Portal vein embolization (PVE) with gelatin sponge and cyanoacrylate is a well-established approach to divert portal flow from one side of the liver to the future liver remnant (FLR) to prepare the liver for extended resections.1 When more than 70% of the liver has to be removed, most often due to extensive tumor load, PVE can help to prepare the small FLR to tolerate the hemodynamic stress of the portomesenteric blood flow and metabolic requirements of the organism and increase the liver volume of the FLR by up to 50%.2,3

This process of conditioning the FLR usually takes about 6 weeks but is not successful in all patients. In some patients, the FLR fails to grow in volume, or cancer progression during the waiting period makes the planned resection impossible. Overall, up to 27% of patients fail to achieve resectability using this strategy, even in the most experienced centers.4 Due to its unreliability and the necessary waiting period, PVE is not a popular option at some centers. Randomized studies have not been able to consistently prove an outcome advantage for all patients, but some subgroups, such as those with cirrhosis undergoing extensive resections, have had improved outcomes over extended resections without preconditioning.5

In 2012, associating liver partition and portal vein ligation for staged hepatectomy (ALPPS), a surgical procedure, was proposed to replace interventional PVE.6 In ALPPS, the portal vein is ligated but not embolized, and the liver parenchyma is transected to separate the deportalized liver and the FLR.7 ALPPS both accelerates the time the liver takes to hypertrophy and increases the amount of liver volume achieved when compared to PVE.8 The novel operation was hailed to increase the resectability of liver tumors and expand the indications for surgical resection.6 Not surprisingly, complications and mortality were higher in a surgical procedure requiring laparotomy instead of a radiologic intervention,9 but in bilobar multifocal liver metastases, which require two surgical procedures for resection anyway, the ALPPS procedure continued to garner support.10

A Scandinavian randomized study recently showed that the complication rate associated with resection of bilobar colorectal liver metastases in a two-stage hepatectomy, using PVE in between, is comparable to that of the two ALPPS stages.11 However, more patients proceed to complete resection with the ALPPS procedure than with PVE.11 In contrast, reports of high complication rates for most other indications for liver resection such as hepatocellular carcinoma and biliary tumors have challenged the potential of ALPPS to replace PVE.12-14 ALPPS remains a second-line intervention behind PVE for all indications for liver resection to increase the function and volume of the FLR except for very extensive colorectal liver metastases.15,16

To maintain the advantages of rapid hypertrophy while reducing the high morbidity and mortality rate of ALPPS, attempts have been made to return to the interventional paradigm. ALPPS reformists proposed interventional embolization of the portal vein instead of ligation (also called hybrid ALPPS),17 as well as interventional transection of the parenchyma using transcutaneous radiofrequency ablation combined with PVE (also called radiofrequency-assisted ALPPS or RALPPS)18 as the first stage of these modified ALPPS procedures. Other authors have proposed a laparoscopic modification of the first stage or even the entire procedure to reduce the complication rate.19 However, it appeared that rapid hypertrophy requires some kind of transection of the parenchyma.

ANIMAL STUDIES

Our group recently showed that after portal vein ligation (PVL) in pigs, extensive collaterals develop within 1 week between the deportalized liver and the liver supplied by the portal vein, whereas these collaterals are abrogated by transection of the parenchyma.20 These collaterals draw portal vein blood from the side supplied by the portal vein to the deportalized side and thereby steal hepatotrophic factors in portal vein blood from the FLR that is supplied with portal vein blood. This phenomenon of portal vein steal after PVL was first described in experiments by Rous and Larimore in 1929, who observed that after PVL in rabbits, certain areas of the deportalized liver that received portal vein blood from small collaterals, which had developed from the side supplied by the portal vein over time, did not atrophy but kept their size and vitality.21 Since then, the literature has documented that collaterals to the deportalized liver weaken the hypertrophic effect on the side supplied by the portal vein not only in PVL, but also in PVE.22-24

DEVELOPMENT OF DOUBLE EMBOLIZATION

Given the results of animal studies, the question arose as to whether collateralization could be prevented without going to the extreme of parenchymal surgical transection.20 One possible interventional strategy was to avoid collateralization by obstructing hepatic vein outflow from the deportalized side. If there is no venous outflow, there should be resistance to portal vein collateralization and thereby to the stealing of hepatotrophic factors.

