The consensus on liver autotransplantation from an international panel of experts

The consensus on liver autotransplantation from an international panel of experts

Qi-Fa Ye and Norbert Senninger

Introduction

More than 1.0 million patients worldwide are diagnosed with space-occupying lesions in the liver every year, with the number approaching 0.5 million per year in China, and only 20% of the lesions are resectable.[1,2]Due to a lack of available donors, only a limited number of patients underwent allogeneic liver transplantation, the remaining patients simply receive palliative care. Therefore, discovering new options for treating these patients is a high priority. Liver autotransplantation (LAT) is a surgical technique that adopts liver transplantation skills to radically treat spaceoccupying hepatic lesions, benign or malignant, parasitic or severe liver trauma that cannot be treated via conventional liver surgery. With the LAT approach, the lesion is resectedante situmorex situunder hepatic perfusion and veno-venous bypass conditions.In situhepatectomy under hypothermic perfusion is excluded because it does not include the vascular transection and anastomosis. Compared to allo-transplantation, LAT technique preserves the autologous liver and eliminates the need for allogeneic liver and subsequent immunosuppressive therapy, along with the related complications. Further, the medical costs of the surgery are reduced, adding the potential for attractive social and economic benefts. LAT was frst reported by Pichlmayr et al in 1988 in Germany.[3]The effcacy and safety of LAT is directly affected by the proportion of liver removed, the preoperative liver function, and the methods of liver perfusion during the procedure. No paradigm or standard has yet been established regarding these factors which may limit the clinical application.

Indications and contraindications

LAT is a technique with high-risk of mortality, hence indications and contraindications should be strictly emphasized.

Indications to LAT

Space-occupying hepatic lesions that cannot be treated via conventional liver surgery.

Contraindications to LAT

1) Lesions in major organs such as the brain, heart, lungs, and kidneys (i.e. patient having a low tolerance for surgery);

2) Currently active tuberculosis;

3) Gastrointestinal ulcer currently active;

4) Severe diabetes that has not been well controlled;

5) Liver functions with Child-Pugh class C, intermediate liver cirrhosis, or fatty liver with fatty proportion ＞50%;

6) Possibility of small-for-size syndrome;

7) Preoperative primary liver tumor assessment indicates poor prognosis or primary lesion of a metastatictumor not radically cured;

8) Mental diseases or poor surgical compliance;

9) Infective lesion, epidemic diseases, AIDS, history of drug or alcohol abuse, or severe drug dependence;

10) Patient is during replicative or progressive phases of any hepatitis virus(es) (A, B, C, D, E, F or G).

Individualized preoperative assessment system for LAT

This system generates an overall score based on the patients' results of the Child-Pugh score, model of endstage liver disease (MELD) score and indocyanine green (ICG) clearance test. The score can be used to assess patients and to reduce risks of operation, including smallfor-size syndrome. Flowchart of assessment for safe resection volume is described in Fig. 1.

Child-Pugh score

The Child-Pugh classifcation has been considered as the most widely accepted measure to evaluate liver function prior to hepatectomy.[4]The highly impaired liver function (Child-Pugh class C or advanced Child-Pugh class B) resulted in poor outcomes of patients referred to hepatectomy.[5]Therefore, the patients with Child-Pugh class C or advanced Child-Pugh class B are not eligible for LAT.

MELD score

Fig. 1. Individualized decision-making system for safe resection volume in LAT. R: residual functional liver volume; S: estimated standard liver volume; SC: surgical contraindication; LC: liver cirrhosis.

Similar to Child-Pugh score, the MELD score has been demonstrated as another effective index to predict the outcomes of patients with liver cirrhosis after hepatectomy. It has been reported that the patients with MELD scores equal to or above 9 prior to hepatectomy had a very high incidence of postoperative complications and liver failure compared with patients with lower MELD scores.[6,7]Hence, in patients with MELD score equal to or above 9, LAT should be avoided.

Indocyanine green retention rate at 15-minute (ICGR15)

The decision for hepatectomy has been based on the Child-Pugh classifcation for years,[8]however, the strategy does not always have the consistent predictive value. In fact, some individuals with Child-Pugh class A already have impaired liver function.[9]ICGR15 can provide more refned assessment of the patients' liver function reserve even they are in the absence of hyperbilirubinemia and ascites.[10]Many reports[10,11]showed that the cirrhotic patients with an ICGR15 between 10% to 20% are able to tolerate major hepatectomy safely. Therefore, we advise that the patients can have LAT if the result of ICGR15 is below 20%.

