Liver transplantation followed by allogeneic hematopoietic stem cell transplantation for atypical mevalonic aciduria.

Mevalonic aciduria because of mutations of the gene for mevalonate kinase causes limited synthesis of isoprenoids, the effects of which are widespread. The outcome for affected children is poor. A child with severe multisystem manifestations underwent orthotopic liver transplantation at age 50 months for the indication of end-stage liver disease. This procedure corrected liver function and eliminated portal hypertension, and the patient showed substantial improvement in neurological function. However, autoinflammatory episodes continued unabated until hematopoietic stem cell transplantation was performed at 80 months. Through this complex therapy, the patient now enjoys a high quality of life without significant disability.

Genetic predisposition to the metabolism of irinotecan (CPT-11). Role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes.

Irinotecan (CPT-11) is a promising antitumor agent, recently approved for use in patients with metastatic colorectal cancer. Its active metabolite, SN-38, is glucuronidated by hepatic uridine diphosphate glucuronosyltransferases (UGTs). The major dose-limiting toxicity of irinotecan therapy is diarrhea, which is believed to be secondary to the biliary excretion of SN-38, the extent of which is determined by SN-38 glucuronidation. The purpose of this study was to identify the specific isoform of UGT involved in SN-38 glucuronidation. In vitro glucuronidation of SN-38 was screened in hepatic microsomes from normal rats (n = 4), normal humans (n = 25), Gunn rats (n = 3), and patients (n = 4) with Crigler-Najjar type I (CN-I) syndrome. A wide intersubject variability in in vitro SN-38 glucuronide formation rates was found in humans. Gunn rats and CN-I patients lacked SN-38 glucuronidating activity, indicating the role of UGT1 isoform in SN-38 glucuronidation. A significant correlation was observed between SN-38 and bilirubin glucuronidation (r = 0.89; P = 0.001), whereas there was a poor relationship between para-nitrophenol and SN-38 glucuronidation (r = 0.08; P = 0.703). Intact SN-38 glucuronidation was observed only in HK293 cells transfected with the UGT1A1 isozyme. These results demonstrate that UGT1A1 is the isoform responsible for SN-38 glucuronidation. These findings indicate a genetic predisposition to the metabolism of irinotecan, suggesting that patients with low UGT1A1 activity, such as those with Gilbert's syndrome, may be at an increased risk for irinotecan toxicity.

Evidence against an abnormal hepatic microsomal lipid matrix as the primary genetic defect in the jaundiced Gunn rat.

The congenitally jaundiced Gunn rat does not conjugate bilirubin but does conjugate bilirubin dimethyl diester. Partial defects in conjugating p-nitrophenol and demethylating aminopyrine are also evident. A proposed mechanism to explain this combination of findings is a defective microsomal membrane. To examine the 'matrix' of Gunn microsomal membranes, hepatic microsomes were isolated from Gunn (jj) and outbred Wistar (JJ) rats and were studied by electron paramagnetic resonance spectroscopy of 7-doxylstearic and 12-doxylstearic acid probes, fluorescence polarization of 1,6-diphenyl-1,3,5-hexatriene, glucose-6-phosphatase activity vs. temperature, and lipid analysis. The data indicate several factors related to lipid bilayer order do not differ in microsomes from jj and JJ.

The effect of two intravenous fat emulsions and their components on bilirubin binding to albumin.

The effect of two intravenous lipid emulsions on the binding of bilirubin to albumin was investigated in vitro. Various concentrations of a soybean (Intralipid) or a safflower (Liposyn) oil emulsion in 0.48 mM albumin were assayed for changed in bilirubin displacement using Sephadex G-25 gel filtration and for alternations of albumin reserve binding capacity by a novel difference spectroscopy technique. Two major components of the emulsions, glycerol and egg phosphatides, were also assayed by difference spectroscopy. A significant enhancement of the total reserve bilirubin binding capacity of albumin was noted with concentrations of 200 to 500 mg/100 ml lipid emulsion using difference spectroscopy. Using salicylate to block secondary albumin binding sites for bilirubin, reserve bilirubin binding capacity at nonsalicylate competitive sites was shown to have increased (maximum 61%) over the range of 50 to 1000 mg/100 ml lipid emulsion. Only changes in nonsalicylate competitive binding sites could be detected at concentrations normally achieved in vivo. Egg phosphatides had little effect and glycerol decreased reserve bilirubin binding capacity. Sephadex studies were unable to detect any significant change in bilirubin retained on the column with 50 or 500 mg/100 ml lipid emulsion at any bilirubin/albumin ratio. The enhancement of reserve bilirubin binding capacity caused by lipid emulsions is mediated through changes in nonsalicylate competitive albumin binding sites. Product differences demonstrated in vitro point out the complexity of their effects on bilirubin-albumin binding and the necessity for in vivo investigations with structurally different nutritional products designed for use in newborns.

