The liver is the largest internal organ, and the bodys second largest, after the skin. It has four lobes and is surrounded by a capsule of fibrous connective tissue called Glissons capsule. Glissons capsule in turn is covered by the visceral peritoneum (tunica serosa), except where the liver adheres directly to the abdominal wall or other organs. The parenchyma of the liver is divided into lobules, which are incompletely partitioned by septa from Glissons capsule. The parenchyma within the lobules is supported only by fine reticular fibres (which are discernible only with special preparations). The blood vessels supplying the liver (portal vein and hepatic artery) enter at the hilum (or porta hepatis), from which the common bile duct (carrying bile secreted by the liver) and lymphatic vessels also leave. Within the liver sinusoids, the oxygen-poor but nutrient rich blood from the portal vein mixes with the oxygenated blood from the hepatic artery. From the sinusoids, the blood enters a system of veins which converge to form the hepatic veins. The hepatic veins follow a course independent of the portal vessels and enter the inferior vena cava.
As mentioned above, the liver receives a dual blood supply. The hepatic portal vein provides about 60% of the incoming blood, the rest comes from the hepatic artery. The blood from the portal vein has already supplied the small intestine, pancreas and spleen, and is largely deoxygenated. It contains nutrients and noxious materials absorbed in the intestine, blood cells and their breakdown products from the spleen, and endocrine secretions from the pancreas. The blood from the hepatic artery supplies the liver with oxygen. Because the blood from the two sources intermingles as it perfuses the liver cells, these cells must carry out their many activities under low oxygen conditions that most cells could not tolerate.
Liver cells, or hepatocytes, are large polygonal cells, usually tetraploid and often binucleate in the adult. Each nucleus has two or more nucleoli. The average life span of liver cells is five months. They contain abundant rough endoplasmic reticulum and mitochondria, large deposits of glycogen and lipid droplets of various sizes, and several small elaborate Golgi complexes. They also contain many peroxisomes, a variable amount of smooth endoplasmic reticulum and lysosomes. In standard histological preparations, liver cells usually appear vacuolated because the glycogen and lipids are removed during processing. Liver cells are capable of considerable regeneration when liver substance is lost.
Functions of the liver
The liver is extremely versatile, having both endocrine and exocrine functions, as well as being involved in numerous metabolic activities and acting as a storage depot. The list below is an attempt to categorize its numerous and diverse activities. (You will note some overlap among the categories listed.)
- Bile secretion
Bile is the exocrine secretion of the liver, released into ducts which eventually form the common hepatic duct. It, in turn, unites with the cystic duct from the gall bladder to form the common bile duct which enters the duodenum. The system of bile ducts in the liver, beginning with the minute bile canaliculi, is described in more detail under "Organization of the liver".
Bile contains bile salts, also called bile acids, which are important in emulsifying the lipids of the digestive tract, thereby promoting easier digestion by lipases and absorption. Bile salts are largely recycled between the liver and gut.
Bile also contains cholesterol and phospholipids, and another function of bile salts is to help keep them in solution. Cholesterol and phospholipids serve as metabolic substrates for other cells and as precursors for components of cell membranes and steroid hormones. They are largely reabsorbed in the gut and recycled.
Bile also contains bile pigments, which detoxify bilirubin, the breakdown product of hemoglobin from aging or abnormal red blood cells destroyed in the spleen. The detoxified bilirubin, mainly in the form of bilirubin glucuronide, is eliminated through the feces (and gives them their color). Failure of the liver to absorb bilirubin, or to conjugate it to its glucuronide, or to secrete the bilirubin glucuronide, results in jaundice.
Finally, bile contains electrolytes, which maintain bile as an isotonic fluid. Electrolytes are also are largely reabsorbed in the gut.
- Protein and lipid synthesis
The liver makes a number of proteins, as suggested by its abundant rER and Golgi. The most important of these are albumins (responsible for colloid osmotic pressure), the protein portions of several kinds of lipoproteins, non-immune alpha and beta globulins, prothrombin, and numerous glycoproteins, including fibronectin. These proteins are considered as endocrine secretions because they are released directly from the liver cells into the blood supply.
