Liver transplantation on the human was launched at 1963 by Starzl et al. [1]. Initial empirical trial of liver transplantation for the human had been approved as one of the standard treatment modalities for the various kinds of end stage liver disease at 1980s [2]. One of the various methods to alleviate organ shortage in liver transplantation, split liver transplantation was introduced late 1980s [3]. Even the successful surgical technique of the split liver transplantation, the outcome of historical first two adult split liver transplantation recipients in French group was not satisfactory. Both the recipients who suffering fulminant hepatitis were died after transplantation postoperative day (POD) 20 due to multi-organ failure and POD 45 due to cytomegalovirus infection, respectively [4]. Split liver techniques eventually applied for one adult of extended right liver graft and the other child of left lateral section [5].

In the pediatric liver transplantation, left lateral liver section of splitting whole liver graft from brain death donor has been a suitable option. However, in the adult recipient, relatively small split liver graft either right of left might not satisfy the functional liver volume to the recipient. Comparable small liver graft should be matched to the individual who is not in urgent situation and small in body. Nearly 80% of the liver transplantation in Korea has been performed using living related donor. Number of deceased organ donation is gradually decreasing due to cultural and social reasons. Waiting list mortality of patient with model for end-stage liver disease (MELD) score 40 has been took place commonly in this country.

Not a few liver transplant centers have considered the organs from marginal donors for transplant backgrounded on this extreme scarcity of deceased donor organ. Liver graft from marginal donors such as elderly donor and high-risk donors based on clinical, laboratory and histologic data has been discarded in general [6]. Split liver itself also regarded as marginal graft so far. In Korea, the first case of split liver transplantation for two adult recipients was published in 2004 [7]. Under the abundant experience of living donor liver transplantation (LDLT), graft damage comes from the split procedure has been diluted. Herein we describe the experience of our split liver transplantation from deceased marginal donor.

Patients

The medical records of 8 consecutive adult patients who underwent split liver transplantation at our institute between 2017 to 2022 were retrospectively reviewed in the present study. Information of relevant four deceased donors were provided Korean Network for Organ Sharing (KONOS). All organ procurement procedures of donors were performed at another hospital. This study was approved by the Institutional Review Board (IRB) of The Catholic University of Korea, Seoul St. Mary’s Hospital (No.KC22RISI0356).

Demographics, liver enzyme profiles and split procedures of the deceased donor were described. Graft type, age, sex, MELD score, disease, previous surgical history, graft-to-recipient body weight ratio (GRWR), cold ischemic time, postoperative hospital stay, 3-month transplant survival and clinical outcomes in recipients were described.

Graft Allocation and Selection, Surgical Procedure and Peri-Transplantation Management

A right split graft was transplanted for the patient allocated based on KONOS policy (Table 1). A patient transplant for the left split liver graft was selected by our Board consideration of estimated GRWR over 1.0 among our institute’s waiting list without nationwide status 1 waiting list patient. A graft liver was transected along Cantlie’s line, surgical technique of right liver graft splitting was performed almost same as that of living donor liver right hepatectomy. If hemodynamic instability precluded in situ split, ex vivo split was performed after transporting the whole graft to our institute. In ex vivo split, parenchymal dissection and the range of the vascular division was same as the in situ procedure. The surgical procedures for recipients of right liver graft were same as standards for LDLT procedures. A graft extrahepatic main portal vein, celiac trunk, common bile duct and inferior vena cava (IVC) were included for the left liver grafts. In short, recipient of left split liver graft implantation was made as side-to-side IVC anastomosis, end-to-end portal, arterial and biliary reconstruction as the whole liver transplantation.

Table 1 .. Timetable for split liver transplantation in this study.

1. Liver allocation from deceased donor (primary recipient) by KONOS.

2. Gross inspection for graft size and pathologic evaluation of graft.

3. If large enough graft for split — decision for split under KONOS permission.

4. If no status 1 waiting list nationwide for split liver.

5. Rapid recruiting for secondary recipient of split liver on the hospital waiting list (patient should be already listed on KONOS).