Prognostic implications of centrilobular necrosis in pediatric liver transplant recipients.

BACKGROUND: We have observed centrilobular necrosis (CLN) in several liver allograft biopsies in our pediatric liver transplant population. The aims of this study were to describe the associated pathologic and clinical features of post-orthotopic liver transplantation CLN and determine its prognostic implications. METHODS AND RESULTS: CLN was identified and characterized in 44 allografts from 40 patients (17 males and 23 females) among our 443 pediatric recipients. Twenty episodes were associated with cellular rejection, either in the same biopsy (n=15) or within the week prior (n=5), and five were associated with ductopenic rejection. Twelve were associated with vascular thrombosis. No clear etiology was identified in seven episodes, but two also had cholangitis lenta. Of the remaining five biopsies, three showed only centrilobular dropout, suggesting a resolution of some previous insult. The outcome of 40 patients following an initial episode of CLN was poor, with graft failure in 33, chronic poor function in 2, and normal recovery in only 5 patients. The results of retransplantation for graft failure due to CLN were equally poor, with 14 deaths, 3 patients with ductopenic rejection, and only 5 with normal recovery. CLN recurred in four grafts. Overall patient outcome was very poor: 25 deaths; 3 ductopenic rejections; 2 chronic poorly functioning livers; and 10 patients alive and well. CONCLUSION: We conclude that CLN in pediatric orthotopic liver transplantation recipients is associated with cellular rejection, ductopenic rejection, or acute vessel thrombosis in the majority cases. The prognostic implications of CLN are grave, with high rates of graft failure requiring retransplantation and death.

Liver transplantation with reduced-size donor organs.

Orthotopic liver transplantation (OLT) of the pediatric patient is often limited by the availability of a size-matched donor organ. Use of reduced liver transplantation (RLT) can increase the proportion of candidates transplanted and may reduce overall mortality. We report herein the initial clinical application of RLT in the United States. Indications for RLT included fulminant hepatic failure (n = 2), acute hepatic artery thrombosis (n = 3), and chronic liver disease unresponsive to inpatient support and more than 30 days on transplant list (n = 4). Donor hepatectomy was performed using standard techniques. Formal hepatic resection was performed ex-vivo to create a size-matched graft, from the larger donor organ, which was implanted in the orthotopic position. Between 11/84 and 4/87, 70 pediatric patients were evaluated for OLT, and 33 of these were transplanted. During this period only 5 patients (7%) died awaiting OLT. Of 33 patients treated at the University of Chicago, 5 received RLT. Donor: recipient weight ratios ranged from 2:1 to 8.1:1. For RLT median operative blood loss was 1.7 blood volumes (range 0.5-11.7) with an operative time of 9.3 + 3.5 hr. Acceptable early graft function was observed in five patients, all of whom were discharged from the hospital. Four of these five patients are alive between 2 and 48 months after transplantation. Marginal graft function with cholestasis and coagulopathy was associated with acute intracranial hemorrhage and neurologic death in one case. One patient died intraoperatively with non-function caused by the use of a liver from a donor with steatosis and a poor size match. Another patient died on day 5 with primary nonfunction and persistent hemorrhage. Systemic cytomegalovirus infection was the cause of death in the other two cases. RLT can provide life-sustaining liver function in urgent clinical settings. The graft can serve as a temporary or permanent liver replacement. With evolution of the technique RLT could eventually be offered to more elective candidates and increase the utilization of available donors by reducing size limitations in OLT.

Improved results of living-related liver transplantation with routine application in a pediatric program.

