Living donor liver transplantation—Adult donor outcomes: A systematic review

Authors


Abstract

The objective of this study was to evaluate the safety and efficacy of adult-to-adult living donor liver transplantation, specifically donor outcomes. A systematic review, with searches of the literature up to January 2004, was undertaken. Two hundred and fourteen studies provided information on donor outcomes. The majority of these were case series studies, although there were also studies comparing living donor liver transplantation with deceased donor liver transplantation. Both underreporting and duplicate reporting is likely to have occurred, and so caution is required in interpretation of these results. Overall reported donor mortality was 12 to 13 in about 6,000 procedures (0.2%) (117 studies). Mortality for right lobe donors to adult recipients is estimated to be 2 to 8 out of 3,800 (0.23 to 0.5%). The donor morbidity rate ranged from 0% to 100% with a median of 16% (131 studies). Biliary complications and infections were the most commonly reported donor morbidities. Nearly all donors had returned to normal function by 3 to 6 months (18 studies). In conclusion, there are small, but real, risks for living liver donors. Due to the short history of adult-to-adult living donor liver transplantation, the long-term risks for donors are unknown. Liver Transpl 12:24–30, 2006. © 2005 AASLD.

The success rate of deceased donor liver transplantation is now high, with 1-year survival rates of 85% to 90% now being reported.1 However, the gap between recipients waiting for liver transplantation and available deceased donor organs appears to be widening. There is currently a waiting list of 17,267 people in the United States for liver transplants,2 and nearly 2,000 patients on the United Network for Organ Sharing waiting list died in 2001.3 The use of livers from living donors may increase the total number of livers available for transplantation.

Currently nearly 4,000 adult-to-child (AC) living donor liver transplants, and over 2,000 adult-to-adult (AA) living donor liver transplants, have been done worldwide. Data from the organ procurement and transplantation network in the United States2 shows that in the U.S. living donor liver transplantation (LDLT) represented 3.8% of all liver transplantations performed between 1988 and 2004. The most commonly used graft for AA LDLT is a right lobe. AA LDLT may therefore involve removal of up to 70% of the living donor's liver, one of the most invasive procedures that could be contemplated for healthy individuals.

While AA living donor liver transplantation outcomes may be similar to those for deceased donor transplantation for the recipients, there are concerns about donor morbidity, and some cases of donor deaths have been reported. To address this issue, we have undertaken a systematic review of safety and efficacy outcomes in AA living donor liver transplantation, and we present here the main findings of this review.

Abbreviations

AC, adult-to-child; AA, adult-to-adult; LDLT, living donor liver transplantation; LLS, left lateral segment; MHV, middle hepatic vein.

METHODS

Review Process

The surgical director of the Australian Safety and Efficacy Register of New Interventional Procedures—Surgical chaired the review group of 7 surgeons and 2 researchers.

Inclusion Criteria

All articles using any surgical technique for transplanting a liver from a live adult (≥18 years old) donor to an adult or child recipient were included. Comparative studies, registry data, or case series were all included, without language restriction. The Australian Safety and Efficacy Register of New Interventional Procedures—Surgical researcher and another reviewer independently examined all retrieved references, and any disagreement over inclusion or exclusion was discussed and a compromise reached.

Search Strategy

Ovid PreMEDLINE and MEDLINE (1990 to January 12, 2004), Current Contents (to December 2001), EMBASE (1988 to week 52, 2003), The Cochrane Library (to Issue 4, 2003) and the Australasian Medical Index (to May 2001) were all searched. Conference proceedings for Transplantation 2001 and the Liver Transplantation Society 1999 were also searched, as were the online journals American Journal of Transplantation abstracts March 2003 (supplement to the American Journal of Transplantation), the Journal of Hepatology (all 2003 issues), Liver Tranplantation (all 2003 issues), Transplantation (all 2003 issues), and Transplantation Proceedings (June 2001 to December 2003). The bibliographies of all retrieved papers were then manually searched for relevant references that may have been missed during the database searches.

Specific search terms to retrieve AA LDLT articles were “liver transplant$,” “liver transplantation (MeSH),” “living donor (MeSH)” in MEDLINE, “liver transplant$ and (live or living),” in PreMEDLINE, the Australasian Medical Index and Current Contents, “liver and donor and (live or living),” “liver transplantation (EMTREE),” “living donor (EMTREE)” in EMBASE, and “liver transplant$” in The Cochrane Library.

