Liver pathology is the cornerstone of our understanding of hepatic disease. The pathologic interpretation of liver tissue consequently assumes an important, and often critical, position in patient care and management, serving to confirm or advance diagnoses, guide additional investigation, evaluate therapeutic efficacy, and gauge prognosis.
An accurate diagnosis of liver disease cannot always be made solely on the basis of clinical history, laboratory findings, and imaging studies. Undoubtedly, advances in immunologic and radiologic means of diagnosis have diminished the need for biopsy in certain circumstances such as biliary obstruction or acute viral hepatitis. In other settings, however, the clinical data alone lead to an erroneous conclusion in 15% to 50% of cases, and careful examination of a liver biopsy is the only avenue to the correct diagnosis.1,2,4 Despite its evolving role over the years, liver biopsy remains the diagnostic gold standard of liver disease.
Pathologic examination nonetheless suffers limitations of its own. The liver has a limited repertoire of pathologic responses to injury, and the resulting histologic picture, particularly in inflammatory diseases, does not always provide a conclusive or specific diagnosis. (Not unexpectedly, however, the assessment becomes more accurate with greater experience.)3 Morphologic appearances, in addition, represent only a static glimpse of a dynamic pathologic process and may not adequately reflect the underlying functional alterations. The inescapable conclusion is that a complete assessment of the biopsy requires that the pathologic changes be integrated with the clinical data; this underscores the need for close cooperation between clinician and pathologist.
A variety of clinical concerns and issues may be addressed by liver biopsy. The more common indications include the assessment and staging of conditions such as chronic hepatitis, cholestatic disorders, and alcohol- or drug-induced liver disease; the evaluation of unexplained liver dysfunction, hepatomegaly, or portal hypertension; the investigation of diverse infectious, metabolic, and other systemic disorders; the detection of neoplastic or infiltrative diseases; and the elucidation of post-transplantation problems.
The liver commands the right upper quadrant of the abdomen. The organ, which weighs between 1200 g and 1500 g in the adult, forms an approximate wedge sitting with its base to the right and apex to the left. It is suspended from the anterior abdominal wall by the falciform ligament and the round ligament -- a fibrous remnant of the fetal umbilical vein -- and from the diaphragm by peritoneal reflections known as the triangular and coronary ligaments. These ligaments represent reflections of the peritoneum, which covers almost the entire hepatic surface, sparing only an area along the retroperitoneal posterior surface.
The liver has a dual blood supply provided through the portal vein and hepatic artery. These vessels pass into the liver through the porta hepatis, a fissure situated along the central inferior border of the liver, and immediately divide into smaller branches. Headed on the opposite course, bile proceeds from the bile canalicular through the bile ducts and eventually into the right and left hepatic bile ducts, which join in the porta hepatis and depart as the common hepatic duct. The venous outflow of the liver drains through the right and left hepatic veins into the inferior vena cava, which lies in a groove in the posterior hepatic surface.
Traditionally, the liver has been separated by its exterior landmarks into four lobes: the large right and left lobes and smaller caudate and quadrate lobes. The insertion of the falciform ligament divides the bulkier right lobe from the left lobe; the caudate lobe is situated on the posterior surface between the inferior vena cava and the porta hepatitis; and the quadrate lobe is found on the inferior surface bounded by the gallbladder and the round ligament. In some patients, the lower border of the right lobe extend downward in a broad projection known as Riedel's lobe.
This traditional description has been supplanted by a more accurate morphologic division based on the distribution of vascular structures (Figure 1-1).13,22 By this scheme, the liver is separated into anatomic right and left lobes of near equal mass, each served by a distinct vascular supply. The two lobes are demarcated by the middle hepatic vein and represented externally by a line that runs from the fossa of the gallbladder posteriorly towards the inferior vena cava.
These two "true" lobes have been further subdivided into various segments and subsegments, but, from a practical perspective, only the four main segments that may be surgically resected by partial hepatectomy need to be considered.16 The right lobe is partitioned into anterior and posterior segments by the path of the right hepatic vein, and the left lobe is separated into medial and lateral segments by the left hepatic vein running along the plane of the falciform ligament. The medial segment thus incorporates the quadrate lobe and a portion of the caudate lobe; the remainder of the caudate lobe is found in the right lobe.
