EASL Clinical Practice Guidelines

Liver transplantation

Different types of liver transplantation

The shortage of available grafts and the large number of indications for LT have led to the research for alternative strategies in order to obtain organs for as many patients as possible [209]. In Europe and the US, the most common type of LT is the so-called “conventional” or “standard”, that uses whole liver grafts [[40], [209]]. However, in Asian countries, where deceased donation is scarce, the most common type of transplantation is partial grafts from living donors [210].

Conventional or “Standard” liver transplantation – Whole liver grafts

The liver graft is implanted in the right upper quadrant, in the place formerly occupied by the diseased liver. The surgical technique differs according to whether or not the recipient’s inferior vena cava (IVC) is preserved. In most European countries, the piggy-back technique is used, which involves the preservation of the native IVC [[211], [212]]. Anastomosis of the donor’s suprahepatic IVC to the recipient’s three hepatic veins is performed (Fig. 2), as well as reconstruction of the portal vein, hepatic artery and biliary tree, using duct-to-duct anastomosis between the donor’s main biliary tract and the recipient’s one [213]. When the recipients IVC cannot be preserved, this surgical procedure involves vascular reconstruction with end-to-end anastomoses between the donors IVC and the recipient infra- and suprahepatic IVC.


Fig. 2
Liver transplantation with piggy-back technique. Anastomosis of the recipient three hepatic vein union with the donor inferior vena cava (IVC).

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Classification depending on donor type
Brain dead donor

This is a graft donation from a donor who is brain dead.

Donation after cardiac death

This is a graft donation from a donor who has suffered an irreversible cardiac arrest.

Domino liver transplantation

The most common indication for this type of procedure is FAP or Corino de Andrade’s Disease. Since the disease involves extrahepatic organs and the liver function is otherwise absolutely normal, the FAP patient liver is given to another patient while he receives a deceased organ (domino effect) [214]. One of the necessary conditions for recipients of FAP domino liver grafts is that they are older than 55 years, to minimize the risk of developing the disease. There are a number of important technical aspects regarding this procedure. One of them is that preservation of the IVC in the FAP patient involves a graft that has three separate suprahepatic veins that require bench surgery for their reconstruction. In the FAP donor, the entire hepatectomy is performed while preserving the blood supply, although the absence of portal hypertension makes it less complex [215].

Partial graft transplantation

Partial liver grafts are used at times. It may be necessary to provide partial support for metabolic needs due to a specific or complete metabolic deficiency. In the latter case, one of the major preconditions is that the volume of the graft must be sufficient in order to have the capacity to sustain life in the patient immediately after transplantation. It is well-established the importance of the correlation between the weight of the patient and of the graft, as defined by the graft to recipient weight ratio. This ratio should be of at least 0.8% that is for a patient who weighs 80 kg a minimum graft weight of 640 g is needed. This is a problem associated with adult living donor liver patients and is usually solved by using the right lobe for transplantation [216].

Auxiliary liver transplantation

Auxiliary transplantation essentially provides an alternative in two situations. The first is in the cases of patients with acute liver failure in whom a partial graft is used to provide support to the patient’s diseased liver while it recovers [217]. Once the native liver returns to normal function, the graft is removed and immunosuppression is withdrawn. The second case is for patients with functional congenital or metabolic disorders affecting a normal liver. Implanting a partial graft while preserving the native liver allows correction of the metabolic disorder while avoiding a full liver transplant [218]. The best results are obtained in young patients with acute liver failure, mainly viral or autoimmune [219]. Poorer outcomes are obtained in Budd-Chiari syndrome and Wilson’s disease [220], while acute hepatitis B is a controversial indication, for the risk of graft reinfection [221]. Auxiliary LT may be performed orthotopically or heterotopically.

Split LT

This alternative involves dividing a liver in two parts and depends on who the intended recipients are. If those sharing the graft are an adult and a child, the liver will be divided into a right lobe that includes also the segment IV and a partial left graft that includes segments II and III (Fig. 3) [[222], [223], [224]]. Whereas, if the liver is to be divided between two adults, it will be split in two, the right lobe (segments V to VIII) and the left lobe (segments I to IV). The major determinant for this type of transplant is, above all, the size of the recipient left lobe, since normally this lobe has a weight of about 450 g, which only allows it to be implanted in patients with low weight (50–55 kg) [[225], [226]].


Fig. 3
Split liver transplantation – adult and child as recipients.

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Living donor LT

The impossibility of transplanting a child with a donor organ of the appropriate size led to the development of a number of alternatives, one of which is the use of segments II and III of an adult donor for transplantation into a child [227]. In Asian countries, where the LT with deceased grafts is negligible [210], the use of LDLT gradually expanded, culminating with the procedure of adult patients receiving right lobe grafts from living donors [228]. Tanaka showed that the procedure was feasible for the recipient from a clinical point of view and safe for the donor [228]. Although LDLT was highly boosted in Asian countries, in the US and Western Europe the practice is still limited, barely exceeding 5% of the number of transplants [40].

