Working up donors for high-urgency and elective adult-to-adult live donor liver transplantation

Authors


  • See Editorial on Page 478

Abstract

Donor workup for adult-to-adult live donor liver transplantation is done to ensure that the donor remains physically and psychologically healthy after saving or improving the life of the recipient. Even though two-thirds of the liver transplants in our center were from live donors, this life-saving procedure remains a mere treatment option, given the magnitude of the donor operation with the associated donor risks. Live donor liver transplantation was also adopted for high-urgency situations provided that the donor was suitable and the recipient considered salvageable. Donor workup in this setting had not been reported in the literature. In this cohort of 399 potential donors, 128 (32.1%) ultimately underwent donor surgery. Donors in the high-urgency situation had a lower operation rate of 28.4% (64/225) compared with that of 36.8% (64/174) of donors in the elective situation (P = 0.049). Dropouts from step 1 mainly because of ABO incompatibility, positive hepatitis serology, comorbidities, and voluntary donor withdrawal were 52.6% (210/399). Only 11.6% (22/189) of the potential donors who proceeded to subsequent steps of the workup dropped out (2 were psychologically unsuitable, 10 were anatomically prohibitive). The transplantation rate of potential recipients with 1 or more potential donors was also high. The rates were similar for the high-urgency (55%, 64/116) and the elective (51%, 64/125) situations. In a region with scarcity of deceased donor liver grafts, careful and expeditious initial donor workup minimizes dropouts from subsequent steps and allows timely transplantation in high-urgency situations. Liver Transpl 13:509–515, 2007. © 2007 AASLD.

Liver transplantation is an effective treatment for end-stage liver disease of various etiologies and the best treatment for small, unresectable hepatocellular carcinoma.1, 2 In a decade's time, live donor liver transplantation (LDLT) has become a practical alternative to deceased donor liver transplantation (DDLT). This is attributable to the refractory shortage of deceased donor liver grafts, predictable recipient survivals, and acceptable donor morbidity and mortality. Nevertheless, the inevitable donor morbidity and mortality remain the major drawbacks of LDLT, as the donors undergo major surgery for the recipients and not for themselves. The donor's gain could be only psychological by saving and improving the life of the recipient.3 This aspect remains the ethical challenge of LDLT.4, 5 Unanimously, the transplant community agreed upon the notion of safety first for the donor.6 Such tenet could be realized only by providing the voluntary live liver donor with holistic care of the highest standard achievable as soon as the option of LDLT comes into the picture. In essence, the altruistic live liver donor should be protected from any harm in excess of the donor procedure itself, which is already a major operation for a healthy human being.

The workup of the potential donor is no less a serious procedure as compared to the donor operation, as the workup itself could be conducive to profound impacts on the potential donor's psyche, decision, satisfaction, and certainly the outcome of the potential recipient. The donor workup has 3 main purposes. First, it is to ensure that the donor could undergo the donor operation with ethically acceptable and lowest possible morbidity and mortality. Second, it is to determine that a part of the donor's liver could be used reliably as a graft for the intended recipient. Third, with such knowledge, the benefit of LDLT over DDLT in each individual case in relation to the deceased donor liver graft availability and potential recipient urgency could be assessed.

We aimed to analyze and report the experience of donor workup in our center, which has a case mix of LDLT and DDLT, and two-thirds of which belong to the former group (Fig. 1). Since 1989, LDLT has progressed from the setting of clinical trials to the standard mode of treatment. The manner in which the potential donor is worked up has evolved in parallel with the recipient and donor outcomes. In our center, LDLT has been practiced as a standard treatment through technical and logistic refinement since our first case in 1993. In contrast to the impetus of other centers, LDLT for recipients of high urgency was the main impetus for initiation of our program in the early 1990s. It has since become a standard practice code in our center.7 This category of recipients includes those who are in acute, acute-on-chronic, or in chronic liver failure and on life-support. High-urgency donors are those who are worked up for these recipients. The criteria for a high-urgency candidate were comparable to those for the United Network for Organ Sharing priority status 1 category. In this study, we focused on our experience in adult-to-adult LDLT (ALDLT). The reasons for declaring a potential donor unsuitable were analyzed. Such information may guide and expedite workup for future potential donors. Results were also compared with those of other series, taking into consideration the different practices of LDLT and availability of deceased donor liver grafts.

Figure 1.

Number and proportion of liver transplantations performed each year. Dots denote adult-to-adult DDLT. Diagonal lines denote pediatric DDLT. Vertical lines denote domino liver transplantation. White areas within bars denote ALDLT. Horizontal lines denote pediatric live donor liver transplantation.

