Chapter 346 Morphogenesis of the Liver and Biliary System

Morphogenesis of the liver and biliary system is a complex process. It follows that altered development has significant consequences, including cholestatic disorders such as Alagille syndrome and biliary atresia.

During the early embryonic process of gastrulation, the 3 embryonic germ layers (endoderm, mesoderm, ectoderm) are formed. The liver and biliary system arise from cells of the ventral foregut endoderm; their development can be divided into 3 distinct processes (Fig. 346-1). First, through unknown mechanisms, the ventral foregut endoderm acquires competence to receive signals arising from the cardiac mesoderm. These mesodermal signals, in the form of various fibroblast growth factors (FGFs) and bone morphogenetic proteins (BMPs), lead to specification of cells that will form the liver and activation of liver-specific genes. During this period of hepatic fate decision, “pioneer” transcription factors, including Foxa and Gata4, bind to specific binding sites in compacted chromatin, open the local chromatin structure, and mark genes as competent. But these will only be expressed if they are correctly induced by additional transcription factors. Newly specified cells then migrate in a cranial ventral direction into the septum transversum in the 4th wk of human gestation to initiate liver morphogenesis.

Figure 346-1 Processes involved in early liver development. A, The ventral foregut endoderm acquires competence to receive signals arising from the cardiac mesoderm. B, Specific cells of the ventral foregut endoderm undergo specification and activation of liver-specific genes under the influence of mesodermal signals. C, Liver morphogenesis is initiated as the newly specified cells migrate into the septum transversum under the influence of signaling molecules and extracellular matrix released by septum transversum mesenchymal cells and of primitive endothelial cells.

(Reprinted from Zaret KS: Liver specification and early morphogenesis, Mech Dev 92:83–88, 2000;

The growth and development of the newly budded liver require interactions with endothelial cells. Certain proteins are important for liver development in animal models (Table 346-1). In addition to these proteins, microRNA, which consists of small noncoding, single-stranded RNA, have a functional role in the regulation of gene expression and hepatobiliary development in a zebrafish model.

Within the ventral mesentery, proliferation of migrating cells forms anastomosing hepatic cords, with the network of primitive liver cells, sinusoids, and septal mesenchyme establishing the basic architectural pattern of liver lobule (Fig. 346-2). The solid cranial portion of the hepatic diverticulum (pars hepatis) eventually forms the hepatic parenchyma and the intrahepatic bile ducts. The hepatic lobules are identifiable in the 6th week of human gestation. The bile canalicular structures, including microvilli and junctional complexes, are specialized loci of the liver cell membrane; these appear very early in gestation, and large canaliculi bounded by several hepatocytes are seen by 6-7 wk.

Figure 346-2 Hepatic morphogenesis. A, Ventral outgrowth of hepatic diverticulum from foregut endoderm in the 3.5 wk embryo. B, Between the two vitelline veins, the enlarging hepatic diverticulum buds off epithelial (liver) cords that become the liver parenchyma, around which the endothelium of capillaries (sinusoids) align (4 wk embryo). C, Hemisection of embryo at 7.5 wk. D, Three-dimensional representation of the hepatic lobule as present in the newborn.

(Reprinted from Andres JM, Mathis RK, Walker WA: Liver disease in infants. Part I: developmental hepatology and mechanisms of liver dysfunction, J Pediatr 90:686–697, 1977.)

Hepatocytes and bile duct cells (cholangiocytes) originate both from hepatoblasts as common precursors. Notch signaling, which is impaired in Alagille syndrome, promotes hepatoblast differentiation into biliary epithelium, whereas hepatocyte growth factor (HGF) antagonizes differentiation. The development of the intrahepatic bile ducts is determined by the development and branching pattern of the portal vein. Around the 8th week of gestation, starting at the hilum of the liver, primitive hepatoblasts adjacent to the mesenchyme around the portal vein branches form a cylindrical sleeve, termed the ductal plate. From 12 weeks of gestation onward, a “remodeling” of the ductal plate occurs, with some segments of the ductal plate undergoing tubular dilatation and excess epithelial tissue gradually disappearing. The ramification of the biliary tree continues throughout fetal life and at the time of birth the most peripheral branches of the portal veins are still surrounded by ductal plates; these require 4 more weeks to develop into definitive portal ducts. Lack of remodeling of the ductal plate results in persistence of primitive ductal plate configurations, an abnormality called ductal plate malformation. This histopathologic lesion has been observed in liver biopsies of a variety of liver conditions, including congenital hepatic fibrosis, Caroli disease, and biliary atresia.

The caudal part (pars cystica) of the hepatic diverticulum becomes the gallbladder, cystic duct, and common bile duct. The distal portions of the right and left hepatic ducts develop from the extrahepatic ducts, whereas the proximal portions develop from the first intrahepatic ductal plates. The extrahepatic bile ducts and the developing intrahepatic biliary tree maintain luminal continuity and patency from the beginning of organogenesis (see Fig. 346-2C).