6. Split liver in situ or ex vivo.

7. Right liver to primary recipient and left liver to secondary recipient.

KONOS, Korean Network for Organ Sharing..

The histidine-tryptophan-ketoglutarate solution was used for graft perfusion. A portocaval shunt was temporarily created if no collateral or anticipated total ischemic time over 300 minutes. Basically, 4 immunosuppressive regimens consisted of basiliximab, tacrolimus, mycophenolate mofetil and methylprednisolone. The dose of immunosuppressants were tapered gradually and tacrolimus was chosen the final maintaining drug. Details of the post-transplant management and immunosuppressive agents were described elsewhere [8].

There were 3 males and 1 female deceased donors. Age ranged 31 to 60 years old. All four donors were hemodynamically supported with single inotrope. A 40-year-old donor case 1’s peak aspartate aminotransferase (AST) level was 132. AST and ALT levels of the second donor were 241, 188 respectively in case 2. Age of the case 3 in this study was 60 years old. AST level of the case 4 was 122. Consecutive initial 3 liver graft splitting procedures performed in situ and 4th donor liver splitting was carried out ex vivo. All four donors were hemodynamically stable with inotropic and organ procurements were performed another four hospitals and the procured liver grafts were transferred with ambulance or express train (Table 2).

Table 2 .. Clinical characteristics of deceased donor who used for splitting liver in the adult liver transplantation.

Case no.	Age (yr)	Sex	AST (IU/L)	ALT (IU/L)	TB (mg/dL)	Plt (/μL)	Alb (g/dL)	Splitting	Inotropics
1	40	M	132	71	1.15	124 k	4.7	In situ	Yes
2	39	M	241	188	0.5	235 k	3.6	In situ	Yes
3	60	M	40	55	1.6	124 k	3.0	In situ	Yes
4	31	F	122	44	0.35	602 k	2.65	Ex vivo	Yes

AST, aspartate aminotransferase; ALT, alanine aminotransferase; TB, total bilirubin; Plt, platelet; Alb, albumin; M, male; F, female..

Eight male patients were transplanted using split liver graft in our series. Age range of recipients was 46 to 67 years. Each brain death donor liver was split with full right and left liver. Four full right liver grafts were transplanted to recipients allocated by KONOS, basically MELD scoring system, all those right liver recipients’ MELD scores were 40s. The other four full left liver grafts were transplanted to the recipients selected from our institute’s own sub-urgent waiting list, whose MELD score 28, 20, 21, and 36 consecutively.

Body weight of four allocated on KONOS waiting list liver recipients were 65, 67, 62, and 54 kg respectively. And the body weight of the other sub-urgent paired recipients of left liver graft were 47, 76, 61, and 62 kg (Table 3).

Table 3 .. Graft weight and recipient body weight according to each deceased donor.

Donor case no.	Total graft liver (g)	Split right liver (g)	Split left liver (g)	Recipient body weight of right split liver (kg)	Recipient body weight of left split liver (kg)
1	2,084	1,424	660	65	47
2	2,202	1,498	704	67	76
3	1,594	936	658	62	61
4	1,466	786	680	54	62

First Split

Right liver graft was transplanted to patient with hepatitis B virus (HBV) related cirrhotic end stage liver disease patient whose MELD score was 40. Left liver was transplanted to patient with HBV related liver cirrhosis underlying myelofibrosis, waiting liver transplant with MELD score 28. GRWR of both patients was 2.2 and 1.4 respectively. Before total liver graft retrieval, split right liver was transferred to our hospital and cold ischemic time was 59 minutes (transportation takes around 20 minutes). Recipient of split right liver graft discharged on POD 19 without clinical problem. Cold ischemic time of split left liver of first donor was 178 minutes and discharged on POD 42 with stable liver function, but this patient expired due to exacerbation of his hematologic disease on POD 11 months.

Second Split

Right liver graft was transplanted to patient with 52 years old male who transplanted ABO blood type incompatible LDLT 9 months ago due to hepatocellular carcinoma, HBV related liver cirrhosis. Biopsy proven antibody mediated rejection of his first LDLT graft was gradually destroyed in spite of repeated steroid pulse therapy and the MELD score of this patient became 40. GRWR of this split right liver graft recipient was 2.2 and cold ischemic time was 292 minutes. He died due to acute cerebral infarct on POD 21.

