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Improved liver function after portal vein embolization and an elective right hepatectomy

  • Raphael P.H. Meier
    Correspondence
    Hepato‐pancreato‐biliary centre, Visceral and Transplantation Surgery, Department of Surgery, University Hospitals of Geneva and Faculty of Medicine, Rue Gabrielle Perret‐Gentil 4, 1211 Geneva, Switzerland. Tel.: +41 22 372 33 11. Fax: +41 22 372 77 81
    Affiliations
    Hepato‐Pancreato‐Biliary Centre, Visceral and Transplantation Surgry, Department of Surgery, University Hospitals of Geneva and Faculty of Medicine, Geneva, Switzerland
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  • Christian Toso
    Affiliations
    Hepato‐Pancreato‐Biliary Centre, Visceral and Transplantation Surgry, Department of Surgery, University Hospitals of Geneva and Faculty of Medicine, Geneva, Switzerland
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  • Sylvain Terraz
    Affiliations
    Department of Radiology, University Hospitals of Geneva and Faculty of Medicine, Geneva, Switzerland
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  • Romain Breguet
    Affiliations
    Department of Radiology, University Hospitals of Geneva and Faculty of Medicine, Geneva, Switzerland
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  • Thierry Berney
    Affiliations
    Hepato‐Pancreato‐Biliary Centre, Visceral and Transplantation Surgry, Department of Surgery, University Hospitals of Geneva and Faculty of Medicine, Geneva, Switzerland
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  • Axel Andres
    Affiliations
    Hepato‐Pancreato‐Biliary Centre, Visceral and Transplantation Surgry, Department of Surgery, University Hospitals of Geneva and Faculty of Medicine, Geneva, Switzerland
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  • Anne‐Sophie Jannot
    Affiliations
    Division of Clinical Epidemiology and Clinical Research Centre, University Hospitals of Geneva and Faculty of Medicine, Geneva, Switzerland
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  • Laura Rubbia‐Brandt
    Affiliations
    Division of Clinical Pathology, University Hospitals of Geneva and Faculty of Medicine, Geneva, Switzerland
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  • Philippe Morel
    Affiliations
    Hepato‐Pancreato‐Biliary Centre, Visceral and Transplantation Surgry, Department of Surgery, University Hospitals of Geneva and Faculty of Medicine, Geneva, Switzerland
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  • Pietro E. Majno
    Affiliations
    Hepato‐Pancreato‐Biliary Centre, Visceral and Transplantation Surgry, Department of Surgery, University Hospitals of Geneva and Faculty of Medicine, Geneva, Switzerland
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      Abstract

      Background

      Portal vein embolization (PVE) is used before extensive hepatic resections to increase the volume of the future remnant liver within acceptable safety margins (conventionally >0.6% of the patient's weight). The objective was to determine whether pre‐operative PVE impacts on post‐operative liver function independently from the increase in liver volume.

      Methods

      The post‐operative liver function of patients who underwent an anatomical right liver resection with (n = 28) and without (n = 53) PVE were retrospectively analysed. Donors of the right liver were also analysed (LD) (n = 17).

      Results

      Patient characteristics were similar, except for age, weight and American Society of Anesthesiologists (ASA) score that were lower in LD. Post‐operative factor V and bilirubin levels were, respectively, higher and lower in patients with PVE compared with patients without PVE or LD (P < 0.05). Patients with PVE had an increased blood loss, blood transfusions and sinusoidal obstruction syndrome. The day‐3 bilirubin level was 40% lower in the PVE group compared with the no‐PVE group after adjustment for body weight, chemotherapy, operating time, Pringle time, blood transfusions, remnant liver volume, pre‐operative bilirubin level and pre‐operative prothrombin ratio (P = 0.001).

      Conclusions

      For equivalent volumes, the immediate post‐operative hepatic function appears to be better in livers prepared with PVE than in unprepared livers. Future studies should analyse whether the conventional inferior volume limit that allows a safe liver resection may be lowered when a PVE is performed.

