A disruption of the hepatic blood flow characterizes several major liver diseases. Often the disruption develops in the major vessels outside the liver or in their larger intrahepatic branches. Conspicuous examples include extrahepatic portal vein obstruction, hepatic artery thrombosis, and the Budd-Chiari syndrome. In these cases, the site of disruption is not accessible by biopsy, and the hepatic changes thus reflect the consequences of events downstream or upstream from the liver. These consequences, as with other organs, include such general histologic features as congestion, atrophy, and ischemia. Although the overall context can suggest the diagnosis, these findings are not generally definitive, and clinical and ancillary information thus become important in biopsy interpretation.

Other conditions, including hepatoportal sclerosis and veno-occlusive disease, affect primarily the smaller vessels. They can be more directly identified with biopsy specimens, although, depending on the distribution of the disruption, sampling error remains a problem. In addition, there are numerous primary vascular lesions that can affect the branches of the hepatic vasculature.

The pathologic basis of most disorders of the portal veins, as with other venous systems, is mechanical obstruction of the lumen. This obstruction can occur at any level of the portal venous system, from the main portal vein formed by the union of the superior mesenteric and splenic veins to its termination in the smallest peripheral branches. The consequences depend on the location, extent, and course of the blockage, but portal vein obstruction is often well-tolerated because of the liver's dual blood supply and the development of collateral circulation. Significant obstruction increases the resistance to portal blood flow and leads to portal hypertension, which thus represents the major clinical manifestation regardless of cause.

Based on the primary level of involvement, portal vein obstruction can be separated into extrahepatic and intrahepatic groups. In extrahepatic obstruction, the blockage occurs primarily in the larger vessels, the portal trunk and its main tributaries. The diagnosis is established by appropriate radiographic imaging studies, including such noninvasive procedures as ultrasonography. The effects on the liver are inconsistent, and there is no specific histologic pattern indicative of extrahepatic portal obstruction. Liver biopsy is therefore of little diagnostic use.

Intrahepatic portal vein obstruction is a more elusive condition than is extrahepatic obstruction. The occlusion may not be apparent on noninvasive radiographic studies, although it can usually be recognized by venous angiography. Suggestive histologic changes can be identified in biopsy specimens, particularly those of larger size, but, because of the irregular distribution of the process, liver biopsy is often not helpful in establishing the diagnosis. As a result, the obstructive nature of the condition has not always been appreciated or accepted, and cases have been reported under less specific labels such as hepatoportal sclerosis, idiopathic portal hypertension, or noncirrhotic portal hypertension. In addition, intrahepatic portal obstruction can develop as a minor component of several other disorders, including congenital hepatic fibrosis, sarcoidosis, schistosomiasis, and cirrhosis of any cause.

Although this classification scheme has pragmatic and heuristic value, the two categories are not mutually exclusive, and obstruction is found at both levels in some cases. In addition, the two groups are linked on a pathogenetic basis, since both are considered usually to result from thromboembolism. A continuum of portal vein obstruction is therefore proposed, extending from the extrahepatic to the intrahepatic veins with the involvement depending on the extent and natural history of the initiating thrombosis.^23,30,47 This spectrum has been further extended by some to nodular regenerative hyperplasia, which is suggested to result from occlusion of the smallest intrahepatic portal vein radicles.⁴⁵ Despite these pathogenetic considerations, the distinction between extrahepatic and intrahepatic portal obstruction should be maintained, whenever possible, because the etiologic connotations are often different. Extrahepatic obstruction usually arises as a complication of a recognized underlying disorder, whereas the cause of intrahepatic obstruction is not known in most instances.

Obstruction of the extrahepatic portal venous system is an unusual condition with an overall prevalence at autopsy ranging from 0.05% to 0.5%.⁸ It can result from a wide range of disorders, but the basis of almost all of them is venous thrombosis. Most of the responsible conditions act to generate vascular injury, stasis, or hypercoagulability, the three classic features predisposing to thrombus formation. On occasion, however, the vein is obstructed in the absence of thrombosis because of congenital atresia, extrinsic compression, or tumor invasion.³⁸ Whatever the cause, the resulting clinical and pathologic manifestations vary greatly depending on the severity, tempo, and course of the occlusion.

