The shortage of cadaveric liver organs has significantly inhibited further expansion of liver transplantation. Split liver transplantation has reduced waiting-list mortality in children, but not in adults. LDLT is currently the most effective alternative to overcome the organ shortage in adults. With the efforts of transplant surgeons in the establishment and popularization of LDLT, the number of LDLT has increased dramatically not only in Japan but also in Europe and the United States as well. Major advantages of LDLT include the good viability of the liver harvested from a healthy individual, the careful selection of the timing of the transplantation, and the potential good tissue matching. The reduced waiting period for a living donor organ may decrease the risks of decompensation or death before transplantation, thereby improving the overall chances for success. Disadvantages are the risk to healthy donors and also that, this modality has a potential psychological burden on the donor[ ^{5 6}]. The surgical procedures for LDLT are technically more challenging and LDLT requires a full understanding of the hepatobiliary anatomy.

A wide range of complication rates are reported in the literature in donors after LDLT. Donor safety has a major importance in LDLT. Published reports on donor outcomes indicated a wide range of complication rates that varied between 9% and 67%[ ^{7 8}]. In the Kyoto University experience 50 complications in 222 right lobe grafts have been encountered, including surgical complications is 18.5% and non-surgical complications is 3.2%[ ⁹]. On the other hand, the American Society of Transplant Surgeons reported a donor complication rate of only 10%. Thus it seems that donor morbidities have not been adequately reported and true extend of complications may be underestimated. A standardized system for reporting complications to a registry should be developed to allow meaningful data analysis. Donor mortality is also a major concern of LDLT. In the United States at least 3 deaths were confirmed. Another 3 deaths in Europe and 1 in Japan had been reported[ ¹⁰].

As living donation permits transplantation to take place independent of either waiting time or the severity of liver disease, the criteria required for LDLT may be modified when compared to deceased donor liver transplantation (DDLT). Estimation of liver volume needed in individual situations is an important factor in donor selection. Aged liver, steatotic liver, and special anatomic variants have the risk of a relatively poor graft quality. Recipient factors such as metabolic load, preoperative latent infections and other organ failures have negative impact on graft survival. The minimally required quantity of graft volume has not been fully clarified, which is one of the major issues of the adult to adult LDLT. The following two methods were developed to express the graft volume: First the ratio of graft volume (GV) in the standard liver volume (SLV) of the recipient, which is calculated by the recipient’s height and body weight. Second, the ratio of graft weight in the recipient’s weight (GRWR: graft to recipient weight ratio). The reported safe limit of small-for-size graft is from 30% to 40% in GV/SLV, while from 0.6 to 0.8 in GRWR[ ¹¹– ¹⁴].

Recipients with a small-for-size graft, suffer from graft dysfunction including hyperbilirubinemia, massive ascites, poor synthetic function that leads to serious conditions such as gastrointestinal bleeding and renal failure. When a graft size is conversely too large for a recipient such as a newborn infant, the graft necrosis occurs due to insufficient blood inflow into the graft.

As pointed out by Ghobrial and Bussuttil, future application of LDLT will be based on the accurate definition of risks imposed on donors compared with potential benefits realized by recipients[ ¹⁵]. As an example to this statement, the number of adult LDLT declined from approximately 400 in 2001 to 280 in 2002. Such a precipitous reduction may have occurred in response to the donor death in US in 2002 which raised increasing concerns for donor safety. While the number of LDLT in the US has declined, the number in Asia as a whole has continued to increase. LDLT accounted for less than 5% of liver transplants in the US but more than 95% of the transplants in Asia excluding mainland China. The overall number of LDLT procedures performed in Asian countries and areas with well-established programs (Japan, Korea, China Hong Kong and China Taiwan) has steadily increased over years[ ¹⁶].

