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Portal hypertension, a common sequela of chronic liver disease, is complicated by variceal hemorrhage, one of its most serious complications. Evidence-based approaches to managing variceal hemorrhage are limited by the scarcity of data related to this rare entity. Multicenter international registries are increasingly utilized to garner critical information about rare diseases. The International Multicenter Pediatric Portal Hypertension Registry (IMPPHR) was developed to acquire pediatric data about the mortality of first variceal hemorrhage and approaches to primary and second prophylaxis of variceal hemorrhage with a goal of improving outcomes in children with portal hypertension. IMPPHR evolved from pediatric portal hypertension symposia at the Baveno V and VI meetings in 2010 and 2015, with a formal executive committee initiating the development of IMPPHR in 2019. The registry opened in 2020, with data closure in 2024, including information from 44 centers and >700 subjects. The complexities and approaches to developing IMPPHR are described., (© 2024 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background: Liver transplantation (LT) in infants can be challenging due to their small size and small vasculature. Although both whole LT (WLT) and split LT (SLT) have been described in infants, the head-to-head comparison of these techniques in this population is sparse., Methods: We retrospectively analyzed the records of all patients with age ≤1 year at Indiana University between 2016 and 2022. All SLT were left lateral segment grafts split in situ., Results: A total of 24 infants were transplanted, with 11 SLT and 13 WLT. The median follow-up time was 52.1 months. Donor and recipient characteristics were comparable except for donor age (19 years vs. 2 years; p < .01) and weight (64 kg vs. 14.2 kg; p < .01). Early allograft dysfunction, primary nonfunction, and hepatic artery thrombosis developed more frequently in the WLT group. There were no biliary complications. There were two early deaths (2 and 4 days) in the WLT group. One-year graft survival (100% vs. 77%; p = .10) and patient survival (100% vs. 85%; p = .18) were numerically higher in the SLT group., Conclusions: SLT with LLS offers a safe and viable option for liver transplantation in infants and is associated with a trend toward superior outcomes. SLT should be considered as a strategy to reduce waitlist times for infants in the absence of small, deceased donors for WLT., (© 2023 Wiley Periodicals LLC.)

Objective: Fat-soluble vitamin (FSV) deficiency is a well-recognized consequence of cholestatic liver disease and reduced intestinal intraluminal bile acid. We hypothesized that serum bile acid (SBA) would predict biochemical FSV deficiency better than serum total bilirubin (TB) level in infants with biliary atresia., Methods: Infants enrolled in the Trial of Corticosteroid Therapy in Infants with Biliary Atresia after hepatoportoenterostomy were the subjects of this investigation. Infants received standardized FSV supplementation and monitoring of TB, SBA, and vitamin levels at 1, 3, and 6 months. A logistic regression model was used with the binary indicator variable insufficient/sufficient as the outcome variable. Linear and nonparametric correlations were made between specific vitamin measurement levels and either TB or SBA., Results: The degree of correlation for any particular vitamin at a specific time point was higher with TB than with SBA (higher for TB in 31 circumstances vs 3 circumstances for SBA). Receiver operating characteristic curve shows that TB performed better than SBA (area under the curve 0.998 vs 0.821). Including both TB and SBA did not perform better than TB alone (area under the curve 0.998)., Conclusions: We found that TB was a better predictor of FSV deficiency than SBA in infants with biliary atresia. The role of SBA as a surrogate marker of FSV deficiency in other cholestatic liver diseases, such as progressive familial intrahepatic cholestasis, α-1-antitrypsin deficiency, and Alagille syndrome in which the pathophysiology is dominated by intrahepatic cholestasis, warrants further study.

