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Towards safer liver resections
Hoekstra, L.T.
Publication date
2012
Link to publication
Citation for published version (APA):
Hoekstra, L. T. (2012). Towards safer liver resections.
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Chapter
Can plasma bile salt, triglycerides and
apoA-V levels predict liver
regeneration?
L.T. Hoekstra
K.P. van Lienden
F.G. Schaap
R.A.F.M. Chamuleau
R.J. Bennink
T.M. van Gulik
Submitted5
Abstract
Background: Preoperative portal vein embolization (PVE) is used to increase the future
remnant liver (FRL) in patients requiring extensive liver resection. CT volumetry, performed not earlier than 3-6 weeks after PVE, is commonly employed to assess hypertrophy of the FRL following PVE. Early parameters to predict effective hypertrophy are therefore desirable. The aim of this study was to assess plasma bile salt levels, triglycerides (TG) and apoA-V in the prediction of the hypertrophy response during liver regeneration.
Methods: Serum bile salt, triglyceride and apoA-V levels were determined in 20 patients
with colorectal metastases before PVE, and 5 hrs, 1 day, and 21 days after PVE, as well as prior to and after (day 1-7, and day 21) subsequent liver resection. These parameters were correlated with liver volume as measured by CT volumetry, and liver function determined by Tc-labled mebrofenin hepatobiliary scintigraphy using SPECT.
Results: Both bile salts and TG 5 hours after PVE positively correlated with the increase
in FRL volume (r=0.672, p=0.024; r=0.620, p=0.042 resp.) and liver function after 21 days (for bile salts r=0.640, p=0.046). Following liver surgery, TG at 5h and one day after resection were associated with liver remnant volume after three months (r=0.921, p=0.026 and r=0.981, p=0.019 resp.). Plasma apoA-V was increased during liver regeneration.
Conclusions: Bile salt and triglycerides levels at 5 hours after PVE/resection are
significant, early predictors of liver volume and functional increase. It is suggested that these parameters can be used for early timing of volume assessment and resection after PVE.
Introduction
Portal vein embolization (PVE) first came to mind in the late 1980s in Japan after the publication of an article reporting atrophy of liver lobes in relation to tumor induced portal vein obstruction, showing an increase in size of the non-obstructed lobes.[1] This publication independently confirmed the experimental results of Rous and Larimore, obtained in the 1920s in a portal vein ligation model in rabbits.[2] Preoperative PVE is now a widely used technique to increase the future remnant liver (FRL) through induction of hepatocellular regeneration in the non-embolized liver lobe in order to perform a liver resection with less risk of postoperative liver failure.[3] The minimal volume for safe liver resection depends on pre-existing, parenchymal liver disease. A FRL of ≥25-30% of total liver volume is considered sufficient to perform a safe resection in patients with normal liver parenchyma, whereas in patients with diseased liver, a FRL of ≥40% is preferred.[4] The hypertrophy response after PVE has shown to correlate with outcome after resection. Liver resection is usually performed 3-6 weeks after PVE, but the exact time optimum remains controversial since the mechanisms of regeneration after PVE (or liver resection) are not fully understood.[5;6] Liver hypertrophy in the non-embolized lobe following PVE is determined by CT volumetry, performed 3-6 weeks following PVE. However, there is increasing evidence that PVE not only stimulates growth of the FRL but also increases tumor proliferation because of growth factors and cytokines released in the process of liver regeneration.[7] Therefore, additional parameters that can be applied at an early time-point to predict sufficient regeneration of the hypertrophic, non-embolized liver lobe are highly in need. In this study, we examined plasma bile salt levels, triglycerides (TG) and apoA-V as possible predictors of liver volume and function after PVE.
Some recent experimental studies have demonstrated correlations between plasma bile salts and liver regeneration.[8-12] However, these associations may depend on the choice of the animal model used. In literature, only one clinical study demonstrated increased serum bile acid levels in patients with effective liver hypertrophy of the non-embolized lobe post-PVE.[13] Apart from a relation between bile salt levels and the hypertrophy response after portal vein embolization or ligation, as well as liver resection, several experimental studies also reported the influence of TG within the regenerating liver.[14-16] In turn, apo-lipoprotein A-V (apoA-V) has been considered a potential factor in determining triglyceride levels, as was initially disclosed while screening genes involved in liver regeneration.[17-19] The underlying mechanisms of bile salts, TG and apoA-V in liver regeneration are not fully elucidated.