Abbreviations

LDLT, live donor liver transplantation; DDLT, deceased donor liver transplantation; ALDLT, adult-to-adult live donor liver transplantation.

PATIENTS AND METHODS

Being a tertiary referral center, the Department of Surgery of the University of Hong Kong provides a liver transplant service covering the entire territory of Hong Kong, which has a population of 6.9 million, 95% of whom are Chinese. The first DDLT was performed on October 5, 1991, and the first adult-to-child LDLT was performed on September 28, 1993. The left liver was used in our initial experience of ALDLT, which could be dated back to July 12, 1994. The first right liver ALDLT was performed in our center on May 9, 1996.8 Prospective data collection for potential donors started in January 2001. Therefore, cases from that date until December 2004 were included in this study.

The annual case load of liver transplants rose to 76 in the year 2004, among which there was 1 domino liver transplant and 55 LDLTs (42 right liver and 5 left liver ALDLTs) (Fig. 1). For ALDLT, the right liver including the middle hepatic is the workhorse of our center. Potential recipients were managed by the surgical team in conjunction with the hepatologists. At the potential-recipient evaluation stage, the patient and the family members were introduced the salient information on liver transplantation. This information included an estimated recipient hospital mortality of 5% and a 5-year overall survival of 75–80%. The estimated donor mortality of 0.5–1% and a complication rate of 15–20% were also explained. These estimates were based on the reported series and our center's experience. We acknowledged that the long-term risks to the donor of the right liver and the left liver beyond 8 and 12 years respectively were not known. To reflect the experience of our center, the number of cases of LDLT performed up to the point of the case being worked up was made known to the potential recipients and potential donors. In our region, the deceased donor liver graft donation rate has been low and remained at an average of 3 liver grafts per million population per year. The possibility of LDLT, a legitimate and realistic alternative, was therefore explicitly explained to the potential recipients and potential donors. The deceased donor liver graft scarcity was responsible for a 50% mortality of potential recipients on the waiting list9 and a 90% mortality for those who required life support.7 Patients with hepatocellular carcinoma and who fulfill the listing criteria for DDLT in general have a 20% recurrence rate for LDLT.

Once the indication for liver transplantation of the recipient was ascertained, the option of LDLT was raised again for the very reason of scarcity of deceased donor liver grafts and the high recipient mortality on waiting list. LDLT has been known to the public already as a result of wide media coverage in recent years. Hepatitis B was endemic and had a high carrier rate of 10% in our population.10 Thus, the issue of introducing LDLT was often found to be unnecessary. Nevertheless, the option of ALDLT was introduced to those who had no prior knowledge of it.

The issue of coercion of the donor is constantly avoided. The voluntary nature of the donation was therefore emphasized. When a potential donor identified himself or herself, donor evaluation proceeded in a stepwise fashion. Results of investigation were disclosed only to the potential donor directly by the transplant coordinator. Freedom of withdrawal was allowed at any stage of the donor workup. A medical reason could be provided by the medical staff on behalf of the potential donor. Potential donors were evaluated in sequence and not in a group to prevent coercion from the group itself. Blood tests would be performed simultaneously for multiple potential donors only in emergent LDLT and when the chance of rejection of the potential donor was high, as in the case of a hepatitis B carrier among siblings. The logistics of the donor workup is listed in Table 1.

Table 1. Synopsis of Workup Protocol For the Potential Live Liver Donor
  1. Abbreviations: HBsAg, hepatitis B surface antigen; HBsAb, hepatitis B surface antibody; HBcAb, hepatitis B core antibody; anti HCV, hepatitis C antibody; HIV, human immunodeficiency virus.

Step 1
Medical history:
Diabetes, hypertension, ischemic heart disease, malignancy, peptic ulcer history, mental illness.
Drug and allergy history.
Contraceptive practice for female of reproductive age (pregnancy test if sexually active).
Physical examination:
Body weight, body height, blood pressure, heart, lung, and abdominal examination.
Urinalysis.
Hematology:
Blood type and screen.
Complete blood picture, international normalized ratio, activated prothrombin time.
Biochemistry:
Liver function test, gamma glutamyl transpeptidase, amylase, renal function test, random glucose.
Serology:
HBsAg, HBsAb, HBcAb, antiHCV, HIV I/II, cytomegalovirus, varicella zoster virus.
Step 2a
Clinical psychological assessment.
Step 2b
Chest radiograph, electrocardiogram.
Computed tomography of liver with bicarbonate cover.
Volumetric analysis (right, left, & caudate lobe; and for pediatric recipients, left lateral segment).
Maximum intensity projections of hepatic veins and portal veins.
3-dimenional reconstruction of hepatic artery.
Step 3
Liver biopsy if signs of fatty liver from computed tomography.
Visceral angiogram if computed tomography angiographic features not informative.
Step 4
Informed consent of LDLT from donor and recipient.
Minor consent from a relative of the potential donor with no direct interest from the recipient.
Human leukocyte antigen typing.
Cross match.

