Quality of life in adolescents with hepatitis C treated with sofosbuvir and ribavirin.

Chronic HCV infection has been associated with impairment of HRQL in both adults and paediatric patients. Our aim was to assess the HRQL of HCV-positive children treated with SOF + RBV. The data for this post hoc analysis were collected in a phase 2 open-label multinational study that evaluated safety and efficacy of SOF (400 mg/day) plus RBV (weight-based up to 1400 mg/day) for 12 or 24 weeks in adolescents with chronic HCV (GS-US-334-1112). Patients and their parents/guardians completed the PedsQL-4.0-SF-15 questionnaire at baseline, at the end of treatment and in post-treatment follow-up. We included 50 adolescents with HCV genotype 2 and 3 without cirrhosis (14.8 ± 1.9 years; male: 58%; treatment-naïve: 82%; vertically transmitted HCV: 70%). After treatment, 100% of patients with HCV genotype 2 and 95% with genotype 3 achieved SVR-12. During treatment with SOF + RBV, there were no significant decrements in any of patients' self-reported or parent-proxy-reported PRO scores regardless of treatment duration (all P > .05). After treatment cessation, we recorded a statistically significant improvement in patients' self-reported Social Functioning score by post-treatment week 12: on average, +4.8 points on a 0-100 scale (P = .02). By post-treatment week 24, parent-proxy-reported School Functioning score increased by, on average, +13.0 points (P = .0065). In multivariate analysis, history of abdominal pain and psychiatric disorders were predictive of impaired HRQL in adolescents with HCV (P < .05). Adolescents with HCV do not seem to experience any HRQL decrement during treatment with SOF + RBV and experience some improvement of their HRQL scores after achieving SVR.

Implementation of feeding guidelines in infants at risk of intestinal failure.

OBJECTIVE: To implement feeding guidelines to reduce advancement time and the incidence of parenteral nutrition-associated liver disease (PNALD) among intestinal surgical infants requiring parenteral nutrition (PN). STUDY DESIGN: Feeding guidelines with higher initial enteral nutrition (EN) volume and specific advancement criteria were implemented for surgical infants aged <6 months. Preimplementation and postimplementation outcomes were compared. RESULTS: There were 57 preimplementation and 33 postimplementation infants. The initial EN volume improved from 10 to 20 ml kg(-1) day(-1) (P<0.001). Time to reach 50% of goal calories from EN decreased by a median of 6 days (P=0.012) without a change in necrotizing enterocolitis incidence after resuming feeding. PNALD incidence decreased from 70% to 48% (P=0.046), and median peak direct bilirubin (DB) decreased from 5.6 to 2.3 mg dl(-1) (P=0.011). CONCLUSION: Feeding guideline implementation with higher initial feeding volume was well tolerated and resulted in faster achievement of 50% goal EN calories. PNALD incidence and peak DB were reduced.

Variability of hepatitis E serologic assays in a pediatric liver transplant recipient: challenges to diagnosing hepatitis E virus infection in the United States.

Hepatitis E virus (HEV) is an emerging cause of viral hepatitis among immunocompromised individuals in developed countries. Yet the diagnosis of HEV infection in the United States remains challenging, because of the variable sensitivity and specificity of currently available tests, and the lack of a US Food and Drug Administration-approved test. We report a case of multiple discordant HEV serology results in a pediatric liver transplant recipient with idiopathic hepatitis, and review the challenges to diagnosis of HEV infection in the United States.

Living donor liver transplantation in children: a single North American center experience over two decades.

