Impact of endotoxin measured by an endotoxin activity assay during liver transplantation.

BACKGROUND: Endotoxin (Et) in the portal vein blood is processed by the hepatic reticuloendothelial system. Thus, it is possible that the Et kinetics of the peripheral venous blood may be useful as a biological index that can be used to evaluate liver function. In this study, we measured Et using the endotoxin activity assay in peripheral venous blood during living donor liver transplantation (LDLT), to study its clinical significance. METHODS: Subjects were 17 patients who underwent LDLT. In the perioperative peripheral venous blood, was measured Et activity (EA) using the endotoxin activity assay at 1 or 2 d before LT, and then on 1, 5, 7, 14, and 21 postoperative days. RESULTS: Patients with infections had significantly higher EA levels compared with those without complications before LDLT and 14 postoperative days (P = 0.038 and 0.027, respectively). The average EA level of patients with infections and without complications before LT was 0.22 and 0.08, respectively (P = 0.038). Patients with an EA level higher than 0.20 before LDLT had a significantly longer period of hospitalization compared with those without complications (P = 0.038). CONCLUSIONS: A preoperative EA level more than 0.20 is a high risk factor for post-transplant infection and a prolonged period of hospitalization.

Transumbilical portal venous catheterization: a useful adjunct in left lobe living donor liver transplantation.

To improve the processes used for perfusion of the explanted graft and measuring the portal venous pressure (PVP) in adult living donor transplantation (LDLT), we performed transumbilical portal venous catheterization (TPVC) to reopen the umbilical vein and insert the catheter for seven adult patients undergoing left lobe LDLT. There were no major complications as a result of this procedure. This procedure prior to implanting the graft was derived from our experience and is a classic diagnostic technique used during liver surgery. It is a simple and effective procedure for perfusion and washout of the graft and for the safe monitoring of the intraoperative PVP. We hope that this technique for left lobe LDLT will be helpful to others using postoperative PVP monitoring, administration of therapeutic drugs through the portal vein, and temporal portal decompression by preparation of extracorporeal shunting in patients with a small-for-size graft.

Liver graft volumetric changes after living donor liver transplantation with segment 2 graft for small infants.

LT for small infants weighing <5 kg with liver failure might require innovative techniques for size reduction and transplantation of small grafts to avoid large-for-size graft, but little is known about post-transplant graft volumetric changes. Five of 172 children who underwent LDLT received monosegment or reduced monosegment grafts using a modified Couinaud's segment II (S2) graft for LDLT. Serial CT was used to evaluate the changes in the GV and other factors before LDLT and one and three months after LDLT. The shape of these grafts was classified into an OL type and an LL type. The GV increased in all patients one month after LDLT, whereas the GV decreased three months after LDLT in OL in comparison with one month after LDLT. The GRWR of the OL type has tended to decrease at three months, whereas the LL type showed a continuous increase with time, but finally they had adapted graft size for their body size. In conclusion, the volume of S2 grafts after LDLT had unique changes toward the ideal volume for the child weight when they received the appropriate liver volume.

Hepatocellular telomere length in biliary atresia measured by Q-FISH.

BACKGROUND: Liver transplantation for biliary atresia is indicated whenever a Kasai portoenterostomy is considered unfeasible. However, the timing of liver transplantation in biliary atresia has not been precisely defined. Excessive shortening of hepatocellular telomeres may occur in patients with biliary atresia, and therefore, telomere length could be a predictor of hepatocellular reserve capacity. METHODS: Hepatic tissues were obtained from 20 patients with biliary atresia who underwent LT and 10 age-matched autopsied individuals (mean age, 1.7 and 1.2 years, respectively). Telomere lengths were measured by Southern blotting and quantitative fluorescence in situ hybridization using the normalized telomere-centromere ratio. The correlation between the normalized telomere-centromere ratio for the hepatocytes in biliary atresia and the pediatric end-stage liver disease score was analyzed. RESULTS: The median terminal restriction fragment length of the hepatic tissues in biliary atresia was not significantly different from that of the control (p = 0.425), whereas the median normalized telomere-centromere ratio of hepatocytes in biliary atresia was significantly smaller than that of the control (p < 0.001). Regression analysis demonstrated a negative correlation of the normalized telomere-centromere ratio with the pediatric end-stage liver disease score in biliary atresia (p < 0.001). CONCLUSIONS: Telomere length analysis using quantitative fluorescence in situ hybridization could be an objective indicator of hepatocellular reserve capacity in patients with biliary atresia, and excessive telomere shortening supports the early implementation of liver transplantation.