Split left liver was transplanted to 48 years old HBV infected male, MELD score 20, recurrent hepatocellular carcinoma who performed right hepatectomy for hepatocellular carcinoma 26 months ago. GRWR of this left split liver recipient was 0.9 and cold ischemic time was 388 minutes. He discharged on POD 29 with unremarkable post-transplantation course. But pulmonary metastasis was detected on post-transplant 7 months in this left split recipient and performed video-assisted lung resection. This patient still survived with regorafenib for 34 post-transplant months.

Third Split

Split right graft was transplanted to patient who suffered from Wernicke encephalopathy of alcoholic liver cirrhosis patient whose MELD score 40. GRWR was 1.6 and cold ischemic time of this right liver graft was 155 minutes. This patient discharged on POD 52 with improved condition and mental status was recovered using sustained thiamin supplement.

Recipient of split left liver, MELD score 21, has a history of LDLT 24 months ago due to hepatocellular carcinoma. Tumor extent at first LDLT was beyond Milan criteria and recurrent intrahepatic tumor detected at post-LDLT 13 months. Recurrent hepatic tumors were treated with twice attempts of radiofrequency ablation. This patient suffered from hepatic abscess derived from following transarterial chemoembolization to the graft liver. GRWR of this split left liver was 1.1 and cold ischemic time was 193 minutes. His uneventful re-transplantation hospital stay was 21 days.

Fourth Split

Procedure for split liver graft was performed ex vivo at the recipient hospital after 250 minutes after graft portal clamp. The hemodynamic instability did not allow prolonged donor surgery. The other reason for back table splitting is that donor hospital located at 450 km away from the recipient hospital.

Split right graft was transplanted to alcoholic liver cirrhosis patient whose MELD score 40. GRWR was 1.5 and cold ischemic time of this right liver graft was 302 minutes. This patient discharged on POD 25 with improved condition. At 2-month after transplantation, laparotomy was performed due to bile leak from the graft parenchymal cut surface.

Recipient of split left liver has a history of alcoholic liver cirrhosis whose MELD score 36. GRWR of this split left liver was 1.1 and cold ischemic time was 329 minutes. Unremarkable hospital stays of this left liver graft was 28 days (Table 4).

Table 4 .. Clinical characteristics and surgical outcome of split liver recipients in adult.

Case no.	Graft type	Age (yr)	Sex	MELD score	Disease	Previous surgery	GRWR	Cold ischemic time (min)	Posttransplant hospital stay (day)	3 months survival	Remarks
1-1	Right	50	M	40	HBV related LC		2.2	59	19	Yes
1-2	Left	54	M	28	HBV related LC, Myelofibrosis		1.4	178	42	Yes	Expire due to myelofibrosis POD 11 mon
2-1	Right	52	M	40	HCC, HBV related LC	ABO-I LDLT 9 mon ago	2.2	292	21	No	Expire due to acute cerebral infarct POD 21 day
2-2	Left	48	M	20	Recurrent HCC, HBV related LC	Rt hepatectomy 26 mon ago	0.9	388	29	Yes	Lung metastasis POD 9 mon
3-1	Right	67	M	40	Alcoholic LC, Wernicke encephalopathy		1.6	155	52	Yes
3-2	Left	46	M	21	Recurrent HCC, HBV related LC	LDLT 24 mon ago	1.1	193	21	Yes
4-1	Right	59	M	40	Alcoholic LC		1.5	302	25	Yes	Postoperative bile peritonitis
4-2	Left	50	M	36	Alcoholic LC		1.1	329	28	Yes

MELD, model for end-stage liver disease; GRWR, graft-to-recipient body weight ratio; M, male; HBV, hepatitis B virus; LC, liver cirrhosis; POD, postoperative day; HCC, hepatocellular carcinoma; ABO-I, ABO blood type incompatible; LDLT, living donor liver transplantation..