      Introduction

      Over the past two decades, pre‐operative portal vein embolization (PVE) has emerged as an effective way to increase the volume of the future remnant liver in patients undergoing major liver resections. PVE interrupts the blood supply of the portal territories to be resected, thus inducing a compensatory hypertrophy of the future remnant liver. This increase in the volume of healthy parenchyma is crucial for many patients, allowing surgery to be performed. Conventionally, a future remnant liver volume of 0.6% of the patient's weight or 25–30% of the total liver volume is considered safe for a liver resection.
      • Fan S.T.
      • Lo C.M.
      • Liu C.L.
      • Yong B.H.
      • Chan J.K.
      • Ng I.O.
      Safety of donors in live donor liver transplantation using right lobe grafts.
      In case of underlying parenchymal disease (i.e. cirrhosis, steatosis, or post chemotherapy liver damage
      • Rubbia‐Brandt L.
      • Audard V.
      • Sartoretti P.
      • Roth A.D.
      • Brezault C.
      • Le Charpentier M.
      Severe hepatic sinusoidal obstruction associated with oxaliplatin‐based chemotherapy in patients with metastatic colorectal cancer.
      ), the safe cut‐off rises up to or beyond 1% of the patient's weight or 40% of the total liver volume.
      • Farges O.
      • Malassagne B.
      • Flejou J.F.
      • Balzan S.
      • Sauvanet A.
      • Belghiti J.
      Risk of major liver resection in patients with underlying chronic liver disease: a reappraisal.
      • Mentha G.
      • Terraz S.
      • Andres A.
      • Toso C.
      • Rubbia‐Brandt L.
      • Majno P.
      Operative management of colorectal liver metastases.
      The current practice requires that a sufficient increase in liver volume be obtained for the patient to undergo surgery. However, little is known on the impact of PVE on liver function, and denying surgery to patients who did not achieve a given liver volume may be inappropriate. A prospective clinical study suggested that after PVE, patients with the chronic liver disease had less post‐operative complications than patients without PVE.
      • Farges O.
      • Belghiti J.
      • Kianmanesh R.
      • Regimbeau J.M.
      • Santoro R.
      • Vilgrain V.
      Portal vein embolization before right hepatectomy: prospective clinical trial.
      Other clinical studies suggested that the increase in future remnant liver function was more pronounced than the increase in future remnant liver volume after PVE, but none used a control group without PVE, nor estimated the function of a given volume of liver tissue per unit of patient's weight.
      • de Graaf W.
      • van Lienden K.P.
      • van den Esschert J.W.
      • Bennink R.J.
      • van Gulik T.M.
      Increase in future remnant liver function after preoperative portal vein embolization.
      • Hirai I.
      • Kimura W.
      • Fuse A.
      • Suto K.
      • Urayama M.
      Evaluation of preoperative portal embolization for safe hepatectomy, with special reference to assessment of nonembolized lobe function with 99mTc‐GSA SPECT scintigraphy.
      • Nishiyama Y.
      • Yamamoto Y.
      • Hino I.
      • Satoh K.
      • Wakabayashi H.
      • Ohkawa M.
      99mTc galactosyl human serum albumin liver dynamic SPET for pre‐operative assessment of hepatectomy in relation to percutaneous transhepatic portal embolization.
      • Yumoto Y.
      • Yagi T.
      • Sato S.
      • Nouso K.
      • Kobayashi Y.
      • Ohmoto M.
      Preoperative estimation of remnant hepatic function using fusion images obtained by (99m)Tc‐labelled galactosyl‐human serum albumin liver scintigraphy and computed tomography.
      The aim of the present study was to test and quantify the assumption that an increase in volume correlates with an increase in function, and to analyse whether post‐operative liver function per unit of liver volume (i.e. specific liver function), rather than just volume, was increased by pre‐operative PVE. Besides the well‐established fact that PVE increases the chance of performing a large hepatic resection, here it is shown that the liver is primed after PVE and that this results in an increase in function per unit of liver volume.

      Patients and methods

      Patients

      Five hundred and forty‐nine patients underwent liver resections at Geneva University Hospitals between 1999 and 2010. Patients who underwent an anatomical right liver resection (segments 5–8, in some patients extended to segment 1 and 4) were identified. To homogenize the cohort, patients older than 70 years, with cirrhosis, with a Pringle manoeuvre exceeding a total of 40 min, with simultaneous left liver resections, or with pre‐operative chronic cholestasis were excluded from the study. A detailed flow chart is available in Fig. S1. Exclusion according to these criteria left 28 patients who had pre‐operative PVE (study group), 70 patients who had no PVE (53 curative right hepatectomy; control group 1) and 17 liver donors (LD) for adult‐to‐adult living donor transplantation (right liver grafts; control group 2). An institution's Computerized Patient Record System was used; a retrospective analysis of prospectively backed up laboratory data, procedures, hospital course and a digitized computed tomography (CT) scan was conducted for every patient. The study was approved by the local research ethics committee of the Departments of Surgery of Geneva University Hospitals (protocol NAC 10‐158R).

      Portal vein embolization

      Percutaneous embolization of the right portal vein and its intrahepatic branches was performed under general anaesthesia, using an ipsilateral (n = 9) or contralateral (n = 19) approach. The portal system was punctured with a 22‐G Chiba needle under ultrasound guidance. After catheterization with a 5‐F catheter, the targeted segmental portal veins were successively embolized under fluoroscopic guidance, using a 1:1 mixture of n‐butyl‐cyanoacrylate (Histoacryl®) and iodized oil (Lipiodol®). In three patients embolization also involved segment 4 and was performed with ethylene‐vinyl alcohol copolymer (Onyx®) through a 2.4‐F micro catheter. PVE was performed in patients with an estimated future remnant liver of less than 30% of the functional liver mass (or 40% after extensive neoadjuvant chemotherapy).
      • Andres A.
      • Toso C.
      • Moldovan B.
      • Schiffer E.
      • Rubbia‐Brandt L.
      • Terraz S.
      Complications of elective liver resections in a center with low mortality: a simple score to predict morbidity.
      The waiting time from PVE to resection was 6 weeks for every patient.