Both children and adults are affected; the age distribution is bimodal with peak incidences at 6 and 40 years.⁴⁸ In children the common associated disorders include infections, either local or systemic, and congenital cardiovascular malformations.^2,8,48 In adults, the major risk factors are cirrhosis and malignant neoplasms, each of which account for about 25% of cases, followed by lesser contributions by many other conditions.⁸ Among patients with compensated cirrhosis, the overall risk of portal vein thrombosis is low, but increases greatly if decompensated disease supervenes or the patient undergoes splenectomy.³⁴ Hepatocellular carcinoma and pancreatic carcinoma are the neoplasms most often implicated, although almost any cancer can be responsible.²⁹ In some instances, no underlying etiology can be identified; with greater recognition of latent myeloproliferative disorders, however, only about 10% to 15% of cases are currently considered idiopathic.^7,43

The major consequence of portal vein occlusion is the eventual development of portal hypertension. Typical clinical findings therefore include variceal bleeding, splenomegaly, and abdominal pain or tenderness. The acute obstructive event is often clinically silent, but it may prompt a sudden episode of ascites, which may, in turn, spontaneously resolve once collateral circulation develops.⁴² Rarely, more serious acute manifestations develop, including severe abdominal pain, fever, hepatic failure, and gastrointestinal bleeding. These findings typically signify the addition of mesenteric venous thrombosis, and life-threatening hepatic or intestinal infarction can follow.⁴⁹

The diagnosis can be established through a variety of radiographic procedures, including ultrasonography, pulsed duplex Doppler ultrasonography, computed tomography, magnetic resonance imaging, and angiography.⁸ In addition to confirming the site of blockage, these techniques can demonstrate the replacement of the portal vein by a sponge-like mass composed of tortuous collateral and recanalized vessels. This appearance, which is typically noted in children, is often referred to as cavernous transformation of the portal tract and was originally considered to represent a vascular malformation.²⁹ Treatment centers on the management and prevention of variceal bleeding, but the specific measures are the subject of controversy. The course of the disorder depends greatly on the underlying etiology; in the absence of cirrhosis or malignancy, five-year survival rates of up to 90% have been reported.^8,35,42

The liver is often unaffected by extrahepatic portal vein occlusion, and the hepatic histology in noncirrhotic cases is frequently unremarkable or characterized only by portal fibrosis.^3,14,27 Sclerosis of the intrahepatic portal vein branches similar to that seen in hepatoportal sclerosis can sometimes be identified (Figure 11-1); this presumably indicates extension of thrombus from the larger veins.^6,20,23,47 In cases complicated by pylephlebitis, intense inflammatory infiltrates containing neutrophils can accumulate in the portal tracts and invade the portal vein walls, often with accompanying thrombosis.¹⁶ Acute portal vein occlusion, especially when concurrent arterial hypoperfusion is present, can produce well-defined zones of hepatocyte atrophy and associated sinusoidal atrophy that are classically (if inaccurately) known as Zahn's infarcts.¹³ Rarely, true infarction can also develop.⁷⁷ Depending on the location of the offending thrombosis, persistent occlusion can lead to generalized or segmental atrophy of the liver, with the left lobe being particularly susceptible.

Hepatoportal sclerosis denotes a distinct clinicopathologic syndrome of noncirrhotic portal hypertension characterized by sclerosis of the intrahepatic portal veins. Depending on the criteria employed, various alternative names have been applied to this disorder, the most popular of which include idiopathic portal hypertension and noncirrhotic portal fibrosis.^6,20,36 All of these terms express one or another of the basic features of the syndrome and, although varying in their exact connotations, they can all be broadly regarded as synonyms. Unfortunately none of them is a completely satisfactory designation. Hepatoportal sclerosis is the most descriptive label and, since it emphasizes the morphologic alterations, is the term employed in this book.

The fundamental abnormality in hepatoportal sclerosis is fibrous thickening and occlusion of the intrahepatic portal venous system. These changes produce a presinusoidal obstruction to portal blood flow and thus appear to be directly responsible for the portal hypertension seen in the disorder, although perisinusoidal fibrosis and increased splanchnic blood flow may also contribute.