Data Extraction and Analysis

Data were extracted from each individual study using standardized study profile tables developed a priori. Where articles could be identified as referring to the same group of patients, these articles were grouped and extracted as a single study.

The safety and efficacy data for both adult donors and adult recipients of LDLT were summarized. Where studies were comparative in nature, data for the comparator were also extracted and summarized in the review. The Australian Safety and Efficacy Register of New Interventional Procedures—Surgical review group assigned safety and efficacy classifications and formulated research and clinical practice recommendations.

Terminology of Graft Anatomy

When referring to graft anatomy, the terminology utilized in this review corresponds to the terminology used in the original studies, except where specific information on the segments utilized has been available. This may lead to some heterogeneity within the study population. For example, “left graft” may refer to a graft comprising segment 2 and segment 3 (usually referred to as “left lobe” or “left lateral” segment [LLS], most often in child grafts), or to a segment 2, 3, and 4 graft (left hemiliver, usually utilized for adult grafts). Different approaches are used for right liver grafts, although generally these can utilize segments 5, 6, 7, and 8, either with or without inclusion of the middle hepatic vein.

RESULTS

Included Studies

A total of 214 studies (307 articles) were included for assessment of donor outcomes. These were mostly level IV (case series), with some comparative studies of level III-2 (concurrent comparisons) or level III-3 (historical comparisons).

Estimated Number and Type of LDLT Procedures Performed Worldwide

The literature suggests that a about 6,000 LDLT procedures have been performed worldwide, as illustrated in Figure 1. This estimate, which is sourced from a number of included studies, mainly large registry data sets, is based on estimates of more than 1,000 procedures in Europe, more than 3,000 in Asia, and more than 2,400 in the United States.

Figure 1.

Estimated numbers of LDLT procedures performed worldwide.

Donor Outcomes

Safety

Mortality.

There have been an estimated 12 to 13 donor deaths (at least 7 involving adult-to-adult donation, at least 3 adult-to-child donations, and 3 late donor deaths) (Table 14–29), for a donor mortality rate of the order of 12 to13 in 6,000, or 0.2% (including donors of [LLS], left or right lobes, and donors to both adult and child recipients). The 10 early donor deaths probably involved 5 right lobe donations, 1 left lobe, 1 LLS, and 3 unspecified graft types.

Table 1. LDLT Donor Mortalities
Reported InDonor DetailsCause of Death
Early Deaths  
 Sterneck et al.4; Broelsch et al.5; Malago et al.6; Sterneck et al.7; Broering et al.8A mother died donating her left lateral segment to her child in Hamburg, Germany in 1994.The donor died from a pulmonary embolism on the second postoperative day, and she was a smoker.
 Malago et al.9; Broering et al.8; Malago et al.10A 38-year-old father died donating his right lobe to his 18-year-old son in Essen, Germany, in the late 1990s.The father developed liver insufficiency and sepsis, and he died four weeks after transplantation, when he himself was being retransplanted. The death was attributed to unrecognized congenital lipodystrophy in the father.
 Broering et al.8Around 2000 in Germany, the donor in an adult-to-adult liver transplantation died. It is not reported whether the left or right lobe was being transplanted, but it was likely to have been a right lobe.Donor died from massive bleeding.
 Boillot et al.11; Broelsch et al.12; Broering et al.8Between 1998 to 2000 in Lyon, France, the donor in a right lobe adult-to-adult liver transplantation died.Died from multiple postoperative complications.
 Strong13; Pomfret14In the United States, before 2000, the donor in a left lobe, adult-to-child liver transplantation.Died from anesthetic complications.
 Renz and Busuttil15In California, the donor in an adult-to-adult liver transplantation died. The donor was a smoker, and it may have been a left lobe being donated.Died from a pulmonary embolism.
 Fair16; Fair et al.17In North Carolina, the donor in a right lobe adult-to-adult liver transplantation.Died from septic (intra-abdominal) complications.
 Brown et al.18; Brown19; Otte20In the United States, a donor was listed for deceased donor liver transplantation, but died before receiving this transplant.Possibly the same death as reported by Fair.16
 Surman21; Josefson22; Vastag23; Miller et al.24In January 2002, at Mount Sinai Hospital in New York, NY, a donor died while donating the right lobe of his liver to his brother.The cause of death was sepsis (nosocomial infection with Clostridium perfringens) and aspiration pneumonia.
 Japan Today25In early 2003 in Kyoto, Japan, the female donor in an adult-to-child liver transplantation died. A right lobe was being donated.Died from multiorgan failure.
Later Deaths  
 Lo26In Asia, a donor died 3 years after transplantation. 
 Umeshita et al.27A donor in Japan died 10 years after transplantation. 
 Cherqui28One late donor death.Death from acute Budd-Chiari caused by remnant liver torsion may have been induced by the operation.
Other Reports  
 Brown19One U.S. donor committed suicide, deemed not to be as a consequence of the experience of donation.
 Vastag23Three donors have died “well after surgery” presumably in the United States, although this is not directly stated.
 Beavers et al.29One donor has died in Argentina, 1 in Korea, and 1 in Hong Kong.

