Gabriella Nebbia

Posttransfusion and community-acquired hepatitis C in childhood

Following a longitudinal study of chronic non-A, non-B hepatitis in Italy and Spain, we evaluated the epidemiologic and clinical features of chronic hepatitis C in 77 consecutively observed children (35 male; mean age, 4 years) without underlying systemic diseases. All subjects were positive for antibody to hepatitis C virus in serum by second-generation tests. Forty-six patients had received blood transfusions in the perinatal period; 12 had a mother with antibodies to HCV in serum (five of these mothers were drug users or partners of a drug user); seven had a history of putative percutaneous exposure; and 12 had not been exposed to any risk factors for viral hepatitis. At presentation, only 22% were symptomatic, mean alanine-aminotransferase levels were three times the upper normal value, and liver histology showed active disease in only nine of 28 cases (32%). During a mean observation period of 6 years, only 11 of 57 patients (19%) complained of symptoms and 11 of 40 cases (27%) had histologic features of active hepatitis. Two patients had severe hepatitis with associated cirrhosis. However, only six of 57 cases (10%) achieved sustained biochemical remission. The clinical features and the outcome were similar in both the posttransfusion and the community-acquired cases. These results indicate that transfusions in the perinatal period are the single most important cause of hepatitis C in otherwise healthy children. Community-acquired cases represent an heterogeneous epidemiologic group in which maternal transmission, whether perinatal or postnatal, could be relevant. Histologically severe hepatitis and cirrhosis seem to be an infrequent feature of chronic hepatitis C virus infection in childhood and adolescence, in spite of persistent liver damage.

Long-term interferon-α treatment of children with chronic hepatitis delta: A multicentre study

Summary We assessed the efficacy of prolonged interferon‐α (IFN) therapy in children with chronic hepatitis caused by hepatitis delta virus (HDV) by treating 26 paediatric cases with IFN‐α2b(5 MU m‐2, then 3 MU m‐2 three times weekly for 12 (medium‐term group, MTG) or 24 months (long‐term group, LTG). Compliance and tolerability were acceptable. At the end of therapy a complete biochemical response [normalization of alanine aminotransferase (ALT)] occurred in 12 children (5/13 in MTG and 7/13 in LTG). A relapse occurred after stopping IFN in 10 cases (five in MTG and five in LTG). Two patients from the LTG had normal liver function tests during 12 months of follow‐up. Six of the eight hepatitis Be antigen (HBeAg) positive children lost HBeAg, while all six hepatitis B virus (HBV) DNA positive patients lost HBV DNA during treatment. HBeAg reappeared later in two children. HDV RNA, present in 10/10 cases of MTG before treatment, persisted after 12 months IFN therapy in 3/10. One year after stopping therapy, 8/10 patients were again HDV RNA positive. Two children cleared hepatitis delta antigen (HDVAg) from the liver. No significant improvements in liver histology were seen in both groups. Our experience suggests that IFN‐α treatment in children with chronic type D hepatitis has a transient effect, and long‐term treatment does not appear to induce a greater therapeutic benefit in terms of biochemical and virological response.

Glucose metabolism and diet-based prevention of liver dysfunction in MPV17 mutant patients

BACKGROUND/AIMS To describe in detail the specific clinical and biological characteristics of three patients with MPV17 gene mutations, a rare hepatocerebral mitochondrial DNA depletion syndrome (MDS) and the positive effects of a novel dietetic treatment based on avoidance of fasting. METHODS We describe the case histories of three members of the same family with MPV17 mutations. RESULTS Two patients had a very severe and progressive liver disease: 1 died in the first year of life and the other underwent liver transplantation. The third patient, now 13 years of age, had a milder form of liver disease and developed progressive ataxia. Psychomotor involvement at onset of disease was mild or absent. No patient had severe hyperlactataemia. In vivo functional studies on two patients showed no hyperlactataemia even after intravenous and oral glucose loading, regular fasting hypoglycemia 3-4h after meals and no response to glucagon. Liver function tests improved when patients received continuous iv glucose infusion or were regularly fed every 3h. CONCLUSIONS These clinical and biochemical features allow us to differentiate patients with MPV17 mutations from other liver MDS and suggest that regular glucose intake at short intervals may be beneficial in slowing the progression of the disease.

Hepatitis C virus (HCV) genotypes in 373 Italian children with HCV infection: changing distribution and correlation with clinical features and outcome

Background and aim: Little is known of hepatitis C virus (HCV) genotypes in HCV infected children. This retrospective, multicentre study investigated genotype distribution and correlation with clinical features and outcome in a large series of Italian children. Methods: Between 1990 and 2002, 373 HCV RNA positive children, consecutively recruited in 15 centres, were assayed for genotypes by a commercial line probe assay. Results: The following genotype distribution pattern was recorded: genotype 1b = 41%; 1a = 20%; 2 = 17%; 3 = 14.5%; 4 = 5%; other = 2.5%. The prevalence of genotypes 1b and 2 decreased significantly (p<0.001) among children born from 1990 onwards compared with older children (46% v 70%) while the rate of genotypes 3 and 4 increased significantly (from 8% to 30%). Children infected with genotype 3 had the highest alanine aminotransferase levels and the highest rate of spontaneous viraemia clearance within the first three years of life (32% v 3% in children with genotype 1; p<0.001). Of 96 children enrolled in interferon trials during the survey, 22% definitely lost HCV RNA, including 57% of those with genotypes 2 and 3. Conclusion: HCV genotypes 1 and 2 are still prevalent among infected adolescents and young adults in Italy but rates of infection with genotypes 3 and 4 are rapidly increasing among children. These changes could modify the clinical pattern of hepatitis C in forthcoming years as children infected with genotype 3 have the best chance of spontaneous viraemia clearance early in life, and respond to interferon in a high proportion of cases.