      Liver resection

      A right or extended right hepatectomy was performed using a standardized technique.
      • Andres A.
      • Toso C.
      • Moldovan B.
      • Schiffer E.
      • Rubbia‐Brandt L.
      • Terraz S.
      Complications of elective liver resections in a center with low mortality: a simple score to predict morbidity.
      Briefly, after exposure of the operative field through a subcostal approach, the liver was fully mobilized, and the hepatic pedicle prepared. A liver parenchymal transection was performed using the ultrasonic scalpel (cavitational ultrasonic surgical aspiration) the monopolar, bipolar and argon‐beam coagulators, metal clips and ligatures. Clamping of the hepatic pedicle was used parsimoniously. Intra‐operative ultrasound was used in every patient.

      Liver histology

      In patients with a curative hepatectomy, histopathology was assessed on the resected liver. Pre‐operative liver biopsies were available for all living donors. Histological slides were analysed by a specialized liver pathologist. Steatosis was graded as follows: none, mild (involving <30% of the hepatocytes), moderate (involving 30–60% of the hepatocytes) and severe (involving >60% of the hepatocytes).
      • D'Alessandro A.M.
      • Kalayoglu M.
      • Sollinger H.W.
      • Hoffmann R.M.
      • Reed A.
      • Knechtle S.J.
      The predictive value of donor liver biopsies for the development of primary nonfunction after orthotopic liver transplantation.
      Parenchymal abnormalities such as nodular regenerative hyperplasia or sinusoidal obstruction syndrome (SOS) were systematically identified.
      • Rubbia‐Brandt L.
      • Audard V.
      • Sartoretti P.
      • Roth A.D.
      • Brezault C.
      • Le Charpentier M.
      Severe hepatic sinusoidal obstruction associated with oxaliplatin‐based chemotherapy in patients with metastatic colorectal cancer.

      Volumetric assessment

      The computerized tomography volumetry was measured by two experienced radiologists (S.T. and R.B.), blinded to group assignment and outcomes, using an open‐source viewing software (OsiriX®). The total liver volume was measured in both groups on the portal phase images of a contrast‐enhanced CT (slice thickness, 1.0–3.0 mm; interval thickness, 0.75–2.0 mm). This examination was performed within 1 week before surgery (i.e. 5 weeks after a PVE) in the study group and within 4 weeks before living donor liver transplantation. The remnant liver volume was calculated by subtracting the weight of the resected liver from the total liver volume, after conversion using the specific gravity of liver tissue (1.067).
      • Weibel E.R.
      Stereological Methods, vol. 1: Practical Methods for Biological Morphometry.
      The remnant liver volume to body weight ratio was calculated and was expressed as a percentage of the body weight.

      Laboratory data

      Pre‐(hereafter known as day 0) and post‐operative total bilirubin, prothrombin ratio, factor V, aspartate transaminase (AST) and alanine transaminase (ALT) levels were collected for every patient using computerized patient's records. Pre‐operative factor V values were not systematically available; however, the pre‐operative prothrombin ratio was available for all patients. When factor V reached 100%, it was not further dosed and considered to stay at 100%.

      Post‐operative indices of liver function

      To illustrate the capacity of a given amount of liver tissue to metabolize bilirubin (i.e. a form of specific function of the liver), an index integrating bilirubin at day 3, patient's weight and remnant liver volume was designed. Day‐3 bilirubin was chosen for its prognostic value, as reported in the literature.
      • Balzan S.
      • Belghiti J.
      • Farges O.
      • Ogata S.
      • Sauvanet A.
      • Delefosse D.
      The, “50‐50 criteria” on postoperative day 5: an accurate predictor of liver failure and death after hepatectomy.
      The index was:
      Bilirubin at day3×PatientsweightRemnant liver volume


      To illustrate the above, the day‐3 bilirubin levels are plotted with the ratio between remnant liver volume and patient's weight for patients in all groups.

      Statistical analysis

      Continuous variables were expressed as means and standard deviations (SD) and categorical variables were expressed as percentages. Comparison between groups was performed using the Mann–Whitney U‐test. A linear regression model was used to model the log of bilirubin concentration at day 3 for each individual as a dependent variable. Independent variables included: group (PVE or no PVE), body weight, chemotherapy, operating time, Pringle time, blood transfusion, remnant liver volume, pre‐operative bilirubin level and the pre‐operative prothrombin ratio. Tests for the difference in the log of bilirubin concentration between groups were performed as likelihood‐ratio tests. Kaplan–Meier estimates were calculated using the Gehan–Breslow–Wilcoxon Test. Statistical significance was defined as P < 0.05.

