Embryology

The hepatic primordium anlage initially appears at the end of the third week of gestation and is
first seen as a hollow midline outgrowth stalk (hepatic diverticulum) of the endodermal epithelium at the distal aspect of the foregut. By the fourth week, the diverticulum enlarges from proliferation of the endodermal cell strands (hepatoblasts) and projects cranially into the mesoderm of the septum transversum, eventually giving rise to the liver hepatic parenchyma and intrahepatic ducts. The cephalic end ultimately develops into the right and left hepatic lobes, while the stalk between the diverticulum and foregut narrows and forms the extrahepatic biliary system and gallbladder. Solid cords are initially formed by proliferating endodermal cells. These eventually anastomose to form vesicles and cribriform tubules with centrally located lumenal structures (biliary canaliculi). The cords eventually merge and develop small channels and capillaries that subdivide the cords to eventually form the hepatic sinusoids. The individual hepatoblasts are progenitor cells that develop into mature hepatocytes, with those immediately adjacent to the portal mesenchyme becoming the ductal plates. The rapid growth rate of the hepatic cords enables the development of sheets of cells (muralium multiplex) that persist until birth, after which the cell sheets narrow to two cells (muralium duplex) and eventually evolve within the first year of life into a one cell thick trabecular cord (muralium simplex). The perisinusoidal cells and Kupffer cells appear by three months gestation. The mesoderm from the septum transversum initially surrounds the liver and is directly in contact with the lesser curvature of the stomach, duodenum, and ventral body wall. The mesoderm eventually forms the lesser omentum, the falciform, coronary, and triangular ligaments, with a portion developing into the liver (Glisson) capsule. The mesoderm on the liver surface is also in continuity with the peritoneum, and the portion that makes contact with the future diaphragm remains uncovered (bare area). The developing hepatic artery and vagus nerve branches follow the mesoderm along and adjacent to the portal vein. The mesoderm is the main focus in the development of hematopoiesis, which begins at about 6 weeks and becomes most active during the fifth month of gestation. This process regresses with increase in bone marrow activity. The erythroid precursors are most prominent during fetal development within the hepatic sinusoids while the myeloid and megakaryocytic precursors reside mostly within the portal structures (Figure 1.1). This hematopoiesis is responsible for the enlarged size of the liver (up to 10% body weight by the tenth week of gestation, with the right and left lobes taking up an equal volume), but this size significantly regresses at birth (5% of body weight) at which time only rare small clusters of normoblasts can be seen. By 4 weeks of age hematopoietic activity has usually ceased.
Additionally with time the left lobe diminishes in size, and the caudate and quadrate lobes develop as subdivisions of the right lobe. The vascular network, originally derived from the development of the vitelline and umbilical veins, occurs at the same time as proliferation of the hepatoblasts, with the sinusoids forming from anastomosis of the hepatic cords and vessels. By the fifth week of gestation most of the major vessels are present and include the right and left umbilical veins, the transverse portal sinus, and the ductus venosus, which shunts blood from the umbilical vein into the inferior vena cava. The portal vein initially develops from the vitelline vein and then subdivides into the right and left branches. The hepatic and portal vein branches divide the parenchyma into the individual lobules and acini. At birth, a sphincter mechanism closes the ductus venosus, resulting in cessation of blood flow through the umbilical vein, with the liver now receiving blood from the left branch of the portal vein. The biliary apparatus develops from membranous infoldings between the junctional complexes located between individual hepatoblasts and initially appears as intercellular spaces with no distinct wall. The biliary canaliculi are first seen at 6 weeks of gestation, with synthesis of bile occurring by the ninth week and secretion of bile by the twelfth week. The ductal plate, which is initially two layers thick, is formed from the periportal hepatoblasts. A lumen develops by the third month (see Figure 1.1) with eventual formation of double-layered tubular (ductular) structures. The true interlobular bile ducts occur immediately after birth from remodeling of these ductular elements. This biliary network receives its blood supply from a complex of arterioles and capillaries formed from the peribiliary plexus. The extrahepatic biliary tree develops from the stalk of the original hepatic outgrowth. Individual cell functions become apparent at different stages of the embryologic development. α-Fetoprotein, found in high amounts at birth, initially is seen within the hepatocytes by one month gestation and continues throughout fetal development, with high serum levels at birth. Fatty change (steatosis), glycogen and glycogen synthesis become most apparent by two to three months gestation, with the glycogen eventually diminishing due to rapid glycogenolysis. Hemosiderin is usually seen early on but gradually decreases, with some often occurring in the periportal hepatocytes at birth.