Background & Aims
To identify prognostic factors for liver disease in children with alpha‐1 antitrypsin deficiency, irrespective of phenotype, using the DEFI‐ALPHA cohort.
Methods
Retrospective, then ...prospective from 2010, multicentre study including children known to have alpha‐1 antitrypsin blood concentration below 0.8 g/L, born in France since 1989. Clinical and biological data were collected. Liver disease was classified as “severe” (portal hypertension, liver failure, liver transplantation or death); “moderate” (persistent abnormal liver biology without portal hypertension); and “mild/none” (normal or almost normal liver biology and native liver). Prognostic factors for severe liver disease were evaluated using a Cox semiparametric model.
Results
In January 2017, 153 patients from 19 centres had been included; genotypes were PIZZ in 81.9%, PISZ in 8.1%, other in 10.0%. Mean ± SD follow‐up was 4.7 ± 2.1 years. Half of patients had moderate liver disease. Twenty‐eight children (18.3%) had severe liver disease (mean age 2.5 years, range: 0‐11.6): diagnosis of alpha‐1 antitrypsin deficiency was made before two months of age in 65.4%, genotypes were PIZZ in 25 (89.3%), PISZ in 2, PIMlikeZ in 1, 15 children underwent liver transplantation, 1 child died at 3 years of age. Neonatal cholestasis was significantly associated with severe liver disease (P = 0.007).
Conclusion
Alpha‐1 antitrypsin‐deficient patients presenting with neonatal cholestasis were likely to develop severe liver disease. Some patients with non‐homozygous ZZ genotype can develop severe liver disease, such as PISZ and M variants, when associated with predisposing factors. Further genetic studies will help to identify other factors involved in the development of liver complications.
See Editorial on Page 1019
Inherited metabolic diseases (IMD) form a heterogeneous group of genetic disorders that surface primarily during childhood and result in significant morbidity and mortality. A prevalence of 1 in ...2500–5000 live births is often reported. The transfer of adolescents from pediatric care to adult health facilities is often difficult for patients and their families and can lead to a breakdown in medical follow-up and therefore serious complications. Existing recommendations for the successful transition of patients with chronic disorders do not specifically address patients with IMDs associated with dietary treatment. Here, the French network for rare inherited metabolic diseases (G2M) presents its reflections and recommendations for a successful transition. Preparations for the transfer must be made well in advance. The transfer must aim for adolescents gaining autonomy by making them responsible and providing them with the knowledge that will enable them to manage their care themselves, know how to react appropriately if there is any change in their condition, and move comfortably within the adult healthcare system. This requires the active participation of the patient, his or her family, and pediatric and adult care teams. It involves multidisciplinary management plus the production and maintenance of an educational therapy program. Finally, the identification of physicians and dietitians trained in IMDs, relevant subspecialists, and even expert patients could improve the continuum of complete and appropriate care for these patients within adult medicine.
Silence, ça tourne Larrauffie, A.; Porcheron, M.; Pariente, J. ...
La revue de medecine interne,
September 2023, 2023-09-00, Volume:
44, Issue:
9
Journal Article
Nouveaux concepts dans l’hémochromatose périnatale Baruteau, J.; Heissat, S.; Collardeau-Frachon, S. ...
Archives de pédiatrie : organe officiel de la Société française de pédiatrie,
July 2012, Volume:
19, Issue:
7
Journal Article
Peer reviewed
L’hémochromatose périnatale (HP) est une maladie à début anténatal caractérisée par une insuffisance hépatocellulaire aiguë (IHA) néonatale avec cirrhose et surcharge en fer intra- et extrahépatique ...épargnant le système réticulo-endothélial. Cette affection est la première cause d’IHA néonatale et son pronostic est redoutable puisque plus de 70 % des enfants décèdent lors de la période périnatale ou bénéficient d’une transplantation hépatique néonatale. Le risque de récurrence dans la fratrie est proche de 90 %. Le diagnostic est difficile et impose d’exclure les autres causes d’IHA néonatale. L’hypothèse physiopathologique actuellement retenue est celle d’une allo-immunisation maternofœtale dirigée contre le foie fœtal. Un anticorps maternel activerait la partie terminale de la voie classique d’activation du complément, responsable de la formation d’un complexe d’attaque membranaire contre l’hépatocyte fœtal. Un traitement anténatal par immunoglobulines intraveineuses des mères ayant une grossesse précédente compliquée d’HP au cours de la grossesse améliore considérablement l’évolution de la maladie et son pronostic. En France, l’indication du traitement par immunoglobulines est validée après expertise des données cliniques et anatomopathologiques du cas index par un comité national pluridisciplinaire.