The efficacy of measurement of the serum beta-D glucan in the patients with biliary atresia.

BACKGROUND: The pediatric end-stage liver disease (PELD) score is not a direct index that reflects the degree of hepatocellular injury. Beta-D glucan (BDG) in the portal vein blood is processed by the hepatic reticuloendothelial system. It is possible that the hepatic clearance of BDG may be used as a biological index to assess the liver function. In this study, the relationship between PELD score and hepatic clearance of BDG was made clear in order to study the efficacy of measurement of the serum BDG. METHODS: This study including 21 patients with biliary atresia (BA) who underwent liver transplantation (LT) was performed. The BDG was measured in the preoperative peripheral vein blood and the portal vein blood at the time of LT. RESULTS: The portal vein blood showed a significantly high level of BDG than the peripheral vein blood (p < 0.01). There was a significant negative correlation between the PELD score and the hepatic clearance of BDG in the 10 patients who were indicated for LT due to liver failure (p < 0.01). CONCLUSION: The serum BDG can be used as a biological index in place of liver metabolism and should be measured in BA patients as a non-invasive indicator of the degree of progression of liver failure.

Endovascular interventions for hepatic artery complications immediately after pediatric liver transplantation.

Hepatic artery complications after living donor liver transplantation (LDLT) can directly affect both graft and recipient outcomes. For this reason, early diagnosis and treatment are essential. In the past, relaparotomy was generally employed to treat them. Following recent advances in interventional radiology, favorable outcomes have been reported with endovascular treatment. However, there is ongoing discussion regarding the best and safe time for definitive endovascular interventions. We herein report a retrospective analysis for six children with early hepatic artery complication after pediatric LDLT who underwent endovascular treatment as primary therapy at our institution. We evaluate the usefulness of endovascular treatment for hepatic artery complication and its optimal timing. The mean patient age was 11.9 months and mean body weight at LDLT was 6.7 kg. The mean duration between the transplantation and first endovascular treatment was 5.3 days. Five of the six patients were technically successful treated by only endovascular treatment. Of these five patients, two developed biliary complications. Endovascular procedures were performed 10 times in six patients without any complications and nine of the 10 procedures were successful. By selecting optimal devices, our findings suggest that endovascular treatment can be feasible and safe in the earliest time period after pediatric LDLT.

Double-balloon enteroscopy for bilioenteric anastomotic stricture after pediatric living donor liver transplantation.

Bilioenteric anastomotic stricture after liver transplantation is still frequent and early detection and treatment is important. We established the management using double-balloon enteroscopy (DBE) and evaluated the intractability for bilioenteric anastomotic stricture after pediatric living donor liver transplantation (LDLT). We underwent DBE at Jichi Medical University from May 2003 to July 2009 for 25 patients who developed bilioenteric anastomotic stricture after pediatric LDLT. The patients were divided into two types according to the degree of dilatation of the anastomotic sites before and after interventional radiology (IVR) using DBE. Type I is an anastomotic site macroscopically dilated to five times or more, and Type II is an anastomotic site dilated to less than five times. The rate of DBE reaching the bilioenteric anastomotic sites was 68.0% (17/25), and the success rate of IVR was 88.2% (15/17). There were three cases of Type I and 12 cases of Type II. Type II had a significantly longer cold ischemic time and higher recurrence rate than Type I (P = 0.005 and P = 0.006). In conclusion, DBE is a less invasive and safe treatment method that is capable of reaching the bilioenteric anastomotic site after pediatric LDLT and enables IVR to be performed on strictures, and its treatment outcomes are improving. Type II and long cold ischemic time are risk factors for intractable bilioenteric anastomotic stricture.

Pediatric living donor liver transplantation for biliary atresia with hepatopulmonary syndrome: the gift of a second wind.