The liver also synthesizes cholesterol and the lipid portion of lipoproteins. The enzymes for these activities are found in the sER.
- Metabolic functions
The liver is involved in a wide range of metabolic activities. Among its major metabolic funtions are gluconeogenesis (the formation of glucose from non-carbohydrate precursors), and the deamination of amino acids to urea. (For more details on these activities, consult a biochemistry textbook.)
In addition to the proteins listed above, the liver also releases a number of other products directly into the blood as endocrine secretions. These include products of carbohydrate metabolism, eg. glucose released from stored glycogen, and modified secretions from other organs, eg. triiodothyronine (T3), the more active deiodination product of the thyroxin.
Liver cells contain abundant peroxisomes, which are involved in the breakdown of hydrogen peroxide, produced in many general cytoplasmic metabolic activities. Peroxisomes also function in gluconeogenesis, and the metabolism of purines, alcohol and lipids.
- Storage of metabolites
Liver cells store large deposits of glucose in the form of glycogen, which can be stained by the periodic acid-Schiff or PAS procedure. They also store lipids in the form of droplets of varying sizes. These can be seen with Sudan staining after being fixed appropriately. The removal of these materials in routine preparations gives liver cells a foamy or vacuolated appearance.
Lysosomes within hepatocytes may be a normal storage site for iron, as a ferritin complex. Excessive amounts of iron may accumulate in cells as an unusable yellowish-brown pigment called hemosiderin, a partly denatured form of ferritin. Liver lysosomes also contain pigment granules (lipofuscin) and partially digested cytoplasmic organelles.
The liver also stores vitamins, especially vitamin A, which is transported from the liver to the retina to be used in the formation of visual pigments. Most of the vitamin A is not stored in the hepatocytes, however, but in special fat-storing cells, called Ito cells, within the sinusoids. Ito cells also store the other three fat-soluble vitamins, D, E and K, as well as vitamin B12.
- Detoxification and inactivation of noxious substances
The liver is the first organ to receive metabolic substrates and nutrients from the intestine, but it is also the first to receive any toxic substances, carcinogens or drugs that have been injested. The sER of liver cells contains enzymes involved in the degradation and conjugation of toxins (in addition to those responsible for synthesizing cholesterol and the lipid portion of lipoproteins). Under conditions of challenge by drugs, toxins or metabolic stimulants, the sER becomes the predominant organelle. Stimulation by one drug, eg. alcohol, enhances its ability to detoxify some other compounds. On the other hand, some toxins can get metabolized to even more damaging compounds.
Organization of the liver
The classical lobule
The sturcutural organization of the liver is traditionally described in terms of the classical lobule. This description is based on the distribution of the branches of the portal vein and hepatic artery, and the pathway that blood from them follows as it perfuses liver cells. The boundaries of the classical lobules are defined by connective tissue septa from the capsule. In a few species, most notably the pig, these CT boundaries are very prominent. In other species, including humans, the CT boundaries of the lobules are much less clearly defined.
The classical lobule is roughly hexagonal in shape. The angles of the hexagon are called portal areas (or portal canals, or portal tracts). The liver cells are arranged in stacks of anastomosing plates, one or two cells thick, radiating from a central vein at the centre of the lobule towards the periphery. The plates of cells are separated by an anastomosing system of sinusoids.
Branches of the portal vein and hepatic artery are found in the connective tissue of the portal areas. These branches are called interlobular vessels. They send distributing vessels around the periphery of the lobule. Blood flows from distributing vessels, via inlet vessels, into the sinusoids and toward the central vein. There is thus a mixing of the oxygenated blood originating from the hepatic artery and deoxygenated, nutrient-laden blood originating from the portal vein within the sinusoids as it flows from the periphery of the lobule to the central vein.