      Results

      Baseline characteristics

      Patient characteristics are summarized in Table 1. Comparison between patients with and without PVE revealed no significant difference in age, gender, weight, size and American Society of Anesthesiologist physical status classification system (ASA) score. As expected, comparison between patients with PVE and liver donors showed that LD were younger, had a lower weight and had a lower ASA score compared with patients who underwent PVE and a right hepatectomy for a disease.
      Table 1Characteristics of patients with and without portal vein embolization and liver donors
      VariablePVE (n = 28)No PVE (n = 53)LD (n = 17)P‐value
      P‐values were calculated using the Mann–Whitney U‐Test (for continuous and categorical variables) or the Chi square test (for binary variables).
      (PVE versus no PVE)
      P‐value
      P‐values were calculated using the Mann–Whitney U‐Test (for continuous and categorical variables) or the Chi square test (for binary variables).
      (PVE versus LD)
      Age (mean ± SD)55.7 (±10.0)53.7 (±13.2)38.4 (±13.4)0.812<0.001
      Gender (male) (%)17 (60.7)24 (45.3)6 (35.3)0.2440.130
      Weight (kg) (mean ± SD)74.1 (±16.7)69.5 (±12.5)65.7 (±8.5)0.2290.050
      Size (cm) (mean ± SD)170.1 (±8.7)168.9 (±9.6)168.5 (±8.2)0.3190.493
      ASA classification (%)
      13 (10.7)10 (18.9)13 (76.5)0.419<0.001
      222 (78.6)38 (71.7)4 (23.5)
      33 (10.7)5 (9.4)0 (0.0)
      40 (0.0)0 (0.0)0 (0.0)
      PVE, portal vein embolization; LD, liver donor; ASA, American Society of Anesthesiologists physical status classification system; SD, standard deviation.
      * P‐values were calculated using the Mann–Whitney U‐Test (for continuous and categorical variables) or the Chi square test (for binary variables).

      Intra‐operative course

      Data regarding the intra‐operative course are shown in Table 2. Patients who underwent PVE had a longer operating time lost more blood and were transfused more often compared with patients without PVE. None of the patients received fresh frozen plasma. In right liver donors, a short Pringle manoeuvre was used only to determine the boundary of the liver to be resected according to the vascularization of the parenchyma. The indication for surgery is listed in Table S1. Of note, patients with cholangiocarcinoma had a biliary drainage before surgery. Comparison between patients with PVE and liver donors revealed that LD had a longer operating time, as reported by others.
      • Gali B.
      • Findlay J.Y.
      • Plevak D.J.
      • Rosen C.B.
      • Dierkhising R.
      • Nagorney D.M.
      Right hepatectomy for living liver donation vs right hepatectomy for disease: intraoperative and immediate postoperative comparison.
      Table 2Intra‐operative course and liver histopathology in patients with and without portal vein embolization, and liver donors
      VariablePVE (n = 28)No PVE (n = 53)LD (n = 17)P‐value
      P‐values were calculated using the Mann–Whitney U‐Test (for continuous and categorical variables) or the chi square test (for binary variables).
      (PVE versus no PVE)
      P‐value
      P‐values were calculated using the Mann–Whitney U‐Test (for continuous and categorical variables) or the chi square test (for binary variables).
      (PVE versus LD)
      Operating time (min) (mean ± SD)432.2 (±69.2)374.4 (±88.9)571.2 (±89.8)0.002<0.001
      Pringle time
      None22 (78.6)47 (88.7)15 (88.2)0.2280.360
      <10 min3 (10.7)3 (5.7)2 (11.8)
      10–40 min3 (10.7)3 (5.7)0 (0.0)
      Blood loss (ml) (mean ± SD)892.5 (±563.4)566.7 (±270.6)559.1 (±299.0)0.0410.079
      Blood transfusion (RBC pack) (%)
      018 (64.3)46 (86.8)11 (64.7)0.0190.762
      14 (14.3)3 (5.7)5 (29.4)
      26 (21.4)4 (7.5)0 (0.0)
      30 (0)0 (0)1 (5.9)
      Steatosis
      None10 (35.7)15 (28.3)8 (47.1)0.4630.284
      Mild (<30%)15 (53.6)31 (58.5)9 (52.9)
      Moderate (30–60%)3 (10.7)4 (7.5)0 (0)
      Severe (>60%)0 (0)3 (5.7)0 (0)
      Sinusoidal obstruction syndrome (%)14 (50.0)12 (22.6)0 (0.0)0.015<0.001
      Nodular regenerative hyperplasia (%)5 (17.9)3 (5.7)0 (0.0)0.1170.140
      Chemotherapy (%)22 (78.6)31 (58.5)0 (0.0)0.088<0.001
      PVE, portal vein embolization; LD, liver donor; SD, standard deviation; RBC, red blood cell.
      * P‐values were calculated using the Mann–Whitney U‐Test (for continuous and categorical variables) or the chi square test (for binary variables).

      Liver histopathology and chemotherapy

      Data on liver histopathology and chemotherapy are presented in Table 2. The prevalence of steatosis was not statistically different in the three groups. Patients with PVE had more often SOS lesions associated with chemotherapy compared with patients without PVE. The prevalence of Nodular Regenerative Hyperplasia was not statistically different between patients with and without PVE, and by definition LD had no chemotherapy‐associated lesions. The type of chemotherapy is listed in Table S2.

