Yasuhiro Fujimoto

Changes in portal venous pressure in the early phase after living donor liver transplantation: pathogenesis and clinical implications.

Background. Although living-donor liver transplantation (LDLT) has been accepted for adult populations, the occurrence and pathogenesis of small-for-size syndrome remain highly controversial. Methods. Portal venous pressure (PVP) was measured in 79 cases of LDLT from anhepatic phase to day 14. PVP was monitored through a catheter inserted via the inferior mesenteric vein. In a separate series of seven cases of adult LDLT, the splenic artery was ligated following arterial reperfusion. Results. For days 2 to 4 and 9 to 11, recipients of small-for-size graft (<0.8% of body weight) displayed significantly higher PVP than recipients of larger grafts. The 13 patients with elevated mean PVP (≥20 mm Hg) early in the first week (days 0–4) demonstrated significantly worse survival (84.5% vs. 38.5% at 6 months;P < 0.01), but this was not applicable to elevated mean PVP late in the first week (days 5–7). Elevated PVP early in the first week was also associated with higher incidence of bacteremia, cholestasis, prolonged prothrombin time, and ascites. Splenic artery ligation (SAL) immediately reduced PVP from 10 to 20 mm Hg (median, 16 mm Hg) to 9 to 13 mm Hg (median, 11 mm Hg;P = 0.02). Posttransplant PVP was significantly lower in SAL patients than in non-SAL patients from days 2 to 7 despite small graft size. Early PVP in SAL patients was consistently below 20 mm Hg, and survival was significantly better than in non-SAL patients with high early PVP (P < 0.01). Conclusion. Elevated PVP in the early phase is strongly associated with poor patient survival attributable, at least in part, to small-for-size graft. Further elucidation of the pathogenesis behind this phenomenon and efforts to modify PVP will be key to improving results.

Living-donor liver transplantation for hepatocellular carcinoma.

In cadaveric liver transplantation, the Milan criteria have been accepted as the selection criteria for hepatocellular carcinoma (HCC) patients in considering organ allocation. However, the situation is different in living-donor liver transplantation (LDLT), in which the donor has a strong preference for altruism. The authors describe herein their experience with LDLT for HCC patients using their patient selection criteria. From February 1999 to March 2002, right lobe LDLT was performed in 56 patients with HCC. The authors’ exclusion criteria included only those with extrahepatic metastasis or vascular invasion detected during preoperative evaluation. Thirty patients (54%) were in tumor, node, metastases stage IVa and 25 patients (45%) did not meet the Milan criteria at the time of LDLT. The follow-up period was 1 to 39 months (median, 11 months). The overall survival rates at 1 and 3 years were 73% and 55%, respectively, and the latter was significantly lower than that of adult right lobe LDLT without HCC (71% at 3 years). Fourteen patients died because of postoperative complications without tumor recurrence. Thirty-six patients survived without recurrence and six patients had recurrence. Among the six patients with recurrence, four had survived for 11 to 36 months after LDLT. In the analysis of patients who survived longer than 3 months after transplantation, 19 of 20 within the Milan criteria survived without recurrence. However, 15 of 20 patients beyond the criteria also survived without recurrence for 3 to 33 months (median, 12 months) and three of five patients with recurrence were alive for 11 to 36 months (median, 20 months). Histopathologic grading and microscopic portal venous invasion had significant negative impact on tumor recurrence. LDLT was an effective treatment for uncontrollable hepatocellular carcinoma. Because many patients who did not meet the Milan criteria survived without tumor recurrence after transplantation, different patient selection criteria are necessary in LDLT to save those with advanced HCC.

Impact of Sarcopenia on Survival in Patients Undergoing Living Donor Liver Transplantation

Skeletal muscle depletion, referred to as sarcopenia, predicts morbidity and mortality in patients undergoing digestive surgery. However, the impact on liver transplantation is unclear. The present study investigated the impact of sarcopenia on patients undergoing living donor liver transplantation (LDLT). Sarcopenia was assessed by a body composition analyzer in 124 adult patients undergoing LDLT between February 2008 and April 2012. The correlation of sarcopenia with other patient factors and the impact of sarcopenia on survival after LDLT were analyzed. The median ratio of preoperative skeletal muscle mass was 92% (range, 67–130%) of the standard mass. Preoperative skeletal muscle mass was significantly correlated with the branched‐chain amino acids to tyrosine ratio (r = −0.254, p = 0.005) and body cell mass (r = 0.636, p < 0.001). The overall survival rate in patients with low skeletal muscle mass was significantly lower than in patients with normal/high skeletal muscle mass (p < 0.001). Perioperative nutritional therapy significantly increased overall survival in patients with low skeletal muscle mass (p = 0.009). Multivariate analysis showed that low skeletal muscle mass was an independent risk factor for death after transplantation. In conclusion, sarcopenia was closely involved with posttransplant mortality in patients undergoing LDLT. Perioperative nutritional therapy significantly improved overall survival in patients with sarcopenia.

