Late graft loss and long-term outcome after isolated intestinal transplantation in children.

BACKGROUND/PURPOSE: The aim of this study was to determine causes of late graft loss and long-term outcome after isolated intestinal transplantation in children at a single center. METHODS: All children who underwent primary isolated intestinal transplantation at our center with a minimum follow-up of 1 year were the subject of this retrospective study. RESULTS: Twenty-eight children underwent primary isolated intestinal transplantation. Median graft survival was 705 days (range, 0 to 2,630 days) and median patient survival was 1,006 days (range, 0 to 2,630 days). There were 6 deaths and 15 graft losses (including the 6 nonsurvivors). Seven of the losses occurred 6 or more months after transplant. Of these, 2 losses occurred because of death of the recipients of sepsis; both recipients had functioning grafts. The 5 remaining late graft losses occurred because of acute rejection in 2 patients, chronic rejection in 2 (1 with concomitant acute rejection) and a diffuse stricturing process without the histologic hallmarks of chronic rejection in the fifth. All late survivors with intact grafts are off total parenteral nutrition (TPN). CONCLUSIONS: Late graft loss remains a concern in a small percentage of patients after isolated intestinal transplantation. Nutritional autonomy from TPN is possible in the majority of these children after transplantation.

A new technique for combined liver/small intestinal transplantation.

The most common application of small bowel transplantation is for the patient with parenteral nutrition-induced liver failure. In this setting, the small intestine is transplanted simultaneously with the liver. We identified three technical problems that we believe contributed to complications in our first eight patients. First, pancreaticoduodenectomy was challenging in the infant donor. Second, the bowel graft was prone to volvulus around the skeletonized donor portal vein. Third, in the pediatric recipient, use of the donor bowel for Roux-en-Y biliary reconstruction was associated with biliary leaks in the early postoperative period. Our surgical technique of liver/small bowel (L/SB) transplantation has evolved since our early experience in 1990. Modifications in the L/SB operation, reported briefly in 1996 and 1997, have led to easier graft preparation and have reduced the incidence of technical complications.

Lack of utility of intestinal fatty acid binding protein levels in predicting intestinal allograft rejection.

INTRODUCTION: The enterocyte-specific protein, intestinal fatty acid binding protein (I-FABP), is detectable in serum only after intestinal injury. Previous studies in animals suggest that I-FABP might be a useful marker of intestinal allograft rejection. MATERIALS AND METHODS: I-FABP was repetitively measured in nine intestinal transplant recipients and correlated with findings of surveillance endoscopy. RESULTS: Average interval between I-FABP determination and biopsy was 3.4 days (SD=4.2 days). Average number of rejection episodes per patient totalled 1.6+/-1.2. General linear modeling demonstrated no tendency for increases in serum FABP to precede histologic graft rejection (P=0.263). Restriction of the analysis to I-FABP determinations 1 day before or on the day of biopsy failed to affect these results. Minor increases in I-FABP were often associated with histologically normal grafts, whereas rejection often occurred when I-FABP was not detectable. DISCUSSION: Serum I-FABP levels do not predict clinical intestinal allograft rejection.

Extracorporeal liver perfusion using human and pig livers for acute liver failure.

BACKGROUND: Patients with fulminant hepatic failure (FHF) often die awaiting liver transplantation. Extracorporeal liver perfusion (ECLP) has been proposed as a method of "bridging" such patients to transplantation. We report the largest experience to date of ECLP using human and porcine livers in patients with acute liver failure. METHODS: Patients with FHF unlikely to survive without liver transplantation were identified. ECLP was performed with human or porcine livers. Patients underwent continuous perfusion until liver transplantation or withdrawal of support. Two perfusion circuits were used: direct perfusion of patient blood through the extracorporeal liver and indirect perfusion with a plasma filter between the patient and the liver. FINDINGS: Fourteen patients were treated with 16 livers in 18 perfusion circuits. Nine patients were successfully "bridged" to transplantation. ECLP stabilized intracranial pressure (ICP) and cerebral perfusion pressure (CPP). Arterial ammonia levels fell from a median of 146 to 83 micromol/liter within 12 hr and this reduction was maintained at least 48 hr. Pig and human ECLP lowered ammonia levels equally. Serum bilirubin levels also fell from a median of 385 to 198 micromol/liter over the first 12 hr but the response was not sustained as well with porcine livers. There was no immunological benefit to using the the filtered perfusion circuit. INTERPRETATION: These data demonstrate that ECLP is safe and can provide metabolic support for comatose patients with fulminant hepatic failure for up to 5 days. While labor and resource intensive, this technology is available to centers caring for patients with acute liver failure and deserves wider evaluation and application.