The aim of the present study is to examine applicability of bile salts, triglycerides and apoA-V as plasma markers for prediction of the hypertrophy response in patients undergoing PVE and subsequent liver resection.
Predictors of liver regeneration
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Methods
Twenty patients (male-female 16-4, median age 62 (range 31-78) years) considered unresectable because of small-for-size FRL and amenable for PVE were included on a consecutive basis. Patients received a single dose of antibiotic prophylaxis before undergoing PVE. All procedures involved the right portal vein and were performed using the percutaneous, ipsilateral approach as described by Avritscher et al.[20] to prevent complications of the left portal vein and liver parenchyma. The procedure is performed under conscious sedation by midazolam (Midazolam Actavis 5mg/ml, Actavisgroup PTC ehf, Iceland), fentanyl (Fentanyl 50 microgram/ml, Bipharma pharmaceuticals, Hameln, Germany), and local infiltration of the skin with lidocaine 2% (Lidocaine HCL 2% , B. Braun AG, Melsungen, Germany).
After ultrasound-guided puncture of an anterior branch of the right portal vein, a 5 French sheath was inserted. Following portography, all right branches of the portal vein were selectively catheterized using a Shepherd’s crook catheter, and embolized using PVA particles (300-500 μm, Cook Incorporated, Bloomington, United States of America) and multiple 6 to 10 mm platinum coils (Tornado Embolization Coils, Cook Incorporated, Bloomington, USA). The procedure was completed with a portogram to assure total occlusion of the right portal system and normal flow through the left, future remnant portal system.
The hypertrophy response of the FRL was measured by CT-volumetry prior to embolization and 22 days (range 18-40) after PVE. Post-PVE CT volumetry and technetium-99m (99mTc)-mebrofenin hepatobiliary scintigraphy (HBS) including SPECT to measure liver function, were performed on the same day. Plasma bile salts, TG and apoA-V were determined at baseline pre-PVE, and after PVE (5 hrs, day 1, day 21), as well as prior to and after (day 1-7, and day 21) subsequent liver resection. These parameters were correlated with liver volume as measured by CT volumetry, and liver function determined by HBS. We also compared the results between patients with a pre-PVE FRL of <25% (n=11) and those with a pre-PVE FRL of 25-40% (n=9).
This study has been approved by the institutional review board of the Academic Medical Center, and written informed consent was obtained from each patient.
Liver volume and function
Assessment of the FRL was based on imaging by CT volumetry as described by Shoup et al.[21] Multiphase contrast-enhanced CT scans were carried out using the multislice helical scanner (Philips Medical Systems, Eindhoven, The Netherlands). Integrated software (Mx-View 3•52; Philips Medical Systems) was used for calculation of the total liver volume (TLV), tumour volume (TV) and FRL volume (FRLV). The volume of the FRL is expressed as a percentage of TLV, determined by the formula %FRL = (FRLV x 100%) / (TLV–TV). PVE was performed preoperatively if the %FRL was <30% in healthy liver parenchyma, or <40% in compromised liver parenchyma.