PURPOSE: Hepatopulmonary syndrome (HPS) is a progressive, deteriorating complication of end-stage liver disease (ESLD) that occurs in 13-47% of liver transplant candidates. Although LT is the only therapeutic option for HPS, it has a high morbidity and mortality, especially in patients with severe hypoxemia before transplantation, but the course of HPS after living donor liver transplantation (LDLT), especially for biliary atresia (BA) patients is not well established. PATIENTS AND METHODS: The present study evaluated 122 patients who received an LDLT for BA and of these, 3 patients had HPS at the time of LDLT in a single-center series. RESULTS: Two patients of the HPS patients them had biliary and/or vascular complications, but they recovered uneventfully with interventional treatment. None of the patients required supplemental oxygen and had no residual cardiopulmonary abnormalities at a follow-up of more than 24 months. CONCLUSION: Although a series of three patients is too small for definitive conclusion and further investigations must be conducted, pediatric LDLT can be a favorable therapeutic option for HPS.

Bowel perforation after pediatric living donor liver transplantation.

PURPOSE: Bowel perforation after liver transplantation (LT) is a rare, but highly lethal complication with a poor prognosis. Here, we report the outcome of cases of bowel perforation after pediatric LT in our department. PATIENTS AND METHODS: The study subjects were 148 patients who underwent pediatric living donor liver transplantation. The 114 with biliary atresia (BA) were divided into two groups: those with associated bowel perforation (Group A) and those without (Group B). RESULTS: Four patients in all (2.5%) suffered bowel perforation. Their original disease was BA and emergency surgery was performed in all cases, with a mortality rate of 50.0%. Comparison of Groups A and B revealed significant differences in the patient age, body weight, duration of surgery, cold ischemic time, and blood loss volume. The survival rates in Groups A and B were 50.0 and 99.1%, respectively (p < 0.01). Duration of surgery was an independent risk factor (p = 0.05). CONCLUSION: Bowel perforation after LT is a potentially fatal complication. LT is a procedure that requires care and precision, and the possibility of bowel perforation should always be borne in mind during post-operative management, when the duration of surgery has been long.

Strategy to prevent recurrent portal vein stenosis following interventional radiology in pediatric liver transplantation.

Portal vein complications after liver transplantation (LT) are serious complications that can lead to graft liver failure. Although the treatment of interventional radiology (IVR) by means of balloon dilatation for portal vein stenosis (PVS) after LT is an effective method, the high rate of recurrent PVS is an agonizing problem. Anticoagulant therapy for PVS is an important factor for preventing short-term recurrence following IVR, but no established regimen has been reported for the prevention of recurrent PVS following IVR. In our population of 197 pediatric patients who underwent living donor liver transplantation (LDLT), 22 patients (22/197, 11.2%) suffered PVS. In the 9 earliest patients, unfractionated heparin was the only anticoagulant therapy given following IVR. In the 13 more recent patients, 3-agent anticoagulant therapy using low-molecular-weight heparin, warfarin, and aspirin was employed. In the initial group of 9 patients, 5 patients (55.6%) suffered recurrent PVS and required repeat balloon dilatation. Among the 13 more recent patients, none experienced recurrent PVS (P = 0.002). In conclusion, our 3-agent anticoagulant therapy following IVR for PVS in pediatric LDLT can be an effective therapeutic strategy for preventing recurrent PVS.

Impact of acute cellular rejection on coagulation and fibrinolysis biomarkers within the immediate post-operative period in pediatric liver transplantation.

We studied restoration of the coagulation and fibrinolysis system in pediatric patients following liver transplantation and biomarkers of blood coagulation and fibrinolysis for suspecting the occurrence of acute cellular rejection. Coagulation activity recovered rapidly within two days following transplantation, but it took approximately 21-28 days for full recovery of the coagulation and fibrinolysis factors synthesized in the liver. PAI-1 levels were significantly higher in patients at the time of acute cellular rejection compared with levels after control of AR, and levels on days 14 and 28 in patients without AR. Plasma protein C and plasminogen levels at the time of rejection were significantly lower than those on day 14 in patients without AR. Statistical analysis suggested that an increase in plasma PAI-1 at a single time point in the post-operative period is a reliable marker among the coagulation and fibrinolysis factors for suspecting the occurrence of acute cellular rejection. These data suggested that appropriate anticoagulation may be required for 14 days after liver transplantation in order to avoid vascular complications and measurement of plasma PAI-1 levels may be useful for suspecting the occurrence of acute cellular rejection in pediatric patients following liver transplantation.

