Hepatic fibrosis denotes the excessive accumulation of connective tissue in the liver and, as an indicator of persistent or progressive hepatic injury, represents a histologic hallmark of chronic liver disease regardless of cause. By interfering with the liver's normal structure to some extent, fibrosis is capable of disrupting the hepatic microcirculation and cellular physiology, particularly when it is severe or strategically located, and can yield such serious clinical consequences as portal hypertension or hepatic insufficiency.

Fibrosis is a complex, dynamic process that involves the synthesis and degradation of the extracellular matrix. In the normal liver, this matrix consists of several collagen types and several noncollagenous glycoconjugates, including certain glycoproteins and glycosaminoglycans, and can be classified as interstitial and basement membrane types.^18,42,43 The interstitial matrix is composed largely of collagen types I and III with lesser contributions by types V and VI. It occurs primarily in the portal tracts but is also distributed in the lobules, particularly in the region of the central vein. Basement membrane matrix is formed from type IV collagen together with laminin and heparan sulfate and is localized, as expected, to the basement membranes of vessels and biliary structures. It also present, however, along the sinusoids and, in conjunction with fibronectin and particular proteoglycans, probably constitutes a basement membrane-like structure for hepatocytes and sinusoidal endothelial cells. This sinusoidal matrix is thought to play an important biologic role in directing and modulating the function and structure of hepatocytes.^8,11,42

The fibrotic liver contains the same matrix components as does normal liver, although in greater quantities. However, there are differences in relative proportions of the various components; type I collagen, laminin, and certain glycosaminoglycans are disproportionately increased, alterations that connote the formation of a permanent scar.^8,43,46

The pathogenesis of hepatic fibrosis is under active investigation, but many of the details concerning the synthesis and degradation of the liver's extracellular matrix remain unsettled. The general pathogenetic concept is that, following suitable hepatic injury, the matrix-producing cells of the liver become inappropriately activated and synthesize excess connective tissue. The identity of these cells is not completely established since in cell culture systems, hepatocytes, lipocytes (Ito cells), endothelial cells, and Kupffer cells are all capable of producing one or more of the matrix components. However, several lines of evidence point to the lipocyte as the leading culprit.^9,14 With proper stimuli, these cells have been shown to transform from quiescent fat-storing cells to proliferating fibroblastic cells, often with myofibroblastic features, that are active producers of extracellular matrix.^20,28,35

The mechanisms by which these cells become activated is an additional problem to be addressed. In most situations, the chief stimulus is hepatocyte necrosis and its resulting inflammatory response. Inflammatory cells involved in the process can release soluble mediators that directly regulate the activity of the matrix-producing cells. Several such cytokines are described, including platelet-derived, Kupffer cell-derived, and epidermal growth factors, tumor necrosis factor, and interleukin-1, but much interest is focused on transforming growth factor β₁.^12,31,43 Other injurious agents have been proposed to directly cause fibrogenesis, independent of overt hepatocyte necrosis or inflammation; prominent examples include alcohol abuse and iron overload.^2,28 In addition, changes in the structure of the matrix alone may alter the regulation of matrix-producing cells and result in increased elaboration.⁸

Fibrosis is an important marker of the extent and distribution of hepatic injury, and based on these features, several histologic patterns can be distinguished. These patterns can occur singly or in combination and, in active disease, may be accompanied by other histologic changes. In some cases, the responsible injury has subsided or is low-grade and indolent, and fibrosis constitutes the only finding. In any case, recognition of the pattern of fibrosis may be helpful, even when not diagnostic, in narrowing the differential diagnosis, suggesting etiologic possibilities, and providing prognostic information.^39,52 The conditions responsible for each pattern are discussed elsewhere, and only those details pertinent to the pattern of fibrosis are noted here.

Portal fibrosis. In this pattern, excess connective tissue forms within the portal tracts, which consequently become densely staining and expanded, but there is no extension into the adjacent parenchyma. Although mild portal fibrosis is a normal finding in elderly individuals, it may also occur in virtually any condition associated with persistent portal inflammation, including chronic hepatitis, steatohepatitis, biliary obstruction, and various systemic infections, and is occasionally seen without an apparent explanation.³⁰ In addition, granulomatous disorders such as sarcoidosis or schistosomiasis may result in the formation of focal, well-delineated portal scars.^22,48

One distinctive form of portal fibrosis is periductal fibrosis, in which a concentric cuff of connective tissues surrounds an interlobular bile duct (Figure 10-1). This may be found to varying degrees in several chronic biliary disorders, but, when combined with epithelial damage and duct atrophy, represents a characteristic feature of primary sclerosing cholangitis. Fibrous obliteration of the duct can develop as the end result.^4,35

Portal fibrosis may also be accompanied by sclerosis or obliteration of the portal vein branches. This occurs to a minor extent in many portal inflammatory conditions, including primary biliary cirrhosis, and is occasionally seen in otherwise normal individuals.^32,49 At its most dramatic, however, it constitutes a distinguishing feature of hepatoportal sclerosis. In this condition, the larger portal tracts are most conspicuously affected, and recanalized venous thrombi or aberrant proliferated vessels may be noted. The lobular architecture is often uninvolved, although some cases are complicated by nodular hyperplasia or thin fibrous septa.⁴⁵ A similar picture can also result from exposure to toxins such as vinyl chloride or arsenic.³⁴

In congenital hepatic fibrosis, densely fibrotic portal tracts accommodate dysmorphic biliary channels with their characteristic elongated or cystic profiles (Figure 10-2). Inflammation and hepatocyte necrosis are usually absent, but portal vein branches may be hypoplastic and portal-based fibrous septa can develop.^5,15

Periportal fibrosis. In this pattern, fibrous tissue occupies the periportal region and may extend into the neighboring parenchyma (Figure 10-3). The circumference of the portal tract may be completely or partially involved, sometimes in association with portal fibrosis, and varying degrees of bile ductular proliferation and attendant inflammation are commonly present. Periportal fibrosis can represent the first stage in the evolution to bridging fibrosis, and it therefore often connotes an aggressive or progressive process.

