Preoperative hepatic hemodynamics in the prediction of early portal vein thrombosis after liver transplantation in pediatric patients with biliary atresia

Shanghai, China

Preoperative hepatic hemodynamics in the prediction of early portal vein thrombosis after liver transplantation in pediatric patients with biliary atresia

Li-Hong Gu, Hua Fang, Feng-Hua Li, Shi-Jun Zhang, Long-Zhi Han and Qi-Gen Li

Shanghai, China

BACKGROUND: Portal vein thrombosis (PVT) is one of the main vascular complications after liver transplantation (LT), especially in pediatric patients with biliary atresia (BA). This study aimed to assess the preoperative hepatic hemodynamics in pediatric patients with BA using Doppler ultrasound and determine whether ultrasonographic parameters may predict early PVT after LT.

METHODS: One hundred and twenty-eight pediatric patients with BA younger than 3 years of age underwent Doppler ultrasound within seven days before LT, between October 2006 and June 2013. The preoperative hepatic hemodynamic parameters were then compared between patients with early PVT (within 1 month following LT) and those without PVT. Receiver operating characteristic analysis was performed to determine the optimal cutoff value for predicting early PVT.

RESULTS: Of the 128 transplant recipients, 41 (32.03%) had a hypoplastic portal vein (PV), 52 (40.63%) had hepatofugal PV fow and 40 (31.25%) had a high hepatic artery resistance index (HARI) of ≥1. Nine cases (7.03%) experienced early PVT. A PV diameter ≤4 mm (sensitivity 88.89%, specifcity 72.27%), and a hepatofugal PV fow (sensitivity 77.78%, specifcity 62.18%) with a high HARI ≥1 (sensitivity 77.78%, specifcity 72.27%) were hepatic hemodynamic risk factors for early PVT.

CONCLUSIONS: Hepatic hemodynamic disturbances in pediatric recipients with BA were more common. Small PV diameter (≤4 mm) and hepatofugal PV fow combined with high HARI (≥1) are strong warning signs of early PVT after LT in pediatric patients with BA. Intense monitoring of vascular patency and prophylactic thrombolytic therapy should be considered in pediatric patients undergoing LT for BA.

(Hepatobiliary Pancreat Dis Int 2015;14:380-385)

liver transplantation;

Doppler ultrasound;

hemodynamics;

portal vein thrombosis;

biliary atresia

Introduction

Biliary atresia (BA) is a destructive infammatory obliterative cholangiopathy of neonates that affects both intrahepatic and extrahepatic bile ducts. The prevalence of BA in the United Kingdom and France ranges from 1 in 17000 to 1 in 19000 live births. It is most common in east Asian, with a reported frequency of 1 in 5000.[1]A study[1]reported that the overall long-term survival rate of children with BA varied from 20% to 45%, with a Kasai portoenterostomy regarded as a palliative procedure in most cases. Unfortunately, early liver failure occurs before 4 years of age in most cases, requiring liver transplantation (LT) to prolong life.[1]

As the surgical and medical care of transplant patients has improved, so has long-term survival. Indeed, in pediatric populations the expected 5-year survival rate is greater than 80%. Portal vein thrombosis (PVT) is one of the main vascular complications after LT, especially in pediatric patients with BA.[2]The reported incidence of PVT varies from 8% to 27%[3-7]in pediatric cases of BA, which is 5 to 9 times higher than that in adults(1.8%-3%).[8-10]PVT is a serious complication and needs immidiate managements which includes the restoration of portal vein (PV) blood fow. Unfortunately, clinical symptoms and signs are usually absent during the early phase of PVT, making a timely intervention challenging. Accordingly, the present study was to assess the preoperative hepatic hemodynamic parameters in pediatric patients with BA using Doppler ultrasound, and determine whether any of these parameters predicts the development of early PVT after LT.