Liver function was evaluated in patients before PVE and 3 weeks after PVE by HBS assessing hepatic 99mTc-mebrofenin uptake, as reported previously.[22-24] Briefly, the hepatic uptake function was assessed on an InfiniaTM II SPECT/CT camera (GE Healthcare). A dynamic acquisition (36 frames of 10 s/frame, 128 matrix) directly after intravenous administration of 200 MBq 99mTcmebrofenin (Bridatec; GEHealthcare, Eindhoven,The Netherlands). Additionally, a low-dose non-contrast-enhanced CT was performed after a fast SPECT acquisition (60 projections at 8 s/projection, 128 matrix) to correct for attenuation and for anatomical mapping on the same gantry. Finally, an additional second dynamic acquisition was made to determine excretion of bile. A Hermes workstation (Hermes Medical Solutions, Stockholm, Sweden) was used for data analysis. The hepatic 99mTc-mebrofenin uptake rate expressed in %/min which represents the function of the total liver, was corrected for height and weight of the patient by dividing this parameter by the BSA (%/min/m2). The (uptake) fraction of the FRL was determined by dividing the summed counts (150–350 s after injection) within the delineated FRL by the total liver counts within the same time frame. This fraction was multiplied by total liver 99mTc-mebrofenin uptake rate to determine the future remnant liver function (FRL-F) expressed in %/min/m2. A cut-off value for FRL-F of 2.69 %/min/m2 identified patients at risk of developing postoperative liver failure.[22] FRL functional volume (FRL-FV) was subsequently calculated by dividing the remnant liver function (FRL-F) by the volume of the FRL (FRL-V).
Biochemical parameters
Liver damage was determined by assessment of plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) by routine clinical chemistry. Hepatic uptake and excretory function was evaluated by plasma bilirubin (bili). Liver regeneration was examined by measurement of plasma levels of triglycerides and bile salts, the latter being assayed by an enzymatic method as per manufacturer’s instructions (Diazyme Laboratories, Poway, USA). Human apoA-V levels were determined by ELISA as described elsewhere.[25]
Statistical analysis
Statistical analysis was performed with Statistical Package for Social Sciences (SPSS 18.0), and GraphPad Prism (GraphPad Software, San Diego, CA). The Mann-Whitney U test was used to compare continuous, non-parametric data, with the Wilcoxon signed rank test for different time points within patient groups. Correlation between variables was tested using the Pearson’s r correlation coefficient. All statistical tests were two-tailed and differences were considered significant at a p-value of ≤ 0.05. Data were expressed as means ± SEM, unless stated otherwise.
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73
Results
Liver volume and function are increased after PVE
Patient characteristics are summarized in table 1. All patients (16 males, 4 females) were diagnosed with colorectal liver metastases, and underwent right PVE with the intention to subsequently perform a (extended) right hemihepatectomy. The results of CT-volumetry and HBS in patients before and after PVE are shown in table 2. Mean FRL-V significantly increased from 26.8±7.7 % to 39.5±7.4% after PVE (p<0.001). Comparison of results between patients with a FRL-V of <25% of TLV prior to PVE and those with a FRL-V between 25% and 40% revealed that the first group showed a greater increase in FRL-V post-PVE (mean 76.3±14.3% vs 32.0±8.2% respectively; p=0.018). Furthermore, a significant increase in FRL-F (pre-PVE mean 26.9±1.6%) was found after PVE (mean 42.5±3.1%; p<0.001).
Table 1. Characteristics of 20 patients undergoing (right) PVE.
N (%)
Male 16 (80)
Female 4 (20)
Median age (range) 62 (31-78) years
Median BMI (range) 24.9 (19.5-28.3) kg/m2
Compromised liver parenchyma 0 (0)
Preoperative radiotherapy 4 (20)
Preoperative chemotherapy 15 (75)
Liver resection
Segmentectomy 1 (5)
Right hemihepatectomy 9 (45)
Extended right hemihepatectomy 9 (45)
Unresectable 1 (5)
Major/minor resection 18/1
Median operation time (min) 272 (185-624)
The positive correlation between pre-PVE FRL-F (%) and FRL-V (%) of the remnant liver was 0.881 (p=0.038). No correlation was observed between volume and functional increase post-PVE. The increase in FRL-F (mean 37.1±13.0%) was greater than the increase in FRL-V (mean 31.5±16.4%; p=0.219), although this did not reach statistical significance (Figure 1).
