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Chapter 2 - Functional Development of the Liver

from Section I - Pathophysiology of Pediatric Liver Disease

Published online by Cambridge University Press:  19 January 2021

Frederick J. Suchy
University of Colorado, Children’s Hospital Colorado, Aurora
Ronald J. Sokol
University of Colorado, Children’s Hospital Colorado, Aurora
William F. Balistreri
Cincinnati Children’s Hospital Medical Center, Cincinnati
Jorge A. Bezerra
Cincinnati Children’s Hospital Medical Center, Cincinnati
Cara L. Mack
University of Colorado, Children’s Hospital Colorado, Aurora
Benjamin L. Shneider
Texas Children’s Hospital, Houston
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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 seven 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 three years of age.

Publisher: Cambridge University Press
Print publication year: 2021

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Greengard, O. Effects of hormones on development of fetal enzymes. Clin Pharmacol Ther 1973;14:721–6.CrossRefGoogle ScholarPubMed
Hashimoto, K, Ogara, Y. Epigenetic switching and neonatal nutritional environment. Adv Exp Med Biol 2018;1012:1925.CrossRefGoogle ScholarPubMed
Hay, WW Jr. Placental-fetal glucose exchange and fetal glucose metabolism. Trans Am Clin Climatol Assoc 2006;117:321–39; discussion 3940.Google ScholarPubMed
Duval, F, Dos Santos, E, Maury, B, et al. Adiponectin regulates glycogen metabolism at the human fetal-maternal interface. J Mol Endocrinol 2018;61:139–52.CrossRefGoogle ScholarPubMed
James-Allan, LB, Arbet, J, Teal, SB, et al. Insulin stimulates GLUT4 trafficking to the syncytiotrophoblast basal plasma membrane in the human placenta. J Clin Endocrinol Metab 2019. pii: jc.2018–02778. doi: 10.1210/jc.2018-02778 [Epub ahead of print].CrossRefGoogle Scholar
Yubero, P, Hondares, E, Carmona, MC, et al. The developmental regulation of peroxisome proliferator-activated receptor-gamma coactivator-1alpha expression in the liver is partially dissociated from the control of gluconeogenesis and lipid catabolism. Endocrinology 2004;145:4268–77.CrossRefGoogle ScholarPubMed
Vaughan, OR, Rosano, FJ, Powell, T, et al. Regulation of placental amino acid transport and fetal growth. Prog Mol Biol Transl Sci 2017;145:217–51.CrossRefGoogle ScholarPubMed
Van den Akker, CH, van Goudoever, JB. Recent advances in our understanding of protein and amino acid metabolism in the human fetus. Curr Opin Clin Nutr 2010;13:7580.CrossRefGoogle ScholarPubMed
van den Acer, CH, Schierbeek, H, Minderman, G, et al. Amino acid metabolism in the human fetus at term: leucine, valine, and methionine kinetics. Pediatr Res 2011;70:566–71.Google Scholar
Battaglia, FC. Glutamine and glutamate exchange between the fetal liver and the placenta. J Nutr 2000;130(4S Suppl):974S977S.CrossRefGoogle ScholarPubMed
Shiojiri, N, Wada, JI, Tanaka, T, et al. Heterogeneous hepatocellular expression of glutamine synthetase in developing mouse liver and in testicular transplants of fetal liver. Lab Invest 1995;72:740–7.Google ScholarPubMed
Thomas, B, Gruca, LL, Bennett, C, et al. Metabolism of methionine in the newborn infant: response to the parenteral and enteral administration of nutrients. Pediatr Res 2008;64:381–6.CrossRefGoogle ScholarPubMed
Bouckenooghe, T, Remacle, C, Reusens, B. Is taurine a functional nutrient? Curr Opin Clin Nutr 2006;9:728–33.CrossRefGoogle ScholarPubMed
Ghio, A, Bertolotto, A, Resi, V, et al. Triglyceride metabolism in pregnancy. Adv Clin Chem 2011;55:133–53.CrossRefGoogle ScholarPubMed
Herrera, E, Amusquivar, E, Lopez- Soldado, I, et al. Maternal lipid metabolism and placental lipid transfer. Horm Res 2006;65(Suppl 3):5964.Google ScholarPubMed
Lewis, RM, Wadsack, C, Desoye, G. Placental fatty acid transfer. Curr Opin Clin Nutr Metab Care 2018;21(2):7882. doi: 10.1097/MCO.0000000000000443.CrossRefGoogle ScholarPubMed