Extremely high-risk patients have been allocated as liver recipients due to scarcity of brain death organ donor in South Korea [9]. It seems to be the primary reason of the poor enthusiasm for the splitting graft liver to the adult recipient who might not meet sufficient liver volume of the liver transplant waiting list individuals. Median MELD score of adult recipients has been maintained around 40 in South Korea since 2016, which Korean liver organ allocation system was changed based on MELD. It has been reflected high demand for deceased donor liver transplantation (DDLT) for various kinds of liver disease and it required additional intensive care during pre- and post-transplantation period [10].

For the split liver for the pediatric population in South Korea, strict prerequisite are follows: (1) AST and AST level should be in the range within 3 times of reference level; (2) age should not beyond 41 years old; and (3) use of inotropic should be minimal. However, the legal policy of split liver transplantation in the adult has not yet been clearly defined compared to that of the pediatric recipients in Korea. Act of organ transplantation has obscure letter of law for the splitting graft liver in adult. Without appropriate pediatric waiting list for split liver graft, once organ allocation has made to adult recipient, decision whether or not split depend on the recipient’s hospital. Even splitting liver for the allocated donor decided by liver procure team which consisted of recipient hospital, nationwide waiting status 1 patient has the priority for the use of additional graft obtained by splitting liver. It is an indisputable fact in the deceased marginal donor. However, most liver transplant centers do not want to transplant split graft to status 1 patient. Practically, hospital of allocated recipient has the opportunity of transplant for urgently obtained split liver graft. Therefore, there is a room for the chance of transplantation for the less urgent but desperate waiting list individuals at the relevant to recipient hospital. If deceased donor whole liver graft volume looks sufficient large to split, we started to prepare potential second recipient for the left liver on our own waiting list on consideration of recipient’s body weight and urgent accessibility to the hospital within 2 hours. All of them including our own waiting list patients should be already listed up to KONOS waiting list.

Elderly donor over 50 years old in LDLT could result in higher mortality rates than using younger donors [11]. So old age liver donor graft has been regarded as marginal graft and marginal graft should be used in young age or non-high risk waiting list in DDLT [12]. The deceased donor age limit of split liver for pediatric liver recipient is confined up to 41 years old, but there is no legal restriction of donor age on the split liver for adult waiting recipient in Korea. In this study 60 years old brain donor was selected for liver split, which this donor had fair general performance and expected short cold ischemic time with geographically nearby donor and recipient hospital.

Even the AST and ALT level limited within 3 times of normal range in the split liver for the pediatric liver transplantation by the law, the liver enzyme profile of our first and second split liver donors showed range beyond that of the pediatric split liver criteria. But liver biopsy findings during the organ procurement in these two donors allowed split liver graft split based on our decision.

In situ split has been preferred in general for the maintenance of good graft condition and less ischemic time [13]. Ex vivo splitting has been performed when donor is not hemodynamically stable enough to allow for in situ hepatic parenchymal transection. Better hepatic parenchymal dissection surface control is regarded as an advantage of in situ split than ex situ procedure. We also experienced relatively long standing liver graft cut surface bleeding during the transplantation surgery in both right and left liver recipients of ex situ split liver. Ex vivo split right liver graft recipient in this report from the fourth deceased donor developed bile peritonitis in post-transplant 2 months. At laparotomy, we found failed control of bile duct at the hepatic parenchymal cut surface.

In this study, transplantation with right liver showed shorter cold ischemic time than the left liver graft. We intentionally did liver transplantation for the high-risk patient first using right liver graft. HTK solution is the commercially available organ preservation media in Korea. How far cold ischemic time can be acceptable to the high-risk liver transplant candidate is a still open question. In liver transplantation using HTK solution, cold ischemic time more than 8 hours generated poor clinical outcome [14]. In this study longest graft ischemic time was 388 minutes in left liver graft on the third deceased donor. Cold ischemic time of the first split liver transplantation case of this study took 59 minutes. For that short ischemic time, split right liver was transferred in advance of total liver procurement.