The liver is composed of hepatocytes arranged in anastomosing plates, forming a three-dimensional labyrinth that directs blood flow to the small tributaries of the hepatic vein. These parenchymal plates are regularly interrupted by the arborescent channels of the portal tracts, which represent the liver's interstitial and afferent vascular component. The regular topographic arrangement of these components organizes the liver into basic architectural subunits; these have been depicted in two alternate ways: the lobule and the acinus (Figure 1-2).
The lobule represents the traditional conception of hepatic histology. Each lobule is a roughly hexagonal structure with an hepatic vein branch, known as the central vein, at its hub. From the central vein, hepatic plates radiate centrifugally towards the portal tracts, three to six of which are situated at the periphery of the lobule. The lobule can be arbitrarily separated into three zones: the centrilobular zone surrounds the central vein, the periportal or peripheral zone adjoins the portal tract, and the midlobular zone falls between the other two.
By contrast, the acini are defined by microcirculatory layout of the liver.25 The simple acinus is an irregular spherical mass of parenchyma that surrounds a central axis composed of a portal tract and its afferent vessels. From the portal area, hepatic plates radiate outward to the hepatic vein branches, termed the terminal hepatic venules, located at the periphery of the acinus. Each acinus therefore occupies parts of two adjacent lobules. Larger combinations of the simple acini are also described: Three simple acini congregate into the complex acinus, and three complex acini further join to form the largest unit, the acinar agglomerate.
The parenchyma of the acinus can be divided into three zones depending upon the distance from the portal axis: zone 1 runs near the portal tract, zone 3 flanks the acinar periphery, and zone 2 is intermediately located. A gradient of oxygen and other nutrients is therefore established; zone 1 being the best supplied and zone 3 the least. This renders zone 3 the area most susceptible to ischemic or toxic injury. The hepatocytes within different zones are also functionally heterogeneous, varying in enzyme content and metabolic activity as well as ultrastructural details; this heterogeneity provides a further explanation for variation in the distribution of hepatocellular damage caused by different insults.12,18 In addition, animal model suggest that the acinar design also reflects the events of normal hepatocellular renewal: Beginning from zone 1, the liver cells advance across the acinus, modifying their metabolic tasks in route, and are eliminated in zone 3.29
Both the lobule and the acinus are adequate descriptions of the liver's histology, and their differing terminology can be roughly correlated: The centrilobular zone is comparable to acinar zone 3, and the periportal zone the approximate counterpart of acinar zone 1. Note, however, that the latter correspondence is correct only for the smallest portal tracts since larger tracts are bounded by hepatocytes from all three acinar zones. The acinus is sometimes the preferred description because it is a more functional model and provides a clearer explanation of certain pathophysiologic processes. Nevertheless, the traditional lobule, as a two-dimensional planar representation of the liver, is easier to visualize and conforms better with what is seen on microscopic slides. Either is acceptable for most purposes, but the lobular terminology will be favored in this book since it is more suitable for descriptive histopathology.
Hepatocytes. The hepatocytes are polygonal cells, 25 µm to 30 µm in diameter, with abundant cytoplasm and centrally placed nuclei. They are organized into interconnecting hepatic plates that, except at sites of anastomosis, are normally one cell layer thick (Figure 1-3). The finding of thickened cell plates suggests hepatocyte hyperplasia, although twin-cell plates are the rule in children under four to six years. Around portal tracts, the hepatic plates form an encircling ring often termed the limiting plate.
