Therapy in Liver Diseases 2003 : Transplantation

Journal of Hepatology, Vol. 38 (S1) (2003) pp. S119-S135
© 2003 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
PII: S0168-8278(03)00009-6

In the 1960s and the 1970s, liver transplantation was slowly developed to become a feasible option in the treatment of end-stage liver disease. By 1984, the results of the first series performed throughout the world were deemed good enough to consider liver transplantation as an accepted treatment for these patients [1]. If until then, liver donor shortage was not a major problem, this was going to change radically in the following decade. The number of liver transplantations performed per year rose at an exponential pace both in Europe and in the American continent. Finally, this growth was limited by an increasing shortage of donors, leading to prolonged waiting times and high mortality on the waiting list.

At the same time, the development of the knowledge of segmental anatomy of the liver and in particular the systematic description by Couinaud contributed very much to liver surgery [2]. Based on this knowledge, anatomical liver resections, respecting the vascular perfusion of the remaining segments, could be performed. Very early it was realised that this would open the road for reduced graft liver transplantation, split-liver transplantation and even living donation [3,4].

In 1984, the first successful transplantation of a partial liver allowing the transplantation of a child with part of the liver of a larger donor, was reported by Bismuth [5]. In 1988, both the teams of Hanover and of Paris [6,7] managed to divide a liver into two grafts, allowing successful transplantation in two recipients.

The practical feasibility of split-liver transplantation as well as the increased safety of conventional liver surgery suddenly opened up the idea of removing part of the liver from a living donor to transplant it in a smaller recipient. Intensive ethical consultations took place at the University of Chicago to determine how uncoerced consent could be obtained and under which conditions a trial with such a surgical procedure could be started [8-10]. First cases were performed in 1989 in Australia and in South America [11,12] and finally a first series was produced under close institutional control by Broelsch et al. in Chicago [13,14]. The procedure was taken over in Europe (Fig. 1) and further developed in Japan, where, because of the unavailability of cadaveric donation, it encountered a huge success [15]. Despite initial heavy criticism in the Western world, living donation soon proved to be an inevitable development if one was to run a successful paediatric transplant program. Indeed, in centres performing both split-liver transplantation and living donor liver transplantation (LDLT), mortality of children on the waiting list fell to almost zero [16,17]. The success in paediatric liver transplantation and the shortage of organs provided the necessary incentive to attempt living donation for adults. The emerging awareness of the importance of graft volume and the suboptimal results with smaller grafts, even when transplanted as auxiliary grafts [18,19], made surgeons move to developing right lobe liver donation for transplanting larger children or adults [20,21]. Despite concerns of donor morbidity and mortality, this procedure has opened up the possibility of living donation to the adult patients with end-stage liver disease and has been on a rapid rise in the last few years. Living liver donation certainly counts amongst the great surgical achievements of the 20th century and has saved the lives of many patients.

Living donor transplantation has been accompanied by an ethical debate from its earliest days on, even before it started the first series. The Chicago program set an example for the handling of innovative procedures by publishing the ethical discussion and demanding criticism from the medical community [8] prior to actually performing the procedure. During this time, the emphasis of the ethical discussion was on two major issues: how can such an innovative procedure be introduced into a first study and how should informed consent be obtained. Almost 10 years later, living donation for adult recipients was started with much less ethical discussion. Ethical considerations were first published [22] after many cases had been performed. The emphasis here was more on the field strength needed before one can embark on this procedure and on the issue whether LDLT can be justified for indications, presently considered as contraindications for cadaveric liver transplantation.

It is important to be aware that living donation for adults takes place in a different dimension from that for children. The donor operation carries a higher risk, whereas the recipient, especially with advanced stage of disease, may have an inferior prognosis. The donor-recipient relationship is usually not that of parent to child. The adult recipient can pressurise his donor more easily. This is not only because he can speak and act independently, but also, facing the risk of death (this is also a major difference to the situation of living kidney donation), he may himself search for a suitable willing donor (whereas the donation from parent to a small child is a spontaneous gift). This anxiety may increase as the recipient's condition deteriorates. Even the possibility that the donor may become aware of his or her refusal of donation adds a substantial amount of coercion. Finally, in contrast to the parent-child situation, the donor may expect excessive gratitude from his adult recipient. For this reason, non-coerced consent is more difficult to obtain. At the same time, the donor is facing a larger donor operation with more risks of short- or long-term complications. It is the view of the authors that these circumstances demand exceptional carefulness of the physicians involved in informing and evaluating the living donor (Table 1).

Table 1. Main differences between living donation for a paediatric and adult recipient
Paediatric Adult
Donor-recipient relationship Usually genetically related Genetically or emotionally related
Recipient No decision capability Decision capability
Cannot request donation Can request donation
Cannot refuse donation Can refuse donation
Donor risk + ++
Graft/recipient liver volume Variable Small-for-size
Recipient risk Graft size
Recipient condition
Biliary complications
Early Hepatitis C recurrence
Surgical skill requirements ++ +++

Donors of recipients suffering from emergency fulminant hepatitis should undergo extensive counselling and psychosocial evaluation because the urgency of the situation may not allow sufficient time to fully comprehend and give a truly informed consent [23]. LDLT in this setting needs daily careful balancing of the donor's risk and the likelihood of acquiring an ABO-compatible cadveric graft. The medical and anatomical evaluation of the donor should not be different from that prior to donation for an elective recipient despite pressure of time and should be started preferable even before listing the patient for high urgency transplantation.

Information about the possibility of living donation is an integral and obligatory part of the general information that should be given to liver transplant candidates. The possibility should not be pushed actively, however [23,24], since it is important that patients and their families feel no pressure in seeking an appropriate person for donation. The ideal situation is one in which the potential donor spontaneously presents himself for evaluation. Fortunately, this situation is becoming increasingly welcome because transplant recipients and their families are better informed about the option of living donation by their local doctor, patient organisations, the internet or public media. In Germany, LDLT is not limited to blood-born relatives, but all persons who have a close, long-term emotional relationship with the recipient are accepted. In contrast, in France the procedure is limited to first-degree relatives. In some countries (USA), living donation between non-relatives is also allowed.