The pathogenetic mechanism is generally thought to involve venous thrombosis with subsequent organization and recanalization, implying that hepatoportal sclerosis represents an intrahepatic variant of portal vein thrombosis.^5,26,31,47 This thrombosis may arise as a result of a primary process localized to the small vessels or via spread from extrahepatic portal thrombi that subsequently undergo dissolution. Such proximal thrombosis is, in fact, identified in occasional cases.^23,30 Some investigators, however, deny a major pathogenetic role for thrombosis and suggest instead that portal fibrosis represents the major event.¹⁷ In most instances, the etiology is obscure, and the disorder may indeed represent the end result of several different vascular insults. Singular cases have been associated with exposure to such agents as vinyl chloride monomer, arsenical compounds, copper sulfate, and cytotoxic chemotherapeutic drugs including thioguanine.^{4,37,41,44,50} Other examples have been conjectured to result from recurrent portal bacteremia or autoimmune-induced vascular damage.^36,40

Hepatoportal sclerosis is uncommon in the United States, but it represents a major cause of portal hypertension in India and Japan. Although prevalence figures are not available, the disorder in these two countries accounts for up to 40% of patients with surgically treated portal hypertension, whereas the corresponding figure in the United States is less than 4%.^10,20,36

Most affected patients are young to middle aged adults between 25 and 50 years, but the age range is wide, extending from 3 to 75 years. The ratio of males to females also varies greatly among different populations; men tend to predominate among patients under 40 years and women among patients over 40 years.^19,32,36 The clinical presentation comprises manifestations of portal hypertension in the face of preserved liver function. Gastrointestinal bleeding from esophageal varices, splenomegaly, and pancytopenia due to hypersplenism are common features. Ascites can occasionally develop, but encephalopathy and hepatic failure are uncommon. Routine liver function tests are usually normal or only mildly elevated. Portal venography by either percutaneous or intraoperative techniques is a valuable diagnostic procedure; it documents the presence and extent of the vascular occlusion and aids in excluding cirrhosis.¹¹ Although the natural history is not well defined, hepatoportal sclerosis has a protracted course and is generally static or progresses only slowly. It does not evolve to cirrhosis, although hepatic failure has been noted as a terminal complication in some cases. With appropriate management of the portal hypertension, the overall prognosis is good; five-year survival rates are estimated at 65% to 75%.^15,32,36

The most notable histologic features involve fibrosis and obliteration of the intrahepatic portal veins. The affected vessels may be of any size, including the major right and left portal veins, medium-sized veins of various order, or small terminal veins. Similar changes are sometimes also noted in the extrahepatic portal vein, which usually remains patent.^1,28,33 The walls of the involved vessels are thickened, either concentrically or eccentrically, by subendothelial connective tissue (Figure 11-2). These alterations are sometimes inconspicuous on routine sections, but they can be suspected by the narrowing and corrugated profile of the vascular lumen and are readily confirmed by trichrome or elastic stains (Figure 11-3). Recent or old thromboemboli, with or without recanalization, can be a complicating feature. With severe involvement the vein completely disappears, leaving only a fibrous scar to mark its site, and numerous thin walled vascular spaces, presumably representing proliferated or recanalized venules, may instead be noted (Figure 11-4).⁴⁰ Those portal vein radicles that are unaffected by phlebosclerosis are frequently dilated, indicating their exposure to elevated portal pressures.

The phlebosclerotic lesions are irregularly distributed across the liver and vary greatly in their severity and extent. As a result, the most suggestive changes may not be adequately sampled by liver biopsy, and the resulting specimens can appear misleadingly normal or near-normal. This is particularly true of needle biopsy specimens, since the diagnostic yield is greater with surgical wedge specimens.^1,28,33

The vascular changes are accompanied by portal and periportal fibrosis of varying extent (Figure 11-5). In cases without conspicuous phlebosclerosis, this fibrosis can be the dominant or sole histologic finding. Mononuclear portal inflammation and ductular proliferation, usually of minor degree, can also be noted. Thin portal-based fibrous septa develop in some cases, yielding an appearance that may be difficult to separate from so-called incomplete septal cirrhosis.¹⁷

A variety of lobular alterations can also be noted. Parenchymal atrophy is recognized by subtle abnormalities in architectural landmarks, including irregularly distributed central veins and closely crowded portal tracts. In the periportal zone, dilated thin-walled sinusoidal structures are occasionally found adjoining the portal tracts (Figure 11-6). In addition, the hepatocytes may undergo nodular hyperplasia, producing ill-defined zones with widened hepatic plates and localized parenchymal compression. The unevenly dispersed parenchymal atrophy and hyperplasia can be striking in the subcapsular region and can result in capsular thickening and a scarred, bosselated appearance that can be mistaken for cirrhosis on gross examination.^1,28 Other abnormalities occasionally noted include perisinusoidal fibrosis and sclerosis or thrombosis of the hepatic veins.³³

