Cirrhosis

CHAPTER 42

Cirrhosis IAN R. WANLESS • JAMES M. CRAWFORD

Definition

Etiology

Pathogenesis

Chronic Hepatitis

Collagen in the Liver

Fatty Liver Disease

Hepatic Arterialization and “Capillarization”

Chronic Biliary Diseases in Adults

Parenchymal Extinction

Biliary Diseases in Pediatric Patients

Shunt Formation

Metal Overload States

Congestive Hepatopathy

Congestive Cirrhosis

Vascular Thrombosis

Drug-Induced Cirrhosis

Regeneration

Diagnosis

Natural History and “Reversibility” of Cirrhosis

Types of Biopsy and Technical Issues

Anatomic Classification and Pathology

Role of Biopsy

Macroscopic Features

Staging Systems

Microscopic Features

Diagnostic Pitfalls

Unusual Variants

Pitfalls in Assessing Fibrosis

Differential Diagnostic Considerations

Pitfalls in Diagnosing Cirrhosis 1115

1116 PART 3 LIVER Cirrhosis is an important cause of morbidity and mortality. In the United States, cirrhosis is the 12th leading cause of death1 and is reported on hospital discharge in at least 1% of adult patients.2 It is found in 4% to 12% of patients at autopsy in developed countries.3-5 Cirrhosis is the morphologic result of many different types of chronic insult to the liver. It may develop rapidly over a period of months, but most often it is a product of many years of chronic injury. The causes include alcohol toxicity, chronic viral or autoimmune hepatitis, biliary obstruction, and a variety of metabolic abnormalities. Cirrhosis is defined by the presence of certain anatomic abnormalities of liver structure. However, a presumptive diagnosis of cirrhosis can often be made when certain clinical consequences of cirrhosis are found. These consequences may be mechanical, functional, or neoplastic. The mechanical effects are related to obstruction of blood flow in the liver that leads to increased pressure in the splanchnic veins and a high risk for rupture of esophageal varices. Obstruction progresses gradually as cirrhosis develops but may worsen suddenly after thrombosis of the portal vein. Obstruction is associated with opening of multiple intrahepatic and extrahepatic collateral channels that allow shunting of splanchnic blood past the hepatic parenchyma. Hepatic functional deficits are, in part, related to this portosystemic shunting but also to loss of hepatocellular mass and intracellular retention of bile salts and other toxic substances. Many of the clinical effects of cirrhosis are found in other organs. Renal and pulmonary failure may occur secondary to the systemic hemodynamic response to cirrhosis. Hemorrhage may occur because of platelet dysfunction, platelet sequestration in the spleen, and decreased synthesis of proteins of the coagulation cascade. Neoplasia is a not infrequent late occurrence in patients with cirrhosis. The lifetime risk of hepatocellular carcinoma exceeds 50% in patients with some forms of cirrhosis. Cholangiocarcinoma may be a late complication of extrahepatic biliary disease. Hence, the development of cirrhosis, and its consequences, is of concern in every form of chronic liver disease.

FIGURE 42-1 Macroscopic appearance of cirrhosis caused by hepatitis B virus. This view from the back shows a coarsely nodular capsular surface, shrinkage of the right lobe, and compensatory hypertrophy of the left lobe.

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Definition Cirrhosis is defined anatomically by the presence throughout the liver of fibrous septa that subdivide the parenchyma into nodules (Fig. 42-1).6-8 Several features in this definition should be emphasized. 1 The entire liver must be involved. Occasionally, a focal injury to the liver may cause changes that are histologically similar to cirrhosis, for example, in focal nodular hyperplasia and in liver parenchyma adjacent to neoplasms, abscesses, and other mass lesions. Because these conditions do not have clinical

5

manifestations of cirrhosis, the term focal cirrhosis may be misleading and should be avoided. The fibrous scarring may be in the form of delicate bands connecting portal tracts and centrilobular terminal hepatic veins in a portal to portal, portal to central, and/or central to central pattern, or they may occur as broad fibrous tracts that obliterate multiple adjacent lobules. Parenchymal nodules are created by fibrotic isolation of islands of hepatic parenchyma. The regenerative response of hepatocytes may produce a spherical conformation to these nodules. However, regeneration and formation of spherical nodules are not required for the definition of cirrhosis; subdivision of the liver by fibrous tissue is required. Cirrhotic livers may appear in different forms that can be traced to a small number of potential variables. These include the specific location within the liver microvasculature of the etiologic injury, the tempo and duration of the disease, and the presence or absence of an inactive period prior to histologic sampling. In the last instance, substantial remodeling of fibrous tissue may occur over time, which can obscure the architectural pattern of the initial injury. Although there are many possible types of injuries to the liver, only those with certain characteristics result in cirrhosis. The injury must not be too severe, otherwise the liver fails quickly and the patient dies, or undergoes a liver transplant, before there is sufficient development of fibrosis and architectural remodeling. Thus, an acute overdose of acetaminophen causes severe hepatic necrosis and may kill the

CHAPTER 42 CIRRHOSIS patient but it will not produce cirrhosis in those who survive. Submassive hepatic necrosis, with healing, may produce deep scars within the liver that on regeneration of residual liver tissue can lead to hepar lobatum, a misshapen liver that also is not cirrhotic. Rather, it is the process of repeated minor injuries with progressive damage that more typically leads to cirrhosis. The progression of chronic liver disease is highly variable. In fact, the point at which a liver becomes cirrhotic is rather subjective and is a frequent source of interobserver disagreement. Establishing cirrhosis on the basis of percutaneous needle biopsy sampling (which represents less than 1/10,000 of the liver mass) may be difficult, particularly if fibrous septa are widely spaced or have regressed. Fortunately, clinical data often provide valuable guidance as to whether any abnormal findings observed in percutaneous liver biopsy tissue are representative of the entire liver. Supporting clinical data include physical examination (e.g., ascites, caput medusae, spider angiomas, gynecomastia) and impressions gained from imaging studies or intraoperative visualization of the organ. Laboratory data may not reveal abnormalities, in that serum levels for albumin, clotting factors, urea, alkaline phosphatase, aminotransferases, and bilirubin may be normal in a patient who has quiescent cirrhosis with minimal ongoing damage and who has not yet developed hepatic failure. Conversely, a patient with massive hepatic necrosis and hepatic failure is not cirrhotic, despite profound abnormalities in the above serum parameters. Hence, laboratory data, per se, do not establish a diagnosis of cirrhosis. Occasionally, a severe focal injury to the liver results in focal histologic changes indistinguishable from cirrhosis on percutaneous needle biopsy; this focal change is not considered true cirrhosis. When this question arises, having definitive information from clinical evaluation, and from imaging studies, on the general status of the liver, or a biopsy sample from elsewhere in the liver, is critical to determine whether a fibrotic process is focal or diffuse.

Pathogenesis The elements in the definition of cirrhosis are used by pathologists to recognize cirrhosis, but the definition does not rely on understanding its pathogenesis. Liver cirrhosis is not, strictly, the end stage of hepatic scarring. Rather, it is a dynamic, biphasic process dominated on the one hand by progressive parenchymal fibrosis and on the other by severe disruption of vascular architecture and distortion of the normal lobular architecture. The main anatomic elements (Table 42-1) include deposition of collagen in the parenchyma and portal tracts, arterialization of parenchymal sinusoids, obliteration of small hepatic and portal veins

1117

TABLE 42-1 Pathobiology of Cirrhosis Deposition of collagen Portal tract Parenchymal (sinusoidal) Arterialization of parenchymal sinusoids Obliteration of portal veins and hepatic veins Parenchymal extinction Vascular pathophysiology Shunt formation Congestive hepatopathy Vascular thrombosis Hepatocyte regeneration Resorption of fibrous tissue “Reversal” of cirrhosis

with resultant loss of hepatocytes through a process called parenchymal extinction, abnormal vascular physiology, and regeneration of hepatocytes. Although the importance of these elements is widely appreciated, there is controversy concerning the role of each in the pathogenesis of cirrhosis.7,9-11 The concepts thought to be operative in the genesis of cirrhosis of any cause are summarized here.9 A discussion of the causes of hepatocellular death is beyond the scope of this chapter.

COLLAGEN IN THE LIVER Collagen accumulation is a prominent feature of cirrhosis. In the normal liver, collagen types I and III are concentrated in the portal tracts and around terminal hepatic veins, with occasional bundles located between hepatocytes and endothelial cells in the space of Disse. Strands of type IV collagen (reticulin) are present in the space of Disse, where they form a delicate and uniform network that supports the liver cell plates. In cirrhosis, excessive types I and III collagen are deposited in the portal tracts, along individual liver cell plates in the spaces of Disse, and in regions of necroinflammatory collapse. A variety of noncollagenous matrix proteins are also deposited in the space of Disse. In cirrhosis, collagen, glycoproteins, and proteoglycans can increase severalfold.12 On a percent area basis, total extracellular matrix components can increase from 5% in normal liver to 25% to 40% in cirrhosis.13 Some of this is an apparent increase only because condensation of the normal structural collagen, and other matrix components, occurs during parenchymal collapse and extinction. The two main cell types that synthesize collagen in the liver are hepatic stellate cells10 and portal fibroblasts.14 Hepatic stellate cells reside in the subendothelial space of Disse in the sinusoidal walls. They are normally distended

1118 PART 3 LIVER with fat globules containing retinoyl esters and other fatsoluble vitamins. During hepatic injury, stellate cells are stimulated by inflammatory mediators to become myofibroblasts: they lose their fat globules, express α-smooth muscle actin in the cytoplasm, and commence proliferation and collagen synthesis. Stellate cell activation and sinusoidal fibrosis are readily reversible within weeks of cessation of injury.8 When stellate cells are activated in chronic low-grade disease, the liver cell plates are able to maintain their structure while collagen is deposited in the space of Disse, giving an appearance known as pericellular fibrosis or sinusoidal fibrosis. This type of delicate collagen is most easily appreciated in the perivenular regions (Rappaport zone 3). With time, collagen is deposited along the entire length of the sinusoid. Alternatively, widespread injury to hepatocytes, as with alcoholic hepatitis or some forms of drug injury (e.g., amiodarone), may activate stellate cells throughout the liver, leading to extensive deposition of sinusoidal collagen. In either instance, the total matrix in the space of Disse increases and changes from one that contains delicate interspersed strands of fibrillar collagen (types III and IV) to one composed of a dense matrix of basement membrane–type matrix proteins, which closes the space of Disse to protein exchange between hepatocytes and plasma. In general, abnormal matrix deposition within the space of Disse occurs in those parts of the parenchyma where cell injury and inflammation are greatest. Portal tract fibroblasts differ from stellate cells in location and physiology.15-17 These cells are activated by injury within the portal tracts, particularly in biliary disease, leading to fibrosis in the region of the ducts and ductules. Peribiliary myofibroblasts are capable of rapid proliferation and deposition of collagen. As a result, fibrosis arising from biliary tract diseases can run an aggressive course, as with complete biliary obstruction seen in extrahepatic biliary atresia, in which the liver becomes cirrhotic by 9 weeks of age (see Chapter 46). At the opposite end of the spectrum is the exceedingly indolent progression of portal tract fibrosis to cirrhosis over 20 or more years in primary biliary cirrhosis (see Chapter 39). In either instance, bridging fibrous septa between portal tracts develop throughout the liver, which fulfills the criteria for cirrhosis. A curious feature of biliary-type fibrosis is that the lobular parenchyma is not induced to regenerate substantially until the liver is extensively fibrotic. Hence, biliary-type fibrosis subdivides the liver into a jigsaw-like pattern during its progression, and cirrhosis may be a very late feature in the course of the disease.