Isolated intestinal transplantation for intestinal failure.

OBJECTIVE: Parenteral nutrition sustains life in patients with intestinal failure. However, some experience life-threatening complications from parenteral nutrition, and in these individuals intestinal transplantation may be lifesaving. METHODS: This is a retrospective review of 28 consecutive isolated small bowel transplants performed in eight adults and 20 children between December 1993 and June 1998 at the University of Nebraska Medical Center. RESULTS: The 1-yr patient and graft survivals were 93% and 71%, respectively. The causes of graft loss were hyperacute rejection (n = 1), acute rejection (n = 5), vascular thrombosis (n = 1), and patient death (n = 1). The median length of time required until full enteral nutrition was 27 days. All 28 patients have experienced acute rejection of their small bowel grafts and rejection led to graft failure in five. Jaundice and/or hepatic fibrosis was present preoperatively in 17 of the 28 recipients and hyperbilirubinemia was completely reversed in all patients with functional grafts within 4 months of transplantation. Three patients developed post-transplant lymphoproliferative disease (11%). Three recipients developed cytomegalovirus enteritis and all were successfully treated. CONCLUSIONS: Patient survival after intestinal transplantation is comparable to parenteral nutrition for patients with intestinal failure. Better immunosuppressive regimens are needed to decrease the risk of graft loss from acute rejection. The incidence of posttransplant lymphoproliferative disorder is higher after intestinal transplantation than after other solid organ transplants and the risk of cytomegalovirus enteritis is low with the use of cytomegalovirus seronegative donors. Liver dysfunction in the absence of established cirrhosis can be reversed.

Disaccharidase activities and fat assimilation in pediatric patients after intestinal transplantation.

BACKGROUND: Intestinal transplantation has become an accepted therapy for short bowel syndrome and other types of intestinal failure. In order to assess digestive capabilities and feeding practices in a group of 22 pediatric patients after intestinal transplantation, we assessed mucosal disaccharidase activities and assimilation of total dietary lipid and vitamin E. Twelve of the patients had undergone contemporaneous liver transplantation. METHODS: Mucosal biopsies were assayed for disaccharidase activities between 15 and 412 days after transplantation in 7 of the 22 when all were receiving some enteral nutrition and were free of rejection. Coefficients of lipid absorption were determined in those patients receiving total enteral feeding (two-thirds polymeric/one-third elemental) between 43 and 1032 days after transplantation; oral vitamin E tolerance tests were done at about the same time. RESULTS: Activities of lactase, sucrase, maltase, and palatinase consistently exceeded reference ranges (P<0.05). Mean coefficient of lipid absorption equaled 86+/-12% and was not influenced by duration of time after transplantation. No patient required dietary lipid restriction. No significant absorption of vitamin E was demonstrated until 160 days after transplantation. Vitamin E absorption did correlate with length of time elapsed after surgery (r=0.64, P<0.0011). CONCLUSIONS: The results of this investigation show that, in the absence of histologic or clinical indications of allograft rejection, pediatric intestinal transplant recipients do not have primary disaccharidase deficiencies. Similarly, absorption of usual dietary lipid content is adequate once weaning from parenteral nutrition is complete. In contrast, early assimilation of vitamin E is poor. Vitamin E absorption subsequently improves, but the mechanism is obscure.

Biliary atresia-polysplenia syndrome: surgical and clinical relevance in liver transplantation.

OBJECTIVE: To review a single center's 10-year experience with liver transplantation (LTx) for the biliary atresia-polysplenia syndrome (BA-PS) and to define surgical and clinical guidelines for its management. SUMMARY BACKGROUND DATA: BA is the most common indication for pediatric liver transplantation (LTx) and is associated with PS in 12% of cases. Only a few studies of LTx for BA-PS have been reported, and the optimal management of BA-PS patients undergoing LTx has yet to be determined. METHODS: From July 1985 to September 1995, 166 liver transplants were performed in 130 patients with BA and were included in the study. The malformations most commonly associated with BA-PS, surgical techniques used to overcome these anomalies, and surgical pitfalls that could have contributed to the outcome were characterized. Actuarial 10-year patient and graft survival for patients undergoing LTx for BA-PS were calculated and compared to those with isolated BA. RESULTS: Ten patients (7.8%) with BA had associated PS. An additional patient with PS without BA was included in the study. The diagnosis of PS was unknown before the transplantation in 72% of cases. Thirteen liver transplants were performed in these 11 patients. Modifications of the usual surgical technique were used to overcome the complex anatomy encountered. There was no association between the type of anomaly and the outcome, nor were there any significant differences in patient survival (72% vs. 73.5%, p = 0.79) or graft survival (56.4% vs. 54.6%, p = 0.54). CONCLUSIONS: The association of BA with various anomalies should be considered a spectrum that may vary widely from patient to patient. The finding of two or more of these malformations in a patient awaiting transplantation should lead the surgeon to look systematically for other associated anomalies. With some special surgical considerations, the outcome in BA-PS patients should not differ from those with isolated BA.