Herrera, E, Lopez-Soldado, I, Limones, M, et al. Lipid metabolism during the perinatal phase, and its implications on postnatal development. Int J Vitam Nutr Res 2006;76:216–24.CrossRefGoogle ScholarPubMed
Ehara, E, Kamei, Y, Yuan, X, et al. Ligand-activated PPARα-dependent DNA demethylation regulates the fatty acid β-oxidation genes in the postnatal genes in the postnatal liver. Diabetes 2015;64:775–84.CrossRefGoogle ScholarPubMed
Pegorier, JP, Prip-Buus, C, Duee, PH, et al. Hormonal control of fatty acid oxidation during the neonatal period. Diabetes Metab 1992;18:156–60.Google ScholarPubMed
Haggarty, P. Effect of placental function on fatty acid requirements during pregnancy. Eur J Clin Nutr 2004;58:1559–70.CrossRefGoogle ScholarPubMed
Hong, L, Rosenbaum, S. Developmental pharmacokinetics in pediatric populations. J Pediatr Pharmacol Ther 2014;19(4):262–76.Google Scholar
Leeder, JS, Kearns, GL, Spielberg, SP, et al. Understanding the relative roles of pharmacogenetics and ontogeny in pediatric drug development and regulatory science. J Clin Pharmacol 2010;50:1377–87.CrossRefGoogle ScholarPubMed
Vyhlidal, CA, Gaedigk, R, Leeder, JS. Nuclear receptor expression in fetal and pediatric liver: correlation with CYP3A expression. Drug Metab Dispos 2006;34:131–7.CrossRefGoogle ScholarPubMed
Blake, MJ, Castro, L, Leeder, JS, et al. Ontogeny of drug metabolizing enzymes in the neonate. Semin Fetal Neonat Metab 2005;10:123–38.Google ScholarPubMed
Matalová, P, Urbánek, K, Anzenbacher, P. Specific features of pharmacokinetics in children. Drug Metab Rev 2016;48(1):70–9.CrossRefGoogle ScholarPubMed
Zhang, J, Cashman, JR. Quantitative analysis of FMO gene mRNA levels in human tissues. Drug Metab Dispos 2006;34:1926.CrossRefGoogle ScholarPubMed
Josephy, PD. Genetic variations in human glutathione transferase enzymes: significance for pharmacology and toxicology. Hum Genomics Proteomics 2010;2010:876940. Published June 13, 2010. doi: 10.4061/2010/876940Google ScholarPubMed
Hein, DW, Doll, MA, Fretland, AJ, et al. Molecular genetics and epidemiology of the NAT1 and NAT2 acetylation polymorphisms. Cancer Epidemiol Biomarkers Prev 2000;9:2942.Google ScholarPubMed
Myllynen, P, Immonen, E, Kummu, M, Vahakangas, K. Developmental expression of drug metabolizing enzymes and transporter proteins in human placenta and fetal tissues. Expert Opin Drug Metab Toxicol 2009;5:1483–99.CrossRefGoogle ScholarPubMed
Han, LW, Gao, G, Mao, Q. An update on expression and function of P-gp/ABCB1 and BCRP/ABCG2 in the placenta and fetus. Expert Opin Drug Metab Toxicol 2018;14:817–29.CrossRefGoogle ScholarPubMed
Chen, HL, Liu, YJ, Feng, CH, et al. Developmental expression of canalicular transporter genes in human liver. J Hepatol 2005;43:472–7.CrossRefGoogle ScholarPubMed
Arrese, M, Ananthananarayanan, M, Suchy, FJ. Hepatobiliary transport: molecular mechanisms of development and cholestasis. Pediatr Res 1998;44:141–7.CrossRefGoogle ScholarPubMed
Colombo, C, Zuliani, G, Ronchi, M, et al. Biliary bile acid composition of the human fetus in early gestation. Pediatr Res 1987;21:197200.CrossRefGoogle ScholarPubMed
Balistreri, WF, Heubi, JE, Suchy, FJ. Immaturity of the enterohepatic circulation in early life: factors predisposing to “physiologic” maldigestion and cholestasis. J Pediatr Gastroenterol Nutr 1983;2:346–54.CrossRefGoogle ScholarPubMed
Watkins, JB, Ingall, D, Szczepanik, P, et al. Bile-salt metabolism in the newborn. Measurement of pool size and synthesis by stable isotope technique. N Engl J Med 1973;288:431–4.CrossRefGoogle Scholar
Watkins, JB, Szczepanik, P, Gould, JB, et al. Bile salt metabolism in the human premature infant. Preliminary observations of pool size and synthesis rate following prenatal administration of dexamethasone and phenobarbital. Gastroenterology 1975;69:706–13.Google ScholarPubMed
Setchell, KD, Dumaswala, R, Colombo, C, et al. Hepatic bile acid metabolism during early development revealed from the analysis of human fetal gallbladder bile. J Biol Chem 1988;263:16637–44.CrossRefGoogle ScholarPubMed