Little data concerning hospital charges and long-term outcomes of LDLT in North American children according to transplant indications have been published. To compare outcomes of patient and graft survival and healthcare charges for LDLT for those with BA vs. other diagnoses (non-BA). A retrospective review of 52 children receiving 53 LDLT (38 BA and 14 non-BA) from 1992 to 2010 at our institution was performed. One-, five-, and 10-yr patient and graft survival data were comparable to national figures reported to UNOS. Average one-yr charges for recipients and donors were $242 849 for BA patients and $183 614 for non-BA (p = 0.074). BA patients were 1.23 ± 1.20 yr of age vs. 4.25 ± 5.02 for non-BA, p = 0.045. Examination of the total population of patients who were alive in 2010 in five chronological groupings showed that the crude five-yr survival rates were 1992-1995: 9/11 (82%); 1995-1997: 6/10 (60%); 1997-1999: 8/10 (80%); 1999-2001: 9/10 (90%); and 2001-2003: 7/7 (100%). Thus, examination of the clinical and financial data together over the entire period of the transplant program suggests that the dramatic improvement in patient survival was accomplished without a dramatic increase in indexed charges. All 53 donors survived, and only 10% had complications requiring hospitalization. LDLT in children results in excellent outcomes for patients and donors. Ways to lower costs and maximize graft outcome should be investigated.

Chronic diarrhea, ascites, and protein-losing enteropathy in an infant with hepatic venous outflow obstruction after liver transplantation.

An 18-month-old female status post-orthotopic liver transplant for biliary atresia presented nine months after transplant with severe diarrhea and intolerance of feeds. She was found to have a PLE as evidenced by a low serum albumin and a persistent elevation of fecal A1AT. Investigation eventually revealed that the cause of the PLE was a stricture at the anastomosis site between the hepatic vein and inferior cava, supported by resolution of the PLE after venoplasty of the stricture. The patient has subsequently required several repeat venoplasties for recurrence of her symptoms correlating with recurrence of the stricture. This is a very rare presentation of hepatic venous outflow obstruction. Moreover, normal duplex ultrasound imaging of liver vasculature and her unusual presentation led to a delay in her diagnosis highlighting the need for an increased index of suspicion.

Longitudinal changes in liver fibrosis in children with sickle cell disease undergoing chronic transfusion therapy.

BACKGROUND AND STUDY AIMS: The progression of liver injury from transfusional iron overload in sickle cell disease (SCD) is poorly understood. We sought to identify predictors liver fibrosis development over time. PATIENTS AND METHODS: We performed a retrospective cohort study of chronically transfused SCD patients who had > or = 2 serial liver biopsies. Core biopsies were scored for fibrosis in a blinded fashion. Primary analyses evaluated longitudinal changes in liver fibrosis and changes in surrogate markers. Secondary analyses determined the relationship between liver iron concentration (LIC) and serum biomarkers. RESULTS: 26 people had > or = 2 serial biopsies for evaluation (n = 70 biopsies total). Fibrosis was Ishak grade 0 or 1 in all biopsies. Evaluation of the first 2 biopsies showed fibrosis regression (n = 6), development (n = 2), persistence (n = 1), and absence (n = 17). There was no consistent association of fibrosis with LIC over time, or between changes in fibrosis status and surrogate markers. For predicting fibrosis on a cross-sectional basis, ALT and ferritin performed moderately (AUCs 0.80 and 0.63, respectively) but LIC performed poorly (AUC 0.30). The highest positive likelihood ratios for fibrosis were for ferritin cutoff of 5000 ng/mL (LR + 5.7) and ALT cutoff of 65 U/L (LR + 5.2). CONCLUSIONS: Liver fibrosis progression is minimal in chronically transfused SCD. LIC does not correlate well with fibrosis development. We propose routine liver biopsies are not necessary components in the standard monitoring of chronically transfused SCD patients.

Minimal hepatic encephalopathy in children: evaluation with proton MR spectroscopy.

