Combination therapy for severe portopulmonary hypertension in a child allows for liver transplantation.

Severe PPHTN is a contraindication to liver transplantation and predicts an abysmal 5-year outcome. It is defined as a resting mPAP >45 mm Hg with a mean pulmonary artery wedge pressure of <15 mm Hg and pulmonary vascular resistance of >3 wood units in the setting of portal hypertension. There have been limited reports of successful treatment of PPHTN leading to successful liver transplantation in adults, and one reported use of monotherapy as a bridge to successful liver transplant in pediatrics. To our knowledge, we describe the first use of combination therapy as a successful bridge to liver transplantation in a pediatric patient with severe PPHTN. This report adds to the paucity of data in pediatrics on the use of pulmonary vasodilator therapy in patients with severe PPHTN as a bridge to successful liver transplantation. Early diagnosis in order to mitigate or avoid the development of irreversible pulmonary vasculopathy that would preclude candidacy for liver transplantation is crucial, but our report demonstrates that combination therapy can be administered safely, quickly, and may allow for successful liver transplantation in patients with severe PPHTN.

A Learning Collaborative Approach Increases Specificity of Diagnosis of Acute Liver Failure in Pediatric Patients.

BACKGROUND & AIMS: Many pediatric patients with acute liver failure (PALF) do not receive a specific diagnosis (such as herpes simplex virus or Wilson disease or fatty acid oxidation defects)-they are left with an indeterminate diagnosis and are more likely to undergo liver transplantation, which is contraindicated for some disorders. Strategies to facilitate complete diagnostic testing should increase identification of specific liver diseases and might reduce liver transplantation. We investigated whether performing recommended age-specific diagnostic tests (AS-DTs) at the time of hospital admission reduces the percentage PALFs with an indeterminate diagnosis. METHODS: We performed a multinational observational cohort study of 658 PALF participants in the United States and Canada, enrolled at 10 medical centers, during 3 study phases from December 1999 through December 2014. A learning collaborative approach was used to implement AS-DT using an electronic medical record admission order set at hospital admission in phase 3 of the study. Data from 10 study sites participating in all 3 phases were compared before (phases 1 and 2) and after (phase 3) diagnostic test recommendations were inserted into electronic medical record order sets. RESULTS: The percentage of subjects with an indeterminate diagnosis decreased significantly between phases 1-2 (48.0%) and phase 3 (to 30.8%) (P = .0003). The 21-day cumulative incidence rates for liver transplantation were significantly different among phase 1 (34.6%), phase 2 (31.9%), and phase 3 (20.2%) (P = .030). The 21-day cumulative incidence rates for death did not differ significantly among phase 1 (17.9%), phase 2 (11.9%), and phase 3 (11.3%) (P = .20). CONCLUSIONS: In a multinational study of children with acute liver failure, we found that incorporating diagnostic test recommendations into electronic medical record order sets accessed at time of admission reduced the percentage with an indeterminate diagnosis that may have reduced liver transplants without increasing mortality. Widespread use of this approach could significantly enhance care of acute liver failure in children.

Intensive Care Management of Pediatric Acute Liver Failure.

Pediatric acute liver failure is rare but life-threatening illness that occurs in children without preexisting liver disease. The rarity of the disease, along with its severity and heterogeneity, presents unique clinical challenges to the physicians providing care for pediatric patients with acute liver failure. In this review, practical clinical approaches to the care of critically ill children with acute liver failure are discussed with an organ system-specific approach. The underlying pathophysiological processes, major areas of uncertainty, and approaches to the critical care management of pediatric acute liver failure are also reviewed.

Incidence of Low Seroimmunity to Hepatitis B Virus in Children With Inflammatory Bowel Disease.