HEPATIC ARTERIALIZATION AND “CAPILLARIZATION” Arterialization of the liver in cirrhosis has been known for over a century. In 1907 Herrick perfused cadaver livers and demonstrated that resistance to flow in the hepatic

artery of cirrhotic livers was markedly decreased.18 This is documented daily by ultrasonographers when they examine patients with cirrhotic livers and find increased arterial flow in the liver, along with sluggish or even reversed flow in the portal vein. Moschcowitz first used the term capillarization to describe the light microscopic appearance of arterialization in the cirrhotic liver as a granulation tissue response, that is, arterial growth into inflamed tissue.19 Schaffner and Popper, thereafter, used the term capillarization as a constellation of ultrastructural changes, including a decrease in the number and size of sinusoidal endothelial fenestrations, loss of hepatocellular microvilli, and an increase in basement membrane material.20,21 By this definition, documentation of capillarization requires electron microscopy. Specifically, in the normal liver, sinusoidal endothelial cells lack a basement membrane and exhibit fenestrations approximately 100 nm in diameter, occupying between 2% to 3% of the area of the endothelial cell. Deposition of extracellular matrix in the space of Disse is accompanied by the loss of fenestrations in the sinusoidal endothelial cells.21 With the development of cirrhosis, the diameter of the fenestrations slightly decreases but the area occupancy (“porosity”) falls to less than 0.5%. More recently, it has been noted that the sinusoidal endothelium in severe cirrhosis may express CD34. Because this expression is a normal property of arterial endothelium, CD34 positivity may be a marker of arterialization of the sinusoids. Sinusoidal arterialization (CD34 positivity) occurs in anatomic situations similar to that of capillarization, but correlation studies have not yet been performed. Sinusoidal arterialization is sometimes accompanied by α-smooth muscle actin staining in the sinusoidal wall (Fig. 42-2). These anatomic sinusoidal changes likely have functional importance. Transformation of perisinusoidal stellate cells into myofibroblasts in thought to increase sinusoidal vascular resistance by tonic contraction of these “myofibroblasts.” Fibrosis in the perivenular region of the lobule may partially obstruct vascular outflow, creating postsinusoidal vascular resistance. This type of transformation of sinusoidal vascular channels is widely considered to be an explanation for functional deficits in blood-hepatocyte solute exchange.21-24 Rapid flow in sinusoids may represent an effective arteriovenous shunt, resulting in a further decrease in solute exchange.25 Although these effects may decrease solute transport into hepatocytes, capillarization/arterialization can also be viewed as a protective form of adaptation that allows the hepatocytes to survive in a high-pressure and high-flow environment.9 Arterialization also occurs at the level of portal tracts, where an increased number (and size) of arterial profiles is seen in a variety of conditions, including cirrhosis and in patients treated with oral contraceptives. Arterialization of small portal tracts in cirrhosis is usually accompanied by obliteration of adjacent portal veins. Portal vein loss

CHAPTER 42 CIRRHOSIS

A

B FIGURE 42-2 Activation of hepatic stellate cells. A, Normal liver, showing smooth muscle surrounding the hepatic artery in a portal tract and little immunoreactivity elsewhere. B, Evolving cirrhosis, with extensive α-smooth muscle actin immunoreactivity in the parenchymal sinusoids.

may be a result of portal tract inflammation in chronic hepatitis, or congestive changes (congestive portopathy) after hepatic venous outflow is compromised, as discussed in the next section. Obliteration of small portal veins increases presinusoidal vascular resistance for blood inflow via the splanchnic system. Hence, resistance to hepatic arterial blood flow decreases, owing to an increased arterial capacity, whereas resistance to portal vein blood inflow increases. Hepatic arterial blood pressure is sufficient to supply blood to the liver, but the low pressure of the splanchnic system is not able to overcome the pressure impedance, leading to portal hypertension.

PARENCHYMAL EXTINCTION Parenchymal extinction is defined as a focal loss of contiguous hepatocytes (Fig. 42-3). Hepatocyte apoptosis and

1119

necrosis occur in all types of liver diseases that progress to cirrhosis. The mechanisms are diverse and include lymphocyte-mediated injury, rupture of triglyceride-laden hepatocytes, bile-salt toxicity, and various metabolic stresses. Most of these injuries, if accompanied by lowgrade spotty necrosis or apoptosis, lead to local replacement and complete healing. Progressive disease occurs when these injuries are accompanied by a stromal reaction that includes deposition of extracellular matrix, increased sinusoidal vascular resistance, and obstruction of blood flow. The convergence of these injuries leads to contiguous loss of hepatocytes (see Fig. 42-3).26 These extinction lesions may involve a small portion of an acinus, larger units of one or more adjacent acini, or even a whole lobe. The contiguous cell loss is ultimately the result of focal ischemia resulting from obstruction of veins or sinusoids. Naturally, the size of extinction lesions depends on the size of the obstructed vessels. The concept of parenchymal extinction is important because it indicates that (1) parenchymal extinction is not directly caused by the initial hepatocellular injury but is an epiphenomenon caused by innocent bystander injury of the local vessels, (2) each parenchymal extinction lesion has its own natural history and may be in an early or late stage of healing, (3) cirrhosis develops simultaneous with the accumulation of numerous independent and discrete parenchymal extinction lesions throughout the liver, and (4) the form of cirrhosis is largely determined by the distribution of the vascular injury. Importantly, parenchymal extinction may progress long after cirrhosis is already established, leading to slow conversion of a marginally functional liver into an organ incapable of sustaining life. The pathogenesis of vascular obstruction depends on the size of the vessels and is detailed in Figures 42-3 and 42-4. Most small vessel obliteration is secondary to local inflammation.27,28 Although thrombosis may be important in veins of all sizes, it is especially important for blockage of large veins. Most parenchymal extinction lesions are produced by blockage of veins larger than 100 μm in diameter, because obstruction at this site cannot be easily circumvented by collateral flow within the sinusoids. Obstruction of several adjacent sinusoids is also difficult to circumvent. This, then, raises the issue of congestion, which occurs whenever blood entering the vasculature exceeds the ability of the outflow tract to carry that blood, a state of in-out imbalance. Congestion is particularly severe when there is total obstruction of the outflow tract or when there is increased inflow in the presence of partial outflow obstruction. Congestive injury is exacerbated by reactive hyperemia, shunt formation, and angiogenesis. When inflow is marked, congestion occurs even when the tissue has normal outflow capacity. Parenchymal extinction lesions are, thus, the result of local failure of the microvasculature, usually because of

1120 PART 3 LIVER

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FIGURE 42-3 Photomicrographs of chronic liver disease showing various phases of the development of parenchymal extinction in chronic hepatitis C. A, Early-stage hepatitis C showing parenchyma in the process of extinction. There is loss of contiguous hepatocytes, atrophy of some adjacent hepatocytes, close approximation of portal tracts to the hepatic vein, thickening of the hepatic vein, and obliteration of the portal veins (elastic trichrome stain). B, Early stage hepatitis C. After collapse, there is close approximation of portal tracts and hepatic veins, indicating the site of parenchymal extinction. Note obliterated hepatic vein (arrow) (elastic trichrome stain). C, Fibrous adhesions between two portal tracts (top right and bottom left) with intervening hepatic vein. The structures are closely approximated, indicating substantial loss of tissue volume. Note the fibrous intimal thickening of the hepatic vein (top right) (Masson trichrome stain). D, In late stage of cirrhosis there is active congestive hepatopathy. Shown here is congestive sinusoidal injury. In the center is a hepatic vein showing the residual vein wall as a ring of thick collagen bundles.

obstruction of hepatic veins or sinusoids. The mechanism of formation of parenchymal extinction lesions is detailed in Figures 42-4 and 42-5. In early chronic liver disease, parenchymal extinction lesions are recognized by the close approximation of the terminal hepatic vein and the adjacent portal tract (see Figs. 42-3 and 42-5). They may be difficult to recognize because damaged small hepatic veins only appear as a few collagen bundles lying adjacent to a portal tract. Parenchymal extinction lesions become more evident as they aggregate and involve larger, and more easily recognizable, hepatic veins. Parenchymal extinction lesion aggregates may be evident as two or more portal tracts bound together with an hepatic vein remnant apparent in the intervening space (see Fig. 42-2). With progression of disease there is progressive obstruction of hepatic veins and secondary arterial dilatation that causes further congestive injury in the tissue located between the lesions. This creates a self-perpetuating pathophysiology, which may eventually interconnect portal tracts throughout the whole liver.

SHUNT FORMATION When a region of parenchyma becomes extinct, it collapses so that a portal tract becomes closely associated with an adjacent terminal hepatic vein. This close approximation offers an opportunity for the artery in the portal tract to drain directly into the collapsed perivenous tissue. Often, these arteries can be seen supplying a pool of blood surrounded by atrophic hepatocytes. In older lesions, there is a well-demarcated blood-filled channel suggesting a stable high-flow and high-pressure conduit connecting a small artery to a small hepatic vein. This appearance, illustrated elsewhere,9 has been interpreted as an arteriovenous shunt. After parenchymal extinction, the formation of bona fide bridging fibrous septa between portal tracts and terminal hepatic veins enables portovenous and arteriovenous shunting through de novo vascular channels, effectively bypassing the parenchymal nodules. Shunted blood flow through the “fast” vascular channels leaves the remainder of the hepatic parenchyma almost bereft of meaningful

CHAPTER 42 CIRRHOSIS

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Tissue pressure

Progressive in-out-imbalance

PV Z1 sinusoid

9. More arterial hyperperfusion 8. More outflow block

E

7. More arterial hyperperfusion 6. More outflow block

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5. More arterial hyperperfusion 4. More outflow block

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3. Arterial hyperperfusion 2. Outflow block

B

1. Normal

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Z3 sinusoid

FIGURE 42-4 Schematic representation of the sequence of microvascular events that occur during the development of cirrhosis, shown in nine steps. 1, The normal curve has a gentle pressure gradient from portal vein (PV) to zone 3 (Z3) sinusoids, allowing antegrade blood flow in the sinusoids. 2, The earliest important lesion is obliteration of terminal hepatic venules. This causes flattening of the curve with congestive changes. 3, Reactive hyperemia (arterial dilatation) restores the pressure gradient but at a higher pressure and with more congestive changes. 4, More outflow block occurs due to further hepatic venule obliteration. 5, There is more reactive hyperemia. 6 to 9, Cycles of obstruction and increased arterial inflow lead to progressive intrahepatic hypertension. The drawings on the right (A-E) show sequential changes in a microvascular domain composed of five terminal hepatic venules (black circles) with a portal vein (blue dot) and artery (red dot). A, Normal vessels. B, The primary chronic liver disease has caused obliteration of a hepatic venule. The artery has become enlarged and other hepatic venules and the portal vein have dilated to accommodate the increased flow. C, With more hepatic venule obliteration the remaining hepatic venules, the portal vein, and the artery have dilated further. D, Rising flow has caused congestive injury to the remaining hepatic venules (congestive hepatic venopathy, open red circles) and the portal vein (congestive portal venopathy, blue dot with red circle). There is further enlargement of the artery. E, An injured hepatic venule and the injured portal vein have become obstructed. The artery has undergone growth (angiogenesis) with arterialization of the sinusoids. The overall results of these changes are progressive obstruction of portal and hepatic veins, destruction of sinusoids, arterialization, and rising intrahepatic pressure. These changes are fueled by an imbalance of hepatic artery flow entering the liver and the capacity of the liver to drain that flow (hepatic artery flow > hepatic outflow capacity). The earliest injury was caused by the primary chronic liver disease causing outflow block, but late events are caused by congestive injury resulting in progressive outflow block. (From Wanless IR: Pathogenesis of cirrhosis: The role of hemodynamic forces causing in-out imbalance and congestive injury (congestive hepatopathy). Histopathology, in press.)

blood flow.25,27 This would also help explain the increased blood flow observed in sinusoids of the cirrhotic liver, in the midst of relative underperfusion of the liver parenchyma as a whole. A remarkable fraction of nutritive blood flow may therefore pass through these intrahepatic functional shunts, contributing to ongoing hepatocellular necrosis and hence, parenchymal extinction and the generation of parenchymal extinction lesions. Unfortunately, further compression of the shunt channels by regenerating nodules maintains an increased transhepatic vascular resistance.

CONGESTIVE HEPATOPATHY Vascular injury in cirrhosis can be divided into an early primary phase, a later congestive phase, and, ultimately, vascular thrombosis. In the primary phase, venous and sinusoidal obstruction is caused by local inflammation occurring in the course of chronic hepatitis (Fig. 42-6).28 The generation of soluble proinflammatory mediators is a

powerful stimulus of fibrogenesis. However, one of the most powerful stimuli of fibrogenesis, in many organs, is the organization of exudates, especially those rich in fibrin.29-36 In the liver, this mechanism is most convincingly demonstrated by capsular fibrosis of congested livers (Fig. 42-7). This is the basis for the schematic diagram in Figure 42-8, which indicates that fibrosis can be divided into that stimulated by conventional inflammation and that stimulated by chronic edema and exudation. These two pathways may converge to generate the pattern of fibrogenesis typical of chronically injured livers. Collagen accumulation is determined by the rates of collagen synthesis and resorption (Figs. 42-8 and 42-9). Most fibrosis likely accumulates late, when congestive forces cause interstitial exudate and collagen deposition that exceeds the resorptive capacity of the liver (see Fig. 42-9). In this formulation, obstructed hepatic veins and parenchymal extinction lesions occur before septa, and before fibrosis; thus, these lesions are at the leading edge of the pathogenesis of cirrhosis.8,9,26,28,37 It can be noted that

1122 PART 3 LIVER

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FIGURE 42-5 Diagrams showing the microvasculature in chronic hepatitis with development of vascular lesions and secondary parenchymal extinction. Parenchymal extinction occurs when the microvasculature fails because of too much arterial blood flow for a progressively diminishing outflow capacity. A, Normal portal tract and adjacent hepatic venules. B, Obliteration of one hepatic venule and the portal vein has occurred in response to hepatitis. Reactive hyperemia has occurred in response to the obstruction of veins. The remaining veins are able to carry the increased flow without congestive injury. C, An additional hepatic venule has become obstructed as part of the hepatitis and the sinusoids and hepatic vein walls become more congested. D, The sinusoids decompensate; hepatocytes become atrophic and die by apoptosis. This is recognizable as a parenchymal extinction lesion as the portal tract and hepatic venules become approximated. E, A congested hepatic venule has become obstructed with increase in sinusoidal and hepatic venule congestion. Arterial twigs grow into the congested tissue, leading to arteriovenous shunting. F, Further hepatocytes are lost, and the parenchymal extinction lesion becomes larger. (From Wanless IR: Pathogenesis of cirrhosis: The role of hemodynamic forces causing in-out imbalance and congestive injury (congestive hepatopathy). Histopathology, in press.)

the preexisting structural collagen of the liver condenses during the formation of parenchymal extinction lesions and, thus, is incorporated into septa. Although this is not true “fibrosis,” the presence of such collagen is a striking feature of these lesions. In the later congestive phase of liver injury, a selfperpetuating pattern of progressive liver injury is created. Specifically, when there is in-out imbalance of blood flow, the high transmural pressure leads to edema, hemorrhage, and narrowing of venous and sinusoidal lumina followed by intimal fibrous thickening of these vessels. This injury, called congestive hepatopathy, causes a decrease in the outflow capacity of the tissue that worsens obstruction and, therefore, congestion. Thus, congestive hepatopathy establishes a positive feedback loop of progressive tissue injury.