A biopsy diagnosis of hepatoportal sclerosis is frequently difficult to establish. The most distinctive features, the portal vein alterations, are often missing from biopsy specimens and, furthermore, are not specific for the disorder. They are found, for example, as part of normal aging; moderate to severe changes are noted at autopsy in approximately 40% of patients older than 60 years of age.⁴⁶ Similar changes are seen with primary biliary cirrhosis, sarcoidosis, congenital hepatic fibrosis, and other portal-based inflammatory or fibrosing disorders, although these do not usually present a differential diagnostic problem.²² The changes may also be present in cases of extrahepatic portal vein thrombosis.

In some cases, the biopsy specimens exhibit normal histology or nondescript portal fibrosis. Despite its nonspecificity, this observation can nonetheless be helpful in the setting of portal hypertension since it serves to eliminate cirrhosis and, by default, raise the possibility of hepatoportal sclerosis. Nodular regenerative hyperplasia is another differential consideration, but it can usually be excluded by its lack of fibrosis and diffuse (rather than focal) parenchymal nodularity. Biopsy specimens do not always permit such a distinction, however, and overlapping features are seen in some cases. Indeed, nodular regenerative hyperplasia has been proposed to result from obliteration of small portal venules, and the two disorders may therefore form a pathogenetic continuum.⁴⁵ Cirrhosis is distinguished by its diffusely distributed fibrosis and parenchymal nodularity, but this is not always apparent with biopsy material. The demarcation between hepatoportal sclerosis and incomplete septal cirrhosis is particularly troublesome, and borderline cases are sometimes encountered that are difficult to categorize.¹⁷

An additional issue focuses on the differential diagnosis of portal hypertension, since liver biopsy is frequently performed for that clinical indication (Table 11-2).¹² Cirrhosis is, of course, the primary suspect, and careful attention should be given the subtle clues to that diagnosis. Similar considerations apply to nodular regenerative hyperplasia and hepatoportal sclerosis, both of which can be diagnostic problems with biopsy specimens. In general, venous outflow obstruction, the various forms of noncirrhotic hepatic fibrosis, and the rare miscellaneous causes have distinctive or suggestive morphologic features.

In unusual instances, the cause of the portal hypertension is obscure: the liver histology is normal and no occlusion of the portal or splenic veins can be identified.⁴⁴ Ultrastructural examination of some of these truly idiopathic cases has, however, demonstrated pericellular or perisinusoidal fibrosis, and this may be the responsible lesion.^24,37

Additional portal vein alterations are nonobstructive and primarily inflammatory in nature. They include endothelialitis, in which lymphocytes and other mononuclear cells are attached to damaged endothelial cells (Figure 11-7). This is a prominent feature of hepatic allograft rejection and graft-versus-host disease and typically coexists with hepatic vein endothelialitis.^18,39 Pylephlebitis resulting from intraabdominal suppuration can give rise to a neutrophil-rich portal inflammatory infiltrate centered on the portal vein and variably accompanied by thrombosis; in severe cases, microabscesses may develop; the bile ducts may be secondarily affected, and confusion with acute cholangitis is thereby possible.^16,25

The most importance consequence of interference with the hepatic arterial supply is the development of ischemia. Compared with other organs, however, the liver is remarkably tolerant of anoxic injury. This relative resistance can be explained by several factors: the liver's two afferent blood supplies, which act reciprocally through poorly understood mechanisms to maintain a constant blood flow; the generous collateral circulation provided by the multiple arterial branches; and the highly efficient extraction of oxygen from the blood.⁵⁵ Nonetheless, with sufficient disruption of blood flow -- particularly the hepatic arterial supply -- this protection can be overwhelmed, and ischemic liver disease can then result.