Periportal fibrosis is a major feature of two major forms of periportal inflammation and hepatocyte necrosis, chronic active hepatitis and chronic cholestasis. In both, spurs of active fibrous tissue radiate from the portal tract, imparting an irregular stellate configuration best seen on connective tissue stains.³ Chronic active hepatitis is additionally characterized by piecemeal necrosis and a mononuclear inflammatory infiltrate composed predominantly of lymphocytes. Chronic cholestasis, a consequence of prolonged interference with bile flow, is commonly encountered in primary biliary cirrhosis and primary sclerosing cholangitis and is distinguished by copper accumulation, Mallory bodies, and a mixed inflammatory infiltrate that includes neutrophils and macrophages.

Periportal fibrosis can also develop following other severe portal and periportal inflammatory reactions and may therefore be noted in such conditions as acute hepatitis or allograft rejection.⁶ Other incriminated disorders include hereditary hemochromatosis, toxicity by agents such as methotrexate, cystic fibrosis, and assorted storage and metabolic disorders such as the mucopolysaccharidoses.^38,47

Pericellular fibrosis. This pattern is characterized by connective tissue strands that extend along the sinusoids to surround single or small groups of hepatocytes (Figure 10-4). On connective tissue stains, pericellular fibrosis has a chickenwire or latticework appearance, and, because of its distribution, is also referred to as perisinusoidal fibrosis.

The most prominent cause of pericellular fibrosis is steatohepatitis in either its alcoholic or nonalcoholic forms. Initially arising in the centrilobular region, the fibrosis is accompanied in active disease by swollen hepatocytes containing Mallory bodies, an inflammatory infiltrate rich in neutrophils, and fatty change. These changes form the basis for the development of bridging fibrosis, but in unusual cases, pericellular fibrosis spreads across entire lobules, producing a pattern of diffuse intralobular fibrosis that is associated with a poor prognosis.

Vitamin A toxicity can also give rise to pericellular fibrosis, sometimes with a diffuse intralobular pattern involving much of the lobule. Associated findings include sinusoidal dilation, sclerosis of central veins, and focal lobular inflammation, but the most distinctive feature is the presence of enlarged vacuolated lipocytes, which demonstrate a transient green fluorescence on frozen sections.^7,19,29

Pericellular fibrosis has also been associated with congenital syphilis, Crohn's disease, thrombocytopenic purpura, and, with a patchy distribution, in several storage disorders such as Gaucher's disease or Wolman's disease.^10,23,37 In addition, the periportal fibrosis of chronic active hepatitis can, in severe cases, occasionally display a pericellular mode of extension into the lobule.

Perivenular fibrosis. In this pattern, the centrilobular zone is chiefly affected with deposition of connective tissue in the vicinity of the central vein (Figure 10-5). The extent of the deposition varies from minor mural thickening, which can occasionally be seen in normal livers, to marked scarring of the centrilobular region.^13,33 With progression, perivenular fibrosis can spread and connect with other centrilobular areas or with portal tracts to create fibrous septa.

Perivenular fibrosis is one of the major features of steatohepatitis and is responsible for the dense zones of stellate centrilobular scarring that are a hallmark of this condition. Generally accompanied by pericellular fibrosis of varying degree, perivenular fibrosis may be complicated by compression or obliteration of the central vein. Other features of steatohepatitis are often present, but in some alcoholic patients, perivenular fibrosis is the sole finding, and the possibility that it represents a primary alcohol-induced lesion has been raised.^16,28,50

Chronic venous outflow obstruction is another general process associated with perivenular fibrosis. The obstruction may be at the level of the heart, the vena cava or the major hepatic veins, or the central veins, and the responsible disorders therefore encompass congestive heart failure, the Budd-Chiari syndrome, and venoocclusive disease. The histologic background includes sinusoidal dilatation and congestion, and often the central veins cannot be identified on routine sections.^1,24,44

Perivenular fibrosis can also develop following confluent necrosis of centrilobular hepatocytes and may thus be seen as a consequence of ischemic or drug-induced injury, severe acute hepatitis, or allograft rejection.²⁷

Bridging fibrosis. Also referred to as septal fibrosis, this pattern designates the presence of connective tissue septa that extend across lobules and connect portal tracts and central veins in various arrangements (Figure 10-6). It represents an extension of periportal or perivenular fibrosis and, as a marker of progressive disease, is an important indicator of prognosis. Bridging fibrosis can occur in an uncomplicated form in which the hepatic architecture remains otherwise intact, but when it is diffusely distributed and associated with parenchymal nodularity, cirrhosis becomes the prime consideration.