In children, living donation has led to a reduction in waiting list mortality. With the improvement of the surgical technique, many paediatric patients are now transplanted adult split liver grafts. The establishment of a single transplantation list, together with the prioritisation under the MELD system, makes it very difficult to perform this procedure, which is limited to highly committed groups [229].

In adults, living donation generally uses the donor’s right liver lobe, which comprises of segments V to VIII. Right hepatectomy requires meticulous dissection on which the right hepatic artery, right portal vein, right bile duct and right suprahepatic vein are isolated. The minimum size of the graft (Fig. 4) must be of at least 0.8% in order to ensure the viability of the patient and the graft [216]. Aside from the technical difficulties in the donor hepatectomy, there is a significant morbidity that affects 38% of donors and a mortality rate estimated to be around 0.18% [3]. Furthermore, the recipient procedure is also challenging, due to the size of the anastomoses, especially of the artery and bile duct that are of 3 to 4 mm in diameter. Nevertheless, outcomes are good and at present they are similar to those obtained with whole grafts from deceased donors [3].


Fig. 4
Adult living donor liver transplantation.

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Donor hepatectomy entails morbidity and mortality risks [230]. Approximately one third of the patients experience some kind of complication, the majority of which are type I or II according to the Clavien-Dindo classification system [231]. Biliary fistulas are the most common complication and are usually managed conservatively. Some donors need to be rehospitalized and even to undergo further surgery [[230], [232]].

The overall complication rate, as well as Clavien II and IIIa complication rate of right lobe donors is significantly higher when compared with that of left lobe donors. Furthermore, left lobe donors seem to present a more rapid normalization of levels of serum bilirubin and prothrombin time [233].

Finally, although the donor mortality is very low, the idea that a healthy individual may die because of an organ donation is something that has had a definite impact on the Western world mindset. The ELTR data has been audited and includes all of the most serious complications. At present, this registry believes the risk of death to be around of 0.18% (Table 5) [3], although the incidence of donor death is generally considered to be underreported [234].

Table 5
Living donor liver transplantation vs. deceased liver transplantation: complications and mortality (1991–2009) – European Liver Transplant Registry [40].


Graft and patient survival in Europe

Since 1988 outcomes of LT have been very good, and have gradually improved over the last several years. Europe keeps a registry that allows continuous monitoring of transplantation activity and outcomes [40]. The large number of indications is a consequence of these good results, and for that reason, although the transplantation activity has increased exponentially, we face a shortage of organs that forces us to develop new alternatives.

At present, after nearly 100,000 transplants, the chances of surviving one year are close to 90% and the 5-year survival rate is around 70% [3]. HCV is the most important determinant with regard to long-term survival. Table 6 shows the probability of survival in relation to different indications. Life expectancy of transplanted patients is excellent, limited mostly by recurrent disease such as HCV or HCC [235], and the occurrence of side effects associated with immunosuppression such as the onset of diabetes, chronic renal failure, hyperlipidaemia, atherosclerosis, or de novo malignancy [236]. At present, the most important objective is to reduce these long-term issues though a modification of immunosuppression, especially considering that there are no new treatments with lower toxicity on the horizon. The possibility at present of an effective treatment for HCV means that 10 years from now there will probably be a decrease in the number of indications due to HCV-related complications (cirrhosis, HCC, etc.) [237].

Table 6
Overall result in liver transplantation by indication (European Registry 1998–2012) [40].


Surgical complications

Although complications from surgery following LT have been significantly reduced, they continue to have a major impact during the post-operative course, and determining the prognosis, not only in the short, but also in the long-term.

Vascular complications
Arterial complications

There is a relatively low incidence of hepatic artery thrombosis, between 1 and 7%. The most common presentation is graft dysfunction, which can change dramatically the graft survival, reported to be as low as 27.4% at 5 years [238]. About 50% of cases are treated with re-intervention and revascularization, while the remainder require retransplantation [239]. The most serious long-term consequence is the occurrence of ischaemic biliary lesions or IC, which in the majority of cases could raise the issue of retransplantation.

Venous complications

Outflow obstruction by IVC anastomosis stenosis following LT is a rare but serious complication, with a reported incidence of 1–6% and generally related to intimal hyperplasia or fibrosis at the anastomotic site [240]. Preservation of the IVC (piggy-back technique) has drastically reduced the occurrence of complications secondary to anastomotic stenosis [240]. Endovascular techniques are the preferred method of treatment [241].

The utilisation of the piggy-back technique and the consequent need for anastomosis of the three hepatic veins initially resulted in outflow problems in the post-operative course, occurring in up to 30% of the patients. This complication has become very rare by performing anastomosis between the union of the three hepatic veins of the recipient and the IVC of the graft [242].

PVT is not uncommon in patients undergoing LT with an incidence between 2.1% and 26% [243]. It may cause problems in paediatric transplantation as a result of hypoplasia due to biliary atresia. On the other hand, in patients with previous partial or complete PVT, LT is associated with a higher surgical complexity. Surgical alternatives including portocaval transposition, renoportal anastomosis, mesentericoportal anastomosis, multivisceral transplantation. However, they are associated with higher morbidity and mortality [243]. In this type of recipient patient, the rate of re-thrombosis is usually higher and may reach 13%. Therefore, short-term anticoagulation is generally recommended [243].