Potential donors should have a blood group compatible with that of the recipient (with the exception of very young recipients with low antibody titres). ABO-incompatible donors for paediatric or adult recipients have been described [25-27] but should remain exceptional and have to be evaluated. They should have no history of major abdominal surgery. Most centres accept donors between 18 and 60 years of age. It is apparent that the risk of missing occult medical problems increases with age. Moreover, it has been shown that younger donor age has beneficial effects on early graft function and regenerative capacity of the liver [14,18,27-31].

Potential donors undergo careful medical investigations, which have three major goals:

1. assessment of the medical risk for the donor;
2. assessment of the remnant donor liver and suitability of the potential graft for the recipient; and
3. psychological assessment of the donor.

Investigations routinely performed at most centres for evaluation of the potential donor are listed in Table 2 [14,18,23,27-33]. One of the most serious potential complications of living donation is the perioperative development of pulmonary embolism. Several cases have been reported in the literature [34-39]. In one case, the mother who donated for her child even died as a consequence of this complication [34]. Known risk factors for thromboembolic events include obesity, treatment with estrogens, older age, presence of varicose veins, smoking and a family history of thrombosis with an underlying inherited procoagulation disorder. Most centres screen potential donors for the presence of factor V Leiden gene mutations, prothrombin gene mutations, protein C, protein S, AT III deficiency, factor VIII elevation, as well as the presence of antiphospholipid or cardiolipin antibodies. It is a matter of debate whether potential donors with a mildly increased risk for thrombotic events should be excluded from donation. For example, heterozygote carriers of a factor V Leiden gene mutation - present in approximately 3-8% of the European population - have a 3-8 times higher chance of developing thrombosis. However, most centres agree that donors have to stop smoking and taking oral contraceptives or estrogens once the evaluation process starts.

Table 2. Evaluation protocol for potential living liver donorsa
Step 0:
Step 1
Clinical evaluation: Medical history and physical examination
Laboratory tests: Erythrocyte sedimentation rate, differential blood count, electrolytes, liver, kidney and pancreas profile, glucose, protein, protein electrophoresis, triglycerides, cholesterol, TSH, C-reactive protein, ferritin, transferrin saturation, alpha-1 antitrypsin level, antinuclear antibody screen, coagulation profile, urianalysis
Serology for HBV, HCV, HIV, CMV, EBV, HSV, detailed screening of procoagulation disorders: protein C, protein S antithrombin III, factors V Leiden mutation, prothrombin mutation, homocystein, factor VIII, cardiolipin and anti-phospholipid antibodies

Step 2 (Non- or little invasive investigations) Electrocardiography
Stress electrocardiography
Chest radiography
Pulmonary function test
Echocardiography (if age of donor>40)
Abdominal ultrasound
Upper abdominal CT-scan with volumetry of the liver

Step 3 (More invasive or special investigations) MRI of liver, biliary system and hepatic vasculature
Doppler ultrasound of the carotid arteries ( if age of donor>40)
Celiac angiography*
Liver biopsy*

Step 4 Final medical evaluation
Formal surgical evaluation and consent of the donor
Preoperative anesthesia evaluation and consent of the donor
Planning of the surgical date and availability of ICU facilities
HBV-vaccination, autologous blood donation
Final psychological and ethical evaluationa * Only before adult living donor liver transplantation.

3.3. Assessment of the remnant donor liver and suitability of the potential graft for the recipient

Suitability of the donor liver as a graft is assessed with regard to quality, size, vascular and biliary anatomy. Obtaining an accurate estimate of liver volume during the donor evaluation is critical to ensure that the right and left lobes contain sufficient liver mass to sustain function in the recipient and donor, respectively. Recent studies have shown that either computed tomography (CT) or magnetic resonance imaging (MRI) are very accurate methods by which liver volume in the donor can be assessed [40-42]. In general, volume of the right lobe estimated by these imaging techniques was within 10-15% of the liver mass determined by weighing the liver after resection. Nowadays many centres prefer to perform volumetric determinations by MRI since anatomical details of the hepatic veins, hepatic arteries, portal vein and bile ducts can be studied using the same procedure. In addition, the risk of allergic reactions to the contrast medium and the radiation exposure are avoided. However, a recent study showed that volumetric measurement together with visualisation of the hepatic arteries, portal veins, hepatic veins and bile ducts can be performed in a single computed CT scan [43,44].

The safety of the donor is a primordial concern in living liver donation. Since, in regular liver resection surgery, a clear relationship between mortality and extent of the resection has been demonstrated [45], it is to be expected that donors with a smaller residual liver volume will have a higher risk of complications and/or mortality. Both remnant liver volume and liver quality play a role.

Remnant liver volume is usually expressed as a percentage of the standard liver volume (SLV). The SLV can be calculated using the Heinemann formula [46] for Caucasians or the Urata formula [47] for Asiatic patients. In general, a remnant liver volume of 40% of the SLV or more is regarded to be safe for the donor. However, Fan et al. [48] showed that also a residual liver volume of only 30% can be tolerated by the donor if steatosis is not present. Indeed, liver quality, particulary the grade of fatty degeneration is of uppermost importance. Some centres evaluate parenchymal liver changes by CT or MRI appearance. Others will systematically perform liver biopsies.

Obtaining an accurate estimate of the liver volume during donor evaluation is critical to ensure that the right and left lobes contain sufficient liver mass to sustain function in both the recipient and donor.

In liver resections for liver tumours, extended hepatectomy with a remnant liver volume of 15-20% of SLV can be tolerated in non-cirrhotic patients [49]. The transplanted volume in LDLT requires periods of cold and warm ischemia, subsequent reperfusion of the graft and immunosuppression. Thus, the minimal graft volume required to meet the metabolic demand of the recipient is undefined till now. There is general agreement that the lower limit depends on the recipient's condition, the quality of the graft as well as the technique of implantation performed.