Two major histologic patterns of ischemic liver disease can be distinguished, centrilobular ischemic necrosis and hepatic infarction. The two represent the same basic pathophysiologic process, but differ in the extent and distribution of the hepatic damage. These factors are, in turn, determined by the location, degree, and rate of the impedance to blood flow, as modified by the status of the portal venous, hepatic venous, and collateral circulations. Other patterns of ischemic hepatic necrosis may be encountered in certain circumstances. For example, periportal ischemic necrosis is noted in some cases of disseminated intravascular coagulation and eclampsia, and irregularly distributed ischemic necrosis can develop in parenchymal nodules of cirrhosis, particularly when variceal bleeding or shock supervene.

Centrilobular ischemic necrosis represents the pathologic manifestation of low cardiac output and hepatic hypoperfusion. Among its clinical synonyms are shock liver and, because of the biochemical similarities with acute hepatitis, ischemic hepatitis. A wide assortment of underlying disorders can be responsible, including left ventricular failure due to acute myocardial infarction or cardiac arrhythmias, septic shock, severe hypovolemia, pulmonary embolism, hyperpyrexia, and heat stroke.^54,60,76 In many of these conditions, additional pathophysiologic factors such as hypoxemia or elevated systemic venous pressure are also often present, but they appear to be secondary contributors to the pathogenesis.^51,70,74 Most often encountered at autopsy, centrilobular ischemic necrosis is an uncommon biopsy diagnosis with a prevalence among patients with acute heart failure of less than 1%.⁵²

The condition is recognized clinically when a patient at risk develops a sudden increase in serum aminotransferase levels, usually with elevations in five-fold to twenty-fold range.^54,60 Lesser rises typically occur in serum bilirubin and alkaline phosphatase levels, and the prothrombin time may be mildly prolonged. Although mild jaundice may be noted, clinical evidence of liver dysfunction is seldom seen. Severe cases, however, can be complicated by the development of fulminant hepatic failure.^66,71 In the proper setting, the diagnosis can be established on the basis of clinical and laboratory features, and liver biopsy is not required. Diagnostic problems may arise when the predisposing cause is not clinically apparent, as the condition may then be mistaken for a primary liver disorder.⁵⁸

The outcome is driven by the severity of the underlying cardiovascular disease. Improvement of the hemodynamic status typically results in a rapid, dramatic hepatic response; the serum aminotransferase levels fall to near normal levels within several days, and complete recovery is the rule. The prognosis is, of course, poorer in cases in cases associated with unresponsive cardiac disease.

The histologic hallmark is coagulative necrosis of hepatocytes in predominantly the centrilobular region (Figure 11-8). The necrotic zone is typically well-delineated with affected liver cells demonstrating eosinophilic necrosis and pyknotic or karyorrhectic nuclei; often the sinusoidal cells remain uninvolved. The centrilobular area (or, more specifically, acinar zone 3) is especially vulnerable to ischemic injury because of it location at the extremes of afferent blood flow. In severe cases, the process may affect much of the lobule, sparing the periportal regions and linking adjacent central veins by zones of confluent bridging necrosis. The degree of involvement, however, often varies among areas within a single specimen. On occasion, a midzonal distribution of necrosis is noted, presumably because of centrilobular regeneration of hepatocytes.⁵⁹

Within several days, the necrotic zone collects an sparse inflammatory infiltrate of neutrophils and mononuclear cells.⁶⁸ The dead hepatocytes disappear, and the reticulin framework collapses, although the lobular architecture remains intact. In time, enlarged, diastase-PAS-positive Kupffer cells (and other phagocytes) accumulate within the ischemic focus. Adjacent hepatocytes can exhibit canalicular cholestasis, mild fatty change, eosinophilic hyaline globules, or features of regenerative hyperplasia.¹⁴⁴ On occasion, the hepatic plates may be replaced by cords packed with erythrocytes in a manner comparable to that seen in venous outflow obstruction, although extravasation into the space of Disse is uncommon.⁶⁴ Sinusoidal dilatation and congestion can be prominent if a component of right-sided heart failure is additionally present.⁵¹

Eventually hepatocyte regeneration repopulates the necrotic zone, and normal histology is restored. Perivenular fibrosis is occasionally noted, particularly with chronic venous congestion, and focal calcification has been described as a residual lesion in patients suffering concurrent uremia.^67,78

The differential diagnosis includes other causes of confluent centrilobular necrosis, including acute viral hepatitis and drug-induced injury, although usually they do not pose a great practical problem. Cases associated with acute viral hepatitis can generally be distinguished by the accompanying features: diffuse lobular and portal mononuclear infiltrates and degenerative changes of the surviving hepatocytes. In drug-induced cases, the histologic overlap is greater, but the discriminating factors include the presence of portal inflammation and the absence of neutrophil infiltrates, sinusoidal dilatation, and congestion. The clinical context is obviously pertinent.

