High prevalence of alpha-1-antitrypsin heterozygosity in children with chronic liver disease.

OBJECTIVE: Alpha-1-antitrypsin (A1AT) deficiency is the most common genetic cause of liver disease in children; however, the role of polymorphic heterogeneity in the A1AT gene as a modifier of other forms of pediatric liver disease is not clear. We hypothesized that non-M A1AT allele variants are more common in children with chronic liver disease than in the general population. METHODS: A retrospective, single-center study was performed in which A1AT phenotypes were obtained by reviewing charts of children with chronic liver disease. Chi-square analysis was used to compare allele frequencies in the population of children with liver disease with published epidemiologic data and to compare allele frequencies among disease subgroups. RESULTS: The frequency of A1AT Z and other alleles was increased in children with chronic liver disease (n = 241) when compared with the published reference database (P < 0.001). This increase remained significant when the population was divided into disease subsets: biliary atresia (n = 67) and other liver disease (n = 174) (P < 0.001 for both). Among children with biliary atresia referred for liver transplant evaluation, the presence of a non-M allele was associated with a lower mean age at transplant listing than the MM phenotype (235 vs 779 days, P = 0.036) and more frequent loss of native liver by 24 months of age (90% vs 65%, P = 0.04). CONCLUSIONS: A1AT non-M alleles are more frequent in children with chronic liver disease than in the general population. We speculate that these non-M alleles may act as genetic modifiers in pediatric liver disease in general and modulate disease progression in children with biliary atresia in particular.

A novel approach to managing variation: outpatient therapeutic monitoring of calcineurin inhibitor blood levels in liver transplant recipients.

OBJECTIVE: To apply the principles of statistical process control (SPC) to manage calcineurin inhibitor (CNI) blood levels. We hypothesized that the use of SPC would increase the proportion of CNI blood levels in the target range. STUDY DESIGN: The study population consisted of 217 patients more than 3 months after liver transplantation. After demonstration of proof of concept using the rapid cycle improvement process, SPC was applied to the entire population. The change package included definition of target ranges for CNI, implementation of a web-based tool that displayed CNI blood levels on a control chart, and implementation of a protocol and a checklist for management of CNI blood levels. The principal outcome measure was the proportion of CNI blood levels in the target range. RESULTS: In the pilot study, the proportion of CNI blood levels in the target range increased from 50% to 85%. When the protocol was spread to the entire population, the proportion of drug levels in the target range increased to 77% from 50% (P < .001), whereas the range of CNI levels decreased. The rate of allograft rejection did not change. CONCLUSIONS: Utilization of SPC increased the proportion of CNI blood levels in target range. These observations may be applicable to the care of other chronic healthcare problems.

Pediatric liver disease in the United States: epidemiology and impact.

Liver diseases which affect children are unique. Diseases such as inborn errors of metabolism are fertile grounds for investigation. Study of these 'experiments of nature' will provide insight into hepatobiliary function and lead to novel treatment modalities. Successful treatment or prevention of liver disease in children will have long-term implications. This report describes the current burden of pediatric liver disease and offers approaches to intervention.