EMBRYOLOGY, HISTOLOGY, 1 AND ANATOMY EMBRYOLOGY intimate contact with the portal mesenchyme At the beginning of fetal development (to- surrounding a portal vein branch (2). In the ward the latter part of the third week of gesta- weeks that follow, certain parts of the ductal tion), the hepatic diverticulum buds from the plates are duplicated by a second layer of cells, ventral foregut. The hepatic diverticulum then to become double-layered ductal plates, which gives rise to the transverse septum (septum then dilate to form cylindrical structures to be transversum), a structure situated between integrated into the mesenchyme of the newly the pericardial and peritoneal cavities (1,2). formed portal region (fig. 1-1). When they are Mesenchymal elements of the transverse sep- integrated into the portal space, the immature tum, which already exist, are invested by liver tubules evolve into bile ducts that are embraced parenchyma formed from hepatic endodermal by connective tissue and gradually situated in cells (also known as hepatoblasts) of the he- their usual location in the portal tracts as the patic diverticulum to give rise to the liver buds portal tracts increase in size (2,7–9). (3). During fetal development the liver buds function as a hematopoietic organ, which is GROSS ANATOMY composed of hepatocytic cords, venous-sinusoi- The liver can be divided into the right and dal plexus, and hematopoietic precursor cells, left lobes by the middle hepatic vein and a plane including Kupffer cells (macrophages residing between the inferior vena cava and the gallblad- in liver). The umbilical vein supplies most of der fossa. Anteriorly, this division is visible by the blood during development of the liver. The the falciform ligament. Viewed from the under remaining smaller amount of blood is supplied surface, there are also the quadrate lobe in the by the portal vein and hepatic artery. vicinity of the gallbladder fossa and the caudate During fetal development, the placenta ex- lobe which in part encases the vena cava. ecutes the major functions performed by the There are dual afferent blood supplies in adult liver, including the absorption of nutri- the liver: hepatic artery and portal vein. The ents and the excretion of bile containing waste hepatic artery (branches from the celiac artery) products; bile secretion by fetal liver is negligible transports 30 to 40 percent and the portal vein before birth. Nonetheless, the fetal liver produc- (drains the intestine) transports up to 70 per- es alpha-fetoprotein and other plasma proteins, cent of the oxygenated blood to the liver. The synthesizes bile acids, and stores fat, glycogen, sinusoids then carry blood from hepatic arteries iron, and copper. and portal veins to the terminal hepatic venules, The anterior portion of the hepatic diver- and subsequently through the hepatic vein to ticulum forms the liver and intrahepatic bile the inferior vena cava. ducts, while the posterior portion gives rise Functionally, the liver is better divided into to the gallbladder and extrahepatic bile ducts eight segments based on the blood supply, (2,4–6). The ultimate formation of intrahepatic known as the Couinaud classification, or Cou- bile ducts occurs late during development, and is inaud scheme (fig. 1-2). The segments are num- completed after birth, during the first year of life. bered in Roman numerals I to VIII. Segment I The development of small intrahepatic bile ducts essentially represents the caudate lobe, which begins when the ductal plate is formed, which drains directly into the inferior vena cava. Seg- is a single-layered sheath of small flat epithelial ments II to VIII are then numbered in a clockwise cells assembled by the periportal hepatoblasts in manner in a frontal plane beginning superiorly 1 Tumors of the Liver Figure 1-1 FETAL LIVER Left: The embryonic ductal plate, composed of cytokeratin-rich cells, forms a layer that surrounds the portal area. This immunostain for cytokeratin (CK) 18 shows that the ductal plate is discontinuous and in a few places forms a double layer of cells with small lumina. Right: Higher magnification of another portal area shows the bile duct forming from the ductal plate, which will eventually disappear as the liver grows. Figure 1-2 SEGMENTAL ANATOMY OF THE LIVER The segments, designated by Ro- man numerals, can be resected sur gically because each is sup- plied by a major branch of the hepatic artery and portal vein and drained by a major tributary of the hepatic vein. from the left lobe. These segments are bounded ing to the Couinaud scheme allows the surgical by the three main branches of the hepatic veins: removal of a single segment, or two or more the left, middle, and right hepatic veins. Each adjacent segments en bloc, in such a fashion to segment drains into branches of the hepatic veins avoid damaging the remaining segments. The and then into the inferior vena cava. Overall, seg- Couinaud scheme also serves as a common ter- ments I to IV represent the functional left lobe, minology for communicating among physicians whereas segments V to VIII are considered the of different disciplines: surgeons, hepatologists, functional right lobe. Division of the liver accord- oncologists, radiologists, and pathologists (10). 