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Keywords:

  • Donor selection;
  • heterozygous carrier;
  • mode of inheritance

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. References

Forty-six pediatric patients who underwent living donor liver transplantation (LDLT) using parental liver grafts for inheritable metabolic disorders (IMD) were evaluated to determine the outcomes of the surgery, decisive factors for post-transplant patient survival and the impact of using donors who were heterozygous for the particular disorder. Disorders included Wilson disease (WD, n = 21), ornithine transcarbamylase deficiency (OTCD, n = 6), tyrosinemia type I (TTI, n = 6), glycogen storage disease (GSD, n = 4), propionic acidemia (PPA, n = 3), methylmalonic acidemia (MMA, n = 2), Crigler-Najjar syndrome type I (CNSI, n = 2), bile acid synthetic defect (BASD, n = 1) and erythropoietic protoporphyria (EPP, n = 1). The post-transplant cumulative patient survival rates were 86.8 and 81.2% at 1 and 5 years, respectively. Post-transplant patient survival and recovery of the growth retardation were significantly better in the liver-oriented diseases (WD, OTCD, TTI, CNSI and BASD) than in the non-liver-oriented diseases (GSD, PPA, MMA and EPP) and pre-transplant growth retardation disadvantageously affected post-transplant outcomes. Although 40 of 46 donors were considered heterozygous for each disorder, neither mortality nor morbidity related to the heterozygosis has been observed. LDLT using parental donors can be recommended as an effective treatment for pediatric patients with IMD. In the non-liver-oriented diseases, however, satisfactory outcomes were not obtained by hepatic replacement alone.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. References

The use of liver transplantation (LT) has steadily increased, including for the treatment of some inborn metabolic deficiencies, irrespective of whether the liver is predominantly or only partly involved in disorder (1, 2). In some cases, however, there is a shortage of deceased donor organs and a living donor who is heterozygous for the disorder in question must be employed (3, 4). In pediatric cases of autosomal recessive disorder in particular, the donor is almost always a heterozygote because a parent is usually employed in such cases.

Between June 1990 and December 2003, 578 pediatric patients (aged less than 18 years) underwent initial living donor liver transplantation (LDLT) at Kyoto University Hospital. Of these 578, 46 underwent an LDLT using parental liver grafts for inheritable metabolic disorders (IMD). Although 24 of these cases have previously been reported (3–7), all were evaluated in the present study in order to determine their LDLT outcomes and decisive factors for post-transplant patient survival, and to clarify the impact of the use of heterozygous donors on both donors and recipients.

Patients and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. References

Forty-six pediatric patients with IMD indicated for LDLT at Kyoto University were examined in the present study. These included patients with Wilson disease (WD, n = 21; cirrhosis, 14; fulminant-type, 7), ornithine transcarbamylase deficiency (OTCD, n = 6), tyrosinemia type I (TTI, n = 6), glycogen storage disease (GSD, n = 4; type Ib, 1; type IV, 3), propionic acidemia (PPA, n = 3), Crigler-Najjar syndrome type I (CNSI, n = 2), methylmalonic acidemia (MMA, n = 2), bile acid synthetic defect of the liver (BASD, n = 1) and erythropoietic protoporphyria (EPP, n = 1) (Figure 1). Clinical records of these patients were reviewed to collect the following data: age at onset, gender, time from onset to LDLT, pre-transplant status (at home, in wards and in the intensive care unit (ICU)), the presence and degree of neurological impairments and growth retardation evaluated at the time of LDLT, ABO-blood-type matching, graft types, mode of operative procedure (auxiliary partial orthotopic liver transplantation (APOLT) or not), graft-to-recipient weight ratio (GRWR) calculated by the following formula: ((graft weight weighed after flushing the preservation solution (g)/ patient's body weight (g)) × 100 (%)), survival outcomes and neurological status, physical growth and quality of life at the latest evaluations. Neurological status was evaluated by a grading scale based on that of Whitington et al. (8) with minor modifications, as shown in Table 1. Physical growth was evaluated by comparing the weight and height of each patient with those in the standard growth curve and is expressed as a multiple of the standard deviation (SD) of the deviation from the standard curve. Growth data were classified into three subgroups, as shown in Table 1. Quality of life was classified into four subgroups also as shown in Table 1.