Living related liver transplantation (LRT) was introduced as a response to the shortage of donor organs that has existed for small children. Results were promising in the initial experience, with a one-year patient survival of 80% and a graft survival of 75%. Since the completion of the protocol, LRT has been considered routinely in the management of children in our center. We present here our experience with 45 consecutive transplants in which LRT accounts for 40% of grafts with an overall patient survival of 90%. Between 4/91 and 4/92, 45 OLT were performed in 41 children. Median age was 2.7 years (3 months to 13 years) and weight was 10.4 kg (3.5-60 kg). Thirty-five were primary grafts, 10 were retransplants. One patient received 2 grafts in the orthotopic auxiliary position. Cholestatic disorders including biliary atresia accounted for 60%, metabolic diseases for 15%. Grafts were obtained from cadaver donors in 27/45 (60%) cases; reduction was required in 12/27 (44%). LRT was performed in 18 cases. Fifty-two percent of recipients of cadaver grafts were UNOS status 4, while 16% of LRT recipients met these criteria. Actual patient survival for cadaver grafts is 21/24 (88%) and graft survival is 20/27 (74%). Patient survival in 18 LRT was 94%. Two grafts were lost to arterial thrombosis for a graft survival of 83%. All donors have been discharged and are well. One patient, a teenager with fulminant hepatitis, was successfully transplanted with a left lobe from his father. This experience demonstrates the programmatic flexibility accorded by use of LRT. Since 40% of grafts were LRT, more livers were available for urgent use for patients who did not have a donor available, as reflected in the 73% incidence of cadaver recipients on status 3 or 4. Therefore, patients are more likely to receive a transplant at the optimal time. We are now prepared to offer LRT for fulminant hepatic failure since the benefit of graft availability appears to outweigh concerns about coerced donation. The successful treatment of a teenaged patient may herald extension of LRT to adults. We conclude that the use of LRT should be expanded.

Biliary complications in pediatric liver transplantation. A comparison of reduced-size and whole grafts.

One of the major changes in liver transplantation has been the application of reduced-size liver transplants(RLT). RLT has the great advantage of expanding the donor pool up to ten times the weight of the recipient, thereby decreasing pretransplant mortality in the pediatric age group. It has been suggested that RLT is a risk factor for biliary complications. To analyze the role of RLT and biliary complications, the results of 213 consecutive liver transplants in 164 pediatric patients over a 6-year period will were reviewed. These included 113 whole-liver transplants and 100 reduced-size liver transplants (49 reduced cadaveric liver transplants (RCLT), 38 split-liver transplants (SLT) and 13 living-related liver transplants (LRLT). The average weight and age were significantly higher in recipients receiving whole-size grafts (average weight 18.4 mg, average age 4.9 years) than in those receiving reduced size grafts (average age 2.3 years, average weight 11.1 kg). Biliary reconstruction consisted of Roux-en-Y, cholangiojejunostomy (n = 203) or choledochocholedochostomy (n = 10). There were 29 total biliary complications, (13.6%) with no significant difference in the complication rate between the whole (n = 13, 11.5%) or reduced livers (n = 16, 16%). Biliary leakage was the most common complication (n = 20), and it occurred at the biliary enteric anastomoses (n = 10), the roux limb (n = 7), or at the cut edge (n = 3). Of the leaks occurring at the biliary enteric anastomoses, 50% were caused by hepatic artery thrombosis. Biliary obstruction accounted for their remaining complications (n = 9) or 4.2%. Actuarial survival from 6 years to a minimum of two months of follow-up was 73% in the whole-size and 70% in reduced-size liver transplants. This series demonstrates that the incidence of biliary complications is similar in reduced-size and full-size grafts. No grafts were lost to biliary complications in the absence of hepatic artery thrombosis.

Hepatic artery thrombosis in infants. A comparison of whole livers, reduced-size grafts, and grafts from living-related donors.

