Living Donor Transplantation
Indiana University School of Medicine
The inability to effectively halt or reverse liver fibrosis, enhance liver regeneration or maintain
liver function with artificial support systems has established liver transplantation as a standard
therapeutic modality for end-stage and fulminant liver disease. However, while the number of cadaveric
organs has plateaued off, the waiting list has grown, calling for innovative ways to provide functional
organs. Split liver transplantation and living donor liver transplantation (LDLT) are 2 such attempts to
increase the donor pool. In the former method, a cadaveric organ is split, in-vivo or ex-vivo, into the
right and left lobes to be transplanted into an adult and pediatric recipient respectively. The
disadvantages of this procedure are longer procurement times and the requirement for perfect organs.
Living donor transplantation, being an elective procedure, has the advantages of minimal preservation
injury and availability of organs at an optimal time before decompensation sets in.
Left lobe LDLT, in which the left lobe or left lateral segment from an adult donor is engrafted into a
child, was first performed in 1988. The adult left lobe provides adequate functional volume in children
and the donor quickly regenerates the lost volume. Harvesting and re-implantation of the left lobe is
relatively easier as this lobe has one portal vein, one hepatic artery and autonomous venous drainage
through the left and middle hepatic veins . The adult left lobe can provide adequate volume
for persons weighing less than 60 kgs but is not enough for an average adult. The adult right lobe, on
the other hand, provides adequate functional volume in adults, but the hilar dissection for procurement
of the right lobe is more complex, exposing the donor to considerable greater surgical risk with
tremendous ethical implications . The biological challenge is to provide adequate functional
volume in a sick recipient while, at the same time leaving behind sufficient volume in the donor.
Right lobe LDLT was first reported in the United States in 1998 . To date, approximately
1000 right lobe LDLT have been performed in the United States and account for 5% of liver transplants in
adults. Fifty percent of 84 surveyed US centers had performed at least one such procedure; fourteen
centers having performed more than 10 . The number of procedures peaked in 2001 followed by a
rapid decline in 2002 in response to a highly publicized donor death. However, the procedure is here to
stay and merely awaits refinements in public policy and procedure. The fact that there is now
considerable cumulative experience in LDLT is testimony both to continuing innovations in surgical
techniques and the inherent proliferative capacity of the liver.
What constitutes a functionally adequate graft? Volume and technical
The main objective of LDLT is to provide adequate functional liver tissue which is estimated to be one
third of standard liver mass of the recipient (>0.8% of the recipient's body weight). This volume is
either expressed as the ratio of graft weight to recipient body weight (GRBW), or as graft weight as a
percentage of standard liver mass. There is excellent linear correlation between these 2 values, and
GRBW of 1% corresponds to approximately 50% of standard liver mass. This requirement is easily met in
adult left lobe or left lateral segments (segments 2,3,4 and segments 2,3 respectively) intended for
children or recipients under 60 kgs, but is a critical issue in recipients over 60 kgs, i.e. most adult
recipients. In the initial days of right lobe LDLT, a GRBW of 1% was considered to be the ideal ratio;
but current cumulative experience allows for a minimum GRBW of 0.8% for successful transplantation.
Successful transplantation has been accomplished with smaller segments (GRBW of 0.6%) ; on the
other hand, small-for-size syndrome has been reported with GRBW of 0.7% . Host factors that
affect regeneration of the liver would expectedly affect the minimum graft volume required for
transplantation. These include the medical condition of the recipient, for e.g., a recipient with
fulminant hepatic failure has additional stressors, and requires more graft volume than a medically
The graft volume is corrected for the degree of steatosis. In cadaveric grafts, the combination of
steatosis and cold ischemia results in graft dysfunction due to microcirculatory disturbances and changes
in cell membranes. While cold ischemia is not a significant problem in LDLT, the degree of steatosis
reduces the functional mass; every 1% of steatosis reducing GRBW by 1% .