Hepatic Infarction

Infarcts of the liver are defined as discrete foci of ischemic necrosis involving more than one contiguous lobule. They are uncommon lesions, noted in one in 50 to one in 1,100 autopsies, and are infrequently diagnosed during life. The leading cause is obstruction of the hepatic artery, which can occur through thrombosis, atherosclerosis, aneurysms, arteritis, or inadvertent surgical ligation. Portal vein occlusion is responsible for some hepatic infarcts, and in other instances, no vascular obstruction can be identified and a low-flow state is the likely culprit.^56,77

The clinical features include abdominal pain and tenderness, nausea, vomiting, fever, and jaundice. With sufficient clinical suspicion, radiographic imaging by computed tomography or magnetic resonance imaging can be employed to demonstrate the lesion.

Infarcts of the liver are morphologically similar to those found in any other organ. Grossly they appear as sharply demarcated areas with an irregular triangular configuration, ranging from than 1 cm to 15 cm or more in greatest dimension (Figure 11-9). Some cases do not exhibit the classic wedge shape based at the hepatic capsule, but are more irregular in shape and location. The histologic abnormalities are characterized by extensive coagulative necrosis of the parenchyma. All lobular structures are typically affected, although the portal tracts and sinusoidal lining cells may be spared in early lesions (Figure 11-10). After about two days, an acute inflammation response becomes apparent, and by approximately one week, collapse of the hepatic stroma heralds the gradual ingrowth of granulation tissue. The final result is a retracted fibrous scar.^56,77

Additional abnormalities of the hepatic arteries parallel those of arteries at any site.⁶² Some of these lesions principally affect the larger branches and are consequently seldom encountered by the surgical pathologist, whereas others involve the arteries accessible through biopsy.

Hepatic artery thrombosis is an infrequent occurrence, but can arise as a complication of abdominal trauma, arterial catheterization, inadvertent ligation of the artery, neoplastic invasion, and arteritis. Cases have additionally been associated with liver transplantation and certain drug exposures such as oral contraceptive usage or intraarterial perfusion with cancer chemotherapeutic agents.⁶³ The consequences of hepatic artery thrombosis vary greatly, although the most important result is hepatic infarction. Atherosclerosis of the hepatic artery is rare seen, even in the face of marked aortic involvement.

Hepatic artery aneurysms, although uncommon lesions, are an increasingly recognized consequence of abdominal trauma. Generally occurring in middle-aged males, they range from 2 cm to 10 cm in diameter, may be intrahepatic or extrahepatic in location, and have a high risk of rupture, often with a poor outcome.⁶⁵ The rare hepatoportal arteriovenous fistula can result from ruptured aneurysms, blunt trauma, or liver biopsy procedures, and may also be associated with hereditary hemorrhagic telangiectasia or infantile hemangioendothelioma.⁶¹

Several types of systemic arteritis can affect the liver, including polyarteritis nodosa (sometimes associated with hepatitis B infection), giant cell arteritis, rheumatoid arteritis, Kawasaki syndrome, and drug-induced vasculitis.^50,73,75 Although occasionally identified by needle biopsy specimens, these lesions are more often encountered in surgical wedge specimens (Figure 11-11).

Obliterative arterial changes, including subintimal foam cells and fibrointimal proliferation, constitute one of the characteristic feature of chronic allograft rejection. Because these alterations primarily affect the larger-order vessels and are segmentally distributed, they are often not demonstrated in biopsy specimens. The small hepatic arterioles are not spared, however, but may disappear in advanced cases.^69,72

Intimal hyperplasia associated with oral contraceptive usage is another arterial consideration.^50,62 This lesion is characterized by enlarged, hyperplastic endothelial cells together with accumulations of acid mucopolysaccharide and, on occasion, medial hypertrophy. Such changes are often found adjacent to contraceptive-related hepatocellular adenomas and may be responsible for the hemorrhage and infarction frequently found in these tumors. They may additionally account for a singular example of multifocal hemorrhagic necrosis described in a woman taking contraceptives.⁸⁰