Methods

Patients

Of the 151 consecutive pediatric recipients of LT performed between October 2006 and June 2013 at the Department of Liver Surgery in our hospital, 128 pediatric patients with BA younger than 3 years old, without preoperative and intraoperative PVT were selected for this study. Patient age ranged from 5 to 36 months at the time of LT. There were 66 boys (51.56%) and 62 girls (48.44%). Among the 128 recipients, 51 had a Kasai portoenterostomy before LT, 31 had a laparotomy and 46 had no surgical history. This retrospective study was approved by an institutional review board, and informed consent was waived.

Operative technique

Living donor LTs were performed in 128 pediatric patients according to standard procedures. The portion of the liver that was transplanted included the left lateral segment (segments II and III). The recipient's right, middle and left hepatic veins were reshaped as a single orifce, which was then anastomosed end-to-side to the graft's left hepatic vein with 5-0 polydioxanone continuous sutures. The PV was reconstructed end-to-end with 6-0 polydioxanone continuous sutures between the recipient's right and left PV bifurcation point and the graft's left PV. Hepatic artery (HA) reconstruction was performed end-to-end under a surgical microscope with 8-0 prolene interrupted sutures.

Doppler ultrasound protocol

Doppler ultrasound was performed by experienced radiologists using an Acuson Sequoia 512 scanner (Acuson, Mountain View, CA, USA) with a 3.5 MHz transducer available for color Doppler imaging. All the pediatric transplant recipients included in this study underwent the Doppler ultrasound examination within 7 days before LT. All patients were sedated with oral chloral hydrate (0.5-1.0 mg/kg body weight) before examination. Patients were placed in the supine position with the right arm abducted. Standard Doppler ultrasound parameters were adjusted to maximal gain without background noise and lowest pulse repetition frequency without aliasing artifacts. The angle between the Doppler beam and long axis of the vessel was held at less than 60 degrees. All PV measurements were obtained at the extrahepatic portion of the main PV near its bifurcation. PV diameter, maximum PV velocity (PVVmax) and the direction of the PV fow were recorded. The ultrasound system's "zoom" function was used to amplify the ultrasound image, and multiple measurements were taken, with the mean value calculated for further analysis. Measurements of the HA, which included the HA diameter, HA peak systolic velocity (HAPSV) and HA resistance index (HARI) were obtained along the hepatic hilum. PV hypoplasia was defned as a PV diameter ≤4 mm.[11]Hepatopetal fow in the PV was considered normal, and hepatofugal fow in the PV (directed away from the liver) was regarded as anomalous. HARI was considered abnormal when it was ≥1.

Statistical analysis

Statistical analyses were performed using SPSS, version 13 for Window (SPSS, Chicago, IL, USA). The demographic characteristics of the patients were summarized with frequency counts, mean±standard deviation (SD) and/or median with a range. Differences in age, body weight, pediatric end-stage liver disease (PELD) score, PV diameter, PVVmax, HA diameter, HAPSV and HARI between the early PVT group and non-PVT group were evaluated by using an independent t test. The PV fow direction in the two groups were compared using a Chi-square test. Logistic regression analyses were used to determine the possible relationship between early PVT and individual variables. The optimal cutoff value was determined by using receiver operating characteristic analysis to identify which parameters that could act as an independent risk factor for early PVT. A P＜0.05 was considered statistically signifcant.

Results

Among the 128 pediatric patients, PV diameter and PVVmax were 4.48±0.84 mm (range 2.80-7.70) and 22.93 ± 8.16 cm/sec (range 7.60-47.30), respectively (Table 1). There were 32.03% (41/128) of patients with a hypoplastic PV (diameter ≤4 mm), and 40.63% (52/128) of patients with hepatofugal PV fow. HA diameter, HAPSV and HARI were 2.71±0.47 mm (range 1.50-4.40),127.81 ± 46.76 cm/sec (range 22.60-300.00) and 0.92±0.11 (range 0.64-1.26), respectively. Finally, 31.25% (40/128) of patients had an HARI of ≥1.