Vitamin E improved liver histology in children and adults with NAFLD who participated in TONIC and PIVENS clinical trials, but with significant inter-individual variability in its efficacy. Cytochrome P450 4F2 (CYP4F2) is the major enzyme metabolizing Vit E, with two common genetic variants (V433M, rs2108622 and W12G, rs3093105) found to alter its activity. We investigated the relationship between CYP4F2 genotypes, α-tocopherol levels and histological improvement in these two trials. V433M and W12G variants were genotyped in TONIC (n = 155) and PIVENS (n = 213) DNA samples. The relationships between CYP4F2 genotypes, plasma α-tocopherol levels at baseline and weeks 48 (w48) and 96 (w96) and histological end points (overall improvement in liver histology and resolution of NASH) were investigated. As a result, the V433M genotype was significantly associated with baseline plasma α-tocopherol in the TONIC trial (p = 0.004), but not in PIVENS. Among those receiving Vit E treatment, CYP4F2 V433M genotype was associated with significantly decreased plasma α-tocopherol levels at w48 (p = 0.003 for PIVENS and p = 0.026 for TONIC) but not at w96. The w96 α-tocopherol level was significantly associated with resolution of NASH (p = 0.006) and overall histology improvement (p = 0.021)in the PIVENS, but not in the TONIC trial. There was no significant association between CYP4F2 genotypes and histological end points in either trial. Our study suggested the a moderate role of CYP4F2 polymorphisms in affecting the pharmacokinetics of Vit E as a therapeutic agent. In addition, there may be age-dependent relationship between CYP4F2 genetic variability and Vit E pharmacokinetics in NAFLD.

Background & Aims: Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disease in American children. Noninvasive means to discriminate between NAFLD and nonalcoholic steatohepatitis (NASH) might diminish the requirement for liver biopsy or predict those at increased risk for progression., Methods: Data obtained prospectively from children (age, 6-17 y) enrolled in the NASH Clinical Research Network were analyzed to identify clinical-pathologic correlates of pediatric NAFLD. All participants underwent liver biopsy within 6 months of clinical data that were reviewed by a central pathology committee., Results: A total of 176 children (mean age, 12.4 y; 77% male) were eligible for inclusion. By using ordinal logistic regression analysis, increasing aspartate aminotransferase (AST) level (odds ratio [OR], 1.017 per U/L; 95% confidence interval [CI], 1.004-1.031) and gamma-glutamyltransferase level (OR, 1.016 per U/L; 95% CI, 1.000-1.033) were associated independently with increasing severity of NASH. Increasing AST level (OR, 1.015 per U/L; 95% CI, 1.006-1.024), increasing white blood cell count (OR, 1.22 per 1000/mm(3); 95% CI, 1.07-1.38), and decreasing hematocrit (OR, 0.87 per %; 95% CI, 0.79-0.96) were associated independently with increasing severity of fibrosis. Area under the receiver operator characteristic curve for a model with AST and alanine aminotransferase was 0.75 (95% CI, 0.66-0.84) and 0.74 (95% CI, 0.63-0.85) for distinguishing steatosis from more advanced forms of NASH and bridging fibrosis from lesser degrees of fibrosis, respectively., Conclusions: Certain components of routine laboratory tests are predictive of NAFLD pattern and fibrosis severity, but do not have adequate discriminate power to replace liver biopsy in evaluating pediatric NAFLD.

Chronic hepatitis C virus (HCV) infection is usually asymptomatic in children, but significant liver disease may occur. We evaluated the efficacy, safety, and pharmacokinetics of interferon alfa-2b and ribavirin in children with chronic HCV. We determined the optimal ribavirin dose in an initial cohort of a phase 1 study and then subsequently used it, in combination with interferon alfa-2b, in a second cohort of this study and a phase 3 trial. The primary efficacy endpoint in all studies was sustained virological response, defined by undetectable serum HCV RNA 24 weeks after completion of therapy. All efficacy and safety analyses were performed on the intent-to-treat population. Children receiving interferon alfa-2b plus ribavirin 15 mg/kg/d in the phase 1 study had the maximum reduction in serum HCV RNA at treatment weeks 4 and 12 with an acceptable safety profile. This ribavirin dose was selected as optimal and used in all subsequent studies. In all, 46% (54/118) of optimally treated children achieved sustained virological response. Sustained virological response was significantly higher in children with HCV genotype 2/3 (84%) than in those with HCV genotype 1 (36%). Adverse events led to dose modification in 37 (31%) and discontinuation in 8 (7%). Multiple-dose interferon alfa-2b and ribavirin peak and trough concentrations and area-under-the-curve were similar between children and adults. In conclusion, interferon alfa-2b in combination with ribavirin is effective and safe in children with chronic hepatitis C virus.

