Estella M. Alonso

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.

Clinical and biochemical findings in progressive familial intrahepatic cholestasis

SummaryThe clinical findings in 33 patients with progressive familial intrahepatic cholestasis (PFIC) are presented. Symptoms developed almost invariably before 6 months of age with severe pruritus and moderate jaundice. Other clinical findings included wheezing and nosebleeds, fat-soluble vitamin deficiency states, and cholelithiasis. Lower values for γ-glutamyl transpeptidase, averaging 15 IU/L before the administration of phenobarbital, and cholesterol, which averaged 156 mg/dl, are helpful in distinguishing PFIC from other pediatric cholestatic liver diseases. Autosomal recessive inheritance is probable. Twenty-six patients are alive at 12.9 ± 6.7 years of age, all having had successful surgical treatment, either partial biliary diversion (n = 17) or orthotopic liver transplantation (n = 10). Seven patients died at a mean age of 3.9 ± 2.4 years, as a result of liver failure in two, hepatocellular carcinoma in two, and complications of liver transplantation in three.

Complete Immunosuppression Withdrawal and Subsequent Allograft Function Among Pediatric Recipients of Parental Living Donor Liver Transplants

CONTEXT Although life-saving, liver transplantation burdens children with lifelong immunosuppression and substantial potential for morbidity and mortality. OBJECTIVE To establish the feasibility of immunosuppression withdrawal in pediatric living donor liver transplant recipients. DESIGN, SETTING, AND PATIENTS Prospective, multicenter, open-label, single-group pilot trial conducted in 20 stable pediatric recipients (11 male; 55%) of parental living donor liver transplants for diseases other than viral hepatitis or an autoimmune disease who underwent immunosuppression withdrawal. Their median age was 6.9 months (interquartile range [IQR], 5.5-9.1 months) at transplant and 8 years 6 months (IQR, 6 years 5 months to 10 years 9 months) at study enrollment. Additional entry requirements included stable allograft function while taking a single immunosuppressive drug and no evidence of acute or chronic rejection or significant fibrosis on liver biopsy. Gradual immunosuppression withdrawal over a minimum of 36 weeks was instituted at 1 of 3 transplant centers between June 5, 2006, and November 18, 2009. Recipients were followed up for a median of 32.9 months (IQR, 1.0-49.9 months). MAIN OUTCOME MEASURES The primary end point was the proportion of operationally tolerant patients, defined as patients who remained off immunosuppression therapy for at least 1 year with normal graft function. Secondary clinical end points included the durability of operational tolerance, and the incidence, timing, severity, and reversibility of rejection. RESULTS Of 20 pediatric patients, 12 (60%; 95% CI, 36.1%-80.9%) met the primary end point, maintaining normal allograft function for a median of 35.7 months (IQR, 28.1-39.7 months) after discontinuing immunosuppression therapy. Follow-up biopsies obtained more than 2 years after completing withdrawal showed no significant change compared with baseline biopsies. Eight patients did not meet the primary end point secondary to an exclusion criteria violation (n = 1), acute rejection (n = 2), or indeterminate rejection (n = 5). Seven patients were treated with increased or reinitiation of immunosuppression therapy; all returned to baseline allograft function. Patients with operational tolerance compared with patients without operational tolerance initiated immunosuppression withdrawal later after transplantation (median of 100.6 months [IQR, 71.8-123.5] vs 73.0 months [IQR, 57.6-74.9], respectively; P = .03), had less portal inflammation (91.7% [95% CI, 61.5%-99.8%] vs 42.9% [95% CI, 9.9%-81.6%] with no inflammation; P = .04), and had lower total C4d scores on the screening liver biopsy (median of 6.1 [IQR, 5.1-9.3] vs 12.5 [IQR, 9.3-16.8]; P = .03). CONCLUSION In this pilot study, 60% of pediatric recipients of parental living donor liver transplants remained off immunosuppression therapy for at least 1 year with normal graft function and stable allograft histology.

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.

Studies of Pediatric Liver Transplantation (SPLIT) : Year 2000 outcomes

Background. Initiated in 1995, the Studies of Pediatric Liver Transplantation (SPLIT) registry database is a cooperative research network of pediatric transplantation centers in the United States and Canada. The primary objectives are to characterize and follow trends in transplant indications, transplantation techniques, and outcomes (e.g., patient/graft survival, rejection, growth parameters, and immunosuppressive therapy.) Methods. As of June 15, 2000, 29 centers registered 1144 patients, 640 of whom received their first liver-only transplant while registered in SPLIT. Patients are followed every 6 months for 2 years and yearly thereafter. Data are submitted to a central coordinating center. Results. One/two-year patient survival and graft loss estimates are 0.85/0.82 and 0.77/0.72, respectively. Risk factors for death include: in ICU at transplant (relative risk (RR)=2.63, P <0.05) and height/weight deficits of two or more standard deviations (RR=1.67, P <0.05). Risk factors for graft loss include: in ICU at transplant (RR=1.77, P <0.05) and receiving a cadaveric split organ compared with a whole organ (RR=2.3, P <0.05). The percentage of patients diagnosed with hepatic a. and portal v. thrombosis were 9.7% and 7%, respectively; 15% had biliary complications within 30 days. At least one re-operation was required in 45%. One/two-year rejection probability estimates are 0.60/0.66. Tacrolimus, as primary therapy posttransplant, reduces first rejection risk (RR=0.70, P <0.05). Eighty-nine percent of school-aged children are in school full-time, 18 months posttransplant. Conclusions. This report provides one of the first descriptions of characteristics and clinical courses of a multicenter pediatric transplant population. Observations are subject to patient selection biases but are useful for generating hypothesis for future studies.

