Serologic test for neonatal hemochromatosis in infants with acute liver failure

描述（由申请人提供）：本申请涉及广泛的挑战领域（04）临床研究和特定的挑战04-DK-104改善肝脏疾病的诊断、分期和治疗。本申请特别寻求开发一种方法，该方法将改善婴儿中急性肝衰竭的诊断，导致药物治疗的显著改善的结果，并减少儿科患者中肝移植的使用。新生儿血色病（NH）是大多数系列中新生儿肝衰竭的主要诊断原因。然而，在高达40%的婴儿中无法诊断为急性肝衰竭。本申请的总体目的是确定NH作为90天龄婴儿急性肝衰竭原因的真实患病率。在确定NH作为急性肝功能衰竭原因的重要性之前，科学知识中需要克服的关键差距是缺乏NH的敏感和特异性诊断生物标志物。由于NH是由母体对胎肝的同种免疫引起的，因此提出的生物标志物是母亲或婴儿血清中存在“抗胎肝细胞IgG抗体”。免疫荧光法对该生物标志物的诊断效用有待确定，然后将其用于评估急性肝衰竭婴幼儿人群中NH的患病率。通常，获得足够大的研究人群来支持这样的研究将需要多年的研究。然而，将使用从儿科急性肝衰竭研究库获得的血清，使得在两年内完成拟定工作是可行的。预期的结果将表明NH构成了所有幼儿急性肝功能衰竭原因的50%。这一发现将产生重大的积极影响，因为NH对特定的药物治疗有反应，这比目前的治疗（包括肝移植）改善了结果。此外，如果本分析中使用的新测试被证明对诊断具有敏感性和特异性，则它可以取代当前的诊断方法，并前瞻性地提高这种情况下的诊断准确性。因此，早期，准确的诊断可能会导致改善的结果和减少利用肝移植。 公共卫生相关性：新生儿血色病（NH）是婴儿肝功能衰竭的重要原因，但诊断可能容易漏诊。一种新的血清学检测将用于确定NH是否是近40%未经诊断的儿科急性肝功能衰竭的原因。由于NH对药物治疗有反应，改善急性肝衰竭的诊断可以挽救许多婴儿的生命，并大大减少儿童肝移植的需要。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (04) Clinical Research and specific Challenge 04-DK-104 Improve the diagnosis, staging and treatment of diseases of the liver. This application specifically seeks to develop an approach that will improve the diagnosis of acute liver failure in infants, result in significantly improved outcome with medical therapy, and reduce the utilization of liver transplantation in pediatric patients. Neonatal hemochromatosis (NH) is the leading diagnosed cause of liver failure in neonates in most series. However, no diagnosis for acute liver failure can be established in up to 40% of infants. The overall objective of this application is to determine the true prevalence of NH as a cause of acute liver failure in infants d 90 days of age. The critical gap in scientific knowledge to be overcome before its importance as cause of acute liver failure can be determined is the lack of a sensitive and specific diagnostic biomarker for NH. Since NH is caused by maternal alloimmunity against fetal liver, the biomarker proposed is the presence of "anti-fetal hepatocyte IgG antibody" in mothers' or infants' serum. The diagnostic utility of an immunofluorescence assay for this biomarker is to be established and then it will be used to assess the prevalence of NH in a population of young infants with acute liver failure. Normally acquiring a study population large enough to power such a study would require many years of study. However, sera obtained from the Pediatric Acute Liver Failure study repository will be used, making it feasible to complete the proposed work within the timeframe of two years. The expected results will show that NH constitutes fully 50% of all causes of acute liver failure in young infants. This finding will have a significant positive impact because NH is responsive to specific medical therapy, which improves outcome over current treatment including liver transplantation. Furthermore, should the novel test used in this analysis prove to be sensitive and specific for the diagnosis, it could replace current diagnostic approaches and prospectively improve diagnostic accuracy in this setting. Thus, early, precise diagnosis could lead to improved outcome and reduced utilization of liver transplantation. PUBLIC HEALTH RELEVANCE: Neonatal Hemochromatosis (NH) is an important cause of liver failure in infants, but the diagnosis may be easily missed. A novel serological test will be used to determine if NH is the cause of the nearly 40% of pediatric acute liver failure without diagnosis. Since NH is responsive to medical treatment, improving the diagnosis of acute liver failure could save the lives of many infants and substantially reduce the need for liver transplantation in children.