Fetal hepatic blood flow is derived from the hepatic artery and from the portal and umbilical veins, which form the portal sinus. The portal venous inflow is directed mainly to the right lobe of the liver and umbilical flow primarily to the left. The ductus venosus shunts blood from the portal and umbilical veins to the hepatic vein, bypassing the sinusoidal network. After birth, the ductus venosus becomes obliterated when oral feedings are initiated. The fetal oxygen saturation is lower in portal than in umbilical venous blood; accordingly, the right hepatic lobe has lower oxygenation and greater hematopoietic activity than the left hepatic lobe.

The transport and metabolic activities of the liver are facilitated by the structural arrangement of liver cell cords, which are formed by rows of hepatocytes, separated by sinusoids that converge toward the tributaries of the hepatic vein (the central vein) located in the center of the lobule (see Fig. 346-2D). This establishes the pathways and patterns of flow for substances to and from the liver. In addition to arterial input from the systemic circulation, the liver also receives venous input from the gastrointestinal tract via the portal system. The products of the hepatobiliary system are released by 2 different paths: through the hepatic vein and through the biliary system back into the intestine. Plasma proteins and other plasma components are secreted by the liver. Absorbed and circulating nutrients arrive through the portal vein or the hepatic artery and pass through the sinusoids and past the hepatocytes to the systemic circulation at the central vein. Biliary components are transported via the series of enlarging channels from the bile canaliculi through the bile ductule to the common bile duct.

Bile secretion is noted at the 12th week of human gestation. The major components of bile vary with stage of development. Near term, cholesterol and phospholipid content is relatively low. Low concentrations of bile acids, the absence of bacterially derived (secondary) bile acids, and the presence of unusual bile acids reflect low rates of bile flow and immature bile acid synthetic pathways.

The liver reaches a peak relative size of about 10% of the fetal weight at the 9th wk. Early in development, the liver is a primary site of hematopoiesis. In the 7th wk, hematopoietic cells outnumber functioning hepatocytes in the hepatic anlage. These early hepatocytes are smaller than at maturity (∼20 µm vs 30-35 µm) and contain less glycogen. Near term, the hepatocyte mass expands to dominate the organ, as cell size and glycogen content increase. Hematopoiesis is virtually absent by the 2nd postnatal month in full-term infants. As the density of hepatocytes increases with gestational age, the relative volume of the sinusoidal network decreases. The liver constitutes 5% of body weight at birth but only 2% in an adult.

Several metabolic processes are immature in a healthy newborn infant, owing in part to the fetal patterns of activity of various enzymatic processes. Many fetal hepatic functions are carried out by the maternal liver, which provides nutrients and serves as a route of elimination of metabolic end products and toxins. Fetal liver metabolism is devoted primarily to the production of proteins required for growth. Toward term, primary functions become production and storage of essential nutrients, excretion of bile, and establishment of processes of elimination. Extrauterine adaptation requires de novo enzyme synthesis. Modulation of these processes depends on substrate and hormonal input via the placenta and on dietary and hormonal input in the postnatal period.

Hepatic Ultrastructure

Hepatocytes exhibit various ultrastructural features that reflect their biologic functions (Fig. 346-3). Hepatocytes, like other epithelial cells, are polarized, meaning that their structure and function are directionally oriented. One result of this polarity is that various regions of the hepatocyte plasma membrane exhibit specialized functions. Bidirectional transport occurs at the sinusoidal surface, where materials reaching the liver via the portal system enter and compounds secreted by the liver leave the hepatocyte. Canalicular membranes of adjacent hepatocytes form bile canaliculi, which are bounded by tight junctions, preventing transfer of secreted compounds back into the sinusoid. Within hepatocytes, metabolic and synthetic activities are contained within a number of different cell organelles. The oxidation and metabolism of heterogeneous classes of substrates, fatty acid oxidation, key processes in gluconeogenesis, and the storage and release of energy occur in the abundant mitochondria.

Figure 346-3 Schematic view of the ultrastructure and organelles of hepatocytes.

(Reprinted from Sherlock S: Hepatic cell structure. In Sherlock S, editor: Diseases of the liver and biliary system, ed 6, Oxford, 1981, Blackwell Scientific, p 10; with permission from Blackwell Scientific.)

The endoplasmic reticulum (ER), a continuous network of rough- and smooth-surfaced tubules and cisternae, is the site of various processes, including protein and triglyceride synthesis and drug metabolism. Low fetal activity of ER-bound enzymes accounts for a relative inefficiency of xenobiotic (drug) metabolism. The Golgi apparatus is active in protein packaging and possibly in bile secretion. Hepatocyte peroxisomes are single-membrane-limited cytoplasmic organelles that contain enzymes such as oxidases and catalase and those that have a role in lipid and bile acid metabolism. Lysosomes contain numerous hydrolases that have a role in intracellular digestion. The hepatocyte cytoskeleton, composed of actin and other filaments, is distributed throughout the cell and concentrated near the plasma membrane. Microfilaments and microtubules have a role in receptor-mediated endocytosis, in bile secretion, and in maintaining hepatocyte architecture and motility.

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