Causes of late mortality in pediatric liver transplant recipients.

OBJECTIVE: This study was undertaken to review the incidence and causes of death in children who have survived long-term (more than 1 year) after liver transplantation (LT). SUMMARY BACKGROUND DATA: No studies of the causes of late mortality in pediatric LT recipients are currently available in the literature. METHODS: The study group consists of 212 pediatric patients who survived more than 1 year after LT. Twenty-three of these patients subsequently died (mean follow-up = 5.3 yr). Hospital records, office charts, and autopsy records were reviewed retrospectively to identify the causes of death. The patients who died were further evaluated by age, gender, length of survival, primary diagnosis, immunosuppression, and retransplantation. RESULTS: The most common cause of death was graft failure, followed closely by infection. In patients dying from graft failure, eight of the nine patients underwent retransplantation and no child survived more than three liver transplants. Overwhelming infections occurred suddenly in eight children who had been previously healthy. Noncompliance was the third most common cause of death, primarily in older children. One child died from a posttransplant lymphoproliferative disorder (PTLD). Actuarial survival at 10 years is 83.7% (based on 100% survival at 1 year). There was no difference in survival based on primary disease. Retransplantation was far more prevalent in the nonsurvivors (47.8%) compared with survivors (13.7%) (p < 0.05). There were no significant differences in survival based on age, gender, or immunosuppression. CONCLUSIONS: Late mortality in children continues to be directly related to complications of LT and immunosuppression, even after the first year of transplantation. This is in contrast to adult liver transplant recipients, where approximately 50% of late deaths were related to LT and the remainder were because of unrelated illnesses.

Cerebral oedema and increased intracranial pressure in chronic liver disease.

BACKGROUND: Cerebral oedema is a cause of morbidity and mortality in fulminant hepatic failure but has not been well documented as a complication of chronic liver diseases. We report here the development of cerebral oedema and increased intracranial pressure in 12 patients with chronic liver disease. METHODS: Between July 1, 1987, and Dec 31, 1993, we studied 12 patients aged 29-67 years with end-stage chronic liver disease. All the patients had cirrhosis, portal hypertension, hypoprothrombinaemia, hepatic encephalopathy, and decreased serum concentrations of albumin (<25 g/L). During the study, the patients developed signs of increased intracranial pressure and had documented intracranial hypertension, cerebral oedema, or both. Intracranial hypertension was suspected on physical examination and confirmed by epidural catheters. We detected cerebral oedema by computed axial tomography of the head and necropsy of the brain when possible. FINDINGS: All the patients had intracranial hypertension and cerebral oedema. Two patients had successful treatment of cerebral hypertension with improvement of intracranial pressure such that orthotopic liver transplantation was undertaken. Both patients became neurologically normal after transplantation. Eight patients had only a transient response to treatment and died of cerebral oedema before a transplant could be done. INTERPRETATION: Cerebral oedema and increased intracranial pressure can occur in chronic liver disease and presents as neurological deterioration. Treatment guided by monitoring of intracranial pressure can lead to the reversal of intracranial hypertension, but in most patients cerebral oedema contributes to death or places them at too high a risk for liver transplantation.

Posttransplant eosinophilic gastroenteritis in children.

The cause of eosinophilic gastroenteropathy in older children and adults is unknown. In this report, two post-liver transplantation children treated with low-dose cyclosporine A and alternate-day low-dose prednisone are described who were administered a single bolus administration of a lympholytic dose of corticosteroids without taper and who developed intestinal symptomatology several weeks later. Histologic examination of mucosal biopsy specimens from various regions of the gastrointestinal tract showed an intense eosinophilic infiltration of the mucosa and lamina propria. The patients recovered after corticosteroid administration was tapered. Post-transplant gastroenteric eosinophilic inflammation may need to be considered in patients on immunomodulatory medications who have chronic intestinal symptomatology.

Long-term follow-up of auxiliary orthotopic liver transplantation for the treatment of fulminant hepatic failure.