VASCULAR THROMBOSIS An important insult is thrombosis. In angiographic and ultrasonographic studies, portal vein thrombosis has been

detected in 0.6% to 16.6% of cirrhotic patients38 and grossly visible portal vein fibrosis, or thrombosis, has been found in 39% of cirrhotic livers at autopsy.39 Venoocclusive lesions of hepatic veins less than 0.2 mm in diameter have been found in up to 74% of cirrhotic livers examined at autopsy.40-42 Obliterative lesions are found in 36% of portal veins and 70% of hepatic veins in livers removed at liver transplantation.26 The distribution of portal vein obliterative lesions is more uniform than those in hepatic veins, consistent with the concept of propagation of multifocal thrombi downstream from their site of origin. Portal vein lesions are associated with prominent regional variation in the size of cirrhotic nodules. Hepatic vein lesions are associated with regions of confluent fibrosis and parenchymal extinction. The compelling conclusion is that thrombosis of mediumand large-sized portal veins and hepatic veins is a common occurrence in cirrhosis and may represent a final common pathway for the propagation of parenchymal extinction to full-blown cirrhosis. Furthermore, cir-

CHAPTER 42 CIRRHOSIS

B

FIGURE 42-6 Small hepatic veins in chronic liver disease showing various degrees of injury. A, Chronic hepatitis B with diffuse mild parenchymal inflammation including hepatic vein phlebitis. B, Chronic hepatitis B with partial occlusion of the inflamed hepatic vein. C, Recurrent hepatitis C with partial occlusion of the hepatic vein. D and E, Alcoholic liver disease with postinflammatory occlusion of hepatic veins. Photomicrograph on right (E) shows the hepatic vein lumen has filled with hepatocytes.

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REGENERATION

FIGURE 42-7 Congestive fibrosis in a liver with chronic hepatitis C. There is prominent fibrous thickening of the capsule (elastic trichrome stain).

rhotic livers are susceptible to thrombosis because of sluggish or reversed blood flow and the prothrombotic effects of sepsis and cholestasis, thus creating an opportunity for continued loss of functional residual liver parenchyma.

After childhood, the normal liver becomes a stable organ with slow turnover of hepatocytes. However, on injury or surgical reduction, the liver cells proliferate. Normal human liver can restore approximately three fourths of its own mass within 6 months. Hepatocytes, bile duct epithelial cells, and hepatic progenitor or stem cells maintain the potential to multiply during adult life.43,44 Depending on the severity of the primary injury, liver regeneration may occur by at least two mechanisms.45 In brief, with mild to moderate hepatocellular loss, mature hepatocytes undergo replication. More extensive or massive hepatic necrosis stimulates proliferation of progenitor cells within the periportal region. Proliferation of these cells gives rise first to “ductular hepatocytes,” in which ductular structures containing cuboidal cells and slightly larger cells with mitochondria-rich cytoplasm are present. With time, these cells mature into definitive hepatocytes and may possibly repopulate damaged bile duct structures as well. Regeneration is recognized initially by the twinning of liver cell plates, evident as a double line of hepatocytes with nuclei seemingly running in parallel. Twinning of cell plates may remain for some months after regeneration, before new sinusoidal channels develop and the nuclear alignment dissipates.46 If regeneration is recent,

1124 PART 3 LIVER the hepatocytes lack lipofuscin, since this pigment accumulates over time in the normal liver. Regeneration also is characterized by increased numbers of binucleate or multinucleate hepatocytes, reflecting replication of nuclear material. Hepatocyte nuclei may be more uniform in size,

Thrombosis Obliterated veins

In-out imbalance

Parenchymal extinction

Inflammation Edema

Inflammatory fibrosis

Congestive fibrosis

Resorption

Resorption

FIGURE 42-8 Diagram showing the main events in the formation of parenchymal extinction and fibrosis. Two mechanisms for venous obstruction are shown. Thrombosis is the initiating event in BuddChiari syndrome whereas inflammation induces venous obstruction in most forms of chronic hepatitis. Venous obstruction and hyperemia lead to in-out imbalance and parenchymal extinction. Fibrosis may be induced by hepatitis-associated inflammation or by organization of congestive injury, designated as inflammatory fibrosis and congestive fibrosis, respectively. In the thrombotic pathway, the fibrosis (and complete cirrhosis) is caused by the congestive injury and the inflammatory pathway is not important. In chronic hepatitis, fibrosis occurs initially by the inflammatory pathway but, as disease advances, congestive fibrosis becomes dominant. Fibrosis from both pathways can resorb, although congestive fibrosis is less likely to do so because of continuing congestive forces occurring in late cirrhosis. (From Wanless IR: Pathogenesis of cirrhosis: The role of hemodynamic forces causing in-out-imbalance and congestive injury [congestive hepatopathy]. Histopathology, in press.)

because anisonucleosis increases with age in the normal liver and hence may not be as evident in regenerating liver. Finally, regeneration imparts a rounded appearance to the expanding contours of residual parenchyma, which is demonstrated with a reticulin stain. To the extent that fibrosis and cell death precede hepatocellular regeneration, a residual parenchymal island may simply be “carved out” of the preexisting parenchyma. It is not until hepatocellular regeneration occurs that the characteristic nodular transformation of cirrhosis becomes manifest. On thickening of the liver cell plates, the parenchyma expands against the constraining fibrous septa and acquires a spherical shape. The hepatocyte plates abutting the fibrous septa become compressed and are bent outward by the less-constrained plates toward the interior of the nodule. Poor regeneration, or failure to keep up with the pace of collapse, results in variants of cirrhosis in which the feature of rounded contours may not be prominent. The ultimate size of the nodule is determined, in part, by the anatomic location of the antecedent fibrous septa. If matrix deposition occurs at the acinar level, then the resulting nodules will grow out of monoacinar units and will be small. If matrix deposition encompasses many acinar units (“multiacinar”), the growing nodules may be much larger and will retain components of the preexisting acini, including intact portal tracts. In some cases of cirrhosis, vast expanses of bile ductules within the fibrous septa coexist with the interspersed hepatocellular nodules. These may occur in cirrhosis of almost any cause and are not necessarily only the result of biliary obstruction.47 Hyperplasia of ductules is associated with lengthening and increased tortuosity of existing channels and with extensive sprouting of new channels. This change is reminiscent of the massive proliferation of ductular structures within the hepatic parenchyma or at the inter-

Inset in A

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FIGURE 42-9 A and B, Fibrous septa regress and disappear with time, as illustrated in this patient with chronic hepatitis B and cirrhosis. C, After successful treatment with lamivudine, a subsequent biopsy 2½ years later showed marked reduction in fibrous septation. (From Wanless IR, Nakashima E, Sherman M: Regression of human cirrhosis: Morphologic features and the genesis of incomplete septal cirrhosis. Arch Pathol Lab Med 124:1599-1607, 2000.)

CHAPTER 42 CIRRHOSIS face between parenchyma and portal tracts that occurs in massive hepatic, necrosis, and implicates a proliferation of periportal progenitor cells.43,48,49 With time, these ductular structures may mature into hepatocellular parenchyma or bile ductules. Thus, the presence of expanses of bile ductules in a cirrhotic liver points toward episodes in the recent past where there was extensive parenchymal destruction; the ductules represent an intermediate stage of a massive regenerative response.50

NATURAL HISTORY AND “REVERSIBILITY” OF CIRRHOSIS Cirrhosis is frequently viewed as an end stage in the evolution of many types of chronic liver diseases. However, in recent years, clinical reports indicate that on cessation of the injurious process, cirrhosis may reverse, or at least improve, histologically.51-59 These reports include patients with established cirrhosis in whom subsequent tissue samples have shown incomplete septal cirrhosis, or apparent absence of fibrosis, after successful treatment. This evolution has been documented in patients with hemochromatosis, autoimmune hepatitis, Wilson’s disease, primary biliary cirrhosis, schistosomiasis, extrahepatic biliary obstruction, alcoholic disease, chronic viral hepatitis B and C, and post–jejunal bypass steatohepatitis. In many different experimental models of cirrhosis “reversal,” collagen is resorbed within weeks of cessation of injury.13 The mechanism of resorption of fibrous extracellular matrix involves activation of tissue metalloproteinases.60 Likewise, stellate cells and activated portal tract fibroblasts may undergo apoptosis and subside. Fibrosis may even disappear in long-term quiescent cirrhosis. In this situation, the diagnosis of cirrhosis may be made by demonstrating severe paucity of small hepatic and portal veins, even when fibrous septa are highly regressed and not well represented within a biopsy specimen. Indeed, a revised definition of cirrhosis can be made wherein it represents a condition of widespread obliteration of small hepatic veins (i.e., venopenia). This definition is sufficient because if there is severe venopenia all other histologic features of cirrhosis will ultimately follow. Thus, the histologic appearance of cirrhosis depends on the age of accumulated tissue damage, and the time of dormancy with an opportunity to resorb fibrous tissue. The presence of parenchymal extinction lesions is a helpful indicator. If the causative injury continues, new parenchymal extinction lesions coexist with old lesions. If the causative injury is long past, the liver will contain lesions only in the late stages of repair. New extinction lesions are easily seen in livers with moderate to severe activity. These lesions are recognized as areas of bridging necrosis, or of focal intense congestion with atrophy and clusters of apoptotic cells.61 More commonly, especially in low-grade chronic hepatitis, the lesions are recognized as subtle atrophy, sinu-

1125

soidal dilatation, clusters of apoptotic cells, and approximation of hepatic veins close to portal tracts. Old extinction lesions predominate in livers where the primary disease has remitted, either spontaneously or after successful treatment.51 Fibrosis is progressively removed from extinction lesions so that broad septa become delicate and delicate septa become incomplete (“perforated”) or disappear. Thus, micronodular cirrhosis may remodel to macronodular cirrhosis, incomplete septal cirrhosis, or nearly normal liver (and only discovered if there is “noncirrhotic” portal hypertension). The problem with diagnosing regression of cirrhosis is discussed later. Even with substantial resorption of fibrous septa, restoration of the hepatic architecture to a normal state probably does not occur. Limiting factors are the persistence of vascular abnormalities: outflow obstruction and arterialization (Figs. 42-10 and 42-11). If these vascular factors are sufficient to cause continued hepatocellular injury or interstitial exudation, septa will not resorb, leaving some degree of cirrhosis or incomplete septal cirrhosis. Arterialization is important because, even if hepatic vein outflow is not limiting, elevated sinusoidal pressure prevents the regeneration of obliterated small portal veins so that noncirrhotic portal hypertension may remain.62 Moreover, residual sclerosis in portal tracts may still lead to persistent presinusoidal resistance to splanchnic blood flow, leading to continued clinical evidence of portal hypertension. The previous description indicates that the equilibrium of injury and repair is dependent on the local balance of inflow and outflow of blood and on the continued presence, or not, of the proinflammatory disease environment. This equilibrium is continually affected by activity of the primary disease, congestive hepatopathy, persistence of fibrosis in anatomically strategic locations, and catastrophic events, such as portal or hepatic venous obstruction by tumor or thrombosis.

Anatomic Classification and Pathology The main macroscopic types of cirrhosis are micronodular and macronodular, where the former consists of nodules mostly less than 3 mm in diameter and the latter are mostly greater than 3 mm in diameter6,62 (Table 42-2). Mixed cirrhosis describes livers in which nodules larger and smaller than 3 mm coexist. The definition of macronodular and micronodular cirrhosis has been modified over the years from an original cutoff of 10 mm (prior to 1976) to the current World Health Organization (WHO) cutoff value of 3 mm.63,64 This modification was intended to help distinguish alcoholic cirrhosis from other etiologic types. However, since these criteria appeared, hepatitis C cirrhosis was shown to be mostly micronodular,65 and alcoholic micronodular cirrhosis was shown to transform to a more

1126 PART 3 LIVER

Local HAF > HOC

HAF < HOC Fibrosis from active disease (inflammation) Preformed structural collagen

Activity

A

Primary hepatitis ceased early

Inflection point Local HAF > HOC

Diffuse HAF > HOC

Fibrosis from congestion Fibrosis from active disease (inflammation) Preformed structural collagen Activity

B

Primary hepatitis ceased late Time

FIGURE 42-10 A and B, Diagrams to show the accumulation of collagen in chronic hepatitis with two different time courses. Collagen from three sources is depicted, that from (1) preformed structural collagen, (2) postinflammatory collagen related to the primary disease activity, and (3) collagen deposited because of tissue congestion. Congestive injury occurs when hepatic artery flow (HAF) exceeds the hepatic outflow capacity (HOC) in any region of tissue (i.e., HAF > HOC), as explained in Figures 42-3 and 42-4. The inflection point is defined as the time after which HAF is greater than HOC in a large proportion of the liver. Physiologically, this means that there is no available venous drainage route so that tissue pressure rises, congestive injury is severe, and lymph forms (creating ascites). A, Chronic hepatitis with early cessation of activity (before the inflection point). Inflammation-associated collagen is deposited during activity. Structural collagen may appear to increase because of loss of parenchyma. Inflammation-associated collagen is largely resorbed after activity ceases. Because HAF is less than HOC in most regions, there is little or no congestion-associated fibrosis. B, Chronic hepatitis with late cessation of activity (after the inflection point). Inflammation-associated collagen may be resorbed after cessation of activity. However, net collagen deposition occurs as congestion-associated collagen deposition continues because of diffuse in-out imbalance (HAF > HOC). (From Wanless IR: Pathogenesis of cirrhosis: The role of hemodynamic forces causing in-out-imbalance and congestive injury [congestive hepatopathy]. Histopathology, in press.)

