The Normal Liver
Samar Said, MD
1.1 GROSS ANATOMY
The liver is located in the right upper quadrant of the abdomen, under the diaphragm. It has a smooth surface and is red-brown in color. The liver consists of a larger right lobe, left lobe, caudate lobe, and quadrate lobe. The right and left lobes are separated by the falciform ligament. The liver weighs 840-2,580 g in adult men and 780-2,400 g in adult women.1,2
The normal gross anatomy is reviewed in more detail in Chapter 2, but the Couinaud classification divides the liver into eight segments, which are defined by the vascular supply and biliary drainage, where each segment has its own vascular pedicle and biliary drainage.3 In this classification, the middle hepatic vein divides the liver into right and left hemilivers—this plane corresponds to a line extending from the left side of the sulcus for the inferior vena cava superiorly to the middle of the fossa for the gallbladder inferiorly; the right hepatic vein divides the right hemiliver into anterior and posterior segments; the left hepatic vein divides the left hemiliver into medial and lateral parts; and the portal vein divides the liver into upper and lower segments. The segments are numbered in a clockwise manner. The eight segments are: segment 1: caudate lobe; segment 2: lateral superior segment of left hemiliver; segment 3: lateral inferior segment of left hemiliver; segment 4a: medial superior segment of left hemiliver; segment 4b: medial inferior segment of left hemiliver; segment 5: anterior inferior segment of right hemiliver; segment 6: posterior inferior segment of right hemiliver; segment 7: posterior superior segment of right hemiliver; and segment 8: anterior superior segment of right hemiliver. The Couinaud classification works best with radiology images but can be hard to use with resection specimens.
1.2 VASCULAR SUPPLY
The liver has a dual blood supply from the hepatic portal vein and hepatic artery. Approximately two-thirds of the blood supply of the liver comes from the portal vein, which drains the spleen and the intestine before reaching the liver. The portal system blood enters into the liver via the portal vein, which quickly divides into the left and right branches of the portal vein. The blood then moves along this route: portal vein branches (located in portal tracts), venules, periportal
sinusoids, hepatic sinusoids, central veins, hepatic veins, inferior vena cava, and finally the right heart. The remaining one-third of the liver’s blood supply comes from the hepatic artery, which carries more richly oxygenated blood and follows one of three routes: a plexus around the portal vein branches, a plexus around the bile ducts, or terminal hepatic arterioles, which move blood from the portal tracts into the sinusoids.4
sinusoids, hepatic sinusoids, central veins, hepatic veins, inferior vena cava, and finally the right heart. The remaining one-third of the liver’s blood supply comes from the hepatic artery, which carries more richly oxygenated blood and follows one of three routes: a plexus around the portal vein branches, a plexus around the bile ducts, or terminal hepatic arterioles, which move blood from the portal tracts into the sinusoids.4
1.3 LYMPHATICS
The hepatic lymph comes primarily from the sinusoids and enters into the space of Disse. After that, it flows to the channels traversing the limiting plate and enters the interstitial space of either the portal tract (parallel to the bile flow and opposite to the blood flow), sublobular veins, or the hepatic capsule. It is thought that 80% or more of the hepatic lymph drains through lymphatic channels located in the portal tracts.5 Most of the lymphatics drain into hepatic nodes located along the hepatic artery and then into celiac lymph nodes. Other efferent routes include parasternal lymph nodes, posterior mediastinal lymph nodes, and left gastric lymph nodes.6,7
1.4 BILE FLOW
Bile canaliculi represent the beginning of the bile drainage system in the liver. The bile canaliculus is an intercellular space between two adjacent hepatocytes, separated from the rest of the intercellular space by tight junctions. Bile canaliculi can only be seen when they are distended because of cholestasis; they are invisible by light microscopy in normal livers. They drain into the canals of Hering (lined by hepatocytes and biliary epithelium), which are connected to small bile ductules in the portal tracts. Both the canals of Hering and the bile ductules are also invisible in the normal liver, but various injuries can elicit a bile ductular reaction, in which case the bile ductules are visible at the periphery of the portal tract. The ductules drain into the interlobular bile ducts, which merge to form septal/trabecular bile ducts and ultimately become the common hepatic duct.8
1.5 NORMAL HISTOLOGY
Portal tracts
The normal portal tract contains at least one profile of three luminal structures: an interlobular bile duct, portal vein, and hepatic arteriole (Fig. 1.1). On average, the portal tracts have two interlobular bile duct profiles, two hepatic artery profiles, and one portal vein profile. These structures are surrounded by connective tissue composed of mainly type I collagen. Depending on the angle of sectioning, one of these structures might not be seen in few portal tracts.9 The portal tracts undergo successive branching, where they divide and get smaller as they move to the periphery. The degree of connective tissue present in a particular portal tract correlates with the size of the portal tract, with larger portal tracts containing more connective tissue than do smaller ones.
