Medical Physiology, 3rd Edition

Functional Anatomy of the Liver and Biliary Tree

Hepatocytes are secretory epithelial cells separating the lumen of bile canaliculi from the fenestrated endothelium of sinusoids

One way of looking at the organization of the liver is to imagine that a classic lobule is a hexagon in cross section (Fig. 46-1A) with a branch of the hepatic vein at its center and, at each of the six corners, triads composed of branches of the hepatic artery, portal vein, and bile duct. Hepatocytes account for ~80% of the parenchymal volume in human liver. Hepatocytes form an epithelium, one cell thick, that constitutes a functional barrier between two fluid compartments with differing ionic compositions: the tiny canalicular lumen containing bile, and the much larger sinusoid containing blood (see Fig. 46-1B). Moreover, hepatocytes significantly alter the composition of these fluids by vectorial transport of solutes across the hepatocyte. This vectorial transport depends critically on the polarized distribution of specific transport mechanisms and receptors that are localized to the apical membrane that faces the canalicular lumen and the basolateral membrane that faces the pericellular space between hepatocytes and the blood-filled sinusoid (see Fig. 46-1B, C). As in other epithelia, the apical and basolateral membrane domains of hepatocytes are structurally, biochemically, and physiologically distinct.

FIGURE 46-1 Hepatocytes, sinusoids, and the intrahepatic bile system.

The space of Disse, or perisinusoidal space, is the extracellular gap between the endothelial cells lining the sinusoids and the basolateral membranes of the hepatocytes. These basolateral membranes have microvilli that project into the space of Disse to facilitate contact with the solutes in sinusoidal blood. The microvilli greatly amplify the surface of the basolateral membrane, which accounts for ~85% of the total surface area of the hepatocyte.

The bile canaliculi, into which bile is initially secreted, are formed by the apical membranes of adjoining hepatocytes. The apical membrane of the hepatocyte runs as a narrow belt that encircles and grooves into the polygonal hepatocyte (see Fig. 46-1B, C). Two adjacent hepatocytes form a canaliculus that is ~1 µm in diameter by juxtaposing their groove-like apical membranes along their common face (i.e., one side of the polygon). Because a hepatocyte has many sides and a different neighbor on each side, the canaliculi form a chicken wire–like pattern along the contiguous surfaces of hepatocytes and communicate to form a three-dimensional tubular network. Although the apical membrane belt is very narrow (i.e., ~1 µm), its extensive microvillous structure amplifies its surface area so that the canalicular membrane constitutes as much as 15% of the total membrane surface area. Because of this high surface-to-volume ratio, the total apical surface area available for the movement of water and solutes in the human liver is in excess of 10.5 m².

The seal that joins the apical membranes of two juxtaposed hepatocytes and that separates the canalicular lumen from the pericellular space—which is contiguous with the space of Disse—comprises several elements, including tight junctions (see Fig. 46-1D) and desmosomes (see p. 45). By virtue of their permeability and morphology, hepatic junctions can be classified as having an intermediate tightness, somewhere between that of tight epithelia (e.g., toad bladder) and leaky epithelia (e.g., proximal tubule). Specialized structures called gap junctions (see pp. 158–159) allow functional communication between adjacent hepatocytes.

Hepatocytes do not have a true basement membrane, but rather they rest on complex scaffolding provided by the extracellular matrix in the space of Disse, which includes several types of collagens (I, III, IV, V, and VI), fibronectin, undulin, laminin, and proteoglycans. Cells are linked to the matrix through specific adhesion proteins on the cell surface. The extracellular matrix not only provides structural support for liver cells but also seems to influence and maintain the phenotypic expression of hepatocytes and sinusoidal lining cells.

The liver contains endothelial cells, macrophages (Kupffer cells), and stellate cells (Ito cells) within the sinusoidal spaces

Slightly more than 6% of the volume of the liver parenchyma is made up of cells other than hepatocytes, including endothelial cells (2.8%), Kupffer cells (2.1%), and stellate cells (fat-storing or Ito cells, 1.4%). The endothelial cells that line the vascular channels or sinusoids form a fenestrated structure with their bodies and cytoplasmic extensions. Plasma solutes, but not blood cells, can move freely into the space of Disse through pores, or fenestrae, in the endothelial cells. Some evidence indicates that the fenestrae may regulate access into the perisinusoidal space of Disse by means of their capacity to contract.

The Kupffer cells are present within the sinusoidal vascular space. N46-1 This population of fixed macrophages removes particulate matter from the circulation. Stellate cells are in the space of Disse and are characterized morphologically by the presence of large fat droplets in their cytoplasm. These cells play a central role in the storage of vitamin A, and evidence suggests that they can be transformed into proliferative, fibrogenic, and contractile myofibroblasts. On liver injury, these activated cells participate in fibrogenesis through remodeling of the extracellular matrix, production of cytokines, and deposition of type I collagen, which can lead to cirrhosis.