The central vein has thin walls consisting only of endothelial cells supported by a sparse population of collagen fibres. As it progresses along the lobule, it receives blood from more and more sinusoids and gradually increases in diameter. It leaves the lobule at its base and merges with a larger sublobular vein. Sublobular veins converge and merge, forming the two or more hepatic veins that empty into the inferior vena cava.
Inside the sinusoids
The liver sinusoids are irregularly dilated capillaries composed only of a discontinuous layer of fenestrated endothelial cells. There is a discontinuous basement membrane that is absent over large areas. Fenestrae are about 100 nanometres in diameter and are grouped into clusters called sieve plates. The endothelial cells are separated from the underlying hepatocytes by a subendothelial space known as the space of Disse or perisinusoidal space. The perisinusoidal space is not identifiable at the light microscopic level, but it is important to understand its function. In this space are found reticular fibres (which constitute the only stroma of the parenchymal portion of the lobule) and microvilli of hepatocytes. Blood fluids easily percolate through the endothelial wall to make intimate contact with the hepatocyte surface facing the perisinusoidal space. The hepatocytes microvilli increase the surface area between the plasma and the hepatocytes by about 6-fold. Microvilli are typical of absorptive cells, and, as discussed above, absorption is an important function of liver cells. Proteins (eg. albumin, prothrombin, fibrinogen, nonimmune alpha- and beta-globulins) and lipoproteins synthesized by the hepatocytes are transferred to the blood via the perisinusoidal space. Because these products are released into the blood for export, they are called the endocrine secretions of the liver.
The sinusoids also contain phagocytic cells derived from monocytes, known as Kupffer cells. Kupffer cells form part of the lining of the sinusoids, although they do not form junctions with neighboring endothelial cells. They have a large nucleus and a substantial amount of cytoplasm. However, in routine preparations, little if any cytoplasmic detail can be seen. Kupffer cells are usually recognized by their ovoid nuclei (as opposed to the more squamous nuclei of endothelial cells) and the fact that they often appear to project into the lumen. You will not be able to identify every individual cell nucleus that you see in the sinusoids.
A third cell type, called the Ito cell (or lipocyte or adipose cell) is found right inside the perisinusoidal space. These cells store fat, and accumulate exogenously administered vitamin A, which is transported to the retina for the synthesis of visual pigments. As discussed above, they also store vitamins D, E, K and B12. Ito cells depleted of lipids resemble fibroblasts, and many investigators believe they secrete the scaffolding of reticular fibres in the perisinusoidal space. You will not be able to identify Ito cells on your slides.
The flow of bile
Bile, the livers exocrine product, is synthesized by all hepatocytes and secreted into a system of minute canals called canaliculi. The canaliculi have no discrete structure of their own, but consist of channels running between hepatocytes. The walls of the channel are formed by the plasma membranes of adjacent hepatocytes. The cell membranes near the canaliculi are joined by occluding junctions.
It is difficult to make out bile canaliculi in standard light microscope preparations. Sometimes they can be seen as a very small circular or oval profiles midway along the boundary between two liver cells. The boundary must have been sectioned transversely; canaliculi will not be identifiable between cells whose boundary has been cut in an oblique plane.
The bile canaliculi form an anastomosing network progressing along the plates of a liver lobule to terminate in small bile ductules called canals of Hering near the periphery of the lobule. These in turn drain into the interlobular bile ducts, which are found, along with the branches of the portal vein and hepatic artery, at the portal areas (the angles of the hexagons). Thus the direction of bile flow is opposite to that of blood flow: it goes from the centre of the classical lobule to its periphery.
The canals of Hering and the interlobular bile ducts are lined by cuboidal cells with a complete basement membrane. The cells become columnar as the ducts continue toward the right and left hepatic ducts, which join to form the common bile duct.
