Chapter 2 - Functional development of the liver

Summary

Introduction

The liver attains its highest relative size at about 10% of fetal weight at the ninth week of gestation. Early in gestation the liver is the primary site for hematopoiesis. At 7 weeks of gestation, hematopoietic cells outnumber hepatocytes. Primitive hepatocytes are smaller than mature cells and are deficient in glycogen. As the fetus nears term, hepatocytes predominate and enlarge with expansion of the endoplasmic reticulum and accumulation of glycogen. Hepatic blood flow, plasma protein binding, and intrinsic clearance by the liver (reflected in the maximal enzymatic and transport capacity of the liver) also undergo significant postnatal maturation. These changes correlate with an increased capacity for hepatic metabolism and detoxification. At birth, the liver constitutes about 4% of body weight compared with 2% in the adult. Liver weight doubles by 12 months of age and increases three-fold by 3 years of age.

The functional development of the liver that occurs in concert with growth requires a complicated orchestration of changes in hepatic enzymes and metabolic pathways that result in the mature capacity of the liver to undertake metabolism, biotransformation, and vectorial transport. Greengard has established a paradigm for hepatic development based on a group of several hepatic enzymes studied in the rat and less extensively in humans. In one pattern of hepatic development, enzymatic activity is high in a fetus and falls during postnatal development. Examples would include thymidine kinase and ornithine decarboxylase [1]. The activities of other enzymes are expressed initially during early fetal development and continue to increase progressively after birth. Examples include glutamate dehydrogenase, fructose-1,6-diphosphatase, and aspartate aminotransferase [1]. Another group of enzymes is expressed perinatally and continues to increase progressively after birth. These enzymes include phosphoenolpyruvate carboxykinase (PEPCK) and uridine 5′-diphosphate glucuronyltransferase (UGT). A final pattern of development occurs with enzymes that are expressed significantly after birth and peak at weaning, including alanine aminotransferase and alcohol dehydrogenase.