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Downloaded from by Guestpediatrics on September Vol.23, 2021 113 No Liver Vı´ctor M. Pin˜eiro-Carrero, MD*, and Eric O. Pin˜eiro, MS‡ ABSTRACT. The liver’s unique metabolism and rela- resolve. Pediatrics 2004;113:1097–1106; hepatotoxicity, xe- tionship to the gastrointestinal tract make it an important nobiotic, drug metabolism. target of the toxicity of drugs and xenobiotics. The de- velopmental changes that occur in the liver’s metabolic activity from birth to adolescence contribute to the varied ABBREVIATIONS. CYP, cytochrome P450; ALT, alanine amino- sensitivity to toxins seen in the pediatric population. transferase; AFB, aflatoxin B; ALP, alkaline phosphatase; VOD, veno-occlusive disease; PCB, polychlorinated biphenyl; PCP, pen- Hepatic drug metabolism, often with an imbalance be- tachlorophenol; TCHQ, tetrachlorohydroquinone. tween the generation of toxic metabolites and detoxifica- tion processes, can influence the degree of hepatotoxic- ity. The decreased capacity of the neonatal liver to he liver’s main function is to synthesize an metabolize, detoxify, and excrete xenobiotics explains array of body proteins and to act as the detox- the prolonged action of drugs such as phenobarbital, ifying center for the multiple toxic metabolic theophyline, and phenytoin. The reduced capacity of T byproducts endogenous to the body and the toxins glucuronide conjugation in the neonate not only predis- ingested daily by the organism. The liver undergoes poses them to physiologic jaundice but also is probably responsible for the chloramphenicol-induced gray infant dramatic changes in structure and function during syndrome. Age-related sensitivity to drugs is attributable development. The developmental changes that occur in part to differences in metabolic activity. For example, in the liver determine the rate and metabolic path- young children are more resistant to acetaminophen hep- ways used in the disposition of drugs and other atotoxicity when compared with adults, whereas children xenobiotics. The resultant metabolic intermediates are more susceptible to valproic acid–induced toxicity. may in themselves be toxic to the liver but may also The resistance to acetaminophen toxicity is attributable cause detrimental effects to other organs of the body. to biochemical differences in young children. In chil- This article discusses some of those xenobiotics that dren, sulfation predominates over glucuronidation, lead- are hepatotoxic, with particular emphasis on sub- ing to decreased formation of toxic intermediates. In stances found to be toxic in the pediatric age group. addition, infants have a greater capacity to synthesize glutathione, thereby inactivating toxic metabolites of For understanding the variable effects of environ- acetaminophen more effectively. Hepatic toxicity as a mental xenobiotic exposures in children, a basic re- result of drugs and environmental toxins presents a wide view of liver anatomy, physiology, and development spectrum of clinical disease. Hepatitis is the most com- is necessary. mon presentation, but every major type of liver pathol- ogy can occur. Most drug reactions are attributable to idiosyncratic hepatotoxins; therefore, liver injury occurs MORPHOLOGY AND FUNCTION OF THE LIVER rarely. The diagnosis of toxin-induced liver disease re- Microscopic Anatomy and Liver Physiology quires a high index of suspicion and often entails the The liver performs many essential functions, in- exclusion of other causes of liver disease in children. Drug or environmental xenobiotic-induced hepatotoxic- cluding the production of bile, regulation of plasma ity should be considered in the setting of identified proteins and glucose, and biotransformation of exposure or when other causes of childhood liver disease drugs and toxins. The liver is the first organ that are excluded. Children who take medications that are comes into contact with enterally absorbed nutrients known to be hepatotoxic, such as anticonvulsants and and xenobiotics via the portal vein. Other products antineoplastic drugs, need frequent monitoring for evi- of metabolism—substances that enter the body dence of hepatic toxicity. The treatment is often nonspe- through other pathways and substances that are not cific; the most important intervention is the prompt dis- extracted from the portal blood during the first continuation of the drug or removal of the environmental pass—reach the liver by the hepatic artery.1 The toxin. A specific antidote is available only for acetamin- newborn liver manifests many unique physiologic ophen intoxication. In cases of severe toxicity, the patient may develop liver failure. Liver transplantation may be traits that are likely part of the normal developmen- necessary for patients whose liver failure does not tal process and may predispose the liver in infants and children to the toxic effect of xenobiotics at levels that may be safe for the adult.2 The neonate has Ͻ From the *Alfred I. duPont Hospital for Children, Wilmington, Delaware; 20% of the hepatocytes that are present in the adult and ‡Ohio State Environmental Protection Agency, Columbus, Ohio. liver, and liver growth continues after birth until it Received for publication Oct 7, 2003; accepted Oct 20, 2003. reaches its mature size.1,2 The liver consists of 4 main Reprints requests to (V.M.P.