For the grafted liver segment to function, it should have adequate portal and arterial blood flow; and
proper venous and biliary drainage. Right lobe allografts usually consist of segments 5-8; extended
right lobes which consist of segments 4-8 increase the complexity of procedure for both donor and
recipient, and are associated with more donor complications . It has emerged that integrity
of the middle hepatic vein which drains segments 5 and 8 is very important for regeneration and function
of the graft. Many surgical techniques have evolved to preserve this vein using vein grafts and
fashioning them on the back table. The integrity of segment 4, on the other hand, is very important for
regeneration of the liver remnant in the donor. There is also a concerted effort to refine biliary
reconstruction and reduce the almost 30% incidence of biliary complications
Rarely, other segments of the liver have been used for LDLT: whole left lobe (segments 1-4), right
posterior segments (S6, S7) or 2 left lateral segments (S2, S3). The inclusion of segment 1 in whole
left lobe grafts (segments 1-4) adds 9% to the graft volume and 3% to GRBW. A right posterior lobes
graft (S6 and S7) provides larger volume than the left liver graft (S2, 3, 4) and accomplishes complete
venous drainage through the right hepatic vein. However, harvesting of these lobes is technically very
Utility of donor biopsy in LDLT
The role of liver biopsy as a mandatory step in donor evaluation and selection for LDLT is uncertain
at the present time, a controversy centered on the relative risks vs. benefits of this invasive
. A survey of transplant centers performing LDLT showed that 14% of centers
performed a liver biopsy in all donors and 26% not in any  (Brown).
The major utility of donor liver biopsy is in the evaluation for steatosis. The accuracy of imaging
studies in predicting hepatic steatosis is perhaps a reflection of the specific imaging modalities
. Additionally, BMI does not adequately predict degree of hepatic
. In one study, 15 of 89 potential donors were excluded on the basis of liver
biopsy that showed significant steatosis . A significant numbers of donors with a high BMI
demonstrate <10% hepatic steatosis
. It is however generally agreed that donors with
BMI<25, normal liver function tests, normal lipid profile, and no history of diabetes, hypertension or
history of excess alcohol consumption can be safely excluded from requiring a biopsy
the other hand, most centers would perform a liver biopsy on donors with BMI >25 who are otherwise
eligible for donation
Confusing the role of liver biopsies as a standard modality of evaluation is the presence of
histological changes in the majority of donors, some of which are of uncertain significance. At least 2
studies have shown the presence of histological findings in 38% and 73% of biopsies from donors with
normal biochemistry; these findings included granulomas, minimal portal inflammation ("triaditis"),
chronic hepatitis, fibrosis, variable degree of steatosis, steatohepatitis, sinusoidal dilatation and
. Obviously, not every histological deviation merits disqualification of
the donor. However, in the study by Ryan et al, 3 donors were excluded on the basis of their
histological findings; 2 patients had chronic hepatitis with fibrosis and 1 had an abnormal vascular
pattern . In the series by Tran, 3 biopsies showed >30% steatosis, 1 showed
steatohepatitis and 4, chronic hepatitis; all had normal liver function tests .
A definite role for liver biopsy exists in evaluation of living donors for a recipient with Alagille's
syndrome, an autosomal dominant condition with variable penetrability, in which close relatives may
express limited manifestations of the syndrome. In one series of transplantation for Alagille's
syndrome, 4 of 11 donors showed bile duct hypoplasia by magnetic resonance cholangiopancreatography in
the form of decreased diameter of bile ducts. Bile duct paucity was confirmed by subsequent
biopsy . There are reports of aborted operations in asymptomatic donors with normal liver
function tests and unsuspected hepatic manifestations of Alagille's syndrome . Another
report describes implantation of a segmental graft inspite of intraoperative diagnosis of bile duct
paucity. A porto-enterostomy was performed but the recipient developed cholestasis and died of
sepsis . Living donor transplantation for Alagille's syndrome may thus constitute an
absolute indication for donor liver biopsy. Another indication for donor liver biopsy in LDLT includes
elevated serum ferritin levels .