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Figure 1. Indications for living donor liver transplantation of 46 pediatric patients with inheritable metabolic disorders at Kyoto University.

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Table 1. Grading scale for evaluating neurological status and classification of physical growth and quality of life
  1. *Physical growth was evaluated by comparing the weight and height of each patient with those in the standard growth curve, and was expressed as a multiple of the standard deviation (SD) of the deviation from the standard curve.

Grading scale for evaluating neurological status
 Grade 0: Seems to be normal spectrum for social interaction, motor skills, language development and learning
 Grade 1: Good social interaction, full ambulation but perhaps partially impaired gross and fine motor skills, use of language, mildly delayed development, only modest learning deficits
 Grade 2: Definite social interaction, fair ambulation, though possibly limited by spasticity
 Grade 3: Limited social interaction, no bipedal ambulation, limited communication through gestures
 Grade 4: Responds to noxious stimuli, but no social interaction, no ambulation, no communication
 Grade 5: Persistent coma or vegetative state
Classification of physical growth
 Normal: More than −1SD* in height
 Slightly delayed: More than −2SD* and equal to or less than −1SD* in height
 Delayed: Equal to or less than −2SD* in height
Classification of quality of life
 Excellent: Neurological status corresponding to a score of 0 on the above scale, and receiving none of or one immunosuppressive drug and no metabolism correcting drugs
 Good: Neurological status corresponding to a score of 0 on the above scale, and receiving 2 or 3 immunosuppressive drugs and/or metabolism correcting drugs
 Fair: Neurological status corresponding to a score of 1 or 2 on the above scale, irrespective of any medication
 Poor: Neurological status corresponding to a score of 3 or more, irrespective of any medication

To clarify decisive factors for post-transplant patient survival, correlations among survival outcomes, whether each disorder predominantly involved the liver (liver-oriented disease group, LOD: WD, OTCD, TTI, CNSI and BASD; n = 36) or partly involved the liver (non-liver-oriented disease group, NLOD: GSD, PPA, MMA and EPP; n = 10), physical growth at the time of LDLT and graft-size matching evaluated by GRWR were investigated.

Whether or not each donor was a heterozygote for the recipient's disorder was determined by the mode of inheritance of each disorder (autosomal recessive inheritance for WD (3), TTI (9), GSD (10), PPA (4), MMA (4), CNSI (4) and BASD (11), autosomal dominant for EPP (12) and X-linked for OTCD (4)). In addition to our standard donor selection criteria, which have been described in detail elsewhere (13,14), some donors who were considered or suspected to be heterozygous carriers for their respective recipient's disorder underwent the following additional medical tests according to the disorder in question: for WD cases, assays for serum ceruloplasmin levels, urine copper excretion and the presence of Kayser-Fleischer corneal ring; for OTCD cases, quantitative serum amino acid analysis (QAAA) and allopurinol loading test (15,16); and for cases of PPA or MMA, serum propionic acid or methylmalonate level and the presence of metabolic acidosis confirmed by blood gas analysis. These additional tests were conducted periodically in the post-transplant period for each heterozygous carrier and each recipient of a heterozygous liver in order to study mortality or morbidity in relation to the use of heterozygous donors. Furthermore, in donor candidates for OTCD patients who showed abnormal findings in the QAAA and/or allopurinol loading test, genetic assay using peripheral blood leukocytes (17) was performed in order to confirm whether or not there were mutations in Xp21, where the ornithine transcarbamylase (OTC) gene lies. We performed genetic assay only for OTCD donors because the presentation of male hemizygotes or female heterozygotes for OTCD can range in severity from fatal neonatal hyperammonaemic coma to asymptomatic adults. Thus, we believe that such individuals require close medical vigilance for the onset of OTCD. With regard to the other autosomal recessive disorders, including the TTI, GSD, CNSI and BASD, no additional examination was performed. For all donors, the recipient's disorder, relationship of the donor to the recipient, donor age, mode of donor hepatectomy, resection rate of the donor hepatectomy calculated from the following equation: (actual graft weight weighed as stated above (g))/ (total liver volume calculated from preoperative computed tomography (CT) volumetry (mL) × 100(%) and immediate and long-term postoperative course were reviewed. In order to determine whether postoperative morbidities were related to the use of heterozygote donors, recipients of heterozygous livers were accompanied by their donors or other family members during follow-up and were asked about their pre-transplant symptoms. Heterozygous donors and other family members were also asked if they suffered symptoms similar to those of the recipients.