TABLE 42-2 Anatomic Classification of Cirrhosis and Related Forms of Chronic Liver Disease Micronodular cirrhosis Micronodular cirrhosis with regional parenchymal extinction Macronodular cirrhosis Mixed micronodular/macronodular cirrhosis Postnecrotic cirrhosis after subacute massive necrosis Noncirrhotic portal hypertension Incomplete septal cirrhosis Nodular regenerative hyperplasia (see Chapter 43) Hepatoportal sclerosis (see Chapter 43) Hepar lobatum Congenital hepatic fibrosis (see Chapter 46)

macronodular form during inactive disease.66 In addition, the progressive stages of biliary cirrhosis from incomplete, macronodular, mixed, and finally micronodular forms of cirrhosis have been described.67 Therefore, this anatomic classification is not adequate to allow a precise correlation with etiology. Rather, it is clear that the severity of activity and duration of inactivity are important. The evolutionary nature of these anatomic types is shown in Figures 42-12 and 42-13. Despite these caveats, certain generalizations can be made. Micronodular cirrhosis is associated with diseases in which there is uniform injury to all acinar units. The result is that most small hepatic veins are damaged, parenchymal extinction extends to involve all portal tracts, and subsequent regenerative nodules are small and devoid of portal tracts. In contrast, livers with macronodular cirrhosis are irregular, with less severe destruction of hepatic veins, so that most regenerative nodules contain some

CHAPTER 42 CIRRHOSIS

1127

NATURAL HISTORY OF CHRONIC LIVER DISEASE Hepatocellular injury

Alcohol NASH

Primary congestion

Hypercoagulable states

Chronic viral & autoimmune hepatitis

Stellate cell activation

Thrombus

Phlebitis

Incomplete septal cirrhosis or macronodular cirrhosis

Congestive hepatic venopathy

Parenchymal extinction

Vascular injury Sinusoidal fibrosis

Congestive heart failure

Regression

Obliterated hepatic veins Cirrhosis mild

Regression (if no venous injury)

Arterialization

Resorption to normal

Obliterated portal veins

Congestive portal venopathy Congestive hepatic venopathy PV or HV thrombosis Biliary phlebitis

Cirrhosis moderate

Cirrhosis severe Portal fibroblast activation

Biliary phlebitis (cholestasis)

Biliary disease Bile duct injury

Phlebitis or arteritis

Regression minimal

NRH

Rheumatoid disease PV or arterial injury

FIGURE 42-11 Diagram summarizing the main factors that determine the natural history of chronic liver disease. There are four principal mechanisms for initiation of chronic liver disease (heavy black boxes). Examples of specific diseases are provided in the light blue boxes, and the vascular lesions caused by these diseases are shown in italics. Activation of fibrogenesis is shown in dashed boxes. Recognizable lesions and patterns of disease are shown in light black boxes. The red and black arrows indicate progression of disease. The green arrows indicate regression. Most patients with chronic liver disease have hepatocellular injury. This may lead to local activation of stellate cells and sinusoidal fibrosis that is largely reversible. Those patients developing obliteration of vessels, especially hepatic veins, develop parenchymal extinction lesions (PELs) that may heal as fibrous septa. When PELs are numerous, the histologic features of cirrhosis are present. In hypercoagulable states, thrombosis is the cause of venous obliteration. In biliary disease, portal inflammation is an early event leading to portal tract fibrosis and obliteration of portal veins (occasionally with presinusoidal portal hypertension). Bile salt accumulation in zone 3 occurs later, leading to hepatic vein (HV) injury and PEL formation. Rheumatoid disease usually affects the portal vessels only, leading to multifocal atrophy without PEL formation (and without fibrous septation), a condition recognized as nodular regenerative hyperplasia (NRH). The long-term outcome depends in part on the time course of disease activity. If injury ceases, regression may occur (green arrows) if current injuries subside and new lesions do not appear. If injury continues, new PELs develop either from the continuing primary injury, secondary congestive injury, or secondary bile salt injury to veins. Once there is widespread microvascular injury, congestive injury is autoprogressive because of the positive feedback loop (red arrow) as explained in the text. The dotted green line indicates that severe cirrhosis is less likely to regress. NASH, nonalcoholic steatohepatitis; PV, portal vein. (From Wanless IR: Pathogenesis of cirrhosis: The role of hemodynamic forces causing in-out-imbalance and congestive injury (congestive hepatopathy). Histopathology, in press.)

portal tracts and intact hepatic veins. Thus, based on the single parameter of hepatic vein destruction, micronodular cirrhosis is more severe than macronodular cirrhosis.

MACROSCOPIC FEATURES Micronodular Cirrhosis In the early evolution of micronodular cirrhosis the overall shape and external appearance of the liver may not be

greatly altered. The organ weight may be normal or increased, and the left lobe may enlarge disproportionately. Parenchymal nodules may be difficult to discern by observation of the capsule of the liver. With time, organ weight decreases and the capsular surface may become studded with a myriad of small protruding nodules between the shallow and regular fibrous indentations that define the nodules. On cut section, the nodules are small and uniform but may be difficult to see without slight magnification. As

1128 PART 3 LIVER FIGURE 42-12 Anatomic classification of cirrhosis indicating transitions. Micronodular cirrhosis occurs when almost all portal tracts are linked by septa. Macronodular cirrhosis occurs when there are residual portal tracts not bound to septa within cirrhotic nodules. Progression or regression determines the evolution of these basic types. PELs, parenchymal extinction lesions.

Early stage

Established cirrhosis

Evolved cirrhosis Progressing

Incomplete cirrhosis with small PELs

Micronodular, often with regional parenchymal extinction

Micronodular

Regressing Incomplete cirrhosis with large PELs

Macronodular

Macronodular or incomplete septal cirrhosis

A

B

C

D

E

F

G

H

FIGURE 42-13 Examples of cirrhosis showing cut surface and trichrome stain with fibrosis highlighted in black and white images. A and E, Micronodular cirrhosis caused by hepatitis C virus. Most nodules are less than 3 mm diameter and septa are fairly broad. B and F, Regressed incomplete cirrhosis caused by hepatitis B virus. The septa are delicate and often incomplete. C and G, Incomplete septal cirrhosis caused by hepatitis B virus. The nodules are more apparent grossly than histologically. Most septa are delicate and incomplete. D and H, Primary biliary cirrhosis with green parenchyma (after fixation) and mixed nodule size. The larger nodules are less cholestatic than the micronodules.

the cirrhotic liver becomes small, the liver becomes progressively firm to the touch and septa are more wide and prominent. In severe examples, residual small islands of parenchyma appear to float in a sea of fibrous tissue.68 Alcohol abuse is the most frequent cause of micronodular cirrhosis in Europe and North America. However, increasingly common is the cirrhotic outcome of nonalco-

holic fatty liver disease. Hepatitis C viral infection, being less prone to bouts of severe necroinflammatory injury, progresses with time from an initial macronodular pattern toward a more micronodular pattern of cirrhosis (unlike hepatitis B viral infection, which remains macronodular). Less common causes for the micronodular pattern of cirrhosis include hemochromatosis, chronic biliary obstruc-

CHAPTER 42 CIRRHOSIS tion due to primary biliary cirrhosis or primary sclerosing cholangitis, drug toxicity, and many types of metabolic diseases of infancy and childhood (see Chapter 46). With chronic extrahepatic venous outflow obstruction (see Chapter 43), the liver also is finely subdivided by fibrous tissue, as discussed later in the section on congestive cirrhosis. Alcoholic liver disease may show a diffuse tan or yellow color due to severe fatty change or, in the setting dominated by alcoholic hepatitis, may be a characteristic red color. In hemochromatosis, heavy iron deposition imparts a dark reddish brown color to the liver. Destructive biliary diseases, such as primary biliary cirrhosis or primary sclerosing cholangitis, while rendering the liver a deep yellow or green, impart to the liver capsule a progressive fine septal scarring pattern resembling “pigskin.” Although any decompensated liver may become yellow or green, it seldom becomes as deeply pigmented as in patients with a biliary disease. There are rarely any distinguishing macroscopic features in micronodular cirrhosis owing to drug toxicity. Cirrhosis with regional parenchymal extinction (also known as confluent hepatic fibrosis) occurs when macroscopic expanses of liver tissue become purely fibrotic (Fig. 42-14).26 This appears to be the natural progression of cirrhosis when there is progressive regional vascular compromise.9 Regional parenchymal extinction may be 1 to 2 cm in greatest dimension or even much larger. The capsular surface overlying large areas of extinction may be finely granular and wrinkled, rendering an appearance also similar to pigskin.

1129

bands that vary considerably in width, but the liver generally retains its overall anatomic shape. Alternatively, the nodules may be more uniform in size (but larger than in micronodular cirrhosis), with intervening marked grooving and retraction that is especially evident on examination of the capsular surface. The more irregular pattern of macronodular cirrhosis reflects the capricious nature of necroinflammatory injury imparted by the causative diseases, which include viral hepatitis (e.g., hepatitis B) and autoimmune hepatitis.

Mixed Cirrhosis Mixed cirrhosis is not rigorously defined and hence is not a very useful term. It can be interpreted as many nodules with a diameter near the 3-mm cutoff or the presence of many nodules larger than 3 mm combined with many nodules smaller than 3 mm. The former appearance is frequent in any type of inactive, formerly micronodular cirrhosis that is undergoing evolution to macronodular cirrhosis through gradual enlargement of the nodules as the fibrous septa are resorbed and the mechanical constraint is eased. The latter appearance is often found in primary biliary cirrhosis and in primary sclerosing cholangitis where there is a distinction between nodules blessed by duct drainage and those without. Conversely, the progressive parenchymal extinction of evolving macronodular cirrhosis can further subdivide parenchymal nodules, reducing their size. Thus, dogmatic distinction between the causation of micronodular and that of macronodular cirrhosis is unwise.

Macronodular Cirrhosis

MICROSCOPIC FEATURES

Liver size and shape in macronodular cirrhosis is highly variable. As with micronodular cirrhosis, the early stages are associated with increased liver weight. The parenchyma exhibits large bulging nodules that are separated by fibrous

The microscopic features of cirrhosis are more easily generalized than the macroscopic features. As expected, fibrous subdivision of the liver parenchyma with isolation of parenchymal islands is the sine qua non for a diagnosis

A

B

C

FIGURE 42-14 Regional parenchymal extinction, also known on imaging studies as confluent hepatic fibrosis, in a liver with cirrhosis caused by alcoholism plus hepatitis C. A, The left lobe has a large depressed region with a finely granular capsular surface. B, In this liver, the regional extinction is largely subcapsular. In other livers, the extinct region extends deep toward the hilum. C, Such large regions of extinction are invariably associated with intimal thickening and luminal narrowing of medium-sized hepatic veins.

1130 PART 3 LIVER of cirrhosis. Applying these criteria, however, brings its challenges, particularly on liver biopsy.

The Evolution of Cirrhosis Before discussing the histology of cirrhosis, further comment must be made about the natural history of this condition. The histologic appearance of cirrhosis depends on the age of the accumulated extinction lesions. If the causative injury continues, new parenchymal extinction lesions will coexist with old lesions. Parenchymal extinction, usually accompanied by inflammation, constitutes “activity”; an “active” cirrhosis is a cirrhotic liver with continued destruction of residual tissue. Conversely, if the causative injury is remote at the time of examination, the liver will contain only lesions in late stages of repair and the cirrhosis is considered quiescent, or “inactive.” New extinction lesions are easily identified as areas of bridging necrosis or focal intense congestion with atrophy and clusters of apoptotic cells. Moreover, careful examination of the vascular channels—both septal and intraparenchymal—may reveal organized thrombi, the result of chaotic and sluggish blood flow, loss of anticoagulant function, and the prothrombotic effects of sepsis and cholestasis. Thrombosis of medium- or large-sized hepatic veins causes large regions of extinction, leading to marked irregularity of the cirrhotic liver.26 Essentially by definition, ongoing parenchymal extinction is seen only in livers with moderate to severe activity. Old lesions of parenchymal extinction predominate in livers where the primary disease has remitted, either spontaneously or after successful treatment.51 Fibrosis is progressively removed from extinction lesions so that broad septa become delicate and delicate septa become incomplete and disappear. Put differently, micronodular cirrhosis may remodel to macronodular cirrhosis, thence to incomplete septal cirrhosis, and eventually to a nearly normal appearance if given enough time. Portal tracts released from septa are seen as remnants lacking portal veins. Indeed, cirrhotic nodules may eventually be fed entirely by arteries. Arteriovenous shunts can be recognized by focal regions of sinusoidal congestion and hepatocellular atrophy, usually marked by CD34-positive sinusoidal endothelial cells.51