Fibrous septa exhibit a variety of shapes and sizes, ranging from slender, well-defined bands to broad irregular collagenous zones that sometimes encompass entire lobules. Varying degrees of inflammatory infiltration and bile ductular proliferation can be noted. Based on the vascular structures involved, bridging fibrosis can be separated into portal-portal, portal-central, and central-central types. Although this classification is conceptually valuable, the nature of a fibrous bridge can be difficult to determine in biopsy specimens, especially in advanced cases with mature fibrosis. In addition, more than one type can sometimes be present, and the distinction then becomes arbitrary.

Portal-portal bridging fibrosis results from the progression of portal and periportal fibrosis. Because of their arborescent architecture, enlarged portal tracts often appear in two-dimensional histologic sections to be connected, and thus portal-portal bridges are a common feature in any disorder associated with portal expansion. They are an especially prominent feature, however, in two settings, biliary fibrosis and hemochromatosis. Biliary fibrosis is further distinguished by chronic cholestasis, a edematous lamellar perimeter, and a jigsaw-like contour of the background parenchyma and is seen in chronic biliary processes including chronic biliary obstruction, primary biliary cirrhosis, and primary sclerosing cholangitis.²⁵ In hemochromatosis, the portal-portal bridging fibrosis is unaccompanied by inflammatory infiltration, but iron accumulation is conspicuous.

Central-portal bridging fibrosis is a consequential feature of several major hepatic disorders. It is generally considered the most important of the three types because its distribution, which corresponds to the periphery (zone 3) of the hepatic acinus, provides a microcirculatory detour and allows blood to bypass the parenchyma.^39,41 Central-portal fibrosis can develop as a complication of bridging necrosis in any condition characterized histologically by chronic active hepatitis, including viral, autoimmune, and drug-related varieties, Wilson's disease, and alpha-1-antitrypsin deficiency as well as primary biliary cirrhosis and primary sclerosing cholangitis (Figure 10-7). Central-portal fibrous bridges are also a central feature of the advanced stages of steatohepatitis, and in both settings, comprises the anatomic basis for progression to cirrhosis.¹⁷

Central-central bridging fibrosis develops by the expansion of centrilobular fibrosis and is most clearly evident in severe instances of chronic venous outflow obstruction. It occurs more often, however, in conjunction with portal-central fibrosis and may therefore be seen with chronic active hepatitis or steatohepatitis.

Other forms of fibrosis. Small fibrotic foci within the parenchyma can result from the healing of epithelioid granulomas or lipogranulomas.²¹ In addition, irregular fibrous scarring can complicate any large localized necrotic lesion; included are various types of infarction, pyogenic abscesses, other infectious processes such as tuberculomas or gummas, and metastatic neoplasms following treatment by chemotherapy or irradiation.^36,40

Fibrosis can also be noted in several hepatic neoplasms and tumor-like conditions and is a regular feature of bile duct adenomas, focal nodular hyperplasia, and the fibrolamellar variant of hepatocellular carcinoma.

Cirrhosis is a generic designation for chronic end-stage liver disease, and it represents the final sequela of many different hepatic insults. One of the leading causes of nonmalignant death in the Western world, particularly among young and middle-aged adults, cirrhosis has an annual incidence estimated at between 150 and 250 per million with an overall prevalence appraised at approximately 0.5.^51,65,85

As a morphologic rather than clinical entity, cirrhosis can be best defined as a diffuse process of architectural disorganization characterized by fibrosis and the formation of structurally abnormal parenchymal nodules.^52,83 This definition encompasses a broad spectrum of appearances and disorders, but reorganization of the normal lobular and vascular architecture of the liver is the basic theme. One consequence of this structural derangement is that, for all practical purposes, cirrhosis is irreversible. Rare exceptions to this rule have been reported, but these cases are subject to challenge.

The three defining features -- diffuse distribution, fibrosis, and parenchymal nodules -- serve to distinguish cirrhosis from conditions with similar appearances but different implications. In this context, a diffuse distribution refers to involvement of the entire liver, and therefore localized lesions such as focal nodular hyperplasia do not qualify as cirrhosis. In addition, cirrhosis is differentiated from disorders with fibrosis but no nodularity, such as congenital hepatic fibrosis, and disorders with nodularity but no fibrosis, such as nodular regenerative hyperplasia. These conditions may produce portal hypertension, but, unlike cirrhosis, they do not generally lead to hepatocellular dysfunction and therefore are designated differently.

From a pathogenetic perspective, cirrhosis reflects the complex interplay of fibrosis and hepatocyte regeneration as modified by ongoing parenchymal injury and inflammation. The initiating process in most instances entails hepatocyte necrosis, but chronic sustained damage is generally required since cirrhosis does not usually follow single episodes of extensive hepatic necrosis.^69,71 Depending on the exact cause, persistent liver cell injury is eventually complicated by the development of fibrosis, and this has several important consequences for the further evolution of the disease. In addition to directly disrupting the hepatic architecture, fibrosis at the level of the central veins, the sinusoids, or the portal vessels interferes with normal hepatic hemodynamics. This results in portal hypertension, portosystemic shunting, and a diminution of the effective parenchymal mass.^41,67,83 Furthermore, the accumulation of connective tissue within the space of Disse can impede the normal metabolic traffic between blood and hepatocytes, impairing the clearance of circulating macromolecules, disturbing the intercellular interactions, and resulting in liver cell dysfunction.^42,82