Jagged-1 mutation analysis in Italian Alagille syndrome patients

Alagille syndrome (AGS) is an autosomal dominant disorder with developmental abnormalities affecting the liver, heart, eyes, vertebrae, and craniofacial region. The Jagged‐1 (JAG1) gene, which encodes a ligand of Notch, has recently been found mutated in AGS. In this study, mutation analysis of the JAG1 gene performed on 20 Italian AGS patients led to the identification of 15 different JAG1 mutations, including a large deletion of the 20p12 region, six frameshift, three nonsense, three splice‐site, and two missense mutations. The two novel missense mutations were clustered in the 5′ region, while the remaining mutations were scattered throughout the gene. The spectrum of mutations in Italian patients was similar to that previously reported. We also studied in detail a complex splice site mutation, 3332dupl8bp, which was shown to lead to an abnormal JAG1 mRNA, resulting in a premature stop codon. With the exception of the missense mutations, the majority of the JAG1 mutations are therefore likely to produce truncated proteins. Since the phenotype of the patient with a complete deletion of the JAG1 gene is indistinguishable from that of patients with intragenic mutations, our study further supports the hypothesis that haploinsufficiency is the most common mechanism involved in AGS pathogenesis. Furthermore, our data confirmed the absence of a correlation between the genotype of the JAG1 gene and the AGS phenotype. Hum Mutat 14:394–400, 1999.

The effect of breakfast composition and energy contribution on cognitive and academic performance: a systematic review

BACKGROUND Most studies that assess the effects of breakfast on subsequent mental abilities compared performance in subjects who had or had not consumed this meal. However, characteristics of breakfast itself may induce metabolic and hormonal alterations of the gastrointestinal tract and potentially modify cognitive performance. Moreover, as far as the evidence on the positive effects of having breakfast is becoming more robust, interest may shift to the specific characteristics of an adequate breakfast. OBJECTIVE The objective was to summarize existing evidence on the role of nutrient composition or energy intake at breakfast on the accomplishment of school-related tasks and cognition. DESIGN We conducted a systematic review of the literature through the PubMed database. RESULTS From the literature search, we identified 102 articles, 15 of which met the inclusion criteria. Of these, 3 studies provided information on the relation between cognitive and academic performance and energy intake at breakfast, 11 provided the same information for the macronutrient composition of breakfast, and 1 investigated both the aspects. Eleven studies considered breakfast meals differing in glycemic index/load. Selected studies were generally carried out in well-nourished children and adults of both sexes from general education. They were mostly experimental studies of short duration and had a limited number of subjects. Cognitive and academic performance was investigated by looking at multiple domains, including memory, attention, reasoning, learning, and verbal and math abilities, with a variety of test batteries scheduled at different time points in the morning. Breakfast options differed in terms of included foods and place and time of administration. CONCLUSIONS There is insufficient quantity and consistency among studies to draw firm conclusions. However, whereas the hypothesis of a better and more sustained performance with a breakfast providing >20% daily energy intake still needs substantiation, there does appear to be emerging, but still equivocal, evidence that a lower postprandial glycemic response is beneficial to cognitive performance.

Immunity to poliomyelitis, diphtheria and tetanus in pediatric patients before and after renal or liver transplantation

Few studies have considered the safety, efficacy and appropriateness of vaccinations in pediatric patients before and after solid organ transplantation. The aim of this study was to evaluate the immune status after primary vaccination to diphtheria, tetanus and poliomyelitis in pediatric patients before and after hepatic transplantation and to poliomyelitis in pediatric patients before and after renal transplantation. All the patients had received a complete primary immunization schedule for diphtheria and tetanus and poliomyelitis. Immunity to the three polioviruses was evaluated in 56 patients with renal transplant, 27 on chronic dialysis and 33 controls and in 39 patients with hepatic transplant, 25 with chronic hepatic failure and their 36 controls. Immunity to diphtheria and tetanus was evaluated in 52 liver transplant patients, 29 children with chronic hepatic failure and 54 healthy children. Renal transplant patients were less protected and had lower antibody geometric mean titers than healthy controls for polioviruses 1 and 2. Whereas, protection in the children liver transplant patients was similar to that in their controls. Patients with chronic hepatic failure had higher antibody geometric mean titers to diphtheria and polioviruses 1 and 3 than their control group. Immunosuppression after transplantation has a negative influence on the immune status after primary vaccination in children with renal transplant. Whereas children with chronic hepatic failure have higher antibodies than a normal population. When possible, it could be advisable to individualize immunization schedules in patients at high risk.