Micronodular Cirrhosis Normal liver acini measure approximately 1 mm in diameter, and because micronodular cirrhosis arises from subdivision of parenchymal acini, cirrhotic nodules may be less than 1 mm in diameter. The tiny nodules enlarge as they regenerate but are severely confined by the surrounding fibrous tissue. Virtually every acinus is affected, and, thus, no anatomically intact acini are normally evident. Fibrous septa connect the smallest portal tracts to their adjacent terminal hepatic venules. Thus, zones 1, 2, and 3 of the acinus are transected by fibrovascular septa; regenerative nodules may form concurrently or

subsequent to this fibrosing event. Fibrosis may be dominant in one zone—around the portal tracts (zone 1) in hemochromatosis, or around the terminal hepatic venules (zone 3) in alcoholic liver disease—but cirrhosis has not developed if the fibrosis is restricted only to these zones. The characteristic feature of micronodular cirrhosis is deposition of fibrous septa along the sinusoidal channels, connecting portal tracts to terminal hepatic veins. Frequently, multiple adjacent sinusoids exhibit fibrosis; this is a characteristic feature of evolving cirrhosis of both alcoholand drug-induced micronodular cirrhosis. These various manifestations of micronodular cirrhosis are illustrated in Figure 42-15. Micronodular cirrhosis seems to be most commonly associated with diseases in which there is a uniform and generalized effect of a hepatotoxic agent or metabolic derangement on the smallest parenchymal units in the liver. For example, in alcoholic liver disease every acinus has been regularly exposed to high levels of alcohol. Interestingly, in cirrhosis arising in the setting of severe alcoholic hepatitis the rate of fibrous tissue deposition may be so rapid (over weeks to months) as to render nodular regeneration almost impossible. In this setting, extensive hepatocellular degeneration with steatosis, ballooning, and Mallory body formation is accompanied by a mixed neutrophilic and mononuclear pattern of inflammation. Nodule formation may be minimal, yet the liver is transformed into a densely fibrotic organ with fibrous septa seeming to traverse almost every sinusoid. This extreme end of micronodular cirrhosis demands the question of whether the definition of cirrhosis is fulfilled, yet few will argue that such a fibrotic liver is not cirrhotic. Alternatively, a smoldering form of alcoholic hepatitis may proceed to a more mixed micronodular-macronodular pattern of cirrhosis, possibly due to a more portal-based pattern of fibrous tissue deposition. The fibrous septa that connect the smallest portal tracts to their adjacent terminal hepatic venules are devoid of portal tracts. In three dimensions, the fibrous septa are actually sheets of fibrous tissue rich in blood vessels.69 Most small portal and hepatic veins are obliterated. In advanced disease, many medium hepatic veins are also thickened or obstructed,28,40-42 attesting to the role of vascular injury in the pathogenesis of cirrhosis. In cirrhosis that has long been quiescent, many regressive changes are seen, representing the hepatic repair complex. This includes thin and incomplete septa, spurs of collagen attached to portal tracts, septa split by ingrowth of hepatocytes, and small buds of hepatocytes and CK 7– positive ductular cells in broader septa. Sinusoidal endothelium is frequently CD34 positive.51 A feature invoking prior injury is close approximation of portal tracts and terminal hepatic veins, either with or without tethering delicate fibrous septa. This is the residua of the parenchymal extinction lesion.

CHAPTER 42 CIRRHOSIS

A

C

Macronodular Cirrhosis The histology of macronodular cirrhosis is highly variable, particularly when evaluated by percutaneous liver biopsy (see later). This pattern exhibits large nodules delimited by septa in which multiple hepatic acini are incorporated into single nodules. During the early to intermediate stages of evolution, residual portal tracts and portal tract/hepatic vein acinar units may be evident (Fig. 42-16). Cell plates within the multiacinar nodules are often single with little evidence of twinning, but do not show the regular radial orientation present between portal tracts and hepatic veins of normal acini. The abnormal cell plate patterns probably reflect altered blood flow through the parenchyma, as discussed earlier under Pathogenesis. The hepatic veins are often dilated giving the impression that they are increased in number. Although this finding cannot be regarded as diagnostic, the possibility of macronodular cirrhosis must be considered when abnormal hepatocellular plate patterns and an apparent excess of veins is present in a needle liver biopsy that does not contain identifiable portal tracts. The presence of identifiable portal tracts correlates inversely with sinusoidal pressure and is, thus, a marker of a milder form of cirrhosis.70

1131

B

FIGURE 42-15 Three images of micronodular cirrhosis in alcoholic patients (Masson trichrome stain). A, Typical micronodular cirrhosis, with nodular islands of parenchyma that do not contain intact portal tracts. B, Alcoholic hepatitis that has evolved into cirrhosis. There is extensive subdivision of parenchyma by sinusoidal fibrosis, so that “nodules” per se are harder to identify but the liver is nevertheless cirrhotic. C, Quiescent micronodular cirrhosis, in which inflammation has subsided, the fibrous septa are thin, and the nodules are more closely approximated.

UNUSUAL VARIANTS Incomplete Septal Cirrhosis Incomplete septal cirrhosis is a highly regressed form of cirrhosis often associated with portal hypertension, but with normal hepatocellular function51,71,72 (see Fig. 42-12). Portal vein thrombosis is a complication that leads to portal hypertension in those cases that would otherwise escape clinical attention. Macroscopically, the septa are usually invisible, but variation in the color of the parenchyma on cut section demonstrates the presence of nodules. The liver may be without significant distortion or may exhibit residual bulging nodules. Because healed portal vein thrombosis is often present, gross examination should include consideration of this possibility. Microscopically, slender fibrovascular septa extend from portal tracts into the parenchyma but often do not connect with other portal tracts or hepatic veins. These septa demarcate large, rather inconspicuous nodules (see Fig. 42-13). Intrasinusoidal collagen away from the septa is not obviously increased, and there is little evidence of hepatocellular damage or inflammation. Portal tracts are variably attenuated, so that venous channels appear relatively increased. This abnormal architecture is present throughout

1132 PART 3 LIVER

A

FIGURE 42-17 Fulminant hepatitis, idiopathic. The green regions contain regenerating hepatocytes. The brown regions are totally collapsed with no residual hepatocytes. Fibrosis in such livers is usually minimal, but patients surviving several months may have sufficient fibrosis to be considered to have a postnecrotic form of cirrhosis.

linear compressed hepatocyte plates in the latter. In every instance, a reticulin stain is very helpful in assessing parenchymal architecture, over and above the obvious need for a trichrome stain for collagen.

Postnecrotic Cirrhosis B FIGURE 42-16 A, Evolving macronodular cirrhosis. The liver parenchyma is partially subdivided by fibrous septa, with a substantial amount of inflammation. B, Established macronodular cirrhosis showing parenchymal nodules of variable size in different stages of being subdivided by fibrous septa. Some intact portal tracts are entrapped in large nodules (Masson trichrome stain).

the liver, because there is a variable mixture of thickened hepatocellular plates, dilated sinusoids, and compression of sinusoids between hyperplastic plates.71 The plate pattern is disorganized, with irregular orientation of plates to portal tracts and terminal hepatic veins. Histologic indicators of the original offender are usually absent. In a patient with portal hypertension undergoing liver biopsy, incomplete septal cirrhosis is difficult to distinguish from hepatoportal sclerosis and nodular regenerative hyperplasia (both discussed in Chapter 43). When large expanses of liver are available for examination, incomplete septal cirrhosis exhibits fibrous septa extending out from portal tracts and disorganized plate architecture, both of which are absent in hepatoportal sclerosis. The chief distinctions between incomplete septal cirrhosis and nodular regenerative hyperplasia are subtle parenchymal nodules, delineated by incomplete delicate fibrous septa in the former, which lack obvious spherical features, versus a complete absence of parenchymal fibrous tissue and the presence of obvious spherical nodules separated by curvi-

Postnecrotic cirrhosis is the fibrotic stage of severe acute hepatitis, occurring in association with large contiguous regions of hepatocyte extinction and lesser regions of regenerative tissue.73 Indeed, the initial massive hepatic necrosis (Fig. 42-17) may subdivide the liver in a very coarse macroscopic fashion, leading to a grossly misshapen liver with large regenerative regions of liver parenchyma separated by very broad regions of parenchymal scar. Because many of these patients suffer subacute hepatic failure, these livers are usually severely cholestatic even though the hepatitis activity may have resolved. The degree of fibrosis depends on the time course. If the patient dies or undergoes transplant before complete evolution of the scarring process, nodules with expanding contours may be less evident and fibrosis may not be mature, leading to difficulty in classifying this as “cirrhosis” versus late acute hepatitis with regenerative features. The term evolving cirrhosis may suffice for these cases.

DIFFERENTIAL DIAGNOSTIC CONSIDERATIONS Lobar Hypertrophy and Atrophy In many cirrhotic livers the left lobe is relatively enlarged compared with the right. In contrast, in Budd-Chiari syndrome (see Chapter 43), the caudate lobe veins are frequently less involved with thrombus, which allows hypertrophy of that lobe.74 This latter situation is not cirrhosis. Conversely, regional compromise of the hepatic vessels, as from hilar malignancy, may lead to atrophy of a

CHAPTER 42 CIRRHOSIS

1133

major hepatic lobe, frequently the left lobe.75 This also is not cirrhosis.

Large Nodules in the Cirrhotic Liver Occasionally, one encounters hepatocellular nodules substantially larger than those in the background liver. These may be large regenerative nodules, dysplastic nodules, or hepatocellular carcinoma.76,77 Given that malignant transformation may occur in nodules less than 0.5 cm in diameter, sectioning the liver at 0.3- to 0.5-cm intervals is requisite for adequate gross examination of the cirrhotic liver. Macroscopic features characteristic of a regenerative nodule are color and texture similar to other cirrhotic nodules, and minimal bulging of the cut surface. Dysplastic nodules often have a softer texture, paler color, and bulging cut section. Early hepatocellular carcinomas are usually ill-defined but are otherwise similar to dysplastic nodules. Early hepatocellular carcinoma may arise within a dysplastic nodule, giving a “nodule-in-nodule” appearance. Moderately differentiated hepatocellular carcinoma is usually well demarcated, with a pale color, but may be variegated when necrosis is present. Metastatic hepatocellular carcinoma in liver often consists of several small and pale nodules, sometimes visible as a treelike structure within the portal vein. These nodules are usually satellites of the primary lesion in the same lobe.

FIGURE 42-18 Hepar lobatum: “potato liver.”

Nodular Regenerative Hyperplasia Nodular regenerative hyperplasia is characterized by small nodules separated by regions of atrophy rather than septa.77 It is a response to microvascular vascular derangement, as described in Chapter 43. Cirrhotic livers may show similar hypertrophic/atrophic variation within nodules and might be mistaken for nodular regenerative hyperplasia if a biopsy fails to sample sufficient fibrous tissue or otherwise demonstrate the classic features of cirrhosis.61

Hepar Lobatum Focal fibrous septation may cause deep linear clefts in the liver capsule such that the liver acquires an irregular shape; it is also known as “potato liver” (Fig. 42-18). This anomaly is caused by obliteration of large hepatic veins and confluent parenchymal necrosis, as occurs in adult-onset syphilis, metastatic breast carcinoma, and Hodgkin’s disease.78 This process is not true cirrhosis, because the large surviving regions of tissue may be normal (see Chapter 43). Supernumerary hepatic lobes, a congenital defect, may have a similar appearance.

Congenital Hepatic Fibrosis Focal fibrous septation also is a feature of congenital hepatic fibrosis (see Chapter 46). The liver parenchyma may or may not become nodular. The fibrous septa are broad, with dense collagen bands. The diagnostic feature for congenital hepatic fibrosis is dilated marginal ductal remnants, aligned longitudinally along the septa/parenchyma interface. These

FIGURE 42-19 Infarcted cirrhotic nodule.

do not represent the ductular reaction of an active cirrhosis but rather are embryonic remnants of the developing biliary tree (the “ductal plate”). The disease usually presents with portal hypertension and normal liver function. Portal vein thrombosis occurs in half the patients. Cholangitis may also occur.

Infarction of Nodules versus Congestive Necrosis of Nodules Necrosis of cirrhotic nodules may occur in association with systemic hypotension, typically after a variceal hemorrhage. In recent years, this finding is often a response to radiofrequency ablation or alcohol injection directed at neoplasms. These lesions, characterized by diffuse and uniform coagulative necrosis of established cirrhotic nodules (Fig. 42-19), should be distinguished from congestive necrosis of nodules as part of the development of progressive regional parenchymal extinction and fibrosis that occurs in severe cirrhotic livers. In the latter situation there is patchy congestive sinusoidal injury in various stages of organization within subregions of a cirrhotic nodule.

1134 PART 3 LIVER

Portal Vein Thrombosis Portal vein thrombosis is a frequent complication of cirrhosis, being found in approximately 10% of livers removed at transplantation.79-81 The healed phase of portal vein thrombosis is easily confused with congestive portal venopathy (see Chapter 43). Portal vein thrombosis is occasionally seen when carcinoma invades the vascular tree.82,83

Patent Paraumbilical Veins In patients with severe portal hypertension there is often spontaneous opening of collateral veins within the round ligament.84,85 These paraumbilical veins connect the umbilical portion of the left portal vein to the umbilicus, where caput medusae and a bruit may be detected on physical examination. Histologic inspection of the round ligament will reveal these patent channels when evaluating a cirrhotic liver.

Capsular Fibrosis Capsular fibrous thickening occurs in the liver and spleen when there is chronic exudation or transudation, especially in patients with cirrhosis or severe congestive heart failure.86,87 Also known as sugar-coating (Zukerguss), the capsule may achieve a thickness up to several millimeters in width with a tough cartilage-like consistency.

