The liver is the largest solid organ of the body, generally weighing between 1,200 and 1,500 g in the adult, accounting for approximately 2% to 5% of the total body weight (6). In the healthy neonate, the liver generally accounts for about 5% of body weight. The liver is regarded as mostly consisting of a dominant right and a lesser left lobe, separated by the falciform ligament, with smaller caudate and quadrate lobes. More significant in terms of modern surgical approaches, however, is the segmental anatomy based on vascular supply and biliary drainage (3,6,7,16,17,18,19,20).
Vascular supply variation occurs particularly with the caudate lobe. It may contribute to some variations in imaging appearance of the liver and, if both the abnormally supplied region and the remainder of the liver are sampled, can contribute to diagnostic confusion. The pathology and pathophysiology of most liver diseases can be well understood only if their microscopic structural basis is appreciated. The liver has a highly complex histologic structure with various elements (Table 4.1). It is a unique elaboration of the vascular system centered between the afferent and efferent vessels. Comprehension of the way in which the portal system eventually drains into the hepatic vein, and the unique structure of the liver plate, which allows for the most direct contact between the hepatocyte and the blood and its contents, is a key to understanding.
Blood enters the liver principally via the portal vein, which branches to become incorporated in the distinctive structural entities of the portal tract. Blood traverses the parenchyma via the sinusoids, where all of the hepatic functions take place, to reach the terminal hepatic venule (“central vein”), and then to hepatic veins, the inferior vena cava, and, ultimately, the heart. The portal veins are the largest vessels in the portal tracts and empty into periportal sinusoids through venules. The hepatic artery is a relatively minor contributor to hepatic blood flow; indeed, it is almost never considered as a potential contributing factor in most hepatic diseases.
THE PORTAL TRACT
The portal tract (Fig. 4.1, e-Figs. 4.1, 4.2) is a well-defined connective tissue structure composed primarily of type I collagen, which interfaces with the limiting plate of hepatocytes. Each portal tract contains at least one small arterial branch, a portal vein branch, and a bile duct. The portal tract system can be thought of as a great oak tree with incalculable numbers of branch points, the first of which occurs at the hilum of the liver. Because of this pattern of progressive branching, the portal tracts exhibit a great range of sizes. Furthermore, when the pyramid-shaped portal tracts are randomly cut they may, in the two-dimensional histologic section, display variation of both shape and components. The largest portal tracts are round or triangular, the medium-sized portal tracts are mostly triangular, the smallest portal tracts tend to be triangular or branching, and the smallest terminal divisions are round or oval (18,20). In any given histologic section, a portal tract may appear triangular or quadrangular, or may even resemble a fibrous septum, and a disease process potentially affecting portal structures cannot be excluded if adequate sampling has not been obtained.
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TABLE 4.1 Microanatomy of the Liver |
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FIGURE 4.1 Photomicrograph of a normal portal tract showing portal vein, hepatic artery, and bile duct, along with the surrounding hepatic parenchyma directly abutting on the portal tract as a limiting plate of continuous hepatocytes. Note that there is only a sprinkling of lymphocytes (hematoxylin-eosin, original magnification ×200). |
In the larger portal tracts, lymphatic channels and autonomic nerve fibers can be visualized. The lymphatic channels drain into the space of Disse, and their flow is opposite to that of blood but parallel to the bile system (18,20). Varying numbers of lymphocytes and rare mast cells are seen in the unaffected liver, but plasma cells and polymorphonuclear leukocytes are generally not seen. The finding of portal lymphocytes, even in significant numbers, should not be interpreted as evidence of chronic hepatitis in the absence of interface hepatitis (“piecemeal necrosis”). Mild portal inflammation without interface hepatitis can be seen with systemic illnesses, in association with drugs and toxins, adjacent to space-occupying lesions, and in individuals without historical, clinical, or biochemical evidence of liver disease (“normal”) (Fig. 4.2).