Shirakata et al. [50] reported that 25% of SLV is approximately the minimum graft size for successful liver transplantation in a canine liver transplantation setting. This critical limit of graft volume was confirmed by Lo et al. in humans. The authors performed successful adult-to-adult LDLT for patients with fulminant hepatic failure (FHF) with a graft volume of only 25% of the SLV [51]. Nevertheless, they also stated that a graft volume of 40% or less of SLV should be considered as a high-risk graft, with a lower success rate [52]. Kawasaki et al. [29] reported a 100% graft survival rate and no small-for-size syndrome in 13 recipients of left lobe grafts with a size between 32 and 59% of SLV. Most of these patients were transplanted because of chronic liver failure.

Alternatively, the graft size can be described using the graft-recipient body weight ratio (GRWR) as suggested by Kiuchi et al. [18]. A GRWR ratio of 1% is, in general, accepted to be a graft of good size. Nashizaki et al. showed that small-for-size grafts less than 30% of SLV can be used with careful intraoperative and postoperative management until the graft regenerates [53]. Kiuchi et al. reported that graft size less than 1% of recipient body weight leads to lower graft survival [18].

Recently, it was demonstrated that the minimal graft volume needed depends also on the severity of the underlying liver cirrhosis and the extent of portal hypertension at time of transplantation [54]. Among transplant recipients with normal liver function or Child A cirrhosis, a GRWR as low as 0.6% could be used safely, whereas recipients with Child B or C cirrhosis required GRWR>0.85% to avoid a small-for-size syndrome and related complications [54]. In general, small adult recipients with a body weight up to 60kg may be transplanted with the left hepatic lobe (segments 1-4). Most recipients with a weight of more than 60kg will require a right hepatic lobe (segments 5-8).

Recipients receiving a small-for-size graft usually develop a characteristic clinical picture post-transplant as first described by Emond et al. [55]. The initial synthetic function of the graft is significantly impaired and usually severe cholestasis develops. Liver histology typically shows a diffuse ischemic pattern, although perfusion of the liver is normal. Emond et al. [55] observed the typical small-for-size syndrome in all patients with a graft size between 23 and 44% of SLV, but in none of the recipients with SLV>50%. To avoid small-for-size syndrome, Boillot et al. described portal flow reduction by meso-caval shunt in cases of portal hyperperfusion [56].

As stated above, in adult-to-adult LDLT using grafts of borderline size and leaving only small remnant liver volumes for the donor, the quality of the liver parenchyma is of particular concern. It is well known that the risk of primary non-function after transplantation of a cadaveric graft increases proportionately with the degree of steatosis [57,58]. Steatosis increases cold ischemic injury and reduces the rate of hepatic regeneration [59-61]. Hepatic steatosis also has been shown to increase mortality after major liver resection [62]. When living donated grafts of sufficient size are transplanted, fatty degeneration of the organs seems to be somewhat less important. This is usually the case in LDLT for paediatric recipients, and therefore at our centre routine liver biopsies are performed only in donors for adult recipients. However, in adult-to-adult LDLT, exact pretransplant information about the grade of fatty degeneration present is essential. Fan et al. [63] reported cholestasis in a donor with a remnant liver volume of 34% and 20% steatosis, whereas in another case, a donor with a remnant volume of only 27%, but less than 5% of steatosis had no postoperative cholestasis. However, the precise effect of steatosis on a living liver allograft and the degree of steatosis that prohibit living donation remain undefined.

Marcos et al. suggested that steatosis simply reduces the percentage of functioning liver, both transplanted and remaining in the donor; this must be taken into account when calculating the GRWR [64,65]. In a recent study, steatosis of the liver was shown to increase linearly with the body mass index (BMI) [63]. Donors with a BMI less than 25 rarely have significant steatosis. On the other hand, adipose persons with a BMI of more than 28 have a substantial hepatic steatosis, in more than 70% of cases. Therefore, it has been recommended that such donors are immediately excluded from the cost-intensive evaluation process for an adult-to-adult living donation [66].

Liver function tests will only be elevated in persons with moderate to severe steatosis hepatis. However, normal liver function tests do not exclude the presence of significant steatosis. Evaluation of the grade of fatty degeneration by using radiological imaging techniques such as ultrasound, CT scan and MRI is more accurate. The specificity of both CT and MRI is very high. However, sensitivity is low. A false negative rate of 30% and 24% has been reported using MRI or CT scan, respectively [67]. Therefore, liver histology remains the golden standard for exact determination of the grade of fatty degeneration in most centres.

Apart from the presence of steatosis, quality of the donor liver has to be assessed with regard to the absence of transmittable infections or metabolic defects. It should be taken into consideration that patients with prior hepatitis C (anti-HCV positive) or prior hepatitis B infection may still harbour active virus in the liver, which may cause posttransplant hepatitis. In many European countries, anti-HCV positive donors are refused from donation since interaction of liver regeneration and further development of liver fibrosis in the donor is not defined. In USA, HCV donors can donate to HCV recipients after informed consent. The risk of transmitting hepatitis B by donors who are anti-HBc positive is well recognised, but also donors positive for anti-HBs and anti-HBc were reported to transmit hepatitis B [68,69]. Recent reports have shown a decrease of the risk of HBV transmission using HBIG or lamivudine post-OLT [70,71]. Vaccination of the recipient may also prevent hepatitis B. However, patients with end-stage liver disease often do not develop a sufficient immune response. Moreover, protective antibodies may vanish under immunosuppression after transplantation.

Little information is available on whether recipients with an autosomal recessive liver-based metabolic disorders such as alpha-1 antitrypsin deficiency, hyperoxaluria and others, can receive an organ from a first line relative with a heterozygote state. Particularly in adult-to-adult LDLT using small grafts and small remnant livers transplantation in such cases may be very dangerous. In genetically related donors of patients with Alagille's disease, care has to be taken to evaluate donor bile ducts.