2 Embryology, Histology, and Anatomy Figure 1-3 HISTOLOGIC ORGANIZATION OF THE LIVER Left: Hepatic Architecture. Two views of the architecture of the liver as seen in microscopic sections. The lobules have a central vein at the center and portal spaces at the corners. A cross section of an acinus superimposed on two lobules shows that zone 3 tends to be centrilobular, zone 2 midzonal, and zone 1 periportal, but all three are crescent shaped and may extend into other parts of the classic lobule. Bottom: Liver Blood Flow. Figure from “Gastro intestinal Tract—Liver Development” from embryology. med.unsw.edu.au. portal tracts at the center. The spherical area of HISTOLOGIC ORGANIZATION those hepatocytes surrounding the portal tract The liver is structurally organized into pa- is referred to as zone 1, which has the richest renchymal, vascular, bile ductal, and interstitial oxygenated blood. The area outside of zone 1 components (11). Traditionally, the smallest is referred to as zone 2. Zone 3 is further out, functional unit has been conceptualized as corresponding to the region surrounding the the hepatic lobule or three dimensionally as terminal hepatic vein, where the oxygen con- the hepatic acinus, as defined by Rappaport tent in blood is the lowest (fig. 1-3). (12). Most oxygenated blood flows from the The two-dimensional concept of the lobule, terminal branches of portal veins and hepatic as seen on slides, serves the purpose of histo- arteries in the portal tracts, via the sinusoids to logic visualization, but zonal subdivision of the supply the hepatocytes, and finally draining acinus incorporates the physiologic concept into the terminal branches of the hepatic (cen- into histologic organization and facilitates the tral) veins at the peripheral part of the acinus recognition of certain liver injury patterns. (11). The acinus can also be conceptualized as These patterns include the gradual increasing a three-dimensional spherical structure with vulnerability to ischemic and toxic/metabolic 3 Tumors of the Liver Figure 1-4 HEPATOCYTES AND ENDOTHELIAL CELLS Left: Normal hepatocytes are polyhedral cells arranged in plates that are one cell thick. They have granular, eosinophilic cytoplasm and usually one nucleus. The sinusoids between the hepatocytes are lined by inconspicuous endothelial cells. Right: The hepatocytic plates are normally one cell layer in thickness and are separated by the sinusoidal space (reticulin stain). injuries from zone 1 through zone 2 to zone 3, Bile ductules and canals of Hering are struc- as well as the distinction between adult nonal- tures at the periphery of the portal tracts and coholic steatohepatitis (zone 3 accentuated) and are not conspicuous by hematoxylin and eosin pediatric nonalcoholic steatohepatitis (zone 1 (H&E) stain in normal liver. They are the con- accentuated) (13–15). duits between the biliary tree and hepatocyte Hepatocytes are formed in plates of one cell canaliculi. The canals of Hering drain bile from in thickness, which can be highlighted by a bile canaliculi into bile ductules, and then into reticulin stain (fig. 1-4, right). The hepatocytic the interlobular bile ducts. Canals of Hering plates are organized in a radial fashion between are important for liver regeneration since the the portal tracts and terminal hepatic venules hepatic progenitor cells reside here (16,17). (fig. 1-5), and are separated by sinusoids lined by endothelial cells, with oxygenated blood HISTOLOGY flowing from the portal tracts to the terminal Cells of the Liver hepatic venules. The radial alignment is most pronounced in the hepatocyte plates surround- Hepatocytes. Hepatocytes, which originate ing the terminal hepatic venules. In normal from endoderm, comprise the primary cell pop- liver, the portal tracts are composed of at least ulation in liver, accounting for 75 to 80 percent one hepatic artery branch, one portal vein of the liver volume (18). They are hexagonal or branch, and one interlobular bile duct (fig. 1-6). polyhedral in cross section, and have an eosin- The boundary between the portal tracts and the ophilic cytoplasm containing a centrally placed first layer of hepatocytes in the parenchyma is round nucleus; occasional hepatocytes may be termed the limiting plate. binucleatic. In the adult liver, hepatocytes are 4 Embryology, Histology, and Anatomy Figure 1-5 Figure 1-6 HEPATIC ARCHITECTURE PORTAL TRACT Plates of hepatocytes extend from the portal area (lower A normal portal tract has at least one portal vein, one left) to the terminal hepatic venule or central vein (upper hepatic artery, and one bile duct. The interlobular bile duct right). Blood that enters the liver through branches of the is approximately the same diameter as the hepatic artery portal vein and hepatic artery perfuses the sinusoids and and is approximately the same distance as its own diameter exits through tributaries of the hepatic vein.