Neighboring hepatocytes form bile canaliculi. These are small biliary channels that are created from the apposition of specialized grooves in the surfaces of the contributing liver cells. They constitute a continuous conduit that extends along the hepatic plates and empties into the bile ductules at the edges of the portal tracts. Unless expanded by canalicular bile plugs, bile canaliculi are not readily seen, but they can be demonstrated by various histochemical techniques or by immunohistochemistry using particular antibodies against carcinoembryonic antigen.19
The abundant cytoplasm of the hepatocyte is granular and eosinophilic, often more densely aggregated in the pericanalicular region, and its appearance varies somewhat depending on the functional status and activity of the cell. Glycogen is usually amply present; it provides a delicate cytoplasmic lucency, but may be unevenly distributed within and among lobules. Scattered fat vacuoles are also commonly noted. The granularity of the cytoplasm is largely conferred by the endoplasmic reticulum and mitochondria. Proliferation of endoplasmic reticulin may be recognized as focal aggregates of basophilic granules; increased mitochondria may yield a finely granular and strongly eosinophilic, oncocytic-like, appearance.10,20
Lipofuscin in varying amounts regularly adorns the cytoplasm. This yellow-brown pigment accumulates most prominently in centrilobular hepatocytes, especially around their canalicular poles, and is acid-fast and often diastase-PAS positive. As a crude marker of cellular longevity, lipofuscin increases in quantity with advancing age.14
Lipofuscin should be distinguished from hemosiderin and bile, two other yellow-brown pigments seen in liver cells. Hemosiderin is abundant in newborn livers, but it gradually disappears over several months, and only minor quantities are normally found in adults.6 Located principally in periportal hepatocytes, hemosiderin granules are coarse, golden-brown, and refractile, and can be readily demonstrated by the Prussian blue reaction for iron. Bile pigment is a feature of cholestatic liver disease and is not found in normal livers. Intracellular bile accumulates as poorly defined granules in hues of yellow, green, and brown distributed primarily in centrilobular areas. Although its nature can be established by several histologic procedures, it is definitively identified by the concomitant presence of bile plugs within canaliculi. The Dubin-Johnson syndrome is characterized by the marked accumulation of a dark brown pigment that may be difficult to distinguish from lipofuscin; the clinical setting provides the appropriate clues to the diagnosis (Chapter 4).
The nuclei of hepatocytes are round to oval and possess a delicate chromatin pattern and one or more nucleoli. Binucleated cells are not uncommon, but mitoses are rarely seen. Most nuclei are diploid and uniform in appearance; with advancing age, the number of nuclei with polypoid karyotypes increases, and variation in nuclear size becomes correspondingly greater (Figure 1-4).28 The nuclei may also develop a clear, vacuolated look resulting from the accumulation of glycogen. This can be seen in normal livers, especially in children or young adults, but it has also been associated with sundry conditions such as diabetes mellitus and Wilson's disease (Figure 1-5).
Sinusoids. The sinusoids are the narrow vascular channels interposed between radiating hepatic plates. They are lined by Kupffer and endothelial cells and supported by a meshwork of delicate reticulin fibers. The sinusoids, although typically empty, may contain a variable number of red blood cells, and their width in biopsy specimens varies greatly.
Both types of sinusoidal lining cells have elongated nuclei and scanty cytoplasm and are difficult to specifically identify in routine sections. Kupffer cells are highly phagocytic members of the mononuclear phagocyte family; in response to hepatocyte damage, they proliferate and enlarge, often amassing so-called ceroid pigment, a material chemically similar to lipofuscin that is derived from phagocytosed cellular debris.14,17 Ceroid pigment is strongly diastase-PAS positive, and therefore this stain is useful in highlighting activated Kupffer cells and indicating sites of previous hepatocellular necrosis (Figure 1-6). Endothelial cells are largely inconspicuous, but form a fenestrated, discontinuous lining along the sinusoid that is important in maintaining a partial barrier between blood and liver cells.15
The zone between the endothelial cells and the hepatocytes, termed the space of Disse, is not usually visualized and becomes perceptible only in poorly preserved liver specimens. This space contains the reticulin framework of the liver, a continuous network of type III collagen fibers that outlines the hepatic plates. In addition, this is where the lipocytes (Ito or interstitial fat-storing cells) are situated. These cells are modified fibroblasts that store fat and vitamin A and, because of their capacity for collagen synthesis, may be involved in the production of hepatic fibrosis.7,27 Lipocytes cannot usually be recognized with certainty on routine sections, but when they become laden with fat, as occurs in hypervitaminosis A, they develop multiple small lipid droplets that encroach on the nucleus (Figure 1-7).