Perinatal hemochromatosis (PH) includes neonatal acute liver failure (ALF) with cirrhosis and extrahepatic iron overload sparing the reticuloendothelial system. This is the main cause of neonatal ALF. Prognosis is very poor, usually with neonatal death or neonatal orthotopic liver transplantation occurring in more than 70%. The recurrence rate is more than 90%. Diagnosis is hard to make and is proved after exclusion of other neonatal ALF causes. A recent physiopathological hypothesis proposed HP as a maternofetal alloimmune disease against the fetal liver. A maternal antibody may activate the terminal complement cascade, responsible for the membrane attack complex directed against fetal hepatocytes. Maternal prenatal treatment after a pregnancy complicated by PH modifies the course and the prognosis of this disease. In France, approval of prenatal IVIG treatment is required after analysis of clinical and pathological data by a national multidisciplinary committee.
Introduction La surcharge glycogénique du foie est la principale cause d’hépatomégalie chez l’enfant atteint de diabète de type 1. D’abord décrite dans le cadre du syndrome de Mauriac, cette ...pathologie se révèle actuellement plus souvent par une atteinte hépatique isolée, qui reste peu connue et décrite. Matériels et méthodes A partir de 3 observations d’adolescents ayant présenté une hépatopathie glycogénique liée au diabète nous décrivons la présentation de cette pathologie ainsi que son évolution et sa physiopathologie. Cas Clinique Trois adolescents, suivis pour un diabète de type 1, ont présenté en période de déséquilibre glycémique une hépatomégalie de taille variable associée à des douleurs abdominales et/ou des vomissements, des œdèmes chez un patient. Les explorations biologiques montraient : une élévation des transaminases et de la γ-glutamyl-tranférase, une hypertriglycéridémie, une hypoalbuminémie pour un patient (taux de prothrombine et bilirubine normaux). L’échographie abdominale retrouvait un aspect hyper-échogène du foie. Après exclusion des principaux diagnostics différentiels, une biopsie hépatique a été réalisée. L’analyse histologique a révélé une surcharge glycogénique associée à une stéatose faible à modérée. L’évolution a été fonction de l’équilibre glycémique : favorable pour le patient dont le diabète a été correctement équilibré, mais persistance d’anomalies clinico-biologiques pour les autres patientes dont le contrôle glycémique est resté insuffisant. La surveillance retrouve chez une de ces patientes un nodule hépatique, dont l’aspect radiologique est en faveur d’un adénome. Discussion L’hépatopathie glycogénique est habituellement décrite comme une pathologie bénigne, régressant lors de l’optimisation de l’insulinothérapie. Lorsque c’est le cas la biopsie hépatique peut être évitée. Cependant cette évolution n’est pas constante, en raison d’un équilibre glycémique parfois difficile à obtenir chez l’adolescent, et il est possible qu’un risque de complications existe. Conclusion L’hépatopathie glycogénique doit être évoquée devant un adolescent diabétique présentant une hépatomégalie et/ou une perturbation de la biologie hépatique. Une fois le diagnostic posé, le suivi doit être prolongé afin de dépister d’éventuelles rechutes ou complications.
Niemann-Pick disease type C (NP-C) is a rare neurovisceral disease characterised by progressive neurological degeneration, where the rate of neurological disease progression varies depending on age ...at neurological onset. We report longitudinal data on functional disease progression and safety observations in patients in the international NPC Registry who received continuous treatment with miglustat.
The NPC Registry is a prospective observational cohort of NP-C patients. Enrolled patients who received ≥1 year of continuous miglustat therapy (for ≥90 % of the observation period, with no single treatment interruption >28 days) were included in this analysis. Disability was measured using a scale rating the four domains, ambulation, manipulation, language and swallowing from 0 (normal) to 1 (worst). Neurological disease progression was analysed in all patients based on: 1) annual progression rates between enrolment and last follow up, and; 2) categorical analysis with patients categorised as 'improved/stable' if ≥3/4 domain scores were lower/unchanged, and as 'progressed' if <3 scores were lower/unchanged between enrolment and last follow-up visit.
In total, 283 patients were enrolled from 28 centers in 13 European countries, Canada and Australia between September 2009 and October 2013; 92 patients received continuous miglustat therapy. The mean (SD) miglustat exposure during the observation period (enrolment to last follow-up) was 2.0 (0.7) years. Among 84 evaluable patients, 9 (11 %) had early-infantile (<2 years), 27 (32 %) had late-infantile (2 to <6 years), 30 (36 %) had juvenile (6 to <15 years) and 18 (21 %) had adolescent/adult (≥15 years) onset of neurological manifestations. The mean (95%CI) composite disability score among all patients was 0.37 (0.32,0.42) at enrolment and 0.44 (0.38,0.50) at last follow-up visit, and the mean annual progression rate was 0.038 (0.018,0.059). Progression of composite disability scores appeared highest among patients with neurological onset during infancy or childhood and lowest in those with adolescent/adult-onset. Overall, 59/86 evaluable patients (69 %) were categorized as improved/stable and the proportion of improved/stable patients increased with age at neurological onset. Safety findings were consistent with previous data.
Disability status was improved/stable in the majority of patients who received continuous miglustat therapy for an average period of 2 years.
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