The median time-interval between PVE and resection was 41 (range 25-74) days. One patient was found unresectable on exploration after PVE because of a distant lymphe node metastasis and was treated with radiofrequency ablation. One patient underwent segmental liver resections of segments 2 and 3, and 5 and 6 because of bilobar liver
metastases, in 9 patients a right hemihepatectomy was performed, and in the remaining 9 patients an extended right hemihepatectomy. Complications after liver resection following PVE as described by Dindo and Clavien et al[26] are summarized in Table 3. Three months (range 61-109 days) after liver resection, the total volume of the liver remnant had increased to 1260 (range 901-1867)mL, and the median fractional increase of FRL was 81.8 (range 8.9-145.9)%.
Table 2. Liver volume and function prior to PVE and post-PVE. Values are expressed as median (range). pre-PVE post-PVE p-value
Time points of CT 15.5 (1-125) 22.0 (18-40)
Total liver volume (mL) 1725 (1122-2697) 1768 (1132-2871) 0.745 Tumor volume (mL) 48.0 (0.4-891.8) 56.6 (1.0-960.2) 0.467 %Tumor volume 2.7 (0.1-33.1) 2.9 (0.1-36.0) 0.509 FRL-volume (mL) 394 (294-825) 608 (368-1234) 0.002* %FRL 26.8 ± 7.7 39.5 ± 7.4 <0.001* Time points of HBS 4.0 (1-113) 21.0 (18-29) Liver 99mTc-mebrofenin 8.5 (3.4-13.0) 8.1 (4.6-10.6) 0.619 uptake rate (%/min/m2)
FRL function (%/min/m2) 2.2 ± 0.8 3.3 ± 1.1 0.001* *Significant difference. 0 20 40 60 80 [% ] FRL-F increase FRL-V increase
Figure 1. Increases in FRL-V and FRL-F showed
no significant differences (boxplots showing mean values, ranges).
Table 3. Complications after liver resection following PVE.
Postoperative complications N (%) Grade I 2 (10) Grade II 1 (5) Grade IIIa 3 (15) Grade IVb 1 (5) Grade V 1 (5)
Predictors of liver regeneration
75
PVE 0 5 10 15 20 25 0 1 21 A Time [days] Bile salts [ µ mol/L] PVE 0.0 0.5 1.0 1.5 0 1 21 B * * Time [days]
Bile salts ratio
LR 0 5 10 15 20 25 0 1 2 3 4 5 7 * * * 21 C Time [days] Bile salts [ µ mol/L] LR 0 1 2 3 4 5 0 1 2 3 4 5 7 * * * 21 D Time [days]
Bile salts ratio
PVE 0.0 0.5 1.0 1.5 2.0 0 1 21 E Time [days] Triglycerides [mmol/L] PVE 0.0 0.5 1.0 1.5 2.0 0 1 21 F Time [days] Triglycerides ratio LR 0.0 0.5 1.0 1.5 2.0 0 1 * * * * * 2 3 4 5 7 * * 21 G Time [days] Triglycerides [mmol/L] LR 0.0 0.5 1.0 1.5 2.0 0 1 * * * * 2 3 4 5 7 * 21 H Time [days] Triglycerides ratio
Figure 2. Plasma bile salt and TG levels are not changed after PVE but increased following liver resection. A decrease
in bile salts and triglycerides is observed directly after PVE, but these values returned to normal within three weeks (NS, except for bile salts ratio after PVE). The same trend is seen after liver resection (LR) . (Data are shown in mean±SEM; *p<0.05).
Bile salt and TG levels are unchanged during PVE
Transaminases or bilirubin levels were not significantly altered at the respective time points after PVE (data not shown). Overall bile salt levels at any of the studied time points after PVE were not different from baseline bile salt levels (Figure 2A,B). Also in the sub-analysis (pre-FRL-V <25% or 25-40%), no significant changes were observed within groups over time. Also for overall TG after PVE, no differences were seen compared to baseline levels (Figure 2E,F).