BACKGROUND AND PURPOSE: Minimal hepatic encephalopathy (MHE) in children is difficult to evaluate because of lack of standardized neuropsychological tests for all age ranges. The purpose of this retrospective study of children with clinically suspected MHE was to investigate relationships between brain MR spectroscopy metabolites and biochemical markers of encephalopathy as well as measures of liver disease severity. MATERIALS AND METHODS: A total of 12 children (age range, 9-19 years; 8 female) with clinically suspected MHE were studied by short TE brain MR spectroscopy on a 1.5T magnet. We estimated gray matter (GM) and white matter (WM) metabolite concentrations using "LCModel" software. Regional metabolite concentrations were examined for correlation with various parameters, including plasma ammonia, the ratio of branched-chain to aromatic amino acids (BCAA/AAA), model for end stage liver disease/pediatric end stage liver disease (MELD/PELD) and Child-Pugh scores, bilirubin, albumin, and platelet counts. RESULTS: Myo-inositol (mIns) levels correlated with BCAA/AAA ratios (r = 0.86; P = .002 for GM and r = 0.77; P = .01 for WM). WM choline (Cho) levels and GM mIns levels showed significant negative correlation with ammonia levels (r = -0.58; P = .04 and r = -0.65; P = .02, respectively). A positive significant correlation trend was present for GM glutamine/glutamate (Glx) and ammonia levels (r = 0.66; P = .05). There was no correlation of brain MR spectroscopy parameters and severity of liver disease. CONCLUSIONS: Brain MR spectroscopy metabolites in children with suspected MHE show significant correlations with plasma ammonia levels and BCAA/AAA. As in adults, brain MR spectroscopy in children may be helpful in establishing a diagnosis of MHE.

Effects of transfusion in anemia of prematurity.

The authors aimed to test the hypothesis that blood transfusions depress hematopoiesis in healthy infants with anemia of prematurity (AOP). They also set out to find markers that predict recovery from AOP. Thirty-nine premature babies underwent weekly and post-transfusion measurements of hemoglobin concentrations, reticulocyte counts (RCC), and erythropoietin levels (EPO). RCC and EPO dropped significantly 7 days after a blood transfusion but had normalized after 14 days. Elevated RCC or EPO levels were not predictive of an increase in hemoglobin. Postnatal HbFg/dL was higher in babies who had received transfusions. The authors conclude that blood transfusions depress erythropoiesis in infants with AOP and stimulate HbF synthesis but this effect is not sustained. Reticulocyte counts and erythropoietin levels are unhelpful in predicting recovery from AOP.

Two siblings with a new Aicardi-Goutières-like syndrome.

We present two siblings (male and female) with very similar characteristics comprising dysmorphic features, severe developmental delay, progressive microcephaly, tonic seizures, and hypothyroidism. The male also had micropenis and cryptorchidism. Both children developed pericardial effusions which caused the death of the female at age 16 months. The male's cardiac function was stable at last follow-up at the age of 15 months. Cerebral imaging showed widespread intracranial calcifications, delay in myelination, hypoplasia of the corpus callosum, and cerebral atrophy. CSF examination showed normal CSF white-cell count and was negative for interferon, although a cytotoxic antibody was thought to be present. Other causes of a neurodegenerative condition and congenital infection were excluded. The combination of these features has not been described before. We believe that these patients represent a new syndrome which has some of the features of Aicardi-Goutières syndrome but is distinct from it.

Alagille syndrome: prenatal diagnosis and pregnancy outcome.

The Alagille syndrome (AGS) is a multisystem autosomal dominant condition. In this case report, we describe a pregnant woman with this unusual disorder, in whom serial fetal sonography revealed severe pulmonary stenosis and progressively severe intrauterine growth retardation, suggesting that the fetus also had AGS, a diagnosis which was confirmed postnatally. In this report, the potential complications for pregnancy, labor and delivery when both mother and fetus are affected with AGS are described.

Increased hepatic oxidative DNA damage in patients with hepatocellular carcinoma.

Since oxidative DNA damage plays a role in experimental carcinogen-induced cancers, the purpose of the present study was to determine if hepatic oxidative DNA damage was increased in patients with HCC compared to patients with benign hepatic tumors or hepatic metastases (non-HCC) or to patients with end-stage alcoholic liver disease undergoing liver transplantation. Oxidative DNA damage was assessed by 8-hydroxy-2'-deoxyguanosine (8-OH-dG). Results showed that peritumoral 8-OH-dG was markedly increased in HCC (N= 51) (180 +/- 74 vs 32 +/- 58-OH-dG/10(6)dG for tumor, P < 0.005) in contrast to patients with non-HCC (N = 17), in whom the peritumoral 8-OH-dG did not differ from that in tumor (39 +/- 7 vs. 31 +/- 108-OH-dG/10(6)dG). Oxidative DNA damage can be both mutagenic and carcinogenic; our data suggested it will be important in future studies to determine the chronology of this type of liver injury relative to hepatocarcinogenesis.