OBJECTIVES: Patients with inflammatory bowel disease (IBD) often receive immunosuppressive therapy, which may make them vulnerable to infections such as hepatitis B. We hypothesized that hepatitis B virus titers are low in the vaccinated pediatric population with IBD. The aims of our study were to identify the incidence of lower titers of hepatitis B surface antibody (HBsAb) and determine which patient factors may be associated with lower HBsAb titers. METHODS: Patients with diagnosis of IBD, ages 5 to 18 years, were prospectively enrolled. Patients were confirmed to have had a full series of hepatitis B vaccination. Quantitative serum HBsAb titers were measured and logistic regression analysis with independent variables of age, sex, race, disease phenotype, surgery, medications and a dependent variable of adequate HBsAb titers (> 10 mIU/mL) was performed. RESULTS: Of the 116 patients enrolled, 57 were boys and 59 were girls. 75 patients had a diagnosis of Crohn disease; 32 had a diagnosis of ulcerative colitis; and 9 patients had been diagnosed as having indeterminate colitis. At the time of the study, 15 patients were taking corticosteroid, 66 on an immunomodulator, and 53 on a biologic. Sixty percent of patients in the 5- to 10-year age group had protective titers versus 22% to 27% in the older groups, P = 0.04. Only 28% of the 116 patients had HBsAb titers of >10m IU/mL. Twenty percent of the patients taking corticosteroids, 27% taking immunomodulators, and 24% taking biologics were found to be seroimmune. CONCLUSIONS: Nearly two-thirds of pediatric patients with IBD have low titers against hepatitis B virus. Titers were highest in the younger patients. No patient-specific variable, such as the use of immunosuppressants, appeared to influence these low titers.

Hepatoblastoma.

Hepatoblastoma is the most common primary malignant hepatic tumor of infancy and childhood, occurring predominantly in the first two years of life. The management of hepatoblastoma has changed markedly over the last 3 decades; neoadjuvant chemotherapy is now standard, particularly in unresectable tumors resulting in considerable preoperative tumor shrinkage and sometimes near total ablation of the tumor. A 20 month old infant was incidentally found to have a 7.6cm right sided retroperitoneal tumor on routine screening ultrasonography for left ureteral stenosis. Serum alpha fetoprotein was elevated. Biopsy revealed hepatoblastoma, mixed epithelial and embryonal type without mesenchymal elements. He underwent neoadjuvant chemotherapy. Although the tumor had decreased considerably in size, close proximity to major vascular structures precluded safe resection. Liver transplantation was performed; the explanted liver showed complete tumor necrosis with no residual malignancy. The postoperative course was uncomplicated and he is continuing on sixth cycle of chemotherapy.

Quality of Life and Its Determinants in a Multicenter Cohort of Children with Alagille Syndrome.

OBJECTIVES: To assess health-related quality of life (HRQOL) in children with Alagille syndrome (ALGS) in comparison with healthy and other liver disease cohorts, and to identify determinants of HRQOL in patients with ALGS. STUDY DESIGN: Within the Childhood Liver Disease Research Network prospective study of cholestasis, Pediatric Quality of Life Inventory (PedsQL) questionnaires were administered to 70 children with ALGS, 95 children with alpha-1-antitrypsin deficiency (A1ATD), and 49 children with other causes of chronic intrahepatic cholestasis (IHC) aged 5-18 years. Parent proxy PedsQL scores were recorded for children aged 2-18 years (98 ALGS, 123 A1ATD, and 68 IHC). RESULTS: Mean ages and total bilirubin (mg/dL) were ALGS 9.4 years; 4.4, A1ATD 9.5 years; 0.7, and IHC 10.3 years; 2.9. ALGS child PedsQL scores were lower than in healthy children and children with A1ATD (mean 73 vs 83; P = .001). Children with ALGS and IHC were similar, except in physical scores (73 vs 79; P = .05). Parents of children with ALGS perceived their children to have worse HRQOL than A1ATD (P ≤ .001) and marginally lower compared with IHC. Univariate analysis revealed ALGS child-reported scores were positively associated with better growth and inversely with total bilirubin. Growth failure, elevated international normalized ratio, and an intracardiac defect were predictive of poor parental scores (P ≤ .05). In multivariate analysis, only weight z-score remained significant for child- and parent-reported scores. CONCLUSIONS: HRQOL is impaired in children with ALGS compared with healthy and children with A1ATD, similar to children with IHC and is associated with growth failure, which is a potentially treatable cause of impaired HRQOL.