The additional pathogenetic element in cirrhosis is the regenerative hyperplasia of hepatocytes. This process is usually viewed as an attempt to restore parenchymal integrity, but it also contributes to the nodularity and overall architectural disorganization of cirrhosis. The proliferative capability of hepatocytes, despite its notoriety, is poorly understood, and the responsible mechanisms are being vigorously explored.⁶³ The normal regulation of hepatocyte growth appears to be controlled by various circulating growth factors, at least twenty of which have been described. Particular interest is directed at hepatocyte growth factor, a potent liver cell mitogen, which is found in hepatic lipocytes but is widely distributed among many other extrahepatic cells.^72,77 Following hepatocyte necrosis, this (and perhaps other) growth factors are thought to trigger hepatocyte proliferation. Because of the disrupted vascular supply, however, this process occurs in an irregular rather than orderly fashion and results in nodular hyperplasia. The structural and functional integrity of the liver is consequentially not maintained.^56,83

Cirrhosis can result from a wide range of conditions spread across almost all pathogenetic categories . These conditions are discussed in detail in appropriate chapters. The relative frequency of the different causes varies greatly depending on geographic, epidemiologic, and demographic factors. In the United States, alcohol abuse is the most common underlying disorder, accounting for up to two-thirds of adult cases, with chronic active hepatitis and chronic biliary disorders each responsible for about 10% of cases. Biliary atresia and other forms of neonatal cholestasis are important considerations in infants and children. Many of the other causes, although of great interest, are uncommon or rare. Cirrhosis is infrequently caused by drugs other than alcohol, but occasional cases are described following treatment with methotrexate, methyldopa, amiodarone, and ticrynafen.^73,79

In about 10% to 20% of cases, no etiology can be defined despite appropriate investigation. These so-called cryptogenic cases may have several explanations. Some are presumably examples of chronic active hepatitis in which serologic markers are missing or have disappeared, as may occur in some late-stage cases of chronic hepatitis B, others likely inactive instances of alcoholic or nonalcoholic steatohepatitis, or undiagnosed cases of alpha-1-antitrypsin deficiency, Wilson's disease, or other metabolic diseases, and still others may result from yet unidentified causes.

Several classifications of cirrhosis have been proposed based on morphology, pathogenesis, or clinical features, but none is entirely satisfactory in expressing the cause, rate of progression, and prognosis of the disease.^52,64,83,84 The etiology of the cirrhosis is obviously an important consideration and represents a logical foundation for primary classification. Unfortunately, the cause is difficult to establish in some cirrhotic livers, and, in other cases, multiple etiologic factors may be responsible. Moreover, the outcome of cirrhosis is often dictated by clinical and functional consequences that are largely independent of etiology.

Another widely employed classification relies on morphologic appearance and, based on the diameter of the parenchymal nodules, divides cirrhosis into three categories: micronodular cirrhosis, macronodular cirrhosis, and mixed cirrhosis.⁵² This categorization, however, suffers from several limitations. Because cirrhosis is a dynamic evolving process, nodular size is not a static features but varies over time. For example, alcoholic cirrhosis is the prototype of micronodular cirrhosis, but nearly half the cases convert to a macronodular pattern when followed over a three-year span.^62,66 The three patterns therefore correlate poorly with the clinical course or etiology; the same pattern can result from a variety of underlying conditions, and, conversely, a single causal agent can yield several morphologic patterns. This categorization is thus more useful as a descriptive terminology than as a basic classification of cirrhotic livers.

The clinical manifestations of cirrhosis encompass a wide spectrum of alterations, reflecting both the nature of the responsible cause and the development of secondary complications. At one end of the spectrum are patients with well compensated disease and few identifiable abnormalities. Some affected individuals are asymptomatic and are recognized only because of abnormal liver function tests or unexplained hepatosplenomegaly, and others exhibit nonspecific constitutional complaints such as weight loss, fatigue, anorexia, and fever.^68,94 Depending on the cause, a variety of additional suggestive findings may be present; examples include xanthomas in primary biliary cirrhosis, Kayser-Fleischer rings in Wilson's disease, or distinctive cutaneous pigmentation in hemochromatosis.

Stronger indications of cirrhosis are found in its advanced decompensated form and derive from the two major complications, hepatic failure and portal hypertension. In hepatic failure, the reduction in functional parenchyma can lead to severe jaundice resulting from the disruption in bilirubin metabolism, coagulopathy and ascites due to inadequate synthesis of clotting factors and albumin, and hepatic encephalopathy presumably reflecting deficient inactivation of metabolites toxic to the central nervous system. In addition, impaired handling of hormones is implicated in such findings as gynecomastia, hypogonadism, diabetes, and spider angiomas. Portal hypertension and the ensuing portosystemic shunting contribute to encephalopathy and ascites, encourage the development of esophageal and gastric varices with the risk of hemorrhage, and produce splenomegaly and hypersplenism, which may lead to anemia, leukopenia, and thrombocytopenia. In addition, various extrahepatic manifestations may develop, including renal failure, pulmonary and cardiac alterations, peptic ulcers, and gallstones.⁵⁹

A provisional diagnosis of cirrhosis can often be made on a combination of clinical history, physical examination, and laboratory data. Additional biochemical tests may be required to determine the cause. Depending on the setting, these tests can entail hepatitis B or C virus markers, antinuclear or antimitochondrial antibody titers, serum iron and ceruloplasmin levels, alpha-1-antitrypsin determinations, serum iron and transferrin concentrations, and determinations of various metabolic products. On occasion, noninvasive imaging techniques such as ultrasonography, scintigraphy, and computed tomography provide useful information, although their overall role is limited.⁵⁹ Liver biopsy is the ultimate diagnostic procedure, but it is not always conclusive and must be interpreted in light of the clinical situation.