Utility of liver biopsy culture in pediatric liver transplant recipients.

The purpose of our study was to determine the utility of the practice of culturing percutaneous liver biopsy specimens obtained from pediatric LT recipients for evaluation of fever and/or elevated serum aminotransferases. Accordingly, a retrospective analysis was done of the 101 liver biopsies obtained during an eight-year period which had been submitted for bacterial, fungal and/or viral culture (out of a total of 174 biopsies in 38 patients). The purpose of the analysis was to ask three questions. (1) What organisms were cultured? (2) Were there clinical profiles that were characteristic of the type of organism? (3) Was the practice cost-effective? The analysis indicated that 34/86 biopsy cultures were positive for bacteria, 4/75 for fungus and 2/81 for virus. Clinical and laboratory data for children with cultures positive for enteric flora (n = 9) were compared to those with cultures positive for Gram-positive organisms (n = 17), laboratory contaminants (n = 8), and those with negative cultures (n = 52). Children with biopsies positive for enteric flora had a 'cholestatic profile': mean direct bilirubin 7 mg/dl, ALT 78 IU/l, direct bilirubin/ALT 0.09, in comparison to children with biopsies positive for Gram-positive flora. These children had a 'hepatocellular profile': mean direct bilirubin 4 mg/dl, ALT 332 IU/l, direct bilirubin/ALT 0.01 (p = 0.04 versus the enteric flora values) and a high percentage of polymorphonuclear leukocytes (mean 69% versus 38% for those with negative cultures, p = 0.001.) The charge for performing each bacterial culture was $28 (total $28 x 86 = $2408: $268 per enteric flora-positive biopsy; $93 per biopsy positive for either enteric flora or Gram-positive flora). The charge for each fungal culture was also $28 (total $28 x 75 = $2100: $525 per positive culture), while the cost for each viral culture was $140 (total $140 x 81 = $11,340: $5670 per positive culture). Thus, discounting the eight cultures positive for laboratory contaminants, a total of $15,848 was spent for 32 positive cultures. Given the high cost of liver transplantation, this information suggests that discretion should be used in submission of liver biopsy samples for culture in pediatric transplant patients. We recommend that when liver biopsies are performed for evaluation of elevated serum aminotransferases and/or fever, culture of biopsy specimens for bacteria should be considered in children with a 'cholestatic profile': direct bilirubin > or = 7 mg/dl and direct bilirubin/ALT > 0.08, or a 'hepatocellular profile': direct bilirubin < or = 4 mg/dl and direct bilirubin/ALT < 0.05, together with polymorphonuclear leukocytes > 70%. Following these guidelines might provide valuable information pertinent to patient management (especially since Gram-negative organisms can sometimes be cultured from the liver and not from blood) while reducing costs. Fungal cultures should be restricted to critically ill children. However, our data suggest that the practice of obtaining fungal and viral cultures of the liver in most pediatric transplant patients has an unacceptably high cost/benefit ratio, particularly since recovery of the organism from the peripheral blood is likely.

High viral load and mild liver injury in children with hemophilia compared with other children with chronic hepatitis C virus infection.

BACKGROUND: In adults with hepatitis C virus (HCV) infection, the severity of liver disease may be influenced by the mode of transmission. The purpose of this study was to evaluate whether the mode of transmission affects liver injury and viral load in children with chronic HCV infection, independent of duration of infection and/or HCV genotype. METHODS: Thirty-nine anti-HCV (EIA-2) positive patients, were divided into three groups: group 1, children with a history of blood transfusion (n = 9; age, 13.3+/-1.3 years), group 2, children with hemophilia (n = 19; age, 11.6+/-0.8 years); and group 3, children with maternal-fetal transmitted disease (n = 10; age, 4.7+/-1.1 years). Serum alanine aminotransferase, HCV viral load, HCV genotype, and liver histology were assessed. RESULTS: Serum HCV viral load was higher in group 2 (4.27+/-1.0x10(6) copies/ml; p = 0.006) than in group 1 (0.73+/-0.3x10(6) copies/ml) and in group 3 (0.83+/-0.2x10(6) copies/ml). Conversely, group 2 had less severe liver injury compared with children of similar age in group 1 (p = 0.022). Despite a shorter duration of infection, group 3 had liver injury similar to that in group 1. Hepatitis C virus genotype did not influence the level of viremia or liver injury. CONCLUSIONS: Although children with hemophilia exhibited a high HCV viral load, liver histopathology was less severe than in children who had acquired HCV by blood transfusion or maternal-fetal transmission. These observations support the need to investigate the role of host immune response rather than the virus per se in the pathogenesis of HCV infection in children.