-C.) Alfred I. duPont Hospital for Children, types of cells. The hepatocytes are the biosynthetic 1600RocklandRd,Box269,Wilmington,DE19899.E-mail:vpineiro@nemours. org engines of the liver. Their prominent Golgi system PEDIATRICS (ISSN 0031 4005). Copyright © 2004 by the American Acad- and rough endoplasmic reticulum enable them to emy of Pediatrics. synthesize and secrete a variety of proteins. The en- Downloaded from www.aappublications.org/news by guestPEDIATRICS on September Vol.23, 2021 113 No. 4 April 2004 1097 dothelial cells line the sinusoids and serve as a bar- Functional Development of the Liver: Differential rier (interface) between the blood and hepatocytes. Vulnerabilities of the Liver at Different Stages of Two other cell types line the sinusoids: the Kupffer Development cells, which function as macrophages, and the stel- The functional development of the liver has been late cells, which store fat and vitamin A.1,3 studied extensively in the rat, less so in humans.7 It From a functional standpoint, the liver has been involves complex changes in liver function in the described as a collection of acini that are present by embryo and the fetus. Some enzyme activity is high the third month of gestation. Each acinus is defined in the fetus and falls during postnatal development as the tissue supplied by the terminal branches of the (thymidine kinase and ornithine decarboxylase), portal vein and hepatic artery and drained by the whereas other enzymes are expressed in the fetus terminal branches of the hepatic vein. The paren- and increase postnatally (fructose-1,6-diphosphatase chyma is divided into 3 zones according to proximity and aspartate aminotransferase). Another group of to the portal triads. The hepatocytes closest to the enzymes is expressed perinatally and continues to portal areas (zone 1) receive the richest oxygen and increase postnatally (uridine 5Ј-diphosphate glucu- nutrient supply and have a high concentration of ronyl transferase). Finally, some enzymes are ex- enzymes involved in cell respiration; they mostly pressed at birth and peak at the time of weaning in synthesize glycogen and other proteins. The hepato- the rat (alanine aminotransferase [ALT] and alcohol 2 cytes in zone 3 are closest to the central veins (ter- dehydrogenase). The development of physiologic minal branches of the hepatic veins). In zone 3, little jaundice in the newborn may be caused in part by oxygen is available and the hepatocytes are involved low glucuronidation activity in the liver (Table 1). in glycolytic energy production and contain cyto- These developmental changes most likely place the chromes P450 (CYP), a class of enzymes responsible developing fetus and infant at differential risk from for metabolizing many xenobiotics. Therefore, the environmental toxins. For example, the reduced ca- pacity of glucuronide conjugation in the neonate is hepatocytes in zone 3 are more specialized in bio- probably responsible for the gray infant syndrome transformation reactions.4,5 Zone 2 is the intermedi- from chloramphenicol.8 Unfortunately, few studies ate area of hepatocytes between zones 1 and 3. Cells are available in the literature exploring the effects of more distant from the portal supply (acinar zones 2 environmental toxins on the liver at various stages of and 3) have a different enzymatic phenotype and development. This is further complicated by the lack respond differently to hypoxia and toxin exposure. of appropriate experimental models available to ex- The liver performs multiple functions: bile forma- amine the effect of xenobiotics at different develop- tion and excretion, synthesis of liver proteins, detox- mental stages. ification of xenobiotic and endogenous compounds, The structural and functional development of the and regulation of blood glucose. Toxicity caused by liver can influence the absorption, excretion, and xenobiotics therefore can cause derangement in any metabolism of drugs and other xenobiotics. Most of of these functions and can be detected by laboratory the knowledge regarding the differential hepatic me- tests used to measure these functions. Bilirubin and tabolism is based on studies of drugs. Some of these bile acids are the 2 primary components of bile and observed differences in drug metabolism
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