The evolution and outcome of cirrhosis varies greatly depending on its cause, severity, and therapeutic responsiveness. The typical course is one of progressive decompensation with death following from worsening hepatic failure and variceal bleeding, although the progression of the disease may be slowed by appropriate therapy.⁶⁰ To gauge the outcome, numerous prognostic indices have been proposed, some of them generally applicable to cirrhosis whereas others are pertain to particular disorders. Although the specifics vary among the various schemes, advanced age, marked ascites, prolonged prothrombin time, severe hyperbilirubinemia, and the presence of encephalopathy or gastrointestinal hemorrhage tend to be associated with a poor prognosis.^70,88

An additional issue is the development of hepatocellular carcinoma. This complication has been reported with almost all types of cirrhosis, but it is particularly associated with hepatitis B and C, hemochromatosis, and alpha-1-antitrypsin deficiency and is less common with primary biliary cirrhosis or autoimmune chronic active hepatitis.^55,57,80

The treatment of cirrhosis is primarily directed at preventing and managing the complications of variceal hemorrhage and encephalopathy. In certain underlying conditions, more specific measures can be employed: abstinence in alcoholic cirrhosis, phlebotomy in hemochromatosis, interferon alfa in cirrhosis resulting from chronic hepatitis B or C, corticosteroids in autoimmune chronic active hepatitis, and D-penicillamine in Wilson's disease. Several studies have suggested that antifibrotic therapy with colchicine or penicillamine may be beneficial, but the efficacy of these agents is not clearly established.⁵⁸ Liver transplantation remains the final therapeutic option in cases with end-stage disease.^75,95

Pathologic Features

In accordance with its definition, cirrhosis is characterized histologically by widely-distributed fibrosis and parenchymal nodularity. These two features are combined in varying proportions, and the resulting morphologic appearances encompass a wide spectrum. On gross examination, cirrhotic livers can be normal size, enlarged, or shrunken, and their weights can range between a few hundred grams and several kilograms.

The morphologic spectrum can be divided on the basis of nodule size into micronodular, macronodular, and mixed patterns.⁵² As noted above, this scheme does not represent an ideal classification, but it is useful in indicating the morphologic range of cirrhosis. Although the assessment is straightforward at autopsy or with large specimens, it is more difficult and less accurate with needle biopsy specimens.

Micronodular cirrhosis is characterized by a preponderance of uniform small nodules of less than 3 mm diameter and is usually accompanied by narrow, regular fibrous septa (Figure 10-8). Although 3 mm is the commonly cited maximum diameter, other standards are proposed ranging from 1.5 mm to 10 mm.^63,66 This pattern has also been referred to as portal, nutritional, regular, or monolobular cirrhosis and generally reflects pathogenetic processes that act uniformly across the liver. The classic examples are cirrhosis due to alcohol abuse, biliary obstruction, and hemochromatosis.

Macronodular cirrhosis has a more varied and heterogeneous appearance. The nodules generally exceed 3 mm, but their size varies greatly and they may reach several cm in diameter; the fibrosis is typically unevenly and irregularly arrayed (Figure 10-9). Synonyms include postnecrotic, posthepatitic, irregular, and multilobular cirrhosis, terms that reflect the presumed origin of the pattern through the development of large zones of parenchymal collapse. Macronodular cirrhosis is therefore usually associated with cirrhosis resulting from chronic active hepatitis, including hepatitis B and C, Wilson's disease, and alpha-1-antitrypsin deficiency. In some cases, large poorly-demarcated nodules are associated with thin, delicate fibrous septa to yield a type of macronodular cirrhosis known as incomplete septal cirrhosis (Figure 10-10). The variant shares several clinical and histologic features with hepatoportal sclerosis and nodular regenerative hyperplasia, and their differentiation can be a problem in individual cases.^54,90

The mixed pattern encompasses those cases with approximately equal contributions of both macronodules and micronodules.

The fibrosis of cirrhosis is primarily represented by bridging connective tissue septa that separate the liver into parenchymal nodules. The topographic configuration of the fibrous bridge can be discerned in some cases, particularly when trichrome or elastic tissue stains are employed, but in well-established cirrhosis, the pattern is often obscured by the continued architectural derangement. The septa vary considerably in breadth and extent, and they contain inflammatory cells and arterial, venous, and biliary structures in varying numbers (Figure 10-11). As viewed in two-dimensional sections, the fibrosis typically surrounds the nodules completely, but in cases of incomplete septal cirrhosis, partial encircling can be noted.

Histologic patterns of fibrosis other than bridging fibrosis can also be encountered in cirrhosis. Often these patterns are incorporated into the diffuse scarring and cannot be separately distinguished. On occasion, however, they point to the underlying disease, for example, with pericellular fibrosis and steatohepatitis.