In the 6 fatal AA donations, causes of donor death included sepsis (n = 3), massive bleeding (n = 1), pulmonary embolism in a smoker (n = 1), and liver insufficiency and sepsis due to an unrecognized congenital lipodystrophy (n = 1). In the 3 fatal AC donations, causes of donor death included pulmonary embolism in a smoker (n = 1), anesthetic complications (n = 1), and multiple organ failure (n = 1). Type of donor and cause of death was not specified in 1 instance.

Based on the 12 to 13 deaths described in Table 1, and a total of 6,000 LDLT procedures, the overall mortality rate is of the order of 0.2%.

The estimated breakdown between procedures for AC and AA recipients ranges from 0.09% AC and 0.4% AA (3/3,500 AC and 10/2,500 AA) to 0.2% AC and 0.24% AA (7/3,500 and 6/2,500, respectively). The estimated breakdown between left and right lobe procedures ranges from 0.05% left and 0.5% right (2/3,800 and 11/2,200, respectively) to 0.21% left and 0.23% right (8/3,800 and 5/2,200, respectively).

Morbidity.

Donor morbidities were reported in 131 studies and ranged from 0% to 100%, with a median of 16.1%. Biliary complications and infections were the most commonly reported morbidities (Fig. 2). The median reported rate of biliary complications, the most common of which were biliary leaks and biliary strictures, was 6.2% (reported in 97 studies), with reported rates ranging from 0 to 38.6%. Rates of infections, most commonly wound infections, as well as urinary tract infections, pneumonia, and other infections, were reported in 50 studies and ranged between 0 and 28.6%. The median reported infection rate was 5.8%.

Figure 2.

Occurrence of donor morbidities following LDLT. Central bar indicates the median of the means from all studies reporting the incidence of morbidities, with column indicating interquartile range. Outliers marked with open circle lie more than 1.5 box lengths from the median.

Ellison et al.30 reported that 2 donors had been placed on a waiting list for liver transplantation. Most studies reported no obvious difference in complications between donors of different graft types, although some studies showed greater complication rates in donors of right lobes compared with left.

Blood loss and transfusion.

Donor blood loss ranged from 72 to 2,000 mL, with a median of 588 mL (55 studies). Blood transfusion was required in a median of 1.9% of donors, ranging from 0 to 80% across 57 studies. LLS grafts showed significantly less blood loss compared with left grafts (6 studies) and with right grafts (2 studies), although 8 studies showed no significant differences. Right grafts did not result in significantly greater blood loss than left grafts, and in 2 studies, left grafts (including the middle hepatic vein [MHV]) showed significantly more blood loss than right grafts.

Liver function.

The vast majority of tests showed that donor liver function normalized in a timeframe of weeks to months following LDLT (although generally about a week following LDLT) (63 studies).

Efficacy

Procedural statistics and donor recovery.

Donor operating time for the LDLT procedure ranged from 205 to 762 minutes (52 studies). The median operating time was 423 minutes. Operating time was generally shorter for LLS grafts than for other types of grafts (5 studies). No significant differences were seen in the time taken for right vs. left grafts (8 studies), or for grafts with or without the MHV (2 studies).