Hepatic artery thrombosis (HAT) is a major cause of patient morbidity and graft loss in pediatric liver transplantation (OLT). Although some grafts may be salvaged by arterial thrombectomy and reconstruction, many patients require retransplantation. Patient survival is reduced by HAT. It has been suggested that the incidence of HAT may be altered by the use of reduced-size grafts (RSG). We analyzed our series of infants receiving OLT to determine the frequency of HAT in full-size OLT, cadaveric RSG, and living-related RSG. The role of arterial anastomotic technique in the development of HAT was also examined. Between 10/1/84 and 12/7/90 433 liver transplants were performed. During this period 100 patients between 3 months and 2 years of age (mean 13 months) received 134 liver grafts. The mean weight at the time of transplant was 7.9 kg. (range: 1.9-15 kg). Of the 134 grafts, 60 were whole livers, 61 were cadaveric RSGs, and 13 were living-related RSGs. The cadaveric RSGs were 9 right lobe grafts, 21 left lobe grafts, and 31 left lateral segment grafts. Twenty-seven of the cadaveric RSGs were from split livers, while the other 34 were simple reductions. All 13 living-related RSGs were left lateral segments. HAT occurred in 15 of 60 (25%) whole livers, 9 of 61 (15%) cadaveric RSGs, and 3 of 13 (23%) of the living-related-donor RSGs (P = NS). Subdividing the cadaveric RSGs revealed that HAT occurred in 3 of 9 (33%) right lobe grafts, 3 of 21 (14%) left lobe grafts, and 3 of 31 (10%) left lateral segment grafts (P = NS). The site of the arterial anastomosis in the recipient correlated with the incidence of HAT (hepatic artery 21/86 [24%], celiac axis 1/9 [11%], aorta 2/32 [6%], P = 0.06). In conclusion, it appears that use of a cadaveric left lobe or left lateral segment graft and an aortic arterial anastomosis reduces the risk of hepatic artery thrombosis in liver transplant recipients less than 2 years of age.

Complete lymphoid chimerism and chronic graft-versus-host disease in an infant recipient of a hepatic allograft from an HLA-homozygous parental living donor.

Living-related donor liver transplantation (LDLT) is an accepted approach to pediatric liver transplantation. Parental donation imposes a significant risk of chimerism with graft-versus-host disease (GVHD) because donors homozygous at all HLA loci (1.6% of the population) present no mismatched HLA antigens to be recognized by their offspring's immune system. The case of a 9-month-old who underwent LDLT with her 23-year-old HLA-homozygous mother as a donor demonstrates the consequences of this occurrence. The patient developed GVHD with aplastic anemia; the patient's nucleated peripheral blood elements were shown to be entirely derived from the donor. Later, after some marrow recovery, the patient's circulating lymphocytes had a donor origin, while the marrow-derived neutrophils had a recipient origin. The patient suffers from chronic GVHD and debilitating skin disease several years posttransplant. Our current protocol calls for HLA typing to eliminate parents who are homozygous at all HLA loci as donors of hepatic allografts to their children.

Liver transplantation in the first three months of life.

BACKGROUND: Pediatric liver transplant recipients have traditionally been grouped according to age. Age-based classification schemes are useful in identifying clinical problems in selected age groups and also for developing solutions to these problems. Although infants in the first 3 months of life have not traditionally been considered a distinct age group, several features of these infants may distinguish them from other pediatric liver transplant recipients. METHODS: The experience with liver transplantation in infants during the first 3 months of life in three large pediatric liver transplant programs (University of Chicago, Stanford University, and UCLA) was analyzed in order to characterize this group. RESULTS: A total of 23 liver transplants were performed at these three centers in children younger than 3 months of age. This group of patients comprised approximately 37% of the U.S. experience between 1988 and 1994 according to United Network for Organ Sharing statistics. Age distribution at the time of transplantation included the following: <1 month, 28%; 1-2 months, 35%; and 2-3 months, 36%. Median age at the time of transplantation was 37 days (range, 7-90 days), and mean age was 57+/-30 days. Mean weight at the time of transplantation was 3.8+/-1.0 kg. Etiology of liver disease included idiopathic hepatitis, 52%; iron storage disease, 17%; and other causes, 31%. Types of liver allografts used included cadaveric, 85% (reduced size, 60%, and full-size, 25%); living donor, 15%; ABO-identical, 65%; and ABO-compatible, 35%. Actuarial patient and graft survival rates were 60% and 60% at 1 year and 60% and 42% at 2 years, respectively. Median follow-up was 1.5 years. Rejection occurred in 42% of patients, with a median time to first rejection of 13 days. Of these patients, 28% required steroids only and 14% required OKT3. Three patients (14%) were retransplanted at a median time to retransplantation of 1.6 years. Vascular thrombosis occurred in three patients (14%). CONCLUSIONS: Liver transplantation performed in infants younger than 3 months of age (1) provides acceptable short- and long-term patient and graft survival, (2) is associated with significant rates of rejection, and (3) is not associated with excessive rates of vascular thrombosis. The etiology of end-stage liver disease occurring in the first 3 months of life is distinct from that in other pediatric liver transplant recipient age groups. These infants should be referred promptly for liver transplantation as reasonable survival can be expected.