BACKGROUND: Auxiliary orthotopic liver transplantation (AOLT) was investigated as a bridge to native liver recovery in patients with fulminant hepatic failure (FHF). METHODS: In the last 5 years seven patients with FHF were treated with AOLT at our institution. Five patients underwent resection of the native left lobe and orthotopic replacement with a donor left lobe (n = 3) or left lateral segment (n = 2). Two patients underwent left trisegmentectomy and whole liver auxiliary grafting. Conventional immunosuppression was used in all patients. RESULTS: One patient had poor initial graft function and required retransplantation. Native liver function returned to normal in the six other patients. Immunosuppression was gradually tapered and completely discontinued in three patients, allowing for atrophy of the allograft. The allograft was removed in the other four patients. Despite evidence of native liver regeneration, two patients with aplastic anemia died after allograft removal. Four patients are alive at a mean follow-up of 3.5 years. CONCLUSIONS: AOLT is technically feasible, rapidly restores liver function, and should be considered an important alternative to standard orthotopic liver transplantation (OLT) in the treatment of FHF. AOLT has the advantage that patients transplanted for FHF are not committed to lifelong immunosuppression with its attendant risks.

Shunt surgery during the era of liver transplantation.

OBJECTIVE: The indications for and the results of portosystemic shunts done in the authors' institution since initiation of a liver transplant program 10 years ago were reviewed. SUMMARY BACKGROUND DATA: With the widespread availability of liver transplantation as definitive treatment of chronic liver disease, the role of shunts in the overall management of variceal bleeding needs to be redefined. METHODS: Seventy-one variceal bleeders with cirrhosis who received a shunt (82% distal splenorenal shunts) because of sclerotherapy failure or because endoscopic treatment was not indicated were reviewed retrospectively. In 44 patients with well-preserved hepatic reserve, the shunt was used as a long-term bridge to transplantation (shunt group 1). The remaining 27 patients with shunts were not transplant candidates mainly because of uncontrolled alcoholism or advanced age (shunt group 2). Survival of both shunt groups was compared to that of 180 adult patients with a history of variceal bleeding who underwent transplantation soon after referral. RESULTS: Because of their more advanced liver disease, the liver transplant group had a higher operative mortality rate (19%) than did either of the shunt groups (5% and 7%, respectively) (p < 0.02). Kaplan-Meier survival analysis showed better survival in shunt group 1 (seven patients thus far transplanted) than in either the liver transplant group or shunt group 2 during the early years and superior survival of shunt group 1 and the liver transplant group as compared to shunt group 2 during the later years of the analysis. Only two patients from shunt group 1 have died of late postoperative hepatic failure without benefit of liver transplantation. CONCLUSIONS: A shunt may serve as an excellent long-term bridge to liver transplantation in patients with well-preserved hepatic reserve. Shunt surgery still plays an important role in treatment of selected patients with variceal bleeding who are not present or future transplant candidates.

Efficacy of tacrolimus as rescue therapy for chronic rejection in orthotopic liver transplantation: a report of the U.S. Multicenter Liver Study Group.

BACKGROUND: A study was performed by 17 different U.S. liver transplantation centers to determine the safety and efficacy of conversion from cyclosporine to tacrolimus for chronic allograft rejection. METHODS: Ninety-one patients were converted to tacrolimus a mean of 319 days after liver transplantation. The indication for conversion was ongoing chronic rejection confirmed by biochemical and histologic criteria. Patients were followed for a mean of 251 days until the end of the study. RESULTS: Sixty-four patients (70.3%) were alive with their initial hepatic allograft at the conclusion of the study period and were defined as the responder group. Twenty-seven patients (29.7%) failed to respond to treatment, and 20 of them required a second liver graft. The actuarial graft survival for the total patient group was 69.9% and 48.5% at 1 and 2 years, respectively. The actuarial patient survival at 1 and 2 years was 84.4% and 81.2%, respectively. Two significant positive prognostic factors were identified. Patients with a total bilirubin of < or = 10 mg/dl at the time of conversion had a significantly better graft and patient survival than patients converted with a total bilirubin > 10 mg/dl (P=0.00002 and P=0.00125, respectively). The time between liver transplantation and conversion also affected graft and patient survival. Patients converted to tacrolimus < or = 90 days after transplantation had a 1-year actuarial graft and patient survival of 51.9% and 65.9%, respectively, compared with 73.2% and 87.7% for those converted > 90 days after transplantation. The mean total bilirubin level for the responder group was 7.1 mg/dl at the time of conversion and decreased significantly to a mean of 3.4 mg/dl at the end of the study (P=0.0018). Thirteen patients (14.3%) died during the study. Sepsis was the major contributing cause of death in most of these patients. CONCLUSIONS: Our results suggest that conversion to tacrolimus for chronic rejection after orthotopic liver transplantation represents an effective therapeutic option. Conversion to tacrolimus before development of elevated total bilirubin levels showed a significant impact on long-term outcome.