Bile salts are increased, and triglycerides are decreased after liver resection
Overall, no differences were seen between pre-PVE and pre-resection bile salt levels (p=0.173). Following LR after PVE, bile salts levels on postoperative day 4 (mean 18.8±2.0μmol/L; p=0.037), day 5 (mean 20.7±1.4μmol/L; p=0.015), and day 7 (mean 21.7±2.4μmol/L; p=0.013; Figure 2C,D) were significantly increased as compared to baseline bile salts (mean 9.2±2.4μmol/L). For patients with a FRL-V <25%, an increase in bile salt levels was found following liver surgery after 5 days (from mean 12.7±3.8μmol/L to 22.2±1.4μmol/L; p=0.046), and 7 days (mean 24.8±2.3μmol/L; p=0.028). For a FRL-V between 25-40%, only significant elevations were observed 4 and 5 days after surgery (p=0.040 and p=0.046 resp.).
A rapid decrease in TG levels was apparent 5 hrs and 1 day after liver resection that gradually returned to baseline levels within a few weeks (Figure 2G,H), which was confirmed in both groups (FRL-V<25% and FRL-V 25-40%). Although TG levels were higher before liver resection (mean 1.28±0.19mmol/L) than prior to PVE (mean 1.02±0.14mmol/L), this difference did not reach statistical significance (p=0.214).
ApoA-V was increased during liver regeneration
In all patients, the mean apoA-V level was 643±108ng/mL prior to PVE, and increased to 976±677ng/mL at 1 day after PVE. After three weeks, apoAV levels gradually declined to 698±66ng/mL. Overall however, ApoAV levels were not significantly different from baseline levels at any of the examined time points (Figure 3A,B), or in any group. Following liver resection there was a transient increase in apoA-V levels in the first week (mean 951±160ng/mL after 2 days compared to baseline 623±79ng/mL; p=0.046), that returned to normal levels after three weeks (Figure 3C,D). In patients with a FRL-V>25% a significant elevation was also found 2 days following surgery (p=0.028).
Bile salts, triglycerides, and apoA-V in relation with liver volume and function
Bile salts at 5 hours after PVE correlated positively with the increase in %FRL-V after 22 days (r=0.672, p=0.024). In addition, plasma bile salt levels at 5 hours after PVE correlated with the hepatic 99mTc-mebrofenin uptake rate determined after 21 days (r=0.640, p=0.046). No associations were found between bile salts and volume or function of the liver remnant after surgery.
Predictors of liver regeneration
77
TG at baseline (r=0.703, p=0.011), 5 hours (r=0.620, p=0.042) and 22 days after PVE (r=0.523, p=0.038) correlated positively with the increase in %FRL-V 22 days following PVE (figure 2). Also after liver resection, TG at 5h and one day after surgery were positively correlated with volume of the liver remnant after three months (r=0.921, p=0.026 and
r=0.981, p=0.0019 resp.). No significant correlations were seen between TG and liver
function as measured by HBS.
There were no significant correlations between apoA-V levels at the evaluated time points and %FRL-V or increase in %FRL-V three weeks after PVE or remnant liver volume after surgery. Nor were any correlations observed between apoA-V and FRL-F.
Discussion
We examined the applicability of bile salts, triglycerides, and apoA-V as predictive factors for remnant liver growth after PVE and liver surgery. The results of our study show that bile salt levels at 5 hours after PVE were positively associated with the increase in %FRL-V as well as with remnant liver function after 22 days determined by HBS. A correlation was also seen between TG 5h following PVE and increased FRL-V, and between TG 5h or 1
Figure 3. ApoA-V was increased during liver regeneration. ApoA-V was elevated in the first hours after PVE
(panel A and B) and liver resection (LR, panel C and D), however, only significant differences were observed in the first days after LR (*p<0.05). Data are expressed as mean±SEM.
LR 0 1 2 3 0 1 2 3 4 5 7 21 * * * D Time [days] ApoA-V ratio LR 0 500 1000 1500 2000 0 1 2 3 4 5 7 21 * C Time [days] ApoA-V [ng/mL] PVE 0.6 0.8 1.0 1.2 1.4 1.6 0 1 21 B Time [days] ApoA-V ratio PVE 0 500 1000 1500 2000 0 1 21 A Time [days] ApoA-V [ng/mL]
78
day after resection and the volume of the liver remnant 3 months following resection. Our results therefore, demonstrate that bile salts and TG can be used for early timing of volume assessment and resection after PVE.