      Pre‐ and post‐operative liver volumes

      Comparisons of liver volumes are summarized in Table 3. No significant difference in pre‐ and post‐operative liver volumes and volumes/body weight ratios was observed between the PVE group and the no PVE group. Comparison between the PVE group and LD showed that the total liver volume was larger in the PVE group; this difference was no longer present when the liver volume was normalized to body weight. When considering all patients together, the mean total liver volume represented 2.3% of the body weight; the functional liver volume (calculated by subtracting the tumor volume to the total liver volume) represented 2.1% of the body weight, and the resected liver and remnant liver volume represented 1.2% each. On average, patients had 54% of their initial functional liver volume after the surgery. Overall, the measurement of pre‐ and post‐operative liver volumes normalized to patient's weight indicated that the extent of the right hepatectomy was similar in the three groups.
      Table 3Liver volumes of patients with and without portal vein embolization and liver donors
      VariablePVE (n = 28)No PVE (n = 53)LD (n = 17)P‐value
      P‐values were calculated using the Mann–Whitney U‐Test.
      (PVE versus no PVE)
      P‐value
      P‐values were calculated using the Mann–Whitney U‐Test.
      (PVE versus LD)
      Total liver volume (cc) (mean ± SD)1654 (±460)1622 (±)1399 (±174)0.5290.011
      Total liver volume/body weight (%) (mean ± SD)2.26 (±0.42)2.44 (±0.67)2.14 (±0.25)0.3760.691
      Tumor volume (mean ± SD)106 (±153)189 (±269)0 (±0)0.492<0.001
      Functional liver volume (cc) (mean ± SD) (Total liver volume minus tumor volume)1547 (±492)1434 (±231)1399 (±174)0.4800.337
      Functional liver volume/body weight (%) (mean ± SD)2.10 (±0.42)2.14 (±0.39)2.14 (±0.25)0.9120.482
      Resected liver (g) (mean ± SD)834 (±301)832 (±245)687 (±123)0.7570.065
      Resected liver/body weight (%) (mean ± SD)1.16 (±0.36)1.23 (±0.47)1.06 (±0.16)0.5380.598
      Functional liver resected (cc) (mean ± SD) (Resected liver minus tumor volume)706 (±267)664 (±228)667 (±119)0.9490.999
      Functional liver resected/body weight (%) (mean ± SD)0.97 (±0.25)0.96 (±0.35)1.02 (±0.15)0.6700.145
      Remnant liver volume (cc) (mean ± SD)850 (±323)818 (±309)711 (±104)0.5580.132
      Remnant liver volume/body weight (%) (mean ± SD)1.15 (±0.34)1.23 (±0.38)1.10 (±0.19)0.8730.436
      Remnant liver volume/Functional liver volume (%) (mean ± SD)53.8 (±11.3)56.2 (±13.8)51.7 (±5.8)0.9990.327
      PVE, Portal vein embolization; LD, liver donor; cc, cubic centimeter; SD, standard deviation.
      a P‐values were calculated using the Mann–Whitney U‐Test.

      Post‐operative course after a right hepatectomy in patients with and without pre‐operative PVE and liver donors

      There was no post‐operative mortality at 3 months. Specific morbidity in the three groups was limited to Clavien's grade III complications
      • Dindo D.
      • Demartines N.
      • Clavien P.A.
      Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey.
      (one late reoperation in a living donor for a pleural empyema secondary to a bile leak). The analysis of liver synthetic function showed that patients with PVE had higher post‐operative factor V values from day 1 to 4 compared with patients without PVE and LD (Fig. 1a). The post‐operative prothrombin ratio confirmed differences observed in factor V levels and were higher in patients with PVE from day 1 to 3 compared with the two other groups (Fig. 1b). The differences were statistically significant at day 2 (Factor V and prothrombin ratio), P ≤ 0.021 (PVE versus no PVE, and versus LD). Patients with PVE had lower post‐operative bilirubin values from day 1 to 7 compared with the two other groups (Fig. 1c). The differences were statistically significant from day 1 to 4, P < 0.050 (PVE versus no PVE, and versus LD). Multivariate linear regression for factors influencing bilirubin levels at day 3 (where the differences were the most important between groups) showed that only Group (PVE versus no PVE) had an impact on day‐3 bilirubin value. On average, the day‐3 bilirubin value was 40% lower in patients with PVE compared with the patients without PVE after adjustment for body weight, chemotherapy, operating time, Pringle time, blood transfusion, remnant liver volume, pre‐operative bilirubin level and the pre‐operative prothrombin ratio (P = 0.001) (Table S3). None of the potential confounders was statistically significant. Hepatic injury, as revealed by increases in ALT and AST, was similar between the PVE group and the no PVE group (Fig. 1d,e). The LD group had lower transaminases' levels before (day 0) and after surgery (day 1) compared with the PVE group. Of note, patients with PVE had significantly lower ALT and AST values 7 days after surgery, compared with the two other groups (P ≤ 0.016).
      Figure thumbnail gr1
      Figure 1Post‐operative serum factor V (a, prothrombin ratio (b), bilirubin (c), alanine transaminase (ALT) (d) and aspartate transaminase (AST) (e) levels for patients with portal vein embolization (PVE) (blue dots), without PVE (black triangles) and liver donors (LD) (red squares). The mean values are reported from day 0 (before the surgery, except for factor V) to post‐operative day 10. Values are expressed as mean ± SD. * and † refers to a significant P value comparing PVE versus no PVE and PVE versus liver donors, respectively. P‐values were calculated using the Mann–Whitney U‐Test