Diagnosis and treatment of pediatric patients with late-onset portal vein stenosis after living donor liver transplantation.

Portal vein stenosis (PVS) after living donor liver transplantation (LDLT) is a serious complication that can lead to graft failure. Few studies of the diagnosis and treatment of late-onset (> or = 3 months after liver transplantation) PVS have been reported. One hundred thirty-three pediatric (median age 7.6 years, range 1.3-26.8 years) LDLT recipients were studied. The patients were followed by Doppler ultrasound (every 3 months) and multidetector helical computed tomography (once a year). Twelve patients were diagnosed with late-onset PVS 0.5-6.9 years after LDLT. All cases were successfully treated with balloon dilatation. Five cases required multiple treatments. Early diagnosis of late-onset PVS and interventional radiology therapy treatment may prevent graft loss.

Lymphocytotoxic crossmatch in pediatric living donor liver transplantation.

To investigate the relationship between the pretransplant LCT results and the outcome after pediatric LDLT in a single center. The clinical data of 76 children undergoing 79 LDLTs including three retransplantations from May 2001 to January 2006 were retrospectively analyzed. All of the children had end-stage liver disease, and their median age was 1.4 yr (range, six months to 16.5 yr). Immunosuppressive therapy consisted of cyclosporine- or FK-based regimens with steroids. The children were classified into two groups (positive or negative) according to the pretransplant LCT results. The incidences of post-transplant surgical complications and of rejection episodes were compared. The relationship between the pretransplant LCT results and patient and graft survival rates was also analyzed. Seventy-nine pretransplant crossmatch tests were done; 13 (16.5%) were positive, and 66 (83.5%) were negative. No significant difference was found in the pretransplant clinical factors between two crossmatch groups. There was no significant difference between the groups in the incidence of vascular and biliary tract complications, in the rate of early or steroid-resistant cellular rejections, or in one- and three-yr patient (91.7%, 91.7%, respectively, in the positive group, 93.5%, 93.5%, respectively, in the negative group, p = 0.80) and graft (92.3%, 92.3%, respectively, in the positive group, 88.8%, 86.4%, respectively, in the negative group, p = 0.63) survival. The present study demonstrates that there is no reason to do pretransplant LCT to select the living donor for pediatric LDLT.

Paralysis in the left phrenic nerve after living-donor liver transplantation for biliary atresia with situs inversus.

A 7-month-old boy with biliary atresia accompanied by situs inversus and absent inferior vena cava (IVC) underwent living-donor liver transplantation (LDLT). Because a constriction in the recipient hepatic vein (HV) was detected during the preparation of the HV in LDLT, a dissection in the cranial direction and a total clamp of the suprahepatic IVC was performed, and the suprahepatic IVC and the graft HV were anastomosed end-to-end. Postoperatively, atelectasis in the left upper lobe and ventilator failure accompanied by an elevation of the left hemidiaphragm were observed and mechanical ventilation was repetitively required. Paralysis in the left phrenic nerve was diagnosed by chest radiograph and ultrasonography. In our patient, conservative treatment was administrated, because weaning him from mechanical ventilation was possible a few days after intubation and the ventilator function was expected to be improved with growth. The disease course was good, and he was discharged from the hospital at 78 days after LDLT. Complications of paralysis in the phrenic nerve after cadaveric liver transplantation have been reported to be high. Although using a conventional technique during the reconstruction of the HV may injure the phrenic nerve directly, use of the piggyback technique with preservation of the IVC is rare. Even if LDLT was undertaken, a dissection of the HV or a total clamp of the suprahepatic IVC as a conventional technique can directly injure the phrenic nerve. Therefore, a dissection of the HV or a total clamp of the suprahepatic IVC at the reconstruction of the HV in LDLT should be carefully performed, and the possibility of paralysis in the phrenic nerve should be considered in patients with a relapse of respiratory symptoms and an elevation of the hemidiaphragm after LDLT.

Effect of pediatric living-donor liver transplantation on splenomegaly.