Appropriate portal and arterial inflow as well as adequate venous hepatic outflow is crucial to sustain liver function of the remnant liver in the donor as well as in the transplanted graft. Therefore, evaluation of the donor's liver anatomy prior to donation is important to recognise anatomical variations which prohibit living donation, e.g. absence of the main portal vein bifurcation or severe biliary or arterial malformations, and to determine the optimal type of graft to be resected to minimise risk for the donor and the recipient.

Prior harvesting of the left lateral graft for a paediatric recipient in which the donor does not lose significant liver mass and the recipient is not likely to receive a small-for-size graft, visualisation of the extrahepatic arterial anatomy by single-session MRI angiography or CT angiography is sufficient. Measurement of the diameter of the left hepatic artery and selection of donors with an appropriate diameter of this artery has been abandoned since the introduction of microsurgical arterial anastomosis.

Preoperative anatomical investigations are more important prior to right lobe or extended right lobe resection especially if the remnant liver volume in the donor approaches the critical limit. In these situations, undisturbed arterial and portal inflow toward every segment of the remnant liver is crucial to prevent liver failure in the donor. Therefore, hepatic conventional angiography is needed to document intrahepatic arterial anatomy, especially arterial blood supply of segment 4. The arterial and portal inflow of segment 4 may arise from the right side as well as from the left side. To date, the intrahepatic blood supply can only investigated by conventional angiography. The portal and hepatic vein system as well the bile duct anatomy can be shown by MRI. ERCP is rarely needed if MRCP and CT-cholangiography failed to clarify biliary anatomy.

In our opinion, anatomical vascular or biliary variations, preoperatively known to require reconstruction in the donor, present a contraindication for LDLT.

In general, the left lateral graft (segments 2 and 3) serves the need of a paediatric recipient up to 30kg of body weight. Children over 30kg and small adults up to 60kg can be transplanted with the left graft (segments 1-4). Medium sized and large adults have to be transplanted with the right liver lobe. If the remnant left liver of the donor is less than 30% of the donor's SLV, safe donation is not possible [48]. To overcome this problem of an insufficient remnant left liver, the right posterior segment graft was introduced as an alternative liver graft [72]. Leelaudomlipi et al. described that 25% of the donors had a large right lobe that accounted for more than 70% of the whole volume [73]. Thus, right lobe donation would be dangerous in this donor population. In 72% of these donors, the right posterior segment (37%) was larger than the left lobe with the caudate lobe (33%) [73].The experience with right posterior sectorial grafts is still very limited. This procedure should, therefore, still be considered as experimental.

If none of these types of resections allows to obtain a large enough graft, leaving sufficient liver volume to guarantee safety for the donor, one should opt for cadaveric liver transplantation. In countries in which LDLT is the only available option, the simultaneous transplantation of two small (full left or left lateral) liver grafts from two different donors can provide a solution to obtain a sufficient total volume of transplanted liver tissue [74]. Lee et al. reported 17 cases of dual grafts without mortality or severe morbidity in the donor. The operation time of the recipient varied between 15 and 32h. The ratio of graft volume of the recipients ranged from 46 to 78%. They observed only three in-hospital deaths. The transplantation of a right and a left lateral graft from two donors was reported recently [75].

The altruistic motivation of the donor justifies the exposure of a healthy person to the risk of major surgery without benefit to his own health [76]. Therefore the psychological evaluation should confirm the close emotional relationship between the recipient and the donor and that no other factors, such as psychological pressure or financial issues have led to the donor's decision. Furthermore, it should be ascertained that the donor fully understands and accepts the risk involved with living donation and is able and willing to give free informed consent [77]. The recipient has to agree to accept a graft from the donor. Many centres require that two written consents, separated in time, are obtained to ensure the donor has indeed given careful reflection to his decision.

Apart from medical and psychological consequences of LDLT, it is also important to discuss the possible social sequelae of donation. Donors should be prepared to be absent from work between 1 and 3 months, depending on the nature of their employment. They should discuss the issue of donation and its potential consequences with their insurance carriers and their employer. It is wise to discuss a contingency plan for the case where major complications occur.

Due to the high costs, most centres have developed a stepwise evaluation programme to identify contraindications to donation as early as possible (Table 2) [31-33]. Basic information, such as relationship to the recipient, age, height, weight, blood group, previous or current medical problems, previous major abdominal surgery, may be gathered already by phone. In some centers, the formal evaluation process is only started after the first medical assessment including a full medical history, physical examination, basic laboratory tests and hepatitis serologies are favourable.

Acceptance rate for donors undergoing the evaluation process is reported to vary between 22 and 66% [31-33,78-80]. In up to 10%, the potential donors are even found to have important, previously unrecognised health problems, which require additional work-up and therapy [81,82]. Taken into consideration that not all recipients qualify for LDLT and that not all potential recipients can present a possibly suitable donor, the chances for a LTx candidate to receive a living donor graft are quite low. In a study by Trotter et al. [32], only 49 of 100 potential recipients were found to be suitable for LDLT. Of these, only 25 had a potential donor of which 15 were finally accepted. In agreement with this experience, other authors were only able to find suitable living donors in 13% of prospective recipients [31,55].

The skill of the surgical team performing LDLT is of paramount importance. The team should be experienced in major hepatobiliary surgery as well as in conventional and segmental liver transplantation.

Donor and recipient operation should be organised in a way that optimal expertise can be combined with a short cold ischemic time. In most cases, this means that donor and recipient operations are performed in adjacent operating rooms.

