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Excess copper in the liver is toxic in humans and other mammals, and may lead to acute or chronic hepatitis, steatohepatitis, acute liver failure, cirrhosis and death. Of the several human copper storage diseases that have been described, the molecular basis of only Wilson disease is understood with the discovery of the Wilson disease gene (ATP7B) in 1993. The therapeutic success using oral copper chelating agents and zinc therapy make Wilson disease one of the few treatable genetic metabolic liver diseases. In cases with a fulminant presentation or advanced disease at diagnosis, copper chelation is ineffective and liver transplantation may be lifesaving. Indian Childhood Cirrhosis (ICC) has been defined as a copper-storage disorder precipitated by increased copper intake which affects young children primarily of Indian descent, and which progresses to cirrhosis and death before age three to four years without treatment. Children from North America, Asia, Austria, Germany and other countries have been described with a similar condition, which has been termed idiopathic copper toxicosis (ICT). Several newer disorders of hepatic copper metabolism have been recently described.
When first encountering an infant or child with cholestatic liver disease, it is essential that diagnostic evaluation be conducted promptly in order to recognize disorders amenable either to specific medical therapy (e.g., galactosemia, tyrosinemia, hypothyroidism, urinary tract infection) or to early surgical intervention (e.g., biliary atresia, choledochal cyst); institute treatment directed toward enhancing bile flow; and prevent and treat the varied medical, nutritional, and emotional consequences of chronic liver disease.
Intestinal failure (IF) is defined as the end result of any gastrointestinal disorder in which functional intestinal mass is insufficient to allow adequate growth, hydration, and electrolyte balance in children and adults. Inherent in this definition is the requirement for parental nutrition (PN), which is provided to maintain fluid, energy, protein, electrolyte, and micronutrient delivery in the absence of adequate intestinal function. In the pediatric population, IF may be the end result of various primary etiologies, although the most common is short bowel syndrome (SBS) following congenital or acquired disorders, including necrotizing enterocolitis (NEC), small intestinal atresia, volvulus, and gastroschisis. Table 15.1 summarizes the most common etiologies of pediatric IF.
Pathologies of mitochondrial structure and function are now recognized as the etiology of a growing list of monogenic mitochondrial disorders as well as contributing to many common diseases. Studying patients with respiratory chain disorders has contributed much to our current knowledge about mitochondrial biology . Mutations impacting mitochondrial proteins as well as ribosomal and transfer RNAs (tRNAs) are the underlying cause of diseases affecting the nervous system, skeletal and cardiac muscle, the liver, bone marrow, the endocrine and exocrine pancreas, kidney, inner ear and small and large intestines (Table 35.1) . Perturbations in mitochondrial function result in defective oxidative phosphorylation (OXPHOS) and ATP generation, increased generation of reactive oxygen species (ROS), accumulation of hepatocytic lipid, impairment of other mitochondria-based metabolic processes and activation of apoptotic, autophagic and necrotic cell death pathways . The spectrum of genetic etiologies of inherited mitochondrial hepatic and gastrointestinal disorders continues to expand. In addition, mitochondrial dysfunction may be one of the key determinants of hepatocyte survival in other disorders that are not monogenic mitochondrial diseases. Thus, the concept of primary (or genetic) and secondary (or acquired) mitochondrial hepatopathies has developed.
Liver disease in children is increasing in prevalence, placing a huge burden on healthcare systems and often requiring long-term management. Offering an integrative approach to the science and clinical practice of pediatric hepatology, this is the definitive reference text for improved diagnosis and treatment strategies. In the new edition of this authoritative text, chapters have been thoroughly revised in line with major advances in the field, such as recognizing the increased frequency of fatty liver disease, and how genetic testing has the potential to establish earlier diagnoses for a variety of diseases. Disorders covered include cholestasis, metabolic disorders and hepatitis, with their presentation across the spectrum of infancy, childhood and adolescence discussed. The indications and surgical aspects of liver transplant are explained and post-transplant care is described in detail. This is a valuable resource for pediatricians, hepatologists, gastroenterologists and all clinicians involved in the care of children with liver diseases.
The fourth edition of this authoritative text covers every aspect of liver disease affecting infants, children and adolescents. As in the previous editions, it offers an integrative approach to the science and clinical practice of pediatric hepatology and charts the substantial progress in understanding and treating these diseases. All of the chapters are written by international experts and address the unique pathophysiology, manifestations and management of these disorders. This edition of the landmark text features extended coverage of viral hepatitis, metabolic liver disease, fatty liver disease and liver transplantation, including a new chapter on post-transplant care and outcomes. All of the chapters have been updated to reflect changing epidemiology and recent advances in molecular medicine and genomics. With the continued evolution of pediatric hepatology as a discipline, this text remains an essential reference for all physicians involved in the care of children with liver disease.
When first encountering an infant or child with cholestatic liver disease, it is essential that diagnostic evaluation be conducted promptly in order to (1) recognize disorders amenable either to specific medical therapy (e.g. galactosemia, tyrosinemia, hypothyroidism, urinary tract infection) or to early surgical intervention (e.g. biliary atresia, choledochal cyst); (2) institute treatment directed toward enhancing bile flow; and (3) prevent and treat the varied medical, nutritional, and emotional consequences of chronic liver disease. Because many of the treatable causes require early diagnosis and prompt institution of therapy, the evaluation of the cholestatic infant should never be delayed. Although “physiologic cholestasis” (hypercholemia or elevated bile acids) may be present in the infant, there is no state of “physiologic conjugated hyperbilirubinemia”. For the jaundiced infant, historical and clinical information such as color of the stools, birth weight, and presence of hepatomegaly may provide important clues as to the etiology of cholestasis. Consanguinity or liver disease in siblings suggests the possibility of metabolic, familial, or genetic disease. Review of the prenatal and postnatal course may reveal intrauterine infection, occurrence of hypoglycemia or seizures, and exposure to toxins/drugs (i.e. total parenteral nutrition (TPN)). Careful physical examination may reveal features of typical disorders or syndromes. For the older child and adolescent, a history of exposure to drugs/toxins (e.g. acetaminophen), the presence of vascular insufficiency, and the presence of underlying disease (e.g. inflammatory bowel disease) provide helpful clues. The diagnostic evaluation of the infant with cholestasis is detailed in Chapter 8.
Seven years have passed since the publication of the third edition of Liver Disease in Children. This text continues to be the premier, comprehensive reference on pediatric liver disease. Pediatric hepatology continues to grow and evolve as a distinct discipline and so it remains a challenge to provide comprehensive coverage without markedly increasing the length of this text. To keep the size of this textbook within limits, the number of references for each chapter has been limited to classical and the most relevant current citations. The editors felt that this was a reasonable compromise, since ready access to the literature is possible through resources such as PubMed.
We have appreciated the contributions of so many of our colleagues over the past two decades, but to ensure a fresh perspective and to involve experts who have emerged in the field, 11 of the chapters are written by authors contributing to this textbook for the first time. These contributors have provided particular expertise in areas such as liver development, autoimmune liver disease, intestinal failure-associated liver disease, fatty liver disease, and inborn errors of metabolism. There is also expanded coverage of liver transplantation.