Surgery-related morbidity in living donors of right-lobe liver graft: lessons from the first 200 cases.

Background. Living‐donor liver transplantation (LDLT) using the left lateral segment or left‐lobe graft has been widely accepted, but currently, right‐lobe grafts are more commonly used in many LDLT programs with yet unknown risks for donors. Methods. We investigated our initial 200 donors of righ‐lobe grafts to focus on the incidence and variety of surgery‐related morbidity. Changes in liver function tests were also analyzed to clarify the relation with donor age, steatosis of the liver, and residual liver volume (RLV). Complications were surveyed for a median period of 28.7 months. Results. In all the donors, liver enzymes and bilirubin were normalized within 1 month. Enzymes on day 1 were significantly higher in donors with older age, macrovesicular steatosis, and larger RLV. Bilirubin on day 1 was significantly higher in donors with smaller RLV. Biliary enzyme was not normalized in the majority at 1 month after donation. Seventy‐five complications occurred in 69 donors. Biliary complications were most common, which consisted of 26 bile leakages (13%) and 3 biliary strictures (1.5%) in 27 donors. No significant dependence of the incidence was observed either for donor age (≥50 years), body mass index (BMI) (≥25 kg/m2), estimated RLV (<40%), or medical history. None of the complications led either to mortality or to long‐term sequelae. Conclusions. Complications occurred in a significant proportion of right‐lobe donors irrespective of donor age, BMI, estimated RLV, and medical history. Living‐liver donor surgery requires more care in right‐lobe transplants.

End-to-side portocaval shunting for a small-for-size graft in living donor liver transplantation

In the development of adult‐to‐adult living donor liver transplantation (LDLT), the small‐for‐size graft has been associated with poor clinical outcome. Persistent portal hypertension or portal venous overperfusion are considered to be causative factors, and partial diversion of portal flow to systemic circulation may be effective for avoiding injuries that occur in the small‐for‐size (SFS) graft. Recently, we constructed an end‐to‐side portocaval shunting using 1 of the portal branches and anastomosed the other branch with the portal vein of the graft in 2 cases of LDLT recipients transplanted with a SFS graft. With the suppression of portal hypertension, as well as sufficient portal flow to the graft, the recipients recovered successfully with favorable graft function. This new and simple technique may be able to be used as a feasible and effective method to attenuate the SFS syndrome. (Liver Transpl 2004;10:807–810.)

Acute humoral rejection and C4d immunostaining in ABO blood type‐incompatible liver transplantation

Complement C4d deposition in graft capillaries has been reported to be associated with antibody‐mediated rejection in kidney and other solid organ transplantation. The correlation of C4d deposits and humoral rejection in liver transplants, however, is not well understood. We investigated the C4d immunostaining pattern in 34 patients whose liver biopsy was taken within the first 3 postoperative weeks for suspected acute rejection after ABO blood type‐incompatible liver transplantation. The staining pattern was classified as positive (portal stromal staining), indeterminate (endothelial staining only), and negative (no staining). Positive C4d immunostaining was seen in 17 (50%) patients and was significantly associated with high (×64 or more) postoperative antidonor A/B antibody (immunoglobulin M (IgM)) titers (88 vs. 35%, P = 0.002) and poorer overall survival rate (41 vs. 88%, P = 0.007). Ten of 11 (91%) cases with histological acute humoral rejection (periportal edema and necrosis (PEN) or portal hemorrhagic edema) were positive for C4d, all of which showed high postoperative antibody titers. The other histologies associated with C4d positivity was purulent cholangitis (n = 4), coagulative hepatocyte necrosis (n = 1), acute cellular rejection (n = 1), and hepatocanalicular cholestasis (n = 1). Full clinical recovery was observed in only 6 of 17 (35%) C4d‐positive patients, and tended to be associated with a lower rejection activity index (RAI). In conclusion, our study indicates that C4d deposits in the portal stroma can be a hallmark of acute humoral rejection in ABO‐incompatible liver transplantation, and allograft damage can be reversible in a minority of cases. Liver Transpl 12:457–464, 2006.

Long-term outcomes of 600 living donor liver transplants for pediatric patients at a single center.