The abdomen is opened through a epigastric midline incision, if needed with a lateral extension. The lesser omentum is checked for the presence of an accessory or replaced left hepatic artery arising from the left gastric artery and opened. The parenchymal bridge between the left lateral lobe and segment 4 is divided and the left portal vein is exposed. The left hepatic artery as well as the left main portal vein are isolated and marked with a vessel loop. The branches arising from the left portal vein to segment 4 are cut between suture ligations. Although one should try to avoid it, it may be necessary to sacrifice the artery to segment 4 (complications of this are very unusual). After complete mobilisation of the left portal vein, the hilar plate containing the left main bile duct is exposed. The left hepatic vein is isolated and marked with a vessel loop to allow vessel-loop guided parenchymal transection [83]. Intraoperative ultrasound allows easy detection of eventual hepatic veins crossing the line of transection. Parenchymal transection along the falciform ligament is performed using one of the modern surgical techniques available today. Once the division of the parenchyma reaches the hilar plate, it is controlled with a dissection clamp to allow safe sharp transection of the left bile duct. After parenchymal transection is completed, the left hepatic artery, left portal and left hepatic vein are clamped, and cut. The graft is perfused with a preservation solution. The right half of the hepatoduodenal ligament remains untouched during the whole procedure.

The abdomen is opened through a right subcostal incision with median extension towards the xyphoid process. After thorough exploration of the abdominal cavity and exclusion of any intraperitoneal disease, investigation of left to right lobar volume relationship and quality of the liver is achieved. Afterwards, cholecystectomy and cholangiography via the cystic duct are performed to rule out anatomical bile duct variations, which prohibit harvesting of either left or right lobe and to mark safe site of transection of the bile duct within the hilar plate. At this point, the final decision if and what type of donor operation (left or right lobe) should be performed is taken. If harvesting of the right graft is chosen, dissection has to be limited right to the main bile duct. Any disturbance of the blood supply of the main bile duct has to be avoided to minimise the risk of later bile duct stenosis. The right hepatic artery and right portal vein are isolated and marked with a vessel loop. Care is taken to preserve the arterial supply to segment 4. The right liver is mobilised from the diaphragm and from the retrohepatic vena cava. Retrohepatic veins with a diameter more than 5mm have to be isolated and marked with a vessel loop to allow separate anastomosis of these veins in the recipient. The right hepatic vein has also to be isolated in the donor to allow later on vessel loop guided parenchymal transection. An ultrasound examination is performed intraoperatively, before parenchymal transection, to rule out the existence of major hepatic veins crossing the line of cantilie. During parenchymal transection, the central venous pressure should be kept below 5mmHg to minimise blood loss [84]. A device for parenchymal transection such us CUSA® or ULTRACISION® should be used to facilitate atraumatic careful parenchymal transection, which reduces the risk of blood loss and bile leakage. The level of transection has to be identified by short clamping of the right hepatic artery and right portal vein with consecutive demarcation of the right lobe. Most teams preserve the middle hepatic vein to the left to avoid any venous outflow obstruction in the donor. In this case, most teams will agree that large veins (>3mm) crossing line of cantilie have to be isolated to allow later anastomosis in the recipient with interposition grafts. Intraoperative ultrasound facilitates their identification and preservation. The mean number of significant segments 8 and 5 veins draining into the middle hepatic vein is 1.33 and 1.22, respectively [85,86]. Other groups keep either the whole [86] or only the distal part [87] of the middle hepatic vein to the right side. To rule out significant venous congestion of the right medial sector, the arterial clamping method can be used as described by Sano et al. [85].

The transection of the right bile duct is one of the most delicate steps of the operation. Any effort should be made to achieve a single bile duct opening on the grafts side while avoiding the risk of opening of the main bile duct of the donor. The rest of the procedure is similar to that of the left lateral lobe.

In order to avoid homologous blood transfusions, preoperative autologous blood donation and intraoperative cell saving should be taken into account. In most series, the need for auto blood transfusion has shown to be less than 20% of the cases. In most centers, donors are kept in the intensive care unit for the first night after the operation.

Standard deep venous thrombosis prophylaxis with low molecular weight heparin should be started on the evening before surgery and continued until the patient is completely mobilised. Other prophylactic measures like intermittent calf compression during surgery and the first 24h after surgery can be added. Intravenous heparin should be avoided since the patient with a small remnant liver is more sensitive to overheparinisation. Pascher et al. experienced a postoperative bleeding, which required reoperation and was related to heparin administration [88]. Unexpected complete heparinisation with temporary bleeding occurred in two of the authors' patients. The further treatment is identical to that of normal liver resection patients. Donors of a left lateral graft can usually be sent home by postoperative day 4 to 6 and donors of a liver half after 6-8 days.

Ethical restraints and donor safety are still issues of intense discussion. The greatest concern regarding donor safety is the risk of donor death. Therefore, donor safety has the highest priority when LDLT is performed. However, some risk is unavoidable and the donor has to be well informed during informed consent.

Major liver resection in non-cirrhotic patients was shown to carry a mortality rate of 0-5% and a morbidity rate as high as 30% [89]. Fig. 3 is illustration of the difference between donation of a left lateral lobe for a paediatric recipient and donation of the right lobe for an adult recipient, regarding postoperative liver function (total bilirubin, Quick) and hepatocellular damage (AST).

There have been at least two cases of donor death from pulmonary embolism in paediatric LDLT, both in women with a history of smoking [90-92]. Another three cases of pulmonary nonfatal embolism in two donors for adult recipients and one for a paediatric recipient underline the need for extensive screening for procoagulation disorders and other known risk factor of deep vein thrombosis [37].