Transforming growth factor-beta1 in plasma and liver of children with liver disease.

Although several liver diseases of childhood, particularly biliary atresia (BA) and cystic fibrosis (CF) liver disease (CFLD) are characterized by hepatic fibrosis, the pathogenesis of this process is incompletely understood. The cytokine transforming growth factor-beta1 (TGF-beta1) has been implicated in hepatic fibrosis in experimental animals, in which both the hepatic expression and plasma concentration of this cytokine are increased. The objective of our study was to determine whether there are similar alterations of TGF-beta1 in patients with hepatic fibrosis secondary to either BA and/or CFLD. The study design was as follows. In study 1, plasma TGF-beta1 was assessed by ELISA in 9 children with BA undergoing liver transplantation, 11 patients with CFLD, and appropriate control subjects. In study 2, hepatic expression of TGF-beta1 protein (assessed immunohistochemically) and hepatic fibrosis were scored semiquantitatively, on a 1-3 scale, by blinded investigators, in archival liver biopsy specimens from 10 children with BA, 10 with CFLD, and from 10 older children with normal hepatic histology, as well as in 4 patients with liver diseases of various etiologies. Simultaneous plasma and liver TGF-beta1 studies were performed in 8 patients with liver disease. Results were as follows. Plasma TGF-beta1 values were inversely correlated with age in healthy subjects (r=-0.54, p < 0.0001). The plasma TGF-beta1 protein of children with BA was decreased (13+/-2 ng/mL) compared with values for healthy children (42+/-6 ng/mL, n=10, p < 0.005). Similarly, the plasma TGF-beta1 concentration in patients with CFLD was also decreased compared with values for children with CF and normal serum liver profiles (n=14) (2+/-1 ng/mL versus 12+/-1, p < 0.05). However, the plasma TGF-beta1 concentration was increased in two patients with other types of liver disease. The hepatic expression of TGF-beta1 was increased in the presence of hepatic fibrosis in all types of liver diseases studied. Forty-six percent of patients had both marked hepatic fibrosis and marked TGF-beta1 labeling; 86% of samples without fibrosis showed no TGF-beta1 labeling, p=0.007. In conclusion, these studies have established the association of hepatic TGF-beta1 protein and hepatic fibrosis in several common liver diseases of childhood. Our data also suggest that, in children, plasma TGF-beta1 does not appear to be a useful marker of hepatic expression of this cytokine.

Kaposi's sarcoma presenting as a protracted multisystem illness in an adolescent liver transplant recipient.

Kaposi's sarcoma (KS) is a common malignancy in patients with acquired immunodeficiency syndrome (AIDS), classically appearing as red to purple plaques containing small papules and nodules. We report our experience with an adolescent orthotopic liver transplant recipient who presented with an unusual presentation of KS. The patient had a protracted multisystem illness that began with hemolytic anemia, fevers, and fatigue and progressed to pancreatitis, sinusitis, lymphadenopathy, and mouth ulcers. The diagnosis was made by a lymph node biopsy that was performed to evaluate for Epstein-Barr virus. The classical subcutaneous nodules characteristic of KS did not become evident until shortly before the patient died. We present this case to emphasize that KS in pediatric liver transplant patients can present as a multisystem disease that progresses to disseminated organ involvement before the characteristic subcutaneous manifestations are evident.

Possible antioxidant effect of vitamin A supplementation in premature infants.