OKT3 therapy for hepatic allograft rejection. Differential response in adults and children.

The clinical courses following OKT3 therapy for hepatic allograft rejection (HAR) in adults and children have not been individually defined. We have reviewed our experience with OKT3 therapy for HAR in adults and children to compare: (1) the initial response to OKT3 therapy, (2) the clinical course following OKT3 therapy, and (3) the antimurine antibody response and immunologic monitoring results. Children required OKT3 therapy more frequently than adults: fourteen courses of OKT3 therapy were required in 130 orthotopic liver transplants (OLT) in 108 adult patients, whereas nineteen courses of OKT3 therapy were required in 94 OLT in 78 children (P less than 0.02). Repeat OKT3 therapy was not required in adults--however, four of nineteen courses of OKT3 therapy in children were repeat OKT3 therapy for rejection. No differences existed between adult and pediatric treatment groups with respect to number of prior OLT procedures, previous graft loss to rejection, percentage of ABO-incompatible grafts, frequency of positive donor-recipient lymphocyte crossmatches, or time to first rejection. The initial response to OKT3 therapy (rapid reversal, delayed reversal, and failure) was remarkably similar in adults and children. However, nine of 13 (70%) children with clear evidence of response to OKT3 treatment experienced breakthrough rejection or early recurrent rejection, whereas none of 12 adults suffered breakthrough rejection or early recurrent rejection (P less than 0.01). Early recurrent rejection did not correlate with delayed reversal of rejection, early return of CD3+ cells by peripheral blood monitoring, or development of anti-OKT3 antibodies. All 4 courses of OKT3 retreatment in children were successful in reversing rejection, and breakthrough rejection and early recurrent rejection did not occur. Overall graft and patient survival in pediatric patients requiring OKT3 therapy (67% and 73%) was not different from that in adults (71% and 79%). Results obtained in one patient provide the first evidence that successful OKT3 retreatment of HAR can be achieved in the presence of preexisting idiotypic anti-OKT3 antibody. In conclusion, OKT3 therapy for HAR was required more frequently in children than in adults. The clinical outcome following OKT3 therapy for HAR also differs markedly, with early recurrent rejection and breakthrough rejection occurring more frequently in children.

Portal vein thrombosis and stenosis in pediatric liver transplantation.

The aim of this study was to determine the outcome of venous conduits used in living donor liver transplantation (LDLT). We analyzed the portal vein complications in 66 LDLT recipients and 48 cadaveric reduced-size liver transplant (RLT) recipients performed from November 1989 through January 1995. Three different venous conduits were utilized in the LDLT recipients: Group 1, reconstructed vein from the living donor, n=18; Group 2, cadaveric cryopreserved iliac vein, n=37; and Group 3, cadaveric cryopreserved femoral vein, n=11. Overall, 47 percent of the patients were less than one year of age; the age distribution was not significantly different among the groups. The incidence of early thrombosis was significantly greater in LDLT Group 1, (33%) than any of the other groups (LDLT Group 2, 8%; LDLT Group 3, 9%; and RLT, 4%:P<0.0005 vs. reduced graft and < 0.03 vs. other LDLT groups). The incidence of late portal vein stenosis or thrombosis was significantly higher in the LDLT Group 2, (51%) than any of the other groups (LDLT 1, 16%; LDLT Group 3, 9%; RLT 4%;P<0.005 vs. cadaveric and < 0.02 vs. LDLT Group 1 and LDLT Group 3). Five year arterial graft and patient survival for patients who have experienced portal vein thrombosis or stenosis is 61% and 67%, respectively, versus 67% and 71% for those patients who have not experienced portal vein pathology, P=ns. Based on this experience, we recommend avoiding the use of cryopreserved iliac vein for portal vein reconstruction in liver transplantation. Every effort should be taken to eliminate the need for venous conduits in liver transplantation. If venous conduits must be utilized, cryopreserved femoral veins seem to provide superior patency rates. Careful clinical and ultrasonopraphic monitoring of patients at high risk for late venous thrombosis permits therapy with excellent graft and patient survival.