BACKGROUND: The effect of pediatric partial liver transplantation on hypersplenism has not yet been clarified. METHODS: Fifty-five consecutive pediatric patients who underwent living-donor liver transplantation were analyzed. The volume of the spleen was measured by computed tomography, and the spleen volume-to-standard spleen volume ratio (R) was calculated in each patient. The platelet counts were examined preoperatively and at 1, 6, 12, 18, 24, 36, and 48 months after the operation. The rate of the decline in this ratio during 1 year was calculated, and correlations with clinical factors were examined. RESULTS: The ratio decreased gradually after the operation in all of the patients except for three with an eventful postoperative course. The rate of the reduction in R within 1 year after the operation was well correlated with preoperative R (R(O); P<0.0001), which led to an equation for R at n months after the operation: R(n) =(0.31-0.21R(O) )Ln(3.3n+1)+R(O). The platelet counts increased rapidly in the patients with the uneventful postoperative course. CONCLUSIONS: The normalization of spleen size can be expected with an uneventful living-donor liver transplantation. The spleen volume decreased more rapidly in patients with a larger spleen.

Advantage in using living donors with aberrant hepatic artery for partial liver graft arterialization.

BACKGROUND: In living-related partial liver transplantation, the feasibility and safety of using left-sided liver grafts from donors with aberrant hepatic arteries remains to be evaluated. METHODS: Between 1996 and 2000, we harvested left-sided liver grafts from 101 living donors. Hepatic arterial variation in the donors was classified into three types: type I (n=69), normal anatomy; type II (n=24), aberrant left hepatic artery arising from the left gastric artery; and type III (n=8), replaced right hepatic artery arising from the superior mesenteric artery. We performed arterial reconstructions using the donor's left hepatic artery in 70 cases (69 in type I, 1 in type II), an aberrant left hepatic artery in 24 cases (23 in type II, 1 in type III), and the common hepatic artery in 7 cases (all in type III). RESULTS: The diameter and length of the anastomosed hepatic artery were larger (2.5+/-0.7 vs. 2.0+/-0.8 mm, P=0.03) and longer (42.0+/-14.7 vs. 9.0+/-7.3 mm, P<0.0001) in cases in which the aberrant left hepatic artery or common hepatic artery was used for the anastomosis (n=31) than in those using the left hepatic artery (n=70). Hepatic arterial occlusion occurred in nine patients, with the incidence of occlusion tending to be lower in the former cases in which aberrant left or common hepatic arteries were used (3.2% vs. 11.4% for the left hepatic artery group, P=0.15). CONCLUSION: Because thicker and longer arterial branches can be obtained in left-sided liver grafts with aberrant hepatic arteries than in grafts with normal left hepatic arteries, their use is advantageous for safe arterialization in partial liver grafts.

Efficacy and safety of immunization for pre- and post- liver transplant children.

BACKGROUND: Infection is a serious complication after liver transplantation. Immunization is one means of controlling infections. The objective of this study was to investigate the efficacy and safety of simultaneous administration of several vaccines before transplantation and the efficacy and safety of administration under immunosuppressive conditions after transplantation. METHODS: Fifty-eight patients who underwent living-related liver transplantation between April 1994 and March 2000 were included in this study. Simultaneous administration of a maximum of six vaccines was performed in a short period of time before transplantation. We also readministered vaccines to 15 patients with waning antibody titers after transplantation from June 1999. We investigated whether patients could seroconvert for measles, rubella, mumps, and varicella after immunization and how long antibody titers could be retained by measuring them several times throughout the period before and after transplantation. We also examined side effects caused by immunization. RESULTS: The rates of seroconversion against measles, rubella, mumps, and varicella after the pretransplantation vaccination were 82%, 100%, 90%, and 95%, respectively. The rates of reseroconversion against measles, rubella, mumps, and varicella after the posttransplantation revaccination were 85%, 100%, 100%, and 71%, respectively. Although antibody titers against these viruses generally waned with time, no patient exhibited any serious illness or side effects. CONCLUSION: Although 12 of 58 patients (21%) had an infection, pretransplantation immunization was effective to prevent serious illness, especially for the 6 months after transplantation. Posttransplantation live-vaccine administration under immunosuppressive conditions is effective and safe.

Impact of graft length on surgical damage after intestinal transplantation in rats.