Bile ducts in the smaller portal tracts, those generally seen in liver biopsies, are known as interlobular bile ducts, whereas those in large portal areas are called septal, or trabecular, ducts (Fig. 4.3). Interlobular bile ducts are lined by cuboidal or low columnar epithelium with an underlying basement membrane consisting of periodic acid-Schiff (PAS)-positive material that is resistant to diastase digestion. In the healthy liver, the duct epithelial cells are well demarcated with uniform round nuclei that are evenly spaced. The epithelial cells do not overlap, and there are no lymphocytes within the limits of the basement membrane. The epithelium of the septal duct also rests on a basement membrane but is tall columnar with a distinctly basal nuclear location and with an internal diameter of more than 100 mm (1,18,20).
In the normal portal tract, the bile duct tends to be adjacent to a hepatic artery branch of approximately the same size, so that the number of bile ducts and the number of artery branches is usually equal or almost equal in a given section when at least four portal tracts are present for evaluation. Bile ducts can be immunohistochemically demonstrated with antibodies to high molecular weight cytokeratin polypeptides (Fig. 4.4).
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FIGURE 4.2 Photomicrographs of liver biopsies from four different living donors showing the great variability in the numbers of lymphocytes present in portal tracts in individuals who have no historical, clinical, or biochemical evidence for liver disease (A,B,D, hematoxylin-eosin, C Periodic acid-Schiff after diastase digestion, original magnification ×200) Note the presence of PAS-positive material in Kuppfer cells and portal macrophages in C and minimal “interphase hepatitis” in D. |
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FIGURE 4.2 (Continued) |
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FIGURE 4.3 Photomicrographs showing interlobular bile ducts and septal bile ducts, taken at the same magnification for comparison purposes (Masson trichrome, original magnification ×200). |
The bile ductules, which are seen only when they proliferate (ductular reaction), are located at the periphery of the portal tracts and have a lumen size of less than 20 mm. They have a cuboidal epithelium and a basement membrane and may be accompanied by a tributary of the portal vein but not by a hepatic artery branch. After injury, the bile duct epithelium may also elaborate hormone polypeptides, which can be demonstrated immunohistochemically (18).
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FIGURE 4.4 Bile ducts immunohistochemically demonstrated with antibodies to high molecular weight cytokeratin polypeptides (antikeratin AE 1/3, original magnification ×200). |
With age, the collagen fibers of the portal tract become increasingly dense, with newly formed type III collagen appearing as delicate light blue fibers, contrasting with the already present thick dark blue fibers of type I collagen. The hepatic artery may sometimes show changes of atherosclerosis in parallel with the aorta. The number of inflammatory cells also increases with age. The left lobe will tend to show more portal fibrosis than the right.
PARENCHYMA
The parenchyma consists primarily of hepatocytes that are arranged as one-liver-cell-thick anastomosing spongelike walls or plates (Fig. 4.5, e-Fig. 4.3), separated from each other by the sinusoids through which blood flows from the portal tracts to terminal hepatic venules. The normal function of the liver is to a great degree owing to the almost direct contact of the hepatocyte with the blood, allowing the efficient and direct removal from circulation of various substances, including normal metabolic products (endobiotics) as well as environmentally acquired substances (xenobiotics), and also allowing for the similarly unimpeded secretion of vital liver cell products, such as albumin and coagulation factors.
The one-cell-thick liver plate pattern prevails throughout the liver and helps to explain the efficiency of the hepatocyte, since it allows for each hepatocyte to be exposed on two sides to sinusoidal blood. Unlike vascular structures almost everywhere else in the body, the sinusoids do not have a basement membrane and the cell surface controls influx and efflux of substances almost entirely (18). In the usual histologic section, two- and even three-cell-thick areas are periodically seen; these represent the areas of anastomosis of liver plates. In healthy children, to the age of 5 or 6 years, the liver cell plates tend to be two-cells-thick.
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FIGURE 4.5 Hepatocytes arranged as one-liver-cell-thick, anastomosing, spongelike walls or plates, which are separated from each other by the sinusoids through which blood flows from the portal tracts to terminal hepatic venules (reticulin, original magnification ×100). |
Another variation is seen bordering the portal tracts where there is a continuous line of liver cells from which the liver cell plates extend; this is the limiting plate (18,20) (Fig. 4.1). The interface between the collagen of the portal tract and the hepatocytes of the limiting plate is, characteristically, an uninterrupted straight line. Despite its apparent homogeneity, however, the limiting plate is functionally heterogeneous. The hepatocytes near the apices of the portal triangle, where the blood supply leaves the portal tract, are truly periportal in terms of both location and function (see “Histologic Organization of the Liver” below), whereas those hepatocytes at the center of the limiting plate are relatively far from the blood supply and respond to injury as do the hepatocytes surrounding the terminal hepatic venule. It is for this reason that conditions that contribute to necrosis of hepatocytes surrounding the terminal hepatic venule (central vein), so-called centrolobular or Rappaport zone 3 necrosis, also cause necrosis of hepatocytes at the central portion of the limiting plate.