Suchy, FJ, Balistreri, WF, Heubi, JE, et al. Physiologic cholestasis: elevation of the primary serum bile acid concentrations in normal infants. Gastroenterology 1981;80:1037–41.CrossRefGoogle ScholarPubMed
Itoh, S, Onishi, S, Isobe, K, et al. Foetomaternal relationships of serum bile acid pattern estimated by high-pressure liquid chromatography. Biochem J 1982;204:141–5.CrossRefGoogle ScholarPubMed
Balistreri, WF. Immaturity of hepatic excretory function and the ontogeny of bile acid metabolism. J Pediatr Gastr Nutr 1983;2(Suppl 1):S207S214.CrossRefGoogle ScholarPubMed
Klinger, W. Biotransformation of drugs and other xenobiotics during postnatal development. Pharmacol Ther 1982;16:377429.CrossRefGoogle ScholarPubMed
Little, JM, Smallwood, RA, Lester, R, et al. Bile-salt metabolism in the primate fetus. Gastroenterology 1975;69:1315–20.Google ScholarPubMed
Bernstein, RB, Novy, MJ, Piasecki, GJ, et al. Bilirubin metabolism in the fetus. J Clin Invest 1969;48:1678–88.CrossRefGoogle ScholarPubMed
Smallwood, RA, Lester, R, Plasecki, GJ, et al. Fetal bile salt metabolism. II. Hepatic excretion of endogenous bile salt and of a taurocholate load.J Clin Invest 1972;51:1388–97.Google ScholarPubMed
Tavoloni, N, Jones, MJ, Berk, PD. Postnatal development of bile secretory physiology in the dog. J Pediatr Gastroenterol Nutr 1985;4:256–67.CrossRefGoogle ScholarPubMed
Mohan, P, Ling, SC, Watkins, JB. Ontogeny of hepatobiliary secretion: role of glutathione. Hepatology 1994;19:1504–12.CrossRefGoogle ScholarPubMed
Ho, ML, Chen, JY, Ling, UP, et al. Gallbladder volume and contractility in term and preterm neonates: normal values and clinical applications in ultrasonography. Acta Paediatr 1998;87:799804.CrossRefGoogle ScholarPubMed
Jawaheer, G, Pierro, A, Lloyd, DA, et al. Gallbladder contractility in neonates: effects of parenteral and enteral feeding. Arch Dis Child Fetal 1995;72:F200F202.CrossRefGoogle ScholarPubMed
Kaplan, GS, Bhutani, VK, Shaffer, TH, et al. Gallbladder mechanics in newborn piglets. Pediatr Res 1984;18:1181–4.CrossRefGoogle ScholarPubMed
Suchy, FJ, Bucuvalas, JC, Goodrich, AL, et al. Taurocholate transport and Na+-K+-ATPase activity in fetal and neonatal rat liver plasma membrane vesicles. Am J Physiol 1986;251(5 Pt 1):G665C673.Google ScholarPubMed
Bellemann, P. Amino acid transport and rubidium-ion uptake in monolayer cultures of hepatocytes from neonatal rats. Biochem J 1981;198:475–83.CrossRefGoogle ScholarPubMed
Belknap, WM, Zimmer-Nechemias, L, Suchy, FJ, Balistreri, WF. Bile acid efflux from suckling rat hepatocytes. Pediatr Res 1988;23:364–7.CrossRefGoogle ScholarPubMed
Stolz, A, Sugiyama, Y, Kuhlenkamp, J, et al. Cytosolic bile acid binding protein in rat liver: radioimmunoassay, molecular forms, developmental characteristics and organ distribution. Hepatology 1986;6:433–9.CrossRefGoogle ScholarPubMed
Hardikar, W, Ananthanarayanan, M, Suchy, FJ. Differential ontogenic regulation of basolateral and canalicular bile acid transport proteins in rat liver. J Biol Chem 1995;270:20841–6.CrossRefGoogle ScholarPubMed
Balasubramaniyan, N, Shahid, M, Suchy, FJ, et al. Multiple mechanisms of ontogenic regulation of nuclear receptors during rat liver development. Am J Physiol Gastriointest Liver Physiol 2005;288:G251G260.CrossRefGoogle ScholarPubMed
Tomer, G, Ananthanarayanan, M, Weymann, A, et al. Differential developmental regulation of rat liver canalicular membrane transporters Bsep and Mrp2. Pediatr Res 2003;53:288–94.CrossRefGoogle ScholarPubMed
Zinchuk, VS, Okada, T, Akimaru, K, et al. Asynchronous expression and colocalization of Bsep and Mrp2 during development of rat liver. Am J Phys – Gastr L. 2002;282:G540G548.Google ScholarPubMed
Wagner, M, Zollner, G, Trauner, M. Nuclear receptors in liver disease. Hepatology 2011;53:1023–34.CrossRefGoogle ScholarPubMed
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