Background: Improved survival in patients with cystic fibrosis (CF) has led to an increased incidence of extrapulmonary complications of this disease. Of these, cirrhosis and pancreatic insufficiency, including CF-related diabetes (CFRD) and exocrine insufficiency, are significant causes of morbidity and mortality. Liver transplantation is the treatment of choice for cirrhosis in this setting, but the addition of an isolated simultaneous pancreas transplant in patients with CFRD has not been reported., Methods: Two female patients with CF underwent simultaneous pancreas and liver transplantation. Both had pancreatic insufficiency, CFRD, cirrhosis, and preserved renal function. In each case, the liver and pancreas were procured from a single cadaveric donor. The liver transplant was performed first. A lower midline extension was added for improved exposure of the iliac vessels. The donor pancreas transplant was performed with systemic venous drainage and enteric exocrine drainage. Immunosuppression included rabbit anti-thymocyte globulin, tacrolimus, mycophenolate mofetil, and early steroid withdrawal., Results: Both patients recovered well with normal liver function, resolution of portal hypertension, and normal blood glucoses independent of insulin. As a result of the enteric exocrine drainage of the pancreas, they are now independent of supplemental pancreatic enzymes., Conclusions: Simultaneous liver and pancreas transplantation in CF patients provides the advantages of normalization of glucose and improved nutrition for patients requiring liver transplantation and should be considered in CF patients with CFRD who require liver transplants.

Purpose: To determine whether the morphologic features of posttransplant lymphoproliferative disease (PTLD) correlated to a response to therapy., Patients and Methods: We reviewed our experience with PTLD in the pediatric population. We identified 32 patients with a total of 36 episodes of PTLD. The diagnosis was confirmed by tissue examination and classified according to the degree of monomorphic features of the lesion. Thirty-four of 36 episodes were managed with immunosuppression reduction, and the patients were assessed for their response to this strategy. Chemotherapy was used to treat 10 of 15 patients who had progressive disease, and their subsequent course was also analyzed., Results: Sixteen of 17 (94%) patients with polymorphic morphology responded to immunosuppression reduction compared with only 5 of 17 (29%) patients with monomorphic features (P < 0.001). All of the patients with progressive disease who did not receive additional therapy died. Standard chemotherapy regimens for lymphoma were administered to 10 patients with progressive disease, with a high response rate (90%), durable remissions, and acceptable toxicity., Conclusions: We conclude that the morphologic characteristics of PTLD provide information to potentially help guide treatment strategies in the management of this disease. Standard chemotherapy regimens for malignant lymphoma appear to be a viable treatment option for patients with progressive disease, although further investigation is needed.

Background: A prospective nationwide screening study initiated more than 20 years ago in Sweden has shown that clinically significant liver disease develops in only 10% to 15% of alpha1-antitrypsin (AT)-deficient children. This study provides information about 85% to 90% of those children, many of whom had elevated serum transaminases in infancy but have no evidence of liver injury by age 18 years. However, there is relatively limited information about the course of alpha1-AT-deficient children who have cirrhosis or portal hypertension. Based on several anecdotal experiences, we have been impressed by the relatively slow progression and stable course of the liver disease in some of these children., Methods: We reviewed the course of patients with homozygous PIZZ alpha1-antitrypsin deficiency seen at this institution since establishing a patient database 16 years ago., Results: Of 44 patients with alpha1-AT deficiency, 17 had cirrhosis, portal hypertension, or both. Nine of the 17 patients with cirrhosis or portal hypertension had a prolonged, relatively uneventful course for at least 4 years after the diagnosis of cirrhosis or portal hypertension. Two of these patients eventually underwent liver transplantation, but seven are leading relatively healthy lives for up to 23 years while carrying a diagnosis of severe alpha1-AT deficiency-associated liver disease. Patients with the prolonged stable course could be distinguished from those with a rapidly progressive course on the basis of overall life functioning but not on the basis of any other more conventional clinical or biochemical criteria., Conclusions: These data provide further evidence for the variable severity of liver disease associated with alpha1-AT deficiency and indicate that some patients have chronic, slowly progressing or nonprogressing cirrhosis.