Step 1

A detailed medical and drug history is taken to identify any medical problem that may increase morbidity or mortality from donor hepatectomy. There is a consensus in the transplant community that donors are healthy subjects.11 History of diabetes, hypertension, ischemic heart disease, malignancy within the last 5 years, and active mental disorders preclude the candidacy of donation. History of peptic ulcer disease mandates an upper endoscopy. Donation is also precluded in the presence of peptic ulcer. Allergic history is clarified. Female potential donors of reproductive age who are sexually active undergo a pregnancy test. The use of oral contraceptive pills indicates perioperative deep vein thrombosis prophylaxis by subcutaneous heparin in addition to physical means.

A body mass index higher than 30 does not automatically preclude the potential donor, but it manifests a cautionary sign for fatty liver and underlying medical problems related to obesity. Blood group compatibility is verified. Hepatitis B surface antigen positivity and hepatitis C positivity preclude donation. The presence of antibody to hepatitis B core antigen represents previous exposure to hepatitis B virus but is not an absolute contraindication for donation. However, lifelong hepatitis B prophylaxis for the recipient by nucleoside analogue reverse transcriptase inhibitor is mandatory if the recipient is hepatic B surface antigen negative.

Step 2a

While the initial screen for the genuineness of the potential donor is done by the surgical team prior to any blood test, a more comprehensive, third-party psychological assessment is performed by a dedicated clinical psychologist. Such evaluation is feasible even at odd hours should the condition of the potential recipient demand an emergent ALDLT. Knowledge of the potential donor on ALDLT is verified. This knowledge includes conversance in donor and recipient morbidity and mortality, and the urgency of the recipient requiring the transplant. The potential donor's ability to cope with the major donor operation is assessed. In addition to psychological assessment, counseling and support are also provided.

Step 2b

Chest radiograph and electrocardiogram are obtained. Computed tomography with maximum intensity projections of the portal and hepatic veins is undertaken, and 3-dimensional reconstruction of the hepatic artery is performed under sodium bicarbonate cover.12 Volumetry has been described elsewhere.13 Attenuation of the liver parenchyma on the plain film is assessed for detection of fatty change. For ALDLT, the right liver is often used unless the donor is substantially heavier than the recipient. The right liver of the donor to the estimated standard liver volume less than 35% is associated with increased recipient mortality,14 and thus donor candidacy will be cancelled. A contraindication exists if the right anterior portal vein arises from the left portal vein distal to the umbilical fissure. Presence of substantial inferior hepatic vein(s) allows anticipation during operation. Attention to the presence of segment 4b hepatic vein or segment 3 hepatic vein draining into the middle hepatic vein calls for a more caudal division of the middle hepatic vein to preserve adequate drainage of segment 4 of the remnant left liver.13 Hepatic artery anatomy is best shown by the 3-dimensional reconstructions. The replaced right hepatic artery provides a long hepatic artery segment in the graft, but the aberrant position is also predisposed to premature severing in the donor procedure. The location of the segment 4 hepatic artery is also determined.

Step 3

Suggestion of fatty change of the liver as detected by computed tomography mandates liver biopsy, which is to be done only after affirmation of suitability of the donor otherwise. A fatty change of up to 10% by histopathology is acceptable. Since case No. 140, visceral angiogram has been done only selectively if the 3-dimensional hepatic artery reconstruction does not provide enough details.

Step 4

Informed consent including donor and recipient morbidity and mortality as spelled out will be obtained from the potential donor. A minor consent is obtained from a donor relative who has no direct benefit from the recipient's operation. Human leukocyte antigen typing and cross-match are then performed.

RESULTS

From January 2001 to December 2004, 137 ALDLTs were performed in our center. The left liver was used in 8 cases. Over this 3-year period, 399 potential donors were evaluated for a total of 456 potential recipients. The ratio of potential donors to potential recipients was 0.88 (399/456). Only half of the potential recipients had 1 or more potential donors (241/456; 52.9%). The ratio of potential donors to potential recipients with 1 or more potential donors was 1.66 (399/241). Dropout of potential donors was 68% (271/399) (Table 2). The potential donor characteristics and their relationship with the potential recipients are listed in Table 3. The majority of potential donors were offspring (133/399; 33.3%) and spouses (103/399; 25.8%), followed by siblings (89/399; 22.3%).