Intensive care unit stay was reported by 7 studies and ranged from 0 to 6.3 days, with a median of 1.5 days. Hospital stay ranged from 4 to 26 days, with a median of 9 days (58 studies). No clear pattern could be seen between hospital stay and graft type.

Donor return to work or normal activity was generally excellent, with a rate of close to 100% at 3- to 6-month follow-up (18 studies).

Liver regeneration.

Donor livers regenerated to about double the size of their remnant liver within several months, reaching a median 89% of the original liver size (from follow-up varying from 7 days to 6 months) (16 studies).

Chen et al.31 reported that donor liver volume regeneration at 6 months was similar between all graft types. While Kido et al.32 reported that there was no difference in the increase in whole remnant liver volume between donors of grafts with and without the MHV at 3 months, Maema et al.33 reported that at 3 months the whole remnant liver was significantly larger in donors of grafts without the MHV than those with the MHV.

Other Donor-Related Outcomes

Donor yield.

On average, about 1 in 3 potential donors eventually donated part of their liver (range, 2.7% to 90.9%) (44 studies). Although some level of “dropout” was due to recipients identifying more than 1 potential donor, most donors were rejected after medical and psychosocial evaluations. In addition, some LDLTs did not proceed for recipient-related reasons, even though a suitable living donor was available (median, 10%; range, 0.7% to 40%; 23 studies). In a very small number of cases, the donor phase of the procedure was aborted intraoperatively on discovery of a previously unrecognized problem with the donor (e.g., macrovesicular steatosis, mother's bile ducts too small for recipient), or with the recipient.

Donor satisfaction and donor attitudes.

In about 70% of cases, the decision to donate was made by the donor, rather than following a request from others, and all, or nearly all (>95%), donors reported no coercion to donate. Eight studies reported that a median of 100% of LDLT donors would donate again, with a range of 77.8 to 100%. Between 90 and 100% of LDLT donors believed that LDLT was a useful procedure (12 studies). While more than 85% of donors stated that the information made available to them was at least “adequate,” 29 to 38% of donors felt that recovery was longer than expected (3 studies), 33 to 53% found the pain worse than expected (3 studies), and 30 to 40% of donors reported that the surgical scar was worse than expected (2 studies).

Donor quality of life.

Eight studies investigated the quality of life of LDLT donors, using techniques including the Short Form-12 and Short Form-36 questionnaires. Interpretation of these findings was difficult due to the reasonably small number of studies looking at this characteristic, as well as the variety of different scales used, and the comparisons made. In comparison to other populations, Fukunishi et al. found that Short Form-36 scores in LDLT donors were equivalent or better than in a healthy U.S. population, better than a general U.S. population (except for “General Health Perceptions,” which was equivalent), and all better than a group of patients with chronic renal failure.

Psychosocial outcomes.

Again, outcomes relating to donor psychosocial outcomes were difficult to collate due to differences in the way these outcomes were reported. Six studies reported the occurrence of depression in donors following LDLT, with rates between 0.2 and 15%. Two studies reported a significantly higher rate of psychiatric disorders in LDLT donors after transplantation, compared to before transplantation, although these values were not significantly different from those seen in living donor kidney transplant donors. There was no association between physical complications and the occurrence of psychiatric disorders.

DISCUSSION

Safety and Efficacy of LDLT Donation

Liver transplantation is the only chance of cure for those with end-stage liver disease. With a extreme shortages of deceased donor organs in Asia (due to problems with acceptance of brain-death criteria), and variable shortages in most other parts of the world, the concept of donating a piece of one's liver to help save the life of a family member has considerable appeal, but reliable information about risks must be provided to prospective donors. Although it should theoretically be possible to deduce accurate estimates of both donor morbidity and mortality from the published literature, duplicate reporting means that the total number of procedures reported is likely to be inflated by about 100%. In addition, mortality and morbidity is likely to be underreported. Until these issues are addressed the available published data need to be treated with some caution.

Our estimate for donor mortality for LDLT (involving adult or child recipients and any graft type) is about 0.2%, but this may be an underestimate. Mortality for donation of a left lobe (0.05–0.21%) is potentially lower than for right lobe donation (0.23–0.5%) but still a substantial risk for a donor, although donor acceptability of the risk of dying may be higher than these mortality rates.35, 36.

