Cholestasis Liver Disease In Children

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Curr Gastroenterol Rep. Author manuscript; available in PMC 2011 February 1.
Published in final edited form as: Curr Gastroenterol Rep. 2010 February ; 12(1): 30–39. doi:10.1007/s11894-009-0081-8.

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Cholestatic Liver Disease in Children
Jorge L. Santos, Hospital de Clinicas andFederal University of Rio Grande do Sul, Rua Ramiro Barcelos, 2350, Bairro Rio Branco, Porto Alegre, RS 90035-903, Brazil Monique Choquette, and Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA Jorge A. Bezerra Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA, Jorge.bezerra@cchmc.org

AbstractInherited syndromes of intrahepatic cholestasis and biliary atresia are the most common causes of chronic liver disease and the prime indication for liver transplantation in children. Our understanding of the pathogenesis of these diseases has increased substantially by the discovery of genetic mutations in children with intrahepatic cholestasis and the findings that inflammatory circuits are operativeat the time of diagnosis of biliary atresia. Building on this solid foundation, recent studies provide new insight into genotype-phenotype relationships and how mutations produce altered bile composition and cholestasis. New evidence exists that although liver transplantation is curative for patients with end-stage liver disease owing to cholestasis, some patients may develop recurrence ofcholestasis because of the emergence of autoantibodies that disrupt canalicular function in the new graft. Progress is also evident in biliary atresia, with recent studies identifying candidate modifier genes and directly implicating lymphocytes and inflammatory signals in the pathogenesis of bile duct injury and obstruction.

Keywords Cirrhosis; Jaundice; Bilirubin; Hemochromatosis; Biliary atresia;Alagille disease; Transplantation

Introduction
Diseases that manifest as cholestasis in children often result from pathologic processes that begin early in postnatal life, when the liver has not reached functional maturity and may be more susceptible to the adverse consequences of endogenous (metabolic, genetic) or environmental insults [1]. Despite the multifactorial nature of the pathology,several diseases are linked to single-gene defects that fundamentally alter physiologic processes and produce clinical syndromes. The discovery of these genes has broadened our understanding of the pathogenesis of disease and improved nosology by incorporating biologic features into disease categories [2,3]. Now, we are learning how the disruption of molecular pathways regulates

© SpringerScience+Business Media, LLC 2010 Correspondence to: Jorge A. Bezerra. Disclosure No potential conflict of interest relevant to this article was reported.

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mechanisms of disease, about new factors that modify the clinical course, and the implications of discoveries for the development of new therapies, which are the focus of this review.

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Before addressing recent advances for specific cholestatic diseases in children, we make note of a study investigating the prevalence of subclinical vitamin deficiency in patients with cholestasis. The demands of postnatal growth and development in the face of fat malabsorption secondary to cholestasis heighten the risk for complications of fat-solublevitamin deficiency (eg, neurologic deficits, bone disease, and hemorrhage). The study, conducted in children and adults with cholestatic syndromes, determined the plasma concentration of protein induced in vitamin K absence II (PIVKA-II), which measures undercarboxylated prothrombin [4]. Although 29% of the subjects had evidence of coagulopathy as indicated by an increased international...