BACKGROUND: Increased lipid peroxidation caused by oxygen free radicals is thought to be one of the common pathogenetic mechanisms for the so-called oxygen radical diseases of prematurity. Since in vitro studies have shown that various forms of vitamin A can exert antioxidant effects that are more potent than those of vitamin E (treatment with which has been ineffective in these diseases), the purpose of this prospective, controlled study was to determine whether administration of supplemental vitamin A to premature infants deficient in this vitamin would have an antioxidant effect in vivo. METHODS: Fourteen infants (1181 +/- 35 g; gestational age 29 +/- 0.04 weeks) with a serum retinol concentration at 7 +/- 2 days of age in the deficient range, lower than 0.7 mumol/l (< 20 micrograms/dl), were enrolled in the study. Infants were randomized to receive the standard amount of vitamin A or standard plus supplemental (2.6 mumol/l [2500 IU] orally each day) vitamin A, beginning at 1 week of age. Antioxidant effects of supplementation were assessed by a decrease in lipid peroxidation, quantified by the ethane content of expired air. RESULTS: Three weeks after study enrollment, total daily vitamin A intake in the infants receiving supplements was 4.565 +/- 0.236 mumol (4354 +/- 225 IU) versus 1.879 +/- 0.317 mumol/l (1792 +/- 302 IU) in infants receiving standard amounts of the vitamin. In spite of the difference in intake of vitamin A, 3 weeks after study enrollment, serum retinol concentrations did not differ between the infants given supplements and those receiving standard amounts of vitamin A, 0.70 +/- 0.21 versus 0.66 +/- 0.07 mumol/l (20 +/- 6 micrograms/dl versus 19 +/- 2 micrograms/dl, respectively). In the infants receiving supplemental vitamin A, breath ethane values declined from baseline values. There was an inverse correlation between the number of weeks of supplementation and breath ethane values, whereas there was no significant correlation between the duration of the study and breath ethane values in the infants not given supplements. CONCLUSIONS: Our data suggest that supplementation with vitamin A in a small group of vitamin A-deficient preterm infants was associated with an antioxidant effect. Although no immediate clinical benefits were associated with supplementation, the data provide the rationale for future investigations of possible antioxidant effects of (larger amounts?) of vitamin A in higher risk premature infants born with subnormal serum retinol concentrations.

Hepatic basolateral sodium-dependent-bile acid transporter expression in two unusual cases of hypercholanemia and in extrahepatic biliary atresia.

The recent cloning of a human sodium-dependent bile acid transporter (NTCP) permits analysis of its expression in human liver disease and investigation of potential primary defects in its expression. NTCP from normal human liver (NHL) was first characterized in detail. Northern blotting of RNA from NHL revealed a 1.8-kb NTCP transcript. Western blotting of crude NHL plasma membranes using a carboxyterminal antipeptide antibody showed that NTCP is a 39-kd polypeptide that is N-glycosylated to a final molecular weight of 56 kd. Indirect immunofluorescent analysis of NHL sections indicated that the NTCP protein is expressed on the basolateral surface of hepatocytes. We hypothesized that the clinical phenotype of a defect in NTCP might be hypercholanemia in the relative absence of liver disease. Accordingly, the coding region of the NTCP gene of two children with this phenotype was sequenced after reverse transcription/polymerase chain reaction (RT/PCR) amplification. No primary defects in the deduced NTCP amino acid sequence were found. Despite the extremely high serum bile salt levels (235 and 126 micromol/L) in these two patients, NTCP messenger RNA (mRNA) and protein expression were quantitatively normal, in contrast to the published observations in a rat model of cholestasis secondary to common bile duct ligation. Hepatic steady-state NTCP mRNA levels in a group of 23 pre- and postportoenterostomy biliary atresia patients were inversely related to total bilirubin, indicating that extrahepatic bile duct obstruction leads to down-regulation of NTCP mRNA levels, similar to that observed in rat common bile duct ligation. Therefore the lack of down-regulation in the two patients with hypercholanemia indicates that elevated serum bile salts are not sufficient to down-regulate NTCP expression, these two patients have abnormal responses to hypercholanemia, or these two patients have a defect in a gene other than NTCP that influences hepatic clearance of bile salts.