Colorectal carcinoma is one of the most common primary malignancies in adults and occurs in older patients after pelvic radiation. It is rare in children and young adults. We report two cases of colonic adenocarcinoma which were second malignant neoplasms following treatment for early childhood malignancies. One child had Wilms' tumor at 9 months of age treated with preoperative radiation and surgery. He developed radiation colitis and multifocal intestinal adenocarcinomas 42 years later and died with abdominal carcinomatosis. The second child had retroperitoneal embryonal rhabdomyosarcoma at age 1 year and was treated with preoperative radiation, surgery, and chemotherapy. At age 2 years he had radiation colitis; at age 11 years he had rectal adenocarcinoma associated with adenomatous polyps, focal adenomatous change and radiation colitis. Immunohistochemical studies revealed p53 positivity in both adenocarcinomas and in adenomas from the second patient, suggesting that p53 mutation was involved in carcinogenesis. The history of high-dose radiation in early childhood and the multifocal lesions suggest the adenocarcinomas in both patients were second malignant neoplasms, with associated reactive and benign neoplastic and premalignant lesions well documented in one case. These two cases document the phenomenon of early onset of adult type tumors in survivors of childhood cancer and emphasize the need for continued clinical evaluation of patients at risk for second malignant neoplasms.

Lymphocytes of donor origin can be demonstrated in the blood of many liver transplant recipients. It has been proposed that this chimerism may imply graft tolerance and permit withdrawal of immunosuppression. We report two children with liver transplants who had lymphocyte chimerism demonstrated at the time of late rejection episodes. One child was chimeric for both of his donors, although he retained the first allograft for only 3 days. Thus, the persistence of donor lymphocytes may be unrelated to the presence of the donor organ. Graft rejection can occur in spite of donor-specific microchimerism. The role of donor-specific microchimerism in graft acceptance or graft tolerance remains to be elucidated.

Examined humor appreciation of cartoons as a function of sex of subject and type of humor. Four broad types of humor were presented: sexual-exploitative, sexual-nonexploitative, nonsexual-hostile, and nonsexual-nonhostile. Sexual-nonexploitative humor was rated as funnier than the other three types but nonsexual-nonhostile humor was given a more positive overall rating than the other types. Relative to males, females gave greater ratings of hostility to the cartoons and rated them less positively. Correlational analyses further suggested that females were not as affected as males by variations in sexuality, exploitation, and hostility. For males, greater ratings of sexuality were associated with greater funniness ratings while the reverse was true for greater ratings of hostility. Possible interpretations of these data were discussed.

The following hypothesis is offered for the etiology of neonatal necrotizing enterocolitis (NEC): that NEC is caused by the acquisition of a potentially pathogenic organism by a susceptible host infant. To test this hypothesis, serum IgM, IgG, IgA, C3, and C4, were measured in 11 neonates with NEC and 11 control infants matched for age and birth weight. Mean initial serum IgA was found to be significantly greater (p less than 0.05) in patients with NEC (8.4 mg/dl) than in control subjects (0.6 mg/dl). This difference persisted during a subsequent period of observation. There were no significant differences in initial concentrations of the other immunoglobulins or complement components. Serum IgM was noted to increase and serum IgG to decrease in both study groups during the period of observation. C3 rose minimally and C4 fell in patients with NEC. An explanation for this alteration in serum IgA concentration in infants with NEC is, at this time, speculative. However, this association, suggests that further evaluation of host susceptibility in this patient group may lead to a better understanding of this disorder.