Residual liver volume assessment

Several studies[11,12]have reported a relationship between the residual liver volume and liver function reserve in patients referred for liver surgery. Individuals who have normal liver function without tumors can tolerate up to 60% of the liver resection.[13]To attenuate the risks-related with LAT, our experience is that residual liver volume after resection must be at least more than 60% by the assessment of preoperative 3-D volumetric CT reconstruction (Fig. 2).

Fig. 2. Assessment of preoperative 3-D volumetric CT reconstruction. Lesion manifestation in CT (A, B) and 3-D space-occupying lesion reconstruction (C, D).

Veno-venous bypass in LAT

In view of the complexity of LAT and the long anhepatic phase (always last for several hours), the utilization of veno-venous bypass is mandatory in maintaining the function of the kidneys and the homeostasis of the hemodynamics and the internal environment;[14-18]the lower limit of bypass fow required is 1000 mL/min.[19]The utilization of a heat exchanger is mandatory to protect against severe hypothermia.[20,21]In general condition, the bypass is from portal vein and iliac vein to axillary vein as shown in Fig. 3. The application of heparin-coated cannulae may reduce the dosage of systemic heparinization, thus alleviate the infuence on coagulation system.[22]Further safety measures such as ultrasoundguided placement of the cannula can be taken into consideration.[23,24]

The procedure without veno-venous bypass as a substitute approach for bypass to maintain the hemodynamic stability was reported.[25]The cost is reduced because this technique shortens the total operation time. An alternative approach can also reduce hemorrhage during operation and alleviate the ischemia/reperfusion injury.En-blocliver is removed after establishment of total vascular exclusion and then a 20-mm ringed polytetrafuoroethylene (PTFE) graft is used to replace the retrohepatic inferior vena cava for bridging suprahepatic inferior vena cava and infrahepatic vena cava.

Perfusion in LAT

Fig. 3. Scheme of veno-venous bypass from portal vein and iliac vein to axillary vein.

Traditional hypothermic perfusion by gravity is performed using histidine-tryptophan-ketoglutarate (HTK) with 6 L intraportally and 0.5 L intra-arterially initially. Perfusion is repeated at an interval of 30-60 minutes with 1 L and 0.2 L as above, respectively.[15]It is commonly used in LAT to reduce cell metabolism and to lessen cellular edema, therefore minimizing damage to the liver. However, cellular anaerobic metabolism continues even at lower temperatures, causing further damage due to the exhaustion of ATP and the accumulation of anaerobic products. As a result, ATP is depleted, cytosolic ion concentrations are changed, and cellular membranes become instable.[26,27]Hepatic sinusoidal endothelium cells are particularly vulnerable to ischemia/reperfusion injury and develop serious alterations during the period without perfusion, such as cell body detachment and apoptosis.[28,29]

Hypothermic machine perfusion with HTK is a more effective method compared to intermittent hypothermic perfusion by gravity in LAT. Perfusate through the hepatic artery and portal vein can continuously remove metabolic products, reduce the accumulation of reactive oxygen species,[30]protect the endothelium,[27]alleviate cold ischemia injury (although cold ischemia injury cannot be completely avoided), and mitigate some warm ischemia injuries.[31,32]During hypothermic machine perfusion, the high portal vein pressure (＞4 mmHg) damages the liver.[33]Thus, hepatic artery and portal vein pressures should be set at 20-25 mmHg and 2-4 mmHg, which are 1/4 of the physiological values, aiming to decrease the physical injuries caused by the hydrodynamic shear stress.[34]Temperature of the perfusate should be maintained at 0-4 ℃. Oxygenation of perfusate has a potential beneft against warm and cold ischemia in various organs and achieved better organ quality.[35]Solutions with no starch and low potassium appear to be advantageous, as low potassium concentration decreases vascular resistance in the cold temperature and avoids cardiac arrhythmia after reperfusion, while the presence of starch increases viscosity.[36]HTK solution is usually used for hypothermic machine perfusion during back-table work of LAT.