Parenchymal nodules derive from variably sized portions of single or multiple preexisting lobules that are altered to some degree by hepatocyte regeneration.^41,92 The nodules are distinguished not only by their fibrous circumscription but by their lack of normal lobular architecture. This trait is most obvious in smaller nodules in which portal tracts and central veins are completely absent (Figure 10-12). Larger nodules, however, often do contain residual or newly-formed vascular structures, and the features of architectural disruption are then more subtle. The vascular structures often do not exhibit normal spatial relationships but are arranged in an irregular haphazard fashion, the central vein-like channels are present in excessive numbers, and the portal tracts are often abnormally small (Figure 10-13 and 10-14).

In addition, evidence of hepatocyte regeneration can be identified in the form of thickened hepatic plates. Normally the plates are formed from a single row of hepatocytes, but with regenerative hyperplasia, their width increases to two or more cells (Figure 10-15). This finding is less helpful in children, however, since twin-cell plates are the rule until about six years of age. In addition, thickened hepatic plates are not a consistent or uniformly distributed feature of cirrhosis, and their absence therefore does not exclude the diagnosis. The regenerative activity can lead to differential hepatocyte growth with irregularities in the orientation of the hepatic plates and zones of compression as one group of hepatocytes expands at the expense of others. The various architectural alterations can be easily overlooked and mistaken for normal liver histology, but reticulin stains are of great aid in their recognition.

One source of diagnostic difficulty is posed by cases with extensive fibrosis but less-than-complete architecture distortion. Certain diseases such as primary biliary cirrhosis progress unevenly across the liver, so that some areas may demonstrate established cirrhosis whereas others display better preserved structure. These cases are best designated by terms such as early or developing cirrhosis that indicate the serious but incompletely evolved nature of the disorder.

An analogous problem arises with the advanced stages of hemochromatosis, chronic biliary obstruction, and chronic venous outflow obstruction. In these disorders, bridging fibrosis connecting portal tracts (as with the first two conditions) or central veins develops, but often the lobular structure remains otherwise intact until late in the course (Figure 10-16). By strict criteria, these cases do not qualify as cirrhotic, but they are frequently labelled as such; because of their potential reversibility, a term such developing cirrhosis may again be more applicable.^25,53,96

The activity of the cirrhosis is defined in histologic terms by the extent of ongoing hepatocyte injury and inflammation. These changes can adopt several forms depending on the nature of the process. Any cirrhosis derived via the chronic active hepatitis pathway can exhibit piecemeal necrosis and intranodular necrosis of varying degree and extent (Figure 10-17). Persistent steatohepatitis can be identified with active alcoholic cirrhosis, and chronic cholestasis as evinced by periseptal liver cell swelling and mixed inflammatory infiltration may contribute to the histologic activity of chronic biliary disorders such as primary biliary cirrhosis (Figure 10-18). The degree of histologic activity provides a rough indication of the tempo of disease progression and is accordingly a useful prognostic feature in several settings.^61,76,81

A host of secondary features can also be noted in cirrhotic independent of its etiology. These include canalicular cholestasis, ductular cholestasis, coagulative necrosis of parenchymal nodules, and focal obliteration and recanalization of small hepatic veins.⁷⁸ Minor degrees of copper accumulation can also be noted, although more substantial deposition points to specific conditions such as Wilson's disease or chronic biliary disorders.⁹¹ Similarly, excessive iron accumulation is characteristic of hemochromatosis, but can rarely develop following portocaval shunt procedures.⁷⁴ Liver cell dysplasia and macroregenerative nodules have a presumed preneoplastic connotation and are discussed in Chapter 15.

Etiologic considerations. Cirrhosis is, by its very nature, end-stage disease, and the underlying cause cannot always be discerned on histologic grounds, particularly in advanced cases. Nonetheless, certain histologic clues to etiology can sometimes be recognized. At times, they indicate a specific diagnosis, but more often they help distinguish various causes and point to additional clinical and laboratory investigation that might be of value. A diagnosis of cryptogenic cirrhosis should only be made after all pertinent data have been assessed.

The overall configuration of the cirrhosis is distinctive in some situations. A biliary pattern of cirrhosis develops through progressive portal fibrosis and formation of portal-portal fibrous bridges, leaving irregular islands of parenchyma with a geographic or jigsaw configuration (Figure 10-19).²⁵ In the developing stages, the lobular architecture remains relatively intact, and central veins are found in their usual positions within the centers of the nodules. Ultimately, true parenchymal nodules with disrupted architecture develop. The periphery of the nodules shows features of chronic cholestasis, including swollen hepatocytes with copper deposition and occasional Mallory bodies. This pattern is noted with chronic biliary obstruction, primary biliary cirrhosis, primary sclerosing cholangitis, and the other rare causes of bile duct destruction and loss (Chapter 5).

Hemochromatosis is another condition that gives rise to portal-based fibrosis and progresses by portal-portal bridging fibrosis. As with biliary cirrhosis, the hemochromatosis pattern is characterized by initial preservation of lobular structures, but eventually architectural abnormalities supervene. The additional clue to the correct diagnosis is the marked accumulation of hepatocellular iron, often with a portal-central distribution gradient.