Unlike end-stage kidney disease patient where dialysis is available as an alternative, long time waiting list in uncompensated liver disease individual is tantamount to death. So-called ‘marginal livers’ are now being used frequently for transplantation. Historically split livers have been considered marginal graft that might confer an increased risk for poor graft and patient survival [15]. With the successful experience of LDLT using right liver graft for the high-risk patient [16], split liver transplantation seems like good option to the desperate condition. Based on the abundant compatible outcome of emergency LDLT using with right liver graft, we used right livers to the high-risk recipients in advance, and the remaining left livers with vasculature were transplanted to the sub-urgent selected waiting list individuals who accessible immediately. The use of small-for-size graft (less than 1% of recipient body weight) leads to lower graft survival [17]. Expected GRWR over 1.0 was the top priority of selection for the split left liver graft in this study. Another vague regulation in Korean act for organ donation is the body weight matching between deceased donor and recipient for liver transplantation. No strict regulation of body weight matching between donor and recipient in liver transplantation could make a room for split liver a little bit widely in this country. Relatively small body weight recipient might have the opportunity of split liver in DDLT. Poor outcome could be derived from the large-for-size graft in liver transplantation. The injuries have been related to the following: (1) poor liver perfusion because of the large donor-recipient mismatch, which leaves a large poorly perfused area of liver parenchyma; (2) poor hemodynamic tolerance after unclamping the portal vein and the IVC; (3) kinking of the reconnected vessels because of the steric mismatch between a large donor graft and the recipient portal and IVC (4) direct mechanical compression by the recipient abdominal cavity over a large graft [18]. Split liver would have the potential of killing two birds with one stone. It can prevent large-for-size risk and provide one more invaluable liver graft to the other waiting list recipient. In split liver transplantation, surgeon’s role of the organ procurement is vital. In general, with not much preoperative imaging information, donor surgeon had to evaluate the size and possibility of split liver. Most of deceased liver donors suffer from the hemodynamic instability. Body fluid imbalance of the deceased donor distorted the gross findings of liver. Discolored liver or expanded liver during the organ procurement might disturbed the split trial of the liver of practically good quality. Once split liver decided, the other important steps were started. Transplant coordinator had to obtain KONOS permission, immediately and recipient for the additional liver graft had to be prepared, urgently. And the other operation team had to be organized timely. Orchestra of liver transplantation team is essential to accomplish the split liver transplantation. In this study, the urgently recruited reserved recipients who would transplant left liver were carefully selected. For the alleviation of transplantation risk of the left liver graft which might insufficient graft liver volume, we excluded the waiting list patient of high-risk and individuals of estimated GRWR less than 1.0.

On the other hand, bonus point to allocated liver from deceased donor is not sufficient in Korea for extreme scarcity of deceased donor in Korea. DDLT for the alcohol related decompensated liver disease has been gradually increasing in this country [8]. For the individual already spend living donor resource who has the occasion of uncontrolled liver graft tumor recurrence or graft failure, opportunity of re-transplantation is almost zero percent. And additional graft from split liver could provide a successful treatment option for recurrent hepatocellular carcinoma in liver transplant recipient even though tumor biology of that situation tends to be more aggressive [19].

Alcohol relapse has not been guaranteed generally in the emergent liver transplantation for not only in acute on chronic liver failure but also in severe alcoholic hepatitis refractory on medical treatment [20]. Consensus and public opinion for the organ donation might be damaged due to fruitless liver transplant result of alcoholics. For the alcoholic candidates split liver transplantation would reduce the pessimistic opinion about spending whole liver graft for unpredictable abstinence and split liver might have the justification of graft allocation to the other desperate waiting list patient. In conclusion, split liver transplantation in this study, eight recipients were transplanted from four deceased marginal donors successfully. Liver splitting is an important tool to reduce the organ shortage and waiting list mortality especially for small adult patient.

There was no funding related to this study.

All authors have no conflicts of interest to declare.

Conceptualization: YKY. Data curation: All. Formal analysis: YKY. Funding acquisition: YKY. Investigation: YKY. Methodology: YKY, HJC. Project administration: YKY. Resources: YKY, YW, JC, YC, JA. Software: YKY. Supervision: YKY. Validation: YKY. Visualization: YKY. Writing – original draft: YKY. Writing – review & editing: YKY, YW.