Central Veins. The central veins or, in acinar terminology, the terminal hepatic venules are the smallest component of the venous outflow tract. Starting from the confluence of the sinusoids in the lobular interior, these radicles join to form the sublobular hepatic veins and then the hepatic veins, which connect to the inferior vena cava. Central veins are lined by endothelial cells and are surrounded, in some instances, by thin collagenous rim (Figure 1-8). A thickened layer of collagen is occasionally seen in normal biopsies, but it also occurs in conditions such as alcoholic hepatitis.8,23
Portal Tracts. Each portal tract embraces a bile duct (and bile ductules), a small hepatic artery, and a portal vein branch (Figure 1-9). Because of their pattern of successive branching, portal tracts throughout the liver exhibit a great range of sizes. When cut longitudinally, larger tracts may resemble fibrous septa, but their true nature is indicated by their comparably sized vessels and ducts.
The portal structures are set within a well-defined connective tissue envelope composed primarily of type I collagen, which becomes progressively coarse and dense with increasing age. Lymphatic channels and, in larger portal tracts, autonomic nerve fibers may be present. Varying numbers of lymphocytes and mast cells are normal constituents, usually in a patchy distribution, but neutrophils or plasma cells are not generally seen.
The smaller bile ducts, known as interlobular bile ducts, are lined by cuboidal or low columnar epithelium, whereas the larger septal (or trabecular) bile ducts are characterized by tall columnar epithelium and a diameter that exceeds 100 µm (Figure 1-10).5,21 Septal ducts, which are infrequently seen in needle biopsy specimens, join to create the segmental and finally the hepatic bile ducts. One or more bile ducts are typically present in each portal tract and are located near a hepatic artery branch of comparable size. Normally, 70% to 80% of the arteries are accompanied by bile ducts, and finding unattended arteries suggests a decrease in the number of intrahepatic bile ducts, an central feature of several important conditions (Chapter 5).
The intrahepatic ducts drain bile from the canaliculi via tiny channels various referred to as bile ductules, cholangioles, or canals of Hering. These structures, lined by a combination of biliary epithelial cells and hepatocytes, are rarely seen in normal livers, but they readily proliferate in a wide variety of pathologic conditions, as noted below. These proliferated ductules are distinguished from interlobular bile ducts by their location at the periphery of the portal tract and their lack of an attendant hepatic artery.
In young children, the hepatic plates are two cells thick and glycogenated nuclei common, but lipofuscin sparse or absent. In addition, the livers of infants often contain foci of extramedullary hematopoiesis and increased quantities of stainable iron and copper. At the other extreme, the ageing liver is distinguished by prominent variation in the size of hepatocytes and their nuclei. Lipofuscin pigment may be conspicuous, and the portal tracts can become prominently fibrotic or hyalinized.
The subcapsular zone is another source of normal variation. Portal tracts in this region can sometimes appear unusually fibrotic and may form thick fibrous bands that join adjacent portal tracts and isolate islands of parenchyma beneath the capsule (Figure 1-11). These changes rarely extend more than 2 mm into the liver, but, in shallow biopsy specimens, they can imitate cirrhosis; this problem can be avoided by recognizing the superficial nature of the specimen.24
The pathologist confronts three main types of liver specimens: needle biopsies, wedge biopsies, and hepatic resections of various extent. Each types has its own advantages and disadvantages in diagnostic utility and clinical applicability, and, depending on the circumstances and indications, is associated a defined role in patient management.
Needle biopsy is a simple, safe, and effective means of sampling the liver, and such specimens are consequently the most common variety encountered. Their chief drawback is their small size: The typical specimen measures from 10 mm to 30 mm in length and between 1.2 mm and 2.0 mm in diameter, representing some 1/50,000 of the total liver mass. This has obvious implications for specimen adequacy and sampling error.