Follow-up was continued until January 2005 or death for both donors and recipients.

SPSS commercial statistics software was used for all statistical analyses (SPSS 12.0 for Windows; SPSS, Chicago, IL, USA). Survival was evaluated by the Kaplan-Meier life table analysis with the Breslow-Gehan-Wilcoxon test. Other variables were evaluated in a non-parametric manner. Values were shown as the median (range). The p-values of less than 0.05 were considered to be significant.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. References

Outcomes of LDLT

Seventeen of 46 patients were admitted to the ICU in the pre-transplant period: four of these 17 were admitted to the ICU for severe pre-transplant neurological impairments necessitating artificial ventilator support and the other 13 required intensive care due to severe worsening of their general condition arising from symptoms of hepatic failure other than neurological impairments (Table 2). The disorders of patients who required artificial ventilator support because of severe neurological impairments corresponding to a score of 4 or 5 on the grading scale described above were OTCD in two cases, fulminant-type WD in one and cirrhosis of WD in one. Marked pre-transplant growth retardation was observed in 16 patients; in 15 of these 16, disease onset was in early infancy. Seven of these 46 patients received ABO-incompatible liver grafts. There were 10 postoperative deaths during this study period. Six of the 10 deaths were hospital mortalities (defined as mortalities occurring during the recuperative hospital stay following the LDLT). The other four were observed during the long-term follow-up and two of these four deaths were unrelated to either the original diseases or the LDLT procedure (Table 3). Although the cause of mortality was related to biliary complications in three of the 10 patients who died (Table 3), three other patients suffering from biliary complications (anastomotic leakage in one patient and anastomotic stricture in 2) were managed with surgical and/or radiological intervention and achieved recovery. Several other postoperative surgical complications including hemoperitoneum in one patient, hepatic venous stenosis in two and portal venous stenosis in one were observed, but all of these patients also recovered after surgical and/or radiological intervention. A second LDLT was required for two patients. One of these cases was a 3-year and 8-month-old boy with GSD type IV (Table 3), who underwent initial LDLT using a maternal ABO-incompatible liver graft, which resulted in graft failure due to antibody-mediated rejection (18) arising from the ABO-incompatibility and was replaced by a paternal ABO-incompatible liver graft 6.2 months after the initial LDLT; unfortunately, the boy died of sepsis a month after the second LDLT. The other case was a 13-year-7-month-old girl who underwent an initial LDLT with a maternal ABO-compatible liver graft for cirrhosis due to WD; whereas this initial graft failed due to chronic portal vein thrombosis 126 months after the initial LDLT and was replaced by a paternal ABO-incompatible liver graft. The patient is currently doing well at 16.6 months after the second LDLT. Thirty-five of the 36 surviving patients currently show a normal neurological status corresponding to a score of 0 on our grading scale. Only one patient, a 13-year-8-month-old boy with fulminant-type WD, in whom the neurological status just before LDLT corresponded to a score of 5 on our grading scale and in whom emergency LDLT using a liver graft from his stepfather was carried out, continues to show neurological impairments pertaining to a score of 3 on our grading scale at 63.7 months after LDLT. Taking these results together, the post-transplant cumulative patient survival rates were 86.9% at 1 year and 81.2% both at 5 and 10 years (Figure 2).