The sinusoids are separated from the hepatocytes by sinusoidal endothelial cells, Kupffer cells, Pit cells, and the space of Disse, which includes the perisinusoidal stellate cells (lipocytes, or Ito cells), reticulin fibers, and nerves (2,3,4,5,6,15,18,20). The sinusoids are generally empty in the usual liver biopsy, or they may contain a few red cells and rare white cells. In neonates, of course, hematopoietic foci are scattered throughout. Circulating megakaryocytes, not associated with myeloid metaplasia, can sometimes be seen, particularly in patients undergoing physiologic stress (e-Fig. 4.4).
The sinusoidal endothelial cell has a sievelike structure, with fenestra of approximately 1,000-Å diameter. These fenestra actively control the interchange between the blood and the perisinusoidal space by the contraction of cytoskeletal elements (8). The cytoskeletal activity is influenced by both endobiotics and xenobiotics. Although sinusoidal endothelial cells are not identical to other vascular endothelial cells (13), they share a wide range of biologic activities (18).
Kupffer cells (6,12,18,20) are slightly stellate. In the healthy liver they may not be easily differentiated from endothelial cells, although the nucleus of the Kupffer cell tends to be slightly more irregular and plumper. Since they function as macrophages fixed to the sinusoidal wall, Kupffer cells contain many kinds of materials, including foreign material as well as the products of injured or dead cells; consequently, they can usually be visualized by staining the section with PAS after diastase (dPAS) digestion to remove the hepatocyte glycogen, which may impede, but not prevent, Kupffer cell identification (Fig. 4.6). Kupffer cells can also be shown to contain nonspecific esterase, muramidase, peroxidase, and low concentrations of α 1-antitrypsin.
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FIGURE 4.6 Kupffer cells stained with periodic acid-Schiff reagent, seen here after diastase digestion to remove glycogen from hepatocytes and highlight the Kupffer cells (diastase periodic acid-Schiff, original magnification ×200). |
Pit cells are located on the endothelial lining (4). They correspond to large lymphocytes with natural killer activity and are considered to have a vital role in defense against viral infections as well as metastasis. They can be visualized only after immunohistochemical studies to demonstrate their CD56 and CD57 markers, as well as with the electron microscope.
The space of Disse is the area between the sinusoidal lining and the liver plate (6,7,18,20). It is generally not appreciated in liver biopsy samples unless there is an impediment to venous outflow, such as congestive heart failure. It is most likely because of heart failure at the time of death that the space of Disse is often seen in liver sections obtained at autopsy. The space of Disse contains the sinusoidal stellate cells (perisinusoidal lipocytes, Ito cells), reticulin fibers, and nerves. It is important to realize that although there is no basement membrane in the normal liver, various matrix components are present (11), including collagen types I, III, IV, and VI, fibronectin, laminin, tenascin, various proteoglycans, and trace amounts of collagen V. The reticulin fibers that are easily demonstrated with various common silver impregnation staining methods (Fig. 4.4, e-Fig. 4.3) have been shown to consist mostly of collagen type III, with attached fibronectin and glycoprotein (18,20). While the lack of a basement membrane contributes to the relatively free access of various molecules from the sinusoidal blood into the liver cell, and vice versa, these other structural elements may contribute to the modulation of the rate of passage of these substances. After liver cell injury, a basement membrane may form (“capillarization” of sinusoids); this is a characteristic of cirrhosis and helps to explain the diminished catabolic and anabolic liver cell activity inherent to that condition.