Table 3. Donor morbitity and mortality in large series
Reference Total number of LDLT Number of right lobes Mortality Morbidity Biliary complications
Pascher et al. [88] 43 43 0 8 (18%) 3 (7%)
Brown et al. [153] 449 449 1 (0.2) 63 (14%) 27 (6%)
Soejima et al. [154] 52 6 0 11 (21%) 1 (2%)
Yamaoka et al. [102] 100 - 0 15 (15%) 4 (4%)
Grewal et al. [104] 100 - 0 13 (13%)
Diaz et al. [115] 41 - 0 12 (28%) 2 (5%)
Boillot et al. [155] 17 17 1 4 (24%) ?
Marcos et al. [64] 40 40 0 7 (18%) ?
Fan et al. [111] 22 22 0 5 (23%) ?
Testa et al. [156] 16 16 0 9 (56%) 1 (6%)
Bak et al. [119] 41 41 0 7 (17%) 3 (7%)
Miller et al. [157] 109 50 0 23 (21%) 4 (4%)
ELTR 2002 [93] 806 308 4 (0.5%) 132 (21%) 31 (5%)
Fujita et al. [108] 470 43 0 80 (17%) 41 (9%)

Further three donor deaths in adult LDLT due to multiple complications, liver insufficiency and massive bleeding were reported from Germany and France at the joint meeting of the ILTS in Berlin 2001 [88]. For a total of 806 LDLT reported to the ELTR, living donor database by the end of the year 2001, four (0.5%) donor deaths were stated [93].

There were seven documented donor deaths in the US [94], three of them in donors of right lobes [32]. Thus an estimated risk between 0.3 an 0.5% for donor death must be assumed [23,32,93].

For living liver donation, an overall complication rate ranging from 0 to 67% [78,95-107] has been reported. This broad range of complication rates from the physician perspective is caused by a lack of consensus on the definition of complications. However, most investigations exclusively or mainly included donors of left lateral liver segments or full left lobes, as performed in transplantation of children or small adults. Adult-to-adult LDLT with right liver grafts presumably carries a higher risk [104,108,109]. An European survey undertaken at 11 centres stated significant complications to be as high as 18%, and mild complications as high as 14% [110]. The corresponding survey of North American centres reported at the same time a 30% complication rate [35]. Japanese studies in adult LDLT reported 15-23% adverse events, depending on the operative technique used [108,111].

Grewal from Chicago reviewed their 100 living donors and reported 14 major complications in 13 patients without long-term adverse sequelae. They also reported that complications were more common in left lobe resections (55%) than in left lateral segment grafts (10%) [104]. They found that surgical experience and technical modifications have resulted in a significant reduction of these complications. Fujita et al. [108] reported their large series of LDLT, and biliary leakage was the most common complication after donor hepatectomy, especially in right lobe grafting.

However, since transplant centres are not routinely reporting their complications to a donor registry, to date no data on larger patient cohorts are available [112-114]. Many transplant physicians and surgeons have therefore expressed their concerns about underestimating mortality and morbidity in LDLT [23]. The living donor registry of the ELTR was founded to close this gap in our knowledge.

Physical symptoms in donors, particularly postsurgical pain and the appearance of the surgical wound, are of increasing concern. Interestingly, 37% of donors reported `greater than expected' pain in a survey of Diaz et al. [115]. Donor reports of pain were also a frequent finding among adult-to-adult LDLT donors in a large series by Marcos et al. [116]. Donor perception of time to `complete' recovery was longer than expected, with one quarter of donors requiring greater than 3 months and 5% of donors requiring greater than 1 year to achieve `complete' recovery [115]. Therefore, we inform our potential donors about the possibility of a prolonged recovery period.

It is notable that, in most published series, nearly all living donors are satisfied with their decision of donation and would choose to donate again if given the chance [95]. Beavers et al. reported about 27 living donors (14 adult-to-adult) with an overall complication rate of 40% and a 22% readmission rate [95]. Mean recovery time was 12 weeks. The donors reported no significant change in physical activity, social activity, or emotional stability after donation. Interestingly, 40% of the donors of a left lateral graft (segments 2 and 3) reported complications that were not noted in the medical report [95]. Adult-to-adult right lobe donors reported a 64% complication rate [95]. The emotional nature of the decision to donate may influence the way in which perioperative events are viewed. Adult-to-adult donors might expect better outcomes than parents who are motivated to save their child's life.

In our center, the evaluation protocol for LDLT recipients is not different from that of cadaveric grafts. At most, some more attention is paid to the patency and length of the recipient vessels, since the vessels of the graft are much shorter in LDLT and interpositioning grafts are more difficult to obtain.

If, after complete evaluation, the patient meets the minimal criteria for listing on the cadaveric waiting list [117,118], LDLT can be considered as an option. At this point, the difficult question arises, which recipient benefits most from LDLT. In our view, the ideal candidate for LDLT is a patient who is still in good general condition (UNOS status 2b, 3 and 4), so that the chances for successful transplantation are high, but who has a high risk of rapid deterioration or mortality whilst waiting for a cadaveric liver transplant. Therefore patients with a small hepatocellular carcinoma or patients with an underlying liver disease that rarely reaches a high urgency priority on the waiting list, for example, patients with primary sclerosing cholangitis or primary biliary cirrhosis, metabolic diseases, or polycystic organ degeneration, seem to benefit the most from living donation. Performing LDLT in patients suffering from decompensated chronic liver disease (status 2A) is associated with a postoperative mortality that is excessive for the donor to be placed at risk. To date, the outcome of LDLT in status 2A recipients has been poor compared with that observed for status 2B recipients [21, 29, 36, 110, 116, 119-121]. Current data suggest that the 1-year survival rate of UNOS 2a recipients is only 66% after LDLT compared with 80-90% for UNOS status 2b patients [122]. This worse outcome in status 2a recipients may be related to the high rate of postoperative bile leakage, which increases the risk of sepsis and the pronounced need of functional hepatocyte mass of these patients. Graft function and survival are influenced not only by pretransplantat condition but also by graft size. Therefore once again, the available graft size of the living donor has also to be taken into account. Ben-Haim et al. showed that a GRBWR as low as 0.6% can be used safely in patients without cirrhosis or in patients with Child's class A. Transplant recipients with Child's class B or C require a GRWR greater than 0.85% to avoid small-for-size syndrome and related complications [54].