      Specific liver function index

      To investigate the intrinsic metabolic capacity of a given amount of liver tissue, an index of liver metabolic function based on bilirubin values and taking into account the volume of functional liver per kilo of body weight was modelled: Bilirubin at day 3 × Patient's weight/Remnant Liver Volume. Patients with PVE had significantly better index values as compared with patients without PVE or LD (Fig. 2a). To illustrate the index of liver metabolic function, the day‐3 bilirubin value was plotted against the residual liver volume/patient's weight ratio (Fig. 2b). A small residual liver volume and a high body weight resulted in an increased day‐3 bilirubin value in the three groups. Overall, when considering patients with similar residual liver volume and body weight, day‐3 bilirubin was lower in the PVE group compared with the no PVE group and LD. The time to bilirubin normalization (i.e. ≤ 25 μmol/l) was significantly shorter in patients who had PVE compared with patients without PVE or LD (P ≤ 0.013) (Fig. 2c).
      Figure thumbnail gr2
      Figure 2(a) Post‐operative liver function index (Bilirubin at day 3 × Patient's weight/Remnant Liver Volume). P‐values were calculated using the Mann–Whitney U‐Test. (b) Bilirubin levels at day 3 as a function of the Remnant Liver Volume to Body Weight ratios. (c) Kaplan–Meier estimates representing the time to bilirubin normalization (i.e. ≤25 μmol/l). P‐values were calculated using the Gehan–Breslow–Wilcoxon Test. Patients are represented as follow: portal vein embolization (PVE) (blue dots), no portal vein embolization (PVE) (red squares) and liver donors (LD) (black triangles)