Attempts to simultaneously embolize both the portal and hepatic veins did not appear very promising based on the existing literature, because it had been shown that sequential portal vein and hepatic vein ligation does not enhance the kinetic growth of the FLR very much.25,26 Sequential portal and hepatic venous embolization was the preferred method in these studies due to the concern about liver necrosis with simultaneous embolization. Likely, this concern was unjustified and underestimated the ability of the liver to develop outflow collaterals across the watersheds in the parenchyma. It appears now that the arterial pressure and flow to the deportalized and hepatic vein–occluded liver are high enough to keep a simultaneously deportalized and hepatic vein–deprived liver alive without necrosis.

Recently, an interventional radiology group in France showed for the first time that simultaneous embolization of the right portal vein and the right hepatic vein, called liver venous deprivation (LVD), is not only feasible without liver necrosis, but it also achieves volume increase comparable to ALPPS.27,28 This group performed 10 LVD procedures before liver surgery. They embolized the right and the middle hepatic vein in some cases with Amplatzer vascular plugs (Abbott Vascular, formerly St. Jude Medical) and cyanoacrylate. Surgery was successfully performed in nine of 10 patients after a median of 31 days (range, 22–45 days) after LVD. LVD and “double embolization” are synonymous.29

LIVER FUNCTION AFTER ALPPS AND LVD

Additional interest in double embolization arose from the fact that liver function assays have demonstrated that ALPPS does not lead to a congruent increase in liver function, despite the volume gains. Regional liver function tests, such as the mebrofenin or hepatobiliary iminodiacetic acid scan, are able to give an estimate of regional liver function based on technetium-labeled mebrofenin uptake kinetics.30 Meticulous studies in ALPPS patients showed that although the right liver lobe grew in volume by a median of 78% with ALPPS, its functional increase was only 29%.31 These data have also been confirmed in animal models.32 The reason for this functional deficit is unknown, but the observation may explain the high morbidity and mortality of ALPPS since the initial reports.33 In contrast, Guiu et al showed that LVD leads to a symmetric increase in volume and function in a very small series of patients.28

The reason that rapid liver growth leads to a significant functional deficit with one method to induce rapid hypertrophy and to a normally functioning liver using another method to induce rapid hypertrophy may be explained by the liver’s ability to regulate the negative trophic effects of increased portal blood, pressure, and shear stress; in double embolization, the parenchyma is left intact and decompressive shunts can develop inside the parenchyma and to small hepatic veins. This is likely not the case with ALPPS. Further studies are needed to support this hypothesis.

OUR EXPERIENCE WITH DOUBLE EMBOLIZATION

Figure 1. Angiogram showing two Amplatzer plugs in the middle hepatic vein. The second one is still connected to the delivery system from a jugular approach (A). A marked decreased of filling of the portal vein system of the right lobe is seen on digital subtraction angiography after previous embolization of the right and middle hepatic vein (B). After glue embolization of the right portal vein, a cast of Lipiodol-Glubran mixture is seen (C).

Figure 2. Equilibrium-phase, T1-weighted axial MRI before (A) and after (B) double embolization showing hypertrophy of the left lobe and a marked decrease of gadoxetic acid in the right lobe, indicating a reduction of functional hepatocytes. Normal excretion is seen on the left lobe.

Thus far, three patients have been treated by our group with simultaneous embolization of the right portal vein and the right hepatic vein (two cases) and the right and middle hepatic vein (one case). All patients had colon cancer with simultaneous liver metastasis. Double embolization was performed as an outpatient procedure. First, the hepatic vein(s) were embolized from a jugular vein approach (Figure 1A). Amplatzer plugs should be placed centrally without prolapsing into the inferior vena cava. Then, the right portal vein was accessed under ultrasound guidance. Portography showed an impressive reduction of portal flow into the right liver lobe secondary to prior hepatic vein embolization (Figure 1B). The right portal vein was then occluded with a mixture of Lipiodol (Guerbet LLC) and Glubran (GEM Srl) in a 1:1 ratio (Figure 1C). T1-weighted, postcontrast, late-phase liver MRI with gadoxetic acid (Primovist, Bayer) showed hypertrophy of the left liver lobe and a markedly decreased contrast uptake into the right liver lobe after double embolization (Figure 2). Right hepatectomy, including segment IV in two cases, was performed 41, 21, and 8 days, respectively, after double embolization, with > 30% FLR in all cases without complications and no posthepatectomy liver dysfunction. After a follow-up of 1, 4, and 5 months, no residual or recurrent liver metastases were found.