The most common single cause of late graft loss after liver transplantation is the recurrence of the disease for which the liver transplantation has been performed[ ¹⁷]. Until last decade, successful long-term outcome after liver transplantation in patients with chronic active hepatitis-B has been limited because of high rate of recurrent of recurrent hepatitis. Long-term passive immunization with high-dose intravenous hepatitis B immunoglobulin (HBIG) led to a significant improvement in the prognosis of these patients. High-dose intravenous HBIG may prevent recurrent hepatitis B virus infection, but the cost has limited its widespread use in countries with endemic hepatitis B virus infection. Low-dose intramuscular HBIG plus nucleoside analogs such as lamivudine was shown to be equally effective and safe and in the long-term prophylaxis against recurrent hepatitis B at less than 10% the cost of the high-dose regimen[ ^{18 19}]. Although lamivudine is effective in most of the patients, lamivudine resistance is becoming a major concern. With adefovir, a potent antiviral drug that became available in recent years, these patients with lamivudine-resistant tyrosine-methionine-aspartate-aspartate mutant can also be treated[ ^{20 21}]. Currently, liver transplantation can be safely performed in chronic active hepatitis B patients with similar survival as for patients transplanted for other indications.

The recurrence of hepatitis C is also a great concern after transplantation. Although short-term graft and patient survival rates of chronic active hepatitis C patients are comparable to those observed in other patients undergoing liver transplantation, HCV recurrence is universal and is associated with poor graft and patient survival[ ²²]. In contrast, survival after retransplantation for recurrent hepatitis C is poor and retransplantation for these patients is controversial[ ^{23 24}]. In a previous study Abbasoglu et al showed that recurrent hepatitis was the most common cause of late graft loss in patients who had undergone liver transplantation for chronic active hepatitis C[ ¹⁷].

Treatment of recurrent hepatitis C, whether preemptive or not, is an important issue. Despite recent achievements in the treatment of hepatitis C infection with pegylated interferons and ribavirin, patients with recurrent hepatitis C after liver transplantation are difficult to treat. Virological response rates in prophylactic and therapeutic approaches of hepatitis C reinfection after liver transplantation are low compared to the pre-cirrhotic hepatitis C infection. Moreover, optimal treatment duration and dosage of recurrent infection with pegylated interferon in combination with ribavirin remains to be defined[ ²⁵]. Despite side effects, long-term antiviral maintenance therapy might be an effective approach for preventing progression to severe allograft fibrosis and thereby improving long-term survival in liver transplant recipients with recurrent hepatitis C[ ²⁶].

The first liver transplantation from a non-heart beating donor (NHBD) was performed by Nakayama in Japan in 1964. NHBD livers are considered as a potential for expanding donor pool. The critical problem with NHBD livers is prolonged warm ischemia time. Despite calls for the use of hepatic grafts from NHBD, there are few studies examining long-term outcome. Although metabolism is slowed 1.5- to 2-fold for every 10°C drop in temperature, considerable metabolic activity still occurs during cold preservation. In NHBD organs, the effects of cold ischemia are superimposed on the injury occurred during warm ischemia. The pattern of injury sustained during warm and cold ischemia is slightly different. Cold ischemia leads to initial injury to sinusoidal endothelial cells whereas warm ischemia mainly injures the hepatocytes[ ³⁰]. It seems that the additional injury resulting from warm ischemia in NHBD donation requires alternative preservation strategies to minimize the ischemic injury. Donor warm ischemic time may predispose hepatic allografts to an increased incidence of ischemic type biliary strictures. Although graft and patient survival has been reported to be similar to that of heart beating donor transplants, caution is urged with the use of these organs[ ³¹].

Despite the increased risk of graft and patient survival, NHBD livers are being increasingly used with acceptable results. Abt et al analyzed data from the United Network for Organ Sharing database. In 144 NHBDs and 16 856 heart beating donors (NHBDs) the 1-year (70.2% vs 80.4%) and 3-year (63.3% vs 72.1%) graft survival were inferior in the NHBD group. The primary non-function risk after transplantation was also significantly higher (11.8 % vs 6.4%) in the NHBD group[ ³²].

