Temporary portal vein embolization as a starter of liver regeneration
Authors: Mickael Lesurtel, Jacques Belghiti
Journal: Journal of Hepatology (2008)

Liver regeneration and recanalization time course following reversible portal vein embolizationJournal of HepatologyVol. 49Issue 3PreviewPermanent portal vein embolization (PVE) is a widely practised technique. The use of an absorbable material would be safer in clinical situations in which the embolized liver is not resected. We evaluated the efficiency of reversible PVE in terms of liver regeneration and analyzed the precise time course of portal recanalization. Full-Text PDF Preoperative portal vein embolization (PVE) has been used clinically to induce hypertrophy of the contralateral lobe and prevent postoperative life-threatening liver failure as a result of anticipated insufficient future liver remnant (FLR) volume following resection. Liver regeneration, which is the characteristic of this parenchyma, is not possible without an adequate portal flow. In 1920, Rous and Larimore [[1]Rous P. Larimore L. Relation of the portal flow to liver maintenance: a demonstration of liver atrophy conditional on compensation.J Exp Med. 1920; 31: 609-632Crossref PubMed Scopus (275) Google Scholar] discovered that ligation of the portal vein branch of rabbits could contribute to the atrophy of pathological lobe and hyperplasia of non-pathological one. Later, clinical studies reported that portal vein occlusion secondary to tumor invasion or ligation leads to atrophy of the ipsilateral liver and hypertrophy of the contralateral liver. In 1990, Makuuchi et al. [[2]Makuuchi M. Thai B.L. Takayasu K. Takayama T. Kosuge T. Gunven P. et al.Preoperative portal embolization to increase safety of major hepatectomy for hilar bile duct carcinoma: a preliminary report.Surgery. 1990; 107: 521-527PubMed Google Scholar] found that if the portal vein of one lobe is embolized by tumor thrombi, hypertrophy of the contralateral lobe of the liver occurs resulting in better tolerance of hepatectomy. These findings have led to the use of preoperative PVE prior to extensive liver hepatic resection. Although, there are few prospective or randomized trials examining the effectiveness of PVE on liver regeneration or its impact on liver resection, a recent meta-analysis, comprising 1088 patients from 37 published series, confirms that PVE is a safe and effective procedure in inducing liver hypertrophy to prevent post-resection liver failure due to insufficient liver remnant [3Farges O. Belghiti J. Kianmanesh R. Regimbeau J.M. Santoro R. Vilgrain V. et al.Portal vein embolization before right hepatectomy: prospective clinical trial.Ann Surg. 2003; 237: 208-217PubMed Google Scholar, 4Abulkhir A. Limongelli P. Healey A.J. Damrah O. Tait P. Jackson J. et al.Preoperative portal vein embolization for major liver resection: a meta-analysis.Ann Surg. 2008; 247: 49-57Crossref PubMed Scopus (515) Google Scholar]. Therefore, the first target of liver teams was to find embolization agents which could induce permanent embolization of the portal vein and its branches with minimal risk of recanalization. These permanent agents include synthetic glue (cyanoacrylate), synthetic embolization particles (polyvinyl alcohol), coils, iodized oil, and absolute ethanol. Drawbacks of these permanent agents are: (a) risk of extension of portal thrombosis in patients with reduced hepatopetal portal flow, as it is commonly seen in patients with chronic liver disease; (b) periportal inflammatory fibrosis of the perivascular connective tissue which may lead to difficulty with hilar dissection; (c) migration of embolized material into portal branches and (d) partial liver parenchymal necrosis when absolute ethanol is used [[5]Madoff D.C. Abdalla E.K. Vauthey J.N. Portal vein embolization in preparation for major hepatic resection: evolution of a new standard of care.J Vasc Interv Radiol. 2005; 16: 779-790Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar]. Absorbable biomaterials including absorbable gelatin sponge (gelfoam) particles with thrombin and fibrin glue allow recanalization, a theoretical drawback associated with these substances. Conversely, unwarranted outcomes induced by migration of embolization materials into portal branches of the contralateral lobe are minimal or absent. All of these agents reportedly yield a similar extent of hypertrophy in the FLR, 2–4 weeks after PVE and there is no general consensus regarding the ideal embolization agent to be used for PVE. In the past, gelfoam has been considered to be less efficient than synthetic agents like cyanoacrylate to induce liver hypertrophy. De Baere et al. [[6]de Baere T. Roche A. Vavasseur D. Therasse E. Indushekar S. Elias D. et al.Portal vein embolization: utility for inducing left hepatic lobe hypertrophy before surgery.Radiology. 1993; 188: 73-77PubMed Google Scholar] reported that cyanoacrylate embolization produces a 69% increase in volume of the FLR after 30 days compared with a 53% increase in volume after 43 days in cases where gelatin and thrombin were used. Huang et al. [[7]Huang J.Y. Yang W.Z. Li J.J. Jiang N. Zheng Q.B. Portal vein embolization induces compensatory hypertrophy of remnant liver.World J Gastroenterol. 