Post-transplantation biopsy pathology in LDLT
Biopsies of right lobe grafts performed to rule out rejection due to elevated liver enzymes in the
early post-operative period often show a combination of findings that include centrilobular hepatocyte
ballooning, cholestasis and biliary proliferation, in the absence of rejection or mechanical obstruction
to the bile duct. In one study, bile duct proliferation with cholestasis and cholate injury, and without
mechanical obstruction of the biliary tree was found in 29% of patients with right lobe LDLT vs. 2% of
those who received cadaveric organs . Similarly, centrilobular hepatocyte ballooning and
cholestasis were found in 13 of 25 biopsies from reduced grafts in another study  . In a
separate series of 9 patients who received right lobe grafts, 5 biopsies performed to rule out acute
cellular rejection showed centrilobular hepatocyte ballooning, canalicular cholestasis and biliary
proliferation. There was no inflammation, necrosis or acute cellular rejection. Two of these patients
had bile leaks, 1 had a stricture and the remaining 2 responded to antibiotics for
Evidence of venous outflow obstruction in the form of sinusoidal dilatation, centrilobular spotty
necrosis and central venous fibrosis (1 case) was found in 18% of patients who received right lobe LDLT;
this finding was not present in patients who received cadaveric organs . This finding might
suggest insufficient venous drainage in the regenerating liver.
Graft loss due to massive vascular engorgement and hemorrhage in zones 1 and 2 has been described in a
patient who had severe portal hypertension before transplantation, and that probably resulted from
massive portal flow in a relatively small graft. The patient subsequently received a cadaveric
There appears to be decreased incidence of rejection in recipients of right lobe
.A study of 48 pairs of patients matched for timing of transplantation, age,
gender and cause of chronic liver disease found a statistically significant difference in the rate of
acute cellular rejection between LDLT from related donors (sibling, parent, child) when compared to
cadaveric donors. This difference was not present when the living donor was not genetically related i.e.
related by marriage, friends. In the group of related LDLT, rejection tended to occur within the first 3
months and/ or 1 year following transplantation . In the series from Marcos, none of the
biopsies performed for elevation of liver function tests showed rejection, clinically significant
rejection not being found either in the earlier phase of rapid proliferation of the graft or the later
slower phase of regeneration .
End-stage liver disease due to hepatitis C (HCV) infection is the commonest indication not only for
cadaveric liver transplantation but for right lobe LDLT as well. While it is known that hepatitis C
infection recurs universally in the allograft, several studies indicate that the infection recurs earlier
and is more severe in right lobe grafts than cadaveric allografts
. A separate study
identified a risk for developing cholestatic hepatitis in patients who had received right lobe grafts.
None of the patients who received cadaveric organs developed this syndrome which was defined as serum
total bilirubin greater than 10 mg/dL, with ductular proliferation and bile stasis on liver biopsy and
without evidence of extraheptic biliary obstruction . This syndrome is characterized by
intense viral replication in serum and liver. It is believed that the actively proliferating hepatocytes
offer replicative advantages to the virus. Upregulation of IRES (internal ribosome entry site) and LDL
receptor in proliferating hepatocytes probably plays an important role, as the former is involved in
viral translation and the latter in viral entry into hepatocytes through endocytosis of the LDL
On the other hand, there are factors specific to right lobe LDLT that are expected to slow down
recurrence of hepatitis C infection. These include (1) lower requirement for immunosuppression in this
group of patients (2) easier weaning from immunosuppression  (3) younger age of donors and
(4) better pre-transplantation control of hepatitis C in the recipient .
Cadaveric grafts from donors with hepatitis C have been used for recipients with end-stage liver
disease without significant adverse effects on outcome. However, positive serology for HCV is a
contradiction to LDLT as it can be expected to complicate any future surgical intervention that the donor
may require. Additionally, regeneration in the donor remnant may accelerate the disease
After the initial disastrous results of liver transplantation for hepatitis B induced end-stage liver
disease, adequate control of the disease has been achieved through lamuvidine and HBIg, making liver
transplantation a viable option for this condition. The use of partial grafts from living donors is
tricky since the proliferative activity of hepatocytes can be expected to offer replicative advantage to
the virus as well leading to its reactivation. However, it has been reported that the use of lamuvidine
and HBIg in right lobe LDLT, as in cadaveric transplantation, can effectively control recurrence of
disease. The fact that these patients require less immunosuppression may additionally abate recurrence.
