Hepatic function and physiology in the newborn

doi:10.1016/S1084-2756(03)00066-6

Seminars in Neonatology

Volume 8, Issue 5, October 2003, Pages 337-346

https://doi.org/10.1016/S1084-2756(03)00066-6 Get rights and content

Abstract

The liver develops from progenitor cells into a well-differentiated organ in which bile secretion can be observed by 12 weeks' gestation. Full maturity takes up to two years after birth to be achieved, and involves the normal expression of signalling pathways such as that responsible for the JAG1 genes (aberrations occur in Alagille's syndrome), amino acid transport and insulin growth factors. At birth, hepatocytes are already specialized and have two surfaces: the sinusoidal side receives and absorbs a mixture of oxygenated blood and nutrients from the portal vein; the other surface delivers bile and other products of conjugation and metabolism (including drugs) to the canalicular network which joins up to the bile ductules. There is a rapid induction of functions such as transamination, glutamyl transferase, synthesis of coagulation factors, bile production and transport as soon as the umbilical supply is interrupted.

Anatomical specialization can be observed across the hepatic acinus which has three distinct zones. Zone 1 borders the portal tracts (also known as periportal hepatocytes) and is noted for hepatocyte regeneration, bile duct proliferation and gluconeogenesis. Zone 3 borders the central vein and is associated with detoxification (e.g. paracetamol), aerobic metabolism, glycolysis and hydrolysis and zone 2 is an area of mixed function between the two zones.

Preterm infants are at special risk of hepatic decompensation because their immaturity results in a delay in achieving normal detoxifying and synthetic function. Hypoxia and sepsis are also frequent and serious causes of liver dysfunction in neonates.

Stem cell research has produced many answers to the questions about liver development and regeneration, and genetic studies including studies of susceptibility genes may yield further insights. The possibility that fatty liver (increasingly recognized as non-alcoholic steatohepatitis or NASH) may have roots in the neonatal period is a concept which may have important long-term implications.

Introduction

The liver contains a diverse group of cell lines that remain in a state of some plasticity until at least 12 months after birth. The liver differentiates from embryonic liver progenitor cells derived from stem cells, into a mature organ containing hepatocytes, cholangiocytes and immune cells, all existing in a stromal network through which approximately one-quarter of the circulating blood is pumped.1, 2This process takes place via several important mechanisms which are only just beginning to be understood. These include apoptosis, morphogenesis, proliferation and polarization.3, 4, 5Aberrations of the normal sequence of embryonic and fetal gene expression can lead to disease, e.g. the notch signalling pathway appears to be important in Alagille's syndrome characterized by cardiac, facial and hepatic abnormalities⁶(Table 1). The liver may play an important role in the maintenance of a healthy feto-placental unit as intra-uterine growth restriction is associated with reduced expression of hepatocyte growth factors.⁷External factors such as the hormonal milieu and hypoxia influence the expression of genes responsible for the transport of amino acids across membranes and the production of insulin growth factors8, 9(Table 2). An imbalance in the transport of molecules such as bilirubin and amino acids can lead to cholestasis and a giant cell hepatitis.

Section snippets

Fetal development

The liver develops from the foregut which folds into the mesoderm. The bile ducts and hepatocytes are derived from stem cells in the endoderm, and Kupffer cells, blood vessels, including the specialized porous endothelium which lines the sinusoids, and fibrous tissue are all derived from mesoderm. The stem cells differentiate into progenitor cells which are then committed to either hepatocyte or cholangiocyte lineage.¹⁰The hepatocytes develop in long cords into the stroma, initially as plates

Events at birth

Two major physiological events at birth affect the liver: the pressure in the lungs drops dramatically with the first few breaths; and 50% of the cardiac output previously going to the placenta is rapidly re-distributed as blood flow through the umbilicus ceases. Within minutes, the venous return from vital organs such as the liver and the small bowel increases, and the pulmonary circulation becomes as dynamic as the systemic circulation, producing a steep rise in dissolved oxygen in arterial

Maturing physiology

After the initial adaptations to circulatory changes in the newborn have taken place, the liver starts to fulfil its role in maintaining homeostasis.

Hypoxia

The neonatal liver is relatively resistant to the effects of hypoxia, but in conditions of hypoperfusion, such as during circulatory collapse caused by sepsis or blood loss, acute hepatocyte necrosis may be evident, especially around the central vein.²⁸Over the next 2–10 days, an increase in plasma transaminases (alanine transaminase, aspartate transaminase) and lactate dehydrogenase are seen which may exceed 500 IU/l,²⁹and a coagulopathy may develop. The rise in transaminases is followed by a

Summary

Although the blood supply and volume of the liver change dramatically at birth, together with its range of required functions, a healthy baby has sufficient physiological reserve for homeostasis to be well maintained with only a short-lived period of mild unconjugated jaundice being apparent. Babies who are of low birth weight, premature or stressed for other reasons (e.g. infection, hypoxia or congenital heart disease) may present with hypoglycaemia, acidosis and prolonged jaundice. Provided

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Hepatic function and physiology in the newborn

Abstract

Introduction

Section snippets

Fetal development

Events at birth

Maturing physiology

Hypoxia

Summary

J Hepatol

Gastroenterology

J Hepatol

Hepatology

Am J Pathol

Gastroenterology

J Pediatr

Biochem Pharmacol

J Pediatr

J Hepatol

J Hepatol

J Lab Clin Med

J Biol Chem

Semin Pediatr Surg

Am J Obstet Gynecol

Best Pract Res Clin Gastroenterol

Isolation of human progenitor liver epithelial cells with extensive replication capacity and differentiation into mature hepatocytes

J Cell Sci

Characterisation of Notch receptor expression in developing mammalian heart and liver

Am J Med Genet