TABLE 42-3 Major Causes of Cirrhosis Chronic hepatitis Hepatitis B infection Hepatitis C infection Autoimmune hepatitis Fatty liver disease Alcoholic liver disease Nonalcoholic fatty liver disease Chronic biliary diseases Adults Primary biliary cirrhosis Primary sclerosing cholangitis Children Biliary atresia Cystic fibrosis Inherited diseases Metal overload states Hereditary hemochromatosis Wilson’s disease Storage disorders α1-Antitrypsin storage disorder Hepatic venous outflow obstruction (congestive cirrhosis)

Etiology Here we give consideration to the diseases that give rise to cirrhosis, with the goal of highlighting histologic features that may be identified in cirrhotic livers (Table 42-3). However, a cautionary note is in order, because most often the histologic features of the originating disease are obliterated or are long since past by the time of liver examination. This applies not only to examination of the whole organ (at autopsy or liver transplantation) but also to examination of liver biopsy tissue from a cirrhotic liver. Nevertheless, in many instances, the pathologist’s opinion is sought to determine the cause of the cirrhosis. With that in mind, the following considerations pertain.

CHRONIC HEPATITIS The most frequent forms of chronic hepatitis are hepatitis B, hepatitis C, and autoimmune hepatitis. These diseases are usually diagnosed with the help of a variety of serologic tests. Histologically, hepatitis B may exhibit “ground glass” cytoplasmic inclusions within hepatocytes; immunohistochemical staining for hepatitis B surface and core antigens is more sensitive. Detection of hepatitis C virions in liver tissue is possible but is not a routine technique. There is no immunohistochemical “test” for autoimmune hepatitis. Hence, the pathologist must still perceive potential histologic features of these chronic hepatitides, despite the difficulty in distinguishing one from another under the best

Budd-Chiari syndrome “Cardiac cirrhosis” Veno-occlusive disease Drug-induced cirrhosis

of circumstances. Each may exhibit a portal lymphoplasmacytic infiltrate and diffuse parenchymal lymphocytosis with acidophilic bodies. However, untreated autoimmune hepatitis is usually more active than the other types, which along with the requisite plasmacytic features also shows extensive necroinflammatory damage of the portal tract/ parenchyma interface and regenerative ductular reaction. The pattern of fibrosis also reflects the activity of the autoimmune disease. Both hepatitis B infection and autoimmune hepatitis may produce large regions of extinction that can lead to a pattern of cirrhosis with large regenerative nodules and macronodular cirrhosis. In contrast, as a low-grade necroinflammatory disease, hepatitis C usually has only small regions of extinction, which more often leads to smaller nodules ab initio. These nodules are not so consistently uniform as to necessarily constitute micronodular cirrhosis, but the tendency of hepatitis C cirrhosis is toward smaller nodules as opposed to hepatitis B and autoimmune hepatitis. Hepatitis C is further suggested by the presence of portal tract lymphoid aggregates and patchy macrovesicular

CHAPTER 42 CIRRHOSIS steatosis. However, these findings are not specific. In the former case, portal tract lymphocytes still accumulate over time in hepatitis B and autoimmune hepatitis, even if they do not seem to organize into structured aggregates. In the latter case, obesity and alcoholic disease may be confounding factors generating parenchymal steatosis in this and in other diseases. The possibility of coinfection with hepatitis B and C viruses must also be kept in mind. The cirrhosis of autoimmune hepatitis may be active or quiescent so that serologic findings are required in most cases. The presence of numerous plasma cells supports a diagnosis of autoimmune hepatitis, but this finding is not required and is also seen in the more active examples of chronic viral hepatitis. Alcoholic and nonalcoholic steatohepatitis also is often associated with a mild portal lymphocytosis. Whenever such lymphocytosis is prominent it is prudent to suggest that serology for viral and autoimmune disease be obtained.

FATTY LIVER DISEASE Fatty liver disease may be caused by alcohol abuse or states of insulin excess, as in obesity or type 2 diabetes mellitus. Non–alcohol-associated cases are collectively known as nonalcoholic steatohepatitis or nonalcoholic fatty liver disease.88 Fatty liver disease is characterized by large droplet steatosis, either with or without evidence of activity in the form of steatohepatitis. Steatohepatitis is defined by the presence of ballooning necrosis. Mallory bodies and neutrophils are found in more active cases. The presence of pigmented macrophages scattered in zone 3 is often an indication of recent necrosis and supports a diagnosis of steatohepatitis, even if ballooned hepatocytes are not readily evident. Alcoholic and nonalcoholic fatty liver disease are often identical in histologic appearance.89 However, severe activity with numerous Mallory bodies and neutrophils is seen more often in alcoholic disease. The diagnosis of steatohepatitis requires large droplet steatosis and some evidence of liver cell injury, such as ballooning or pigmented macrophages, but Mallory bodies and neutrophils are not required. As noted, minimal steatohepatitis often occurs in patients with chronic hepatitis C so that the cause of elevated aminotransferases may be difficult to determine except by a trial of dietary restraint. Simple steatosis (absent “steatohepatitis”) on biopsy generally does not progress to cirrhosis.90 However, there are exceptions, probably because features of minimal steatohepatitis may be missed on biopsy and metabolic derangements in the patient may become more severe with time, leading to steatohepatitis. Fibrosis develops in steatohepatitis with deposition of delicate fibers in the walls of zone 3 sinusoids. When small hepatic veins are obliterated during this process, there is focal parenchymal extinction and approximation of portal tracts and adjacent

1135

hepatic veins. Collagen deposition varies from minimal to severe.28 Such sinusoidal (pericellular) fibrosis is often considered suggestive of fatty liver disease. However, this is not entirely reliable. Sinusoidal fibrosis may occur by two mechanisms: as a local response to activation of hepatic stellate cells, and in the repair of quiescent chronic liver disease by the splitting and repopulation of broad fibrous septa. The first of these occurs in early fatty liver disease but also late in severely congested cirrhotic nodules of any etiology. The latter mechanism can be seen in any cirrhotic liver undergoing repair and recovery. As the liver becomes cirrhotic, the presence of steatotic droplets in hepatocytes may substantially decrease. Hence, when examining the cirrhotic liver by microscopy, scattered residual features of macrovesicular steatosis may be the only footprints left of prior steatotic liver disease— alcoholic or nonalcoholic. In end-stage cirrhosis caused by fatty liver disease, steatosis and steatohepatitis may be focal or completely absent, so that biopsies may not be able to confirm the diagnosis. Lastly, Mallory bodies are not specific for fatty liver disease, because they are seen in chronic cholestasis and copper-overload states as well.

CHRONIC BILIARY DISEASES IN ADULTS Chronic biliary diseases are characterized by chronic retention of biliary products. Although usually caused by duct obstruction, they may also be caused by hepatocellular defects in bile secretion as seen with cholestatic drug reactions or familial transport defects.91 In adults, chronic duct obstruction is most often due to primary biliary cirrhosis and primary sclerosing cholangitis.92 Rarer biliary causes of cirrhosis are chronic graft rejection and graft-versus-host disease. Although the clinical settings for the latter are obvious, in liver transplants distinguishing chronic rejection from recurrent biliary disease actually can be quite difficult (see Chapter 44). In primary biliary cirrhosis there is inflammatory destruction of ducts that mostly measure less than 40 μm diameter. Although these lesions can be easily seen in needle biopsies, it is the exception rather than the rule that a liver biopsy succeeds in sampling diagnostic duct lesions (see Chapter 39). Indeed, by the time the liver is cirrhotic these lesions are long gone. In primary sclerosing cholangitis, there is inflammation and concentric periductal fibrosis around ducts larger than 200 μm in diameter and these lesions are seldom observed in small biopsy specimens. In either disease, when diagnostic duct lesions are not available for examination, chronic biliary disease can be suspected by the presence of a prominent fibrous expansion of the portal tracts accompanied by ductular proliferation, portal edema, and neutrophilic infiltration. A portal mononuclear infiltrate may be prominent, especially in primary biliary cirrhosis. Importantly, with evolution of portal tract

1136 PART 3 LIVER fibrosis from any cause, including chronic hepatitis, activation of peribiliary myofibroblasts may impart a periductal “onionskin” pattern of fibrosis. Care must therefore be taken to observe genuine ductal withering before invoking a diagnosis of primary sclerosing cholangitis (see Chapter 39). In the late cirrhotic stage of any biliary or nonbiliary disease, there may be swelling of periportal hepatocytes (feathery degeneration), often with paraseptal Mallory bodies, owing to obstruction to bile outflow. By this time, the phases of inflammatory bile duct destruction in primary biliary cirrhosis and primary sclerosing cholangitis are complete and, thus, diagnostic histologic lesions are not usually present. Instead, only nonspecific features of biliary obstruction may be variably seen, such as septal edema and neutrophilic inflammation, bile ductular proliferation (although this, too, may be sparse), ductular and hepatocellular cholestasis, degenerative swelling of periseptal hepatocytes (cholate stasis), Mallory body formation and copper retention in periseptal hepatocytes, swelling of periportal hepatocytes, liver cell rosettes, feathery degeneration of parenchymal hepatocytes, and clusters of bile-stained foamy macrophages within the nodules. Biliary fibrosis is topographically variable, especially when larger ducts are involved, as in primary sclerosing cholangitis and cystic fibrosis. Whole liver segments may undergo extinction or they may be spared, depending on the distribution of duct obstruction. The differential diagnosis of chronic biliary disease includes extrahepatic obstruction, hepatolithiasis, choledochal cyst, congenital hepatic fibrosis, oriental cholangiohepatitis (liver fluke disease), cystic fibrosis, and a variety of transport disorders. Onionskin fibrosis with fibrous obliteration of medium-sized ducts is suggestive of primary sclerosing cholangitis, but this may be seen in most diseases with medium-sized and large duct obstruction. Note also is made of the peribiliary fibrosis without duct obliteration that can occur in any evolving cirrhosis. That being said, a well-delineated fibrous cord in a larger portal tract is a characteristic residuum of primary sclerosing cholangitis (Fig. 42-20). Congenital hepatic fibrosis seldom presents as cholestasis and is characterized by multiple dilated ductlike structures in almost all portal tracts. Drug reactions, especially caused by various antibiotics and angiotensin-converting enzyme inhibitors, may have clinical features similar to large duct obstruction; necrosis of small ducts in a biopsy is helpful in this differential diagnosis. CK 7 stain is also helpful in this assessment. Cirrhosis rarely ensues if drug use is discontinued. A frequent error is to assume that the presence of visible bile in a biopsy defines biliary disease. Moreover, visible bile in the tissue is almost never seen in primary biliary cirrhosis and primary sclerosing cholangitis until there is late cirrhosis, with functional decompensation. The finding of bile-stained hepatocytes, bile-stained macrophages, or canalicular bile plugs in a liver specimen without cirrhosis

FIGURE 42-20 Primary sclerosing cholangitis. Near the artery is a fibrous cord, which is the only remains of the bile duct.

suggests an acute cholestatic disorder, usually a drug reaction or recent complete obstruction of the external biliary tract. In most cirrhotic livers there are regenerative bile ductules at the margins of nodules and within septa (Fig. 42-21). This may occur in cirrhosis of almost any cause and is not necessarily indicative of chronic biliary obstruction.50 A similar type of ductular proliferation occurs after massive hepatic necrosis and implicates a proliferation of periportal progenitor cells.43,48,49 Proliferating ductular structures are often admixed with small clusters of hepatocytes to form “buds” that appear to enlarge into small cirrhotic nodules.44,51 Hence, identification of proliferating bile ductules, per se, does not directly implicate chronic biliary disease. Lastly, prominent regenerative changes in cholestatic liver disease may result in thickening of the hepatocellular plates and increased nucleus-to-cytoplasm ratio of the hepatocytes, features that may be mistaken for dysplasia or malignancy (see Fig. 42-21D).

BILIARY DISEASES IN PEDIATRIC PATIENTS Biliary Atresia The histologic features of biliary atresia in percutaneous liver biopsies, in comparison with neonatal hepatitis, are discussed in Chapter 46. Here we discuss aspects of cirrhosis arising from biliary atresia. Explanted livers demonstrate progressive findings that occur with increasing age in children. These include progressive portal and periportal fibrosis and ballooning degeneration of hepatocytes at the portal vein/parenchyma interface, with copper accumulation, Mallory bodies, and bile lakes in severe examples. Although the inciting injury is obliteration of the extrahepatic biliary tree, paucity of intrahepatic bile ducts develops by 4 to 5 months of age and a biliary pattern of cirrhosis occurs by 8 or 9 months of age. The rapidity of progression

CHAPTER 42 CIRRHOSIS

A

B

C

D

E

F

1137

FIGURE 42-21 The use of cytokeratin 7 (CK 7) to evaluate regeneration and cholestasis in cirrhosis. CK 7 immunostain is useful to demonstrate ducts, ductules, and intermediate hepatobiliary cells. A, Cirrhosis caused by hepatitis C, as an example of a nonbiliary type of cirrhosis. Cirrhotic nodules are surrounded by a rim of CK 7–positive ductules. Thus, ductules are usually found in cirrhosis and do not necessarily indicate cholestasis. B and C, Cirrhotic nodule in primary biliary cirrhosis. B, CK 7 shows variable numbers of ductules at the margins of the nodule. The ductules may have been destroyed by cholestatic injury. There are occasional CK 7–positive intermediate hepatobiliary cells within the nodule. C, Trichrome stain of the same nodule shows a rim of fibrosis at the periphery of the nodule. D to F, Cirrhotic stage of primary biliary cirrhosis. D and E show feathery degeneration of hepatocytes at the margin of a nodule, a feature also known as “cholate stasis.” The pale hepatocytes are swollen and often contain Mallory bodies. In D there are wide hepatocellular plates, a feature that may be mistaken for dysplasia or hepatocellular carcinoma. In F there is a cluster of foamy macrophages (center), a frequent finding in chronic cholestasis of any cause.

to cirrhosis depends on the severity of large duct obstruction remaining after Kasai portoenterostomy. The one exception to the above pathogenetic sequence is a form of biliary atresia in which there is an intrinsic malformation of the intrahepatic biliary tree.93,94 This form is termed early severe biliary atresia. The biliary tree does not form normally from the embryonic ductal plate,95 which results in portal tracts that do not contain interlobular bile ducts but rather have residual ductal plate remnants concentrically placed around the periphery of portal tracts.96,97 Accompanying this “ductal plate malformation” are hypertrophic hepatic arterial elements toward the center of portal tracts and a robust fibrous mesenchyme. Rapidly evolving cirrhosis retains the circumferential ductal plate remnants embedded in broad fibrous septa. Identification of these features in a liver explant favors a diagnosis of early severe biliary cirrhosis over the more conventional form of biliary atresia.

