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Journal of Pediatric Gastroenterology & Nutrition:
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Introduction to the Pediatric Liver Research Agenda: A Blueprint for the Future

Sokol, Ronald J.

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University of Colorado School of Medicine and The Children's Hospital, Denver, Colorado, U.S.A.

The serious impact of liver diseases in infants and children is only now becoming evident. A wide spectrum of disorders can present at birth, within the first few years of life, or later in childhood, of which many are unique to children. Liver diseases lead to significant morbidity throughout childhood, including impaired growth and development, diarrhea, pruritus, gastrointestinal hemorrhage, and abdominal distention, and may progress to cirrhosis and its many life-threatening complications. Although some notable advances have been made recently in treating several metabolic liver diseases (e.g., hereditary tyrosinemia), treatment for most pediatric liver disorders is inadequate and does not alter significantly the natural history of the disease. Thus, liver transplantation all too frequently becomes the only option available to most children with end-stage liver disease. In 1999, a total of 525 liver transplantations were performed in children in the United States. In addition, more than 15,000 children are hospitalized for liver diseases each year at a cost of more than $350 million per year in the United States. The distress of caring for an infant or child with liver disease also has a profound effect on the family. Despite this considerable impact of liver disease on the health of children, on the family unit, and on healthcare expenditures, sufficient research funding for investigations into the causes and treatments of pediatric hepatobiliary disorders is lacking.

The incidence of liver disease in infants is approximately 1 in 2,500 live births; the most clinically important of these disorders is biliary atresia. Approximately half of all pediatric liver transplantations are performed in children with biliary atresia in whom surgical and medical therapies have failed. In addition, recent surveys now show that evidence of chronic infection with the hepatitis C virus is present in 1 in 500 children aged 6 to 11 years and 1 in 250 children aged 12 to 19 years in the United States. The optimal age and method of treating hepatitis C virus in children has yet to be determined, particularly in view of the multitude of side effects of the currently available treatments, yet the long-term risk for cirrhosis and hepatocellular carcinoma looms before each infected child. Many other metabolic, genetic, autoimmune, structural, and infectious causes of liver disease become evident throughout childhood. Overall, a lack of awareness of the varied manifestations of these liver diseases frequently leads to delayed diagnosis, with increased morbidity and mortality.

To conquer pediatric liver diseases, the American Liver Foundation has identified four critical actions that must be initiated. These include the following:

1. Setting the research priorities—the purpose of this research agenda

2. Increasing support from federal and private funding agencies for basic and applied research in these areas

3. Establishing and supporting a national network of centers with expertise in caring for children with liver disorders and in conducting clinical investigations and trials

4. Supporting the training of more pediatric gastroenterologists/hepatologists who have special expertise in liver disease and transplantation and of other scientists to investigate important issues relating to the research agenda.

The proposed national network of centers would enable improved clinical evaluation and treatment, a structure under which national registries for tracking patients with pediatric liver diseases could be maintained. The network also would enable multicenter clinical investigations of the causes and pathogenesis of liver diseases unique to children and clinical trials for childhood liver diseases. Without this network, little progress can be made in this area.

For this Pediatric Liver Research Agenda, the Children's Liver Council of the American Liver Foundation assembled a group of recognized experts who have identified 11 priority areas that require the urgent attention of the scientific community and of research funding sources. Our goal is to highlight the scientific issues of greatest importance and to provide a blueprint for the basic and applied research that must be performed to conquer these disorders. Given the many potential years of productive life for a healthy child, developing treatment and preventive strategies in this age group may be particularly cost-effective. We hope that this agenda will help direct the efforts of this nation's researchers and funding agencies to answer the many questions about the causes, treatments, prevention, and cures of childhood liver diseases. Private and federal sources of research funding must place pediatric liver diseases high on their priority lists, and a national network of centers that care for children with pediatric liver disease must be established and funded to facilitate investigations and treatment trials of childhood liver disorders. The specific areas of emphasis of this research agenda are as follow:

1. Development of the liver and bile ducts: Knowledge of the biochemical and molecular events that affect liver and bile duct development is critical to understanding how birth defects of the liver and bile ducts occur, to understand the unique nature of the function of the infant's liver, and to develop strategies for stimulating hepatic regeneration.

2. Liver injury and fibrosis: It is critical to understand the processes that regulate liver cell injury and the contribution of necrotic cell death and programmed cell death, or apoptosis, to the pattern of liver injury in childhood liver disorders. The role that the various cell types play in the developing liver's response to injury must be characterized. Determining these basic mechanisms of liver injury in children should assist in developing new strategies for therapeutic intervention.

3. Biliary atresia: This disorder is the most common indication for liver transplantation in childhood, although its cause is not understood and effective therapies are not available. A concerted research effort must be launched to improve understanding of biliary atresia.

4. Intrahepatic cholestasis: This heterogeneous group of diseases includes neonatal infections, defects in bile formation and transport, and structural abnormalities of the bile ducts. Understanding the pathophysiology and molecular defects that underlie these disorders will allow development of specific therapies to prevent progression to end-stage liver disease and to prevent the need for liver transplantation. As a byproduct of these studies, better understanding of the normal development of the liver and bile ducts will emerge.

5. Metabolic liver disease: Metabolic and genetic liver diseases lead to considerable morbidity and account for 30% of liver transplantations performed in children. The use of animal models to understand the scientific basis for these disorders and the possible use of hepatocyte transplantation or gene therapy to treat these disorders are high priority areas for investigation.

6. Viral hepatitis: Infection with the hepatitis A, B, and C viruses is now recognized as a major public health issue in childhood. We must understand how hepatitis B and C infections become chronic and how we can implement effective therapies to resolve liver damage before liver transplantation becomes necessary. Research into the best preventive strategies for each of these infections is needed desperately.

7. Fulminant hepatic failure in children: Fulminant hepatic failure is a devastating disorder to the family and child, and its etiologic basis must be defined. Effective therapeutic strategies must be developed that improve liver regeneration and that bridge to recovery or transplantation.

8. Immune diseases of the liver and biliary tract: Autoimmune diseases of the liver, primarily autoimmune hepatitis and primary sclerosing cholangitis, are the most common serious liver diseases in adolescents in the United States and frequently progress to end-stage disease and the need for liver transplantation. A better understanding of the pathogenesis of these disorders is necessary to develop effective and safe therapies.

9. Liver transplantation in children: Although liver transplantation saves many children's lives, several important areas of investigation are essential. Better understanding is needed of the unique immunologic aspects of graft tolerance and rejection and of Epstein-Barr virus and posttransplant lymphoproliferative disease in children. Improved immunosuppression regimens must be studied, and more knowledge about the long-term outcome of liver transplantation in children must be obtained.

10. Gene therapy and pediatric liver disease: Gene transfer therapy, which offers hope for curing many genetically based diseases of the liver, will require considerable investigative efforts to become an effective and safe treatment for pediatric patients.

11. The impact of liver disease on growth and nutrition: Chronic liver disease in childhood has a significant impact on nutritional status and growth in children, leading to lifelong issues such as osteoporosis, short stature, and impaired brain development. Research must be directed at identifying factors that contribute to malnutrition and at developing evidence-based interventions to prevent or treat malnutrition with simple, safe, and effective methods.

© 2002 Lippincott Williams & Wilkins, Inc.

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