Furthermore, normothermic and subnormothermic machine perfusion protects the liver from damage, increasing the number of donor livers and improves graft function in LAT, which would be used in LAT in the future.[37,38]

Operation procedure of LAT

In liver transplantation, grafts are procured with long enough vessels, constantly with an aortic patch, in contrast, long vessels or patches are not available to theante situmorex situprocedure. Meticulous operation including dissection and reanastomosis of vessels is mandatory.[15]The intrahepatic lesion is assessed by palpation and intraoperative ultrasound when the liver has been completely freed from its ligamentous attachments.[38]Anatomical locations of lesions are shown based on the classifcationof hepatic veins[39]and the relationship between intrahepatic vessels/inferior vena cava with the lesions (Fig. 4). In principle, malignant lesions with extrahepatic manifestations and vascular invasion are deemed as contraindication.

Ante situm

For cases in which complex major hepatectomy is required, including hepatic vein dissection and reconstruction, a technique was developed allowing the suprahepatic area to be exteriorized without dividing the porta hepatic.[21,40-44]The infrahepatic vena cava can be transected as well if it is necessary, which is also appropriate for treating retrohepatic lesions.[45]One indication forante situmresection and autotransplantation is that the lesions invade the hepatic veins close to the inferior vena cava confuence or even wrap the inferior vena cava, which have a high-risk of hemorrhage and air embolismin situdisection. After establishment of total vascular exclusion, the portal vein and arteriae gastroduodenalis should be isolated and opened, followed by the insertion of the perfusion tubes. During the continuous hypothermic machine perfusion of hepatic artery and portal vein with 0-4 ℃ HTK solution, hepatic veins are transected at their entry into the vena cava. If the lesion has invaded one of the hepatic veins, part of the inferior vena cava (Fig. 4A, B, C, J, K) is resected and closed with polypropylene sutures or a vascular patch if required. The liver remains attachedin vivoby the porta hepatis, but can be completely exteriortizedex situand placed on temperature control plates for cooling down. The Cavitron ultrasound surgical aspirator is used to excise the spaceoccupying lesion and No. 0 sutures are used to ligate the tubular structure on the section. The cooling system is removed after completion of the tumor resection and tubular reconstruction. The reconstructed hepatic vein is reimplanted onto its original inferior vena cava orifce if possible and the orifce of the hepatic vein that is resected with the tumor is closed with 4/0 polypropylene sutures. If reanastomosis onto the original orifce is diffcult, then this is also closed and reimplantation is performed using a cavotomy.[3]

Fig. 4. Anatomical locations of space-occupying lesions based on the classifcation of hepatic veins and the relationship between intrahepatic vessels/inferior vena cava with the lesions. A: Lesion within the triangular area between left hepatic vein, middle hepatic vein & retrohepatic inferior vena cava; B: Lesion within the triangular area between right hepatic vein, middle hepatic vein & retrohepatic inferior vena cava; C: Lesion within the triangular area between middle hepatic vein & retrohepatic inferior vena cava; D: Lesion within the triangular area between left branch and right branch of portal vein & retrohepatic inferior vena cava; E: Lesion within the triangular area between right branch of portal vein & retrohepatic inferior vena cava; F: Lesion within the triangular area between secondary branch under right branch of portal vein & retrohepatic inferior vena cava; G: Lesion within the triangular area between left branch of portal vein, main trunk of portal vein & retrohepatic inferior vena cava; H: Lesion surrounding inferior vena cava within the caudate lobe; I: Lesion within the triangular area between left branch of portal vein, middle branch of portal vein & retrohepatic inferior vena cava; J: Lesion near the third porta hepatis, with lesion surrounding retrohepatic inferior vena cava; K: Lesion near the second porta hepatis, with lesion surrounding hepatic vein of the second porta hepatis.