Comparative Analysis of rs12979860 SNP of the IFNL3 Gene in Children with Hepatitis C and Ethnic Matched Controls Using 1000 Genomes Project Data

The rs12979860 single nucleotide polymorphism located on chromosome 19q13.13 near the interferon L3 gene (formerly and commonly known as interleukin 28B gene) has been associated in adults with both spontaneous and treatment induced clearance of hepatitis C virus. Although the exact mechanism of these associations remains unclear, it suggests that variation in genes involved in the immune response against the virus favours viral clearance. Limited and preliminary data are available on this issue in children. The aim of the present study was to evaluate, in a representative cohort of children with perinatal infection, the potential association between rs12979860 single nucleotide polymorphism and the outcome of hepatitis C virus infection. Alleles and genotypes frequencies were evaluated in 30 children who spontaneously cleared the virus and in 147 children with persistent infection and were compared with a population sample of ethnically matched controls with unknown hepatitis C status obtained using the 1000 Genomes Project data. The C allele and the C/C genotype showed greater frequencies in the clearance group (76.7% and 56.7%, respectively) when compared with both children with viral persistence (C allele 56.5%, p = 0.004; C/C genotype 32.7%, p = 0.02) and with the ethnically matched individuals (C allele 59.7%, p = 0.02; C/C genotype 34.7%, p = 0.03). Children with the C/C genotype were 2 times more likely to clear hepatitis C virus relative to children with the C/T and T/T genotypes combined (odds ratio: 2.7; 90% confidence intervals: 1.3–5.8). The present study provides the evidence that the rs12979860 single nucleotide polymorphism influences the natural history of hepatitis C virus in children.

Liver Steatosis in Children With Chronic Hepatitis C

OBJECTIVES:Steatosis is common in adults with chronic hepatitis C, and is involved in the progression of fibrosis. Because little is known about steatosis in pediatric hepatitis C, the aims of this study were to determine the prevalence and severity of steatosis in a pediatric population with chronic hepatitis C, and to evaluate its correlation with clinical parameters.METHODS:Liver biopsies were obtained from 66 consecutive Italian and Spanish children with chronic hepatitis C (87.6% genotype 1). Grade and stage were assessed according to Ishaks system. Steatosis was scored as absent, minimal (less than 5% of steatosic hepatocytes), mild (>5%, ≤33%), moderate (>33%, ≤66%), and severe (>66%); moderate and severe scores were combined for statistical purposes. The BMI-for-age percentile (BMI%) was calculated in all cases at the time of liver biopsy. Cholesterol and triglyceride serum levels were available in 55 cases.RESULTS:The prevalence of steatosis was 27% (18/66 cases, 16/18 with genotype 1), and it was higher in Italian than in Spanish patients (10/21 vs.7/45, P = 0.01). BMI% correlated significantly with both the presence of steatosis (P = 0.002) and its severity (P = 0.000). Steatosis also correlated with serum triglyceride levels (P = 0.04).CONCLUSION:Steatosis is associated with BMI in children with chronic hepatitis C due mainly to genotype 1, and with no confounding hepatotoxic factors (alcohol or drugs). This may reflect its metabolic rather than viral origin and raise new issues in the management of children with hepatitis C.

JAG1 loss-of-function variations as a novel predisposing event in the pathogenesis of congenital thyroid defects

CONTEXT The pathogenesis of congenital hypothyroidism (CH) is still largely unexplained. We previously reported that perturbations of the Notch pathway and knockdown of the ligand jagged1 cause a hypothyroid phenotype in the zebrafish. Heterozygous JAG1 variants are known to account for Alagille syndrome type 1 (ALGS1), a rare multisystemic developmental disorder characterized by variable expressivity and penetrance. OBJECTIVE Verify the involvement of JAG1 variants in the pathogenesis of congenital thyroid defects and the frequency of unexplained hypothyroidism in a series of ALGS1 patients. DESIGN, SETTINGS, AND PATIENTS A total of 21 young ALGS1 and 100 CH unrelated patients were recruited in academic and public hospitals. The JAG1 variants were studied in vitro and in the zebrafish. RESULTS We report a previously unknown nonautoimmune hypothyroidism in 6/21 ALGS1 patients, 2 of them with thyroid hypoplasia. We found 2 JAG1 variants in the heterozygous state in 4/100 CH cases (3 with thyroid dysgenesis, 2 with cardiac malformations). Five out 7 JAG1 variants are new. Different bioassays demonstrate that the identified variants exhibit a variable loss of function. In zebrafish, the knock-down of jag1a/b expression causes a primary thyroid defect, and rescue experiments of the hypothyroid phenotype with wild-type or variant JAG1 transcripts support a role for JAG1 variations in the pathogenesis of the hypothyroid phenotype seen in CH and ALGS1 patients. CONCLUSIONS clinical and experimental data indicate that ALGS1 patients have an increased risk of nonautoimmune hypothyroidism, and that variations in JAG1 gene can contribute to the pathogenesis of variable congenital thyroid defects, including CH.