The sinusoidal stellate cell (perisinusoidal lipocyte, Ito cell, hepatic lipocyte, fat-storing cell) (5,18,20) is perisinusoidal, with cytoplasmic extensions that envelop the sinusoidal endothelial cells, similar to pericytes in other locations (2,5). This cell contains small droplets of fat in the cytoplasm, not usually visible with hematoxylin-eosin. The droplets are rich in vitamin A. Consequently, these cells can be recognized when studied with ultraviolet illumination, since vitamin A has a specific autofluorescence at 330 nm (5,8). The perisinusoidal cells are thought to have a role in regulating sinusoidal blood flow, but are also considered as the major cellular contributor to the maintenance of the normal liver matrix and also to the development of hepatic fibrosis (15). It is thought that hepatocytes, when damaged, may release proteins that, along with cytokines from inflammatory cells, macrophages, and platelets, contribute to activation, proliferation, and transformation of sinusoidal stellate cells, with the result that these cells synthesize and secrete various collagens and matrix substances at an accelerated rate. Quiescent stellate cells are not visualized on routine stains. However, activated stellate cells are highlighted with antibody to smooth muscle actin. In the normal liver, sinusoidal stellate cells can also elaborate enzymes needed to degrade matrix components; these enzymes may also be active in abnormal states to help modulate the degree of fibrosis.
The individual hepatocyte is a polygonal epithelial cell, approximately 25 mm in diameter, with abundant eosinophilic cytoplasm, a single round centrally placed nucleus with finely dispersed chromatin, and at least one nucleolus, with a well-defined plasma membrane. In the healthy young adult, only occasional hepatocytes are binucleate. The number of binucleate hepatocytes increases with age and also in response to various stimuli and injuries (9,14,21) (Fig. 4.7, e-Figs. 4.5-4.7). Nuclear variability, seen as larger, more irregular, and hyperchromatic nuclei, also occurs with age and after injury. This nonspecific finding, sometimes called “hepatocyte unrest,” can also be a subtle sign of drug effect (21) (Fig. 4.8).
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FIGURE 4.7 Liver biopsy from a 92-year-old woman showing increased numbers of binucleate hepatocytes (hematoxylin eosin, original magnification ×200). |
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FIGURE 4.8 Liver biopsy from a 32-year-old woman who had been using oral contraceptive pills for 7 years and had a slight, otherwise unexplained, increase in serum transaminase values. There is variability in size and shape of hepatocytes, with many enlarged nuclei and increased numbers of binucleate hepatocytes. After she stopped taking the contraceptive pills, her transaminase values returned to reference range. Liver biopsy was not repeated (hematoxylin-eosin, original magnification ×200). |
There are distinctive hepatocyte polar domains that differ morphologically and functionally (10,20). The sinusoidal domain of the plasma membrane has irregular microvilli, which greatly increase the surface area of the cell and enable it to better participate in exchange of substances with the blood that enters the space of Disse, within which the microvilli project. This portion of the plasma membrane is the site of receptors for glycoprotein, asialoglycoprotein, various peptides, hormones, growth factors, and immunoglobulin A, as well as multiple carrier-mediated transport processes. The sodium pump is at this region of the cells. This is also the site for endocytosis and for transmembrane proteins that recognize specific matrix components, such as laminin, collagen, and integrin (11).
The intercellular domain is specialized for intercellular adhesion but also for intercellular communication. Junctional complexes ensure the attachment and include desmosomes, tight junctions, and intermediate junctions. Intercellular communication occurs via gap junctions (8).
The bile canaliculus is a specialized portion of the intercellular domain, comprising approximately 15% of the hepatocyte plasma membrane, and is the beginning of the bile drainage system of the liver. The bile canaliculus is the portion of the hepatocyte that corresponds to the apex of an exocrine secretory cell. It is an intercellular space between two adjacent hepatocytes, isolated from the rest of the intercellular space by tight junctions. The bile canaliculus is approximately 1 mm in diameter and is not easily recognized with the light microscope unless distended as a part of parenchymal cholestasis. The bile canaliculi form a chicken wire-like network (18,20) in the center of the liver cell plate and connect to small portal bile ductules via the canals, or ducts, of Hering. Bile canaliculi can also be recognized with polyclonal antibody to carcinoembryonic antigen.
The canal of Hering connects the bile canaliculus to the bile ductule. The canal of Hering is lined partly by biliary epithelial cell and partly by hepatocyte and is thought to be the site of origin for the proliferating bile ductules that are seen after liver injury.
