months, 1 patient died of septic conditions unrelated to HAS 11.1 months after transplantation, and the remaining patient died 17.4 months after transplantation because of tumor recurrence. The findings of 47 cases are summarized in Table 2. The accuracy, sensitivity, specificity, positive predictive

5 CONTRAST-ENHANCED ULTRASOUND OF HEPATIC ARTERY STENOSIS 733 value, and negative predictive value of CEUS were 91.5%, 92.3%, 87.5%, 97.3%, and 70%, respectively. Location and Type of HAS CEUS accurately demonstrated the location of the stenosis in 36 of 39 cases (92.3%), including 2 around the arterial interposition graft (Fig. 4) and 34 at the anastomosis between the donor and recipient HAs. CEUS accurately delineated the type of stenosis in 33 of 39 patients (84.6%), including 30 focal stenoses and 3 multiple stenoses (Fig. 5). In the 6 remaining patients, 3 multiple stenoses were demonstrated to be focal, 1 was demonstrated to be multiple, and 2 cases of focal HAS were not depicted on CEUS. DISCUSSION CDUS is currently the initial imaging modality for evaluating HA complications after liver transplantation. The diagnosis of HAS is based on the detection of a focal high-velocity jet faster than 2 m/second at the extrahepatic artery or the tardus parvus waveform at the intrahepatic arteries. 8 However, demonstration of the highvelocity jet at the deep-seated HA is sometimes impossible, and velocity measurements are not always accurate because of the difficulty in obtaining the appropriate Doppler angle and accurate gate placement. 13,14 Dodd et al. 8 reported these findings in only 30% of patients with marked HAS. The tardus parvus waveform may TABLE 1. HA Findings in Ten Cases Suspected of HAS on CDUS Case CEUS Findings Reference Standard/Findings 1-4 Normal HA with portal vein CTA/normal HA with portal vein thrombosis thrombosis 5-7 Mild HAS CTA/mild HAS 8 Normal HA CTA/severe stenosis at the arterial interposition graft 9 Normal HA Conventional angiography/severe stenosis at the arterial interposition graft 10 Mild HAS Conventional angiography/severe HAS also be found in long-term HAT with collateral vessel formation, portal vein thrombosis, and atherosclerotic disease. 8,9,15 In our study, the tardus parvus waveform was present in 7 patients without substantial HAS. CEUS has recently been introduced to delineate tissue microcirculation. 16 SonoVue, a second-generation sonographic contrast agent, has a strong nonlinear harmonic response from microbubble oscillations when it is insonated with low acoustic power. It is licensed for abdominal and vascular imaging in Europe and Asia. 17 Contrast-specific imaging technique such as MVD and CnTI allow the detection of signals from the intravascular contrast agent and suppress background signals from the surrounding tissues; this results in an angiographic-like image. 18 Improved visualization of the HA and portal vein, a shorter scanning time, and an accurate diagnosis of HAT after liver transplantation with CEUS with 100% sensitivity and specificity have been reported. 10,19 In our study, the sensitivity (92.3%) and specificity (87.5%) for the diagnosis of HAS with CEUS were also improved in comparison with the reported sensitivity and specificity of 73% with CDUS. 8 This may result from the direct visualization of the stenosis on CEUS instead of indirect findings of the tardus parvus waveform on CDUS. Sidhu et al. 14 reported improved diagnostic accuracy for HAT with CEUS, and this reduced the need for invasive angiography. In our study, 7 patients suspected of having HAS on CDUS were demonstrated to be negative on CEUS. CTA or conventional angiography could have been avoided in these patients. In addition, CEUS allows a comprehensive evaluation of the location, type, and degree of HAS, and this is important for treatment planning and even prognosis prediction. 20 Compared with CTA and magnetic resonance angiography (MRA), CEUS has the following advantages. First, UCAs used in CEUS are not nephrotoxic, and adverse reactions are very rare because the gas within microbubbles is eliminated from circulation by exhalation via the lungs and the shells are metabolized 17 ; this is particularly important for transplant recipients as many have renal insufficiency. 21 Patients with severe HAS on CEUS could directly undergo interventional angiography without referrals for CTA, and this may save critical time for prompt treatment and decrease the dose accumulation of contrast required in both CTA and interventional angiography. Furthermore, CEUS is easily carried out and can be conducted as a bedside procedure for some severe patients in the intensive care unit; this is not possible with CTA and MRA. Finally, CEUS has TABLE 2. HA Findings on CEUS and Reference Standard CTA or Conventional Angiography Severe or Moderate HAS Mild HAS or Normal HA Total CEUS Severe or moderate HAS Mild HAS or normal HA Total

6 734 ZHENG ET AL. Figure 4. A 43-year-old male recipient with arterial inflow based on the infrarenal aorta with an iliac AG tunneled through the transverse mesocolon. (A) CEUS and (B) conventional angiography show stenosis at the graft vessel (arrow). Figure 5. A 41-year-old man with multiple stenoses at the HA. (A) CEUS shows multiple stenoses (long arrows) of the HA, and (B) conventional angiography confirms this (arrows). The portal vein (short arrow) is also demonstrated. (C) The HA was widely patent after stent placement. no radiation and can be performed as a repeated followup modality for HA assessment. On the basis of our study, we suggest a new algorithm in the follow-up of arterial complications after liver transplantation. CEUS can be performed immediately on patients with abnormal CDUS to confirm and assess the degree and type of HAS. Patients with substantial HAS on CEUS can undergo conventional

7 CONTRAST-ENHANCED ULTRASOUND OF HEPATIC ARTERY STENOSIS 735 angiography or interventional treatment if necessary. CTA or MRA may be performed only if there is discordance between CEUS and clinical findings, and this will expedite the diagnosis and treatment and reduce the cost. Nevertheless, a potential problem with this algorithm is the relative insensitivity of CDUS in detecting HAS, and this may result in a missed diagnosis. There are a few limitations to our study. We used multidetector CTA in place of conventional angiography as the gold standard in more than two-thirds of the patients because of the invasive nature and cost of conventional angiography. 7,22 The complex spatial anatomy of the HA with marked tortuosity could result in a false diagnosis of HAS on CEUS. A careful examination of the HA in different directions with repeated injections of UCAs or perhaps 3-dimensional CEUS may overcome this problem. In addition, 2 of 4 stenoses in the vascular grafts were not demonstrated on CEUS because of acoustic interference from bowel gas. CTA or conventional angiography may be required for these patients. In conclusion, CEUS is efficacious for depicting HAS after liver transplantation. It may be incorporated into the diagnostic algorithm for liver transplant recipients suspected of having HAS. ACKNOWLEDGMENT The authors thank Dr. Margaret Pui for her editorial assistance in the preparation of this article. REFERENCES 1. Buell JF, Funaki B, Cronin DC, Yoshida A, Perlman MK, Lorenz J, et al. Long term venous complications after full-size and segmental pediatric liver transplantation. Ann Surg 2002;236: Langnas AN, Marujo W, Stratta RJ, Wood RP, Shaw BW Jr. Vascular complications after orthotopic liver transplantation. Am J Surg 1991;161: Abbasoglu O, Levy MF, Vodapally MS, Goldstein RM, Husberg BS, Gonwa TA, Klintmalm GB. 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