Abstract
Background
Publications using the ALPPS (associating liver partition and portal vein ligation for a staged hepatectomy) procedure have demonstrated a future liver remnant growth of 40–160% in only 6–9 days. The present study aimed to develop and describe the first large animal model of ALPPS that can be used for future studies.
Methods
A total of 13 female domestic pigs underwent ALPPS stage 1 (portal vein division and parenchymal transection) followed by ALPPS stage 2 (completion left-extended hepatectomy) 7 days later. An abdominal computed tomography (CT) scan was performed immediately prior to ALPPS stage 1 surgery and again 7 days later to assess hypertrophy immediately prior to ALPPS stage 2 surgery. Blood samples, as well as tissue analysis for Ki-67, were performed.
Results
On CT volumetric analysis, the mean size of the future liver remnant (FLR) prior to ALPPS stage 1 was 21 ± 2% and 40 ± 6% prior to ALPPS stage 2. The median degree of growth was 75% with a mean kinetic growth rate of 11% per day. Liver weights at autopsy correlated well with CT volumetric analysis (r = 0.87). There was no significant difference in mean lab values [asparate aminotransferase (AST), alanine aminotransferase (ALT), ammonia, International Normalized Ratio (INR) or bilirubin] from baseline until immediately prior to ALPPS stage 2. Post ALPPS stage 2 there was a significant increase in INR from baseline 1.1 to 1.6 (P = 0.012). No post-operative deaths secondary to liver failure were observed.
Conclusion
The present study describes the first reproducible large animal model of the ALPPS procedure. The degree of liver growth and the kinetic rate of growth were similar to that which has been demonstrated in human publications. This model will be valuable as future laboratory studies are performed.
Introduction
A liver resection remains the only potentially curative option for many patients with primary or metastatic tumours of the liver. Surgeons continue to expand what is defined as ‘resectable’ disease by performing increasingly extensive liver resections. In this setting, post-operative liver failure owing to an insufficient liver remnant remains a significant concern, especially in patients that have received extensive chemotherapy. Multiple reports describing the novel ALPPS procedure (associating liver partition and portal vein ligation for a staged hepatectomy) have demonstrated rapid growth in the future liver remnant (FLR).1 Publications using the ALPPS procedure have demonstrated a FLR growth of 40–160% in only 6–9 days.1–11 This technique may allow for a liver resection in patients with large or multiple liver tumours that would otherwise be at high risk of liver failure owing to a small FLR.
Questions regarding the mechanism of profound growth seen with ALPPS remain unanswered.12 It has been proposed and demonstrated that closure of the right portal branch by ligation or embolization is followed by a reactive perfusion of ‘deportalized’ liver, from the contralateral one, through the intrahepatic branches and collaterals presents between the two lobes.13,14 It is possible that the parenchymal division component of ALPPS results in ligation of the collateral branches that could account for the different rates of growth seen between ALPPS and portal vein embolization (PVE). It has also been suggested that that the deportalized liver may be responsible for the release of circulating inflammatory or growth factors that may account for the accelerated growth.15 Undoubtedly in all settings, liver growth is multifactorial.
A large animal model is paramount to study the effects of this new technique on the growth of the FLR. Such a model would allow the understanding of molecular changes, blood flow and growth characteristics that are associated with ALPPS. Ideally this increased understanding would allow transition into human clinical scenarios. The present study aimed to develop and describe a large animal porcine model that could be used for future research.
Materials and methods
This study was performed with the approval of the Mayo Clinic Rochester Institutional Review Board. All animals received humane care in compliance with the regulations of the Institutional Animal Care and Use Committee at the Mayo School of Graduate Medical Education. The number of study animals for development of the model was determined by consensus of the research team.