No non-invasive markers to assess liver regeneration in the early stages after PVE or liver resection are currently available. CT-volumetry, performed 3 to 6 weeks after embolization of the portal vein, results in a delay when examining liver regeneration during the early post-PVE period. Firstly, we determined bile salts after PVE and liver resection to assess a possible earlier predictor of liver regeneration. Experimental studies already demonstrated an association between bile salts and liver growth. In rats, increased bile salts were found during four days after portal vein ligation[10] or 24 hours after partial hepatectomy.[12] Furthermore, reduced bile acid levels were associated with a delay in liver regeneration[8;11] or even inhibited liver regrowth.[9] This is in line with our findings, showing a positive correlation between bile salts 5 hours after PVE and the increase in FRL volume and function. To our knowledge, only one single study has addressed a predictive correlation between bile salts and FRL growth in patients undergoing right PVE. They concluded that the increase in bile acid levels on day 3 is a useful predictor of liver regeneration[13], although we showed this correlation was already obtained at 5h post-PVE.
Secondly, we examined the role of plasma TG as a liver regeneration marker. A previous study has shown that the level of hepatic TG continued to rise within 20 hours following partial hepatectomy in rats[14], which was essential for proper liver regeneration. Newberry et al, using different murine genetic models with altered hepatic lipid metabolism showed that hepatic TG was elevated in the regenerating liver 12–24 hours after 70% hepatectomy, while plasma TG decreased.[16] Overall, no correlations were observed between hepatocyte proliferation and the amount of TG within these mice models.[16] We showed in this study that plasma TG levels were significantly decreased directly following surgery, which is in agreement with the data described above.
Finally, another possible, early regeneration predictor is apoA-V. A 5-fold elevation in plasma apoA-V levels was seen in early stages of liver regeneration after partial hepatectomy in rats.[27;28] These results are comparable with the outcomes of our study, showing a transient increased apoA-V level during early regeneration after liver resection. Our study has some limitations. We were able to analyze patient samples only shortly (5 hr, day 1) and 3 weeks after PVE. No intermediate time points were analyzed as patients usually leave hospital within one day after PVE, having been referred from other, distant hospitals. Therefore, we might have missed substantial information from the time period in between. On the other hand, the profiles of bile salts and TG examined after liver resection showed no differences between the data obtained within the first seven days of regeneration and the data found after 3 weeks. It would also be of interest to determine whether these predictive parameters are equally useful in patients with compromised livers, such as in cirrhosis, steatosis, or fibrosis, with an impaired capacity for liver regeneration.
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79
Our study bears relevance from the clinical point of view. Although the mechanisms of liver regeneration are not completely understood, the process is mediated by cytokines and growth factors interacting with all liver cells. Several studies described enhancement of tumor growth after PVE as a result of above mentioned, growth inducing factors in addition to compensatory increased arterial blood supply.[29-37] Growth of the primary tumor may be accelerated, or micrometastases in the non-embolized remnant liver may be stimulated and progress. The potential boost of tumor proliferation therefore, creates a dilemma in terms of optimal waiting time until resection. Recently, we compared the increase in FRL-F after PVE as measured by HBS, with the increase in FRL volume as measured by CT volumetry.[38] We showed that 23±4.9 days following PVE, the increase in FRL function exceeded the increase in FRL volume. In the present series, we also observed a trend towards a greater increase in FRL-F (mean 37.1±13.0%) than the increase in FRL-V (mean 31.5±16.4%; ns) post-PVE. This difference was however, not significant, probably because in the present series, only patients with uncompromised livers were included. As the recommended waiting time until operation may be shorter than usually indicated by CT volumetry, additional parameters that can be applied at earlier time-points to predict sufficient regeneration of the FRL are helpful to shorten the waiting period before hepatectomy.
In conclusion, bile salts and triglycerides at 5 hours after PVE or resection are significant, early predictors of liver volume and functional increase during human liver regeneration. These parameters are associated with liver regeneration and therefore, we suggest that they can be used for early timing of volume assessment and resection after PVE.
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