Contributed by Emile Boulpaep, Walter Boron

Kupffer cells—or Browicz-Kupffer cells—are part of the reticuloendothelial system. They were originally described in 1876 by Karl Wilhelm von Kupffer, who incorrectly thought that they were part of the endothelium of the liver. In 1898, Tadeusz Browicz correctly identified them as macrophages.

The liver has a dual blood supply, but a single venous drainage system

The blood supply to the liver has two sources. The portal vein contributes ~75% of the total circulation to the liver; the hepatic artery contributes the other 25% (Fig. 46-2A). Blood from portal venules and hepatic arterioles combines in a complex network of hepatic sinusoids (see Fig. 46-2B). Blood from these sinusoids converges on terminal hepatic venules (or central veins), which, in turn, join to form the hepatic veins (see Fig. 46-2C). Branches of the portal vein, hepatic artery, and a bile duct (i.e., the triad), as well as lymphatics and nerves, travel together as a portal tract.

FIGURE 46-2 Blood supply to the liver.

The arterial supply for the bile ducts arises mainly from the right hepatic artery (see Fig. 46-2C). These arterioles give rise to an extraordinarily rich plexus of capillaries that surround the bile ducts as they pass through the portal tracts. Blood flowing through this peribiliary plexus empties into the sinusoids by way of branches of the portal vein so that this blood may pick up solutes from the bile ducts and cycle them back to the hepatocytes. Thus, the peribiliary plexus may provide the means for modifying biliary secretions through the bidirectional exchange of compounds such as proteins, inorganic ions, and bile acids between the bile and blood within the portal tract.

Hepatocytes can be thought of as being arranged as classic hepatic lobules, portal lobules, or acinar units

The complex structure of the liver makes it difficult to define a single unit—something analogous to the nephron in the kidney—that is capable of performing the functions of the entire liver. One way of viewing the organization of the liver is depicted in Figures 46-1 and 46-2, in which we regard the central vein as the core of the classic hepatic lobule. Thus, the classic hepatic lobule (Fig. 46-3A) includes all hepatocytes drained by a single central vein, and it is bounded by two or more portal triads. Alternatively, we can view the liver as though the triad is the core of a portal lobule (see Fig. 46-3B). Thus, the portal lobule includes all hepatocytes drained by a single bile ductule and is bounded by two or more central veins. A third way of viewing the liver is to group the hepatocytes according to their supply of arterial blood (see Fig. 46-3C). Thus, the portal acinus is a small three-dimensional mass of hepatocytes that are irregular in size and shape, with one axis formed by a line between two triads (i.e., high ) and another axis formed by a line between two central veins (i.e., low ).

FIGURE 46-3 Zones in the acinus. A, The classic lobule includes all hepatocytes drained by a single central vein. At each corner of the hexagon are triads composed of branches of the hepatic artery, portal vein, and bile duct. B, The portal lobule includes all hepatocytes drained by a bile ductule. C, The portal acinus emphasizes the arterial blood supply to the hepatocytes and thus the oxygenation gradient between a branch of the hepatic artery and branches of the hepatic vein (i.e., central vein).

Periportal hepatocytes specialize in oxidative metabolism, whereas pericentral hepatocytes detoxify drugs

Rappaport first proposed that a zonal relationship exists between cells that constitute the portal acini and their blood supply (see Fig. 46-3C). Hepatocytes close to the vascular core formed by the terminal portal venule and terminal hepatic arteriole are perfused first and thus receive the highest concentrations of oxygen and solutes. These periportal hepatocytes are said to reside in zone I, and as a consequence of their location, they are the most resistant to the effects of circulatory compromise or nutritional deficiency. These cells are also more resistant to other forms of cellular injury and are the first to regenerate. Hepatocytes in the intermediate zone II and the most distal population of pericentral hepatocytes located near the terminal hepatic venule (central vein) in zone III are sequentially perfused with blood that is already modified by the preceding hepatocytes; thus, they are exposed to progressively lower concentrations of nutrients and oxygen. The exact boundaries of these zones are difficult to define.

The concept of zonal heterogeneity of liver function has evolved as a result of these differences in access to substrate. Because of the specialized microenvironments of cells in different zones, some enzymes are preferentially expressed in one zone or another (Table 46-1). For example, in zone I, oxidative energy metabolism with β-oxidation, amino-acid metabolism, ureagenesis, gluconeogenesis, cholesterol synthesis, and bile formation is particularly important. Localized in zone III are glycogen synthesis from glucose, glycolysis, liponeogenesis, ketogenesis, xenobiotic metabolism, and glutamine formation. Molecular techniques have allowed an even more precise definition of which hepatocytes express particular messenger RNA (mRNA) and proteins. For example, the enzyme glutamine synthetase is expressed exclusively in only one or two hepatocytes immediately adjacent to the hepatic venules. Hepatocytes of zone III also seem to be important for general detoxification mechanisms and the biotransformation of drugs. The zonal distribution of drug-induced toxicity manifested as cell necrosis may be attributed to zone III localization of the enzymatic pathways involved in the biotransformation of substrates by oxidation, reduction, or hydrolysis. Although it appears that each hepatocyte is potentially capable of multiple metabolic functions, the predominant enzymatic activity appears to result from adaptation to the microenvironment provided by the hepatic microcirculation. In some cases, it has been possible to reverse the zone I–to–zone III gradient of hepatocyte function by experimentally reversing the direction of blood supply (i.e., nutrient flow).