Procedure and peri-operative care
The first portion of the study involved six pigs in which the techniques of ALPPS stage 1 were mastered, and initial liver weights were determined after pig euthanasia. The second portion of the study involved seven pigs in which ALPPS stage 1, followed by a 7-day interval in which the FLR grew and then subsequently ALPPS stage 2 were performed. Computed tomography (CT) and surgical procedures were performed under general anaesthesia. Post-operative liver failure was defined according to a peak total bilirubin level > 7 mg/dl.16 The porcine liver is comprised of a right lateral (RL), right medial (RM), left medial (LM), left lateral (LL) and caudate lobes. The porcine vena cava is located intrahepatically on the right side of the liver making a left extended hepatectomy the resection procedure of choice.17,18 The caudate lobe and a portion of the RL lobe have previously been shown to account for 15–20% of the liver.19 Therefore, it was planned for the caudate lobe and a portion of the RL lobe to be the FLR. ALPPS stage 1 involved portal vein division (at the junction of the RL and RM lobes) and parenchymal transection thus preserving portal flow to the RL and caudate lobes and the arterial supply and venous outflow to all portions of the liver (Fig.1). This was followed by ALPPS stage 2 (completion left-extended hepatectomy). Liver specimens were weighed upon removal at the time of resection and all post-mortems.
Figure 1.
Porcine liver anatomy showing right lateral (RL), right medial (RM), left medial (LM), left lateral (LL) and caudate lobes. During ALPPS stage 1: (a) site of transection to remove a portion of the RL lobe is shown with a solid line, (b) second line shows the level of portal vein ligation, (c) site of parenchymal transection shown by a dashed line. Future liver remnant (FLR) is shown in shaded and accounted for 15–20% of the liver volume
Pre-operative and day 7 CT scans
An abdominal CT scan was performed immediately prior to ALPPS stage 1 surgery and again 7 days later to assess hypertrophy immediately prior to ALPPS stage 2 surgery. Intravenous contrast (Omnipaque 100 ml) was administered via the femoral vein during CT scans for better definition of hepatic structures. Both arterial and portal phases were obtained.
CT data were acquired and loaded onto 3-D volumetric software (TeraRecon, Inc., Foster City, CA, USA). FLR (%) was calculated accordingly as FLR/total liver volume*100%. The degree of growth/hypertrophy (DH) was defined as the percentage-point difference between the FLR volume prior to ALPPS stage 1 and FLR volume prior to ALPPS stage 2. Kinetic growth rate (KGR) was calculated as both percentage growth per day [DH at the first post-intervention volume assessment (%)/time elapsed since] as well as the volume (cc) growth per day (FLR after intervention – FLR prior to intervention/time elapsed).20
ALPPS surgery stage 1
Pigs do not tolerate > 500 ml of blood loss, and so a successful surgical technique requires the risk of blood loss to be minimized. The liver was mobilized by the division of the peritoneal reflections to the diaphragm and a cholecystectomy was performed. The adventitia was carefully dissected from the surface of the portal vein at RL and the RM lobe junction. The hepatic artery branches to the RL and RM lobes can be seen crossing the anterior surface of the main portal vein at this location and must be preserved. The portal vein was then encircled between the takeoff of the branch to the RL and RM lobes. This was not divided until the resection of the RL lobe was performed to minimize bleeding once all of the portal flow is diverted to the RL lobe and caudate. A parencymal resection was performed between two rows of #1 Vicryl sutures placed along the resection line in the RL lobe. The parenchyma was then transected using a CUSA (Cavitron Ultrasonic Surgical Aspirator) device without inflow control. There are three large veins located at the centre of the lobe and these were ligated using haemoclips.
The parenchyma was then divided so that there were no intrahepatic portal branches to the deportalized portion of the liver (RM, LM and LL). The transection plane divided the parenchyma over the anterior surface of the liver by the hepatic veins extending this through the lateral part of the RM lobe and in the groove between the RL and RM lobes making a trajectory towards the left side of the caudate lobe. The inferior vena cava and intraparenchymal hepatic veins have extremely thin walls and are easily damaged. Once this was performed, a right angle dissector was used to dissect bluntly behind the hilar plate dropping it down. The hilar plate was then looped with a vessel loop. A vessel loop was then also placed around the isolated hepatic veins (Fig.2). A sterile plastic sheet was placed between the FLR and the deportalized portion of the liver as well as under the midline wound to avoid adhesions at the second stage surgery.