The customary needle biopsy is obtained through a blind, percutaneous approach using the Menghini suction-type needle. Since fibrous tissue does not aspirate well, the specimen often fragments in cases of cirrhosis and the interpretation is correspondingly more difficult. Biopsy needles with cutting edges, such as the Tru-Cut instrument, avoid this problem, but at the price of greater distortion and compression of the tissue and a increased risk of post-biopsy hemorrhage.36,55
Blind percutaneous biopsy is most useful in assessing diffuse liver diseases. As a general rule, a specimen of 15 mm is often adequate for an accurate evaluation, although a length of 25 mm or more is preferable.44,60 Unfortunately, the procedure misses some irregularly distributed processes and focal masses, notably including cirrhosis, neoplasms, and other mass lesions. Multiple biopsies may be used to lessen the sampling error, but another valuable tactic is to guide the biopsy to a particular abnormality, either by direct vision during laparotomy or laparoscopy, or with the aid of ultrasonography or computed tomography.30,31,49
An increasingly popular form of needle biopsy is fine-needle aspiration biopsy. Under radiographic direction, this technique can sample focal lesions anywhere in the liver, providing material for both cytologic and histologic examination. Although it has sometimes been used to assess nonneoplastic conditions, its greatest advantage lies with tumors of various nature -- benign, malignant, primary, or metastatic -- where its diagnostic accuracy ranges from 80% to over 95%.40,43,53,61
Needle biopsies may also be obtained by a transvenous approach using a catheter that is introduced into the internal jugular vein and routed through the vein cava into a hepatic vein; this technique is particularly useful when other procedures are contraindicated because of coagulation disorders.50
Surgical wedge biopsy specimens are useful in assessing lesions that either have eluded percutaneous biopsy or are unexpectedly discovered at laparotomy. The advantages of these specimens are their larger size and targeted nature, but, depending on their size, a sizable portion may consist of subcapsular zone, which may not be representative of the remainder of the liver. The surgeon should therefore take a specimen to at least 10 to 15 mm in depth.
Hepatic resections are performed for therapeutic as much as diagnostic reasons, and the indications include traumatic laceration, benign lesions, and localized primary or metastatic neoplasms. The extent of resection can be tailored to the exact indication, varying from small local excisions to removal of single segments, multiple segments, or entire hepatic lobes.16 The extreme case is, of course, liver transplantation, where total hepatectomy specimens are obtained.
A carefully handled, processed, and sectioned specimen of liver tissue is imperative for accurate morphologic assessment and interpretation. Needle biopsy specimens must be handled careful to prevent crush artifact but can be briefly examined and completely submitted for processing with little bother. Wedge and resection specimens need to be sectioned and their cut surfaces closely inspected; sectioning is best accomplished by parallel cuts perpendicular to the capsule at intervals of 5 mm to 10 mm. In cases where neoplasms have been excised, the surgical resection margins can be inked to aid microscopic identification.
In special circumstances, hepatic tissue can also be supplied for specific examinations, including microbiologic cultures, enzyme analysis to detect inborn errors of metabolism, biochemical assays of stored substances such as iron, copper, or other hepatocellular materials, and molecular biology investigations. Frozen sections may be indicated for rapid diagnosis during surgery, particular histochemical techniques (such as neutral fat stains, for example), for immunohistochemical procedures, or for evaluation of porphyrin or vitamin A fluorescence. These special examinations are the exception, and the need will generally be known beforehand so that proper preparations can be made.
Gross examination of most needle or wedge biopsy specimens yields little diagnostic information, but with larger specimens, these observations become increasingly important. As a minimum, the gross description of every specimen should record the size, color, and any inhomogeneity in appearance.
The normal liver is a uniform brown or tan and is regularly punctuated by pinpoint depressions that represent the portal areas. Cirrhotic or severely fibrotic livers frequently yield fragmented needle biopsies and may exhibit irregular parenchymal nodules. Alterations in color can also point to certain pathologic processes: green denotes cholestasis; yellow implies fat accumulation; red-brown evinces heavy iron deposition; gray-black prompts consideration of Dubin-Johnson syndrome; and orange raises the question of cholesterol ester storage disease and Wolman's disease.