The canalicular domain of the hepatocyte has recently been shown to have at least three adenosine triphosphate-dependent export carriers: a leukotriene, a bile salt carrier (gp 110), and a multidrug export carrier (gp 170) (7).
Each hepatocyte is filled with an array of organelles, including smooth and rough endoplasmic reticulum, more than 1,000 mitochondria, approximately 300 lysosomes, an equal number of peroxisomes, approximately 50 Golgi complexes, and an organized cytoskeleton (7). Sometimes the cytoplasm has poorly defined eosinophilic and basophilic areas that most commonly are light microscopic indications of smooth and rough endoplasmic reticulum. Rough endoplasmic reticulum is more easily appreciated in hematoxylin-eosin-stained sections as indistinct basophilic granules or fibers, which become more prominent in association with some xenobiotics, including many drugs, even at therapeutic levels. In liver cell regeneration, as in the cirrhotic liver, mitochondria-rich cells can be recognized as slightly enlarged, intensely eosinophilic, slightly granular hepatocytes. In the normal liver cell, mitochondria cannot be seen.
The normal hepatocyte also contains abundant glycogen, which is not seen with hematoxylin-eosin but is easily demonstrated with the PAS reaction. Glycogen can also be seen as vacuoles that herniate into the nucleus and appear, in routine sections, to be optically clear intranuclear inclusions with a thicker-than-usual nuclear membrane (Fig. 4.9, e-Figs. 4.8, 4.9). These “glycogen nuclei” or “glycogenated nuclei” are present in small numbers in individuals free of recognizable disease and are located in periportal (zone 1) hepatocytes but are present in greater numbers in persons with Wilson disease, diabetes mellitus, prolonged congestive heart failure, and some other disorders; they can also be seen in increased numbers in adolescents and elderly people. With the electron microscope they are seen to consist of smooth endoplasmic reticulum distended with rosettes of glycogen.
The cytoplasm of the perivenular (zone 3) hepatocytes contains uniform fine, refractile, gold-brown granules of lipofuscin. This “wearand-tear” pigment becomes more prominent with age and progressively is seen in midzonal (zone 2) and periportal (zone 1) hepatocytes. The granules tend to be oriented along the canalicular domain of the hepatocyte (Fig. 4.10). Lipofuscin can be stained with the Ziehl-Neelson method, usually used to demonstrate acid-fast bacilli.
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FIGURE 4.9 Glycogen (“glycogenated”) nuclei in the liver biopsy of a 75-year-old man (hematoxylin eosin, original magnification ×400). |
Other normal cell constituents, such as albumin and many enzymes, can be demonstrated with special histochemical or immunohistochemical methods (12,18,20).
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FIGURE 4.10 Lipofuscin pigment in zone 3 hepatocytes (hematoxylin-eosin, original magnification ×200). |
The hepatocyte has an orderly cytoskeleton, which includes microtubules, microfilaments, and intermediate filaments, and which can also be visualized using immunohistochemical methods (8). Microtubules are formed from tubulin and involved in the secretion of proteins into the plasma. They are present throughout the cytoplasm but are most prominent in the region of the Golgi apparatus and along the sinusoidal plasma membrane. Microfilaments consist of myosin and actin and are particularly concentrated around the bile canaliculus, where they are involved with bile secretion and with the functioning of sinusoidal surface microvilli. Intermediate filaments are cytokeratins that extend from the plasma membrane to the perinuclear zone. Hepatocytes normally have cytokeratins 8 and 18 but, after injury, may acquire subtypes 7 and 19 (12,18). Intermediate filaments form an irregular meshlike network, which extends from the plasma membrane to the perinuclear zone, where they are in greatest concentration. They are thought to be the principal micro-filament responsible for the spatial organization of the hepatocyte.
