Philippe Goyens

Impact of chronic hepatitis B and interferon-α therapy on growth of children

Interferon‐α (IFN) has been approved as treatment for children with chronic hepatitis B (CHB). The aims of this study were to assess the impact on children’s growth of the disease itself and of IFN treatment. The growth of 142 children with CHB (70 IFN‐treated, 72 untreated) was monitored for a minimum of one year. Regression analysis models were used to determine which of the variables most affected children’s growth. After adjusting for racial differences, the population of 142 children with CHB had a mean baseline height for age percentile of 39 and a mean baseline weight for age percentile of 38, which were significantly different (Pu2003<u20030.0001) from the 50th percentiles of their respective reference populations. The height for age Z score of untreated children was inversely correlated with serum hepatitis B virus DNA and aspartate aminotransferase levels, and the weight for age Z score was inversely correlated with serum hepatitis B virus DNA levels. While undergoing IFN therapy, children displayed a ‘U‐shaped’ growth pattern, such that height for age and weight for age Z scores at 3 or 6u2003months were lower than scores at baseline or 12u2003months. In this study the average child with CHB showed compromised growth even in the absence of IFN therapy. During IFN therapy, children’s growth was temporarily disrupted.

Chronic hepatitis B infection: long term comparison of children receiving interferon alpha and untreated controls.

Objectives: To investigate the virological outcome of chronic hepatitis B (CH-B) in children who received interferon alpha (IFN) compared with no treatment. Methods: Seventy-four children with CH-B (median age, 6.1 years; 44 boys) selected from a cohort of 158 cases were included and divided into two groups: IFN-treated (n = 37) and control (n = 37). The controls were matched with the treated children by baseline alanine aminotransferase (ALT) levels, sex and age. The Kaplan-Meier method was performed to estimate the time to clearance of hepatitis B e antigen (HbeAg) and hepatitis B surface antigen (HbsAg). Results: Mean duration of follow-up was comparable in two groups (5.2 ± 3.8 years in treatment group versus 5.2 ± 3.7 years in control group, NS). HBeAg and HBsAg loss occurred in 20 (54.1%) and three treated children versus 13 (35.1%) and one untreated children (NS), respectively. The 7-year cumulative HBeAg and HBsAg clearance rates were 47.5% and 8.9% after the first visit in the treatment group versus 33.5% and 4.0% in untreated children (NS), respectively. Elevated baseline ALT (two times upper limit of normal) had a significant effect on the long-term cumulative rate of HBeAg seroconversion in treated patients (P = 0.01) but not in the untreated group. Conclusions: These findings show that the overall long-term virological outcome does not differ significantly between IFN-treated and untreated children but that a significant benefit of treatment on the long term rate of HBeAg seroconversion is obtained in children with higher baseline ALT levels.

Effects of thirty elements on bone metabolism

The human skeleton, made of 206 bones, plays vital roles including supporting the body, protecting organs, enabling movement, and storing minerals. Bones are made of organic structures, intimately connected with an inorganic matrix produced by bone cells. Many elements are ubiquitous in our environment, and many impact bone metabolism. Most elements have antagonistic actions depending on concentration. Indeed, some elements are essential, others are deleterious, and many can be both. Several pathways mediate effects of element deficiencies or excesses on bone metabolism. This paper aims to identify all elements that impact bone health and explore the mechanisms by which they act. To date, this is the first time that the effects of thirty minerals on bone metabolism have been summarized.

Copper deficiency in infants with active celiac disease.

Celiac disease was diagnosed in two unrelated infants aged 7 and 7.5 months with severe malnutrition. They showed typical clinical, biological, and histological signs of the disease. Moreover, accompanying copper deficiency was suggested by severe hypocupremia and persistent neutropenia; bone radiographs were also compatible with this diagnosis. Rapid and complete correction of these anomalies could only be obtained after addition of oral copper sulfate to the gluten-free diet. Mechanisms possibly involved in the development of copper deficiency in young infants with celiac disease are: chronic malabsorption; high copper needs in rapidly growing infants; and possibly increased biliary and digestive losses. It is therefore suggested that young children with severe celiac disease should be monitored for their copper status.

Hepatocyte transplantation using the domino concept in a child with Tetrabiopterin non-responsive phenylketonuria.

Phenylketonuria is a metabolic disease caused by phenylalanine hydroxylase deficiency. Treatment is based on a strict natural protein-restricted diet that is associated with the risk of malnutrition and severe psychosocial burden. Oral administration of tetrahydrobiopterin can increase residual enzyme activity, but most patients with severe clinical phenotypes are nonresponders. We performed liver cell transplantation in a 6-year-old boy with severe tetrahydrobiopterin nonresponsive phenylketonuria who failed to comply with diet prescriptions. The transplanted hepatocytes were obtained in part from an explanted glycogen storage type 1b liver. Following two infusions, blood phenylalanine levels returned within the therapeutic target while the phenylalanine half-life assessed by loading tests decreased from 43 to 19 h. However, 3 months later, blood phenylalanine concentrations increased and the phenylalanine intake had to be reduced. Cell-based therapy is a promising therapeutic option in phenylketonuria, and the domino concept may solve the issue of cell sources for hepatocyte transplantation.

Neuropsychological outcome of NTBC-treated patients with tyrosinaemia type 1

Corinne De Laet, Vanessa Terrones Munoz, Jaak Jaeken, Baudouin FranAois, Dietbrandt Carton, Etienne M Sokal, Bernard Dan, Philippe J Goyens 1 Nutrition and Metabolism Unit, H pital Universitaire des Enfants Reine Fabiola, Universit Libre de Bruxelles (ULB), Brussels, Belgium. 2 Centre for Metabolic Diseases, University Hospital Gasthuisberg, Leuven, Belgium. 3 Pinocchio Centre for Inborn Metabolic Diseases, Esperance Hospital, Li ge, Belgium. 4 Centre for Metabolic Diseases, Ghent University Hospital, Ghent, Belgium. 5 Paediatric Department, St Luc Clinics, Brussels, Belgium. Correspondence to: corinne.delaet@huderf.be

Micronutrient status in phenylketonuria.