 Figure 1.1 Normal portal tract. This portal tract is normal and shows a bile duct, hepatic arteriole, and portal vein, with minimal inflammatory cells. |
The bile ducts and the hepatic arterioles are usually of similar caliber and are located close to each other. This can be used as guidance when looking for the bile ducts in inflamed portal tracts or other conditions where bile ducts are difficult to see, such as in ductopenia. Bile ductules can be seen in response to biliary tract disease or other forms of liver injury, but should not be confused with the bile ducts. Bile ductular proliferations are located at the periphery of the portal tracts and are not paired with arterioles.
A minimal amount of chronic inflammation is present in the portal tracts, typically composed of small lymphocytes with rare mast cells. This is needed for normal liver hemostasis and function.10 The portal tracts also contain lymphatics, fibroblasts, and nerves. The latter are seen on hematoxylin and eosin stain (H&E), only in the largest branches of the portal tracts. The hepatocytes located next to the portal tract form the limiting plate. With age, the number of inflammatory cells increases slightly and the collagen fibers of the portal tracts become denser.
Bile ducts
The interlobular bile ducts have cuboidal to low columnar epithelium with a centrally located nucleus, whereas the lining epithelium of the larger septal ducts is tall columnar with basally located nuclei. The biliary epithelial cells are well demarcated with uniform, round nuclei that do not overlap. The larger bile ducts are surrounded by Periodic acid-Schiff (PAS)-positive, diastase-resistant basement membrane. In normal liver, no inflammatory cells are seen inside the basement membrane of the bile ducts.
Hepatic lobules
The hepatic lobules contain polygonal-shaped hepatocytes with well-defined cell borders, eosinophilic cytoplasm, centrally located round nuclei, and visible nucleoli. Hepatocytes lack basement membranes, and most of them contain one nucleus; however, it is not uncommon to see a few cells with two nuclei. The number of binucleated hepatocytes increases with age, as does nuclear variability, with occasional large irregular and hyperchromatic nuclei. Glycogen-rich cytoplasm can herniate into the nuclei and form glycogenated nuclei, which may be seen in a few hepatocytes in healthy individuals. The hepatocyte cytoplasm has abundant glycogen and multiple organelles, including mitochondria, smooth and rough endoplasmic reticulum, lysosomes, peroxisomes, Golgi complexes, and organized cytoskeleton. Hepatocytes also produce albumin and many enzymes. Endoplasmic reticulum appears as basophilic granules or fibers, which may become more prominent in association with some medications. Mitochondria are not visible in most hepatocytes, but megamitochondria can be seen occasionally in hepatocytes in normal livers and more frequently in diseased livers.
Hepatocytes are arranged in plates separated by the sinusoidal labyrinth. The plates are one cell thick, but a few might appear thicker, depending on the angle of sectioning. This unique structure of the liver plates allows for direct contact between hepatocytes and the blood. In children less than 6 years old, however, the liver cell plates tend to be two cells thick. In normal liver biopsy and resection specimens, the sinusoids are either empty or may contain a few red blood cells and rarely white blood cells. Circulating megakaryocytes can also be occasionally seen. In neonates, the sinusoids may contain hematopoietic foci.
Hepatocytes frequently contain lipofuscin in the normal liver. Lipofuscin pigments are fine, gold-brown, retractile granules that orient along the canalicular domain of hepatocytes and are found mainly in zone 3 (pericentral vein). Lipofuscin consists of insoluble, highly oxidized fatty acids and misfolded proteins that are not degradable by the proteasome system or lysosomal enzymes. This “wear-and-tear pigment” tends to increase with age.
Hepatocytes exhibit functional heterogeneity.11, 12, 13, 14, 15, 16, 17 The hepatocytes located near the portal tracts have the highest metabolic activity. They are exposed to blood with highest content of oxygen, insulin, glucagon, and amino acids, and they are the main site of protein synthesis, gluconeogenesis, glycolysis, and fatty acid metabolism. In addition, most enzymes (such as transaminase, glutamyltranspeptidase, and alcohol dehydrogenase) are located mainly in periportal hepatocytes, with the exception of glutamine synthetase and carbamoyl phosphate synthetase I, which are found predominantly in pericentral vein hepatocytes that have a higher capacity for detoxification of various molecules. Hepatocytes are also the storage site for copper18,19 and a key site for storage of iron.
The space located between the hepatocytes and the sinusoidal endothelium is called the space of Disse. It contains hepatic stellate cells, nerve fibers, reticulin fibers (which consist mostly of type III collagen), and other components of the extracellular matrix. Neither stellate cells nor the space of Disse are visible in normal livers. Central veins are lined by endothelial cells. The smallest central vein branches have minimal or no collagen around them in the normal liver, although larger ones will have a thin collar of collagen.
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