Flow of lymph
Plasma that remains in the perisinusoidal space drains toward the connective tissue around the portal areas where there is a small space (of Mall) between the connective tissue stroma and the hepatocytes. From this collecting site, the fluid enters lymphatic capillaries that travel with the other structures of the portal areas (interlobular vessels of hepatic artery and portal vein, bile ducts). Thus the lymph moves in the same direction as the bile, from liver cells toward the portal areas, and eventually to the hilum. Lymph vessels from the liver drain into the thoracic duct. Most of the lymph in the thoracic duct comes from the liver.
The portal triads (tetrads?)
Because interlobular bile ducts are often found together with the interlobular branches of the portal vein and hepatic artery in the portal areas, the grouping is called a hepatic triad (or trinity). This term should not be taken too literally, as two or more of one component, and none of another, may be found in a "triad" (eg. 3 arteries, 1 vein, no bile duct). Furthermore, one or more lymph vessels are generally among the triad. The term triad reflects the fact that the lymph vessels are mostly entirely inconspicuous.
Other models used to describe the organization of the liver: the portal lobule and the liver acinus
When looking at sections of liver tissue, it is easiest to describe its morphological organization in terms of the classical lobule drained by a central vein. (The central vein is now being called, with increasing frequency, the terminal hepatic venule.) However, at least two other concepts concerning the organization of liver parenchyma have been suggested, and one of them, the liver acinus, is beginning to supercede the classical lobule.
The portal lobule:
The portal lobule model emphasizes the exocrine function of the liver, namely bile secretion. In this description, the portal bile duct (one of the components of the hepatic triad) is taken as the centre of the lobule. Its outer margins are imaginary lines drawn between the three central veins that are closest to that portal triad. This roughly triangular block of tissue includes those portions of three classic lobules that secrete the bile that drains into its axial bile duct. This model allows description of liver parenchyma in terms comparable to those used for other exocrine glands.
The liver acinus:
The liver acinus model defines a more or less egg- or losange-shaped area, with a short and a long axis. The short axis is defined by a portal triads distributing branches that run along the border of two classical lobules. The long axis is a line drawn between the two central veins closest to the short axis. In contrast to the classical model, this model has at its centre the blood supply (portal and arterial) to liver parenchyma, rather than its venous drainage.
The liver acinus model describes the smallest functional unit in the liver parenchyma. Cells in the liver acinus are arranged into three concentric, elliptical zones around the short axis. There are no sharp boundaries between the zones. Cells in zone 1 are closest to distributing arteries and veins and are the first to be affected by or to alter the incoming blood. They are the first to receive both nutrients and toxins. They are they first to take up glucose to store as glycogen after a meal, and the first to break down glycogen in response to fasting. They are also the first to show morphological changes following bile duct occlusion. If circulation is impaired, they are the last to die and the first to regenerate. Cells in zone 3 are farthest from the distributing vessels and closest to the central vein. They are the first to show ischemic necrosis, and the first to show fat accumulation. They are the last to respond to toxic substances and bile stasis. Cells in zone 2 have functional and morphological characteristics intermediate between those of zones 1 and 3.
The liver acinus is very useful as a functional or physiological model. It is harder to visualize morphologically, since the distributing vessels are very difficult to find in uninjected routine sections, and the only morphological landmark that marks the outer limits of the acinus is the central vein.
Because the classical model is the most obvious from a morphological perspective, the images below are described in terms of it.
Figure 14 shows a very low power view of the pig liver and its organization into lobules. The diversity in size and appearance of the lobules reveals why their description as "hexagons" must be taken loosely. The portal areas of the large lobule at the centre are indicated by asterisks. Sometimes the portal areas, such as the one indicated by the right-hand asterisk, appear more extensive than just an angle of the hexagon. The large profile below that asterisk belongs to an interlobular vessel or bile duct. Another portal area with large profiles, belonging to a different lobule, is also indicated. The size of the vessels and bile ducts in portal areas can vary greatly.
Central veins can also be identified in a number of the lobules. They also vary in size and are frequently not in the centre of the sectioned lobule. Some lobules are sectioned such that a central vein is not evident.