Table 2. Overall Outcomes of Donor Candidacy
 ALDLT
  1. NOTE: Value underlined indicates high-urgency.

Potential recipients456
Potential recipients with potential donors241
Potential donors399
Ratio of potential donors to potential recipients399/456 (0.87)
Ratio of potential donors to potential recipients with at least one potential donor399/241 (1.66)
Live donor liver transplantation performed (high-urgency/elective)128 (64/64)
Potential donor dropouts271
Dropouts of potential donors271/399 (68%)
Table 3. Potential Donor Characteristics and the Donor's Relationship With the Potential Recipient
Potential Donor CharacteristicsALDLT
  • *

    Values are expressed as median with range in parentheses.

Potential donor399
Gender (M/F)165: 234
Age (yr)*35 (18–61)
Relation 
 Parent14 (3.5%)
 Grandparent0 (0%)
 Spouse103 (25.8%)
 Sibling89 (22.3%)
 Offspring133 (33.3%)
 2nd degree relative34 (8.5%)
 3rd degree relative7 (1.8%)
 Friend19 (4.8%)

Workup was conducted in a stepwise fashion. Potential donors rejected in each step and their reasons for rejection are tabulated in Figure 2. Of the 399 potential donors, 210 (52.6%) dropped out in step 1. Among them, 144/395 were either ABO incompatible or hepatitis carriers and had other medical reasons, whereas 42 withdrew voluntarily. A total of 24 potential donors dropped out because there was another suitable potential donor simultaneously.

Figure 2.

Reasons for dropout of potential donors.

Dropouts from step 2a onward were few. Only 2 potential donors were rejected following clinical psychological assessment. Of the 189 potential donors who proceeded to step 2b, 20 were rejected for reasons primarily due to liver anatomy. Inadequate size of the remnant left liver (n = 5) and fatty change (n = 7) were the main reasons for rejection. The lower limit for remnant left liver was 30%.15 Inadequate size of the graft was an uncommon reason (1 potential donor; Fig. 2). because the right liver including the middle hepatic vein was used. A lower limit of 35% of the estimated standard liver mass was adopted.14 Ultimately, 128 (32.1%) of these 399 potential donors were found suitable and underwent donor surgery.

A total of 36 adults did not proceed to LDLT because of changes in conditions of the potential recipients. Details of these unaccomplished LDLTs are listed in Table 4. Among them, 13 adults were able to undergo DDLT.

Table 4. Recipient Reasons For Adult-To-Adult Live Donor Liver Transplantation Not Accomplished
Recipient condition High-urgencyElective
Uncontrolled sepsis413
Tumor progression404
Deceased donor liver transplantation1385
Recipient declined LDLT110
Condition improved541
Neurological complication220
Uncontrolled gastrointestinal bleeding110
Multiple organ failure321
Intraoperative severe adhesions101
Myeloproliferative disease110
Respiratory failure110
Total362115

Complications During the Workup Period

No complication occurred in the donors during the workup phase. Since June 2004, donors undergoing computed tomography have received bicarbonate cover and hydration to prevent contrast-induced nephropathy.12 Visceral angiographies were performed only when 3-dimensional reconstruction of the hepatic arteries was not informative enough. No complication resulted from this invasive procedure in the minority of potential donors who underwent angiography.

High Urgency vs. Elective LDLT

Of the 456 adult potential recipients, 241 had 1 or more potential donors. These 241 potential recipients with potential donors had a transplantation rate of 58.5% (141/241). For these 141 transplants, 128 were ALDLTs and 13 were DDLTs. The rate was slightly lower than that of our study reported previously in which the transplantation rate was 72% for potential recipients who had potential donors.9 In 2000, only 9 DDLTs were performed (Fig. 1). Subgroup analysis showed that 64 (55%) of the 116 high-urgency adult potential recipients and 64 (51%) of the 125 elective adult potential recipients proceeded to ALDLT eventually (P = 0.537). More potential recipients in the high-urgency situation dropped out because of potential recipient reasons (21 vs. 15) (Table 4). Among these 21 potential recipients, 8 underwent DDLT, reflecting the deceased donor graft allocation policy of transplanting the sickest. The ultimate donation (operation) rates of donors in high-urgency and elective ALDLT were 28.4% (64/225) and 36.8% (64/174), respectively (P = 0.049). This lower potential donor operation rate in the high-urgency ALDLT was mirrored by the higher dropout rate of 71.6% (161/252) and when compared with that of 63.2% (110/174) in the elective situation. Potential donor dropouts were mainly a result of ABO incompatibility and comorbidities (Fig. 2). The time for commencement of donor workup to transplant operation was much shorter for high-urgency ADLT (0.33 [range, 0.33–31] days vs. 24 [range, 2–453] days) (P = 0.000).