An analogous but inverted situation is noted in the congestive pattern of cirrhosis resulting from chronic venous outflow obstruction. This pattern evolves via centrilobular fibrosis and the formation of central-central fibrous bridges. Normal lobular architecture again persists until late in the course, although in this case, the appearances are reversed: intact portal tracts are present within the centers of the evolving nodules (Figure 10-20).

Other etiologic clues are provided by the ongoing features of the antecedent disorder. These are noted in Table 10-1 and discussed in detail in appropriate sections of the book.

Biopsy interpretation. The pathologist has several tasks when confronting cirrhosis: affirming the diagnosis, assessing the histologic activity and stage of the process, and searching for etiologic clues. When possible, the morphologic subtype can be noted, but this has limited utility and is less important than the other evaluations.

The ease with which cirrhosis can be diagnosed depends on the size of the specimen; the smaller the specimen, the more difficult the diagnosis. With surgical wedge biopsies, cirrhosis is readily recognized, although care must be taken not to overinterpret prominent subcapsular fibrosis. Needle biopsy specimens, however, pose a greater problem; they are smaller in width than many parenchymal nodules and frequently do not sample fibrosis well.

The diagnosis is virtually guaranteed if several well-defined nodules completely surrounded by fibrous tissue are found (Figure 10-21). Many biopsies, however, lack these overt features and the correct diagnosis may be missed if they are the sole criteria employed. Attention must then be give to less striking abnormalities. Although these changes do not always provide an unequivocal diagnosis, they are useful in suggesting the possibility of cirrhosis, and depending on one's degree of suspicion and confidence, a diagnosis of probable or possible cirrhosis can generally be advanced. As always, correlation with clinical information is necessary.^53,86,89

A common clue on low-power examination is fragmentation of the specimen, which results because the softer parenchyma is preferentially retrieved by the biopsy needle. The individual fragments exhibit rounded contours and thin peripheral rims of fibrous tissue that are best appreciated on trichrome or reticulin stains (Figure 10-22). Other suggestive changes involve abnormalities in the lobular architecture including aberrant spacing of portal tracts and central veins, a disproportionate number of central veins, or an absence of vascular structures. Regenerative hyperplasia may also be evident as demonstrated by thickened hepatic plates with disordered orientation, and hepatocyte populations that vary in size and appearance (Figure 10-23). Some liver cells may appear dysplastic and display enlarged atypical nuclei, particularly in cirrhosis caused by the hepatitis viruses.

Differential diagnosis

The differential considerations of cirrhosis include those conditions that share one or another of the features of cirrhosis but lack the entire constellation of findings.

Congenital hepatic fibrosis exhibits portal fibrosis and portal-portal fibrous septa, but, unlike cirrhosis, the lobular architecture is preserved and the septa contain irregular dysmorphic bile ducts and little inflammation.

Nodular regenerative hyperplasia is characterized by multiple parenchymal nodules without fibrosis. This provides a clearcut difference with cirrhosis, but the distinction may be difficult with needle biopsy specimens. Fibrosis may not be adequately disclosed by the specimen, and the nodules display similar architectural and regenerative features in either condition. However, other clues to fibrosis, such as fragmentation of the specimen, can be of help.

In hepatoportal sclerosis, the histologic features include portal and periportal fibrosis, sclerosis of the intrahepatic portal vein branches, and occasional nodular regeneration of hepatocytes. Typically these changes are unevenly distributed across the liver, but, depending on the sampling, the appearances may be difficult to distinguish from cirrhosis in biopsy specimens. The features in some instances merge with those of incomplete septa cirrhosis, and the two conditions have been suggested to form a clinicopathologic spectrum.⁹⁰

Portal hypertension, one of the main complications of cirrhosis, is also the chief clinical manifestation of all three of the above disorders. Biopsy specimens obtained because of portal hypertension should therefore be carefully and specifically examined to exclude the three before a diagnosis of cirrhosis is rendered. This distinction is of practical importance because they are not associated with hepatic failure and thus display a better prognosis and more favorable outcome following portosystemic shunt procedures than does cirrhosis.

Examples of bridging fibrosis unaccompanied by parenchymal nodularity are sometimes uncritically diagnosed as cirrhosis, but the distinction between the two should be maintained. The discrimination is based on an assessment of the underlying architectural features; when normal lobular landmarks can be identified, cirrhosis is not present. In needle biopsy specimens the distinction is not always straightforward, and a designation as possible or early cirrhosis may be appropriate.

Confluent hepatic necrosis of any cause can produce an appearance that resembles cirrhosis: islands of surviving parenchyma are variably surrounded by zones of connective tissue. However, the acute nature of the necrosis is usually apparent by the lack of mature fibrosis, and well-defined parenchymal nodules are not present. The use of elastic tissue stains may also be helpful; elastic tissue develops within fibrous septa but is not found in recent parenchymal collapse.^87,93

Normal liver is another differential problem in cirrhosis. Some biopsy specimens from cirrhotic livers may be surprisingly normal appearing, and only the minor architectural changes noted above can be found. Before making a diagnosis of normal liver, particularly when the clinical setting suggests chronic disease or portal hypertension, give some thought to such conditions as cirrhosis, nodular regenerative hyperplasia, and hepatoportal sclerosis, as the alterations may easily be missed.