Recipients with advanced liver disease or previous major liver surgery reducing the chance for a successful outcome should only be accepted for living donation on individual decision. In these cases, the family and the transplantation team have to weigh carefully the risk of the donor procedure against the chances for the recipient. This may be difficult because the situation increases the pressure on potential donors to insist on donation despite the imbalance between donor risk and recipient benefit.

LDLT for FHF has been performed at several centres [123-127]. Pretransplantation mortality in FHF is significant, and the 1-year posttransplantation survival rate is only 60-70% [128]. The reduced waiting time associated with LDLT may enable these critically ill patients to avoid the fatal neurological and septic complications.

Furthermore, there is no general consensus whether patients who do not meet the accepted criteria for liver transplantation should be offered a living donation. These include, in particular, patients with a more advanced tumour disease or with ongoing or only short abstinence from substance abuse. Some authors argue that patients with advanced hepatocellular carcinoma or even some patients with metastases may benefit from LDLT by offering them a better 3- and 5-year survival chance than other therapies [129]. It is our opinion that one should differentiate between marginal indications based on a rational fundament suggesting a substantial potential benefit to the recipient as opposed to those based on an emotional or heroic attempt to save the recipient's life in extremis. It is our opinion that only the first category is justified if these LDLT take place in the context of a study or registry in order to confirm the above named benefit.

Many techniques nowadays used in right lobe grafting derived from those established in paediatric segment liver transplantation. LDLT require a caval preserving hepatectomy of the diseased liver. This can be performed without the use of veno-venous bypass in children and adults [130]. Small children easily tolerate complete caval clamping during hepatic venous anastomosis, which is needed in most cases. In adults, venous anastomosis can be performed without complete clamping of the vena cava, which results in less haemodynamic changes for the recipient. The recipient's right and left hepatic artery as well as the right and left portal branch should kept as long as possible. The left portal vein of the native liver to be removed should be preserved in right lobe grafting to allow eventually using this vessel as interpositioning graft between veins of the resection plane and the recipients stump of the middle hepatic vein [131]. Additionally, the main bile duct bifurcation has to be kept in continuity with the main bile duct of the recipient to allow separate duct-to-duct anastomosis even if the graft carries two or three bile duct stumps. In some cases, the recipient's middle hepatic vein can be used for reconstruction of the middle hepatic vein. In cases of extremely small-for-size transplantations, portal vein decompression by portocaval vein shunt has shown to represent an important factor in preventing graft injury after graft recirculation [132].

In all types of implantation of segmental grafts, longitudinal partial clamping of the caval vein with longitudinal incision is crucial to achieve wide opening of the vena cava, thus allowing wide anastomosis to the graft's main vein. Additional reconstruction of veins draining the segmental graft is only needed if a full right graft is transplanted. Several studies show that reconstruction of the middle hepatic vein is necessary if the resection plane carries segments 5 or 8 veins with a diameter of more than 5mm. Reconstruction can be performed with the donor's ovarial vein, inferior mesenteric vein, vena saphena, left portal vein, jugular vein or the middle hepatic vein of the resected liver. Preserved retrohepatic veins of the graft can be connected to the caval vein without interpositioning grafts. The stump of the grafts portal vein has to be anastomosed end-to-end either to the main, left or right portal vein of the recipient as appropriate. Arterial anastomosis is safe if performed with microsurgical techniques and without pressure of time. Bilioenteric anastomosis still represents the Achille's heel of the procedure. Some studies show that end-to-end bile duct ananstomosis between the recipient common hepatic duct and the stump of the bile duct(s) is feasible [133,134]. We perform the bile duct anastomosis with fine absorbable sutures in a single stitch-technique in one layer with the aid of loupes (magnification 4¥). The use of T-tubes as well as internal or external stents of the biliary anastomosis is still under debate. We prefer to use neither t-tubes nor stents.

Preoperative preparation and postoperative treatment of the recipient does not differ substantially from that before full-size cadaveric transplantation. We use standard immunosuppression regimes after LDLT. At our institution, we use monoclonal antibodies against the interleukin 2 receptor and either tacrolimus or cyclosporin in low doses in addition to steroids in the immediate post-LDLT period to best prevent early rejection during the period of maximum regeneration. Trotter et al. reported that LDLT recipients achieve higher blood levels of tacrolimus and cyclosporin A for a given dose compared with cadaveric adult liver recipients, and this difference is observed up to 6 months after transplantation, when hepatic regeneration is completed [66,135].

Adequate arterial blood flow is confirmed by intraoperative Doppler ultrasonography Anticoagulant therapy is maintained during and after the operation if a hypercoagulable state exists. Follow-up Doppler ultrasonography should be done daily in the early postoperative period [136].

LDLT for children has a significant impact on waiting time and death on the paediatric waiting list [137]. The incidence of primary non-function in living donor recipients is extremely rare and mostly related to a small-for-size situation [55,138,139].

Implantation of a segmental graft from a living donor is technically more challenging compared to the implantation of a full-sized liver from a cadaveric donor. Therefore, the superiority of the graft from a living donor due to the higher organ quality and the shorter ischemic time will be abolished by the technical disadvantages. Thus, in most studies, the results in terms of patient and graft survival are only equal to that of cadaveric liver transplantation [140].

Patient survival after LDLT is reported in most centres at more than 80% [138,140-145] (Table 4). Young and very sick children may benefit more from this technique [98] because the number of available full-size cadaveric organs is limited with following high mortality on the waiting list [145,146].