Liver transplantation for the treatment of urea cycle disorders

The principal goal of therapy when liver transplantation is used for the treatment of metabolic disease is to correct the metabolic error. By doing so, liver transplantation eliminates the hepatic and peripheral consequences of the error. Inborn errors involving the urea cycle appear on theoretical grounds to be amenable to treatment using liver transplantation and, indeed, published data demonstrate that this approach to therapy can be successful. The purpose of this study is to examine the outcome of liver transplantation done for the indication of urea cycle defects in a large group of patients. The first goal of the study is to determine with certainty that liver transplantation corrects hyperammonaemia and halts the progress of disease. A second goal is to determine the extent of neurological recovery in children previously injured by hyperammonaemia. The final goal is to understand whether the quality of life is improved and medical expense is reduced by transplantation. The study involved a survey of major transplantation centres. Four centres provided data about 16 patients, 14 of whom were alive 11 months to 6 years after transplantation. The results demonstrate that liver transplantation resulted in correction of hyperammonaemia in all patients. The neurological outcome after transplantation correlated closely with the condition prior to transplantation. This population of patients has had relatively few problems in the long term related to the liver transplant itself. The quality of life seems to be much improved, but further study will be needed to confirm this. Limited data involving two patients show a reduction in the cost of care. We conclude from our experience that liver transplantation can be an effective treatment for children with urea cycle defects.

Histologic pathology of the liver in progressive familial intrahepatic cholestasis.

SummaryThis work details the histologic findings in 84 liver biopsy specimens from 28 patients with progressive familial intrahepatic cholestasis (PFIC), who met the clinical criteria of early onset of chronic unremitting cholestasis, exclusion of any known metabolic or anatomic etiology, and low serum γ-glutamyl transpeptidase (GGTP) values. Hepato-canalicular cholestasis and disruption of the liver cell plate arrangement were early, uniform findings, and giant cell transformation was found in 56% of initial biopsies. Duct loss was a prominent finding; 70% of patients had ductal paucity, and many had abnormal bile duct epithelium, suggesting degeneration. Fibrosis was seen in the samples from 16 patients, including bridging fibrosis in specimens obtained from six patients during the first 2 years of life. Proliferating ductules at the margins of portal tracts increased as fibrosis progressed and were especially prominent in end-stage histology. Cirrhosis developed in nine of these patients and had a characteristic histologic pattern, consisting of biliary cirrhosis with diffuse stellate lobular fibrosis associated with severe cholestasis and pseudoacinar transformation. Mallory hyalin and hepatocellular carcinoma were observed in materials from some patients with advanced cirrhosis. The constellation of histologic findings in PFIC forms a recognizable pattern, and the liver histology appears to have a predictable progression.

High sustained virologic response rates in children with chronic hepatitis C receiving peginterferon alfa-2b plus ribavirin

BACKGROUND & AIMS Pegylated interferon (PEG-IFN) alfa-2b plus ribavirin (RBV) is the standard of care for adults with chronic hepatitis C but was not approved for the treatment of children at the time of this study. The aim of this study was to evaluate the efficacy and safety of PEG-IFN alfa-2b plus RBV in children. METHODS Children and adolescents ages 3-17 years were treated with PEG-IFN alfa-2b (60microg/m(2)/week) plus RBV (15mg/kg/day). The duration of therapy was 24 weeks for genotype (G) 2 and G3 patients with low viral load (<600,000IU/ml) and 48 weeks for G1, G4, and G3 with high viral load (>or=600,000IU/ml). The primary end point was sustained virologic response (SVR), defined as undetectable hepatitis C virus (HCV) RNA 24 weeks after completion of therapy. RESULTS SVR was attained by 70 (65%) children. Genotype was the main predictor of response: G1, 53%; G2/3, 93%; G4, 80%. SVRs were similar in younger and older children. Baseline viral load was the main predictor of response in the G1 cohort. No new safety signals were identified, and adverse events (AEs) were generally mild or moderate in severity. Dose was modified because of AEs in 25% of children; 1 child discontinued because of an AE (thrombocytopenia). No serious AEs related to study drugs were reported. CONCLUSION Therapy with PEG-IFN alfa-2b plus RBV in children and adolescents with chronic hepatitis C offers favorable efficacy, reduced injection frequency, and an acceptable safety profile.