Being an elective procedure, LDLT can be to be put off until adequate control of viral DNA titres has
been achieved as this strategy offers a distinct advantage towards preventing recurrence in the
An important issue in LDLT for hepatitis B is the use of anti-HBc positive donors. The anxiety
results not only from the risk of recurrence in the recipient, but also a similar risk to the donor with
an actively replicating liver. While evidence of prior exposure to hepatitis B may be considered a
contraindication to donation in the United States
, this would significantly affect the
donor pool in other regions where hepatitis B is endemic. A study addressing this issue comes from Hong
Kong where prevalence of HBV carriers is 10% and 33.3% of the population has had past exposure as
evidenced by positivity for anti-HBc in the absence of HBsAg positivity. Since hepatitis B infection
tends to cluster in families, 54% of living donors were positive for anti-HBc so that elimination of
these donors would have significantly undermined the rationale of the program. Luckily, use of grafts
from these anti-HBc positive donors did not demonstrate any difference in post-operative AST levels and
prothrombin time between donors who were positive for anti-HBc and those who were not; however bilirubin
levels at days 6 and 7 were significantly higher in donors who were anti-HBc positive, but this
difference did not persist at 1 month. The anti-HBc positive donors were older and the impact of this
factor on the presence of cholestasis is not clear. More importantly however, these donors did not
experience clinical episodes of hepatitis or liver disease at a mean follow-up of 32 months (range 21-76
Graft function in right lobe living donor allografts
Recipients who receive partial grafts experience persistent hyperbilirubinemia following
transplantation, even when the graft size represents 60% of expected liver volume. The biopsy findings
are those of ballooning change and parenchymal cholestasis
. The bilirubin levels however,
normalize within 1 week and are subsequently no different from that seen in cadaveric grafts. Donors
have normal bilirubin levels at 1 week post-transplantation. No significant differences are observed in
levels of ALT and AST or prothrombin time between donors, recipients of partial grafts and recipients of
cadaveric grafts. Levels of factor VII were significantly different between recipients of cadaveric
grafts vs. those of partial grafts and donors for the first 3 days post-transplantation but normalized
Proliferation in right lobe living donor allografts
LDLT takes advantage of the legendary regenerative capacity of the liver, a truly unique biological
phenomenon in which a mature, terminally differentiated organ not only increases its volume
exponentially, but also miraculously stops once optimal volume is achieved. Donors for LDLT are the
first group of completely healthy individuals to undergo major hepatic resection and recipients,
especially of right lobes, the first group of patients who receive organs that are significantly smaller
than normal. In essence, LDLT is an elective technically complicated surgical procedure carried out in a
perfectly healthy individual to benefit another that is sick. So, what secrets has this experiment in
normal human regeneration, that tests the very limit of "primum non nocere", revealed so far?
Several studies show that liver regeneration begins almost immediately after transplantation and
near-normal volumes are reached within 7 -14 days
. In a 16 year old Japanese male who
received an extended left lobe (361 gm, 0.59% of body weight, 30.3% of standard liver volume) for
fulminant hepatic failure, the PCNA labeling index was 50% on post-operative day 3. HGF was expressed in
non-parenchymal cells; c-met in the cytoplasm and EGFR on the cell membranes of regenerating hepatocytes
in this liver biopsy obtained on the third post-operative day. TGF-a was negative. At 2 weeks,
regeneration was 195% in the recipient and 110% in the donor . A separate study showed
rapid increases in serum HGF and IL-6 in recipients of right lobe grafts, reaching peak levels 3 hours
after reperfusion and then declining rapidly at 6 hours to reach pre-operative levels on the second
post-operative day. Levels of TGF-b1 did not show any significant change for the 5 days of
post-operative follow-up .