CONCLUSION

Preliminary results after double embolization show consistent and rapid growth of the FLR comparable to ALPPS but without severe complications. This novel approach has the potential to improve PVE, especially by reducing the waiting period prior to surgery. The approach allows rapid hypertrophy by endovascular means, particularly for two hepatectomies required for bilobar colorectal liver metastases, which remains the most common indication for liver resection in the Western world.

1. van Lienden KP, van den Esschert JW, de Graaf W, et al. Portal vein embolization before liver resection: a systematic review. Cardiovasc Intervent Radiol. 2013;36:25-34.

2. Denys A, Prior J, Bize P, et al. Portal vein embolization: what do we know? Cardiovasc Intervent Radiol. 2012;35:999-1008.

3. Madoff DC, Vauthey JN. Re: portal vein embolization: what do we know? Cardiovasc Intervent Radiol. 2013;26:870-871.

4. Shindoh J, Truty MJ, Aloia TA, et al. Kinetic growth rate after portal vein embolization predicts posthepatectomy outcomes: toward zero liver-related mortality in patients with colorectal liver metastases and small future liver remnant. J Am Coll Surg. 2013;216:201-209.

5. Farges O, Belghiti J, Kianmanesh R, et al. Portal vein embolization before right hepatectomy: prospective clinical trial. Ann Surg. 2003;237:208-217.

6. de Santibanes E, Clavien PA. Playing Play-Doh to prevent postoperative liver failure: the “ALPPS” approach. Ann Surg. 2012;255:415-417.

7. Schnitzbauer AA, Lang SA, Goessmann H, et al. Right portal vein ligation combined with in situ splitting induces rapid left lateral liver lobe hypertrophy enabling 2-staged extended right hepatic resection in small-for-size settings. Ann Surg. 2012;255:405-414.

8. Schadde E, Hernandez-Alejandro R, Lang H, et al. ALPPS offers a better chance of complete resection in patients with primarily unresectable liver tumors. Results of a multicentre analysis: reply. World J Surg. 2015;39:1850-1851.

9. Shindoh J, Vauthey JN, Zimmitti G, et al. Analysis of the efficacy of portal vein embolization for patients with extensive liver malignancy and very low future liver remnant volume, including a comparison with the associating liver partition with portal vein ligation for staged hepatectomy approach. J Am Coll Surg. 2013;217:126-33.

10. Hernandez-Alejandro R, Bertens KA, Pineda-Solis K, Croome KP. Can we improve the morbidity and mortality associated with the associating liver partition with portal vein ligation for staged hepatectomy (ALPPS) procedure in the management of colorectal liver metastases? Surgery. 2015;157:194-201.

11. Sandström P, Rosok BI, Sparrelid E, et al. ALPPS improves resectability compared with conventional two-stage hepatectomy in patients with advanced colorectal liver metastasis: results from a Scandinavian multicenter randomized controlled trial (LIGRO trial) [published online September 11, 2017]. Ann Surg.

12. D’Haese JG, Neumann J, Weniger M, et al. Should ALPPS be used for liver resection in intermediate-stage HCC? Ann Surg Oncol. 2016;23:1335-1343.

13. Olthof PB, Coelen RJ, Wiggers JK, et al. High mortality after ALPPS for perihilar cholangiocarcinoma: case-control analysis including the first series from the international ALPPS registry. HPB (Oxford). 2017;19:381-387.

14. Belghiti J, Dokmak S, Schadde E. ALPPS: innovation for innovation’s sake. Surgery. 2016;159:1287-1288.

15. Vauthey JN, Mise Y. Commentary on “Can we improve the morbidity and mortality associated with the associating liver partition with portal vein ligation for staged hepatectomy (ALPPS) procedure in the management of colorectal liver metastases?” Surgery. 2015;157:207-210.

16. Nagorney DM. Commentary on “Can we improve the morbidity and mortality associated with the associating liver partition with portal vein ligation for staged hepatectomy (ALPPS) procedure in the management of colorectal liver metastases?” Surgery. 2015;157:202-203.

17. Li J, Kantas A, Ittrich H, et al. Avoid “all-touch” by hybrid ALPPS to achieve oncological efficacy. Ann Surg. 2016;263:e6-e7.