TERMINAL HEPATIC VENULE
The terminal hepatic venules (central veins) collect all of the blood that traverses the sinusoids. The terminal hepatic venules are the smallest efferent veins and are an integral part of the hepatic parenchyma. There is no direct connection between the terminal hepatic venules and the vessels contained within the portal tracts, requiring, in the normal liver, that blood traverse the parenchyma to leave the liver. The terminal hepatic venule has a thin wall lined by endothelial cells and is not surrounded by collagen in the normal state, although interrupted islands of collagen can be seen in the subintima of the larger venules, in an otherwise normal liver, as they approach the hepatic vein (Fig. 4.11, e-Fig. 4.10). The terminal hepatic venules empty into three main hepatic veins. The intrahepatic portion of the hepatic veins, which are without valves as are the terminal hepatic venules, then empty directly into the inferior vena cava.
HISTOLOGIC ORGANIZATION OF THE LIVER
The precise definition of the smallest structural and functional unit of the liver remains controversial. The Kiernan and Mall models, developed in the 19th and early 20th century, were based on the distribution pattern of the hepatic blood vessels with the terminal hepatic venule regarded as the center of the lobule (central vein) and is the pattern seen in subhuman mammals, such as the pig (Fig. 4.12, e-Figs. 4.11, 4.12). Today the Rappaport concept of the hepatic acinus is widely regarded as the functional unit of the liver. In this model, the acinus is a complex entity whose center is the portal tract and whose sinusoids are drained by neighboring terminal hepatic venules (16,20). This model remains the most useful for understanding the pathology of the liver but may not be entirely accurate in terms of the biology of the liver (10).
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FIGURE 4.11 Terminal hepatic venule (central vein) showing interrupted islands of collagen in the subintima (van Giesen, original magnification ×200). |
In the Rappaport scheme, the hepatocytes of each acinus have been designated as belonging to one of three zones in terms of their relationship to the portal tract and particularly in relationship to the blood flow emanating from the apices of the portal triangle. The zones reflect functional variations of the hepatocytes because they are farther from the portal tract (9), but they are not readily identified in routine histologic material. Those in the one third nearest to the apex of the portal tract are zone 1 (formerly called “periportal”), and those in the one third farthest away, and closest to the terminal hepatic venule, are zone 3 (formerly called “pericentral” or “centrolobular”), with the intervening, and less easily identified, one third called zone 2 (formerly called “midzonal”). In this way, also the hepatocytes at the angle formed by the junction of the limiting plates are zone 1, whereas those in the middle of the limiting plate are zone 3.
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FIGURE 4.12 Photomicrograph of pig liver showing the classic hepatic lobule, with the terminal hepatic venule (central vein) at the center (periodic acid-Schiff, original magnification ×100). |
Zone 1 hepatocytes are exposed to the blood when it has the highest content of oxygen, insulin, glucagon, and amino acids, and these zone 1 liver cells are the principal site of gluconeogenesis and glycolysis. This activity has been used to explain why zone 1 hepatocytes have the highest metabolic activity and also why they are the first sites of regeneration. Protein synthesis occurs mostly in zone 1, and transaminases, glutamyl transpeptidase, alcohol dehydrogenase, and other enzymes are most easily demonstrated in this zone (12). In contrast, glutamine synthetase, required for the conversion of ammonia and glutamic acid to glutamine, is predominantly found in perivenular zone 3.
The functional activity of the hepatocytes has also been shown in experimental settings to be determined by the microenvironment of the hepatocytes. For example, when blood flow is altered by retrograde perfusion of the liver, the perivenular zone 3 becomes the site of maximal activity for some of the previously zone 1 functions, such as gluconeogenesis and glycolysis. Similarly, when isolated hepatocytes are transplanted to the spleen, they lose some of their enzyme productivity; this loss is reversible when they are returned to the milieu of the liver.
Anatomic Structures Contributing to the Misdiagnosis of Cirrhosis
With age, the left lobe of the liver may become increasing fibrotic and atrophic (e-Figs. 4.13, 4.14) and can be misinterpreted as representing cirrhosis. The liver capsule itself is often overrepresented in left lobe biopsies and is also sometimes obtained with right lobe biopsies. Capsule fibrous tissue can extend into the parenchyma and can even seem to be encircling portions of the lobule, mimicking a regenerative nodule and septa formation (e-Figs. 4.15-4.21). This is particularly a problem with wedge biopsies, which should be discouraged except for focal disease, such as tumors. Transjugular biopsies often include a portion of the hepatic vein wall (e-Figs. 4.22, 4.23).
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