A study using imaging techniques to observe hepatic regeneration found a rapid increase in the first
week following transplantation (101% increase in donors and 87% in recipients); the peak regeneration in
donors was 144% at 60 days, and 119% in recipients at 30 days . In a study of 47 follow-up CT
scans of 10 donors and 8 recipients taken for a period of 8 months – 14 months, it was observed that the
liver regenerated in the immediate post-operative period. The process was more rapid and reached a
higher peak in the recipient than the donor; the liver volume peaking in donors at 6 months (74%
increase) and at 2 weeks in recipients at 120%. The difference in volume was statistically significant
between these 2 groups at 10 days, 1 month and 2 months post-transplant but not after 2
months . Similarly, a study on left lobe adult donors showed more rapid regeneration in
pediatric recipients than their donors . This observed difference in regeneration rates
between donors and recipients has not been reported by all investigators. Furthermore, the underlying
mechanisms are uncertain but may involve pro-proliferative action of immunosuppressive drugs, or
increased portal flow in the recipient due to a persistent hyperdynamic state or denervation of the
graft. Needless to say, factors affecting regeneration are multifactorial and include medical condition
of the recipient, warm ischemia time, immunosuppression, steatosis and donor age .
In a histopathological study of liver biopsies from recipients of right lobe allografts, it was
observed that the restoration of liver volume observed by imaging studies occurs by proliferation of
mature hepatocytes as seen by an increase in the labeling index of MIB-1. The difference in the labeling
index between right lobe allografts and that of whole organ allografts was found to be statistically
significant within the first 2 months but not after that period, confirming that most of the regeneration
occurs in the immediate post-operative period. The proliferation of hepatocytes is accompanied by a
statistically significant decrease in the number of portal tracts in biopsies obtained from patients who
have received right lobe grafts when compared with those who have received cadaveric
organs . This observation raises questions about the integrity of the hepatic
microarchitecture and function over the long-term. These answers will undoubtedly be provided by LDLT
donors and recipients in the decades to come.
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- Wachs ME, Bak TE, Karrer FM et al. Adult living donor liver transplantation using a right hepatic lobe. Transplantation 1998; 66: 1313-6.
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- Marcos A, Fisher RA, Ham JM et al. Liver regeneration and function in donor and recipient after right lobe adult to adult liver transplantation. Transplantation 2000: 69: 1375-9.
- Marcos A. Right lobe living donor liver transplantation: A Review. Liver Transpl 2000; 6: 3-20.
- Ryan CK, Johnson LA, Germin BI et al. One hundred consecutive hepatic biopsies in the workup of living donors for right lobe liver transplantation. Liver Transpl 2002; 8: 1114-22.
- Rinella ME, Abecassis MM. Liver biopsies in living donors. Liver Transpl 2002; 8: 1123-5.
- Tran T, Colquhoun S, Changsri C et al. Living donor liver transplantation: The majority of donors have histologic abnormalities on liver biopsy [abstract]. Gastroenterology 2003; 124 (S): A692.
- Rinella ME, Alonso E, Rao S et al. Body mass index as a predictor of hepatic steatosis in living related liver donors. Liver Transpl 2001; 7: 409-14.
- Brandhagen D, Fidler J, Rosen C. Evaluation of the donor liver for living donor liver transplantation. Liver Transpl 2003; 9 (S): S16-28.
- Kasahara M, Kiuchi T, Inomata Y et al. Living-related liver transplantation for Alagaille syndrome. Transplantation 2003; 75: 2147-50.
- Gurkan A, Emre S, Fishbein TM et al: Unsuspected bile duct paucity in donors for living-related liver transplantation: Two case reports. Transplantation 1999; 67: 416-8.
- Trotter JF. Selection of donors for living donor liver transplantation. Liver Transpl 2003; 9 (S2): S2-S7.
- Shiffman ML, Fisher RA, Contos MJ et al. Liver histology in recipients of living donor liver transplantation (LDLT) [Abstract]
- Edmond JC, Renz JF, Ferrell LD et al. Functional analysis of grafts from living donors. Implications for the treatment of older recipients. Ann Surg 1996; 224: 544-54.