Although patient numbers are too small to determine clear patterns of causes of death after donation, there is some indication that right lobe donors may not be left with sufficient liver reserve. Other causes of death have been attributed to inappropriate donor selection and poor aftercare, and some “near misses” have been due to technical problems, such as injuries to hepatic vasculature. Some of the near misses have resulted in liver failure in the donor, with the need for the donor to be listed for a liver transplantation.

Reported donor morbidity averaged about 16% across the studies in this review, with biliary problems and infections being the most common complications. This is reasonably consistent with the literature, perhaps even a little lower than other reviews have reported (particularly for right lobe donors). As with donor mortality, morbidity may be underestimated due to incomplete reporting. Beavers et al.37 reported that nearly half of the complications in 27 donors were not listed in their medical records, and in a prospective study specifically designed to quantify complications, Pomfret et al.38 found a complication rate of 39% in 51 right lobe donors. There was little evidence that donor morbidity was related to presence or absence of the MHV in the graft, donor age, or learning curve for the procedure, although there is some indication that right lobe donors and those with smaller remnant liver volume may suffer more morbidities than left or LLS donors. After a median hospital stay of 9 days, most donors returned to normal function within 3 to 6 months of donation. However, long-term effects on LDLT donors are not yet known, with liver regeneration taking many months to complete. Standardized and comprehensive reporting would enable these effects to be properly monitored.

Very few donors reported any degree of coercion to donate. While most donors exhibited a positive attitude towards the concept of LDLT, about a third reported that recovery took longer than they had expected, and about half said that the pain was worse than they expected. Some studies reported that donors rated more highly on quality-of-life scales than the general population, indicating that donors may be healthier. In 1 study, donors reported some improvements in their quality of life and in some psychosocial measures after LDLT.

Impact of LDLT

Deceased donor organ availability is already low in many countries and is dropping further due to the decreasing number of road traffic accident deaths in some countries.39 However, the demand for livers is growing in many countries, particularly as a result of hepatitis C. In the United States, 20 to 30% of people currently suffering from chronic hepatitis C virus will require a liver transplant in the next 10 years40 (although this may differ elsewhere). LDLT has been seen as one way of increasing the availability of livers for transplant. In the United States, LDLT is not making a large impact on the waiting list for liver transplantation, amounting to 5% of all liver transplants in 2003. Numbers of LDLT procedures in the United States dropped in 2002 and 2003, perhaps due to the publicity of a donor death in New York and possibly also due to the influence of the new model for end-stage liver disease score, which has shortened the deceased donor liver transplantation waiting list.41 However, projections for 2004 (extrapolated from March 2004) indicated that the number of procedures will return to the 2001 levels of more than 400 a year. Although the pool of potential living donors is large, not all potentially eligible donors can be expected to decide that they wish to be assessed for LDLT. Of those who do, only about 1 in 3 will eventually donate. The most common reasons for excluding potential donors are medical, such as blood incompatibility with the recipient and donor steatosis. This is further limited by the number of potential donors with large right lobes: A quarter of potential donors may have right lobes over 70% of the total volume of their liver precluding them as right lobe donors.42 More stringent evaluation will lower the yield even further, but this is necessary in order to avoid donor mortality and morbidity and to optimize recipient outcomes.

There are also potential alternatives to LDLT. Since recipient outcomes seem to be similar for LDLT and deceased donor liver transplantation, one way of increasing the number of livers would be to increase the availability of deceased donor livers. As Ploeg et al. point out,43 there is a donation shortage rather than a donor shortage, and efforts should be made to encourage more individuals to nominate themselves as organ donors (and make their wishes known to their immediate families). Many centers are expanding their deceased donor selection to include the use of livers from more marginal donors such as donors who are older, overweight, or drug or alcohol abusers, or who have other medical comorbidities, but this may increase recipient morbidity and mortality.44 Centers are also using techniques such as split liver transplants to increase the availability of deceased donor livers.

CONCLUSION

While this review counters the view that “the pursuit of living donors as a source of lobes of liver for transplant has proceeded in something of a data vacuum,”45 there are concerns about the comprehensiveness and reliability of much of the published information and thus concerns about donor safety. Since the LDLT procedure (particularly for right lobe donation) has such a short history, long-term outcomes are not known, and the risks for live liver donors are small but real.

Ancillary