Table 2. Patients' characteristics
  1. *Living donor liver transplantation; intensive care unit; represented in how far from the standard growth curve expressed as a multiple of the standard deviation; §standard deviation; Пevaluated by the grading scale as shown in Table 1; auxiliary partial orthotopic liver transplantation; **left lateral section liver graft (segments II–III according to the Couinaud's nomenclature for liver segmentations); ††left liver graft (segments II–IV); ‡‡right liver graft (segments V–VIII); §§graft-to-recipient weight ratio.

Patients' backgrounds
 Age at the onset (months)48.6 (0–196)
 Gender (Boy/ Girl)21/ 25
 Time from onset to LDLT* (months)3.9 (0.3–181)
 Age at LDLT* (months)86.5 (1.4–199)
Pre-transplant status
 At home/ in wards/ in the ICU11/18/17
Pre-transplant status of physical growth
 Height−0.35SD§
 (−9.0SD§ to +3.4SD§)
 Weight−0.40SD§
 (−9.0SD§ to +3.1SD§)
 Delayed/slightly delayed/normal16/2/28
Pre-transplant neurological statusП
 Grade 0/1/2/3/4/526/6/9/4/3/1
 APOLT/total hepatic replacement3/43
Donors for initial LDLT*
 Father/mother/stepfather22/23/1
 ABO blood type combination (Identical/compatible/incompatible)26/13/7
 Heterozygote/non-heterozygote40/6
 Graft liver (LLS**/LL††/RL‡‡)25/17/4
 GRWR§§ (%)1.35 (0.61–9.68)
Table 3. Details of the 10 dead patients
Phase of mortality Disease Gender Age at LDLT* (yr, mo)Time from onset to LDLT* (months) Cause of mortalityDuration of survival after LDLT* (months)
  1. *Living donor liver transplantation; graft-to-recipient weight ration; glycogen storage disease; §methylmalonic acidemia; ΠWilson disease; ornithine transcarbamylase deficiency; **bile acid synthetic defect of the liver.

Hospital mortalitiesTyrosinemia type IGirl0y 4m3.1Severe graft congestion due to remarkable imbalance between body and graft sizes (GRWR= 9.68%)0.6
GSD type IbBoy13y 2m156Systemic candidasis1.4
GSD type IVBoy3y 8m33.3Antibody-mediated rejection due to the use of ABO-incompatible liver graft7.2
MMA§Girl1y 1m12.3Intra-abdominal infection due to major biliary anastomotic leakage0.5
MMA§Girl12y 2m146Aspergillosis2.2
ProtoporphyriaBoy15y 6m84.3Major biliary anastomotic leakage and candidasis3.3
Late deathsWDΠ (fulminant-type)Boy16y 6m2.8Chronic cholangitis due to biliary anastomotic stricture50.7
OTCDGirl7y 2m14.1Died in a traffic accident4.2
Tyrosinemia type IGirl0y 3m3.0Died in a traffic accident18.9
BASD**Girl0y 9m8.0Hemolytic ureic syndrome caused by Escherichia coli infection5.4
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Figure 2. Cumulative post-transplant patient survival rates of living donor liver transplantation for 46 pediatric patients with inheritable metabolic disorders. Post-transplant survival of patients who underwent living donor liver transplantation for inheritable metabolic disorders at Kyoto University resulted in cumulative patient survival rates of 86.9% at 1 year and 81.2% both at 5 and 10 years.

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Decisive factors for post-transplant patient survival and evaluation of post-transplant physical growth and quality of life