      Discussion

      PVE induces hepatocyte proliferation
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      and on short‐ as well as long‐term outcomes after surgery.
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      Preoperative selective portal vein embolization before hepatectomy for liver metastases: long‐term results and impact on survival.
      • Oussoultzoglou E.
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      • Lucescu I.
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      Right portal vein embolization before right hepatectomy for unilobar colorectal liver metastases reduces the intrahepatic recurrence rate.
      • Tanaka H.
      • Hirohashi K.
      • Kubo S.
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      • Higaki I.
      • Kinoshita H.
      Preoperative portal vein embolization improves prognosis after right hepatectomy for hepatocellular carcinoma in patients with impaired hepatic function.
      • Liu C.L.
      • Fan S.T.
      • Lo C.M.
      • Tso W.K.
      • Lam C.M.
      • Wong J.
      Improved operative and survival outcomes of surgical treatment for hilar cholangiocarcinoma.
      • Wicherts D.A.
      • de Haas R.J.
      • Andreani P.
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      • Castaing D.
      Impact of portal vein embolization on long‐term survival of patients with primarily unresectable colorectal liver metastases.
      The aim of this study was to determine whether pre‐operative PVE had a positive impact on liver function (i.e. independently from the positive effect on liver volume) in patients who underwent a major hepatectomy. Using two different control groups, pre‐operative PVE was shown to increase liver synthetic and metabolic functions in patients with similar remnant liver volumes after a right hepatectomy.
      The synthetic function of the liver, as assessed by factor V activity and the prothrombin ratio, was markedly diminished after a right hepatectomy. The decrease was dependent of the volume of remnant liver normalized to body weight. In patients with pre‐operative PVE, the postoperative drop in synthetic function was significantly less important. These results were consistent with differences observed in liver metabolic function between groups; liver primed with PVE required a shorter time to serum bilirubin normalization than unprepared liver.
      One of the strengths of this study is that the pre‐ and post‐operative liver and tumour volumes were meticulously analysed. The extent of the right liver resections was similar between the three groups. Of note, the assessment of the percentage of post‐operative functional liver volume (i.e. taking into account tumour volume) confirmed that patients in the three groups underwent the same loss in functional liver volume.
      The reasons why liver function per unit of liver volume is better after PVE are not completely elucidated, but it is likely that the PVE‐primed liver can manage sequentially the tasks that stress simultaneously the residual liver after an unprepared hepatectomy. Ninomiya et al.
      • Ninomiya M.
      • Shirabe K.
      • Terashi T.
      • Ijichi H.
      • Yonemura Y.
      • Harada N.
      Deceleration of regenerative response improves the outcome of rat with massive hepatectomy.
      showed that the deceleration of the regenerative response improved the outcome of rats after a massive hepatectomy. Based on this work, it can be hypothesized that, immediately after a liver resection, the hepatocytes face two competing tasks: proliferating and metabolizing; these tasks stress the capacities of the cellular machinery and are thus in competition. This hypothesis is supported by studies in which liver regeneration correlates negatively with metabolic function.
      • Wu T.J.
      • Dahiya D.
      • Lee C.S.
      • Lee C.F.
      • Chou H.S.
      • Chan K.M.
      Impact of portal venous hemodynamics on indices of liver function and graft regeneration after right lobe living donor liver transplantation.
      • Xu X.
      • Man K.
      • Zheng S.S.
      • Liang T.B.
      • Lee T.K.
      • Ng K.T.
      Attenuation of acute phase shear stress by somatostatin improves small‐for‐size liver graft survival.
      • Zhao Y.
      • Man K.
      • Lo C.M.
      • Ng K.T.
      • Li X.L.
      • Sun C.K.
      Attenuation of small‐for‐size liver graft injury by FTY720: significance of cell‐survival Akt signaling pathway.
      • Belghiti J.
      • Liddo G.
      • Raut V.
      • Zappa M.
      • Dokmak S.
      • Vilgrain V.
      “Inherent limitations” in donors: control matched study of consequences following a right hepatectomy for living donation and benign liver lesions.
      Also, during the days after a liver resection, the new hepatocytes do not have the corresponding sinusoidal cells needed to constitute a working functional unit. Ding et al.
      • Ding B.S.
      • Nolan D.J.
      • Butler J.M.
      • James D.
      • Babazadeh A.O.
      • Rosenwaks Z.
      Inductive angiocrine signals from sinusoidal endothelium are required for liver regeneration.
      confirmed the critical role of sinusoidal cells and transcription factor Id1 (Vascular Endothelial Growth Factor dependent) in liver regeneration. An indication of the fundamental role of sinusoidal cells during liver regeneration is suggested by the remarkable ability of regeneration seen in patients with fulminant A hepatitis,
      • Schiodt F.V.
      • Davern T.J.
      • Shakil A.O.
      • McGuire B.
      • Samuel G.
      • Lee W.M.
      Viral hepatitis‐related acute liver failure.
      in whom the sinusoidal scaffold is intact, despite a loss of 90% of hepatocytes.
      • Boudjema K.
      • Jaeck D.
      • Simeoni U.
      • Becmeur F.
      • Schieffer F.
      • Bientz J.
      [Temporary auxiliary orthotopic transplantation of a reduced liver for fulminant hepatitis. A successful case in a child].
      Also consistent with this double stress hypothesis, portocaval shunt, by reducing the portal hypertension signals leading to hepatocyte replication, reduces overall mortality in small‐for‐size syndrome.
      • Troisi R.
      • Ricciardi S.
      • Smeets P.
      • Petrovic M.
      • Van Maele G.
      • Colle I.
      Effects of hemi‐portocaval shunts for inflow modulation on the outcome of small‐for‐size grafts in living donor liver transplantation.
      • Boillot O.
      • Delafosse B.
      • Mechet I.
      • Boucaud C.
      • Pouyet M.
      Small‐for‐size partial liver graft in an adult recipient; a new transplant technique.
      In summary, it may be hypothesized that PVE triggers liver regeneration (both of hepatocytes and of sinusoidal cells) at a time when metabolic demand is low (i.e. 6 weeks before the hepatectomy), leaving the cellular machinery free to accomplish the metabolic tasks immediately after the major liver resection.
      This study has some limitations. First, a retrospective study does not allow definitive conclusions. A prospective randomized study would allow the assessment of the impact of PVE on liver function (as opposed to volume) in greater details. However, PVE is now a fully accepted procedure for patient's preparation before a right hepatectomy, and because randomization would be difficult to justify. Another limitation is that the methods to estimate liver function did not include other more subtle techniques such as indocyanine green, xylocaine, galactose retention tests or the LiMAx test
      • Stockmann M.
      • Lock J.F.
      • Malinowski M.
      • Niehues S.M.
      • Seehofer D.
      • Neuhaus P.
      The LiMAx test: a new liver function test for predicting postoperative outcome in liver surgery.
      because they were not available in this retrospective setting. The fact that we had access only to standard laboratory values is one limitation of this study. Nevertheless, factor V and the prothrombin ratio, as well as bilirubin blood levels, are a reliable indicator of liver function as supported by the present results and by the literature: they predict post‐operative liver failure and mortality, and at present no valid and consensual substitutes are available in clinical practice.
      • Balzan S.
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      • Farges O.
      • Ogata S.
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      • Delefosse D.
      The, “50‐50 criteria” on postoperative day 5: an accurate predictor of liver failure and death after hepatectomy.
      Young living donors with healthy parenchyma were used as a second control group. This comparison is of interest because liver donors are the best controls to analyse liver function without the effect of any prior regeneration stimuli before a hepatectomy. This comparison confirmed the differences observed between the PVE group and the no PVE group, namely that the same volume of primed PVE liver shows better liver function immediately after the operation. This despite the fact that important biases, such as a younger age, lower weight, lower ASA score, smaller operative blood losses and the absence of chemotherapy or of chemotherapy‐associated lesions, all favoured the living donors group.
      • Gali B.
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      • Plevak D.J.
      • Rosen C.B.
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      • Nagorney D.M.
      Right hepatectomy for living liver donation vs right hepatectomy for disease: intraoperative and immediate postoperative comparison.
      • Ettorre G.M.
      • Sommacale D.
      • Farges O.
      • Sauvanet A.
      • Guevara O.
      • Belghiti J.
      Postoperative liver function after elective right hepatectomy in elderly patients.
      Another clinically relevant difference between the groups was that patients with PVE lost more blood and needed more transfusions than the patients in the no PVE groups. Potential explanations for this difference are that the transection surface is larger, and that the interruption of portal vein flow into the right liver slightly increases the blood flow to the left liver further causing more bleeding during surgery after PVE, as previously reported by others.
      • Kim S.H.
      • Kim I.K.
      • Hong Y.K.
      • Chol S.B.
      • Lee K.H.
      • Park S.W.
      The effect of preoperative portal vein embolization on liver regeneration after extended hepatic resection.
      It was also observed that sinusoidal obstruction syndrome was more frequent in PVE patients. This is most likely as a result of a combination of two factors: the interruption of the portal vein flow and the higher prevalence of extended chemotherapy in the PVE group compared with the no PVE groups. Thus, the benefit brought by PVE, namely the lower bilirubin values and increased factor V, should be balanced with potential additional risks such as an increased intra‐operative blood loss and the higher occurrence of sinusoidal obstruction syndrome in patients with PVE. Further, the possibility of non/malperfused areas of the liver could add some variability in the measurement of remnant functional volume and post‐operative liver function.
      Other investigators addressed the question of the possible increase in liver function after PVE with different techniques, estimating liver function before liver resection with 99mTc‐labelled galactosyl–human serum albumin scintigraphy,
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      99m Tc‐labelled mebrofenin hepatobiliary scintigraphy
      • de Graaf W.
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      and the indocyanine‐green clearance test.
      • Uesaka K.
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      • Nagino M.
      Changes in hepatic lobar function after right portal vein embolization. An appraisal by biliary indocyanine green excretion.
      Others suggested that portal vein occlusion together with in situ splitting allow an extended right hepatic resection in small‐for‐size settings (ALPPS, Associated Liver Partition and Portal vein ligation for Staged hepatectomy).
      • Schnitzbauer A.A.
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      ALPPS offers a better chance of complete resection in patients with primarily unresectable liver tumors compared with conventional‐staged hepatectomies: results of a multicenter analysis.
      Farges et al.
      • Farges O.
      • Belghiti J.
      • Kianmanesh R.
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      • Santoro R.
      • Vilgrain V.
      Portal vein embolization before right hepatectomy: prospective clinical trial.
      prospectively compared post‐ right hepatectomy outcomes in 27 patients with and 28 without PVE in a non‐randomized study. Similar to this study, PVE improved the post‐operative liver function in patients but the advantage was significant only in patients with the chronic liver disease. In this investigation, additional evidence is provided by quantifying the increase in liver function per unit of liver volume, and showed that this increase is also present in patients without underlying liver disease. Furthermore, recent studies showed that PVE combined with coiling led to an increased liver hypertrophy
      • Malinowski M.
      • Geisel D.
      • Stary V.
      • Denecke T.
      • Seehofer D.
      • Jara M.
      Portal vein embolization with plug/coils improves hepatectomy outcome.
      and this improvement might strengthen the significance of the present findings.
      These results suggest that, in patients who have undergone PVE, the immediate post‐operative liver function per unit of volume (the specific liver function) is improved compared with patients who undergo hepatectomy on an unprepared liver. The volume criteria that would preclude safe liver resection in the absence of PVE may be revaluated in future prospective studies.