Use of polytetrafluoroethylene patch for temporary wound closure after pediatric liver transplantation.

Despite numerous options for pediatric transplantation, closure of the abdominal wall after liver transplantation is occasionally difficult, resulting in increased abdominal pressure and possible vascular compromise. Since 1990, we have utilized a 2-mm thick sheet of polytetrafluoroethylene (PTFE) to overcome this situation in 21 transplants for 17 patients. The median age was 0.9 months. Ten of the 21 transplants utilized full-size grafts. The donor to recipient weight ratio was 1.7+/-1.2. Cadaveric left lateral segments were used in 8 of 21 transplants (weight ratio, 7.4+/-5.9), living donor left lateral segments were used in 3 of 21 transplants (weight ratio, 13.2+/-6.7). We were able to remove 14 of 21 patches with one additional operation, whereas 4/21 patches required two operations and 3/21 required three operations. Reoperations identified two cases of hepatic artery thrombosis not previously identified by duplex ultrasonography. There were no technical problems or adverse effects associated with the use of the PTFE patch. After patch removal, the fascia was closed with a nonabsorbable suture and the skin was allowed to close by secondary intention. There were no wound infections, portal vein thrombosis, or fluid and electrolyte abnormalities. PTFE is a safe, temporary alternative to primary wound closure in liver transplantation when the size of the graft or intestinal and graft edema does not allow conventional closure of the abdomen. Infectious, fluid/electrolyte, or ventilatory complications were not noted. The necessity of a second-look operation is useful in assessing the graft and vascular patency. The majority of patches can be removed within the first postoperative week.

An analysis of hepatic retransplantation in children.

BACKGROUND: The limited supply of organ donors has led some groups to reconsider the role of retransplantation. Historically, except for children with malignancies, extrahepatic sources of sepsis, or severe irreversible neurologic injuries, our institution has offered all children with failing liver grafts the option of retransplantation regardless of their current severity of illness. The purpose of this study was to examine the outcome of hepatic retransplantation in children in an attempt to identify factors predictive of outcome and to assess the results of our approach to retransplantation. METHODS: Between October 1984 and December 1995, 314 children less than 15 years of age underwent a total of 441 liver transplants. Data were obtained retrospectively by review of hospital records. RESULTS: With a mean follow-up period of 5.3+/-2.7 years, the overall patient survival rates at 1 and 5 years were 77.1% and 67.1%, respectively. Primary allograft survival rates were 65.6% and 56.5%, respectively. Of the 137 patients who developed failure of their primary allograft, 92 underwent retransplantation (29.3% of all primary transplants). Both patient and allograft survival rates were significantly decreased after retransplantation (P<0.0001 versus primary transplants). Univariate and multivariate analysis of retransplanted patients revealed only two factors that were statistically related to patient and graft survival: age at the time of retransplantation (P<0.02 univariate and P<0.05 multivariate) and retransplantation with a reduced-size allograft (P<0.005 univariate and P<0.05 multivariate). In this series, the effect on patient survival of differences in medical condition as reflected by United Network for Organ Sharing (UNOS) status approached, but did not achieve, significance (P=0.08 for UNOS 1 versus UNOS 2 and 3). UNOS status did not affect graft survival. Neither the cause of primary allograft loss or the timing of retransplantation relative to the first transplant were related to outcome. CONCLUSIONS: These data demonstrate that the failure of primary hepatic allografts remains a major problem in pediatric liver transplantation and that the overall results of retransplantation were significantly worse than those associated with primary transplants. We have identified a group of children who experienced a significantly worse outcome after retransplantation. This group consisted of children less than 3 years of age retransplanted using reduced-size grafts. Based on this finding, we now attempt to avoid retransplanting young children with reduced-size grafts. By using this approach, we hope to be able to offer children the option of retransplantation with improved results and simultaneously minimize the negative impact on patients awaiting primary transplants.

Posttransplant lymphoproliferative disease in pediatric liver transplantation. Interplay between primary Epstein-Barr virus infection and immunosuppression.