This report concerns the long‐term outcome of living donor liver transplantation (LDLT) for pediatric patients at a single center. Between June 1990 and December 2003, a total of 600 LDLTs, including 568 primary transplantations and 32 retransplantations, were performed for pediatric patients, who were immunosuppressed with FK506 and low‐dose corticosteroids. Patient survival at 1, 5, and 10 years were 84.6%, 82.4%, and 77.2%, respectively, and the corresponding findings for graft survivals were 84.1%, 80.9%, and 74.5%. Multivariate analysis demonstrated that fulminant hepatic failure (FHF), a graft vs. body weight (GBWR) ratio of <0.8, and ABO‐incompatible transplants were independently associated with both patient and graft survival. The retransplantation rate was 6%, and 55 patients (9.7%) have been completely weaned off immunosuppressants. Long‐term patient and graft survival after pediatric LDLT for a large cohort of children at our hospital were found to be as good as those for cadaveric liver transplantation, although this series includes 13% liver transplantations with ABO‐incompatible donors, which are obviously inferior in patient and graft survival. To obtain better outcomes for patients with FHF and for patients with ABO‐incompatible transplants, immunosuppressive therapy needs to be improved. Liver Transpl 12:1326‐1336, 2006.

Simultaneous Quantification of Epstein-Barr Virus, Cytomegalovirus, and Human Herpesvirus 6 DNA in Samples from Transplant Recipients by Multiplex Real-Time PCR Assay

ABSTRACT We developed a multiplex real-time PCR assay using 6-carboxyfluorescein, 6-carboxy-4′,5′-dichloro-2′,7′-dimethoxyfluorescein, and carbocyanine 5-labeled probes to simultaneously quantify Epstein-Barr virus (EBV), cytomegalovirus (CMV), and human herpesvirus 6 (HHV-6) DNA. When previously tested and stored DNA samples were examined, results of the multiplex real-time PCR assay were as sensitive and specific as those of a single real-time PCR assay. The multiplex assay was used to quantify the EBV, CMV, and HHV-6 DNA in 46 transplant recipients. A total of 303 whole-blood and plasma specimens were collected and analyzed. According to the results of the multiplex assay, the detection rates for viral DNA in whole blood and plasma were 23.8% and 5.9% for EBV, 11.2% and 5.3% for CMV, and 12.5% and 2.0% for HHV-6, respectively. All forms of viral DNA were detected more frequently in whole blood than in plasma. During the symptomatic period, EBV DNA was detected in all whole-blood specimens but not in all plasma specimens. Furthermore, the EBV DNA load in whole blood was higher during the symptomatic period than during the asymptomatic period, whereas the EBV DNA load in plasma was similar for both periods. These results demonstrate that whole blood is more suitable for the quantification of EBV DNA in transplant patients. However, a cutoff value with clinical relevance still needs to be determined.

Living-donor liver transplantation with monosegments.

Background. Living-donor liver transplantation is now an established technique to treat children with end-stage liver disease. Implantation of left-lateral segment grafts can be a problem in small infants because of a large-for-size graft. We report 10 cases of transplantation using monosegment grafts from living donors. Method. Of 506 children transplanted between June 1990 and June 2002, 10 patients (median age 196 days, median weight 5.9 kg) received monosegment living-donor liver transplants. The indication for using this technique was infants with an estimated graft-to-recipient weight ratio of over 4.0%. Results. Graft and patient survival was 80.0%. There were no differences in donor operation time and blood loss between monosegmentectomy and left-lateral segmentectomy (n=281). Monosegmental transplantation had a high incidence of vascular complications (20.0%). Conclusion. Monosegmental living- donor liver transplantation is a feasible option with satisfactory graft survival in small babies with liver failure.

Impact of Right Lobe with Middle Hepatic Vein Graft in Living-Donor Liver Transplantation

Technical improvements in adult‐to‐adult living‐donor liver transplantation (LDLT) have led to the use of right‐lobe grafts to overcome the problems encountered with ‘small‐for‐size grafts’. The major controversy remains that the venous drainage from anterior segment substantially depends on tributaries of the middle hepatic vein (MHV), and deprivation of such tributaries may critically influence the postoperative graft function. Right‐lobe grafts with MHV could resolve the potential problem of congestion in anterior segment. From December 2000 to January 2004, we performed 217 right‐lobe LDLTs for adult patients. Of these, 40 patients received a right lobe with MHV graft (18.4%). The overall cumulative 3‐year graft survival rate of a right lobe with (n = 40) and without MHV (n = 177) was 86.2% and 74.8% (p = NS). The proximal side of the MHV and the drainage vein of segment IV to the MHV (the left medial superior vein) were preserved in 24 patients. All of them needed venous interposition graft for anastomosis. All patients had a patent right hepatic vein (RHV) and MHV anastomosis during the follow‐up period. We adopted the right lobe with MHV graft in 40 LDLT cases. Vein graft is essential for safe MHV anastomosis in cases which preserve proximal side of the MHV.