Early PVT was defned as PVT detected within 30 days after LT.[12]The incidence of early PVT was 7.03% (9/128) in our study. All cases of PVT were detected by Doppler ultrasound and confrmed by surgery or com-puted tomography angiography. Eight (88.89%) of the 9 patients with early PVT were identifed within the frst 7 days after LT. One patient was diagnosed on postoperative day 25. PV hypoplasia (diameter ≤4 mm) occurred in 8 of the 9 patients with PVT, hepatofugal PV fow in 7, and high HARI (≥1) in 7. Operative interventions were performed for 7 patients, including thrombectomy (n=3), thrombectomy with stent implantation (2) and thrombectomy with anastomotic revision (2). The remaining two patients were treated with thrombolysis and followed clinically because they were asymptomatic with normal allograft function. There were no retransplantation case in our study. Four patients with early PVT died 4, 6, 26, and 30 days after transplantation, respectively. The deaths occurring at 4 and 6 days were due to allograft failure associated with vascular thrombosis, and the deaths at 26 and 30 days were due to multiple system organ failure. Long-term PV patency was achieved in the 5 survivors and all had good allograft function (Table 2).

Table 1. Preoperative hepatic hemodynamic parameters in pediatric patients with BA

PV diameter (P＜0.001), PVVmax (P=0.021), hepatofugal PV fow direction (P=0.045) and HARI (P＜0.001) were signifcantly different between the early PVT group and the non-PVT group (Table 3 and Fig.). Statisticalanalysis showed the following parameters to be hepatic hemodynamic risk factors for early PVT: a PV diameter≤4 mm (sensitivity 88.89%, specifcity 72.27%), a hepatofugal PV fow (sensitivity 77.78%, specifcity 62.18%), and a high HARI ≥1 (sensitivity 77.78%, specifcity 72.27%), respectively. There were no statistical difference in age and body weight between the early PVT group and the non-PVT group.

Table 2. Clinical and ultrasound data of the pediatric recipients with early PVT after LT

Table 3. Preoperative hepatic hemodynamic risk factors for early PVT based on univariate analysis

Fig. Hepatic hemodynamics in the non-PVT and PVT groups: PV diameter (A), PVVmax (B) and HARI (C).

Discussion

PVT was one of the main vascular complications in pediatric recipients with BA after LT, causing a high rate of graft failure and recipient mortality. We routinely divided the occurrence of PVT into two categories according to the time of occurrence.[12]Early PVT was defned as PVT detected within 30 days after LT, and late PVT was defned as PVT detected more than 30 days after LT.[12]In the early phase of PVT development, clinical symptoms and signs are usually absent. In this study, we used Doppler ultrasound to assess hepatic vascular fow because it can quantitate vascular fow.[11]The survival rate of the LT recipients with early PVT after LT is lower than that of those without this complication, therefore it is important to evaluate the preoperative hepatic hemodynamic parameters and identify risk factors associated with early PVT after LT.

It has previously been reported that a history of pre-PVT, insertion of a surgical shunt before LT and splenectomy during LT were risk factors for PVT.[13-16]In a pediatric age group, pre-existing portosystemic shunts with decreased PV fow, graft interposition, age at frst LT, low recipient body weight and a PV with small size are risk factors for early PVT.[17-19]Low intraoperative PV fow is a high risk factor for intraoperative PVT and Cheng et al[20]reported an intraoperative PV fow ≤7 cm/sec is a high risk factor for PVT. When the intraoperative PV fow was ＜10 cm/sec in our patients, collateral vein occlusion, reanastomosis of PV or PV stent implantation was performed.

It is known that PV hypoplasia is frequently observed in children with BA. Diem et al[21]studied a group of patients with BA (median age 18 months, range 5-174) and found that 19.5% had PV hypoplasia. In our study, the LT recipients were relative young (median age 12 months, range 5-36), and we found that 32.03% (41/128) of the patients had PV hypoplasia. It is thought that the particularly intense portal hypertension observed in pediatric recipients with BA may lead to a sclerotic rearrangement of the PV wall, with a corresponding reduction in vessel diameter. This rapidly progressing sclerosis and fbrosis will also affect the liver and the biliary tract, and lead to a high rate of PV hypoplasia.[2]