- Ayata G, Pomfret E, Pomposelli JJ et al. Adult-to-adult live donor liver transplantation: A short-term clinicopathologic study. Hum Pathol 2001; 32: 814-22.
- Liu LU, Schiano TD, Trotter JF et al. Differences in cellular rejection rates between living donor and cadaveric liver transplant recipients [abstract]. Hepatology 2001; 34: 234A
- Gaglio PJ, Malireddy S, Levitt BS et al. Increased risk of cholestatic hepatitis C in recipients of grafts from living versus cadaveric liver donors. Liver Transpl 2003; 9: 1028-35.
- Zimmerman MA, Trotter JF. Living donor liver transplantation in patients with hepatitis C. Liver Transpl 2003; 9 (S): S52-7.
- Ghobrial RM, Amersi F, Farmer DG et al. Rapid and severe early HCV recurrence following adult living donor liver transplantation [abstract]. Am J Transplant 2002; 2: 163A.
- Takatsuki M, Uemoto S, Inomata Y et al. Weaning of immunosuppression in living donor liver transplant recipients. Transplantation 2001; 72: 449-54.
- Sugawara Y, Makuuchi M, Kaneko J et al. Living donor liver transplantation for hepatitis B cirrhosis. Liver Transpl 2003; 9: 1181-4.
- Fontana RJ, Merion RM. Are we ready for marginal hepatitis B core antibody-positive living liver donors? Liver Transpl 2003; 9: 833-6.
- Lo C, Fan S, Liu C et al. Safety and outcome of hepatitis B core antibody-positive donors in right lobe living donor liver transplantation. Liver Transpl 2003; 9: 827-32.
- Kita Y, Harihara Y, Hirata M et al. Factors influencing persistent hyperbilirubinemia following adult-to-adult living-related liver transplantation. Transplant Proc 2000; 32: 2193-4.
- Eguchi S, Okudaira S, Azuma T et al. Changes in liver regenerative factors in a case of living-related liver transplantation. Clin Transplant 1999; 13: 536-44.
- Kamel IR, Erbay N, Warmbrand G et al. Liver regeneration after living adult right lobe transplantation. Abd Imaging 2003; 28: 53-7.
- Asakura T, Ohkohchi N, Satomi S. Changes of serum cytokines associated with hepatic regeneration after living-related liver transplantation. Tranplant Proc 2000; 32: 2199-203.
- Kawasaki S, Makuuchi M, Ishizone S et al. Liver regeneration in recipients and donors after transplantation. Lancet 1992; 339: 580-1.
- Olthoff KM. Hepatic regeneration in living donor liver transplantation. Liver Transpl 2003; 9 (S): S35-S41.
- Huang RQ, Schiano T, Kim P, et al. Hepatic proliferation and liver microarchitecture of right lobe allografts in adult transplant recipients [abstract]. Hepatology 2001; 34 (S): 497.
General reviews on LDLT:
- Ito T, Kiuchi T, Egawa H et al. Surgery-related morbidity in living donors of right-lobe liver graft: lessons from the first 200 cases. Transplantation 2003; 76: 158-63.
- Ghobrial RM, Amersi F, Busuttil RW. Surgical advances in liver transplantation. Living related and split donors. Clin Liver Dis 2000; 4: 553-65.
- Shiffman ML, Brown RS Jr., Olthoff KM et al. Living donor liver transplantation: Summary of a conference at the National Institutes of Health. Liver Transpl 2002; 8: 174-88.
- Miller C. Living donor liver transplantation – overview after 178 cases. Transplant Proc 2003; 35: 964-5.
- Chen C, Fan S, Lee S et al. Living-donor liver transplantation: 12 years of experience in Asia. Transplantation 2003; 75 (S): S6-11.
- Lo C. Complications and long-term outcome of living liver donors: A survey of 1,508 cases in five Asian centers. Transplantation 2003; 75 (S): S12-5.