Cystic Fibrosis In cystic fibrosis, thick mucus-laden bile focally blocks bile flow, which leads to focal biliary fibrosis. Cirrhosis develops in less than 10% of patients with cystic fibrosis.98 The

pattern of cirrhosis is irregular, showing focal loss of bile ducts accompanied by cholestasis and fibrosis in the obstructed regions.99,100 There may be large duct strictures resembling primary sclerosing cholangitis. Classically, there is inspissated mucinous material in the ducts, but this may be minimal and difficult to demonstrate.

METAL OVERLOAD STATES Iron and copper are deposited in the liver in hemochromatosis and Wilson’s disease, respectively (see Chapter 46). However, both iron and copper may accumulate in severe cirrhosis of any etiology and, therefore, their presence is not diagnostic of hemochromatosis or Wilson’s disease. The pattern of fibrosis is not diagnostically useful in these conditions. Although presumptive diagnoses can be made in the appropriate clinical setting, definitive diagnosis rests on molecular analysis of the genome.101,102

Iron Iron overload in hemochromatosis is genetically determined but also is influenced by oral ingestion, ineffective

1138 PART 3 LIVER hematopoiesis, hemolysis, transfusion, and portosystemic shunting.103 Thus, severe iron overload may occur in thalassemia, even without a history of blood transfusion. Low to moderate levels of iron may accumulate in severe cirrhosis of other causes as well. This may be attributable to portosystemic shunting.104,105 Iron overload also is a well-documented phenomenon in alcoholic cirrhosis,106 attributable to redistribution of iron stores from other sites in the body.107 In general, a limited degree of hemosiderosis is common in nonbiliary forms of cirrhosis, but it is uncommon in biliary forms of cirrhosis.108 The mechanism of iron-induced liver injury is believed to involve the ability of iron to catalyze the generation of free radicals.101 Even large amounts of iron may cause very slow progression of fibrosis, and this progression is often enhanced by cofactors such as steatohepatitis or viral infection.109 Iron, in the form of hemosiderin, may be detected in the liver by histochemistry. Various grading systems have been proposed (see Chapter 46). Quantitative iron assay is rarely performed for diagnostic purposes because there is an acceptable correlation with histochemistry. Genetic testing is less cumbersome than chemical assays and more diagnostically precise. Iron accumulation may be heterogeneous in cirrhotic livers of hereditary hemochromatosis. This may be caused by dilution in regenerating, dysplastic, or malignant hepatocytes.110 Paradoxically, some dysplastic nodules selectively accumulate stainable iron in otherwise iron-free cirrhotic livers.111

A

B

Copper WILSON’S DISEASE

The most frequent copper overload state is Wilson’s disease, in which copper deposition occurs in the liver, eyes, and basal ganglia. Copper in the cirrhotic liver is distributed throughout the nodules, in contrast to biliary cirrhosis in which copper accumulates in paraseptal hepatocytes.112 In fact, not all cirrhotic nodules in Wilson’s disease are affected, so that the diagnosis may be missed, even with large specimens. Similarly, the copper stain is often negative so that chemical assays on fresh or paraffin-embedded liver are highly recommended if Wilson’s disease is suspected clinically. Hepatocellular degenerative features include mild steatosis, Mallory bodies, ballooning degeneration, and glycogenated hepatocellular nuclei (Fig. 4222). These histologic features are often present in obesity and other toxic conditions as well, so that care must be taken in interpreting the histology. Hemosiderin deposition may be caused by depressed iron clearance from hepatocytes after therapy that depletes hepatic copper.113 NON-WILSONIAN COPPER TOXICOSIS

Cirrhosis may develop in infants with marked hepatic copper overload. Most of these patients occur in the Indian subcontinent (Indian childhood cirrhosis) and in Austria

C FIGURE 42-22 Wilson’s disease. A, Early Wilson’s disease showing portal tract inflammation and prominent glycogenated nuclei of hepatocytes. B, Cirrhotic stage of Wilson’s disease showing micronodular cirrhosis (Masson trichrome stain). C, Cirrhotic stage of Wilson’s disease showing accumulation of orange-hued copper within hepatocytes embedded in dense collagenous stroma (rhodanine stain for copper, hematoxylin counterstain).

(Tyrolean copper toxicosis).114,115 Rare cases have been reported from other countries. The Indian form of the disease has been attributed to the use of brass and copper vessels for storage of milk. In Austria, the disease has been associated with acidic well water delivered to homes by copper pipes and also use of unlined copper vessels for food

CHAPTER 42 CIRRHOSIS storage. However, this disease has virtually disappeared since these environmental sources have been removed. A genetic predisposition has been suggested but not yet proved. Liver tissue from this group of patients typically shows hepatocellular ballooning, prominent Mallory bodies, and marked pericellular fibrosis, with progression to micronodular cirrhosis. Thus, the appearance is similar to alcoholic steatohepatitis but without the steatosis component. A prominent feature is marked accumulation of copper, as detected by copper and orcein stains. Copper chelation therapy has caused remarkable regression of fibrosis and cirrhosis in some cases.116,117

1139

A

CONGESTIVE CIRRHOSIS There is a congestive element in the genesis of all types of cirrhosis (see Chapter 43). Therefore, congestive cirrhosis refers only to livers in which the initiating lesion is obstruction of medium- to large-sized hepatic veins, the vena cava, or heart, as in hepatic vein thrombosis or congestive heart failure. In these conditions, congestive features are usually evident at the sinusoidal level, although chronic lesions may remodel and recanalize, making the heritage of large vessel obstruction difficult to document without access to the whole liver for histologic examination. Congestive cirrhosis is characterized by venocentric cirrhosis, also called reversed-nodularity cirrhosis (Fig. 4223).118 This pattern is caused by dominant hepatic vein outflow obstruction with relatively intact portal veins that serve as outflow tracts. In this situation, hepatic vein to hepatic vein fibrosis results in nodules composed of portal tracts in the center and hepatic veins at the periphery within the fibrous septa. If portal veins also become obstructed due to congestive venopathy or thrombosis, the nodules lose their outflow tract and undergo congestive injury and eventual hepatocyte extinction, leading to fibrous septation that bridges portal tracts and hepatic veins together. This results in a veno-portal pattern of septation. Congestive heart failure, by itself, usually causes only sinusoidal dilatation and mild parenchymal atrophy. Livers in this condition develop parenchymal extinction and fibrous septa only when there is additional obliteration of hepatic and portal veins.119 Venous lesions typically occur in an irregular fashion so that congestive fibrosis is usually quite variable from one region to another. Severe cirrhosis is seldom, if ever, attributed to congestive failure alone. Thus, other causes should always be considered as cofactors, including hepatic vein thrombosis. In Budd-Chiari syndrome, hepatic vein thrombosis leads to a more severe degree of outflow obstruction than that which can be achieved due to congestive heart failure alone. This greater degree of obstruction leads to more severe parenchymal extinction. The histology is otherwise similar to that of severe congestive heart failure. Finding

B FIGURE 42-23 Cardiac cirrhosis. A, Gross image of cut liver surface showing nodular subdivision of liver parenchyma. B, Low-power image of reticulin stain showing bridging fibrous septa between terminal hepatic veins, with intact portal tracts within the center of parenchymal islands.

thrombus material within the hepatic veins histologically, or on imaging studies, is the only certain way to differentiate these two conditions (see Chapter 43). Veno-occlusive disease (see Chapters 43 and 44) is a distinct cause of congestive hepatic damage accompanied by occlusion of the smallest tributaries of the hepatic venous system. It is most commonly associated with toxic induction therapy before bone marrow transplantation but may also develop from other toxic causes, such as exposure to the alkaloids contained in certain herbal remedies. If the patient survives the initial acute occlusive sequence there may be brisk and severe deposition of fibrous tissue within the parenchymal sinusoids. Within a few months, the liver may be transformed into a fibrotic organ and, in those surviving for years, a form of cirrhosis without specific features develops.

DRUG-INDUCED CIRRHOSIS Drugs rarely cause cirrhosis. This is because most drugs cause clinically evident “acute” disease so that drug

1140 PART 3 LIVER exposure is terminated before cirrhosis can develop. However, some drugs such as methotrexate, oxyphenisatin, and amiodarone cause asymptomatic low-grade injury that may lead to cirrhosis. Cofactors such as alcohol and nonalcoholic steatohepatitis are important in many of these patients who develop cirrhosis. Severe drug-induced subacute, or chronic, hepatitis may also lead to cirrhosis (e.g., with allopurinol, methyldopa, nitrofurantoin, and isoniazid). In addition to the conditions that lead to venoocclusive disease, thioguanine has been associated with hepatic vein thrombosis as well.

Diagnosis The diagnosis of cirrhosis has undergone many changes over the past 200 years and continues to evolve. These changes may be divided into three eras based on the dominant methodology used for diagnosis: (1) clinical, (2) histologic, and (3) post-histologic. Prior to the advent of needle liver biopsies in about 1950, antemortem diagnosis was based on clinical features. The diagnosis of cirrhosis was presumptive, based on clinical criteria such as the presence of varices and ascites. Anatomic or histologic confirmation was occasionally possible at surgery or autopsy. We currently rely on histology criteria for definitive diagnosis of cirrhosis, to which this chapter is devoted. The post-histologic era is rapidly emerging, with the development of new noninvasive techniques for assessing liver fibrosis, advancing knowledge of the natural history of cirrhosis, and the desire for less invasive tests. This era will employ imaging and acoustic techniques and chemical, physiologic, and molecular parameters, usually by analysis of peripheral blood. Determination of liver stiffness, estimated by sound transmission properties of the liver, is also a promising new approach.

TYPES OF BIOPSY AND TECHNICAL ISSUES The four main types of liver biopsy procedures are wedge biopsy, cutting liver biopsy, fine-needle aspiration biopsy, and transvenous (transjugular or transfemoral) biopsy. Wedge biopsies of the liver provide the most liver tissue. They are obtained from incising the convexity of the liver surface or by resection of a small portion of the most inferior edge of the right lobe. In the former, Glisson’s capsule is present on one of the three faces of the triangular specimen. In the latter, Glisson’s capsule is present on two of the three faces. The risk in histologic evaluation of such specimens is misinterpretation of normal anatomy. There is a normal array of fibrous septa that penetrate from Glisson’s capsule to a depth of approximately 0.5 cm in the liver parenchyma, partially ensheathing subcapsular portal tracts in more than 50% of individuals120 and linking subcapsular portal tracts to terminal hepatic veins in 25% of

individuals.121 Hence, normal fibrous tissue may be erroneously diagnosed as cirrhosis. If a wedge biopsy is the only tissue available, then staging of liver fibrosis cannot be performed accurately. Surgeons are encouraged to obtain an open cutting needle biopsy as well, to sample deeper portions of liver tissue. In our experience a needle biopsy is almost always more informative, despite its smaller size. Percutaneous cutting needle biopsies are performed with a 16- to 20-gauge needle and can usually provide a diagnosis of cirrhosis on the first biopsy; multiple needle passes are needed only if tissue is not obtained on the first pass.122 Unfortunately, biopsy needles, particularly the smaller ones, tend to glance off hard fibrous tissue and selectively sample softer parenchyma.123-126 This yields tissue that is more difficult to interpret. Because a cutting needle may harvest mainly parenchymal nodules, fragmentation of the liver tissue on ejection from the cutting needle is an important clinical observation. This fragmentation carries through into the tissue sections (Fig. 42-24). The degree of fragmentation alone cannot be used as a criterion of cirrhosis because even normal liver may be fragmented by the time final histologic sections are prepared.127 Rather, a critical feature of a cirrhotic liver is rounded fragments of parenchyma with concentrically oriented compressed liver cell plates at the periphery and curvilinear rims of connective tissue (see Fig. 42-24B). Transjugular biopsies yield useful tissue if a length of 2 to 2.5 cm is obtained. Fine-needle aspiration, usually performed with a 21-gauge or smaller needle, yields an array of small fragments of hepatic parenchyma regardless of liver status (see Chapter 37). Applying histologic criteria for diagnosis of cirrhosis with fine-needle biopsies is difficult. Regardless of the method used to obtain a tissue sample, biopsy specimens from patients with chronic liver disease should be examined for lobular architecture (including the relationship between portal tracts and terminal hepatic veins), the degree of hepatocyte damage, the degree of fibrosis, inflammatory infiltration, and parenchymal regeneration and nodule formation. When fibrous septa encompass regenerative nodules within tissue samples, a definitive diagnosis of cirrhosis can be established. The pathologist must always be alert to the presence of hepatocellular carcinoma and its antecedent lesions.