Larger specimens should be inspected for any grossly identifiable lesions, including focal masses, nodules, or cysts, and note taken of their size, number, nature, consistency, boundaries, and relationship to other structures. The surrounding liver should be perused for any alterations, the surgical margins examined for completeness of excision, and evidence of vascular invasion searched for. Tissue sections should be obtained to illustrate and document each of these aspects, including blocks from the lesions (and their junction with adjacent parenchyma), the uninvolved liver, the major bile ducts and blood vessels, the surgical resection margins, and any attached lymph nodes. In failed hepatic allografts, particular attention should be directed to the anastomotic sites and hilar region.37
Routine formalin fixation and paraffin processing suffice for most purposes, although given the small size of the needle specimens, care must be taken to avoid overprocessing. In some centers, plastic embedding is employed; this permits the cutting of very thin sections with enhanced microscopic detail but is not generally necessary. Sections should be cut at several levels through the paraffin block to insure an adequate examination of the tissue; serial sectioning is rarely indicated but may be useful when small focal lesions such as granulomas, metastatic deposits, or parasite eggs are suspected. Some of the sections can then be stained with hematoxylin and eosin and other selected stains, and the remaining sections retained for any additional procedures that may be necessary. This is particularly helpful with tiny specimens where tissue is at a premium.
Hematoxylin and eosin is the mainstay of diagnostic histopathology. Although this stain will demonstrate most major histologic findings, a variety of special stains are often useful in identifying features that are otherwise inapparent or obscure. Which special stains should be performed routinely is largely a matter of personal preference: Some favor a large standard battery, while others opt for a selected few. If a low threshold is maintained for ordering appropriate supplementary stains, this choice has little practical importance.
Stains for connective tissues are among the most valuable. Reticulin stains highlight the type III collagen framework that normally delineates the hepatic plates (Figure 1-12). Alterations in hepatic architecture are therefore readily appreciated: Hepatocyte necrosis is detected by areas of collapsed framework, hepatocyte regeneration by thickening of the hepatic plates, and fibrosis by zones of dense gray or, in untoned sections, brown fibers. Trichrome stains of various hues demonstrate type I collagen, which is normally present in portal tracts and the walls of larger hepatic veins branches, and thus conveniently accentuate the degree and distribution of fibrosis (Figure 1-13).
An iron stain is a reliable means for detecting even scanty quantities of hemosiderin and is therefore useful in assessing iron overload (Figure 1-14).32,33 By its pale counterstain, this stain also accentuates bile and lipofuscin pigments, which appear in striking green and yellow-brown tints, respectively.
The periodic acid-Schiff stain with diastase predigestion plays several diagnostic roles. It highlights lipofuscin and ceroid pigment within Kupffer cells (signifying foci of active hepatocellular injury), demonstrates the basement membranes of bile ducts and ductules, and indicates the presence of various nonglycogen carbohydrates (Figures 1-6 and 1-15). The most renowned of these are the cytoplasmic globules seen in periportal hepatocytes in alpha-1-antitrypsin deficiency (Chapter 9).51,56
Orcein, Victoria blue and aldehyde fuchsin stains have the same diverse applications. They are traditional markers of elastic fibers, which are normally distributed in parallel with type I collagen (Figure 1-16). Since zones of developing fibrosis also acquire elastic fibers, these stains are helpful in distinguishing areas of acute hepatic necrosis from chronic fibrous septa.58,62 In addition, they stain hepatitis B surface antigen, which accumulates in cases of chronic hepatitis B infection, and identify so-called copper-associated protein, insoluble aggregates of metallothionein within lysosomes (Figure 1-17).57,59
Copper can also be detected directly by rhodanine or rubeanic acid methods, but the staining may be inconsistent in tissue fixed in unbuffered formalin or Bouin's or Zenker's fixatives (Figure 1-18).45 These stains give results comparable to the orcein and like stains, but the latter are frequently more reliable because of the insolubility of copper-associated protein.41,42,47 Accumulation of copper occurs in chronic cholestasis (Chapter 4), Wilson's disease (Chapter 9) and occasional hepatic neoplasms and is a normal feature of fetal and neonatal livers.
Additional histochemical stains, such as those for microorganisms, amyloid, or fibrin, can be obtained as needed, depending on the circumstances.