Post-transplant cumulative patient survival rates were significantly better in the LOD group than in the NLOD group (Figure 3). Furthermore, post-transplant cumulative patient survival rates of patients with normal physical growth or slightly delayed physical growth at the time of LDLT were significantly higher than that of patients with delayed physical growth at the time of LDLT (Figure 4). In addition, physical growth, represented by the deviation from the standard growth curve at the time of LDLT, was significantly correlated with both the age of onset of each disorder and the time from onset to LDLT (Figure 5). Specifically, the earlier the age of onset or the longer the time from onset to LDLT in each patient, the worse the retardation of growth. An ICU-stay during the pre-transplant period did not affect post-transplant cumulative patient survival (Figure 6). Although graft-size matching was not significantly correlated with post-transplant cumulative patient survival rates, the post-transplant survival of patients with GRWR ≥ 4.0 tended to be worse than those of other patient groups (Figure 7). The age at onset of each disorder, time from onset to LDLT and physical growth evaluated at the time of LDLT were significantly younger, longer and more inhibited in the NLOD group than in the LOD group, respectively (Table 4). With regards to the 36 surviving patients, a comparison of physical growth and quality of life at the latest evaluations between patients with LOD and those with NLOD showed that physical growth was significantly better in the LOD group than in the NLOD group, whereas quality of life was similar between the two groups (Table 5). Concerning the quality of life, an excellent or good quality of life has been maintained in all surviving patients, irrespective of whether belonged to the LOD or NLOD group, with the single exception of a patient with fulminant-type WD who continues to show neurological impairments corresponding to a score of 3 on our grading scale, as stated above. With regard to the six patients in whom quality of life was determined to be not excellent but good (Table 5), all of these patients are still taking two or more immunosuppressive and/or metabolism correcting drugs. Two patients who underwent LDLT for WD developed de novo autoimmune hepatitis (19), at 18.6 months after LDLT and 87.6 months after LDLT and both of these patients are still receiving three immunosuppressive drugs (a calcineurin inhibitor (CI), azathiopurine and prednisolone), at 38.0 months and 89.6 months after LDLT, respectively. One patient who underwent LDLT for WD is still receiving CI and mycophenolate mofetil at 24.4 months after LDLT because of mild but refractory acute cellular rejection. The other three patients, all of whom underwent LDLT for PPA, are still receiving CI and carnithine supplementation (6) at 59.3 months, 29.9 months and 21.2 months after LDLT, respectively.

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Figure 3. Comparison of post-transplant survival between liver-oriented diseases (LOD) and non-liver-oriented diseases (NLOD) groups. Post-transplant cumulative patient survival rate was significantly higher in patients with LOD than in those with NLOD.

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Figure 4. Comparison of post-transplant survival among three classifications of physical growth (normal, slightly delayed and delayed) at the time of living donor liver transplantation (LDLT). Post-transplant cumulative patient survival rates of patients with normal physical growth or slightly delayed physical growth at the time of LDLT were significantly higher than that of patients with delayed physical growth at the time of LDLT.

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Figure 5. Correlation between physical growth and the age at onset of each disorder or time from onset to living donor liver transplantation (LDLT) in each patient. Physical growth represented in how far form the standard growth curve expressed as a multiple of the standard deviation (SD) at the time of LDLT was significantly correlated with both the age of onset of each disorder and the time from onset to LDLT. Namely, the earlier the age of onset in each patient was or the longer the time from onset to LDLT was, the worse the growth retardation was.

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Figure 6. Comparison of post-transplant cumulative patient survival between patients who required the intensive care unit (ICU) stay in the pre-transplant period and those who did not. ICU stay in the pre-transplant period did not affect post-transplant patient survival.

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Figure 7. Correlation between post-transplant cumulative patient survival rates and graft-size matching evaluated by the graft-to-recipient weight ratio (GRWR). Although post-transplant cumulative patient survival rates were not different among patients with a graft-to-recipient weight ratio (GRWR) < 1.0, those with 1.0 ≤ GRWR < 4.0 and those with a GRWR ≥ 4.0, post-transplant cumulative patient survival rates tended to be worse in patients with a GRWR ≥ 4.0 than in other patient groups.