ROLE OF BIOPSY The clinical indications for liver biopsy include: ● ●

Evaluation of abnormal laboratory or clinical findings Staging known chronic liver disease up to and including cirrhosis

CHAPTER 42 CIRRHOSIS

1141

A B

FIGURE 42-24 A, Percutaneous needle biopsy of a cirrhotic liver showing fragmentation into many pieces. Most of the fragments have a curved edge, suggesting that the fracture planes are at the margins of cirrhotic nodules. Regions at the arrows are enlarged in B and C. B, Nodule with a rounded edge and a circumferential rim of connective tissue. C, Connective tissue is often absent at the edge of the nodules, but rounded shapes (long arrows) are suggestive of fracture at sites of fibrous septa. Fracture lines not occurring at fibrous septa are usually not curved but are either straight or irregular (short arrow) (Masson trichrome).

● ●

Searching for a cause of portal hypertension of unknown etiology Evaluating a focal “mass” lesion (see Chapters 37 and 47)

Determination of etiology in a cirrhotic liver is a very difficult exercise. When a specific etiology has not been established on clinical grounds before biopsy there is very limited ability to identify a specific etiology in endstage cirrhotic liver tissue. Moreover, accuracy in staging liver disease depends both on the observer and on tissue sampling. Observer error may be minimized if the pathologist has a complete knowledge of the clinical situation, particularly regarding clinical features of portal hypertension and venous pressure measurements. Overinterpretation of the histologic features, with regard either to staging fibrosis or establishing an etiology, is often based on the desire to assist the clinician with a specific diagnosis. Limited sampling of liver tissue may preclude assessment of either stage or etiology. Such “sampling error” is impossible to avoid entirely, because the definition of cirrhosis requires involvement of the

entire liver. Rather, sampling error depends on the character of the liver disease and is greatest in those diseases having a low density of diagnostic lesions in the tissue. In macronodular cirrhosis, septa may be more than 1 cm apart so that a small needle biopsy may not contain any septa. In contrast, a biopsy measuring 1 to 2 mm in length (and 0.2 cm in diameter) may be sufficient for the diagnosis of micronodular cirrhosis because entire nodules may be encompassed within the 0.6- to 1.4-mm diameter of most tissue fragments. Many authors have recommended that needle biopsies should be at least 2.5 cm in length, so at least to encompass parenchymal nodules longitudinally.121,122 In one study, agreement of stage and hepatic vein pressure gradient was excellent when specimens of more than 1.5 cm in length were evaluated.128 Transjugular biopsies are generally smaller than percutaneous biopsies in both length and width. However, the transjugular technique provides an opportunity to measure pressure during the same procedure. Regardless of methodology, biopsy reports should include comments on the size of biopsy and the presence

1142 PART 3 LIVER of fragmentation as indicators of possible adequacy of the biopsy. The goal of liver biopsy is to establish the severity of necroinflammatory and fibrotic liver injury (grade and stage, respectively) and provide insights into the specific etiology as well. However, clinically cirrhotic patients are not without comorbidity, and the risks of liver biopsy, especially hematoma and intra-abdominal hemorrhage, are potentially increased, owing to the presence of coagulopathy and ascites. If the need for biopsy is high, despite the presence of contraindications, transvenous hepatic biopsy may be required. Although these biopsies typically yield small tissue specimens, in experienced hands diagnostic tissue is obtained in more than 90% of cases.129 Although liver biopsy will continue to be important for a variety of diagnostic purposes, it may not remain as the dominant modality for the diagnosis of cirrhosis. For example, to estimate prognosis and response to therapy, hepatic vein pressure gradient may be the best measure.130 Importantly, anatomic proof of cirrhosis is not required for clinical management, especially when the cause is known and the clinical syndrome is internally consistent. That said, cirrhosis remains an anatomic diagnosis and tissue examination may be necessary in difficult cases.

STAGING SYSTEMS Many publications describe methods for semiquantitative estimation of fibrosis in chronic hepatitis and steatohepatitis, as reviewed by Brunt131 and Theise132 (see also Chapters 38 and 41). The Laennec system, presented in Table 42-4, can be applied to all liver diseases and so offers its own advantages.128,133 In particular, in order to recognize the variable severity of cirrhosis, the highest fibrosis stage of 4 is subdivided into substages 4A, 4B, and 4C. The defini-

tions of each lower stage (0 to 3) focus on the single histologic parameter of fibrous septa, according to their width and number. The expanded scale allows documentation of changes in fibrosis over time. As with the other systems, the Laennec system also reports grade of activity on a scale of 0 to 4, as well as noting etiology-specific features (not discussed here). Regardless of staging system, stage must be estimated with a connective tissue stain, such as Masson trichrome. The reticulin stain is a useful adjunct to detect delicate highly resorbed septa. The presence of curved hepatocyte plate contours, well demonstrated by reticulin stain, helps confirm the presence of a nodule and septal rim when the lesion is otherwise indefinite on H&E stain.

Diagnostic Pitfalls This chapter has given extensive consideration to the manifestations of different liver diseases in cirrhotic liver and how these diseases might present in tissue obtained by liver biopsy. Some final considerations pertain.

PITFALLS IN ASSESSING FIBROSIS Assessment of the degree of fibrosis and architectural derangements requires solid knowledge of normal hepatic structure120,127,134 and the appearance of artifacts and diagnostic pitfalls (Table 42-5). An overstained trichrome stain may easily be misinterpreted as showing evidence of pericellular fibrosis. When in doubt, note that the cytoplasm of hepatocytes should not stain the same color as collagen. When fibrosis is truly present, there are usually other clues to confirm the abnormality, such as obliteration of portal or hepatic veins and abnormal distribution of hepatic veins.

TABLE 42-4 Laennec Scoring System for Staging Fibrosis in Liver Biopsies Criteria Stage

Name

0

No definite fibrosis

1

Septa (Thickness and Number)

Examples

Minimal fibrosis

+/−

No septa or rare thin septum; may have portal expansion or mild sinusoidal fibrosis

2

Mild fibrosis

+

Occasional thin septa; may have portal expansion or mild sinusoidal fibrosis

3

Moderate fibrosis

++

Moderate thin septa; up to incomplete cirrhosis

4A

Cirrhosis, mild, definite, or probable

+++

Marked septation with rounded contours or visible nodules. Most septa are thin (one broad septum allowed)

4B

Moderate cirrhosis

++++

At least two broad septa, but no very broad septa and less than half of biopsy length composed of minute nodules

4C

Severe cirrhosis

+++++

At least one very broad septum or more than half of biopsy length composed of minute nodules (micronodular cirrhosis)

CHAPTER 42 CIRRHOSIS

1143

TABLE 42-5 Pitfalls in Diagnosing Cirrhosis on Liver Biopsy Overinterpretation Misinterpretation of normal anatomy Subcapsular fibrous septa Large portal tracts and accompanying fibrous stroma Longitudinal sampling of portal tracts Fragmentation of normal liver tissue Technical issues Overstained Masson trichrome stain Misinterpretation of collapsed parenchyma Massive hepatic necrosis Submassive hepatic necrosis

A

Misinterpretation of focal nodular hyperplasia as cirrhosis Misinterpretation of tumor “mass effect” on adjacent parenchyma Underinterpretation Sampling Biopsy diameter or length less than size of nodules Fibrous septa not sampled Regressed cirrhosis, with reduced fibrosis Parenchymal extinction interpreted as chronic hepatitis Incomplete septal cirrhosis not recognized Nodular regenerative hyperplasia not recognized

B Fibrous portal expansion also is frequently overdiagnosed. Normal large portal tracts may be present in biopsy specimens; these contain large vessels and ducts. A normal portal vein should have a thin collagen wall close to the limiting plate. Such mesenchyme may be quite prominent in larger normal portal tracts. The texture of normal portal tract collagen is coarse bundles; acquired fibrosis has a finer pattern of bundles (Fig. 42-25). Longitudinally cut normal portal tracts—whether large or small—may traverse the entire width of the biopsy fragment. These can easily be mistaken for fibrous septa. The clue to their normality is that longitudinally arranged blood vessels and ducts are present.

PITFALLS IN DIAGNOSING CIRRHOSIS Moderate to severe cirrhosis does not usually present a diagnostic problem, even on tissue obtained by needle biopsy. However, the following features may be seen. Large regions of parenchymal extinction, commonly present in severe cirrhosis, are often misdiagnosed as severe hepatitis with active bridging necrosis. This is particularly likely when there are numerous mononuclear cells within the collapsed area. This possibility can be discounted

FIGURE 42-25 Comparison of portal tract fibrous tissue. A, Normal medium-sized portal tract showing investing collagen fibers within the mesenchyme and surrounding the bile duct. B, Medium-sized portal tract in active cirrhosis showing disorganized collagen fibers in the midst of inflammation, a disrupted parenchymal interface with ductular regeneration, and adjacent hepatocytes entrapped in fibrous tissue (Masson trichrome stain).

if the margins of the collapsed parenchymal regions show clear-cut evidence of a curved fibrous margin, which is an indicator of cirrhosis. Conversely, massive hepatic necrosis can be misinterpreted as cirrhosis if the collapse of normal parenchymal reticulin fibers is not appreciated as the cause of “increased” connective tissue matrix, either on H&E stain or Masson trichrome stain (Fig. 42-26). On Masson trichrome stain, the lighter tinctural qualities of the type III and IV collagen in regions of parenchymal collapse can help distinguish massive hepatic necrosis from cirrhosis, which has strongly staining type I collagen fibers within bridging septa separating parenchymal nodules. Immunostain for CD34 may detect arterialized sinusoids that also indicate advanced disease (Fig. 42-27).

1144 PART 3 LIVER

A

B

FIGURE 42-26 Massive hepatic necrosis illustrating collapse of connective tissue. A, Needle biopsy of patient with fulminant hepatic failure showing residual hepatocellular parenchyma between portal tract zones exhibiting ductular proliferation at the interface (left) and interface collapse of preexisting extracellular matrix (right). The approximation of portal tracts and narrow rim of residual hepatocellular parenchyma also indicate collapse. B, Adjacent tissue section, stained with Masson trichrome, showing even greater loss of hepatocellular parenchyma, extensive collapse of extracellular matrix, and entrapped proliferating ductules. Despite the prominent “blue” features of this tissue section, this is not cirrhosis.

A

B

FIGURE 42-27 Angiogenesis in cirrhosis. The CD34 immunostain shows endothelium of arteries and veins. Normal sinusoidal endothelial cells are negative. In cirrhosis there is a variable degree of arterialization of the sinusoids, seen as CD34 positivity. A, Mild cirrhosis. There is minimal CD34 positivity of sinusoidal endothelium at the periphery of the nodule. B, Severe cirrhosis. All sinusoidal endothelium is positive for CD34. Arrows show the margins of a cirrhotic nodule.

Incomplete septal cirrhosis has delicate fibrous septa within liver tissue that exhibits large expanses of parenchyma devoid of portal tracts. The number of portal tracts, the distance between them, the presence of curved contours within the parenchyma, and the presence of thin and perforated fibrous septa are clues that point toward a regressed form of cirrhosis. Evidence in favor of cirrhosis includes the finding of portal veins or hepatic veins that are obliterated or hepatic veins that are closely approximated to portal tracts. These residual histologic lesions may be all that is left to support incontrovertible clinical evidence of portal hypertension. Nodular regenerative hyperplasia is suspected when there are narrow curvilinear regions of hepatocellular atrophy that alternate with normal or hypertrophied hepatocytes, in the absence of fibrous septa. As noted

earlier, reticulin stain is helpful to accentuate subtle nodular lesions. Focal nodular hyperplasia, as a lesion with fibrous septation, ductular reaction, and benign-appearing hepatocytes (see Chapter 43), may be mistaken for cirrhosis on percutaneous biopsy. Awareness of the clinical setting of a needle biopsy of a focal lesion is the first step in avoiding an interpretive error. The finding of a large dystrophic artery will also point in the correct direction of focal nodular hyperplasia. Mass lesions will often show areas of parenchymal extinction, portal tract inflammation, and parenchymal fibrosis at the margin. These parenchymal changes represent a “mass effect” and should not be overinterpreted as cirrhosis of the background liver. Peritumoral parenchyma should not be used to stage chronic liver disease.

CHAPTER 42 CIRRHOSIS In the end, interpretation of liver biopsy tissue in a patient suspected of being cirrhotic consists of: ● ●

Assessment of fibrosis, up to and including a diagnosis of cirrhosis Identification of possible etiologic features, as required for clinical management

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cirrhosis may reverse through gradual resorption of connective tissue in the absence of further injury. For the foreseeable future the pathologist will have a key role to play in the management of cirrhosis.

REFERENCES Cirrhosis is not a disease unto itself, but rather is a stage of evolution for many forms of chronic liver disease. Likewise, it is not the end stage in all instances, as on occasion

References, with PubMed access, are available in the online edition through Expert Consult.