Autoimmune hepatitis as a late complication of liver transplantation

Background The development of de novo autoimmune hepatitis as a long-term complication after liver transplantation has been recently reported. The authors describe five liver allograft recipients who developed chronic hepatitis associated with autoimmune features. Methods Five of 155 liver transplant recipients at risk (2.5%) developed this particular form of graft dysfunction. The authors review the clinical records, liver histology, therapy, and outcome of these five patients. Results Patients included two boys and three girls. Median age at transplantation was 3.5 years (range, 0.5–14 years), median age at presentation was 9 years (range, 2–17 years), and median interval after transplantation was 5.1 years (range, 1.5–9 years). Indications for liver transplant included biliary atresia in four patients and primary sclerosing cholangitis in one patient. At the time of presentation, all patients were receiving cyclosporine as their primary immunosuppressive agent. Only one patient had a history of rejection, which had resolved. All patients presented with increased transaminase levels, and one had a mildly elevated conjugated bilirubin level. Only one patient had constitutional complaints. Acute and chronic rejection, viral hepatitis, vascular insufficiency, and biliary tract obstruction were excluded. Antinuclear antibody levels were elevated in four patients (titer range, 1:160–1:640), one of whom also had positive antismooth muscle antibody (titer 1:80) results. The fifth patient had an elevated serum total protein level. Histologic analysis of liver biopsy samples from the five patients showed findings consistent with chronic autoimmune hepatitis. All patients were treated with standard therapy for autoimmune hepatitis, which included daily steroids and azathioprine. Cyclosporine doses were reduced in three patients and eliminated in two. All patients responded with normalization (n = 2) or improvement (n = 3) of liver transaminases within the first 3 months of therapy. Histologic analysis of the 3-month follow-up liver biopsy was normal (n = 2) or showed improvement in inflammation (n = 2). Two patients developed acute allograft rejection within 6 to 12 months after discontinuation or reduction in cyclosporine. Conclusions Autoimmune hepatitis occurs after liver transplantation in patients without a previous history of autoimmune hepatitis. The risk of developing autoimmune hepatitis appears to be greater in children after liver transplantation than in the general pediatric population. Standard therapy for autoimmune hepatitis is effective.

Experience With the Rex Shunt (Mesenterico-Left Portal Bypass) in Children With Extrahepatic Portal Hypertension

BACKGROUND/PURPOSE Extrahepatic portal vein thrombosis (EPVT) in children can lead to severe bleeding from gastrointestinal varices, ascites, thrombocytopenia from hypersplenism, and other coagulation disorders. The authors have used the superior mesenteric vein to intrahepatic left portal vein (Rex) shunt in 5 children with symptomatic EPVT and report their results with this novel technique. METHODS Children with symptomatic portal hypertension were screened for the underlying cause. All children with essentially normal livers and obstruction of the extrahepatic portal vein were considered for the Rex shunt. Evaluation included liver function tests, liver biopsy, and radiological evaluation of the intrahepatic vascular anatomy. RESULTS Five patients between the ages of 2.8 and 10.5 years underwent evaluation for portal hypertension secondary to extrahepatic portal vein obstruction. Three patients had idiopathic extra hepatic portal vein thrombosis with cavernous transformation, 1 had thrombosis after a living-related liver transplant, and 1 had compression and obstruction of the main portal vein from enlarged lymph nodes after treatment of systemic histoplasmosis. All patients were symptomatic. Three patients had intermittent bleeding from esophageal and gastric varices, and all 5 had relative degrees of hypersplenism with enlarged spleens and thrombocytopenia (11,000 to 77,000). Three patients had significant leukopenia. Results of imaging studies suggested that 3 patients had inadequate intrahepatic portal veins for shunting, but all patients at exploration underwent successful shunting. There were no serious intraoperative complications. Postoperative complications included ascites in 2 patients that resolved within 1 month. There were no early shunt thromboses. The median postoperative length of stay was 7 days. Clinical follow-up ranged from 7 to 21 months. Gastrointestinal bleeding did not recur in any patient, and ascites resolved in all. Spleen size decreased significantly (P < .01) from 9.4 +/- 4.0 cm to 5.0 +/- 3.7 cm below the left costal margin. Mean platelet count and white blood cell count rose after shunting from 79 +/- 42 to 176 +/- 73 (P < .02) and 5.4 +/- 2.3 to 7.5 +/- 3.9 (P = .06), respectively. All shunts were studied at 1 and 7 days, and 3 and 6 months after the procedure. Shunt patency was documented in all cases. Subsequently, shunt blockage occurred in 2 patients. CONCLUSIONS The Rex shunt has proven to be an effective method of resolving portal hypertension caused by EPVT including thrombosis after living donor transplantation. This shunt is preferable to other surgical procedures because it eliminates portal hypertension and its sequelae by restoring normal portal flow to the liver.