Figure 15 shows a slightly higher power view of one lobule from the pig liver. Parts of surrounding lobules are also seen. The lobule is rectangular in appearance and three of its portal areas are in the field of view. Interlobular vessels and/or ducts (not specifiable at this magnification) can be seen in all three. Distributing branches from the interlobular vessels travel along the connective tissue boundaries between portal areas and give rise to inlet vessels that enter the sinusoids. These distributing vessels are not prominent in routine uninjected sections, so there is no point in trying to find them.
The central vein is prominent and centrally located in this lobule. The structure of the parenchyma can be seen to a limited extent. The cords of hepatocytes are the darker staining bands, the many purple spots are the hepatocyte nuclei. The paler areas between the hepatocytes are the sinusoids that drain into the central vein. Even at this magnification (with some eyestrain), two sinusoids can be seen entering the left side of the central vein.
Figure 16 shows a very large portal area with many profiles lying among four liver lobules. A central vein can be seen in the lobule at the right. The magnification is the same as in the previous image.
Figure 17 illustrates why pig livers are so popular in histological studies. It shows a secion of human liver at the same magnification as the lobule of pig liver in Figure 15. The organzation of the human liver is identical to that of the pig, but it is not nearly as obvious because the connective tissue septa between lobules are so reduced. It is often very difficult to identify individual lobules in the human liver.
Much of the field of view in Figure 17 is taken up by one lobule. The approximate boundary of the lobule is shown by the dotted line. Two portal areas are evident at the top of the figure, and the central vein is identifiable. (The dark spot at the lower left is an artifact.)
Figure 18 shows a high power view of a portal area (in the pig liver) bordered on the left and below by cords of hepatocytes and their intervening sinusoids. Two arteries in the portal area can be identified by their relatively thick tunica medias. The nuclei of their endothelial cells can be seen, and are most obvious in the artery on the left where they bulge into the lumen. The two labelled veins have a much thinner tunica media. Red blood cells (very pale) and some white blood cells can be seen in the lower vein, which has been sectioned longitudinally and runs toward the cords of hepatocytes at the left. The discontinuity on its upper left (asterisk) might indicate the beginning of a distributing vessel. The small profile below the artery on the left is probably a vein but could be a lymph vessel. The bile duct is made of cuboidal cells (in larger ducts they can be columnar) with prominent round nuclei. The cell boundaries are not distinct.
Figure 19 shows a high power view of a central vein and surrounding parenchyma. The arrangement of the hepatocytes into cords is evident. Sinusoids can be seen entering the cental vein in several places, some of which are indicated by asterisks. The central vein is supported by a small amount of connective tissue, here visible as a pinkish bar along its lower edge, and lined by endothelial cells. Flattened endothelial cell nuclei can be seen in the central vein and in the sinusoids. Red blood cells are present in the central vein. They appear very pale toward the centre of the vein, but are more darkly stained around its edges. (The asterisks indicating opening to sinusoids are located on RBCs.) The larger, more rounded nuclei in the sinusoids belong to Kupffer cells. (The dark shadow near top centre is an artifact.)
Figure 20shows a high power view of sinusoids in the human liver. On this slide (#45), the boundaries between individual liver cells can sometimes be seen as a pink line. This occurs only if the boundaries have been cut in perfect cross-section. Two such boundaries are encircled. If these boundaries are viewed under the oil immersion lens, a small round dot can sometimes be seen in the middle of them this is the bile canaliculus. Bile canaliculi, with a bit of eyestrain, can sometimes also be seen under high dry power. The image here was captured under high dry (X400) but the bile canaliculi are too subtle to be picked up during the digitization to make computer images. They will be easier to see when viewed under the microscope. (In order to see bile canaliculi very clearly with the light microscope, it is necessary to use special fixation techniques and embed the tissue sections in plastic.) As in the pig liver, the nuclei of endothelial and Kupffer cells can be found in the sinusoids between the liver cells. A bi-nucleated liver cell is shown at the arrow.
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