Intravenous N-acetylcysteine in pediatric patients with nonacetaminophen acute liver failure: a placebo-controlled clinical trial.

UNLABELLED: N-acetylcysteine (NAC) was found to improve transplantation-free survival in only those adults with nonacetaminophen (non-APAP) acute liver failure (ALF) and grade 1-2 hepatic encephalopathy (HE). Because non-APAP ALF differs significantly between children and adults, the Pediatric Acute Liver Failure (PALF) Study Group evaluated NAC in non-APAP PALF. Children from birth through age 17 years with non-APAP ALF enrolled in the PALF registry were eligible to enter an adaptively allocated, doubly masked, placebo-controlled trial using a continuous intravenous infusion of NAC (150 mg/kg/day in 5% dextrose in water [D5W]) or placebo (D5W) for up to 7 days. The primary outcome was 1-year survival. Secondary outcomes included liver transplantation-free survival, liver transplantation (LTx), length of intensive care unit (ICU) and hospital stays, organ system failure, and maximum HE score. A total of 184 participants were enrolled in the trial with 92 in each arm. The 1-year survival did not differ significantly (P = 0.19) between the NAC (73%) and placebo (82%) treatment groups. The 1-year LTx-free survival was significantly lower (P = 0.03) in those who received NAC (35%) than those who received placebo (53%), particularly, but not significantly so, among those less than 2 years old with HE grade 0-1 (NAC 25%; placebo 60%; P = 0.0493). There were no significant differences between treatment arms for hospital or ICU length of stay, organ systems failing, or highest recorded grade of HE. CONCLUSION: NAC did not improve 1-year survival in non-APAP PALF. One-year LTx-free survival was significantly lower with NAC, particularly among those <2 years old. These results do not support broad use of NAC in non-APAP PALF and emphasizes the importance of conducting controlled pediatric drug trials, regardless of results in adults.

Clinical, endoscopic, and histologic features of eosinophilic inflammation of the gastrointestinal tract in pediatric liver transplant patients.

Immunosuppression during the post-transplantation period has led to dramatic outcome improvements in PLTR patients. There have been reports describing the development of food allergies and an increased predilection for development of EGI in PLTR. We aimed to identify the clinical, endoscopic and histologic features of EGI in PLTR patients. In this retrospective case series we analyzed medical record of all PLTR who underwent EGD and/or colonoscopy at our institution from 2000 to 2006. From 2000 to 2006, 32 PLTR patients underwent endoscopic evaluation. Seventeen (53%) of 32 patients were diagnosed with EGI. Endoscopic abnormalities were seen in the esophagus, stomach, and small intestine in 11 (65%), 11 (65%), and four (24%) patients, respectively. Eosinophilic inflammation was seen in the esophagus, stomach, and small intestine in 13 (76%), 10 (59%), and five (29%) patients, respectively. Nine of 17 patients underwent colonoscopy and endoscopic abnormalities were seen in four (44%) patients. Five patients (56%) had eosinophilic inflammation. In conclusion, we have characterized the clinical, endoscopic, and histologic features of EGI. Histologic and endoscopic examination reveals that, when present, EGI is often found at multiple segments along the gastrointestinal tract.

Exploring potential noninvasive biomarkers in eosinophilic esophagitis in children.