The incidence, risk factors, and outcome of posttransplant lymphoproliferative disease (PTLD) were examined for 298 children undergoing liver transplantation. The overall incidence of PTLD was 8.4% (25 of 298). Intensity of immunosuppression was found to be a major risk factor for the development of PTLD. Cyclosporine and tacrolimus when used as primary immunosuppression were associated with the development of PTLD in 4.3% and 6.6% of cases (P=NS). OKT3 and tacrolimus, when used as rescue therapy for steroid-resistant rejection, were associated with a comparable increase in the risk of developing PTLD (10.9% and 11.1%, P=NS). Patients requiring both OKT3 and tacrolimus to treat refractory rejection were at significantly increased risk for PTLD (28.1% vs. 4.3% or 6.6%, P<0.0001). PTLD was more common in patients who received transplants for Langerhans cell histiocytosis relative to other indications for transplantation (66% vs. 8.4%, P=0.0005). The data also support an association between primary Epstein-Barr virus (EBV) infections following transplantation and the development of PTLD. While only three patients were EBV seropositive before transplantation (14%), 19 patients were EBV seropositive at the time of diagnosis of PTLD (90%), confirming a high incidence of primary EBV infections in patients with PTLD (21 patients had both pre- and posttransplant EBV serologies). In this series, PTLD was associated with a mortality rate of 60%, and 12 of the 15 patients who died had persistent tumor at the time of death. Five of the 13 patients rendered disease-free developed ductopenic rejection. Of the four with severe liver dysfunction, two have undergone successful retransplantation and are alive without evidence of PTLD. In conclusion, intense immunosuppression using OKT3 and tacrolimus as rescue agents was associated with a significant increase in the incidence of PTLD. Primary EBV infection after transplantation further accentuated this risk. Independent of these risk factors, patients with Langerhans cell histiocytosis were at significantly increased risk for PTLD. The identification of high-risk patients should allow the development of protocols to screen patients for primary EBV infections and early indications of PTLD, as well as the institution of preemptive antiviral and antitumor therapies.

Soy protein intolerance: four patients with concomitant cow's milk intolerance.

An infrequently encountered and poorly understood infantile disorder is gastrointestinal soy protein intolerance. Four patients who had intractable diarrhea of infancy and who failed to thrive were tested by oral challenge with soy protein isolate and were found to have soy protein intolerance. All four exhibited concomitant sensitivity to cow's milk protein. The response to challenge with soy protein included diarrhea, vomiting, hypotension, lethargy, and fever. These symptoms were immediate, of short duration, and occurred with each subsequent challenge dose. No patient exhibited cutaneous, pulmonary, or hematologic evidence of allergy although it was prominent in their families. A diet devoid of intact soy and cow's milk protein allowed symptomatic recovery and rapid weight gain. Oral disodium cromoglycate therapy was ineffective in one trial. Soy protein intolerance should be suspected in infants with diarrhea resistant to therapy with soy based formulas.

Portal hypertension in children.

This chapter reviews the common causes of portal hypertension in children. It specifies how the treatment strategy for portal hypertension in patients without significant hepatic dysfunction differs from the management of children with cirrhosis. It describes the application of newer treatment modalities such as TIPS and partial splenic embolization in children and reviews the current recommendations for surgical intervention in these patients.

Gastroesophageal reflux causing stridor.

We describe an infant with stridor associated with gastroesophageal reflux (GER). This is the first report in which there is clear documentation by pH probe of a temporal association between individual episodes of GER and stridor. We review the literature and speculate on the relationship between these two phenomena. GER should be considered in patients with stridor.

Successful hepatic transplantation in congenital absence of recipient portal vein.

The first case of hepatic transplantation in a patient with congenital absence of the portal vein (CAPV) is reported. A 10-year-old girl with biliary atresia and CAPV underwent successful hepatic transplantation and has normal liver function 9 months after transplantation. This case is only the seventh reported case of CAPV. Patients with CAPV commonly have additional liver anomalies, cardiac and inferior vena cava anomalies, and polysplenia. Surprisingly, hepatic encephalopathy is not a prominent feature in patients with CAPV despite systemic drainage of mesenteric venous blood. CAPV should not be considered a contraindication to hepatic transplantation.