Patients with phenylketonuria (PKU) encompass an at risk group for micronutrient imbalances. Optimal nutrient status is challenging particularly when a substantial proportion of nutrient intake is from non-natural sources. In PKU patients following dietary treatment, supplementation with micronutrients is a necessity and vitamins and minerals should either be added to supplement phenylalanine-free l-amino acids or given separately. In this literature review of papers published since 1990, the prevalence of vitamin and mineral deficiency is described, with reference to age of treatment commencement, type of treatment, dietary compliance, and dietary practices. Biological micronutrient inadequacies have been mainly reported for zinc, selenium, iron, vitamin B12 and folate. The aetiology of these results and possible clinical and biological implications are discussed. In PKU there is not a simple relationship between the dietary intake and nutritional status, and there are many independent and interrelated complex factors that should be considered other than quantitative nutritional intake.

Familial adrenocorticotropin unresponsiveness associated with alacrima and achalasia: biochemical and molecular studies in two siblings with clinical heterogeneity.

The syndrome of familial adrenocorticotropin (ACTH) unresponsiveness is a rare form of primary adrenal insufficiency, usually without mineralocorticoid deficiency. It is characterized by elevated plasma ACTH concentration and undetectable plasma cortisol levels not responding to exogenous ACTH. Alacrima and achalasia have also been occasionally associated with adrenal insufficiency (triple A syndrome). Pathogenetic mutations have beein indentified in the ACTH receptor gene in families with isolated familial ACTH unresponsiveness. Whether the ACTH receptor represents the locus of the defect for the triple A syndrome is not known. Here we report two siblings with familial ACTH unresponsiveness who were discrenant for skin pigmentation and mineralocorticoid function. In addition, achalasia and alacrima wer documented only in the older sibling. The boy, studied at the age of 2 years, was hyperpigmented, in contrast to his normally pigmented siter, studied at the age of 9 years; basal plasma α-melanocyte stimulating hormone immunure-acitivity levels wer 79 and 38 pg/ml, respectively (normal <40 pg/ml). Furosemide-induced diuresis resulted in normal rises of plasma rein activity in both patients; however, plasma aldosterone levels increased only in the boy and not in his sister. Screening for abnormalities of the ACTH receptor gene by single strand conformation polymorphism analysis revealed no abnormality. Direct sequencing of the entire conding area of the ACTH receptor gene was also normal.ConclusionThe syndrome of familial ACTH unresponsiveness can vary clinically and biologically within the same family. In contrast to results from some families with isolated familial ACTH unresponsiveness, the ACTH receptor gene does not appear to be the locus of the defect in this pedigree, suggesting a different molecular aetiology for the triple A syndrome which assciates adrenal insuficiency alacrima and achalasia.

Key features and clinical variability of COG6-CDG.

The conserved oligomeric Golgi (COG) complex consists of eight subunits and plays a crucial role in Golgi trafficking and positioning of glycosylation enzymes. Mutations in all COG subunits, except subunit 3, have been detected in patients with congenital disorders of glycosylation (CDG) of variable severity. So far, 3 families with a total of 10 individuals with biallelic COG6 mutations have been described, showing a broad clinical spectrum. Here we present 7 additional patients with 4 novel COG6 mutations. In spite of clinical variability, we delineate the core features of COG6-CDG i.e. liver involvement (9/10), microcephaly (8/10), developmental disability (8/10), recurrent infections (7/10), early lethality (6/10), and hypohidrosis predisposing for hyperthermia (6/10) and hyperkeratosis (4/10) as ectodermal signs. Regarding all COG6-related disorders a genotype-phenotype correlation can be discerned ranging from deep intronic mutations found in Shaheen syndrome as the mildest form to loss-of-function mutations leading to early lethal CDG phenotypes. A comparison with other COG deficiencies suggests ectodermal changes to be a hallmark of COG6-related disorders. Our findings aid clinical differentiation of this complex group of disorders and imply subtle functional differences between the COG complex subunits.

Main issues in micronutrient supplementation in phenylketonuria

For almost all patients with PKU, a low phenylalanine diet is the basis of the treatment despite a widely varying natural protein tolerance. A vitamin and mineral supplement is essential and it is commonly added to a phenylalanine-free (phe-free) source of L-amino acids. In PKU, many phe-free L-amino acid supplements have age-specific vitamin and mineral profiles to meet individual requirements. The main micronutrient sources are chemically derived and their delivery dosage is usually advised in three or more doses throughout the day. Within the EU, the composition of VM (vitamin and mineral) phe-free L-amino acid supplements is governed by the Foods for Special Medical Purposes (FSMP) directive (European Commission Directive number 1999/21/EC and amended by Directive 2006/141/EC). However the micronutrient composition of the majority fails to remain within FSMP micronutrient maximum limits per 100 kcal due to their low energy content and so compositional exceptions to the FSMP directive have to be granted for each supplement. All patients with PKU require an annual nutritional follow-up, until it has been proven that they are not at risk of any vitamin and mineral imbalances. When non-dietary treatments are used to either replace or act as an adjunct to diet therapy, the quality of micronutrient intake should still be considered important and monitored systematically. European guidelines are required about which micronutrients should be measured and the conditions (fasting status) for monitoring.