Smaller arteries can display thickened, hyalinized walls in either arteriolosclerosis or amyloidosis. As a feature of normal aging and systemic hypertension, arteriolosclerosis is commonly noted in specimens from older individuals, although the liver is typically less affected than other organs.⁷⁹ Amyloid deposits in portal vessels is a regular finding in both primary (AL) and secondary AA forms and is sometimes noted in the absence of parenchymal involvement.^53,57 Rare cases of arterial calcification have been described in idiopathic arterial calcification of infancy and hypercalcemia due to hyperparathyroidism.⁶²

Sinusoidal dilatation is a familiar histologic lesion, often encountered at autopsy but also discovered in about 5% of liver biopsy specimens.⁸⁵ It is characterized by an increase in luminal caliber, ranging from mild to severe in degree, with intact sinusoidal lining cells and, in many cases, atrophy of the corresponding hepatic plates. The dilated lumens can appear congested and packed with erythrocytes, but frequently the red cells leak from biopsy during processing and leave the sinusoids empty.

Although the appearance is generally distinctive, sinusoidal dilatation should be distinguished from artifactual spreading of the hepatic plates. This pseudo-dilatation can be produced by excessive negative pressure being applied during needle aspiration or by uneven stretching of the specimen during handling. Artifactual dilatation typically occurs at the periphery of the biopsy, lacks a zonal distribution, and is unaccompanied by hepatic plate atrophy. Mild degrees of sinusoidal dilatation may be difficult to distinguish from normal liver, but the distinction usually has few clinical consequences.

Based on the predominant distribution within the lobule, sinusoidal dilatation can be classified into centrilobular, periportal, and irregular categories.

Centrilobular sinusoidal dilatation is the most common variety, characterized by primary involvement of the centrilobular zone with extension to the midzonal region in more severe cases (Figure 11-12). It is an integral feature of venous outflow obstruction, as discussed below, and is therefore a prominent finding in Budd-Chiari syndrome, veno-occlusive disease, and cardiac-related venous congestion. Drug-related dilatation may also exhibit a centrilobular distribution, and among the incriminated agents are azathioprine, particularly in renal or liver transplant recipients, and hypervitaminosis A.^92,99,110 With either agent, sinusoidal dilatation can coexist with other histologic patterns including veno-occlusive disease, nodular regenerative hyperplasia, peliosis hepatis, and perisinusoidal fibrosis. Endothelial cell injury has been incriminated in the pathogenesis of all these lesions, and they may therefore constitute a pathologic spectrum.^110,137

A centrilobular dilatation is also reported with rheumatoid arthritis and either intrahepatic or extrahepatic involvement by malignant neoplasms (including Hodgkin's disease and various visceral carcinomas) or granulomatous diseases (including tuberculosis, brucellosis, and Crohn's disease).^85,86,95 A primarily midzonal distribution has also been described as a paraneoplastic phenomenon with renal cell carcinoma.⁸¹

Periportal sinusoidal dilatation principally affects the sinusoids surrounding the portal tracts, although in more marked cases the ectasia can extend centripetally into the midzonal area. An unusual but striking pattern, it was first described in association with long-term oral contraceptive use.^50,83,116 Periportal dilatation is additionally found in preeclampsia and eclampsia, usually accompanied by sinusoidal fibrin thrombi and periportal ischemic necrosis, although rare examples have also been reported in uncomplicated pregancies.^90,201 Similar features of sinusoidal dilatation, often periportal in location, with thrombosis and necrosis are seen at autopsy in cases of disseminated intravascular coagulation.^89,107

An irregular or nonzonal distribution of sinsuoidal dilatation is noted in many settings, and often a particular cause cannot be identified. Of particular note, however, is its occurrence in the vicinity of intrahepatic space-occupying lesions such as granulomas, neoplasms, or abscesses. This feature, combined with obstructive-type portal changes, provides circumstantial evidence of a mass lesion missed by biopsy sampling and, in appropriate circumstances, should prompt additional investigation.⁹¹ Irregular sinusoidal dilatation has also been associated with exposure to arsenic, thorotrast, and vinyl chloride, where it appears to represent an early change in the eventual development of angiosarcoma, and with a variety of systemic inflammatory disorders including the acquired immunodeficiency syndrome.^{41,50,105,106}

Sinusoidal dilatation can also develop as a secondary feature resulting from parenchymal atrophy with thinning of the hepatic plates, as seen in so-called Zahn's infarcts associated with portal vein obstruction.