Nodular regenerative hyperplasia is defined by diffuse parenchymal nodularity in the absence of accompanying fibrosis. Several additional names, all focusing on the same essential morphologic changes, have also been applied to the condition, including nodular transformation, micronodular transformation, and diffuse nodular hyperplasia.^110,112,115 In addition, some cases reported as liver adenomatosis or multiple hepatic adenomas likely represent the same disorder.^98,99

Most cases occur in adults between 50 and 70 years of age, although occasional examples are also described in children, and men and women are affected about equally.^97,101,110 In autopsy series, the prevalence is estimated as high as 2.6%, but most of these cases are asymptomatic and not associated with clinical disease.^102,112 The prime manifestations include hepatomegaly, splenomegaly, and evidence of portal hypertension with esophageal varices and ascites. In rare cases, larger nodules have ruptured and produced hemoperitoneum. Serum alkaline phosphatase levels can be mildly elevated, but serum transaminase levels are usually normal.^97,110 The natural history of nodular regenerative hyperplasia is not well defined, although, in contrast to cirrhosis, hepatic decompensation rarely develops.

A notable feature of nodular regenerative hyperplasia is its association with a wide and ever-growing group of extrahepatic diseases and therapeutic agents . Although their etiologic roles are not well understood, the associated conditions include various immunological disorders, hematopoietic and lymphoproliferative diseases, renal and bone marrow transplantation, and treatment with several immunosuppressive or chemotherapeutic agents.^{100,107,109,111,113,116}

The pathogenesis is likewise not well understood, but the leading proposal suggests that the nodules arise because of irregularity in the hepatic blood flow; poorly-perfused parenchymal areas become atrophic and the better supplied neighboring zones undergo compensatory hyperplasia evinced by nodularity.^105,112,113 The reason for the uneven perfusion probably varies among cases, but obliteration of intrahepatic portal vein branches is suggested as a common underlying factor. This concept is supported by morphometric studies showing a decrease in portal venular size, but corresponding histologic lesions are not regularly identified. Alternately, nodular regenerative hyperplasia has been suggested to represent a neoplastic process.¹¹⁰

On gross examination, multiple pale or tan nodules are scattered throughout the liver, and the appearances may be mistaken for metastatic neoplasms or cirrhosis. These nodules usually measure between 1 mm and 3 mm in diameter, although they occasionally range up to several cm. Histologically, the nodules are composed of hyperplastic hepatocytes arranged in thickened and irregularly oriented hepatic plates (Figure 10-24). They grow in an expansile but non-encapsulated fashion, compressing the surrounding liver cells and central veins and impinging on adjacent nodules. Sinusoidal dilatation and congestion may outline the nodular periphery.

The nodules develop in a background of preserved hepatic architecture. The smaller lesions are distributed in the periportal regions, and the coalescence of neighboring nodules gives rise to the larger lesions, which thus sometimes contain recognizable portal tracts or central veins. Otherwise the portal areas are usually unremarkable, although thrombosis or sclerosis of the portal vein radicles is occasionally noted. The hyperplastic hepatocytes resemble normal liver cells; they may be enlarged and exhibit pale-staining cytoplasm because of glycogen or fat accumulation, but lipofuscin pigment is usually absent (Figure 10-25). Cholestasis and nodular hemorrhage or necrosis are rare complications, and the development of hepatocellular carcinoma is an extraordinary occurrence.^108,110

Nodular regenerative hyperplasia is a histologic diagnosis usually requiring a surgical wedge biopsy specimen, although sometimes a needle biopsy specimens suffices.¹⁰⁴ The nodularity may be subtle, particularly with smaller nodules, and is apt to be missed; maintaining an appropriate suspicion whenever a normal-appearing biopsy is encountered is the key to the diagnosis. Reticulin stains are diagnostically invaluable in demonstrating the nodules and illustrating the thickened cell plates and compressed internodular zones (Figure 10-26a, 10-26b). Since regenerative hepatocytes express alpha-1-antitrypsin, immunostaining for this substance can also be helpful; the staining has a diffuse cytoplasmic distribution, unlike the globular pattern seen with alpha-1-antitrypsin deficiency.¹⁰³

Cirrhosis is distinguished from nodular regenerative hyperplasia by the presence of fibrosis, but this distinction can be a problem with needle biopsy specimens that have failed to provide an adequate sampling of the connective tissue. Hepatoportal sclerosis is characterized by obliterative changes in the portal veins, sometimes associated with thin septa extending from the portal tracts. Although these changes may permit a distinction from nodular regenerative hyperplasia, there is histologic overlap between the two conditions: occlusive portal vein lesions have been reported in nodular regenerative hyperplasia and hyperplastic parenchymal nodules can be seen in hepatoportal sclerosis. The suggestion is therefore advanced that they form a clinicopathologic continuum with incomplete septal cirrhosis, and their separation in individual cases may be arbitrary.⁹⁰

The term partial nodular transformation refers to the presence of parenchymal nodules, 3 to 40 mm diameter, located predominantly in the perihilar area.¹⁰⁶ The nodules are composed of hyperplastic hepatocytes and resemble those of nodular regenerative hyperplasia, although peripheral fibrosis or central scars are sometimes noted. Because of their clinical and pathologic similarities, partial nodular transformation has been considered a type of nodular regenerative hyperplasia that develops from thrombosis or obstruction of the extrahepatic and large intrahepatic portal veins.¹¹⁴