BACKGROUND: Intestinal grafts greatly affect nutrition and immunology in the host. The growth of the recipient and incidence of graft-versus-host disease depend on graft length. A larger graft may affect the host immune system, but little is known about how the length of the intestinal graft severely affects surgical intervention. We developed a cervical small bowel transplantation (SBT) rat model that minimized technical variations using a cuff method and studied the effects of graft length on surgical damage in SBT. MATERIALS AND METHODS: We transplanted a whole (70 cm) or partial (15 cm) intestine into a syngeneic rat combination of LEW (MHC haplotype: RT1(l)) to LEW and evaluated changes in perioperative hemodynamics and the endogenous endotoxin level. Natural killer (NK) cell activity in the peripheral blood and the immunologic response of the recipient spleen were also studied. RESULTS: In the whole SBT model, body weight loss was more severe than in the segmental SBT model; the rats in the former model often died, while all in the latter survived indefinitely. The systemic blood pressure markedly decreased in the whole SBT group immediately after reperfusion. The proliferative activity of splenic lymphocytes stimulated by concanavalin A was also more severely inhibited in the former model than in the latter postoperatively. NK cell activity in the whole SBT rats declined more severely than the segmental SBT rats 3 days postoperatively. CONCLUSION: The longer graft severely induced surgical intervention; and influenced host immunosuppression, resulting in the higher mortality in rats undergoing whole SBT.

Impact of previous multiple portoenterostomies on living donor liver transplantation for biliary atresia.

BACKGROUND/AIMS: The present study examined the impact of portoenterostomy on the morbidity and mortality of patients who later underwent living donor liver transplantation for biliary atresia. METHODOLOGY: Sixty-one consecutive patients from January 1996 to May 2001 were analyzed. They were divided into two groups according to the number of previous portoenterostomies: once (group A, n=26) and twice or more (group B, n=35). Preoperative status, mortality, morbidity, hospital duration and survival were examined and compared between the groups. RESULTS: Preoperative parameters regarding liver function and urgency status were comparable between the groups. The operation duration tended to be longer in group B than in group A (p=0.07). The blood loss and transfusion volumes in group B were greater than those in group A (p=0.03 for both comparisons). Vascular complications tended to be more frequent in group B patients. However, this difference was not significant (12% vs. 29%, p=0.06). The duration of hospitalization was longer in group B (p=0.04). Survival rates were comparable between the groups. CONCLUSIONS: Our surgical results suggest that multiple previous portoenterostomies might have negative short-term effects in patients who undergo living donor liver transplantation for biliary atresia.

[Postoperative management and complications in living-related liver transplantation].

Living-related liver transplantation is widely accepted as a treatment for patients with end-stage liver disease, with survival rates of up to 80%. Liver transplant recipients are at risk for the same postoperative complications as any patient undergoing a major intraabdominal operation, in addition to several complications specific to this procedure. Maintenance immunosuppression relies principally on administration of tacrolimus and methylprednisolone. Nevertheless, approximately 36% of liver transplant recipients suffer acute rejection in the early posttransplant period and require bolus steroid therapy as a rescue agent. Vascular complications, including hepatic arterial thrombosis and portal vein thrombosis, are additional major problems. When they occur in the immediate postoperative period, they can produce fulminant hepatic necrosis requiring retransplantation, so intensive anticoagulation therapy is needed as prophylaxis against these vascular complications. If thrombosis of the hepatic artery or portal vein is diagnosed early in the postoperative course, emergency thrombectomy with reanastomosis should be attempted. Outflow obstruction by hepatic vein stenosis sometimes causes liver dysfunction, pleural effusion, and hepatosplenomegaly. Percutaneous transhepatic or transjugular approached hepatic vein dilatation is very useful in case of hepatic vein stenosis. Recipients are generally immunocompromised secondary to immunosuppressive therapy and their poor clinical condition and are at high risk for postoperative infection. Infection is a major cause of morbidity and the most common cause of death in liver transplant recipients. Antibiotic, antifungal, and antiviral agents are used empirically, and serologic examinations and bacterial investigations of blood, sputum, stool, urine, and discharge from drains should be performed as well as antibiotic sensitivity tests when necessary. Other complications related to the operation are intraabdominal bleeding, bile leakage, biliary anastomotic stenosis, and intestinal perforation. The postoperative course of liver transplant recipients with these complications depends on making an accurate diagnosis promptly and initiating appropriate management. Postoperative complications of living-related liver transplantation are protean, so it is very important to communicate with professionals in each specialized field to ensure optimal treatment.