Figure 2.
Isolated hilum and hepatic veins at completion of ALPPS stage 1. All other connecting parenchyma have been divided
ALPPS surgery stage 2
The pigs formed a relatively large number of adhesions even in the short 7-day period between surgeries and, therefore, care must be taken in mobilizing the liver at the time of the second operation. Prior to performing any significant mobilization, the remaining portal structures in the left side of the hepatoduodenal ligament were divided. Care must be taken to avoid injury to the bile duct as it courses posteriorly to the RL lobe. The common bile duct was dissected from the other structures in the hilar plate, dropping it down to avoid injury. To divide the remaining liver, a vascular clamp was placed on the staying side, and a 60-mm endovascular stapler with the vascular load was used to divide the liver above it. A 3-0 Prolene suture was then used to perform a running mattress suture under the vascular clamp prior to removal. This technique was repeated until only the FLR remained (Fig.3).
Figure 3.
Hypertrophied future liver remnant (FLR) [caudate and portion of the right lateral (RL) lobe] after ALPPS Step 2 resection. Vessel loop around protected bile duct
Light microscopy and evaluation of regeneration
For histomorphological evaluation, all liver specimens were fixed in 4% phosphate-buffered paraformaldehyde. Liver specimens were subsequently dehydrated and embedded in paraffin wax to process sections at a thickness of 6 mm. The sections were conventionally stained by hematoxylin and trichrome and then examined using computer-assisted brightfield microscopy, with 40× magnification. To evaluate the histological regeneration of the remnant liver, the area of the periportal fields was evaluated. Immunostainings were performed for the presence of Ki67, a cellular marker for proliferation. The number of Ki67 positive hepatocytes was determined by manual counting in 20 random visual fields at 100× magnification.
All statistical analyses were performed using STATA 12 (Stata Corp., College Station, TX, USA). Differences between values were analysed using the unpaired t-test for continuous variables and by the χ2 test or continuity correction method for categorical variables. Wilcoxon's rank-sum was used for variables that did not display a normal distribution or when subject numbers were small. The degree of correlation was assessed by Spearman's rank correlation. All statistical tests were two-sided, and differences were considered significant when P < 0.05.
Results
A total of 13 female domestic pigs with a mean weight of 31 ± 1 kg were used. Survival after ALPPS stage 1 was seen with all pigs. Laboratory values are shown in Table1.
Table 1.
Blood work prior to stage 1, prior to stage 2 and after stage 2
| Prior to stage 1 | Prior to stage 2 | Post stage 2 | P-value a versus b | P-value b versus c | |
|---|---|---|---|---|---|
| INR | 1.1 ± 0.1 | 1.1 ± 0.1 | 1.6 ± 0.1 | NS | 0.005 |
| Bilirubin (mg/dl) | 0.12 ± 0.1 | 0.15 ± 0.1 | 3.3 ± 0.9 | NS | <0.001 |
| AST (U/l) | 27.6 ± 6.5 | 29.2 ± 7.0 | 30.5 ± 1.5 | NS | NS |
| ALT (U/l) | 46.6 ± 3.9 | 45.5 ± 4.0 | 50.0 ± 2.0 | NS | 0.02 |
| Alk P (U/l) | 161.2 ± 13.8 | 91.4 ± 30.0 | 117.5 ± 7.5 | 0.001 | NS |
| NH3 (ug/dl) | 68.5 ± 20.3 | 95.0 ± 40.4 | 53.0 ± 5.0 | NS | 0.02 |
| Hb (g/dl) | 8.9 ± 0.6 | 8.5 ± 0.6 | 7.9 ± 0.4 | NS | 0.04 |
ALT, alanine aminotransferase; AST, asparate aminotransferase; Alk P, alkaline phosphatase; Hb, haemoglobin.