HCC is the most common primary liver cancer and most patients with HCC also suffer from coexisting cirrhosis. For the treatment of patients without cirrhosis, resection should be considered whenever possible. Hepatic reserve is the one of the major determinants of liver resection. When compared with resection, transplantation restores liver function and has the advantage of removing tissue with an oncogenic potential[ ³⁴]. To obtain the optimal benefit from the limited number of organs available, strict selection criteria has been developed to offer liver grafts to patients with the highest likelihood of survival after transplantation. In 1996 Mazzaferro et al showed that when strict criteria were applied, transplantation of patients with early HCC has resulted in excellent results with 4-year survival rate of 75%. This led to the development of Milan criteria from a retrospective analysis of 48 patients. This survival rate was achieved in patients with solitary tumor of less than 5 cm and those who have up to 3 tumor nodules each of which is smaller than 3 cm without vascular invasion or extra hepatic metastasis[ ³⁵]. With the achievement of good results in HCC patients with more advanced tumors, the Milan criterion was expanded. Yao et al proposed UCSF criteria (solitary tumor smaller than 6.5 cm or 3 of fewer nodules with the largest lesion smaller than 4.5 cm or total tumor diameter less than 8.5 cm without vascular invasion[ ³⁶]. In this study the expansion of Milan criteria did not impact on survival adversely. On the other hand, this approach reduced the availability of cadaveric grafts for patients with other liver diseases. The Barcelona Clinic Liver Cancer Group has proposed expanding the Milan criteria to single tumor of 7 cm or less, or 5 tumors of 3 cm or less, in patients who showed a partial response to any treatment lasting for more than 6 mo[ ³⁷]. However organ shortage, higher dropout rate, and less favorable results render these attempts to a controversial issue. With the expansion of listing criteria, liver transplantation could be performed in more advanced cancer patients but this lead in turn to poor survival rates. All patient selection criteria rely on radiological imaging to assess intrahepatic disease and exclude extra hepatic spread. It may be possible to improve patient selection by increasing the sensitivity of imaging studies and detection of micrometastasis[ ³⁸].

Two antigen systems (ABO and HLA) play role in transplantation. In liver transplantation the ABO system is important while HLA system has a minor role. Crossing the ABO barrier in liver transplantation is usually not performed except for emergency conditions and results of ABO incompatible liver transplantation have been markedly inferior with an increased incidence of vascular and biliary complications and rejection, when compared to ABO compatible grafts. In children below the age of three years, ABO incompatible liver transplantations have been more successful[ ⁴⁶]. In recent years, promising results with ABO incompatible liver transplantation using A ₂ donors (subgroup of A which is less reactive and occur in approximately 20% of group A individuals) have been reported. In a Swedish study of 10 adult blood group O recipients who received A ₂ cadaveric grafts, patient and graft survival was 10/10 and 8/10 respectively at 8.5 mo median follow up with tacrolimus based protocol and initial immunosuppression with antithymocyte globulin, interleukin-2-receptor antagonists or anti-CD20 antibody[ ⁴⁷]. In 16 pediatric ABO-incompatible pediatric liver transplantation, Heffron et al reported one-year actuarial graft survival of 92% utilizing standard immunosuppression with selective postoperative plasmapheresis and without splenectomy[ ⁴⁸]. Plasmapheresis may be useful by reducing the recipients’ antibody titers before and after transplantation. ABO incompatible liver transplantation may be the only available option in LDLT, if the patients have no ABO identical or compatible donors. According to the Japanese Registry of LDLT Across ABO Blood Type Barrier, 97 ABO incompatible LDLTs were performed in Japan before 2005 and 5-year survival rate of the patients was 38% before 2001 and improved to 63% among patients who underwent transplantation after 2002[ ⁴⁹].