Biliary tract complications
Leakage

Biliary leakage is a rare problem, which depending on what the cause is, often has a relatively easy solution, ranging from performance of an ERCP and sphincterotomy, to the temporary placement of a prosthesis. Incidence is around 5% [244]. In cases of partial grafts, the leak is sometimes on the raw surface of the split liver and is caused by tubules whose flow progressively decreases. Very rarely the embolization of these tubules or the reoperation are required [245].

Ischaemic bile duct injuries

Ischaemic bile duct injuries may have different causes: ABO incompatibility, artery thrombosis, ischaemia/reperfusion injury etc. It is also one of the most common complication in LT with livers from DCD donors, being described in 15–37% of the patients who are receiving a DCD graft [246]. One other cause is the recurrence of PSC, which has been described in 20–30% of transplanted patients [[247], [157]]. They are characterized by intrahepatic strictures and primarily affect their confluence, producing a beaded appearance along with stenosis and dilatation along the entire biliary tract. Usual symptoms are cholestasis with intractable pruritus, repeated episodes of cholangitis of hepatic abscesses. Retransplantation is the treatment [248].

Anastomotic type

Anastomotic stenosis has a reported incidence of 4–9% [249]. In contrast to non-anastomotic stenosis, the underlying causes for anastomotic strictures are linked with a suboptimal surgical technique (with resulting fibrosis or ischaemia) or with bile leak [250]. The majority of which are presented in the first year after LT, although incidence continues to increase even after this period [250]. The first diagnostic tool that can be used is magnetic resonance cholangiography, which has a sensitivity and specificity close to 90% [251], but lacks therapeutic ability. The conventional treatment is endoscopic treatment (ERCP) with balloon dilatation and use of protesis with an overall success rate of 70–100% [249]. The role of percutaneous transhepatic cholangiography is reserved for cases of endoscopic treatment failure or with complicated hepatico-jejunostomies, with a success rate of 50–75% [252]. In cases without response to such therapies, a hepatico-jejunostomy must be performed.

Associated to partial grafts

Anastomotic stenosis is one of the major problems of partial liver grafts. One of the most important related factors seems to be the presence of bile leak [253]. The underlying process is not known, although it has been suggested that it may be related with the local inflammatory effect of the bile or with the poor local vascularity. There are studies, which associate the size of the duct-to-duct anastomosis with the presence of stenosis [254]. The incidence can reach 50% of the recipients (some groups have reported a rate of less than 5%), and although it does not seem to affect long-term survival, it does affect QoL [249]. The success rate of endoscopic treatments is statistically lower than in anastomotic stenosis after whole graft LT, reaching 60–75% [255]. Therefore, interventional radiology plays an important role in its treatment, through dilatation or stent insertion. About 50% of patients require reoperation and the duct-to-duct anastomosis ends up becoming a hepatico-jejunostomy [245].

Recommendations

Retransplantation

After LT, graft loss still occurs in 7–10% of adults [256] and liver retransplantation is the only suitable therapy for this type of patient [257]. The main causes have to be divided in early (hepatic artery thrombosis or primary graft non-function) and late (IC, chronic rejection or recurrence of the primary liver disease). The timing of retransplantation represents a key point in both patient and graft survival. Patients with a retransplantation interval less than 30 days display lower survival rates when compared to those with later retransplantation [258]. Retransplantation carries a high morbidity and mortality compared with LT, with statistically lower survival rates [256]. One-, five- and 10-year patient survival rates after retransplantation were 61%, 53.7%, and 50.1%, respectively. These percentages were significantly less than those after LT during the same period: 82.3%, 72.1%, and 66.9%. In some centres patients could receive three, four, or more transplants.

At present, multiple elective retransplants are becomingly rare and whether the indications for elective retransplantation should be the same as for chronic liver disease is still an open issue.

Timing for retransplantation

There is no consensus among transplant physicians to define specific retransplantation survival outcomes below which retransplantation is to be avoided. Only the MELD scoring system for organ allocation provides an objective stratification of retransplantation candidates based on severity of illness.

A reduction in short-term survival to less than 60% was observed in all retransplantation patients with a MELD score over 25 [259]. While mortality was increased in all groups with a concomitant rise in MELD score, patients with a score over 30 had a survival rate from 20% to 40%. While retransplantation may exhibit survival rates similar to primary transplant in select patients, it is more likely to be successful in healthier recipients with a lower MELD score.

The effect of allograft quality is exceedingly recognised as one of the important parameters that determine success of transplantation in general and retransplantation in particular. More studies are needed to clearly define parameters but older donors and long cold ischaemia time (>8 h) seem to be critical factors.

HCV used to be considered as an independent risk factor for higher mortality rate. Nevertheless, several studies tend to show that reasonable survival can be achieved following retransplantation and no significant survival differences are observed between HCV positive, cryptogenic, cholestatic, or alcoholic liver disease patients when adjusted for age and MELD scores [[260], [261], [262]].

These data suggests that the selection of the recipient should integrate the severity of the illness, the interval time since the primary LT and the graft quality more than the cause of retransplantation.

Recommendations