DISCUSSION

All too frequently, the risks and potential harm that the potential donor faces overcast the benefit of LDLT of saving the potential donor's child, spouse, parent, and other beloved. Our data indicated that a high proportion of potential donors were subsequently determined suitable candidates and underwent the donor operation (32.1%). This finding was much in contrast with another series in which only 14% of the donors16 and 17% of the recipients17 actually proceeded to ALDLT surgery. The high rate of donors undergoing the operation in our study could be attributed to the fact that a substantial portion of the subjects had had blood tests already performed while considering for the donation. This fact particularly applies to those relatives of the potential recipients living in another region and coming to Hong Kong specifically for the donor operation. For female potential donors who had given birth to children, blood group and hepatitis status had already been known. Nevertheless, there was a slightly but significantly lower ultimate donation rate of potential donors in high-urgency ALDLT.

Under our current donor workup scheme, half of the dropouts (210/399, 52.5%) were determined in step 1. Beyond step 1, 128/189 (67.7%) potential donors eventually underwent ALDLT as donors. This percentage is higher than that of other series: 15/26 (57.7%),18 46/89 (51.7%),19 51/164 (31.1%).20 The low wastage of our series could be ascribed to a number of factors. It could well be the result of screening already done by the surgeon even before step 1. Although a structured evaluation was not actually performed by the surgeon, interpersonal reactions of the potential donor to the issue of LDLT were carefully appraised. The importance of the surgeon's experience in handling this issue was, however, hard to validate. Only 2 of the 189 potential donors were determined not suitable for psychological reasons, whereas 10 potential donors were found unsuitable due to anatomical reasons. Practically, apart from potential recipient reasons (n = 36), the remaining potential donors proceeded to operation. Therefore, in the high-urgency situation, step 1 of donor workup is logistically crucial and should be accomplished expeditiously. Among the 20 potential donors who dropped out in step 2b, 7 were excluded due to fatty liver as revealed by computed tomography. Other centers have a routine21 or a much lower threshold22 for performing liver biopsy on potential donors. Our experience counts on screening with computed tomography of the liver. Liver biopsy is not performed on potential donors with moderate-to-severe fatty change as revealed by computed tomography. It is performed only to ascertain the degree of fatty change when anticipated to be mild. Furthermore, routine liver biopsy is not practical in high-urgency ALDLT. The degree of fatty change also varies throughout the liver; thus, the biopsy result is subjected to sampling error.

Technical refinement of ALDLT both for the recipient and the donor circumvents a number of anatomical variations, rendering them contraindications no longer. Such refinement included venoplasty of the anterior and posterior branches of the right portal vein.23 Hepatic vein venoplasty to provide reliable venous outflow without compromising remnant left liver venous drainage has been adopted. A low insertion of the segment 4b hepatic vein into the middle hepatic vein posed no major problem.13 Seamless hepatic artery anastomosis under the operating microscope also gave reliable results regardless of the arterial configurations.24 Safety margin of graft size has also been extended as a result of technical innovations and skill perfection. The minimal graft size has decreased from 40%25 to 35%.14 This experience may be applied only to the right liver graft including the middle hepatic vein.

A significant portion of the recipients underwent high-urgency ALDLT. The time allowed for workup and evaluation of the donor was short, and in 1 case it took only 8 hours. There was much concern about donor coercion due to the pressing situation of the recipient's rapid deterioration. On the other hand, a gradually deteriorating recipient could as well be a constant source of uneasiness for the close family members, which arguably could be a source of pressure. Alternatively, donation from a distant relative could be more altruistic. The argument could go as far as the undirected donation from a Good Samaritan.

In conclusion, the voluntary donor should undergo careful and expeditious workup. This workup should include provision of salient information about donor risks, possible harm, and recipient benefit. Even though a live donor will not benefit from the operation physically, the loss from failure to save the recipient can result in much psychological remorse. Based on the personal values of the donor and the recipient, they both should have a say.26 Voluntarism should not be hampered by negativism from the transplant community.

Ancillary