On CT volumetric analysis, the mean size of the FLR prior to ALPPS stage 1 was 174 ± 33 cc. TLV had a mean size of 816 ± 139 cc, with the FLR representing a mean 21 ± 2% of the TLV. Immediately (POD 7) prior to stage 2, the mean size of the FLR and the TLV were 330 ± 53 cc and 831 ± 127 cc, respectively. This resulted in FLR representing a mean of 40 ± 6% of the total liver volume. The median degree of growth was 76% (range 61–174%) (Fig.4). The kinetic growth rate was 23 cc/day (range 12–31 cc/day) in absolute growth, or 11%/day (9–24%/day) in percentage growth.
Figure 4.
Computed tomography (CT) scan showing baseline future liver remnant (FLR) and hypertrophied FLR
Liver weights at autopsy correlated well with CT volumetric analysis (r = 0.87).
Histopathological Analysis of Liver Regeneration was performed. The size of the portal fields increased significantly between baseline (1.5 ± 0.4 mm) and immediately prior to ALPPS stage 2; after the 7-day time period (2.2 ± 0.6 mm) (P < 0.001) (Fig.5). The number of Ki67 positive nuclei per field (100×) also increased significantly between baseline (12 ± 3) and immediately prior to ALPPS stage 2 (35 ± 7) (P < 0.001).
Figure 5.
Trichrome stain with 40× magnification showing an increase in the size of the portal fields from baseline to immediately prior to ALPPS stage 2
Discussion
The present study is the first to describe a reproducible large animal model of ALPPS. This study confirms that the significant growth of the FLR after ALPPS stage 1 seen in humans can also be demonstrated in pigs. This study demonstrates that the increase in FLR volume seen on CT scan is associated with an increase in the size of the portal tracts and Ki67 index on histology.
The use of PVE to increase the size of FLR has become standard practice, with many centres demonstrating excellent results.21,22 The ALPPS approach has emerged as a method to induce rapid FLR growth. Unlike PVE, which enhances liver growth 20–35% in 30–45 days, the ALPPS technique allows an FLR growth of 40–160% in only 6–9 days.1–11 While the rapid growth seen with the ALPPS technique has been well described, questions regarding the mechanism of this profound growth remain unanswered. Also, the initial volume evaluation is usually performed at 2–4 weeks after PVE, and the dynamic volume change during the very early phase after PVE remains unclear. Therefore, actual dynamic volume changes after ALPPS and right PVE should be compared using animal models.23
While previous studies have described techniques of PVE in pigs,13 the present study represents the first publication describing a large animal model of the ALPPS procedure. Development of this model is important to further characterize the mechanism of the growth seen with ALPPS procedure as well as to provide direct comparisons with PVE. Domestic swine are commonly used in experimental surgery because of the numerous similarities between porcine and human anatomy and physiology.16,23 Previous authors have recorded the presence of macroscopic anastomosis between the branches of the portal vein, demonstrating intrahepatic collateralization.24,25 Moreover, the size match with human organs makes results of experimental surgical procedures more relevant as compared with small animal models. Using a porcine model, CT volumetrics can be used to evaluate liver growth in a similar fashion to what is performed with humans with some variability.
Recently, a study describing a murine animal model of ALPPS was published by Schlegel et al.15 In that study a significant volume gain in the FLR was seen compared with portal vein ligation or transection alone. Plasma obtained from mice 1 h after completion of ALPPS step 1, was also injected into mice that had undergone portal vein ligation alone. This induced comparable liver weight gain and hepatocyte proliferation, leading authors to propose that circulating factors play a large role in the growth seen with ALPPS. These results are very promising and highlight the importance of future research into the mechanisms of liver growth.