Peliosis hepatis designates the presence of blood-filled cavities within the hepatic parenchyma. These lesions were initially recognized as an incidental autopsy finding in patients with chronic debilitating diseases such as tuberculosis or cancer.¹¹⁸ Current cases, however, are more often related to anabolic steroid therapy, usually for hematologic disorders or malignant neoplasms.⁵⁰ Several other drugs are also implicated: corticosteroids, tamoxifen, danazol, hypervitaminosis A, azathioprine, 6-thioguanine, and exposure to arsenic, thorotrast, and vinyl chloride.^{88,96,97,101,129}

Peliosis hepatitis has also been associated with oral contraceptives, usually in conjunction with hepatocellular adenomas, although exceptions are reported.¹¹³ Other reported settings include marasmus, bacterial endocarditis, angioimmunoblastic lymphadenopathy, Waldenström's macroglobulinemia with sinusoidal light-chain deposition, and the acquired immunodeficiency syndrome (AIDS).^{87,106,108,114}

The rounded cyst-like spaces, which range from 0.1 cm to several cm in diameter, are typically scattered across the liver without a preferential lobular distribution (Figure 11-13). They contain pooled blood, sometimes with fibrin or thrombi, and are bounded by compressed hepatocytes and an incomplete lining of damaged endothelial cells.^117,119 Sinusoidal dilatation is common in the background, and communications are generally seen between the lesions and dilated sinusoids (Figure 11-14).

The pathogenesis of peliosis hepatis is not known, but the lesions appear to form through cystic expansion of the sinsusoids or space of Disse and thus represent an extreme localized version of sinusoidal dilatation. Suggested initiating events include endothelial cell injury, focal hepatocyte necrosis with secondary cyst formation, and obstruction at the junction of the sinusoids and central veins.¹¹⁹ The latter process could result from the herniation of hepatocytes into the central vein that has been identified with androgen therapy.¹⁰³ Other organs can also be affected by peliosis, usually in combination with hepatic involvement, including the spleen, bone marrow, lungs, pleura, kidney, and gastrointestinal tract.¹¹⁵

In many cases the lesions produce no clinical evidence of liver disease, although some patients with severe involvement can develop hepatomegaly, manifestations of portal hypertension such as ascites and esophageal varices, or hepatic failure. Death may also result from rupture of the lesions and consequent hemoperitoneum.^82,100,111 The diagnosis can be suggested by various radiographic imaging with computed tomography or hepatic angiography.¹¹²

A peculiar variant of peliosis hepatis, known as bacillary peliosis hepatis or visceral bacillary epithelioid angiomatosis, occurs in patients infected with the human immunodeficiency virus.^94,104 These lesions are characterized by peliotic blood-filled parenchymal spaces admixed with a fibromyxoid stroma containing multiple small vascular structures and clusters of bacillary organisms. The organisms, which measure 2.5 μm in length, are best seen with Warthin-Starry or analogous stains and have now been identified as a rickettsial pathogen Rochalimaea henselae.¹⁰⁹

Veno-occlusive disease denotes the fibrous occlusion of small branches of the hepatic venous system, including the central veins and the sublobular (or intercalated) veins. Although the occlusion is not overtly thrombotic in nature, local fibrin deposition can be found in early cases, implying a role in the pathogenesis of the lesions. The affected veins, which have diameters less than about 300 μm, are not directly visualized by radiographic studies, but are generally present in liver biopsy specimens. In theory, the diagnosis can therefore be established histologically, although this is not always possible, particularly with small biopsy specimens. Whether considered as a subgroup of the Budd-Chiari syndrome (by an inclusive definition) or as a distinct entity, veno-occlusive disease merits separate attention because of its special etiologic associations.

Although mild fibrous thickening of the central vein walls is occasionally noted in normal livers, more extensive phlebosclerosis is a characteristic feature of alcoholic hepatitis and nonalcoholic steatohepatitis. In this setting, the venular walls are typically more than 3 μm thick, as contrasted with the normal value of less than 2 μm, and the lumen is compressed and eventually obliterated.^127,158,162