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Table 4. Comparison of age at onset, time from onset to living donor liver transplantation (LDLT) and physical growth at the time of LDLT between patients with liver-oriented diseases (LOD) and those with non-liver-oriented diseases (NLOD)
 Patients with LOD* (n = 36)Patients with NLOD (n = 10) P-value
Age at onset (months)89.5 (0.1–196)1.7 (0–102).003
Time from onset to LDLT (months)3.1 (0.3–181)35.3 (3.6–156)<.001
Physical growth evaluated at the time of LDLT
Height§0SDΠ (−9.0SDΠ–3.4SDΠ)−3.0SDΠ (–6.0SDΠ–0SDΠ).001
Weight§−0.1SDΠ (–6.0SDΠ–3.1SDΠ)−2.0SDΠ (-3.0SDΠ− 4SDΠ).009
Normal/slightly delayed/delayed26/2/82/0/8.003
Table 5. Comparison of physical growth and quality of life at the latest evaluation between patients with LOD and those with NLOD in the 36 surviving patients.
 Patients with LOD* (n = 31)Patients with NLOD (n = 5) P-value
  1. *Liver oriented diseases; non-liver-oriented diseases; living donor liver transplantation; §represented in how many far from the standard growth curve expressed as a multiple of the standard deviation; Πstandard deviation.

  2. Numerical variables were evaluated by the Man-Whitney's U-test, and categorical variables were evaluated by the Fischer's exact probability test.

Observation period (months)78.7 (24.4–145.9)59.3 (21.2–133.8).533
Physical growth at the latest evaluation
Height§0.70SDΠ (−2.0SDΠ−3.9SDΠ)−2.0SDΠ (−3.0SDΠ−0.6SDΠ)< .001
Weight§0.10SDΠ (−2.0SDΠ−2.2SDΠ)−0.8SDΠ (−2.0SDΠ−2.0SDΠ).040
Normal/slightly delayed/ delayed28/2/11/1/3.001
Quality of life: excellent/ good/fair/poor27/3/0/12/3/0/0.084

Impact of the use of heterozygous donor

In addition to the 46 donors for initial LDLT, two donors were employed for a second LDLT, as stated above. Both were fathers of patients with autosomal recessive disorders. A preoperative QAAA and allopurinol loading test were performed for the six parental donors of the girls with OTCD. The former analysis revealed normal QAAA profiles in all six parents. The latter test yielded no abnormal findings in the four fathers, but the two mothers had almost twice normal upper values of peak urine orotic acid and orothidine levels after the allopurinol loading. These results suggest that these four fathers were not hemizygotes for OTCD, whereas these two mothers were determined to be heterozygotes for OTCD. As a result, 42 of the 48 donors were heterozygous carriers for the patients' disorders and the other six were non-heterozygotes. No significant differences suggesting the deleterious effects of use of the heterozygous donors on donors' postoperative course were observed between the heterozygote donors and non-heterozygote donors (Table 6). One maternal donor, 37 years of age, of a patient who underwent LDLT for WD underwent right hepatectomy, for which resection rate was 61.2% and developed postoperative bile leakage from the cut surface of the liver remnant, which necessitated biliary decompression with the use of endoscopic retrograde nasal biliary drainage. Although the bile leakage was refractory and necessitated a prolonged hospital stay of 59 days before the donor was considered cured, the leakage did not lead to serious difficulties and the donor is currently doing well at 48.2 months after LDLT without any other complications. Two maternal donors of girls with OTCD, both of whom were determined to be heterozygous for OTCD as stated above, were genetically confirmed to have mutations in Xp21, where the OTC gene lies (4), but showed normal OTC activity in liver tissues extracted during donor surgery. No genetic assay was performed in the other 40 heterozygous donors, because the usefulness of genetic evaluations for disorders other than OTCD was considered uncertain at the time of LDLT. Regardless of whether or not they were heterozygotes, no major complications have been observed in any donors. All 48 donors are currently doing well.

Table 6. Details of donors' characteristics
 Heterozygous donors (n = 42)Non-heterozygous donors (n = 6) P-value
  1. *Living donor liver transplantation; left lateral sectionectomy (segments II–III according to the Couinaud's nomenclature for liver segmentations); left hepatectomy (segments II–IV); §right hepatectomy (segments V–VIII).