      Acknowledgements

      The authors thank Thomas Perneger, MD from the Division of Clinical Epidemiology of Geneva University Hospitals for helpful assistance during statistical analysis and Jorge Remuinan for CT‐Scan analysis. Raphael P. H. Meier, MD‐PhD and Pietro E. Majno, MD had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Professor Gilles Mentha, MD, passed away unexpectedly on 25 May 2014, after bringing key input into the study. He was a world‐renowned hepatobiliary and transplant surgeon, and will be greatly missed.

      Author's contribution

      R.M., C.T., S.T., G.M. and P.M. designed the study. R.M., S.T., R.B., Ph.M., G.M. and Ph.M. collected the data. R.M., A.J., Ph.M., G.M. and P.M. analysed the data. R.M. and A.J. performed the statistical analysis. R.M., C.T., S.T., R.B., T.B., A.A., A.J., L.R., Ph.M., G.M. and P.M. interpreted the data and wrote the manuscript. R.M. and P.M. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

      Conflicts of interest

      None declared.

      Funding sources

      This study was supported by the Artères Foundation / Fondation privée HUG. Christian Toso was supported by a Professorship from the Swiss National Science Foundation (PP00P3 139021).

      Supporting Information

      Additional Supporting Information may be found in the online version of this article:
      Figure S1 Patient selection flow chart
      Table S1 Indication for surgery in patients with and without PVE
      Table S2 Type of chemotherapy in patients with and without PVE
      Table S3 Factors influencing bilirubin levels at day 3: univariate analysis and multivariate analysis. The linear regression model integrates the log ofbilirubin concentration at day 3 as a dependent variable, and group (PVE or no PVE), body weight, chemotherapy, operating time, Pringle time, blood transfusion, remnant liver volume, pre-operative bilirubin level and the preoperative prothrombin ratio level as independent variables. Multiplicative coefficients were unlogged for clarity

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