Bile drains from canaliculi into small terminal ductules, then into larger ducts, and eventually, via a single common duct, into the duodenum

The adult human liver has >2 km of bile ductules and ducts, with a volume of ~20 cm³ and a macroscopic surface area of ~400 cm². Microvilli at the apical surface magnify this area by ~5.5-fold.

As noted above, the canaliculi into which bile is secreted form a three-dimensional polygonal meshwork of tubes between hepatocytes, with many anastomotic interconnections (see Fig. 46-1). From the canaliculi, the bile enters the small terminal bile ductules (i.e., canals of Hering), which have a basement membrane and in cross section are surrounded by three to six ductal epithelial cells or hepatocytes (Fig. 46-4A). The canals of Hering then empty into a system of perilobular ducts, which, in turn, drain into interlobular bile ducts. The interlobular bile ducts form a richly anastomosing network that closely surrounds the branches of the portal vein. These bile ducts are lined by a layer of cuboidal or columnar epithelium that has microvillous architecture on its luminal surface. The cells have a prominent Golgi apparatus and numerous vesicles, which probably participate in the exchange of substances among the cytoplasm, bile, and blood plasma through exocytosis and endocytosis.

FIGURE 46-4 Structure of the biliary tree. A, The bile canaliculi, which are formed by the apical membranes of adjacent hepatocytes, eventually merge with terminal bile ductules (canals of Hering). The ductules eventually merge into perilobular ducts, and then interlobular ducts. B, The interlobular ducts merge into septal ducts and lobar ducts (not shown), and eventually the right and left hepatic ducts, which combine as the common hepatic duct. The confluence of the common hepatic duct and the cystic duct gives rise to the common bile duct. The common bile duct may merge with the pancreatic duct and form the ampulla of Vater before entering the duodenum, as shown in the figure, or have a completely independent lumen. In either case, there is a common sphincter—the sphincter of Oddi—that simultaneously regulates flow out of the common bile duct and the pancreatic duct.

The interlobular bile ducts unite to form larger and larger ducts, first the septal ducts and then the lobar ducts, two hepatic ducts, and finally a common hepatic duct (see Fig. 46-4B). Along the biliary tree, the biliary epithelial cells, or cholangiocytes, are similar in their fine structure except for size and height. However, as discussed below (see pp. 960–961), in terms of their functional properties, cholangiocytes and bile ducts of different sizes are heterogeneous in their expression of enzymes, receptors, and transporters. Increasing emphasis has been placed on the absorptive and secretory properties of the biliary epithelial cells, properties that contribute significantly to the process of bile formation. As with other epithelial cells, cholangiocytes are highly cohesive, with the lateral plasma membranes of contiguous cells forming tortuous interdigitations. Tight junctions seal contacts between cells that are close to the luminal region and thus limit the exchange of water and solutes between plasma and bile.

The common hepatic duct emerges from the porta hepatis after the union of the right and left hepatic ducts. It merges with the cystic duct emanating from the gallbladder to form the common bile duct. In adults, the common bile duct is quite large, ~7 cm in length and ~0.5 to 1.5 cm in diameter. In most individuals, the common bile duct and the pancreatic duct merge before forming a common antrum known as the ampulla of Vater. At the point of transit through the duodenal wall, this common channel is surrounded by a thickening of both the longitudinal and the circular layers of smooth muscle, the so-called sphincter of Oddi. This sphincter constricts the lumen of the bile duct and thus regulates the flow of bile into the duodenum. The hormone cholecystokinin (CCK) relaxes the sphincter of Oddi via a nonadrenergic, noncholinergic neural pathway (see pp. 344–345) involving vasoactive intestinal peptide (VIP).

The gallbladder lies in a fossa beneath the right lobe of the liver. This distensible pear-shaped structure has a capacity of 30 to 50 mL in adults. The absorptive surface of the gallbladder is enhanced by numerous prominent folds that are important for concentrative transport activity, as discussed below. The gallbladder is connected at its neck to the cystic duct, which empties into the common bile duct (see Fig. 46-4B). The cystic duct maintains continuity with the surface columnar epithelium, lamina propria, muscularis, and serosa of the gallbladder. Instead of a sphincter, the gallbladder has, at its neck, a spiral valve—the valve of Heister—formed by the mucous membrane. This valve regulates flow into and out of the gallbladder.