BACKGROUND AND AIMS: Eosinophilic esophagitis (EE) continues to present clinical challenges, including a need for noninvasive tools to manage the disease. To identify a marker able to assess disease status in lieu of repeated endoscopies, we examined 3 noninvasive biomarkers, serum interleukin (IL)-5, serum eosinophil-derived neurotoxin (EDN), and stool EDN, and examined possible correlations of these with disease phenotype and activity (symptoms and histology) in a longitudinal study of children with EE. SUBJECTS AND METHODS: Children with EE were studied for up to 24 weeks (12 weeks on 1 of 2 corticosteroid therapies and 12 weeks off therapy). Twenty children with normal esophagogastroduodenoscopies with biopsies were enrolled as controls. Serum IL-5, serum EDN, and stool EDN were measured at weeks 0, 4, 12, 18, and 24 in children with EE, and at baseline alone for controls. Primary and secondary statistical analyses (excluding and including outlier values of the biomarkers, respectively) were performed. RESULTS: Sixty subjects with EE (46 [75%] boys, mean age 7.5 ±â€Š4.4 years) and 20 normal controls (10 [50%] boys, mean age 6.7 ±â€Š4.1 years) were included. Significant changes in serum EDN (significant decrease from baseline to week 4, and then rebound from week 4 to week 12) occurred. Serum EDN levels were stable after week 12. Serum IL-5 and stool EDN levels in subjects with EE were not statistically different from those of the control subjects when each time point for the cases was compared with the controls' 1-time measurement. CONCLUSIONS: Serum EDN levels were significantly higher in subjects with EE than in controls, and the results suggest a possible role, after additional future studies, for serum EDN in establishing EE diagnosis, assessing response to therapy, and/or monitoring for relapse or quiescence.

Intestinal transplantation in infants with intestinal failure.

Intestinal failure (IF) occurs when a person's functional intestinal mass is insufficient. Patients with IF are placed on parenteral nutrition (PN) while efforts are made to restore intestinal function through surgical or medical intervention. Patients who fail standard IF therapies may be candidates for intestinal transplantation (IT). Clinical outcomes for IT have improved to make this therapy the standard of care for patients who develop complications of PN. The timing of referral for IT is critical because accumulated complications of PN can render the patient ineligible for IT or can force the patient to await multiorgan transplantation.

Pediatric nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the pediatric population. Increased recognition of this form of liver disease parallels the dramatic rise in childhood and adolescent obesity over the past 2 decades. Like adults, most children with NAFLD are obese, and comorbidities include insulin resistance, hypertension, and dyslipidemia. Unfortunately, pediatric NAFLD is not always a benign condition, with some children progressing to hepatic fibrosis and even cirrhosis in severe cases. The etiology of nonalcoholic steatohepatitis is not yet fully understood; however, hepatic steatosis in the context of insulin resistance and increased oxidative stress may lead to progressive disease. Although physical examination, laboratory evaluation, and radiographic findings provide clues to the potential presence of fatty liver disease, liver biopsy remains the gold standard for diagnosis. Lifestyle modification, including slow and steady weight loss, improved dietary habits, and increased daily, aerobic physical activity, remains the first-line approach in treating pediatric fatty liver disease. Antioxidant pharmacologic therapy such as use of vitamin E has shown some benefit in patients with biopsy-proven steatohepatitis. Nutrition plays an essential role not only in the development of fatty liver disease but also potentially in the treatment and prevention of progression to more severe disease.

Haematological abnormalities in neonatal necrotizing enterocolitis.

OBJECTIVE: Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality in preterm infants born prior to 32 weeks gestation or with a birth weight less than 1500 grams. In this article, we review hematological abnormalities associated with NEC. METHODS: A literature search was performed using the databases PubMed, EMBASE, and Scopus, and the electronic archive of abstracts presented at the annual meetings of the Pediatric Academic Societies. RESULTS: Thrombocytopenia, disseminated intravascular coagulation, increased or decreased neutrophil counts, and hemolytic anemia are frequent events in NEC. CONCLUSIONS: NEC is associated with several hematological abnormalities, which may play a direct or indirect role in the pathogenesis of gut mucosal injury, and may also carry important prognostic information.