18. Gall TM, Sodergren MH, Frampton AE, et al. Radio-frequency-assisted liver partition with portal vein ligation (RALPP) for liver regeneration. Ann Surg. 2015;261:e45-46.

19. Machado MA, Makdissi FF, Surjan RC, Bet al. Transition from open to laparoscopic ALPPS for patients with very small FLR: the initial experience. HPB (Oxford). 2017;19:59-66.

20. Deal R, Frederiks C, Williams L, et al. Rapid liver hypertrophy after portal vein occlusion correlates with the degree of collateralization between lobes-a study in pigs. J Gastrointest Surg. 2018;22:203-213.

21. Rous P, Larimore LD. Relation of the portal blood to liver maintenance: a demonstration of liver atrophy conditional on compensation. J Exp Med. 1920;31:609-632.

22. Denys AL, Abehsera M, Sauvanet A, et al. Failure of right portal vein ligation to induce left lobe hypertrophy due to intrahepatic portoportal collaterals: successful treatment with portal vein embolization. AJR Am J Roentgenol. 1999;173:633-635.

23. Wilms C, Mueller L, Lenk C, et al. Comparative study of portal vein embolization versus portal vein ligation for induction of hypertrophy of the future liver remnant using a mini-pig model. Ann Surg. 2008;247:825-834.

24. van Lienden KP, Hoekstra LT, Bennink RJ, van Gulik TM. Intrahepatic left to right portoportal venous collateral vascular formation in patients undergoing right portal vein ligation. Cardiovasc Intervent Radiol. 2013;36:1572-1579.

25. Hwang S, Lee SG, Ko GY, et al. Sequential preoperative ipsilateral hepatic vein embolization after portal vein embolization to induce further liver regeneration in patients with hepatobiliary malignancy. Ann Surg. 2009;249:608-616.

26. Hwang S, Ha TY, Ko GY, et al. Preoperative sequential portal and hepatic vein embolization in patients with hepatobiliary malignancy. World J Surg. 2015;39:2990-2998.

27. Guiu B, Chevallier P, Denys A, et al. Simultaneous trans-hepatic portal and hepatic vein embolization before major hepatectomy: the liver venous deprivation technique. Eur Radiol. 2016;26:4259-4267.

28. Guiu B, Quenet F, Escal L, et al. Extended liver venous deprivation before major hepatectomy induces marked and very rapid increase in future liver remnant function. Eur Radiol. 2017;27:3343-3352.

29. Deshayes E, Schadde E, Piron L, et al. Extended liver venous deprivation leads to a higher increase in liver function that ALPPS in early assessment: a comment to “Sparrelid, E. et al. Dynamic Evaluation of Liver Volume and Function in Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy. Journal of Gastrointestinal Surgery (2017).” J Gastrointest Surg. 2017;21:1754-1755.

30. de Graaf W, Vetelainen RL, de Bruin K, et al. 99mTc-GSA scintigraphy with SPECT for assessment of hepatic function and functional volume during liver regeneration in a rat model of partial hepatectomy. J Nucl Med. 2008;49:122-128.

31. Olthof PB, Tomassini F, Huespe PE, et al. Hepatobiliary scintigraphy to evaluate liver function in associating liver partition and portal vein ligation for staged hepatectomy: liver volume overestimates liver function. Surgery. 2017;162:775-783.

32. Olthof PB, Schadde E, van Lienden KP, et al. Hepatic parenchymal transection increases liver volume but not function after portal vein embolization in rabbits. Surgery. 2017;162:732-741.

33. Schadde E, Raptis DA, Schnitzbauer AA, et al. Prediction of mortality after ALPPS stage-1: an analysis of 320 patients from the International ALPPS Registry. Ann Surg. 2015;262:780-785.

Erik Schadde, MD, FACS, FEBS (HPB)
Department of Surgery, Division of Transplantation
Rush University Medical Center
Chicago, Illinois
Department of Surgery
Cantonal Hospital Winterthur
Zurich, Switzerland
Institute of Physiology, Center for Integrative Human
Physiology
University of Zurich
Zurich, Switzerland
Disclosures: None.

Christoph A. Binkert, MD, FCIRSE, FSIR
Department of Radiology, Interventional Radiology
Cantonal Hospital Winterthur
Zurich, Switzerland
christoph.binkert@ksw.ch
Disclosures: None.