Immunohistochemistry has become a routine procedure in most pathology laboratories. Although it has tremendous applications for investigative studies, its role in diagnostic hepatic pathology is currently limited but will undoubtedly expand.
One major role involves the evaluation of hepatic neoplasms. For example, advantage can be taken of the differences in cytokeratin expression between hepatocytes, which possess cytokeratins 8 and 18 alone, and biliary epithelium, which additionally expresses cytokeratins 7 and 19, to help distinguish hepatocellular carcinoma from cholangiocarcinoma (Figure 1-19).34,48 Several other tumor antigens, including alpha-fetoprotein, carcinoembryonic antigen, and epithelial membrane antigen, are of occasional help in this situation but are frequently not conclusive.34,35,38 Other markers may help the recognition of mesenchymal or hematopoietic tumors affecting the liver.
The other prime application of immunohistology is in the detection or verification of infectious organisms, particularly the hepatitis B and D viruses and the various members of the herpes virus family.39,46,52 In addition, alpha-1-antitrypsin deficiency can be confirmed by the specific immunostaining of the distinctive cytoplasmic globules that accumulate.
Electron microscopy has contributed greatly to our understanding of many liver diseases, but its main application in the diagnostic domain, as discussed in Chapter 9, is in the diagnosis of inherited metabolic diseases.54
GENERAL APPROACH TO LIVER PATHOLOGY
The pathologist's prime objective is to translate morphologic abnormalities into clinically relevant terms useful in patient evaluation and management. At best, these abnormalities are definitive, and a specific diagnosis can be rendered. This primarily occurs with neoplastic disorders and is seldom the case with inflammatory disorders. More often, the specimen shows only nonspecific changes, an anticipated outcome given the limited range of hepatic responses to injury, and a conclusive diagnosis cannot be made. The findings may nonetheless assist in eliminating or supporting a clinical impression or in suggesting further evaluation. In other cases, the specimen unfortunately yields little useful information.
A general approach to the interpretation of liver specimens involves recognizing the basic histologic pattern (or patterns) presented by the specimen. This pattern can then be used to formulate a pathologic differential diagnosis, and a directed search conducted for specific diagnostic clues. Since most histologic patterns can result from several different injurious agents, this differential diagnosis must then be correlated with the clinical, laboratory, and radiographic data before a final diagnosis is established. Examining the liver blindly -- without knowledge of the clinical information -- is a good means of avoiding interpretive bias, but the conclusion is presumptive and needs to be followed by clinicopathologic correlation: To do otherwise is to invite unnecessary errors.
Recognition of histologic patterns depends upon an thorough assessment of the pathologic changes. This is best accomplished through an organized, systematic examination to insure that no significant finding is missed. An example of such an approach is presented in Table 1-1, and the remainder of the book delineates the basic patterns and their differential considerations.
A low-power scanning of the slides is a valuable initial procedure. The hepatic architecture is assessed by examining the spatial relationships of portal tracts and central veins and the arrangement of the hepatic plates. Disturbances in the normal regular structure such as collapse or fibrosis are often best shown on reticulin or trichrome stains (Figure 1-20). These stains can be indispensable for detecting minor alterations, which may be the only biopsy clues to such processes as cirrhosis or nodular hyperplasia. In addition at low-power examination, a general impression can be gained of the distribution and extent of any abnormalities and note taken of any focal lesions deserving of particular attention, including fibrous septa, granulomas, or tumor deposits.
Once a general view is obtained, the various structural components can then be methodically examined. The status and integrity of each individual element can be assessed and any changes characterized by their nature, location, distribution, and intensity, as suggested in Table 1-1. The portal tracts and centrilobular hepatocytes are the focus of a wide range of lesions, but they should not divert attention from the remainder of the lobule.
In certain situations, a liver biopsy may look misleadingly normal and careful scrutiny required to identify the subtle alterations. The greatest difficulties occur with cirrhosis, nodular regenerative hyperplasia, and hepatoportal sclerosis (Chapters 10 and 11). Since these conditions are all associated with portal hypertension, that clinical setting should prompt a close examination of the hepatic architecture and portal veins for any minor disturbances. The biopsy may also appear normal, despite clinical liver disease, in some cases of drug-related toxicity or because of sampling error.