Ex situ

Ex situresection and autotransplantation was selected for these lesions can not be resected byante situmprocedure.[3,21,46-54]All afferent and efferent structures have to be divided excepted the retrohepatic inferior vena cava, followed by the insertion of the perfusion tubes. Hypothermic liver perfusion commencedin situafter clamping of the suprahepatic inferior vena cava, infrahepatic vena cava. During the continuous hypothermic perfusion of hepatic artery and portal vein, suprahepatic inferior vena cava, infrahepatic vena cava and porta hepatis are transected meticulously. During theex situhepatectomy, the borders of the liver excision should be determined based on the plan and actual status of the operation combined with the preoperative 3-D liver reconstruction, virtual operation design and preserved liver volume assessment. After isolating the essential structures which must be preserved, hepatectomy can be performed in a manner of conventional liver surgery. During continuous perfusion, the Cavitron ultrasound surgical aspirator is used to excise the space-occupying lesion and No. 0 sutures are used to ligate the tubular structure on the section. After the completion of lesions resection, unligated and opened vessels or bile ducts can be identifed by perfusion. Large vessels should be sewn or ligated to avoid severe bleeding after implantation. Methylene blue can be used to check the closure after repair of all small leaks, especially the tiny holes along larger veins. The reconstruction of vessels required for reanastomosis should be doneex situ. The implementation of reanastomosis is commenced in the normal sequence: suprahepatic inferior vena cava, infrahepatic vena cava, hepatic artery and portal vein. Finally, reconstruction of the bile duct is carried out according to the individual situation, either by an end-to-end anastomosis of the common bile duct or Roux-en-Y loop of jejunum.[20]

Points for attention

The success of LAT is based on: (1) When restoring blood fow to the liver, calcium and sodium bicarbonate solution should be rapidly administered through an intravenous drip to prevent arrhythmia and cardiac arrest caused by disturbance of the internal environment; (2) Prior to the opening of the hepatic blood fow, 350-500 mL of blood should be released from the liver via the suprahepatic inferior vena cava or the right hepatic vein to prevent the sudden release of potassium and an acute cardiac hyperkalemia with the risk of cardiac arrest; (3) Severe metabolic, coagulation and internal environment disturbances may occur 2-3 hours after establishment of total vascular exclusion. Marked fbrinolysis and the depletion of hemostatic factors result in coagulopathy which can be prevented by early and prophylactic substitution of fresh frozen plasma and platelets; (4) The hypothermic perfusion of the portal veins and hepatic arteries should be sustained prior to the opening of the hepatic blood fow; (5) The openings in the portal and inferior veins should be incised and sutured longitudinally to prevent possible postoperative stenosis; (6) It is mandatory to perform an intraoperative ultrasound for checking the vessels; (7) At the end of the procedure, the portal vein pressure should be measured. In the case of a higher pressure than normal, caution should be taken regarding small-for-size syndrome; (8) Finally, the outfow tract should be checked to prevent blockage and subsequent swelling and overstressing of the liver.

Funding:This study was supported by the National Natural Science Foundation of China: United Foundation with Xinjiang (U1403222) and National Natural Science Foundation of China (81570079).

Competing interest:No benefts in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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Received October 21, 2016

Accepted after revision January 10, 2017

Cease to struggle and you cease to live.

—Thomas Carlyle

Author Affliations: Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan 430071, China; Research Center of National Health Ministry on Transplantation Medicine Engineering and Technology, The 3rd Xiangya Hospital of Central South University, Changsha 410013, China (Ye QF); Department of General Surgery, University Clinics of Münster, Münster 48249, Germany (Senninger N)

Qi-Fa Ye (Email: yqf_china@163.com); Norbert Senninger (Email: Senning@ukmuenster.de)

In addition to the authors, this experts group consists of Jeremy R Chapman (University of Sydney), Ke Cheng (The 3rd Xiangya Hospital of Central South University), Francis Delmonico (Harvard Medical School), Lin Fan (Zhongnan Hospital of Wuhan University), Xiao-Li Fan (Zhongnan Hospital of Wuhan University), Zhen Fu (The 3rd Xiangya Hospital of Central South University), Yasuko Iwakiri (Yale University), Ying-Zi Ming (The 3rd Xiangya Hospital of Central South University), Philip J O'Connell (University of Sydney), Gui-Zhu Peng (Zhongnan Hospital of Wuhan University), Zhi-Hai Peng (Shanghai Jiaotong University), Rutger Ploeg (University of Oxford), Hendrik Tevaearai Stahel (University Hospital and University of Bern), Wei-Lin Wang (Zhejiang University), Yan-Feng Wang (Zhongnan Hospital of Wuhan University), Qiang Xia (Shanghai Jiaotong University), Shao-Jun Ye (Zhongnan Hospital of Wuhan University), Shu-Sen Zheng (Zhejiang University), and Zi-Biao Zhong (Zhongnan Hospital of Wuhan University).

? 2017, Hepatobiliary Pancreat Dis Int. All rights reserved.

10.1016/S1499-3872(16)60175-3

Published online January 16, 2017.