Pediatric Liver Disease: Translating Discoveries into Practice

The transformation of the practice of pediatric hepatology has begun. Characterization of molecular etiologies, pathogenesis, and clinical phenotypes of childhood liver diseases in recent years has legitimized the further development of this distinct discipline. As an illustration, delineation of the molecular underpinnings of the various clinical phenotypes of progressive familial intrahepatic cholestasis has led to a nosology that is of growing clinical utility and that begins to have implications far beyond the pediatric population. For example, MDR3 (ABCB4) deficiency is responsible for a chronic cholestatic disease, PFIC type 3, in childhood, but is now known to cause recurrent intrahepatic cholelithiasis and intrahepatic cholestasis of pregnancy in adults. Furthermore, basic and translational research evolving from clinical observations in children has brought forth an improved understanding of bile formation and identification of new targets for treatment of cholestasis. The remarkable success of liver transplantation as a lifesaving therapy in previously fatal pediatric liver disorders underscores the advances that have transformed the practice of pediatric hepatology. Applying the new biotechnologies of translational research to liver diseases in coming years holds the promise to build on these successes in both common and rare childhood liver diseases. Moreover, the publication of pediatric liver disease research agendas combined with the development of collaborative clinical research networks have put in place the infrastructure to prioritize and target resources toward answering important clinical and scientific questions. In this issue of Seminars in Liver Disease, we have highlighted recent translational research advances in 8 important childhood liver diseases, as described by recognized experts, which will illustrate this transformational process.

In the first article of this issue, Mack tackles one of the major enigmas of pediatric hepatology: what causes biliary atresia (BA)? Over the past decade, a leading theory for the majority of BA cases is that a perinatal viral (or other infectious) insult leads to biliary injury and subsequent inflammatory obliteration of the extrahepatic bile ducts. Recent work by Mack and others suggests that the host adaptive immune response plays a significant role in this process, perhaps modulated by underlying, and currently unknown, genetic factors of the individual. Furthermore, Mack outlines emerging evidence supporting a role for aberrant autoreactive T cells attacking the infant's intrahepatic bile ducts after portoenterostomy, raising the possibility that interruption of this process could substantially improve outcomes after portoenterostomy. In this regard, the randomized, placebo-controlled corticosteroid trial in BA infants conducted by the Biliary Atresia Research Consortium may shed more light on this proposed mechanism.

Another fascinating liver disease that only occurs in the infant, neonatal hemochromatosis, is now proposed to be caused by a transplacental alloimmune mechanism, similar to Rh incompatibility. Recent elegant translational work is highlighted in the article by Whitington, which presents both laboratory proof and clinical trial results that support this notion of pathogenesis. Management guidelines, based on extensive personal experience, for the affected infant and future pregnancies (in which there is a very high rate of reoccurrence) are also provided. Infants are also the age group most susceptible to severe liver injury associated with short bowel syndrome and total parenteral nutrition administration, what Carter and Karpen appropriately have dubbed intestinal failure-associated liver disease (IFALD). The authors present a timely evaluation of potential etiologies and pathogenesis, emphasizing the emerging role of small intestinal flora and the innate immune system, as well as the effects of intravenous lipid emulsions, in its pathogenesis. Current preventative approaches and novel therapies, including new surgical techniques for bowel lengthening, are reviewed. This disease begs for a multidisciplinary, multicentered approach to defining its pathogenesis and optimal strategies for prevention and treatment.

Our understanding of inherited disorders of mitochondrial respiration is growing out of its infancy, with new causative genes and their protein products literally discovered each year. An expanded role has also been uncovered for mitochondrial dysfunction in the pathogenesis of a variety of hepatic and systemic diseases. Lee and Sokol review our current understanding of the genotypes and phenotypes of mitochondrial hepatopathies of most importance and present suggested diagnostic algorithms. Another metabolic disease of particular importance in pediatrics, α₁-antitrypsin deficiency, was discovered more than 30 years ago, yet treatment has not changed radically. Investigations of the molecular and cell biology of this deficiency, however, have led to the new field of “quality control” handling of misfolded proteins, with ramifications at many levels. Teckman reviews the biology of this protein and provides the most recent thorough review of clinical and diagnostic features. The explanation of why only 15% of PIZZ individuals develop overt liver disease in childhood remains unanswered but will surely shed light on other similar disorders. Heubi et al review the expanding field of bile acid synthesis defects, demonstrating the successful marriage of biochemistry and molecular genetics in delineating 9 separate disorders of bile acid metabolism. For most of these disorders, medical treatment is now available, avoiding acute liver failure and death or the need for liver transplantation. Thus, the clinical clues and diagnostic testing for these diseases are important for all hepatologists to understand.

The 2 most common chronic liver diseases in adults are also important entities in pediatrics but are managed differently. Narkewicz et al present a thorough review of the unique pediatric aspects of hepatitis C virus infection, including a discussion of the predominant mode of transmission in children: vertical perinatal transmission. A review of current and future therapies with evidence-based recommendations are provided. Schwimmer points out that nonalcoholic fatty liver disease (NAFLD) has become the most common liver disease among children over the past decade, based largely on the burgeoning epidemic of childhood obesity. Detailed epidemiologic and histologic studies in recent years have led to a better understanding of the risk factors and pathogenesis of NAFLD in children. Moreover, differences between pediatric and adult NAFLD have been highlighted by the 2 histologic patterns of nonalcoholic steatohepatitis (NASH) that distinguish the age groups. Much remains to be learned in the prevention and effective treatment, as well as the natural history, of NAFLD in children.

I would like to thank the authors for their dedication and collaboration in this effort to summarize recent advances in the science of pediatric hepatology that have led to improvements in clinical practice. It is hoped that their efforts will energize others to continue to meet the challenges our patients will face in the future.