Evaluation of neutropenia and neutrophilia in preterm infants.

OBJECTIVE: Neutrophil counts are used routinely as part of the sepsis evaluation in newborn infants. In this article, we review the normal blood neutrophil concentrations and the clinical approach to neutropenia and neutrophilia in the neonatal period. METHODS: A literature search was performed using the databases PubMed, EMBASE, and Scopus, and the electronic archive of abstracts presented at the annual meetings of the Pediatric Academic Societies. RESULTS: Neutropenia and neutrophilia are documented frequently in premature infants. Neutropenia can be seen in up to 8% of all infants admitted to neonatal intensive care. Neutrophilia is even more common, reported in up to 40% of all preterm infants. CONCLUSIONS: Neutrophil counts should be carefully evaluated in premature neonates. Maternal and perinatal history, physical examination, and a limited laboratory assessment is usually adequate for making a diagnosis in most infants.

Association between red cell transfusions and necrotizing enterocolitis.

OBJECTIVE: Several case reports and retrospective studies have reported a temporal association between red blood cell (RBC) transfusions and necrotizing enterocolitis (NEC). In this article, we review the clinical evidence and biological plausibility of the association between RBC transfusions and NEC. METHODS: A literature search was performed using the databases PubMed, EMBASE, and Scopus, and the electronic archive of abstracts presented at the annual meetings of the Pediatric Academic Societies. RESULTS: Among all cases of NEC, 25 -40% patients were noted to have received an RBC transfusion within a 48 hour period prior to onset of NEC. Compared to infants who developed NEC unrelated to transfusion, neonates with transfusion-associated NEC were born at an earlier gestation, had lower birth weights, and had a delayed onset at 3-5 weeks of postnatal age. CONCLUSIONS: Based on current clinical evidence, transfusion-associated NEC appears to be a plausible clinical entity. However, there is a need for cautious interpretation of data because all the studies that have been conducted until date are retrospective, and therefore, susceptible to bias. A large, prospective, multi-center trial is needed to evaluate the association between RBC transfusion and NEC.

Incidence, etiology, and risk factors for liver dysfunction in children following hematopoietic stem cell transplantation.

AIMS: To identify risk factors which predispose children to develop liver dysfunction (LD) during the initial 100 days following hematopoietic stem cell transplantation (HSCT). METHODS: Retrospective analysis of all patients (<21 yr) who had undergone HSCT from July 1998 to June 2003. LD was defined by the presence of clinical jaundice and/or elevated alanine aminotransferase (ALT) or gamma-glutamyl transferase (GGT) (1.5 times normal). RESULTS: One hundred and six patients underwent HSCT during the study period. LD was seen in 91 (85.5%) patients and the majority (58.2%) had moderate to severe LD. The primary cause of LD could be ascertained in 2/3 of patients and was multifactorial in the rest. The odds ratio and 95% CI for risk factors associated with LD following HSCT on univariate analysis were as follows: allogeneic source of stem cells 4.2 (1.2-14.2), engraftment >12 days 4.3 (1.3-14.2), total parenteral nutrition >35 days 8.2 (1.1-66.2), pretransplant ALT >40 U/L 7.4 (0.9-58.6), use of cyclosporine and methotrexate 9.5 (1.2-77.9), and use of amphotericin-B 3.1 (0.9-10.6). On multivariate analysis only elevated pre transplantation ALT and delayed engraftment were associated with post-HSCT LD. LD was seen in all 13 patients who died within 100 days following HSCT, and it was felt to be the primary cause of death in six (46%) patients. The factors associated with increased risk of mortality were: allogeneic source of stem cells, delayed engraftment (>18 days), higher mean peak GGT (>250 U/L), and total bilirubin (>6 mg/dL). CONCLUSION: LD was common and severe in the majority of children following HSCT. Risk of LD was higher in children who had elevated pretransplantation ALT or had delayed engraftment. LD contributes significantly to morbidity and mortality following HSCT.