Table 4. Results after living donor liver transplantation in large series
Reference N Adult (n) Paediatric (n) Graft-survival (%) Patient-survival (%) Biliary complications (n(%)) Vascular complications (n(%))
Grewal et al. [130] 11 11 82 91 8 (73%) 2 (18%)
Lee et al. [158] 157 157 86 (3y) 17 (11%) 12 (8%)
Bak et al. [119] 41 41 88 93 14 (34%) 3 (7%)
Miller et al. [157] 109 59 50 81 (1y) 88 (1y) 27 (25%) 13 (12%)
Hashikura et al. [159] 110 72 38 88 (1y) 88 (1y) 11 (10%) 4 (4%)
Sugawara et al. [160] 82 82 89 (2y) 89 (2y) 18 (22%) 6 (7%)
Inomata et al. [121] 26 26 73 73 4 (15%) 1 (4%)
Testa et al. [156] 16 16 81 93 5 (31%) 2 (13%)
Marcos [116] 40 40 85 87.5 7 (18%) 0
ELTR 2002 [93] 796 351 75 (3y)

The graft survival rate is also reported to be more than 80% in most centres [18,55,140-144] (Table 4).

Vascular complications have dropped down over time due to increased experience and introduction of technical refinements. An international survey gave an incidence of 6.4% for arterial and 5.4% for portal thrombosis [142]. Due to the use of microsurgical techniques arterial thrombosis ranges today between 0 and 2% [79,138,145,147]. The rate of portal vein thrombosis was higher than that of cadaveric liver in the early experience [148], probably because of the large use of cryopreserved venous segments to enlarge the portal vein. Today the rate has dropped down to 3-5% [79,142]. Complications on the hepatic vein anastomosis have shown to be extremely rare.

Biliary complications are the Achille's heel of all segmental liver transplantations. In most series, they persist to range between 15 and 40% [27,140,142-145,149,150] (Table 4). In many cases, they do not affect patient and graft survival but are responsible for relaparotomies and a significant early and late morbidity. Leaks should be managed surgically to avoid early morbidity.

The impact of adult LDLT on the waiting list is not yet defined. In Germany, mortality on the adult waiting list is unaffected, despite introduction of adult LDLT. Several studies show that the 1-year patient and graft survival reaches 80-90%. This is in concordance with the results of cadaveric liver transplantation performed in the same period. Graft survival is in concordance with the results of cadaveric liver transplantation performed in the same period and patient survival lay close together. The main cause of graft loss is death of the recipient with a functioning graft. Reasons for septic complications are often that the recipients demand of hepatocellular mass could not be fulfilled by the transplanted graft, which mostly represents a small-for-size graft. Partial necrotic liver tissue in segment 5 or 8 due to diminished outflow or affected arterial inflow to these two segments has shown to be trigger septic complications and graft failure. Furthermore, the high rate of biliary complications led to septic complications and represents also the Achille's heel in adult LDLT.

Reason for this high rate of biliary complications is the larger resection plane and the more complex biliary anatomy of the right liver lobe. But also in this case, experience of the surgeon can minimise this complication. Marcos et al., in a report on 40 adult-to-adult LDLT using the right lobe, mentioned that the incidence of biliary complications decreased from 35% in the first 20 cases compared to 0% in the second 20 adult LDLT. Besides the increase in experience, he introduced the routine use of biliary stents. Testa et al. reported that in right lobe LDLT bile duct complications occurred in eight of 30 cases (27%). The main cause of biliary complications was related to multiple bile ducts requiring multiple anastomosis. Conversely using the left lobe (segments 1-4) as a graft, in almost all cases, the left lobe graft has a single left hepatic duct, resulting in a technically easier biliary anastomosis.

Nishizaki et al. reported about transplantation patients with a FHF with left lobe grafts corresponding to 23-57% of SLV. They found a patient and graft survival of 80% out of 15 patients [151]. In a recent study by Liu et al., in which 50 patients with acute liver failure were offered a LDLT, the survival of those who accepted the procedure was greater (17/34) than of those who did not accept (1/16) [145]. Mortality rate of status 2a patients on the waiting list is 31.5% [36]. It remains highly controversial whether status 2a or T2 patients, i.e. patients with decompensated end-stage liver disease (DELD), should undergo transplantation with a living donor graft. The main argument of opponents of LDLT for status 2a patients is that in view of suboptimal results in terms of graft and patient survival, risks taken by the donor are not justified. Testa et al. reported on seven patients transplanted with DELD, a patient and graft survival of 43% after a follow-up of 15.1 months [36]. Donor morbidity was 43%. Marcos et al. reported a short-term survival rate of 20% [65]. These results have convinced many centres performing LDLT to consider status 2a as a contraindication to the procedure because of the potential risk for the donor. Status 2a patients are the patients most in need of a liver transplant and are those who most often die while waiting for liver transplantation.

Auxiliary partial orthotopic liver transplantation from a living donor is an established procedure for small-for-size grafts and metabolic liver disease, and the future establishment of its successful application to cases of acute liver failure is anticipated [152].

LDLT is a powerful tool for the treatment of end-stage liver disease. For the first time, it opens up the possibility for the hepatologist to choose the exact timing of transplantation. However, these treatment concepts demand exceptional skills and qualities of the transplant team, which surpass the evident need of excellent surgical expertise. The donor evaluation, the psychological counselling, the radiological diagnosis and volumetry, are some of the other skills needed.

The experience with LDLT in children has proven that short- and long-term high survival rates can be achieved. However, it also failed to prove a clear superiority to cadaveric liver transplantation, with the exception of avoiding pretransplant mortality and primary graft non-function. The situation in adults is different because usually a small-for-size graft is transplanted. More time is needed to determine whether the early success also translates in late patient and graft survival. In particular, little is known about the rates of disease recurrence.

The absolute prerogative for this procedure is the safety of the donor and his free informed consent. Extensive interdisciplinary discussion is needed here to make the right decision. The risks taken by living donors can only be justified if the society and the medical community have done everything in their power to provide sufficient cadaveric grafts.

In children, near zero mortality on waiting lists could be reached with the combination of living donation and split-liver transplantation. For adults, the rate of suitability for living donation is lower, making it clear that living donation alone will not be able to cover the need of grafts. It is undeniable, however, that living donation has opened a new way of hope for many patients with end-stage liver disease.

The authors who have taken part in this study have not a relationship with the manufacturers of the drugs involved either in the past or present and did not receive funding from the manufacturers to carry out their research.
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