Many surgical biopsy specimens show small aggregates of neutrophils within the parenchyma. These may be found beneath the capsule, within sinusoids, or, accompanied by focal hepatocyte necrosis, within the hepatic plates (Figure 1-21) . A centrilobular predominance is often noted. This so-called surgical hepatitis is more frequently seen in biopsies taken late in the course of an operative procedure, presumable because of hypoxia or local procedural trauma, and is rarely noted in nonoperative percutaneous biopsy specimens.64,65,68 The changes need to be distinguished from the neutrophil infiltration seen with alcoholic hepatitis and similar lesions (Chapter 7).
The liver is subject to the same technical artifacts as any tissue. Undue squeezing of the specimen can distort and elongate the nuclei of inflammatory and other cells, complicating their recognition. In addition, the foam sponges used in processing cassettes can irregularly compress biopsy specimens and imprint them with angular or hooked holes that may be mistaken for central veins (Figure 1-22).66 Improper fixation or processing can cause spurious hepatocyte swelling or shrinkage and produce inconsistencies in cytoplasmic staining; these artifacts can be recognized by their anomalous distribution along the periphery or interior of the specimen (Figure 1-23).
A common but nonspecific hepatic response to injury is bile ductular proliferation. This is characterized by an increase in the number and prominence of small biliary channels in and around the portal tracts (Figure 1-24). The proliferated ductules vary in appearance: They may have tubular to elongated profiles, are lined by cuboidal or columnar epithelium, and may or may not have well-defined lumens. A neutrophil infiltration is a regular accompaniment.63,70
Proliferated ductules need to be distinguished from interlobular bile ducts since the two structures carry different diagnostic implications (Chapter 5). In general, ducts are larger and are accompanied by an hepatic artery of comparable size, whereas the ductules, typically small and sometimes irregular, lack an arterial affiliation. The distinction may be difficult when the ductules are large or contain prominent lumens, and the overall context must then be taken into account.
Ductular proliferation is seen with varying severity in many conditions, including biliary obstruction, acute or chronic cholestasis, sepsis, massive hepatic necrosis, and fibrosis or cirrhosis of diverse etiology. This broad range of underlying causes implies that it represents a heterogenous process with no single pathogenetic explanation. The possible mechanisms, much debated over many years, include sprouting of preexisting bile ductules, tortuosity of elongated ductules, or ductular (biliary) metaplasia of hepatocytes; evidence for each can be advanced.69,72-74 The conclusion is that, in response to diverse insults, modulation can occur between the normal bile ductules and adjoining periportal hepatocytes; both may transform to produce what is recognized under the microscope as ductular proliferation.
The liver may also exhibit a variety of nonspecific secondary changes in response to disease elsewhere in the body or the liver. Although these changes do not constitute a distinct entity, they are often referred to under the general rubric of nonspecific reactive hepatitis.71 In some instances, the term hepatitis may be too dignified a designation for what are often slight and insignificant changes.
The associated diseases include many systemic illnesses and infections, various inflammatory conditions, and several gastrointestinal or pancreatic diseases. In addition, similar changes can also seen in the vicinity of hepatic masses such as cysts, abscesses, and benign or malignant neoplasms. Nonspecific reactive hepatitis is therefore a common finding in hospitalized patients who are biopsied because of unexplained fever, hepatomegaly, or mild liver function test abnormalities.
The histologic features encompass a variable combination of portal and parenchymal changes, typically of minor degree and distributed in a patchy, uneven manner: portal infiltration by mononuclear cells (primarily lymphocytes), fatty change, focal hepatocellular necrosis, and lobular inflammation (Figure 1-25).11,71 The latter may comprise enlarged or hyperplastic Kupffer cells (sometimes forming small granulomatoid clusters), other macrophages, or lymphocyte aggregates of assorted size.67 The distinction from resolving acute hepatitis or mild chronic persistent or chronic lobular hepatitis may be difficult and arbitrary, and clinical information is often required.
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