2006; 12: 408-414PubMed Google Scholar] compared gelfoam, coil-gelfoam and absolute ethanol as portal vein embolization agents to induce hypertrophy of the FLR in dogs. They concluded that gelfoam alone was inefficient to induce compensatory liver hypertrophy. However, in both studies, gelfoam embolization was performed with gelfoam sponge cut in strips measuring 20 × 2 mm or 10 × 1 mm. In the present study, authors used gelfoam powder which is supposed to clog more distal branches of the portal vein bed than strips, resulting in more complete and immediate obstruction. Another way to induce hypertrophy of the liver is to perform a portal vein ligation (PVL) on the side of the future resected liver during the first stage of a two-step liver resection for bilobar hepatic lesions. Extraparenchymal ligation of the portal branch is performed using a nonabsorbable suture. We recently showed that right PVL is as efficient as right PVE to induce hypertrophy of the left liver remnant [[8]Aussilhou B. Lesurtel M. Sauvanet A. Farges O. Dokmak S. Goasguen N. et al.Right portal vein ligation is as efficient as portal vein embolization to induce hypertrophy of the left liver remnant.J Gastrointest Surg. 2008; 12: 297-303Crossref PubMed Scopus (136) Google Scholar]. Interestingly, all PVL patients had a revascularization of the right portal vascular bed due to porto-portal shunts on the 4-week volumetric CT-scan. This observation supports the idea that temporary portal vein occlusion is enough to start liver regeneration. The article by Lainas at al. [[9]Lainas P. Boudechiche L. Osorio A. Coulomb A. Weber A. Pariente D. et al.Liver regeneration and recanalization time course following reversible portal vein embolization.J Hepatol. 2008; 49: 354-362Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar] challanges the old concept of definitive and total occlusion of the portal vein bed to induce an efficient hypertrophy of the non-embolized liver lobe. These new insights are in favor of a less mechanistic concept of PVE. In this experimental study, the authors' aim was to assess the effect of reversible PVE by powdered absorbable gelfoam (Curaspon, Curamedical, Zwaneburg, The Netherlands) on liver regeneration in a pre-clinical model using monkeys. Liver regeneration was assessed by BrdU incorporation and CT-scan liver volume measurements, and portal recanalization by repeated portograms. After reversible embolization, complete portal vein revascularization occurred within 13 days, on average. It induced a significant increase of hepatocyte proliferation and a significant hypertrophy of liver volume in the non-embolized lobes. They concluded that reversible PVE induces efficient liver regeneration and avoids long-term liver scarring. There are two main advantages to using powered gelfoam as an embolization agent. First, an unwarranted migration of the embolization agent in the non-embolized lobe would not preclude liver regeneration as described in one case in this study. Second, the complete revascularisation of the vascular bed 2 weeks after embolization would minimize injury of the embolized liver if not finally resected. Two issues must be noted in this study. The main issue is the lack of control group receiving saline instead of gelfoam. This bias has been worked around using each animal as its own control for liver volume assessment and BrdU incorporation using biopsies of the embolized lobes as control. Then, it would have been of interest to compare the results of reversible PVE with definitive PVE group using cyanoacrylate. It must be said in the authors' defense that experimentation in large animal models is cumbersome and expensive. The data from Lainas et al. [[9]Lainas P. Boudechiche L. Osorio A. Coulomb A. Weber A. Pariente D. et al.Liver regeneration and recanalization time course following reversible portal vein embolization.J Hepatol. 2008; 49: 354-362Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar] support that an initial occlusion of the portal branch, even if not permanent, is sufficient to start the mechanisms of liver regeneration in the contralateral lobe. This new concept was already suggested by the efficacy of PVL despite recanalization of the portal bed after ligation. The early recanalization of the embolized portal territory within about 2 weeks does not preclude the increase of liver volume. This is consistent with the kinetic of liver hypertrophy after portal occlusion consisting of quick initial liver hypertrophy within 2–3 weeks before reaching a "plateau" period [[10]Ribero D. Abdalla E.K. Madoff D.C. Donadon M. Loyer E.M. Vauthey J.N. Portal vein embolization before major hepatectomy and its effects on regeneration, resectability and outcome.Br J Surg. 2007; 94: 1386-1394Crossref PubMed Scopus (375) Google Scholar]. At the end of this initial period, the non-embolized liver already reaches more than 75% of its hypertrophy. Asian hepatic surgeons had already anticipated these results and do not hesitate to perform major liver resection 3 weeks after PVE. The beauty of the reversible PVE is both the short-term liver regeneration and the potential preservation of the embolized liver which may lead to great importance in clinical practice. If embolized liver recovers after recanalization, at least three clinical outcomes would be expected. First, reversible PVE would increase the possibilities of multi-step strategies in the surgical treatment of malignant bilobar tumours like colorectal metastases, in order to spare non tumoral liver parenchyma. Second, in the field of the basic research topic of the authors, reversible PVE would help to improve hepatocyte transplantation by providing a temporary window to improve the yield of hepatocyte engraftment in recipient liver. Finally, in living donor liver transplantation, why should it not be expected that reversible right PVE would allow hypertrophy of the future left liver graft in saving the right liver in the donor? Although, the functional recovery of the embolized liver after recanalization was not proven, the authors open a new field of future experimental research to investigate this hypothesis. Taken together, the data from Lainas et al. [[9]Lainas P. Boudechiche L. Osorio A. Coulomb A. Weber A. Pariente D. et al.Liver regeneration and recanalization time course following reversible portal vein embolization.J Hepatol. 2008; 49: 354-362Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar] provide new arguments suggesting that PVE-induced liver hypertrophy is not only a matter of definitive vessels occlusion but is probably dependant on many others factors which remain to be understood. This paper opens up new perspectives in the field of preoperative liver regeneration and preoperative portal flow modulation before liver resection in order to save liver parenchyma. The authors must be congratulated for that.