Age at the time of LDLT* (years)37 (23–53)36 (27–44).338
Gender (male/female)20/225/1.114
Observation period (months)89.1 (16.6–154.9)87.8 (60.0–163.6).550
Mode of donor hepatectomy
 LLS/LL/RL§23/14/53/3/0.834
 Resection rate (%)27.4 (16.3–69.5)25.7 (21.5–34.3).820
Postoperative complications
 None/wound complications/bile leak35/6/14/1/1.265
 Long-term complications00
Postoperative hospital stay (days)9 (6–59)9 (7–13).703

Additional specific medical tests for heterozygous donors and recipients of heterozygous livers of the WD, OTCD, PPA and MMA cases have shown no problematic findings. Namely, all donors of WD cases have shown normal serum ceruloplasmin levels and undetectable levels of urine copper excretion in all evaluations and were negative for Kayser-Fleischer corneal ring. The serum ceruloplasmin level was normalized immediately after LDLT and has been maintained in all patients with WD. Urine copper excretion decreased gradually after LDLT and was completely eradicated at around 12 months post-transplantation in all WD patients; accordingly, none of the patients with WD have received no chelator of copper after 12 months. Two patients with OTCD and their heterozygous-donor mothers have shown normal QAAA profiles and almost twice the upper normal values of urine orotic acid and orothidine after allopurinol loading in all annual evaluations. Both heterozygous-donor mothers of patients with OTCD have shown neither hyperammonemia nor any episodes suggestive of hyperammonemia. No episodes of heyperammonemia without evidence of graft dysfunction were observed in either of the recipients of heterozygous livers for OTCD. Donor and recipient pairs in three of the PPA cases and two donors in MMA cases showed no episode of metabolic acidosis and neither serum propionic acid nor methylmalonate was undetectable in any of the evaluations.

Of the 36 surviving patients, 32 were matched with heterozygous donors. None of these 32 has shown any evidence of recurrence of the original diseases and symptoms they suffered in the pre-transplant period. The 42 heterozygous donors also have shown no symptoms resembling those of the patients. Although eight of the 10 patients who died received heterozygous livers, their causes of death were considered to be unrelated to the heterozygosis (Table 3). Thus, neither mortality nor morbidity related to heterozygosis was observed in either donors or recipients.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. References

The present study corroborated that LDLT could provide acceptable survival outcomes and excellent quality of life for patients with IMD, although most donors in the present study were heterozygotes for their respective recipients' disorders and further demonstrated that growth retardation at the time of LDLT disadvantageously affected the outcomes of LDLT. Particularly in our patients with NLOD, the outcomes were unsatisfactory: five of 10 patients with NLOD died. These unsatisfactory outcomes for NLOD resulted from not only the growth retardation but also the fact that extrahepatic manifestations of these disorders disadvantageously affected the postoperative course of these patients. Recently, some therapeutic options for these extrahepatic manifestations of NLOD after LT have been reported to be efficacious (10,20–23). However, all of these reported therapies were symptomatic treatments and the evidence of their efficacy seemed to be anecdotal. To achieve a satisfactory outcome in the treatment for NLOD, a breakthrough of some sort will be needed, such as development of a gene therapy (24–26) to eradicate the intrinsic underlying disorders. At this time, however, LT combined with these reported symptomatic therapies is the sole therapeutic procedure for NLOD patients with severe manifestations. Thus, to gain a better outcome, precise recognition of the optimal timing of LT is necessary. In the present study, we demonstrated that patients with growth retardation of less than −2SD in height showed significantly worse survival outcomes compared to those without growth retardation, irrespective of whether they had LOD or NLOD and growth retardation was significantly correlated with both the age of onset and the time from onset to LDLT. That is, LT must be conducted for patients with IMD before growth retardation reaches −2SD and thus in some patients with IMD, LT must be carried out in early infancy according to the disorders. At the beginning of LT as well as LDLT, infants who were unusually small missed the optimal timing for LT because their bodies were so small and thus there was a scarcity of appropriate sized livers (27,28). For the present, however, split liver graft has become a common procedure (27, 29) and monosegmental liver graft has been gaining wider acceptance even for premature neonates (28). Furthermore, we also demonstrated that the post-transplant survival of patients receiving grafts with a GRWR > 4.0 tended to be worse than that of those with a GRWR ≤ 4.0, although the difference did not reach the level of statistical significance. Application of monosegmental grafts is also reasonable for eradicating these remarkable imbalances between body and graft sizes. In addition, as far as we were able to tell, the use of heterozygous donors has no negative impact on either donors or recipients. Hence, LDLT for pediatric patients with IMD using parental liver grafts could be an ideal treatment to prevent missing the optimal timing of LT, because one of the biggest advantages of LDLT over deceased donor LT is the ability to schedule surgery. Therefore, pediatric patients with these IMDs must always be managed with consideration for the optimal timing of LT. When growth retardation becomes apparent, LDLT must be carried out immediately if a deceased donor is unavailable.