The growth of the FLR seen with the current model (74.5%) was similar to that described in the human literature.1–11 While standardized total liver volume (sTLV) has been used in humans to calculate a standardized future liver remnant volume (sFLR) no such equation has been validated in a porcine model.26 This equation was designed to avoid inclusion of tumour volume or dilated bile ducts in the setting of cholangiocarcinoma when estimating TLV, neither of which represented an issue in the present model. All pigs were from a similar breeding lineage and had a similar starting weight. Also, it was demonstrated that TLV showed only minimal variability at the time of the ALPPS stage 1 in the initial six pigs.
On histological analysis, a significant increase in the size of the portal fields and the number of Ki67 positive nuclei was seen when compared with baseline. This highlights that the volume increase of the FLR seen on CT volumetrics is associated with liver regeneration and is not simply caused by congestion or another phenomenon.
Pigs in the 30-kg weight range are very sensitive to blood loss. In the development of the current model, it was observed that pigs were not able to tolerate a blood loss of greater than 500 cc. Transfusion was not used in the present study. The techniques employed in the present study allowed completion of both stages of the ALPPS model with less than 500 cc of blood loss. Pigs in the present model also developed significant adhesions in the 7-day interval between stage 1 and 2. While adhesions are certainly an issue in human ALPPS, they are even more profound in pigs. It is, therefore, important to stress that completion of as much of the parenchymal transection as possible in the first stage and the use of vessel loops to tag critical structures should be employed.
Previous porcine liver models looking at liver failure after an left extended liver resection (LL, LM, RM and portion of right medial lobe) demonstrated liver failure leading to animal death within 3 days after surgery in 65% of pigs.27 This was the same extent of liver that was deportalized and ultimately resected in ALPPS stage 2 in the present study. Despite the similar extent of resection, none of the pigs demonstrated clinical or biochemical signs of liver failure and no deaths were observed in the 7 days between ALPPS stage 1 and stage 2. This highlights the presumed auxiliary function of the deportalized liver as the FLR is allowed to hypertrophy, as well as the functionality of the FLR after ALPPS stage 2.
In conclusion, the present study describes the first reproducible large animal model of the ALPPS procedure and demonstrates similar levels of growth to those seen in humans. This model will be important to advance the understanding of the mechanism of growth seen with this procedure.
Author contributions
Participated in research design: Kris Croome, David Nagorney, Scott L. Nyberg. Participated in the writing of the paper: Kris Croome, David Nagorney. Participated in the performance of the research: Kris Croome, David Nagorney, Shennen A. Mao, Jaime M. Glorioso, Scott L. Nyberg. Participated in data analysis: Kris Croome, David Nagorney.
Conflicts of interest
None declared.
Funding sources
None.
Supporting Information
Additional Supporting Information may be found in the online version of this article:
Figure S1. Experiment Timeline. Baseline CT scan and bloodwork were performed followed by ALPPS Stage 1 and then a 7 day period to allow for liver hypertrophy. This was followed by a second CT scan and then ALPPS Stage 2. Pigs were then observed for a day, bloodwork was then drawn and then pigs were euthanized
Figure S2. ALPPS stage 1. (a) Divided portal vein. (b) portal vein showing openings for caudate (C) and RL lobe branches
Figure S3. Ki67 showing increase in the number of positive staining cells from baseline to immediately prior to ALPPS stage 2. Positive staining for Ki67 can be seen in brown
Table S1. Future liver remnant growth
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Figure S1. Experiment Timeline. Baseline CT scan and bloodwork were performed followed by ALPPS Stage 1 and then a 7 day period to allow for liver hypertrophy. This was followed by a second CT scan and then ALPPS Stage 2. Pigs were then observed for a day, bloodwork was then drawn and then pigs were euthanized
Figure S2. ALPPS stage 1. (a) Divided portal vein. (b) portal vein showing openings for caudate (C) and RL lobe branches
Figure S3. Ki67 showing increase in the number of positive staining cells from baseline to immediately prior to ALPPS stage 2. Positive staining for Ki67 can be seen in brown
Table S1. Future liver remnant growth