Moon et al[17]analyzed 96 living donor LT recipients with a median age of 11 months and demonstrated that a PV diameter ＜5 mm was a highly signifcant factor for PV complications. Similarly, Suzuki et al[22]showed that a PV diameter ＜3.5 mm was the most sensitive, specifc single parameter to predict PV stenosis. In our study, 41 (32.03%) patients with BA had a hypoplastic PV (diameter ≤4 mm). In agreement with the studies cited above, the association of a small PV diameter (≤4 mm) with early PVT occurrence after LT had a high sensitivity of 88.89% and a high specifcity of 72.27%. We speculate a small PV diameter in LT recipients leads to a larger discrepancy in PV diameter between the donor and the recipient, thereby causing a higher occurrence of early PV complications.

In our study, hepatofugal PV fow was observed in 52 (40.63%) pediatric patients with BA. Among the 9 LT recipients with early PVT, 7 (77.78%) had a hepatofugal PV fow before LT. Our analysis indicates that a hepatofugal PV fow is a risk factor for early PVT, with relatively a high sensitivity of 77.78%. The most common cause of hepatofugal PV fow in the portal venous system is portal hypertension. The prevalence of hepatofugal PV fow in the portal venous system in studies of patients with cirrhosis evaluated with ultrasound varies between 3% and 23%.[23]It is thought that a hepatofugal PV fowhad an increase in the hepatic sinusoidal resistance along with the presence of portosystemic shunts, which drains blood away from the liver. A collateral pathway causes poor portal venous infow and contributes to the risk for early PVT.

HARI is an indicator of the resistance to arterial fow through the liver. An HARI of ≥1 could be considered as an indicator of particularly severe portal hypertension and is more frequently reported in pediatric patients with BA. Several studies[24-26]have described an HARI ≥1 as a poor prognostic factor for children waiting for LT, especially in BA, which contributes to surgical diffculties in PV reconstruction. In our study, most pediatric LT recipients with BA had severe portal hypertension when LT was chosen as the fnal course of treatment. Accordingly, in our study 40 (31.25%) LT recipients had a high HARI (HARI ≥1).

In conclusion, a detailed Doppler ultrasound examination of the hepatic vascular system by an experienced radiologist is suffcient for most pediatric patients with BA scheduled for LT. We believe that Doppler ultrasound serves as a vital initial assessment for vascular evaluation and has the advantage in determining hemodynamic disturbances. Hepatic hemodynamic disturbances including PV hypoplasia (32.03%), hepatofugal PV fow (40.63%) and high HARI (31.25%) observed in pediatric LT recipients with BA were more common. Furthermore small PV diameter (≤4 mm) and hepatofugal PV fow combined with a high HARI (≥1) are strong warning signs that may predict the development of early PVT after LT in BA patients. We suggest that pediatric LT recipients with a small PV diameter or hepatofugal PV fow and a high HARI should be intensively monitored for vascular patency, prophylactic thrombolytic therapy should be considered after LT in order to prevent early PVT.

Contributors:LFH and HLZ proposed the study. GLH and FH performed research and wrote the frst draft. ZSJ and LQG collected and analyzed the data. All authors contributed to the design and interpretation of the study and to further drafts. LFH is the guarantor.

Funding:This study was supported by a grant from the Science and Research of Shanghai Municipal Health Bureau (20134Y019).

Ethical approval:This study was approved by the Institutional Review Board of Renji Hospital and in accordance with the guidelines of the Chinese government and the Declaration of Helsinki.

Competing interest:No benefts in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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Received July 14, 2014

Accepted after revision November 6, 2014

Author Affliations: Department of Ultrasound (Gu LH, Fang H, Li FH and Zhang SJ) and Department of Liver Surgery (Han LZ and Li QG), Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China

Feng-Hua Li, MD, Department of Ultrasound, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China (Tel: +86-21-68383396; Fax: +86-21-50896639; Email: renjilfh@163.com)

The abstract of the article was presented as an oral presentation at the 26th European Congress of Radiology (ECR 2014, Vienna, Austria).

© 2015, Hepatobiliary Pancreat Dis Int. All rights reserved.

10.1016/S1499-3872(15)60377-0

Published online May 21, 2015.