On the other hand, living liver donor morbidity appears to have increased in recent years (30, 31). However, this increasing in morbidity has been attributed mainly to the wider acceptance of right liver donation (30). In the present study, right liver donation was employed in five cases, one of which showed biliary leakage necessitating a prolonged hospital stay even if it did not lead to serious difficulties, as stated above. In some pediatric LDLT cases, right liver donation is inevitable due to the patient's age at the onset of the disorder. For example, WD can range in age of onset from infancy to adulthood. Indeed, all five of the right liver donations in the present study were implemented for patients with WD. Conversely, however, all five of the present right liver donations were performed for heterozygous carrier donors and the bile leakage in a right liver living donor mentioned above was not considered to be related to the heterozygosis. Our results suggest that right liver donation for heterozygous carrier donors as well as for non-heterozygous donors under the standard donor selection criteria as described in detail elsewhere (13,14,30) can be performed safely, though it is true that right liver donation must be more carefully performed than other types of graft. Additionally, the present results may confirm that the use of heterozygous donors has no negative impact on either donors or recipients.

Although we did not perform any preoperative genetic assays for possible heterozygous carriers in the present study, genetic and enzymatic assays of OTC using liver tissue must be included hereafter in the parental donor selection criteria for females affected with OTCD. Male hemizygotes of OTCD can range in severity from fatal neonatal hyperammonaemic coma to asymptomatic adults. Indeed, it was reported that the recipient of a liver harvested from an adult male deceased donor who had unrecognized OTCD died as a result of hyperammonemia (32). Therefore, a genetic assay is necessary to exclude male hemizygotes from blood relative donor candidates for females with OTCD, and if male hemizygotes for OTCD are identified, they must be strictly followed-up, because such individuals may themselves be candidates for LT due to their risk of developing sudden hyperammonaemic coma. On the other hand, female heterozygotes for OTCD may be used as donors only if an enzymatic assay using liver tissue shows normal OTC activity, because normal OTC activity in female heterozygotes for OTCD suggests that there is considerable degree of X-inactivation in the liver (17). With regard to disorders other than OTCD, we believe that preoperative genetic assays are not essential, because the results of the present study suggest that the use of heterozygous donors has no negative impact on either donors or recipients. However, we also recognize that the use of heterozygous carrier donors has not yet been fully verified to have no negative impact on outcomes of LDLT, and further studies including more cases and more prolonged observation periods are required. Enzymatic and/or genetic assays using liver tissue of both donors and recipients with the use of heterozygotes as donors to better understand the pathophysiology of these IMDs may help us to definitively determine whether or not the use of heterozygous donors has any negative impact. Thus, extraction of liver tissue for these assays should be mandatory. A part of the liver tissue should be used to examine the correlation between currently known genetic mutations and the clinical manifestations of these IMDs. The remainder of the liver tissue must be preserved for more advanced analyses in the future.

In conclusion, our results indicate that LDLT for pediatric patients with IMD using parental donors can be recommended as an effective treatment for pediatric patients with IMD. However, in the case of patients with NLOD, some optional treatments may be necessary to achieve a better outcome of LDLT.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. References
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